Mayo Test Catalog, (Sorted By Test Name)

Rochester 2017 Interpretive Handbook Sorted By Test Name

Current as of August 23, 2017 7:11 am CDT

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Copyright and Trademark Information The marks "Mayo," "Mayo Clinic," "Mayo Medical Laboratories," and the triple-shield Mayo logo are trademarks and/or service marks of Mayo Foundation for Medical Education and Research. The content and design of Mayo Medical Laboratories are protected by U.S. and international copyright laws. You may not copy, reproduce, republish, upload, post, display, transmit, or frame any of these materials without prior written consent from the copyright owners, except that you may view, download, display and print a single copy of these materials on a single computer for personal, noncommercial use only, so long as: (1) you do not alter or modify the materials in any way; (2) you include all applicable notices and disclaimers (including copyright notices); and (3) you do not use the materials in a way that suggests an association with Mayo Medical Laboratories or an affiliated Mayo entity. You understand and agree that title to these materials shall not pass to you or any other user. Complete Terms of Use is available at http://www.mayomedicallaboratories.com/customer-service/terms.html

Definition of Specimen "Minimum Volume" Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.


800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com

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Policies – Mayo Medical Laboratories [POL 056279.001]

Effective Date: 05/18/2015

Mayo Clinic Laboratories RST Mayo Collaborative Services

Policies - Mayo Medical Laboratories POLICY STATEMENTS Animal Specimens We do not accept animal specimens for laboratory testing. Billing Client—Each month you will receive an itemized invoice/ statement which will indicate the date of service, patient name, CPT code, test name, and test charge. Payment terms are net 30 days. When making payment, please include our invoice number on your check to ensure proper credit to your account. Patient—Mayo Medical Laboratories does not routinely bill patient’s insurance; however, if you have made advanced arrangements to have Mayo Medical Laboratories bill your patient’s insurance, please include the following required billing information: responsible party, patient’s name, current address, zip code, phone number, Social Security number, and diagnosis code. Providing this information will avoid additional correspondence to your office at some later date. Please advise your patients that they will receive a bill for laboratory services from Mayo Medical Laboratories for any personal responsibility after insurance payment. VISA® and MasterCard® are acceptable forms of payment. Billing—CPT Coding It is your responsibility to determine correct CPT codes to use for billing. While this catalog lists CPT codes in an effort to provide some guidance, CPT codes listed only reflect our interpretation of CPT coding requirements and are not necessarily correct. Particularly, in the case of a test involving several component tests, this catalog attempts to provide a comprehensive list of CPT codes for all of the possible components of the test. Only a subset of component tests may be performed on your specimen. You should verify accuracy of codes listed. Where multiple codes are listed, you should select codes for tests actually performed on your specimen. MAYO MEDICAL LABORATORIES ASSUMES NO RESPONSIBILITY FOR BILLING ERRORS DUE TO RELIANCE ON CPT CODES LISTED IN THIS CATALOG. For further reference, please consult the CPT Coding Manual published by the American Medical Association. If you have any questions regarding use of a code, please contact your local Medicare carrier. Business Continuity and Contingency Planning In the event of a local, regional, or national disaster, Mayo Clinic and Mayo Medical Laboratories’ performing sites have comprehensive contingency plans in place in each location to ensure that the impact on laboratory practice is minimized. With test standardization between our performing sites and medical practice locations throughout the country, we have worked to ensure that patient care will not be compromised. Cancellation of Tests Cancellations received prior to test setup will be honored at no charge. Requests received following test setup cannot be honored. A report will be issued automatically and charged appropriately. Chain-of-Custody Chain-of-custody, a record of disposition of a specimen to document who collected it, who handled it, and who performed the analysis, is necessary when results are to be used in a court of law. Mayo Medical Laboratories has developed packaging and shipping materials that satisfy legal requirements for chain-of-custody. This service is only offered for drug testing. 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Current as of August 23, 2017 7:11 am CDT Page 2 Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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Compliance Policies Mayo Medical Laboratories is committed to compliance with applicable laws and regulations such as the Clinical Laboratory Improvement Amendments (CLIA). Regulatory agencies that oversee our compliance include, but are not limited to, the Centers for Medicare and Medicaid Services (CMS), the Food and Drug Administration (FDA), and the Department of Transportation (DOT). Mayo Medical Laboratories develops, implements, and maintains policies, processes, and procedures throughout our organization which are designed to meet relevant requirements. We expect clients utilizing our services will ensure their compliance with patient confidentiality, diagnosis coding, anti-kick back statutes, professional courtesy, CPT-4 coding, CLIA proficiency testing, and other similar regulatory requirements. Also see “Accreditation and Licensure,” “HIPAA Compliance,” and “Reportable Disease.” Confidentiality of Results Mayo Medical Laboratories is committed to maintaining confidentiality of patient information. To ensure Health Insurance Portability and Accountability Act of 1996 (HIPAA) and the College of American Pathologists (CAP) compliance for appropriate release of patient results, Mayo Medical Laboratories has adopted the following policies: Phone Inquiry Policy—One of the following unique identifiers will be required: • Mayo Medical Laboratories’ accession ID number for specimen; or • Client account number from Mayo Medical Laboratories along with patient name; or • Client accession ID number interfaced to Mayo Medical Laboratories; or • Identification by individual that he or she is, in fact, “referring physician” identified on requisition form by Mayo Medical Laboratories’ client Under federal regulations, we are only authorized to release results to ordering physicians or health care providers responsible for the individual patient’s care. Third parties requesting results including requests directly from the patient are directed to the ordering facility. We appreciate your assistance in helping Mayo Medical Laboratories preserve patient confidentiality. Provision of appropriate identifiers will greatly assist prompt and accurate response to inquiries and reporting. Critical Values The “Critical Values Policy” of the Department of Laboratory Medicine and Pathology (DLMP), Mayo Clinic, Rochester, Minnesota is described below. These values apply to Mayo Clinic patients as well as the extramural practice administered through affiliate Mayo Medical Laboratories. Clients should provide “Critical Value” contact information to Mayo Laboratory Inquiry to facilitate call-backs. To facilitate this process, a customized form is available at mayomedicallaboratories.com Definition of Critical Value—A critical value is defined by Mayo Clinic physicians as a value that represents a pathophysiological state at such variance with normal (expected values) as to be life-threatening unless something is done promptly and for which some corrective action could be taken. Abnormals are Not Considered Critical Values— Most laboratory tests have established reference ranges, which represent results that are typically seen in a group of healthy individuals. While results outside these reference ranges may be considered abnormal, “abnormal” results and “critical values” are not synonymous. Analytes on the DLMP Critical Values List represent a subgroup of tests that meet the above definition. Action Taken when a Result is Obtained that Exceeds the Limit Defined by the DLMP Critical Values List—In addition to the normal results reporting (eg, fax, interface), Mayo Medical Laboratories’ staff telephone the ordering physician or the client-provided contact number within 60 minutes following laboratory release of the critical test result(s). In the event that contact is not made within the 60-minute period, we continue to telephone until the designated party is reached and the result is conveyed in compliance and adherence to the CAP. Current as of August 23, 2017 7:11 am CDT


Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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Semi-Urgent Results— Semi-Urgent Results are defined by Mayo Clinic as those infectious disease-related results that are needed promptly to avoid potentially serious health consequences for the patient (or in the case of contagious diseases, potentially serious health consequences to other persons exposed to the patient) if not acknowledged and/or treated by the physician. While not included on the Critical Values List, this information is deemed important to patient care in compliance and adherence to the CAP. To complement Mayo Medical Laboratories’ normal reporting mechanisms (eg, fax, interface), Mayo Medical Laboratories’ staff will telephone results identified as significant microbiology findings to the ordering facility within 2 hours following laboratory release of the result(s). In the event that contact is not made within the 2hour period, we will continue to telephone until the responsible party is reached and the result is conveyed. In addition, in most instances, you will see the comment SIGNIFICANT RESULT appear on the final report. For information regarding the Mayo Clinic Critical Value List, contact Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 or visit mayomedicallaboratories.com. Disclosures of Results Under federal regulations, we are only authorized to release results to ordering physicians or other health care providers responsible for the individual patient’s care. Third parties requesting results, including requests directly from the patient, are directed to the ordering facility. Fee Changes Fees are subject to change without notification and complete pricing per accession number is available once accession number is final. Specific client fees are available by calling Mayo Laboratory Inquiry at 800-5331710 or 507-266-5700 or by visiting mayomedicallaboratories.com. Framework for Quality “Framework for Quality” is the foundation for the development and implementation of the quality program for Mayo Medical Laboratories. Our framework builds upon the concepts of quality control and quality assurance providing an opportunity to deliver consistent, high-quality and cost-effective service to our clients. In addition, our quality program enhances our ability to meet and exceed the requirements of regulatory/ accreditation agencies and provide quality service to our customers. A core principle at Mayo Medical Laboratories is the continuous improvement of all processes and services that support the care of patients. Our continuous improvement process focuses on meeting the needs of you, our client, to help you serve your patients. “Framework for Quality” is composed of 12 “Quality System Essentials.” The policies, processes, and procedures associated with the “Quality System Essentials” can be applied to all operations in the path of workflow (eg, pre-analytical, analytical, and post-analytical). Performance is measured through constant monitoring of activities in the path of workflow and comparing performance through benchmarking internal and external quality indicators and proficiency testing. Data generated by quality indicators drives process improvement initiatives to seek resolutions to system-wide problems. Mayo Medical Laboratories utilizes “Failure Modes and Effects Analysis (FMEA),” “Plan Do Study Act (PDSA),” “LEAN,” “Root Cause Analysis,” and “Six Sigma” quality improvement tools to determine appropriate remedial, corrective, and preventive actions. Quality Indicators—Mayo Medical Laboratories produces hundreds of Key Performance Indicators for our business and operational areas, and we review them regularly to ensure that we continue to maintain our high standards. A sampling of these metrics includes: • Pre-analytic performance indicators o Lost specimens* Current as of August 23, 2017 7:11 am CDT 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 4 Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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On-time delivery Special handling calls Specimen acceptability* Specimen identification* Incoming defects* Analytic performance indicators o Proficiency testing o Test reliability o Turnaround (analytic) times o Quantity-not-sufficient (QNS) specimens* Post-analytic performance indicators o Revised reports* o Critical value reports* Operational performance indicators o Incoming call resolution* o Incoming call abandon rate o Call completion rate o Call in-queue monitoring o Customer complaints o Customer satisfaction surveys o o o o o

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The system provides a planned, systematic program for defining, implementing, monitoring, and evaluating our services. *Measured using Six Sigma defects per million (dpm) method. HIPAA Compliance Mayo Medical Laboratories is fully committed to compliance with all privacy, security, and electronic transaction code requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). All services provided by Mayo Medical Laboratories that involve joint efforts will be done in a manner which enables our clients to be HIPAA and the College of American Pathologists (CAP) compliant. Infectious Material The Centers for Disease Control (CDC) in its regulations of July 21, 1980, has listed organisms/diseases for which special packaging and labeling must be applied. Required special containers and packaging instructions can be obtained from us by using the “Request for Supplies” form or by ordering from the online Supply Catalog at mayomedicallaboratories.com/customer-service/supplies/index.php. Shipping regulations require that infectious substances affecting humans be shipped in a special manner. See “Infectious Material.” A copy of the regulations can be requested from the International Air Transport Association (IATA); they may be contacted by phone at 514-390-6770 or faxed at 514-874-2660. Informed Consent Certification Submission of an order for any tests contained in this catalog constitutes certification to Mayo Medical Laboratories by ordering physician that: (1) ordering physician has obtained “Informed Consent” of subject patient as required by any applicable state or federal laws with respect to each test ordered; and (2) ordering physician has obtained from subject patient authorization permitting Mayo Medical Laboratories to report results of each test ordered directly to ordering physician. On occasion, we forward a specimen to an outside reference laboratory. The laws of the state where the reference laboratory is located may require written informed consent for certain tests. Mayo Medical Laboratories will request that ordering physician pursue and provide such consent. Test results may be delayed or denied if consent is not provided. Current as of August 23, 2017 7:11 am CDT 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 5 Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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Non-Biologic Specimens Due to the inherent exposure risk of non-biologic specimens, their containers, and the implied relationship to criminal, forensic, and medico-legal cases, Mayo Medical Laboratories does not accept nor refer non-biologic specimen types. Example specimens include: unknown solids and liquids in the forms of pills, powder, intravenous fluids, or syringe contents. Patient Safety Goals One of The Joint Commission National Patient Safety goals for the Laboratory Services Program is to improve the accuracy of patient identification by using at least 2 patient identifiers when providing care, treatment, or services. Mayo Medical Laboratories uses multiple patient identifiers to verify the correct patient is matched with the correct specimen and the correct order for the testing services. As a specimen is received at Mayo Medical Laboratories, the client number, patient name, and patient age date of birth are verified by comparing the labels on the specimen tube or container with the electronic order and any paperwork (batch sheet or form) which may accompany the specimen to be tested. When discrepancies are identified, the Mayo Laboratory call center will call the client to verify discrepant information to assure Mayo Medical Laboratories is performing the correct testing for the correct patient. When insufficient or inconsistent identification is submitted, Mayo Medical Laboratories will recommend that a new specimen be obtained, if feasible. In addition, Anatomic Pathology consultation services require the Client Pathology Report. The pathology report is used to match the patient name, patient age and/or date of birth, and pathology case number. Since tissue blocks and slides have insufficient space to print the patient name on the block, the pathology report provides Mayo Medical Laboratories another mechanism to confirm the patient identification with the client order and labels on tissue blocks and slides. Parallel Testing Parallel testing may be appropriate in some cases to re-establish patient baseline results when converting to a new methodology at Mayo Medical Laboratories. Contact your Regional Manager at 800-533-1710 or 507-2665700 for further information. Proficiency Testing We are a College of American Pathologists (CAP)-accredited, CLIA-licensed facility that voluntarily participates in many diverse external and internal proficiency testing programs. It is Mayo Medical Laboratories’ expectation that clients utilizing our services will adhere to CLIA requirements for proficiency testing (42 CFR 493.801), including a prohibition on discussion about samples or results and sharing of proficiency testing materials with Mayo Medical Laboratories during the active survey period. Referring of specimens is acceptable for comparison purposes when outside of the active survey period or when an approved proficiency testing program is not available for a given analyte. Mayo Medical Laboratories’ proficiency testing includes participation in programs conducted by CAP and the Centers for Disease Control and Prevention (CDC) along with independent state, national, and international programs. Our participation includes: • American Association of Bioanalysts (AAB) • AABB (Formerly American Association of Blood Banks) Immunohematology Reference Laboratory • The Binding Site • Centers for Disease Control and Lipid Standardization Program • Centers for Disease Control and Prevention (CDC) • College of American Pathologists (CAP) Surveys • Cystic Fibrosis European Network • EMQN EQA Scheme Current as of August 23, 2017 7:11 am CDT 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 6 Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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Health Canada Interlaboratory Comparison Program International Tay-Sachs Program Laboratoire De Biochimie Et De Toxicologie (Interlaboratory Aluminum Quality Control) Le Centre de Toxicologie du Quebec – Quality Assessment Scheme Le Centre de Toxicologie du Quebec – Comparison Program New York State Department of Health Pennsylvania State Department of Health Vitamin D External Quality Assessment Scheme Wisconsin State Laboratory of Hygiene Women & Infants Hospital (WIH) First Trimester

We conduct internal assessments and comparability studies to ensure the accuracy and reliability of patient testing when an approved proficiency-testing program is not available or additional quality monitoring is desired. We comply with the regulations set forth in Clinical Laboratory Improvement Amendments (CLIA-88), the Occupational Safety and Health Administration (OSHA), or the Centers for Medicare & Medicaid Services (CMS). It is Mayo Medical Laboratories’ expectation that clients utilizing our services will adhere to CLIA requirements for proficiency testing including a prohibition on discussion about samples or results and sharing of proficiency testing materials with Mayo Medical Laboratories during the active survey period. Referring of specimens is acceptable for comparison purposes when outside of the active survey period or when an approved proficiency-testing program is not available for a given analyte. Radioactive Specimens Specimens from patients receiving radioactive tracers or material should be labeled as such. All incoming shipment arriving at Mayo Medical Laboratories are routed through a detection process in receiving to determine if the samples have any levels of radioactivity. If radioactive levels are detected, the samples are handled via an internal process that assures we do not impact patient care and the safety of our respective staff. This radioactivity may invalidate the results of radioimmunoassays (RIA). Record Retention Mayo Medical Laboratories retains all test requisitions and patient test results at a minimum for the retention period required to comply with and adhere to the CAP. A copy of the original report can be reconstructed including reference ranges, interpretive comments, flags, and footnotes with the source system as the Department of Laboratory Medicine’s laboratory information system. Referral of Tests to Another Laboratory Mayo Medical Laboratories forwards tests to other laboratories as a service to its clients. This service should in no way represent an endorsement of such test or referral laboratory or warrant any specific performance for such test. Mayo Medical Laboratories will invoice for all testing referred to another laboratory at the price charged to Mayo Medical Laboratories. In addition, Mayo Medical Laboratories will charge an administrative fee per test for such referral services. Reflex Testing Mayo Medical Laboratories identifies tests that reflex when medically appropriate. In many cases, Mayo Medical Laboratories offers components of reflex tests individually as well as together. Clients should familiarize themselves with the test offerings and make a decision whether to order a reflex test or an individual component. Clients, who order a reflex test, can request to receive an “Additional Testing Notification Report” which indicates the additional testing that has been performed. This report will be faxed to the client. Clients who wish to receive the “Additional Testing Notification Report” should contact their Regional Manager or Regional Service Representative. Current as of August 23, 2017 7:11 am CDT



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Reportable Disease Mayo Medical Laboratories, in compliance with and adherence to the College of American Pathologists (CAP) Laboratory General Checklist (CAP GEN. 20373) strives to comply with laboratory reporting requirements for each state health department regarding reportable disease conditions. We report by mail, fax, and/or electronically, depending upon the specific state health department regulations. Clients shall be responsible for compliance with any state specific statutes concerning reportable conditions, including, but not limited to, birth defects registries or chromosomal abnormality registries. This may also include providing patient address/demographic information. Mayo Medical Laboratories’ reporting does not replace the client/physician responsibility to report as per specific state statues. Request for Physician Name and Number Mayo Medical Laboratories endeavors to provide high quality, timely results so patients are able to receive appropriate care as quickly as possible. While providing esoteric reference testing, there are times when we need to contact the ordering physician directly. The following are 2 examples: When necessary to the performance of a test, the ordering physician’s name and phone number are requested as part of “Specimen Required.” This information is needed to allow our physicians to make timely consultations or seek clarification of requested services. If this information is not provided at the time of specimen receipt, we will call you to obtain the information. By providing this information up front, delays in patient care are avoided. In some situations, additional information from ordering physician is necessary to clarify or interpret a test result. At that time, Mayo Medical Laboratories will request physician’s name and phone number so that 1 of our staff can consult with the physician. We appreciate your rapid assistance in supplying us with the ordering physician’s name and phone number when we are required to call. Working together, we can provide your patients with the highest quality testing services in the shortest possible time. Special Handling Mayo Medical Laboratories serves as a reference laboratory for clients around the country and world. Our test information, including days and time assays are performed as well as analytic turnaround time, is included under each test listing in the Test Catalog on mayomedicallaboratories.com. Unique circumstances may arise with a patient resulting in a physician request that the specimen or results receive special handling. There are several options available. These options can only be initiated by contacting Mayo Laboratory Inquiry at 800-533-1710 and providing patient demographic information. There is a nominal charge associated with any special handling. •

Hold: If you would like to send us a specimen and hold that specimen for testing pending initial test results performed at your facility, please call Mayo Laboratory Inquiry. We will initiate a hold and stabilize the specimen until we hear from you. • Expedite: If you would like us to expedite the specimen to the performing laboratory, you can call Mayo Laboratory Inquiry and request that your specimen be expedited. Once the shipment is received in our receiving area, we will deliver the specimen to the performing laboratory for the next scheduled analytic run. We will not set up a special run to accommodate an expedite request. • STAT: In rare circumstances, STAT testing from the reference laboratory may be required for patients who need immediate treatment. These cases typically necessitate a special analytic run to turn results around as quickly as possible. To arrange STAT testing, please have your pathologist, physician, or laboratory director call Mayo Laboratory Inquiry. He/she will be connected with one of our medical directors to consult about the patient’s case. Once mutually agreed upon that there is a need for a STAT, arrangements will be made to assign resources to run the testing on a STAT basis when the specimen is received. Current as of August 23, 2017 7:11 am CDT 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com Page 8 Master copies are retained online. Printed copies are considered current only on the date printed unless stamped Controlled.

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Specimen Identification Policy In compliance with and adherence to the CAP and the Joint Commission’s 2008 Patient Safety Goals (1A), Mayo Medical Laboratories’ policy states that all specimens received for testing must be correctly and adequately labeled to assure positive identification. Specimens must have 2 person-specific identifiers on the patient label. Person-specific identifiers may include: accession number, patient’s first and last name, unique identifying number (eg, medical record number), or date of birth. Specimens are considered mislabeled when there is a mismatch between the person-specific identifiers on the specimen and information accompanying the specimen (eg, computer system, requisition form, additional paperwork). When insufficient or inconsistent identification is submitted, Mayo Medical Laboratories will recommend that a new specimen be obtained, if feasible. Specimen Rejection All tests are unique in their testing requirements. To avoid specimen rejection or delayed turnaround times, please check the “Specimen Required” field within each test. You will be notified of rejected or problem specimens upon receipt. Please review the following conditions prior to submitting a specimen to Mayo Medical Laboratories: • Full 24 hours for timed urine collection • pH of urine • Lack of hemolysis/lipemia • Specimen type (plasma, serum, whole blood, etc.) • Specimen volume • Patient information requested • Proper identification of patient/specimen • Specimen container (metal-free, separation gel, appropriate preservative, etc.) • Transport medium • Temperature (ambient, frozen, refrigerated) Specimen Volume The “Specimen Required” section of each test includes 2 volumes - preferred volume and minimum volume. Preferred volume has been established to optimize testing and allows the laboratory to quickly process specimen containers, present containers to instruments, perform test, and repeat test, if necessary. Many of our testing processes are fully automated; and as a result, this volume allows hands-free testing and our quickest turnaround time (TAT). Since patient values are frequently abnormal, repeat testing, dilutions, or other specimen manipulations often are required to obtain a reliable, reportable result. Our preferred specimen requirements allow expeditious testing and reporting. When venipuncture is technically difficult or the patient is at risk of complications from blood loss (eg, pediatric or intensive care patients), smaller volumes may be necessary. Specimen minimum volume is the amount required to perform an assay once, including instrument and container dead space. When patient conditions do not mandate reduced collection volumes, we ask that our clients submit preferred volume to facilitate rapid, cost-effective, reliable test results. Submitting less than preferred volume may negatively impact quality of care by slowing TAT, increasing the hands-on personnel time (and therefore cost) required to perform test. Mayo Clinic makes every possible effort to successfully test your patient’s specimen. If you have concerns about submitting a specimen for testing, please call Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700. Our staff will discuss the test and specimen you have available. While in some cases specimens are inadequate for desired test, in other cases, testing can be performed using alternative techniques. Current as of August 23, 2017 7:11 am CDT



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Supplies Shipping boxes, specimen vials, special specimen collection containers, and request forms are supplied without charge. Supplies can be requested using 1 of the following methods: use the online ordering functionality available at mayomedicallaboratories.com/supplies or call Mayo Laboratory Inquiry at 800-533-1710 or 507266-5700. Test Classifications Analytical tests offered by Mayo Medical Laboratories are classified according to the FDA labeling of the test kit or reagents and their usage. Where appropriate, analytical test listings contain a statement regarding these classifications, test development, and performance characteristics. The classifications include: • •

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Standard Method - This test uses a standard method. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. FDA Approved, Cleared, or Exempt (IVD) - This test has been cleared or approved by the U.S. Food and Drug Administration (or is exempt from FDA review) and is used per manufacturer’s instructions. Performance characteristics were verified by Mayo Clinic in a manner consistent with CLIA requirements. FDA Modified - This test has been modified from the manufacturer's instructions. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. Analyte Specific Reagent (ASR) - This test was developed using an analyte specific reagent. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration. Laboratory Developed Test - This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration. Investigational Use Only (IUO) - This test uses a kit labeled by the manufacturer as "investigational use only" and it is used per manufacturer's instructions. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration. Research Use Only (RUO) - This test uses a reagent or kit labeled by the manufacturer as "research use only" and it is used per manufacturer's instructions. Its performance characteristics were determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

Test Development Process Mayo Medical Laboratories serves patients and health care providers from Mayo Clinic, Mayo Health System, and our reference laboratory clients worldwide. We are dedicated to providing clinically useful, cost-effective testing strategies for patient care. Development, validation, and implementation of new and improved laboratory methods are major components of that commitment. Each assay utilized at Mayo Clinic, whether developed on site or by others, undergoes an extensive validation and performance documentation period before the test becomes available for clinical use. Validations follow a standard protocol that includes: • • • • • • • •

Accuracy Precision Sensitivity Specificity and interferences Reportable range Linearity Specimen stability Specimen type comparisons Current as of August 23, 2017 7:11 am CDT



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Urine preservative studies: stability at ambient, refrigerated, and frozen temperatures and with 7 preservatives; at 1, 3, and 7 days Comparative evaluation: with current and potential methods Reference values: using medically evaluated healthy volunteers, male and female, across age groups. The number of observations required for each test is determined by biostatistic analysis. Unless otherwise stated, reference values provided by Mayo Medical Laboratories are derived from studies performed in our laboratories. When reference values are obtained from other sources, the source is indicated in the “Reference Values” field. Workload recording Limitations of the assay Clinical utility and interpretation: written by Mayo Clinic medical experts, electronically available (MayoAccess™)

Test Result Call-Backs Results will be phoned to a client when requested from the client (either on Mayo Medical Laboratories’ request form or from a phone call to Mayo Medical Laboratories from the client). Time-Sensitive Specimens Please contact Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700 prior to sending a specimen for testing of a time-sensitive nature. Relay the following information: facility name, account number, patient name and/or Mayo Medical Laboratories’ accession number, shipping information (ie, courier service, FedEx®, etc.), date to be sent, and test to be performed. Place specimen in a separate Mayo Medical Laboratories’ temperature appropriate bag. Please write “Expedite” in large print on outside of bag. Turnaround Time (TAT) Mayo Medical Laboratories’ extensive test menu reflects the needs of our own health care practice. We are committed to providing the most expedient TAT possible to improve diagnosis and treatment. We consider laboratory services as part of the patient care continuum wherein the needs of the patient are paramount. In that context, we strive to fulfill our service obligations. Our history of service and our quality metrics will document our ability to deliver on all areas of service including TAT. Mayo Medical Laboratories defines TAT as the analytical test time (the time from which a specimen is received at the testing location to time of result) required. TAT is monitored continuously by each performing laboratory site within the Mayo Clinic Department of Laboratory Medicine and Pathology. For the most up-to-date information on TAT for individual tests, please visit us at mayomedicallaboratories.com or contact our Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700. Unlisted Tests Mayo Medical Laboratories does not list all available test offerings in the paper catalog. New procedures are developed throughout the year; therefore, some tests are not listed in this catalog. Although we do not usually accept referred tests of a more routine type, special arrangements may be made to provide your laboratory with temporary support during times of special need such as sustained instrumentation failure. For information about unlisted tests, please call Mayo Laboratory Inquiry at 800-533-1710 or 507-266-5700.




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GAAZ 35430

Pompe Disease, Full Gene Analysis Clinical Information: Pompe disease, also known as glycogen storage disease type II, is an autosomal recessive condition caused by deficiency of acid alpha-glucosidase. Enzyme insufficiency results in symptoms such as muscle weakness, cardiomyopathy, and respiratory problems. Mutations in the GAA gene (which encodes acid alpha-glucosidase) are associated with Pompe disease. The diagnosis of this heterogeneous condition relies on both clinical and laboratory evaluation. Clinically, the condition is categorized into infantile and late-onset forms based on age of onset, organ involvement, and rate of progression. The infantile form (or classic Pompe disease) is the most severe form and is characterized by early onset and rapid progression of cardiac, liver, and muscle problems resulting in death within the first year. The infantile variant form has a similar age of onset but a milder clinical presentation. On the less severe end of the spectrum is the late-onset form with childhood, juvenile, or adult onset. The rate of progression and severity of symptoms is quite variable, particularly in the late-onset forms. The incidence varies by clinical type and ethnic population; the combined incidence is approximately 1 in 40,000 individuals. Biochemical testing of acid alpha-glucosidase in blood spot specimens or fibroblasts is useful for individuals with a suspected diagnosis of Pompe disease (GAABS / Acid Alpha-Glucosidase, Blood Spot). When clinical manifestations and results of that analysis are supportive of a diagnosis of Pompe disease, mutation analysis of the GAA gene is warranted. Over 250 different mutations have been identified in this gene including point mutations and large deletions. GAA full gene sequencing provided by this test will detect 2 mutations in approximately 83% to 93% of individuals with confirmed GAA enzyme deficiency. Identification of mutations provides confirmation of the diagnosis and allows for subsequent testing of at risk family members.

Useful For: Confirmation of diagnosis of Pompe disease (as a follow-up to biochemical analyses) Interpretation: All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Reference Values: An interpretive report will be provided.

Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300 2. Kishnani PS, Steiner RD, Bali D, et al: Pompe disease diagnosis and management guideline. Genet Med 2006 May;8(5):267-288 3. Van der Ploeg AT, Reuser AJJ: Pompe's disease. Lancet 2008;372(9646):1342-1353 4. Kroos M, Pomponio RJ, van Vliet L, et al: Update of the Pompe disease mutation database with 107 sequence variants and a format for severity rating. Hum Mut 2008;29(6):E13-26 5. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: (acid maltase) deficiency. In Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Edited by CR Scriver, AL Beaudet, WS Sly, et al: New York, McGraw-Hill, Inc., available at www.ommbid.com Accessed 3-6-08

DHVD

1,25-Dihydroxyvitamin D, Serum

8822

Clinical Information: Vitamin D is a generic designation for a group of fat-soluble, structurally similar sterols including ergocalciferol D2 from plants and cholecalciferol D3 from animals. Vitamin D in the body is derived from 2 sources: exogenous (dietary: D2 and D3) and endogenous (biosynthesis: D3). Endogenous D3 is produced in the skin from 7-dehydrocholesterol, under the influence of ultraviolet light. Both forms of vitamin D are of similar biologic activity. Vitamin D is rapidly metabolized in the liver to form 25-hydroxy (OH) vitamin D. Additional hydroxylation of 25-OH vitamin D takes place in the kidney by 1-alpha hydroxylase, under the control of parathyroid hormone, to yield 1,25-dihydroxy vitamin D. 1,25-Dihydroxy vitamin D is the most potent vitamin D metabolite. It stimulates calcium absorption in the intestine and its production is tightly regulated through concentrations of serum calcium, phosphorus, and parathyroid hormone. 1,25-Dihydroxy vitamin D levels may be high in primary hyperparathyroidism and in physiologic hyperparathyroidism secondary to low calcium or vitamin D intake. Some patients with granulomatous diseases (eg, sarcoidosis) and malignancies containing



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nonregulated 1-alpha hydroxylase in the lesion may have elevated 1,25-dihydroxy vitamin D levels and hypercalcemia. 1,25-Dihydroxy vitamin D levels are decreased in hypoparathyroidism and in chronic renal failure. While 1,25-dihydroxy vitamin D is the most potent vitamin D metabolite, levels of the 25-OH forms of vitamin D more accurately reflect the body's vitamin D stores. Consequently, 25HDN / 25-Hydroxyvitamin D2 and D3, Serum is the preferred initial test for assessing vitamin D status. However, in the presence of renal disease, 1,25-dihydroxy vitamin D levels may be needed to adequately assess vitamin D status.

Useful For: As a second-order test in the assessment of vitamin D status, especially in patients with renal disease Investigation of some patients with clinical evidence of vitamin D deficiency (eg, vitamin D-dependent rickets due to hereditary deficiency of renal 1-alpha hydroxylase or end-organ resistance to 1,25-dihydroxy vitamin D) Differential diagnosis of hypercalcemia

Interpretation: 1,25-Dihydroxy vitamin D concentrations are low in chronic renal failure and hypoparathyroidism. 1,25-Dihydroxy vitamin D concentrations are high in sarcoidosis and other granulomatous diseases, some malignancies, primary hyperparathyroidism, and physiologic hyperparathyroidism. 1,25-dihydroxy vitamin D concentrations are not a reliable indicator of vitamin D toxicity; normal (or even low) results may be seen in such cases.

Reference Values: Males or =16 years: 18-64 pg/mL Females or =16 years: 18-78 pg/mL

Clinical References: 1. Endres DB, Rude RK: Vitamin D and its metabolites. In Tietz Textbook of Clinical Chemisty. Third edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1999, pp 1417-1423 2. Bringhurst FR, Demay MB, Kronenberg HM: Vitamin D (calciferols): metabolism of vitamin D. In Williams Textbook of Endocrinology. Ninth edition. Edited by JD Wilson, DW Foster, HM Kronenberg, PR Larsen. Philadelphia, WB Saunders Company, 1998, pp 1166-1169

TXBU

11-Dehydro-Thromboxane B2, Urine

83335

Clinical Information: Antiplatelet medications are frequently utilized in the prevention of stroke, myocardial infarction, and vascular thrombotic diseases due to the fundamental role of platelet aggregation in a variety of atherothrombotic processes. Modulation of the prostaglandin thromboxane A2 (TxA2) pathway is 1 of the pivotal routes of activation involved in stimulating platelet aggregation. Synthesis of TxA2 is mediated in platelets by the cyclooxygenase 1 (COX-1) enzyme, which must be functional for stimulating the production of TxA2 from arachidonic acid. The importance of TxA2 is demonstrated by the reduction in risk of myocardial infarction (MI) or death in patients with acute coronary syndrome (ACS) following administration of aspirin, which irreversibly inhibits platelet COX-1 and inhibits the production of TxA2. TxA2 has an extremely short half-life, converting to 2 stable, inactive metabolites: 11-dehydro-thromboxane B2 (TxB2) and 2, 3-dinor-11-dehydrothromboxane B2. Excretion of TxB2 in the urine has been shown to reflect in vivo platelet activation. Elevated concentrations of TxB2 have been noted in up to 85% of patients with acute ischemic stroke and demonstrate further diagnostic and prognostic utility in patients with ACS. Aspirin therapy has been reported to reduce cardiovascular events in men and women by up to 40%. However, use of aspirin is not without risk and is associated with higher frequencies of gastrointestinal bleeding and hemorrhagic stroke. Identification of patients most likely to benefit from antiplatelet therapy with aspirin or other pharmaceutical agents has great clinical utility. Quantitation of urinary TxB2 offers an advantage over platelet-activation markers measured in plasma or blood because measurements are not subject to interference from in vitro platelet activation, which commonly occurs as a result of preanalytical variables such as local vein trauma or insufficient anticoagulation during phlebotomy. Measurement of urine TxB2 may be performed in patients to assess the effectiveness of specific inhibition in the TxA2 pathway, along with identification of a patientâ€™s ability to benefit from antiplatelet therapy, and their associated risk



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for developing future cardiovascular events.

Useful For: Assessing if a patient will derive benefit from aspirin therapy Determining an individualâ€™s risk of coronary heart disease and stroke Identifying the effectiveness of antiplatelet therapies

Interpretation: The normal reference range was derived from an in-house normal donor study with individuals who were self-reported as not taking any aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or other lipid-lowering therapies. Elevated concentrations of urine thromboxane B2 (TxB2) may indicate an increase in platelet activation and thrombosis resulting from atherosclerotic deposits or other vascular obstructions and may identify those individuals who may be at increased risk for an ischemic cardiovascular event. Elevations of TxB2 in patients already receiving antiplatelet therapies suggest a failure in the suppression of laboratory-assessed platelet function, a continued hypercoagulable state, and alternative antithrombotic or antiplatelet therapies may be considered. The liquid chromatography-tandem mass spectrometry method is specific for TxB2 and is not subject to interference from the other metabolite of thromboxane A2, the 2,3-dinor-TxB2 component.

Reference Values: > or =18 years: 0-2,211 pg/mg creatinine Reference values have not been established for patients who are 90% of cases), with the third most common form of CAH (3-beta-steroid dehydrogenase deficiency, 0.02 nmol/L are consistent with a diagnosis of acquired myasthenia gravis (MG), provided that clinical and electrophysiological criteria support that diagnosis. The assay for muscle acetylcholine receptor (AChR) binding antibodies is positive in approximately 90% of nonimmunosuppressed patients with generalized MG. The frequency of antibody detection is lower in MG patients with weakness clinically restricted to ocular muscles (71%), and antibody titers are generally low in ocular MG (eg, 0.03-1.0 nmol/L). Results may be negative in the first 12 months after symptoms of MG appear or during immunosuppressant therapy. Note: In follow up of seronegative patients with adult-acquired generalized MG, 17.4% seroconvert to positive at 12 months (ie, seronegativity rate at 12 months is 8.4%). Of persistently seronegative patients, 38% have muscle-specific kinase (MuSK) antibody. Sera of nonmyasthenic subjects bind per liter 0.02 nmol or less of muscle AChR complexed with (125)I-labeled-alpha-bungarotoxin. In general, there is not a close correlation between antibody titer and severity of weakness, but in individual patients, clinical improvement is usually accompanied by a decrease in titer.

Reference Values: < or =0.02 nmol/L

Clinical References: 1. Lennon VA: Serological diagnosis of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 1997;48(Suppl 5):S23-S27 2. Lachance DH, Lennon VA: Chapter 19, Paraneoplastic neurological autoimmunity. In Neuroimmunology in Clinical Practice. Edited by B Kalman, T Brannagan III. Blackwell Publishing Ltd, 2008, pp 210-217

ACHE_

Acetylcholinesterase, Amniotic Fluid (AChE-AF), Amniotic Fluid

9287

Clinical Information: Neural tube defects (NTD) are a type of birth defect involving openings along the brain and spine. They develop in the early embryonic period when the neural tube fails to completely close. NTD can vary widely in severity. Anencephaly represents the most severe end of the spectrum and occurs when the cranial end fails to form, resulting in an absence of the forebrain, the area of the skull that covers the brain, and the skin. Most infants with anencephaly are stillborn or die shortly after birth. NTD along the spine are referred to as spina bifida. Individuals with spina bifida may experience hydrocephalus, urinary and bowel dysfunction, club foot, lower body weakness, and loss of feeling or paralysis. Severity varies depending upon whether the NTD is covered by skin, whether herniation of the meninges and spinal cord are present, and the location of the lesion. NTD not covered by skin are referred to as open NTD and are typically more severe than closed NTD. Likewise those presenting with herniation and higher on the spinal column are typically more severe. Most NTD occur as isolated birth defects with an incidence of approximately 1 in 1,000 to 2 in 1,000 live births in the United States. Rates vary by geographic region with lower rates being observed in the North and West than the South and East. A fetus is at higher risk when the pregnancy is complicated by maternal diabetes, exposed to certain anticonvulsants, or there is a family history of NTD. Studies have shown a dramatic decrease in risk as a result of maternal dietary supplementation with folic acid. The March of Dimes currently recommends that all women of childbearing age take 400 micrograms of folic acid daily, increasing the amount to 600 mg/day during pregnancy. For women who have had a prior pregnancy affected by an NTD, the recommended dose is at least 4,000 mg/day starting at least 1 month preconception and continuing



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through the first trimester. When an NTD is suspected based upon maternal serum alpha-fetoprotein (AFP) screening results or diagnosed via ultrasound, analysis of alpha-fetoprotein (AFP) and acetylcholinesterase (AChE) in amniotic fluid are useful diagnostic tools. AChE is primarily active in the central nervous system with small amounts of enzyme found in erythrocytes, skeletal muscle, and fetal serum. Normal amniotic fluid does not contain AChE, unless contributed by the fetus as a result of an open NTD.

Useful For: Diagnosing open neural tube defects, and to a lesser degree, ventral wall defects Interpretation: The presence of acetylcholinesterase in amniotic fluid is consistent with open neural tube defects and, to a lesser degree, ventral wall defects.

Reference Values: Negative (reported as negative [normal] or positive [abnormal] for inhibitable acetylcholinesterase) Reference values were established in conjunction with alpha-fetoprotein testing and include only amniotic fluids from pregnancies between 14 and 21 weeks gestation.

Clinical References: Wilson RD, Audibert F, Brock JA, et al: Prenatal screening, diagnosis, and pregnancy management of fetal neural tube defects. J Obstet Gynaecol Can 2014 Oct;36(10):927-939

ACHS

Acetylcholinesterase, Erythrocytes

8522

Clinical Information: Acetylcholinesterase (AChE) is anchored to the external surface of the RBC. Its appearance in a lysate of red cells is diminished in paroxysmal nocturnal hemoglobinuria (PNH). The use of red cell AChE for PNH has not gained widespread acceptance, and flow cytometry testing is most often used for PNH (see PANH/81156 PI-Linked Antigen, Blood). Red cell AChE is most often used to detect past exposure to organophosphate insecticides with resultant inhibition of the enzyme. Both the pseudocholinesterase activity in serum and red cell AChE are inhibited by these insecticides, but they are dramatically different vis-a-vis the temporal aspect of the exposure. The half-life of the pseudo-enzyme in serum is about 8 days, and the "true" cholinesterase (AChE) of red cells is over 3 months (determined by erythropoietic activity). Recent exposure up to several weeks is determined by assay of the pseudo-enzyme and months after exposure by measurement of the red cell enzyme. The effect of the specific insecticides may be important to know prior to testing.

Useful For: Detecting effects of remote (months) past exposure to cholinesterase inhibitors (organophosphate insecticide poisoning)

Interpretation: Activities less than normal are suspect for exposure to certain insecticides. Reference Values: 31.2-61.3 U/g of hemoglobin

Clinical References: 1. Robinson DG, Trites DG, Banister EW: Physiological effects of work stress and pesticide exposure in tree planting by British Columbia silviculture workers. Ergonomics 1993;36:951-961 2. Fuortes LJ, Ayebo AD, Kross BC: Cholinesterase-inhibiting insecticide toxicity. Am Fam Phys 1993;47:1613-1620

64709

Achaete-Scute Homolog 1 (ACSL1) (hASH1), Immunostain Without Interpretation Clinical Information: Achaete-scute homolog 1 (ACSL1), alternatively titled hASH1 or MASH1, is a member of the basic helix-loop-helix family of transcription factors. ACSL1 may play a role at early stages of development of specific neural lineages in most regions of the central nervous system, and of several lineages in the peripheral nervous system. The protein has been shown to be highly expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these cancers.

Useful For: Identification of the presence of Achaete-scute homolog 1 (ASCL1) Current as of August 23, 2017 7:11 am CDT


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Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Au NH, Cheang M, Huntsman DG, et al: Evaluation of immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers. J Pathol 2004;204:101-109 2. Kosari F, Ida CM, Aubry M-C, et al: ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. Oncogene 2014;33:3776-3783 3. Ralston J, Chiriboga L, Nonaka D: MASH1: a useful marker in differentiating pulmonary small cell carcinoma from merkel cell carcinoma. Mod Pathol 2008 Nov;21(11):1357-1362 4. Somasundaram K, Reddy SP, Vinnakota K, et al: Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene 2005;24:7073-7083

GAABS

Acid Alpha-Glucosidase, Blood Spot

89210

Clinical Information: Pompe disease, also known as glycogen storage disease type II, is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase (GAA). This leads to an accumulation of glycogen in the lysosome causing swelling, cell damage, and progressive organ dysfunction. Pompe disease is caused by mutations in the GAA gene, and it is characterized by muscle hypotonia, weakness, cardiomegaly, hypertrophic cardiomyopathy, and eventual death due to either cardiorespiratory or respiratory failure. The clinical phenotype, in general, appears to be dependent on residual enzyme activity, with complete loss of activity causing onset in infancy. Untreated, this leads to death, typically within the first year of life. Juvenile and adult-onset forms are characterized by later onset and longer survival. Primary symptoms of later-onset Pompe disease include muscle weakness and respiratory insufficiency. Rarely, clinically significant cardiomyopathy can be seen. The estimated incidence is 1 in 40,000 live births. Enzyme replacement therapy (ERT) improves outcome in many patients with either classic infantile onset or later onset forms of Pompe disease. Early initiation of treatment improves the prognosis and makes early diagnosis of Pompe disease desirable. Because of this, newborn screening for Pompe disease has recently been implemented in some states. The early identification and treatment of infants with Pompe disease has been shown to be helpful in reducing the morbidity and mortality associated with this disease. Since Pompe disease is considered a rare condition that progresses rapidly in infancy, the disease, in particular the juvenile and adult-onset forms, is often considered late if at all, during the evaluation of patients presenting with proximal muscle weakness and respiratory insufficiency. Testing traditionally required a skin or muscle biopsy to establish cultures for enzyme testing. More recently, molecular genetic testing of the GAA gene (GAAZ / Pompe Disease, Full Gene Analysis) became clinically available. Determination of the enzyme activity in dried blood spot specimens can be performed in a timely fashion and provide better guidance in the decision to submit samples for further confirmatory testing by molecular genetic analysis (GAAZ / Pompe Disease, Full Gene Analysis).

Useful For: Evaluation of patients of any age with a clinical presentation suggestive of Pompe disease (muscle hypotonia, weakness, or cardiomyopathy)

Interpretation: Normal results (>0.5 nmol/hour/mL) in properly submitted specimens are not consistent with classic Pompe disease. Affected individuals typically have levels of 0.5 nmol/hour/mL or less; however, some later onset cases may show higher enzyme activity. Results of 0.5 nmol/hour/mL or less can be followed up by molecular genetic analysis of the GAA gene (GAAZ / Pompe Disease, Full Gene Analysis) to determine carrier, pseudodeficiency, or disease status.

Reference Values: Normal >0.5 nmol/mL/hour

Clinical References: 1. Chien YH, Hwu WL, Lee NC: Pompe Disease: early diagnosis and early Current as of August 23, 2017 7:11 am CDT


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treatment make a difference. Pediatr Neonatol 2013;54:219-227 2. Gungor D, Kruijshaar ME, Plug I, et al: Quality of life and participation in daily life of adults with Pompe Disease receiving enzyme replacement therapy: 10 years of international follow-up. J Inher Metab Dis 2015 Nov;38:495-503 3. Katzin LW, Amato AA: Pompe disease: a review of the current diagnosis and treatment recommendations in the era of enzyme replacement therapy. J Clin Neuromuscul Dis 2008 Jun;9(4):421-431 4. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. McGraw-Hill, Medical Publishing Division, 2009, pp 750-751 5. Matern D, Gavrilov D, Oglesbee D, et al: Newborn screening for lysosomal storage disorders. Semin Perinatol 2015 Apr;39(3):206-216

ACPHS

Acid Phosphatase Stain (Bill Only)

80869

Reference Values: This test is for billing purposes only. This is not an orderable test. Order MPCT / Muscle Pathology Consultation or MBCT / Muscle Biopsy Consultation, Outside Slides and/or Paraffin Blocks. The consultant will determine the need for special stains.

SAFB

Acid-Fast Smear for Mycobacterium

8213

Clinical Information: Mycobacterium tuberculosis is a leading infectious disease cause of death worldwide. The Centers for Disease Control and Prevention has reported a rise in the incidence of tuberculosis associated with AIDS, foreign-born cases, and increased transmission in high-risk populations. There has also been a rise in the number of M tuberculosis strains that exhibit resistance to one or more antituberculosis drugs. The public health implications of these facts are considerable. Because M tuberculosis is readily spread by airborne particles, rapid diagnosis and isolation of infected persons is important. Nontuberculous mycobacteria infections also cause significant morbidity and mortality in humans, particularly in immunocompromised persons. Detection of acid-fast bacilli in sputum specimens allows rapid identification of individuals who are likely to be infected with mycobacteria while definitive diagnosis and treatment are pursued.

Useful For: Detection of acid-fast bacilli in clinical specimens Interpretation: Patients whose sputum specimens are identified as acid-fast positive should be considered potentially infected with Mycobacterium tuberculosis, pending definitive diagnosis by molecular methods or mycobacterial culture.

Reference Values: Negative (reported as positive or negative)

Clinical References: 1. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Controlling Tuberculosis in the United States. Am J Respir Crit Care Med, 2005;172:1169-1227 2. American Thoracic Society: An Official ATS/IDSA Statement: Diagnosis, Treatment, and Prevention of Nontuberculous Mycobacterial Diseases. Am J Respir Crit Care Med, 2007;175:367-416

60801

Actin, Smooth Muscle (SMActin), Immunostain Without Interpretation Clinical Information: Smooth muscle actin reacts with the alpha-smooth muscle isoform of actin, and labels the smooth muscle cells of vessels, myoepithelial cells, pericytes, some stromal cells in the intestine, testis, and ovary, and tumors derived from smooth muscle cells. The antibody does not react with actin from fibroblasts, striated muscle, and myocardium. This immunostain is a useful tool in the identification of leiomyomas, leiomyosarcomas, and pleomorphic adenomas.



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Useful For: Identification of cells expressing the alpha-smooth muscle isoform of actin Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Arora G, Girdhar M, Gaghla A, et al: Comparing the expression of myoepithelial cell markers CD10 and smooth muscle actin with the estrogen receptor status in the invasive carcinoma breast: An immunohistochemical study. Clin Cancer Invest J 2013;2:20-24 2. Nishio J, Iwasaki H, Skashita N, et al: Undifferentiated (embryonal) sarcoma of the liver in middle-aged adults: smooth muscle differentiation determined by immunohistochemistry and electron microscopy. Hum Pathol 2003;34(3):246-252. 3. Tse GM, Tan PH, Lui PC, et al: The role of immunohistochemistry for smooth-muscle actin, p63, CD10 and cytokeratin 14 in the differential diagnosis of papillary lesions of the breast. J Clin Pathol 2007;60(3):315-320

ACT

Actinomyces Culture

8221

Clinical Information: Anaerobic Actinomyces are nonsporeforming, thin branching, gram-positive bacilli that are part of the normal flora of the human oral cavity and may also colonize the gastrointestinal and female genital tracts. Their presence is important in preserving the usual bacterial populations of the mouth and in preventing infection with pathogenic bacteria. Actinomyces are generally of low pathogenicity but may be an important factor in the development of periodontal disease and may cause soft tissue infections in colonized areas of the body following trauma (surgical or otherwise). The typical lesion consists of an outer zone of granulation around central purulent loculations containing masses of tangled organisms ("sulfur granule"). Chronic burrowing sinus tracts develop. Typical actinomycotic infections occur around the head and neck, in the lung and chest wall, and in the peritoneal cavity and abdominal wall. Actinomycosis of the female genital tract occurs in association with use of intrauterine contraceptive devices. Purulent collections containing "sulfur granules" may drain from some sinus tracts opening to the skin.

Useful For: Diagnosing anaerobic Actinomyces involved in infections Interpretation: Isolation of anaerobic Actinomyces in significant numbers from well collected specimens including blood, other normally sterile body fluids, or closed collections of purulent fluid indicates infection with the identified organism.

Reference Values: No growth Identification of probable pathogens

Clinical References: 1. Summanen P, Baron EJ, Citron DM, Jousimies-Somer HR, et al: Wadsworth Anaerobic Bacteriology Manual, Sixth edition. Belmont CA, Star Publishing Co. 2002 2.. Hall V, Copsey SD: Propionibacterium, Lactobacillus, Actinomyces, and Other Non-Spore-Forming Anaerobic Gram-Positive Rods. In Manual of Clinical Microbiology. 11th edition. Edited by J Jorgensen. Washington DC, ASM Press, 2015 Chapters 52, pp 920-939 3. Morton A, Hall, GS: Anaerobic Gram-Positive Bacilli. In Clinical Microbiology Procedures Handbook. Third edition. Vol. 1. Edited by LS Garcia. Washington DC, ASM Press, 2010

APTTP

Activated Partial Thromboplastin Time (APTT), Plasma

40935

Clinical Information: The activated partial thromboplastin time (APTT) assay is used as a screening test to evaluate the overall integrity of the intrinsic/common coagulation pathway and to monitor patients on heparin therapy. This test reflects the activities of most of the coagulation factors in the intrinsic and common procoagulant pathway, but not the extrinsic procoagulant pathway, which includes factor VII and



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tissue factor, nor the activity of factor XIII (fibrin stabilizing factor). Effective November 2016, APTT will no longer be used as the primary method for therapeutic heparin monitoring, for that purpose, order the heparin anti-Xa assay HEPTP / Heparin Anti-Xa Assay, Plasma.

Useful For: Monitoring heparin therapy (unfractionated heparin) Screening for certain coagulation factor deficiencies Detection of coagulation inhibitors such as lupus anticoagulant, specific factor inhibitors, and nonspecific inhibitors

Interpretation: Prolongation of the activated partial thromboplastin time (APTT) can occur as a result of deficiency of one or more coagulation factors (acquired or congenital in origin), or the presence of an inhibitor of coagulation such as heparin, a lupus anticoagulant, a nonspecific inhibitor such as a monoclonal immunoglobulin, or a specific coagulation factor inhibitor. Prolonged clotting times may also be observed in cases of fibrinogen deficiency, liver disease, and vitamin K deficiency. Shortening of the APTT usually reflects either elevation of factor VIII activity in vivo that most often occurs in association with acute or chronic illness or inflammation, or spurious results associated with either difficult venipuncture and specimen collection or suboptimal specimen processing.

Reference Values: 25-37 seconds

Clinical References: 1. Clinical and Laboratory Standards Institute (CLSI). One-stage PT and APTT test; Approved Guideline Second Edition. H47-A2, 2008 2. Greaves M, Preston FE: Approach to the bleeding patient. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, JB Lippincott Co, 2001, pp 1197-1234

APCRV

Activated Protein C Resistance V (APCRV), Plasma

81967

Clinical Information: Protein C, a part of the natural anticoagulant system, is a vitamin K-dependent protein zymogen (molecular weight=62,000 da) that is synthesized in the liver and circulates at a plasma concentration of approximately 5 mcg/mL. Protein C is activated to activated protein C (APC) via proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell surface membrane protein. APC downregulates the procoagulant system by proteolytically inactivating procoagulant factors Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein, catalyzes APC inactivation of factors Va and VIIIa. APC interacts with and proteolyses factors V/Va and VIII/VIIIa at specific APC binding and cleavage sites, respectively. Resistance to activated protein C (APC resistance) is a term used to describe abnormal resistance of human plasma to the anticoagulant effects of human APC. APC resistance is characterized by a reduced anticoagulant response of patient plasma after adding a standard amount of APC. For this assay, the activated partial thromboplastin time clotting test fails to prolong significantly after the addition of APC. The vast majority of individuals with familial APC resistance have a specific point mutation in the procoagulant factor V gene (1691G-A, factor V Leiden) encoding for a glutamine (Q) substitution for arginine (R)-506 in the heavy chain of factor V (factor V R506Q). This amino acid change alters an APC cleavage site on factor V such that factor V/Va is partially resistant to inactivation by APC. The carrier frequency for the factor V Leiden mutation varies depending on the population. Approximately 5% of asymptomatic white Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier frequency among African Americans, Asian Americans, and Native Americans is less than 1%, and the carrier frequency for Hispanics is intermediate (2.5%). The carrier frequency can be especially high (up to 14%) among whites of Northern European or Scandinavian ancestry. Homozygosity for factor V Leiden is much less common, but may confer a substantially increased risk for thrombosis. The degree of abnormality of the APC-resistance assay correlates with heterozygosity or homozygosity for the factor V Leiden mutation; homozygous carriers have a very low APC-resistance ratio (eg, 1.1-1.4), while the ratio for heterozygous carriers is usually 1.5 to 1.8.

Useful For: Evaluation of patients with incident or recurrent venous thromboembolism (VTE) Evaluation of individuals with a family history of VTE

Interpretation: An activated protein C (APC) resistance ratio of or =2.3 Pediatric reference range has neither been established nor is available in scientific literature. The adult reference range likely would be applicable to children older than 6 months.

Clinical References: 1. Nichols WL, Heit JA: Activated protein C resistance and thrombosis. Mayo Clin Proc 1996;71:897-898 2. Dahlback B: Resistance to activated protein C as risk factor for thrombosis: molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol 1997;34(3):217-234 3. Rodeghiero F, Tosetto A: Activated protein C resistance and Factor V Leiden mutation are independent risk factors for venous thromboembolism. Ann Intern Med 1999;130:643-650 4. Grody WW, Griffin JH, Taylor AK, et al: American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med 2001;3:139-148 5. Press RD, Bauer KA, Kujovich JL, Heit JA: Clinical utility of factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med 2002;126:1304-1318

APCRR 60547

Activated Protein C Resistance V (APCRV), with Reflex to Factor V Leiden, Plasma Clinical Information: Protein C, a part of the natural anticoagulant system, is a vitamin K-dependent protein zymogen (molecular weight=62,000 da) that is synthesized in the liver and circulates at a plasma concentration of approximately 5 mcg/mL. Protein C is activated to activated protein C (APC) via proteolytic cleavage by thrombin bound to thrombomodulin, an endothelial cell surface membrane protein. APC downregulates the procoagulant system by proteolytically inactivating procoagulant factors Va and VIIIa. Protein S, another vitamin K-dependent coagulation protein, catalyzes APC inactivation of factors Va and VIIIa. APC interacts with and proteolyses factors V/Va and VIII/VIIIa at specific APC binding and cleavage sites, respectively. Resistance to activated protein C (APC resistance) is a term used to describe abnormal resistance of human plasma to the anticoagulant effects of human APC. APC resistance is characterized by a reduced anticoagulant response of patient plasma after adding a standard amount of APC. For this assay, the activated partial thromboplastin time clotting test fails to prolong significantly after the addition of APC. The vast majority of individuals with familial APC resistance have a specific point mutation in the procoagulant factor V gene (1691G->A, factor V Leiden) encoding for a glutamine (Q) substitution for arginine (R)-506 in the heavy chain of factor V (factor V R506Q). This amino acid change alters an APC cleavage site on factor V such that factor V/Va is partially resistant to inactivation by APC. The carrier frequency for the factor V Leiden mutation varies depending on the population. Approximately 5% of asymptomatic white Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier frequency among African Americans, Asian Americans, and Native Americans is 50%) to chronic disease. In the United States, HCV infection is quite common, with an estimated 3.5 to 4 million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of chronic HCV. See HBV Infection-Diagnostic Approach and Management Algorithm and Testing Algorithm for the Diagnosis of Hepatitis C in Special Instructions.

Useful For: The differential diagnosis of recent acute viral hepatitis Interpretation: Hepatitis A: Antibody against hepatitis A antigen is usually detectable by the onset of symptoms (usually 15-45 days after exposure). The initial antibody consists almost entirely of IgM subclass antibody. Antibody to hepatitis A virus (anti-HAV) IgM usually falls to undetectable levels 3 to 6 months after infection. Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the serum 6 to 16 weeks following hepatitis B virus (HBV) infection. In acute cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms. Hepatitis B surface antibody (anti-HBs) appears with the resolution of HBV infection after the disappearance of HBsAg. Anti-HBs also appears as the immune response following a course of inoculation with the hepatitis B vaccine. Initially, hepatitis B core antibody (anti-HBc) consists almost entirely of the IgM subclass. Anti-HBc, IgM can be detected shortly after the onset of symptoms and is usually present for 6 months. Anti-HBc may be the only marker of a recent HBV infection detectable following the disappearance of HBsAg, and prior to the appearance of anti-HBs, ie, window period. Hepatitis C: Hepatitis C antibody is usually not detectable during the early months following infection and is almost always detectable by the late convalescent stage of infection. Hepatitis C antibody is not neutralizing and does not provide immunity. If HBsAg, anti-HAV (IgM), and anti-HCV are negative and patient's condition warrants, consider testing for Epstein-Barr virus or cytomegalovirus. See HBV Infection-Diagnostic Approach and Management Algorithm and Testing Algorithm for the Diagnosis of Hepatitis C in Special Instructions.

Reference Values: HEPATITIS B SURFACE ANTIGEN Current as of August 23, 2017 7:11 am CDT


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Negative HEPATITIS B CORE ANTIBODY, IgM Negative HEPATITIS A IgM ANTIBODY Negative HEPATITIS C ANTIBODY SCREEN Negative Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profiles in Special Instructions.

Clinical References: 1. Roque-Afonso AM, Desbois D, Dussaix E: Hepatitis A virus: serology and molecular diagnostics. Future Virology 2010;5(2):233-242 2. De Paula VS: Laboratory diagnosis of hepatitis A. Future Virology 2012;7(5):461-472 3. Bonino F, Piratvisuth T, Brunetto MR, et al: Diagnostic markers of chronic hepatitis B infection and disease. Antiviral Therapy 2010;15(Suppl. 3):35-44 4. Wasley A, Fiore A, Bell BP: Hepatitis A in the era of vaccination. Epidemiol Rev 2006;28:101-111 5. American Association for the Study of Liver Diseases/Infectious Diseases Society of America/International Antiviral Society-USA. Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed on January 27, 2015. Available at www.hcvguidelines.org

AMLF

Acute Myeloid Leukemia (AML), FISH

35255

Clinical Information: Acute myeloid leukemia (AML) is one of the most common adult leukemias, with almost 10,000 new cases diagnosed per year. AML also comprises 15% of pediatric acute leukemia and accounts for the majority of infant ( or =8 years (nmol/mL) Acetylcarnitine, C2

2.14-15.89

2.00-27.57

2.00-17.83

Acrylylcarnitine, C3:1 Propionylcarnitine, C3 Formiminoglutamate, FIGLU Iso-/Butyrylcarnitine, C4 Tiglylcarnitine, C5:1 Isovaleryl-/2-Methylbutyrylcarn C5 3-OH-iso-/butyrylcarnitine, C4-OH Hexenoylcarnitine, C6:1 Hexanoylcarnitine, C6 3-OH-isovalerylcarnitine, C5-OH Benzoylcarnitine Heptanoylcarnitine, C7 3-OH-hexanoylcarnitine, C6-OH Phenylacetylcarnitine Salicylcarnitine Octenoylcarnitine, C8:1 Octanoylcarnitine, C8 Malonylcarnitine, C3-DC Decadienoylcarnitine, C10:2 Decenoylcarnitine, C10:1 Decanoylcarnitine, C10 Methylmalonyl-/succinylcarn, C4-DC 3-OH-decenoylcarnitine, C10:1-OH Glutarylcarnitine, C5-DC Dodecenoylcarnitine, C12:1 Dodecanoylcarnitine, C12 3-Methylglutarylcarnitine, C6-DC 3-OH-dodecenoylcarnitine, C12:1-OH 3-OH-dodecanoylcarnitine, C12-OH Tetradecadienoylcarnitine, C14:2 Tetradecenoylcarnitine, C14:1 Tetradecanoylcarnitine, C14 Octanedioylcarnitine, C8-DC 3-OH-tetradecenoylcarnitine C14:1OH 3-OH-tetradecanoylcarnitine, C14-OH Hexadecenoylcarnitine, C16:1 Current as of August 23, 2017 7:11 am CDT


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Hexadecanoylcarnitine, C16 3-OH-hexadecenoylcarnitine,C16:1-OH 3-OH-hexadecanoylcarnitine, C16-OH Octadecadienoylcarnitine, C18:2 Octadecenoylcarnitine, C18:1 Octadecanoylcarnitine, C18 Dodecanedioylcarnitine, C12-DC 3-OH-octadecadienoylcarn, C18:2-OH 3-OH-octadecenoylcarnitine C18:1-OH 3-OH-octadecanoylcarnitine, C18-OH

Clinical References: 1. Matern D: Acylcarnitines, including in vitro loading tests. In Laboratory Guide to the Methods in Biochemical Genetics. Edited by N Blau, M Duran, KM Gibson. Springer Verlag 2008 pp 171-206 2. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. Genet Med 2008;10:151-156 3. Smith EH, Matern D: Acylcarnitine analysis by tandem mass spectrometry. Curr Protoc Hum Genet 2010;Chapter 17:Unit 17.8.1-20

ACYLG

Acylglycines, Quantitative, Urine

81249

Clinical Information: Acylglycines are glycine conjugates of acyl-CoA species. Acylglycines are normal intermediates of amino acid and fatty acid metabolism; however, in abnormal concentrations acylglycines are biochemical markers of selected inborn errors of metabolism (IEM). Analysis of acylglycines is a useful screening test in the evaluation of patients with a suspected IEM, though additional studies are necessary to establish a diagnosis. The biochemical diagnosis of these disorders is a complex process achieved by multiple tests and their integrated interpretation. Although acylglycines are often ordered in conjunction with organic acids, acylglycine analysis is more sensitive and specific for the identification of asymptomatic patients and those with mild or intermittent biochemical phenotypes that could be missed by organic acid analysis alone. The quantitative analysis of urinary acylglycines is particularly effective for identifying asymptomatic patients affected with disorders including: -Short chain acyl-CoA dehydrogenase (SCAD) deficiency -Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency -Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency -Glutaric acidemia type II -Ethylmalonic encephalopathy -2-Methylbutyryl-CoA dehydrogenase deficiency -Isovaleryl-CoA dehydrogenase deficiency -Glutaryl-CoA dehydrogenase deficiency

Useful For: Biochemical screening of asymptomatic patients affected with 1 of the following inborn errors of metabolism: -Short chain acyl-CoA dehydrogenase (SCAD) deficiency -Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency -Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency -Glutaric acidemia type II -Ethylmalonic encephalopathy -2-Methylbutyryl-CoA dehydrogenase deficiency -Isovaleryl-CoA dehydrogenase deficiency -Glutaryl-CoA dehydrogenase deficiency

Interpretation: When abnormal results are detected, a detailed interpretation is given including an overview of the results and of their significance; a correlation to available clinical information; elements of differential diagnosis; recommendations for additional biochemical testing and in vitro confirmatory studies (enzyme assay, molecular analysis); name and phone number of key contacts who may provide these studies at Mayo Clinic or elsewhere; and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.

Reference Values: Control Values Results Expressed as mg/g Creatinine Range Current as of August 23, 2017 7:11 am CDT


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Ethylmalonic Acid

0.5-20.2

2-Methylsuccinic Acid

0.4-13.8

Glutaric Acid

0.6-15.2

Isobutyrylglycine

0.00-11.0

n-Butyrylglycine

0.1-2.1

2-Methylbutyrylglycine

0.3-7.5

Isovalerylglycine

0.3-14.3

n-Hexanoylglycine

0.2-1.9

n-Octanoylglycine

0.1-2.1

3-Phenylpropionylglycine

0.00-1.1

Suberylglycine

0.00-11.0

trans-Cinnamoylglycine

0.2-14.7

Dodecanedioic Acid (12 DCA)

0.00-1.1

Tetradecanedioic Acid (14 DCA)

0.00-1.0

Hexadecanedioic Acid (16 DCA)

0.00-1.0

Clinical References: 1. Rinaldo P: Laboratory diagnosis of inborn errors of metabolism. In Liver Disease in Children. Second edition. Edited by FJ Suchy. Philadelphia, Lippincott, Williams and Wilkins, 2001, pp 171-184 2. Rinaldo P, Hahn SH, Matern D: Inborn errors of amino acid, organic acid, and fatty acid metabolism. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2005, pp 2207-2247 3. Rinaldo P: Organic Acids. In Laboratory Guide to the Methods in Biochemical Genetics. Edited by N Blau, M Duran, KM Gibson. Springer-Verlag Berlin Heidelberg, 2008, pp 137-170

FAAAB

Adalimumab Concentration and Anti-Adalimumab Antibody

58031

Useful For: To monitor anti-adalimumab therapy for individuals with Crohn's disease, inflammatory bowel disease, ulcerative colitis, rheumatoid arthritis, or other autoimmune conditions. This test provides adalimumab drug concentration levels as well as the level of anti-adalimumab antibodies.

Reference Values: Adalimumab Drug Level -Quantitation Limit: A), and p.Ile244Thr (c.731T->C). These mutations account for at least 1 of the 2 affected alleles in approximately 70% of individuals with PH1. Direct sequencing of the AGXT gene is predicted to identify 99% of alleles in individuals who are known by enzyme analysis to be affected with PH1. While age of onset and severity of disease is variable and not necessarily predictable by genotype, a correlation between pyridoxine responsiveness and homozygosity for the p.Gly170Arg mutation has been observed. (Note: testing for the p.Gly170Arg mutation only is available by ordering AGXTG / Alanine:Glyoxylate Aminotransferase [AGXT] Mutation Analysis [G170R], Blood). Pyridoxine (vitamin B6) is a known cofactor of AGT and is effective in reducing urine oxalate excretion in some PH1 patients treated with pharmacologic doses. Individuals with 2 copies of the p.Gly170Arg mutation have been shown to normalize their urine oxalate when treated with pharmacologic doses of pyridoxine and those with a single copy of the mutation show reduction in urine oxalate. This is valuable because not all patients have been shown to be responsive to pyridoxine, and strategies that help to identify the individuals most likely to benefit from such targeted therapies are desirable.

Useful For: Confirming a diagnosis of primary hyperoxaluria type 1 Carrier testing for individuals with a family history of primary hyperoxaluria type 1 in the absence of known mutations in the family

Interpretation: All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for Current as of August 23, 2017 7:11 am CDT


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standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300 2. Milliner DS: The primary hyperoxalurias: an algorithm for diagnosis. Am J Nephrol 2005;25(2):154-160 3. Monico CG, Rossetti S, Olson JB, Milliner DS: Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005;67(5):1704-1709 4. Monico CG, Rossetti S, Schwanz HA, et al: Comprehensive mutation screening in 55 probands with type 1 primary hyperoxaluria shows feasibility of a gene-based diagnosis. J Am Soc Nephrol 2007;18:1905-1914 5. Rumsby G, Williams E, Coulter-Mackie M: Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004;66(3):959-963 6. Williams EL, Acquaviva C, Amoroso, A, et al: Primary hyperoxaluria type I: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-917 7. Williams E, Rumsby G: Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1. Clin Chem 2007;53(7):1216-1221 8. Communique April 2007: Laboratory and Molecular Diagnosis of Primary Hyperoxaluria and Oxalosis

ALT

Alanine Aminotransferase (ALT) (GPT), Serum

8362

Clinical Information: Alanine aminotransferase (ALT) is present primarily in liver cells. In viral hepatitis and other forms of liver disease associated with hepatic necrosis, serum ALT is elevated even before the clinical signs and symptoms of the disease appear. Although serum levels of both aspartate aminotransferase (AST) and ALT become elevated whenever disease processes affect liver cell integrity, ALT is a more liver-specific enzyme. Serum elevations of ALT are rarely observed in conditions other than parenchymal liver disease. Moreover, the elevation of ALT activity persists longer than does AST activity.

Useful For: Diagnosis and monitoring of liver disease associated with hepatic necrosis Interpretation: Elevated alanine aminotransferase (ALT) values are seen in parenchymal liver diseases characterized by a destruction of hepatocytes. Values are typically at least 10 times above the normal range. Levels may reach values as high as 100 times the upper reference limit, although 20- to 50-fold elevations are most frequently encountered. In infectious hepatitis and other inflammatory conditions affecting the liver, ALT is characteristically as high as or higher than aspartate aminotransferase (AST), and the ALT:AST ratio, which normally and in other condition is less than 1, becomes greater than unity. ALT levels are usually elevated before clinical signs and symptoms of disease appear.

Reference Values: Males > or =1 year: 7-55 U/L Reference values have not been established for patients who are or =1 year: 7-45 U/L Reference values have not been established for patients who are or =12 months: 3.5-5.0 g/dL Reference values have not been established for patients who are or =1 year: 2.0-20.0 mcg/24 hours *Loeuille GA, Racadot A, Vasseur P, Vandewalle B: Blood and urinary aldosterone levels in normal neonates, infants and children. Pediatrie 1981;36:335-344

Clinical References: 1. Young WF Jr: Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999;7:207-214 2. Young WF Jr: Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:801-827

AIVC

Aldosterone, Inferior Vena Cava, Serum

6503

Clinical Information: Aldosterone stimulates sodium transport across cell membranes, particularly in the distal renal tubule where sodium is exchanged for hydrogen and potassium. Secondarily, aldosterone is important in the maintenance of blood pressure and blood volume. Aldosterone is the major mineralocorticoid and is produced by the adrenal cortex. The renin-angiotensin system is the primary regulator of the synthesis and secretion of aldosterone. Likewise, increased concentrations of potassium in the plasma may directly stimulate adrenal production of the hormone. Under physiologic conditions, pituitary adrenocorticotropic hormone is not a major factor in regulating aldosterone secretion. See Steroid Pathways in Special Instructions.

Useful For: Investigation of primary aldosteronism (eg, adrenal adenoma/carcinoma and adrenal cortical hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium Current as of August 23, 2017 7:11 am CDT


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loading, cardiac failure with ascites, pregnancy, Bartter syndrome)

Interpretation: A high ratio of serum aldosterone (SA) in ng/dL to plasma renin activity (PRA) in ng/mL per hour, is a positive screening test result, a finding that warrants further testing. An SA/PRA ratio > or =20 is only interpretable with an SA > or =15 ng/dL and indicates probable primary aldosteronism. Renal disease, such as unilateral renal artery stenosis, results in elevated renin and aldosterone levels. Renal venous catheterization may be helpful. A positive test is a renal venous renin ratio (affected/normal) >1.5. See Renin-Aldosterone Studies and Steroid Pathways in Special Instructions. Note: Advice on stimulation or suppression tests is available from Mayo Clinic's Division of Endocrinology and may be obtained by calling Mayo Medical Laboratories.

Reference Values: No established reference values.

Clinical References: 1. Young WF Jr: Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999;7:207-214 2. Young WF Jr: Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:801-827 3. Hurwitz S, Cohen RJ, Williams GH: Diurnal variation of aldosterone and plasma renin activity: timing relation to melatonin and cortisol and consistency after prolonged bed rest. J Appl Physiol 2004;96:1406-1414

ALAV

Aldosterone, Left Adrenal Vein, Serum

6349


Useful For: Investigation of primary aldosteronism (eg, adrenal adenoma/carcinoma and adrenal cortical hyperplasia) and secondary aldosteronism (renovascular disease, salt depletion, potassium loading, cardiac failure with ascites, pregnancy, Bartter syndrome)




ARAV

Aldosterone, Right Adrenal Vein, Serum

6348

Clinical Information: Aldosterone stimulates sodium transport across cell membranes, particularly in the distal renal tubule where sodium is exchanged for hydrogen and potassium. Secondarily, aldosterone is important in the maintenance of blood pressure and blood volume. Aldosterone is the major



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mineralocorticoid and is produced by the adrenal cortex. The renin-angiotensin system is the primary regulator of the synthesis and secretion of aldosterone. Likewise, increased concentrations of potassium in the plasma may directly stimulate adrenal production of the hormone. Under physiologic conditions, pituitary adrenocorticotropic hormone is not a major factor in regulating aldosterone secretion. See Steroid Pathways in Special Instructions.





ALDS

Aldosterone, Serum

8557




Reference Values: 0-30 days: 17-154 ng/dL* 31 days-11 months: 6.5-86 ng/dL* 1-10 years: < or =40 ng/dL (supine)* < or =124 ng/dL (upright)* > or =11 years: < or =21 ng/dL (a.m. peripheral vein specimen) Current as of August 23, 2017 7:11 am CDT


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*Loeuille GA, Racadot A, Vasseur P, Vandewalle B: Blood and urinary aldosterone levels in normal neonates, infants and children. Pediatrie 1981;36:335-344


FALPE

Alfalfa (Medicago sativa) IgE

57945

Interpretation: Class IgE (kU/L) Comment 0 99.99 Very High Positive Very High Positive Very High Positive

Reference Values: or =19 years: 45-115 U/L Females 4 years: 169-372 U/L 5 years: 162-355 U/L 6 years: 169-370 U/L 7 years: 183-402 U/L 8 years: 199-440 U/L 9 years: 212-468 U/L 10 years: 215-476 U/L 11 years: 178-526 U/L 12 years: 133-485 U/L 13 years: 120-449 U/L 14 years: 153-362 U/L 15 years: 75-274 U/L 16 years: 61-264 U/L 17-23 years: 52-144 U/L 24-45 years: 37-98 U/L 46-50 years: 39-100 U/L 51-55 years: 41-108 U/L 56-60 years: 46-118 U/L 61-65 years: 50-130 U/L > or =66 years: 55-142 U/L Reference values have not been established for patients that are 40 alpha-1-antitrypsin (A1A) phenotypes (most of these are associated with normal quantitative levels of protein). The most common normal phenotype is M (M, M1, or M2), and >90% of Caucasians are genetically homozygous M (MM). A1A deficiency is usually associated with the Z phenotype (homozygous ZZ), but SS and SZ are also associated with decreased A1A levels.

Reference Values: ALPHA-1-ANTITRYPSIN 100-190 mg/dL ALPHA-1-ANTITRYPSIN PHENOTYPE The interpretive report will identify the alleles present. For rare alleles, the report will indicate whether or not they have been associated with reduced quantitative levels of alpha-1-antitrypsin. Current as of August 23, 2017 7:11 am CDT


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Clinical References: 1. Morse JO: Alpha-1-antitrypsin deficiency. N Engl J Med 1978;299:1045-1048;1099-1105 2. Donato LJ, Jenkins SM, Smith C, et al: Reference and interpretive ranges for alpha(1)-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol 2012 Sep;138(3):398-405

A1ALC

Alpha-1-Antitrypsin Proteotype S/Z by LC-MS/MS, Serum

61767

Clinical Information: Alpha-1-antitrypsin (A1A) is a protein that inhibits the enzyme neutrophil elastase. It is predominantly synthesized in the liver and secreted into the bloodstream. The inhibition function is especially important in the lungs because it protects against excess tissue degradation. Tissue degradation due to A1A deficiency is associated with an increased risk for early onset panlobular emphysema, which initially affects the lung bases (as opposed to smoking-related emphysema, which presents with upper-lung field emphysema). Patients may become symptomatic in their 30s and 40s. The most frequent symptoms reported in a National Institute of Health study of 1,129 patients with severe deficiency (mean age 46 years) included cough (42%), wheezing (65%), and dyspnea with exertion (84%). Many patients were misdiagnosed as having asthma. It is estimated that approximately one-sixth of all lung transplants are for A1A deficiency. Liver disease can also occur, particularly in children; it occurs much less commonly than emphysema in adults. A1A deficiency is a relatively common disorder in Northern European Caucasians. The diagnosis of A1A deficiency is initially made by quantitation of protein levels in serum followed by determination of specific allelic variants by isoelectric focusing (IEF). While there are many different alleles in this gene, only 3 are common. The 3 major alleles include: M (full functioning, normal allele), S (associated with reduced levels of protein), and Z (disease-causing mutation associated with liver disease and premature emphysema). The S and Z alleles account for the majority of the abnormal alleles detected in affected patients. As a codominant disorder, both alleles are expressed. An individual of SZ or S-null genotype may have a small increased risk for emphysema (but not liver disease) due to slightly reduced protein levels. On the other hand, an individual with the ZZ genotype is at greater risk for early onset liver disease and premature emphysema. Smoking appears to hasten development of emphysema by 10 to 15 years. These individuals should be monitored closely for lung and liver function. Historically, IEF has been the primary method for characterizing variants, though in some cases the interpretation is difficult and prone to error. Serum quantitation is helpful in establishing a diagnosis, but can be influenced by other factors. A proteomic method using trypsin-digested sera can detect the mutated peptides of the S and Z alleles, but can miss disease alleles other than the S and Z alleles. This test combines all of these methods to provide a comprehensive result.

Useful For: Determining the specific proteotype for prognosis and genetic counseling for patients with alpha-1-antitrypsin deficiency

Interpretation: For each of the possible alpha-1-antitrypsin (A1A) genotypes there is an expected range for the total serum level of A1A. However, a number of factors can influence either the A1A serum level or the A1A proteotype results, including acute illness (A1A is an acute-phase reactant), protein replacement therapy, the presence of other rare variants, or the presence of DNA polymorphisms. When the serum level differs from what is expected for that proteotype (ie, discordant), additional studies are performed to ensure the most appropriate interpretation of test results. Additional follow-up may include A1A phenotyping by isoelectric focusing, obtaining additional clinical information, and DNA sequencing. See Alpha-1-Antitrypsin Reflex Table in Special Instructions.

Reference Values: ALPHA-1-ANTITRYPSIN 100-190 mg/dL ALPHA-1-ANTITRYPSIN PROTEOTYPE Negative for S and Z phenotype (Non S Non Z)

Clinical References: 1. Stoller JK, Aboussouan LS: Alpha-1-antitrypsin deficiency. Lancet 2005;365:2225-2236 2. McElvaney NG, Stoller JK, Buist AS, et al: Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency. Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest 1997;111:394-403 Current as of August 23, 2017 7:11 am CDT


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A1AF

Alpha-1-Antitrypsin, Random, Feces

182

Clinical Information: Alpha-1-antitrypsin (A1A) is resistant to degradation by digestive enzymes and is, therefore, used as an endogenous marker for the presence of blood proteins in the intestinal tract. A1A clearance is reliable for measuring protein loss distal to the pylorus. Gastrointestinal protein enteropathy has been associated with regional enteritis, sprue, Whipple intestinal lipodystrophy, gastric carcinoma, allergic gastroenteropathy, intestinal lymphangiectasia, constrictive pericarditis, congenital hypogammaglobulinemia, and iron deficiency anemia associated with intolerance to cow's milk.

Useful For: Diagnosing protein-losing enteropathies, especially when used in conjunction with serum alpha-1-antitrypsin (A1A) levels as a part of A1A clearance studies

Interpretation: Patients with protein-losing enteropathies generally have alpha-1-antitrypsin stool concentrations over 100 mg/mL. Borderline elevations above the normal range are equivocal for protein-losing enteropathies.

Reference Values: < or =54 mg/dL

Clinical References: 1. Florent C, L'Hirondel C, Desmazures C, et al: Intestinal clearance of alpha 1-antitrypsin. A sensitive method for the detection of protein losing enteropathy. Gastroenterology 1981;81:777-780 2. Crossley JR, Elliott RB: Simple method for diagnosing protein-losing enteropathy. Br Med J 1977;1:428-429 3. Perrault J, Markowitz H: Protein-losing gastroenteropathy and the intestinal clearance of serum alpha-1-antitrypsin. Mayo Clin Proc 1984;59:278-279

AAT

Alpha-1-Antitrypsin, Serum

8161

Clinical Information: Alpha-1-antitrypsin (A1A) is the most abundant serum protease inhibitor and inhibits trypsin and elastin, as well as several other proteases. The release of proteolytic enzymes from plasma onto organ surfaces and into tissue spaces results in tissue damage unless inhibitors are present. Congenital deficiency of A1A is associated with the development of emphysema at an unusually early age and with an increased incidence of neonatal hepatitis, usually progressing to cirrhosis. See Alpha-1-Antitrypsin-A Comprehensive Testing Algorithm in Special Instructions.

Useful For: Workup of individuals with suspected disorders such as familial chronic obstructive lung disease Diagnosis of alpha-1-antitrypsin deficiency

Interpretation: Patients with serum levels 6.0 ng/mL is suspicious but not diagnostic of ascites related to hepatocellular carcinoma (HCC). This clinical decision limit cutoff yielded a sensitivity of 58%, specificity of 96% in a study of 137 patients presenting with ascites. AFP concentrations were significantly higher in ascites caused by HCC. Ascites caused by malignancies other than HCC routinely had AFP concentrations or =2.50 MoM and may indicate an increased risk for open NTDs. The actual Current as of August 23, 2017 7:11 am CDT


Page 97

risk depends on the level of AFP and the individual's pre-test risk of having a child with NTD based on family history, geographical location, maternal conditions such as diabetes and epilepsy, and use of folate prior to conception. A screen-positive result does not infer a definitive diagnosis of a NTD, but indicates that further evaluation should be considered. Approximately 80% of pregnancies affected with an open NTD have elevated AFP MoM values >2.5. Follow up: Upon receiving maternal serum screening results, all information used in the risk calculation should be reviewed for accuracy (ie, weight, diabetic status, gestational dating, etc.). If any information is incorrect the laboratory should be contacted for a recalculation of the estimated risks. Screen-negative results typically do not warrant further evaluation. Ultrasound is recommended to confirm dates for NTD screen-positive results. If ultrasound yields new dates that differ by at least 7 days, a recalculation should be considered. If dates are confirmed, high-resolution ultrasound and amniocentesis (including amniotic fluid AFP and acetylcholinesterase measurements for NTDs) are typically offered.

Reference Values: NEURAL TUBE DEFECTS An AFP multiple of the median (MoM) or =2.5 (singleton and twin pregnancies) are reported as screen positive. An interpretive report will be provided.

Clinical References: Christensen RL, Rea MR, Kessler G, et al: Implementation of a screening program for diagnosing open neural tube defects: selection, evaluation, and utilization of alpha-fetoprotein methodology. Clin Chem 1986;32:1812-1817

AFPSF

Alpha-Fetoprotein (AFP), Spinal Fluid

8876

Clinical Information: Alpha-fetoprotein (AFP) is an oncofetal glycoprotein, homologous with albumin that is produced both in early fetal life and in tumors arising from midline embryonic structures. AFP is synthesized in the yolk sac, liver, and gastrointestinal track of the fetus. In adults, the liver synthesizes AFP. AFP is not normally expressed in the central nervous system (CNS). AFP levels in liver are increased in hepatomas and hepatocellular and colon carcinomas, as well as in germ-cell tumors arising from the ovaries and nonseminomatous germ-cell tumors of the testes, testicular teratocarcinomas, and primary germ-cell tumors arising within the CNS. The presence of germinomas in the CNS and CNS involvement in metastatic cancer and meningeal carcinomatosis results in increased levels of AFP in cerebrospinal fluid.

Useful For: An adjunct in the diagnosis of central nervous system (CNS) germinomas and meningeal carcinomatosis Evaluating germ-cell tumors, including testicular cancer metastatic to the CNS in conjunction with beta-human chorionic gonadotropin measurement(1) An adjunct in distinguishing between suprasellar dysgerminomas and craniopharyngiomas A supplement to cerebrospinal fluid cytologic analysis

Interpretation: Alpha-fetoprotein (AFP) concentrations that exceed the upper end of normal are consistent with the presence of central nervous system germinoma, meningeal carcinomatosis, or metastatic nonseminomatous testicular cancer. AFP is not elevated in the presence of a craniopharyngioma.

Reference Values: or =0.32 nmol/min/mg protein

Clinical References: 1. Cowan TM, Yu C: Laboratory investigations of inborn errors of metabolism. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 867-868 2. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 747-748 3. Thomas GH: Chapter 140: Disorders of Glycoprotein Degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMMBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Medical Division. Accessed 3/19/2015. Available at www.ommbid.com/

FAGPL

Alpha-Gal Panel

57717

Interpretation: Class IgE (kU/L) Comment 0 or = 100 Very High Positive

Reference Values: Beef IgE or =2.8 nmol/mL/hour An interpretive report will be provided.

Clinical References: 1. Chamoles NA, Blanco M, Gaggioli D: Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta 2001;308:195-196 2. De Schoenmakere G, Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant 2008;23:4044-4048 3. Spada M, Pagliardini S, Yasuda M, et al: High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet 2006;79:31-40 4. Matern D, Gavrilov D, Oglesbee D, et al: Newborn screening for lysosomal storage disorders. Semin Perinatol 2015 Apr;39(3):206-216 5. Mehta A, Hughes DA: Fabry Disease. In GeneReviews. Accessed 1/23/2017. Available atwww.ncbi.nlm.nih.gov/books/NBK1292/

AGA

Alpha-Galactosidase, Leukocytes

8785

Clinical Information: Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the subsequent deposition of glycosylsphingolipids in tissues throughout the body, in particular, the kidney, heart, and brain. Fabry disease is due to mutations within the GLA gene, and more than 630 mutations have been identified in individuals diagnosed with Fabry disease. Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic form of Fabry disease occurs in males who have less than 1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal opacity, and proteinuria. In addition, progressive renal involvement leading to end-stage renal disease typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The estimated incidence varies from 1 in 3,000 infants detected via newborn screening to 1 in 10,000 males diagnosed after onset of symptoms. Males with residual a-Gal A activity greater than 1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in life: a renal variant associated with end stage renal disease (ESRD) but without the pain or skin lesions; a cardiac variant typically presenting in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; and a cerebrovascular variant presenting as stroke or transient ischemic attack. The variant forms of Fabry disease may be



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underdiagnosed. Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected. Measurement of alpha-Gal A activity is not generally useful for identifying carriers of Fabry disease, as many of these individuals have normal levels of alpha-Gal A. Therefore, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) is recommended as the most appropriate diagnostic test to detect carriers. Unless irreversible damage has already occurred, treatment with enzyme replacement therapy (ERT) has led to significant clinical improvement in affected individuals. For this reason, early diagnosis and treatment are desirable, and in a few US states early detection of Fabry disease through newborn screening has been implemented. Absent or reduced alpha-Gal A in blood spots, leukocytes (AGA / Alpha-Galactosidase, Leukocytes), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. Molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) allows for detection of the disease-causing mutation in males and females. See Fabry Disease Testing Algorithm and Fabry Disease: Newborn Screen-Positive Follow-up in Special Instructions.

Useful For: Diagnosis of Fabry disease in males Verifying abnormal serum alpha-galactosidase results in males with a clinical presentation suggestive of Fabry disease

Interpretation: Deficiency of alpha-galactosidase A (alpha-Gal A) is diagnostic for Fabry disease in males. Urine sediment analysis (CTSA / Ceramide Trihexosides and Sulfatides, Urine) for the accumulating trihexoside substrate is also recommended. Carrier females usually have alpha-galactosidase levels in the normal range; therefore, molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) is recommended as the appropriate diagnostic test for females.

Reference Values: > or =23.1 nmol/hour/mg protein An interpretative report will be provided. Note: Results from this assay do not reflect carrier status because of individual variation of alpha-galactosidase enzyme levels.

Clinical References: 1. Desnick RJ, Ioannou YA, Eng CM: Chapter 150: Alpha-galactosidase A deficiency: Fabry disease. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle, AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 01/23/15. Available at www.ommbid.com 2. De Schoenmakere G, Poppe B, Wuyts B, et al: Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. Nephrol Dial Transplant 2008;23:4044-4048 3. Mehta A, Hughes DA: Fabry Disease. In GeneReviews. 2002 Aug 5, Updated 2013 Oct 17. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle; 1993-2015. Accessed 1/23/17. Available at www.ncbi.nlm.nih.gov/books/NBK1292/ 4. Laney DA, Bennett RL, Clarke V, et al: Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns 2013;22:555-564 5. Laney DA, Peck DS, Atherton AM, et al: Fabry disease in infancy and early childhood: a systematic literature review. Genet Med 2014; Epub ahead of print. Accessed 1/23/15. Available at www.nature.com/gim/journal/vaop/ncurrent/pdf/gim2014120a.pdf

AGAS

Alpha-Galactosidase, Serum

8784

Clinical Information: Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A) and the subsequent deposition of glycosylsphingolipids in tissues throughout the body; in particular, the kidney, heart, and brain. Fabry disease is caused by mutations within the GLA gene, and more than 630 mutations have been identified in individuals diagnosed with Fabry disease. Severity and onset of symptoms are dependent on the amount of residual enzyme activity. The classic form of Fabry disease occurs in males who have less than 1% alpha-Gal A activity. Symptoms usually appear in childhood or adolescence and can include acroparesthesias (burning pain in the extremities), gastrointestinal issues, multiple angiokeratomas, reduced or absent sweating, corneal opacity, and proteinuria. In addition, progressive renal involvement leading to end-stage renal disease typically occurs in adulthood, followed by cardiovascular and cerebrovascular disease. The estimated incidence varies from 1 in 3,000 infants detected via newborn screening to 1 in 10,000 males diagnosed after onset of symptoms. Males with residual a-Gal A activity greater than 1% may present with 1 of 3 variant forms of Fabry disease with onset of symptoms later in



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life: a renal variant associated with end stage renal disease (ESRD) but without the pain or skin lesions; a cardiac variant typically presenting in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; and a cerebrovascular variant presenting as stroke or transient ischemic attack. The variant forms of Fabry disease may be underdiagnosed. Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected. Measurement of alpha-Gal A activity is not generally useful for identifying carriers of Fabry disease, as many of these individuals have normal levels of alpha-Gal A. Therefore, molecular genetic analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) is recommended to detect carriers. Unless irreversible damage has already occurred, treatment with enzyme replacement therapy (ERT) has led to significant clinical improvement in affected individuals. For this reason, early diagnosis and treatment are desirable, and in a few US states early detection of Fabry disease through newborn screening has been implemented. Absent or reduced alpha-Gal A in blood spots, leukocytes (AGA / Alpha-Galactosidase, Leukocytes), or serum (AGAS / Alpha-Galactosidase, Serum) can indicate a diagnosis of classic or variant Fabry disease. Molecular sequence analysis of the GLA gene (FABRZ / Fabry Disease, Full Gene Analysis) allows for detection of the disease-causing mutation in males and females. See Fabry Disease Testing Algorithm and Fabry Disease: Newborn Screen-Positive Follow-up in Special Instructions.

Useful For: Diagnosis of Fabry disease in males Preferred screening test (serum) for Fabry disease Interpretation: Deficiency (C). Point mutations other than HbCS and alpha-thalassemia Saudi are not detected by this assay. Alpha-thalassemia occurs in all ethnic groups but is especially common individuals of Southeast Asian and African ancestry. It is also frequent in individuals of Mediterranean ancestry. The carrier frequency is estimated to be 1 in 20 for Southeast Asians, 1 in 30 for African Americans, and 1 in 30 to 1 in 50 for individuals of Mediterranean ancestry. Both deletional and nondeletional (caused by point mutations) forms of alpha-thalassemia are found in individuals with Mediterranean ancestry. Deletions in cis (deletions on the same chromosome) are rare in African or Mediterranean populations, but are prevalent in Asian populations. Couples in which both partners carry deletions in cis are at risk of having a child with the fatal hemoglobin Bart hydrops fetalis syndrome.

Useful For: Diagnosis of alpha-thalassemia Prenatal diagnosis of deletional alpha-thalassemia Carrier screening for individuals from high-risk populations for alpha-thalassemia

Interpretation: An interpretive report will be provided. Reference Values: An interpretive report will be provided.

Clinical References: 1. Harteveld CL, Voskamp A, Phylipsen M, et al: Nine unknown rearrangements in 16p13.3 and 11p15.4 causing alpha- and beta-thalassaemia characterized by high resolution multiplex ligation-dependent probe amplification. J Med Genet 2005;42:922-931 2. Harteveld CL, Higgs DR: Alpha-thalassemia. Orphanet J Rare Dis 2010;5:13 3. Bunn HF, Forget BG: Hemoglobin: Molecular, Genetic and Clinical Aspects. Philadelphia, WB Saunders Company, 1986 4. Weatherall DJ, Higgs DR, Clegg JB, et al: Heterogeneity and origins of the alpha-thalassemias. Birth Defects: Original Article Series 1987;23:3-14

AGLYP

Alpha-Glycerophosphate Stain (Bill Only)

50125

Reference Values: This test is for billing purposes only. This is not an orderable test. Order MPCT / Muscle Pathology Consultation or MBCT / Muscle Biopsy Consultation Outside Slides and/or Paraffin Blocks. The consultant will determine the need for special stains.

IDSWB

Alpha-L-Iduronidase, Blood

60618

Clinical Information: The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate, also known as glycosaminoglycans (GAG). Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs. There are 11 known disorders that involve the accumulation of GAGs. MPS disorders involve multiple organ systems characterized by coarse facial features, cardiac abnormalities, organomegaly, intellectual



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disabilities, short stature, and skeletal abnormalities. Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by a reduced or absent activity of the enzyme alpha-L-iduronidase due to mutations in the IDUA gene. More than 100 mutations have been reported in individuals with MPS I. Deficiency of alpha-L-iduronidase can result in a wide range of phenotypes categorized into 3 syndromes: Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S). Because these syndromes cannot be distinguished biochemically, they are also referred to as MPS I and attenuated MPS I. Clinical features and severity of symptoms of MPS I are variable, ranging from severe disease to an attenuated form that generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, progressive dysostosis multiplex, hepatosplenomegaly, corneal clouding, hearing loss, intellectual disabilities or learning difficulties, and cardiac valvular disease. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. A diagnostic workup in an individual with MPS I typically demonstrates elevated levels of urinary GAG (MPSQN / Mucopolysaccharides [MPS], Quantitative, Urine) and increased amounts of both dermatan and heparan sulfate being detected (MPSSC / Mucopolysaccharides [MPS] Screen, Urine). Reduced or absent activity of alpha L-iduronidase can confirm a diagnosis of MPS I; however, enzymatic testing is not reliable for carrier detection. Molecular sequence analysis of the IDUA gene allows for detection of the disease-causing mutation in affected patients and subsequent carrier detection in relatives. To date, a clear genotype-phenotype correlation has not been established.

Useful For: Diagnosis of mucopolysaccharidosis I, Hurler, Scheie, and Hurler-Scheie syndromes in whole blood specimens

Interpretation: Specimens with results below 1.0 nmol/hour/mL in properly submitted specimens are consistent with alpha-L-iduronidase deficiency (mucopolysaccharidosis I). Further differentiation between Hurler, Scheie, and Hurler-Scheie is dependent upon the clinical findings. Normal results (> or =1.0 nmol/h/mL) are not consistent with alpha-L-iduronidase deficiency.

Reference Values: > or =1.0 nmol/hour/mL An interpretive report will be provided.

Clinical References: 1. Neufeld EF, Muenzer J: The mucopolysaccharidoses. Chapter 136. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle, AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 1/25/2017. Available at: www.ommbid.com 2. Chamoles NA, Blanco M, Gaggioli D, Casentini C: Hurler-like phenotype: enzymatic diagnosis in dried blood spots on filter paper. Clin Chem 2001;47:2098-2102 3. Martins AM, Dualibi AP, Norato D, et al: Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009 Oct:155(4 Suppl):S32-S46 4. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders: mucopolysaccharidoses. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. McGraw-Hill, Medical Publishing Division, 2009, pp 721-730 5. Clarke LA. Mucopolysaccharidosis Type I. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger et al. University of Washington, Seattle. Updated 2016 Feb 11. 1993-2017. Available at www.ncbi.nlm.nih.gov/books/NBK1162/

IDSBS

Alpha-L-Iduronidase, Blood Spot

60617

Clinical Information: The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate, also known as glycosaminoglycans (GAG). Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs. There are 11 known disorders that involve the accumulation of GAGs. MPS disorders involve multiple organ systems characterized by coarse facial features, cardiac abnormalities, organomegaly, intellectual disabilities, short stature, and skeletal abnormalities. Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by a reduced or absent activity of the enzyme alpha-L-iduronidase due to mutations in the IDUA gene. More than 100 mutations have been reported in individuals with MPS I. Deficiency of alpha-L-iduronidase can result in a wide range of phenotypes categorized into 3 syndromes: Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S). Because these syndromes cannot be distinguished biochemically, they are also referred to as MPS I and



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attenuated MPS I. Clinical features and severity of symptoms of MPS I are variable, ranging from severe disease to an attenuated form that generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, progressive dysostosis multiplex, hepatosplenomegaly, corneal clouding, hearing loss, intellectual disabilities or learning difficulties, and cardiac valvular disease. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. A diagnostic workup in an individual with MPS I typically demonstrates elevated levels of urinary GAG (MPSQN / Mucopolysaccharides [MPS], Quantitative, Urine) and increased amounts of both dermatan and heparan sulfate detected on thin-layer chromatography (MPSSC / Mucopolysaccharides [MPS] Screen, Urine). Reduced or absent activity of alpha-L-iduronidase in blood spots, fibroblasts (IDST / Alpha-L-Iduronidase, Fibroblasts), leukocytes, or whole blood (IDSWB / Alpha-L-Iduronidase, Blood) can confirm a diagnosis of MPS I; however, enzymatic testing is not reliable for carrier detection. Molecular sequence analysis of the IDUA gene allows for detection of the disease-causing mutation in affected patients and subsequent carrier detection in relatives. To date, a clear genotype-phenotype correlation has not been established.

Useful For: Diagnosis of mucopolysaccharidosis I, Hurler, Scheie, and Hurler-Scheie syndromes using dried blood spot specimens

Interpretation: Specimens with results below 1.0 nmol/hour/mL in properly submitted specimens are consistent with alpha-L-iduronidase deficiency (mucopolysaccharidosis I). Further differentiation between Hurler, Scheie, and Hurler-Scheie is dependent on the clinical findings. Normal results (> or =1.0 nmol/hour/mL) are not consistent with alpha-L-iduronidase deficiency.

Reference Values: > or =1.0 nmol/h/mL An interpretive report will be provided.

Clinical References: 1. Neufeld EF, Muenzer J: The mucopolysaccharidoses. Chapter 136. In The Metabolic and Molecular Basis of Inherited Disease. Eighth edition. Edited by D Valle, AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 1/25/2017. Available at: www.ommbid.com 2. Chamoles NA, Blanco M, Gaggioli D, Casentini C: Hurler-like phenotype: enzymatic diagnosis in dried blood spots on filter paper. Clin Chem 2001;47:2098-2102 3. Martins AM, Dualibi AP, Norato D, et al: Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009 Oct:155(4 Suppl):S32-S46 4. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders: mucopolysaccharidoses. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. McGraw-Hill, Medical Publishing Division, 2009, pp 721-730 5. Clarke LA. Mucopolysaccharidosis Type I. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger et al. University of Washington, Seattle. Updated 2016 Feb 11. Available at www.ncbi.nlm.nih.gov/books/NBK1162/

IDST

Alpha-L-Iduronidase, Fibroblasts

8780

Clinical Information: The mucopolysaccharidoses are a group of lysosomal storage disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate also known as glycosaminoglycans (GAGs). Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs. There are 11 known disorders that involve the accumulation of GAGs. MPS disorders involve multiple organ systems characterized by coarse facial features, cardiac abnormalities, organomegaly, intellectual disabilities, short stature, and skeletal abnormalities. Mucopolysaccharidosis I (MPS I) is an autosomal recessive disorder caused by a reduced or absent activity of the enzyme alpha-L-iduronidase due to mutations in the IDUA gene. More than 100 mutations have been reported in individuals with MPS I. Deficiency of alpha-L-iduronidase can result in a wide range of phenotypes categorized into 3 syndromes: Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S). Because these syndromes cannot be distinguished biochemically, they are also referred to as MPS I and attenuated MPS I. Clinical features and severity of symptoms of MPS I are variable, ranging from severe disease to an attenuated form that generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, progressive dysostosis multiplex, hepatosplenomegaly, corneal



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clouding, hearing loss, intellectual disabilities or learning difficulties, and cardiac valvular disease. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. A diagnostic workup in an individual with MPS I typically demonstrates elevated levels of urinary GAGs (MPSQN / Mucopolysaccharides [MPS], Quantitative, Urine) and increased amounts of both dermatan and heparan sulfate detected via liquid chromatography-tandem mass spectrometry (LC-MS/MS) (MPSSC / Mucopolysaccharides [MPS] Screen, Urine). Reduced or absent activity of alpha-L-iduronidase in blood spots, fibroblasts (IDST / Alpha-L-Iduronidase, Fibroblasts), leukocytes, or whole blood (IDSWB / Alpha-L-Iduronidase, Blood) can confirm a diagnosis of MPS I; however, enzymatic testing is not reliable for carrier detection. Molecular sequence analysis of the IDUA gene allows for detection of disease-causing mutations in affected patients and/or pseudodeficiency alleles that cause reduced enzyme activity in vitro but do not cause disease. To date, a clear genotype-phenotype correlation has not been established.

Useful For: Diagnosis of mucopolysaccharidosis I (MPS I), Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S) in fibroblasts

Interpretation: Mucopolysaccharidosis I is characterized by very low or absent activity of alpha-L-iduronidase; differentiation between Hurler syndrome (MPS IH), Scheie syndrome (MPS IS), and Hurler-Scheie syndrome (MPS IH/S) is dependent on clinical findings.

Reference Values: > or =0.87 nmol/min/mg protein

Clinical References: 1. Martins AM, Dualibi AP, Norato D, et al: Guidelines for the management of mucopolysaccharidosis type I. J Pediatr 2009 Oct:155(4 Suppl):S32-S46 2. Neufeld EF, Muenzer J: The Mucopolysaccharidoses. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein B, et al: New York, McGraw-Hill, 2014. Accessed April 3, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62642135 3. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders: mucopolysaccharidoses. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. McGraw-Hill, Medical Publishing Division, 2009, pp 721-730 4. Clarke LA. Mucopolysaccharidosis Type I. 2002 Oct 31 (Updated 2016 Feb 11). In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle; 1993-2016. Accessed February 23, 2016. Available at www.ncbi.nlm.nih.gov/books/NBK1162/

ALFA

Alpha-Lactoalbumin, IgE

82897

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergens that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease, the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).

Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens.

Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the Current as of August 23, 2017 7:11 am CDT


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concentration of IgE antibodies expressed as a class score or kU/L.

Reference Values: Class IgE kU/L Interpretation 0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4

17.5-49.9 Strongly positive

5


6

> or =100 Strongly positive Reference values apply to all ages.

Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB Saunders Company, New York, 2007, Part VI, pp 961-971

MANN

Alpha-Mannosidase, Leukocytes

62511

Clinical Information: Alpha-mannosidosis is an autosomal recessive lysosomal storage disorder caused by reduced or absent acid alpha-mannosidase enzyme activity. This enzyme is involved in glycoprotein catabolism, with absent or reduced activity resulting in the accumulation of undigested mannose-containing complex oligosaccharides in the lysosomes, disrupting the normal functioning of cells. Clinical features and severity of symptoms are widely variable within alpha-mannosidosis but, in general, the disorder is characterized by skeletal abnormalities, immune deficiency, hearing impairment, and mental retardation. Three clinical subtypes of the disorder have been described and vary with respect to age of onset and clinical presentation. Type 1 is generally classified by a mild presentation and slow progression with onset after 10 years of age and absence of skeletal abnormalities. Type 2 is generally a more moderate form with slow progression and onset prior to 10 years of age with skeletal abnormalities and myopathy. Type 3 is the most severe form with onset in early infancy, skeletal abnormalities (dysostosis multiplex), and severe central nervous system involvement. Although treatment is mostly supportive and aimed at preventing complications, hematopoietic stem cell transplant has been reported to be a feasible therapeutic option. The incidence of alpha-mannosidosis is estimated at 1 in 500,000 live births. An initial diagnostic workup may include a multi-enzyme screening assay for several oligosaccharidoses, including mannosidosis in leukocytes or fibroblasts (OLIGU / Oligosaccharide Screen, Urine; OLIWB / Oligosaccharidoses Screen, Leukocytes; or OLITC / Oligosaccharidoses Screen, Fibroblasts). If the screening assay is suggestive of alpha-mannosidosis, enzyme analysis of acid alpha-mannosidase can confirm the diagnosis.

Useful For: Diagnosis of alpha-mannosidosis Interpretation: Values below 0.54 nmol/min/mg protein are consistent with a diagnosis of alpha-mannosidosis.


Clinical References: 1. Malm D, Nilssen O: Alpha-Mannosidosis. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 2001 Oct 11 (Updated 2012 May 3). Accessed 3/6/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1396/ 2. Thomas GH: Chapter 140: Disorders of Glycoprotein Degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMMBID). Edited by D Valle, B Vogelstein, SE Antonarakis, et al. McGraw-Hill Medical Division. Accessed 3/16/2017. Available at http://ommbid.mhmedical.com/ 3. Mynarek M, Tolar J, Albert MH, et Current as of August 23, 2017 7:11 am CDT


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al: Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant 2012 Mar;47(3):352-359. doi: 10.1038/bmt.2011.99

ANAS

Alpha-N-Acetylglucosaminidase, Serum

8782

Clinical Information: The mucopolysaccharidoses (MPS) are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans GAG). Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders. Sanfilippo syndrome (MPS type III) is an autosomal recessive MPS with 4 recognized types (A-D). Each type is caused by a deficiency in 1 of 4 enzymes involved in the degradation of heparan sulfate resulting in its lysosomal accumulation. Though biochemically different, the clinical presentation of all types is indistinguishable. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but other symptoms seen in MPS, such as coarse facial features and skeletal involvement, tend to be milder. Onset of clinical features usually occurs between 2 and 6 years in a child who previously appeared normal. The presenting symptoms are most commonly developmental delay and severe behavioral problems. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by age 20, although individuals with an attenuated phenotype may have a longer life expectancy and remain functional into their third and fourth decades. Sanfilippo syndrome type B is due to the absence of the enzyme N-acetyl-alpha-D-glucosaminidase (alpha-hexosaminidase), caused by mutations in the NAGLU gene. Affected individuals demonstrate elevations of heparan sulfate in urine. Diagnostic sequencing of the NAGLU gene (MP3BZ / Mucopolysaccharidosis IIIB, Full Gene Analysis) and deletion/duplication studies are available for patients with an enzyme deficiency. Patients with Mucolipidosis II/III (I-cell disease) may demonstrate elevations of alpha-N-acetylglucosaminidase in addition to abnormalities of other hydrolases. I-cell disease is an autosomal recessive lysosomal storage disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay. Measurement of alpha-N-acetylglucosaminidase activity is not the preferred diagnostic test for I-cell disease but may be included in the testing strategy.

Useful For: Preferred assay for diagnosis of Sanfilippo syndrome type B (mucopolysaccharidoses type IIIB)

Interpretation: Deficiency of alpha-N-acetylglucosaminidase is diagnostic for Sanfilippo syndrome type B.

Reference Values: 0.09-0.58 U/L

Clinical References: 1. Heron B, Mikaeloff Y, Froissart R, et al: Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A 2011;155A(1):58-68 2. Neufeld EF, Muenzer J: Chapter 136: The Mucopolysaccharidoses. In The Metabolic and Molecular Bases of Inherited Disease. Eighth edition. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Book Company. Accessed 01/13/2015. Available at www.ommbid.com 3. Valstar MJ, Bruggenwirth HT, Olmer R, et al: Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J Inherit Metab Dis 2010;33:759-767 4. Neufeld EF, Muenzer J: Neufeld E.F., Muenzer J Neufeld, Elizabeth F., and Joseph Muenzer.The Mucopolysaccharidoses. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. Valle D, Beaudet A.L., Vogelstein B, Kinzler K.W., Antonarakis S.E., Ballabio A, Gibson K, Mitchell G Eds. David Valle, et al.New York, NY: McGraw-Hill; 2014. Accessed March 09, 2017. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62642135

ANS 80870

Alpha-Naphthyl Stain (Bill Only)



Page 109


APGH

Alpha-Subunit Pituitary Tumor Marker, Serum

9003

Clinical Information: The 3 human pituitary glycoprotein hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), and the placenta-derived chorionic gonadotropin (hCG), are closely related tropic hormones. They signal through G-protein-coupled receptors, regulating the hormonal activity of their respective endocrine target tissues. Each is composed of an alpha- and a beta-subunit, coupled by strong noncovalent bonds. The alpha-subunits of all 4 hormones are essentially identical (92 amino acids; molecular weight [MW] of the "naked" protein:10,205 Da), being transcribed from the same gene and showing only variability in glycosylation (MW of the glycosylated proteins:13,000-18,000 Da). The alpha-subunits are essential for receptor transactivation. By contrast, all the different beta-subunits are transcribed from separate genes, show less homology, and convey the receptor specificity of the dimeric hormones. Under physiological conditions, alpha- and beta-chain synthesis and secretions are tightly coupled, and only small amounts of monomeric subunits are secreted. However, under certain conditions, coordinated production of intact glycoprotein hormones may be disturbed and disproportionate quantities of free alpha-subunits are secreted. In particular, some pituitary adenomas may overproduce alpha-subunits. Although most commonly associated with gonadotroph- or thyrotroph-derived tumors, alpha-subunit secretion has also been observed in corticotroph, lactotroph, and somatotroph pituitary adenomas. Overall, depending on cell type and tumor size, between 5% to 30% of pituitary adenomas will produce sufficient free alpha-subunits to result in elevated serum levels, which usually fall with successful treatment. Stimulation testing with hypothalamic releasing factors (eg, gonadotropin releasing hormone [GnRH] or thyrotropin-releasing hormone [TRH]) may result in further elevations, disproportionate to those seen in individuals without tumors. Measurement of free alpha-subunit after GnRH-stimulation testing can also be useful in the differential diagnosis of constitutional delay of puberty (CDP) versus hypogonadotrophic hypogonadism (HH). CDP is a benign, often familial, condition in which puberty onset is significantly delayed, but eventually occurs, and then proceeds normally. By contrast, HH represents a disease state characterized by lack of gonadotropin production. Its causes are varied, including hypothalamic and pituitary inflammatory or neoplastic disorders, a range of specific genetic abnormalities, as well as unknown causes. In children, HH results in complete failure to enter puberty without medical intervention. In children with CDP, in normal pubertal children, in normal adults and, to a lesser degree, in normal prepubertal children, GnRH administration results in increased serum LH, FSH, and alpha-subunit levels. This response is greatly attenuated in patients with HH, particularly with regard to the post-GnRH rise in alpha-subunit concentrations.

Useful For: Adjunct in the diagnosis of pituitary tumors As part of the follow-up of treated pituitary tumor patients Differential diagnosis of thyrotropin-secreting pituitary tumor versus thyroid hormone resistance Differential diagnosis of constitutional delay of puberty versus hypogonadotrophic hypogonadism

Interpretation: In the case of pituitary adenomas that do not produce significant amounts of intact tropic hormones, diagnostic differentiation between sellar- and tumors of nonpituitary origin (eg, meningiomas or craniopharyngiomas) can be difficult. In addition, if such nonsecreting adenomas are very small, then they can be difficult to distinguish from physiological pituitary enlargements. In a proportion of these cases, free alpha-subunit may be elevated, aiding in diagnosis. Overall, 5% to 30% of pituitary adenomas produce measurable elevation in serum free alpha-subunit concentrations. There is also evidence that an exuberant free alpha-subunit response to thyrotropin-releasing hormone (TRH) administration may occur in some pituitary adenoma patients that do not have elevated baseline free alpha-subunit levels. A more than 2-fold increase in free alpha-subunit serum concentrations at 30 to 60 minutes following intravenous administration of 500 mcg of TRH is generally considered abnormal, but some investigators consider any increase of serum free alpha-subunit that exceeds the reference range as abnormal. TRH testing is not performed in the laboratory, but in specialized clinical testing units under Current as of August 23, 2017 7:11 am CDT


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the supervision of a physician. In pituitary tumors patients with pre-treatment elevations of serum free alpha-subunit, successful treatment is associated with a reduction of serum free alpha-subunit levels. Failure to lower levels into the normal reference range may indicate incomplete cure, and secondary rises in serum free alpha-subunit levels can indicate tumor recurrence. Small thyrotropin (TSH)-secreting pituitary tumors are difficult to distinguish from thyroid hormone resistance. Both types of patients may appear clinically euthyroid or mildly hyperthyroid and may have mild-to-modest elevations in peripheral thyroid hormone levels along with inappropriately (for the thyroid hormone level) detectable TSH, or mildly-to-modestly elevated TSH. Elevated serum free alpha-subunit levels in such patients suggest a TSH secreting tumor, but mutation screening of the thyroid hormone receptor gene may be necessary for a definitive diagnosis. Constitutional delay of puberty (CDP), is a benign, often familial condition, in which puberty onset is significantly delayed, but eventually occurs and then proceeds normally. By contrast, hypogonadotrophic hypogonadism (HH) represents a disease state characterized by lack of gonadotropin production. Its causes are varied, ranging from idiopathic over specific genetic abnormalities to hypothalamic and pituitary inflammatory or neoplastic disorders. In children, it results in complete failure to enter puberty without medical intervention. CDP and HH can be extremely difficult to distinguish from each other. Intravenous administration of 100 mcg gonadotropin releasing hormone (GnRH) results in much more substantial rise in free alpha-subunit levels in CDP patients, compared with HH patients. A >6-fold rise at 30 or 60 minutes post-injection is seen in >75% of CDP patients, while a 150 pg/mL) and relatively low aluminum (40.0 mcg/mL

Clinical References: 1. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide, 2008 2. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs. national academy of clinical biochemistry. Clin Chem 1998 May;44(5):1129-1140 3. Gonzalez LS III, Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820

RAMIK

Amikacin, Random, Serum

37033

Clinical Information: Amikacin is an aminoglycoside used to treat severe blood infections by susceptible strains of gram-negative bacteria. Aminoglycosides induce bacterial death by irreversibly binding bacterial ribosomes to inhibit protein synthesis. Amikacin is minimally absorbed from the gastrointestinal tract, and thus can been used orally to reduce intestinal flora. Peak serum concentrations are seen 30 minutes after intravenous infusion, or 60 minutes after intramuscular administration. Serum half-lives in patients with normal renal function are generally 2 to 3 hours. Excretion of aminoglycosides is principally renal, and all aminoglycosides may accumulate in the kidney at 50 to 100 times the serum concentration. Toxicity can present as dizziness, vertigo, or, if severe, ataxia and a Meniere disease-like syndrome. Auditory toxicity may be manifested by simple tinnitus or any degree of hearing loss, which may be temporary or permanent, and can extend to total irreversible deafness. Nephrotoxicity is most frequently manifested by transient proteinuria or azotemia, which may occasionally be severe. Aminoglycosides also are associated with variable degrees of neuromuscular blockade leading to apnea.

Useful For: Monitoring adequacy of blood concentration during amikacin therapy Interpretation: For conventional (nonpulse) dosing protocols, clinical effects may not be achieved if the peak serum concentration is 35.0 mcg/mL, or trough concentrations are maintained at >10.0 mcg/mL.

Reference Values: Peak: 20.0-35.0 mcg/mL Toxic peak: >40.0 mcg/mL Trough: 10.0 mcg/mL

Clinical References: 1. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide, 2008 2. Hammett-Stabler CA, Johns T: Laboratory Guidelines for Monitoring of Antimicrobial Drugs. National Academy of Clinical Biochemistry. Clin Chem. 1998 May;44(5):1129-1140 3. Gonzalez LS III, Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820



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TAMIK

Amikacin, Trough, Serum

37031

Clinical Information: Amikacin is an aminoglycoside used to treat severe blood infections by susceptible strains of gram-negative bacteria. Aminoglycosides induce bacterial death by irreversibly binding bacterial ribosomes to inhibit protein synthesis. Amikacin is minimally absorbed from the gastrointestinal tract, and thus can been used orally to reduce intestinal flora. Peak serum concentrations are seen 30 minutes after intravenous infusion, or 60 minutes after intramuscular administration. Serum half-lives in patients with normal renal function are 2 to 3 hours. Excretion of aminoglycosides is principally renal, and all aminoglycosides may accumulate in the kidney at 50 to 100 times the serum concentration. Toxicity can present as dizziness, vertigo, or, if severe, ataxia and a Meniere disease-like syndrome. Auditory toxicity may be manifested by simple tinnitus or any degree of hearing loss, which may be temporary or permanent, and can extend to total irreversible deafness. Nephrotoxicity is most frequently manifested by transient proteinuria or azotemia, which may occasionally be severe. Aminoglycosides also are associated with variable degrees of neuromuscular blockade leading to apnea.

Useful For: Monitoring adequate clearance of amikacin near the end of a dosing cycle Interpretation: For conventional (nonpulse) dosing protocols, trough concentrations should fall to 10.0 mcg/mL for prolonged periods of time.

Reference Values: Trough: 10.0 mcg/mL

Clinical References: 1. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide, 2008 2. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs. National Academy of Clinical Biochemistry.. Clin Chem 1998 May;44(5):1129-1140 3. Gonzalez LS III, Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820

AAMSD

Amino Acids, Maple Syrup Urine Disease Panel, Plasma

60200

Clinical Information: Maple syrup urine disease (MSUD) is an inborn error of metabolism caused by the deficiency of the branched-chain ketoacid dehydrogenase (BCKDH) complex. The BCKDH complex is involved in the metabolism of the branched-chain amino acids (BCAA): isoleucine (Ile), leucine (Leu), and valine (Val). MSUD patients can be divided into 5 phenotypes: classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase (E3)-deficient depending on the clinical presentation and response to thiamine administration. Classic MSUD which is the most common and most severe form, presents in the neonate with feeding intolerance, failure to thrive, vomiting, lethargy, and maple syrup odor to urine and cerumen. If untreated, it progresses to irreversible mental retardation, hyperactivity, failure to thrive, seizures, coma, cerebral edema, and possibly death. Age of onset for individuals with variant forms of MSUD is variable and some have initial symptoms as early as 2 years of age. Symptoms include poor growth and feeding, irritability, and developmental delays. These patients can also experience severe metabolic intoxication and encephalopathy during periods of sufficient catabolic stress. MSUD is a panethnic condition, but is most prevalent in the Old Order Mennonite community in Lancaster, Pennsylvania with an incidence there of 1:760 live births. The incidence of MSUD is approximately 1:185,000 live births in the general population. Treatment of MSUD aims to normalize the concentration of BCAA by dietary restriction of these amino acids. Because BCAA belong to the essential amino acids, the dietary treatment requires frequent adjustment, which is accomplished by regular determination of BCAA and allo-isoleucine concentrations. Orthotopic liver transplantation has been used with success and is an effective therapy for MSUD.

Useful For: Follow-up of patients with maple syrup urine disease Monitoring of dietary compliance for patients with maple syrup urine disease

Interpretation: The quantitative results of isoleucine, leucine, valine, and allo-isoleucine with age-dependent reference values are reported without added interpretation. When applicable, reports of abnormal results may contain an interpretation based on available clinical interpretation.

Reference Values: Current as of August 23, 2017 7:11 am CDT


Page 120

ISOLEUCINE < or =23 months: 31-105 nmol/mL 2-17 years: 30-111 nmol/mL > or =18 years: 36-107 nmol/mL LEUCINE < or =23 months: 48-175 nmol/mL 2-17 years: 51-196 nmol/mL > or =18 years: 68-183 nmol/mL VALINE < or =23 months: 83-300 nmol/mL 2-17 years: 106-320 nmol/mL > or =18 years: 136-309 nmol/mL ALLO-ISOLEUCINE < or =23 months: or =18 Years (n=148) Phosphoserine (PSer) Phosphoethanolamine (PEtN) Taurine (Tau)

37-177

38-153

42-156

Asparagine (Asn)

25-91

29-87

37-92

Serine (Ser)

69-271

71-208

63-187

Hydroxyproline (Hyp)

8-61

7-35

4-29

Glycine (Gly)

111-426 149-417

126-490

Glutamine (Gln)

316-1020 329-976

371-957

Aspartic Acid (Asp)

2-20

Ethanolamine (EtN) Histidine (His)

10-116

12-132

39-123

Threonine (Thr)

47-237

58-195

85-231

Citrulline (Cit)

9-38

11-45

17-46

Sarcosine (Sar) b-Alanine (bAla) Alanine (Ala)

139-474 144-557

200-579

Glutamic Acid (Glu)

31-202

13-113

22-131

1-Methylhistidine (1MHis) 3-Methylhistidine (3MHis)

2-9

Argininosuccinic Acid (Asa) Carnosine (Car) Anserine (Ans) Homocitruline (Hcit) Arginine (Arg)

29-134

31-132

32-120

7-28

7-31

9-37

Proline (Pro)

85-303

80-357

97-368

Ornithine (Orn)

20-130

22-97

38-130

a-Aminoadipic Acid (Aad) g-Amino-n-butyric Acid (GABA) b-Aminoisobutyric Acid (bAib) a-Amino-n-butyric Acid (Abu) Hydroxylysine (Hyl)

Cystathionine (Cth) Current as of August 23, 2017 7:11 am CDT


Page 122

Cystine (Cys)

2-32

2-36

3-95

Lysine (Lys)

49-204

59-240

103-255

Methionine (Met)

11-35

11-37

4-44

Valine (Val)

83-300

106-320

136-309

Tyrosine (Tyr)

26-115

31-106

31-90

Isoleucine (IIe)

31-105

30-111

36-107

Leucine (Leu)

48-175

51-196

68-183

Phenylalanine (Phe)

28-80

30-95

35-80

Tryptophan (Trp)

17-75

23-80

29-77

Alloisoleucine (Allolle)

Clinical References: Scriver's The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Part 8 Amino Acids. Accessed July 6, 2016. Available at http://ommbid.mhmedical.com/book.aspx?bookid=971

AAPD

Amino Acids, Quantitative, Random, Urine

60475

Clinical Information: Amino acids are the basic structural units that comprise proteins and are found throughout the body. Many inborn errors of amino acid metabolism that affect amino acid transport or metabolism have been identified, such as phenylketonuria and tyrosinemia. Amino acid disorders can manifest at any age, but most become evident in infancy or early childhood. These disorders result in the accumulation or the deficiency of 1 or more amino acids in biological fluids, which leads to the clinical signs and symptoms of the particular amino acid disorder. The clinical presentation is dependent upon the specific amino acid disorder. In general, affected patients may experience failure to thrive, neurologic symptoms, digestive problems, dermatologic findings, and physical and cognitive delays. If not diagnosed and treated promptly, amino acid disorders can result in mental retardation and death. In addition, amino acid analysis may have clinical importance in the evaluation of several acquired conditions including endocrine disorders, liver diseases, muscle diseases, neoplastic diseases, neurological disorders, nutritional disturbances, renal failure, and burns. General elevations in urine amino acid levels, called aminoaciduria, can be seen in disorders with amino acid transport defects such as lysinuric protein intolerance and Hartnup disease, as well as in conditions with renal tubular dysfunction including Lowe syndrome and Dent disease.

Useful For: Evaluating patients with possible inborn errors of metabolism May aid in evaluation of endocrine disorders, liver diseases, muscle diseases, neoplastic diseases, neurological disorders, nutritional disturbances, renal failure, and burns

Interpretation: When no significant abnormalities are detected, a simple descriptive interpretation is provided. When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing and in vitro confirmatory studies (enzyme assay, molecular analysis), name and phone number of key contacts who may provide these studies at Mayo or elsewhere, and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.

Reference Values: Urine Amino Acid Reference Values Age Groups (nmol/mg creatinine) < or =12 Months (n=515) Current as of August 23, 2017 7:11 am CDT

13-35 Months

3-6 Years

7-8 Years

9-17 Years > or =18 Years

(n=210)

(n=197)

(n=74)

(n=214)


(n=835) Page 123

Phosphoserine

PSer

Phosphoethanolamine

PEtN

15-341

33-342

19-164

12-118

Taurine

Tau

37-8300

64-3255

76-3519

50-2051

57-2235

24-1531

Asparagine

Asn

25-1000

62-884

28-412

38-396

22-283

25-238

Serine

Ser

18-4483

284-1959

179-1285

153-765

105-846

97-540

Hydroxyproline

Hyp

Glycine

Gly

362-18614

627-6914

412-5705

449-4492

316-4249

229-2989

Glutamine

Gln

139-2985

263-2979

152-1325

164-1125

188-1365

93-686

Aspartic Acid

Asp

Ethanolamine

EtN

282-3782

256-947

193-643

137-564

158-596

95-471

Histidine

His

145-3833

427-3398

230-2635

268-2147

134-1983

81-1128

Threonine

Thr

25-1217

55-763

30-554

25-456

37-418

31-278

Citrulline

Cit

Sarcosine

Sar

Beta-Alanine

bAla

Alanine

Ala

93-3007

101-1500

64-1299

44-814

51-696

56-518

Glutamic Acid

Glu

1-Methylhistidine

1MHis

17-419

18-1629

10-1476

19-1435

12-1549

23-1339

3-Methylhistidine

3MHis

88-350

86-330

56-316

77-260

47-262

70-246

Argininosuccinic Acid

Asa

Carnosine

Car

27-1021

16-616

18-319

Anserine

Ans

Homocitrulline

Hcit

Arginine

Arg

10-560

20-395

14-240

Alpha-aminoadipic Acid Aad

10-275

15-324

10-135

24-511

11-286

12-128

11-158

Gamma Amino-n-butyric GABA Acid Beta-aminoisobutyric Acid

bAib

Alpha-amino-n-butyric Acid

Abu

Hydroxylysine

Hyl

Proline

Pro

Ornithine

Orn

Cystathionine

Cth

Cystine

Cys

12-504

11-133

Lysine

Lys

19-1988

25-743

Methionine

Met

Valine

Val

11-211

11-211


18-3137

15-1039

28-2029

10-98 14-307

17-276

10-240

16-91


15-271

11-61

Page 124

Tyrosine

Tyr

Isoleucine

Ile

Leucine

Leu

Phenylalanine

Phe

Tryptophan

Trp

Allo-isoleucine

AlloIle

39-685

38-479

23-254

22-245

12-208

15-115

15-167

12-100

13-73

14-280

34-254

20-150

21-106

11-111

13-70

14-315

14-315

10-303

10-303

15-229

18-114

Clinical References: 1. Scriver's The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Part 8 Amino Acids. Accessed July 6, 2016. Available at: http://ommbid.mhmedical.com/book.aspx?bookid=971 2. Camargo SMR, Bockenhauer D, Kleta R: Aminoacidurias: Clinical and molecular aspects. Kidney Int 2008;73:918-925

AACSF

Amino Acids, Quantitative, Spinal Fluid

81934

Clinical Information: Amino acids are the basic structural units that comprise proteins and are found throughout the body. Many inborn errors of amino acid metabolism that affect amino acid transport and metabolism have been identified. Amino acid disorders can manifest at any age, but most become evident in infancy or early childhood. These disorders result in the accumulation or deficiency of 1 or more amino acids in biological fluids, which leads to the clinical signs and symptoms of the particular amino acid disorder. The clinical presentation is dependent upon the specific amino acid disorder. In general, affected patients may experience failure to thrive, neurologic symptoms, digestive problems, dermatologic findings, and physical and cognitive delays. If not diagnosed and treated promptly, amino acid disorders can result in mental retardation and death. Cerebrospinal fluid (CSF) specimens are highly informative for a subset of these conditions, such as nonketotic hyperglycinemia and serine biosynthesis defects. CSF specimens are most informative when a plasma specimen is drawn at the same time and the ratio of the amino acid concentrations in CSF to plasma is calculated.

Useful For: Evaluating patients with possible inborn errors of amino acid metabolism, in particular nonketotic hyperglycinemia and serine biosynthesis defects, especially when used in conjunction with concomitantly drawn plasma specimens.

Interpretation: When no significant abnormalities are detected, a simple descriptive interpretation is provided. When abnormal results are detected, a detailed interpretation is provided. This interpretation includes an overview of the results and their significance, a correlation to available clinical information, elements of differential diagnosis, and recommendations for additional biochemical testing and in vitro confirmatory studies (enzyme assay, molecular analysis), name and phone number of key contacts who may provide these studies at Mayo Clinic or elsewhere, and the telephone number to reach one of the laboratory directors in case the referring physician has additional questions.

Reference Values: CSF Amino Acid Reference Values Age Groups (nmol/mL) < or =31 Days (n=73)

32 Days-23 Months 2-18 Years (n=189) > or =19 Years (n=88) (n=32)

Phosphoserine (PSer) Phosphoethanolamine (PEtN) Taurine (Tau)

8-48

Asparagine (Asn)

8-34

5-16

Serine (Ser)

44-136

26-71

5-20 21-51

19-40

Hydroxyproline (Hyp) Glycine (Gly) Current as of August 23, 2017 7:11 am CDT

5-115 800-533-1710 or 507-266-5700 or MayoMedicalLaboratories.com

Page 125

Glutamine (Gln)

467-1832

301-1128

326-1092

380-1348

Ethanolamine (EtN)

11-193

7-155

7-153

7-153

Histidine (His)

11-70

9-28

9-21

9-28

Threonine (Thr)

32-143

11-77

14-38

23-57

24-124

16-53

12-34

19-60

5-39

11-35

11-27

11-32

11-63

9-33

10-25

13-42

Valine (Val)

14-61

9-28

8-20

11-40

Tyrosine (Tyr)

8-83

5-24

Leucine (Leu)

12-41

6-21

Phenylalanine (Phe)

7-40

5-18

Aspartic Acid (Asp)

Citrulline (Cit) Sarcosine (Sar) Beta-alanine (bAla) Alanine (Ala) Glutamic Acid (Glu) 1-Methylhistidine (1MHis) 3-Methylhistidine (3MHis) Argininosuccinic Acid (Asa) Carnosine (Car) Anserine (Ans) Homocitrulline (Hcit) Arginine (Arg) Alpha-aminoadipic Acid (Aad) Gamma-amino-n-butyric Acid (GABA) Beta-aminoisobutyric Acid (bAib) Alpha-amino-n-butyric Acid (Abu) Hydroxylysine (Hyl) Proline (Pro) Ornithine (Orn) Cystathionine (Cth) Cystine (Cys) Lysine (Lys) Methionine (Met)

5-17

Homocystine (Hcy) Isoleucine (Ile) 7-16

7-29 7-21

Tryptophan (Trp) Allo-isoleucine (AlloIle)

Clinical References: Rinaldo P, Hahn S, Matern D: Inborn errors of amino acid, organic acid, and Current as of August 23, 2017 7:11 am CDT


Page 126

fatty acid metabolism. In Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis, WB Saunders Company, 2005, pp 2207-2247

AAUCD

Amino Acids, Urea Cycle Disorders Panel, Plasma

60202

Clinical Information: Urea cycle disorders (UCD) are a group of inherited disorders of nitrogen detoxification that result when any of the enzymes in the urea cycle (carbamoylphosphate synthetase I: CPS I; ornithine transcarbamylase: OTC; argininosuccinic acid synthetase; argininosuccinic acid lyase; arginase; or the cofactor producer, N-acetyl glutamate synthetase: NAGS), have deficient or reduced activity. The urea cycle serves to break down nitrogen, and defects in any of the steps of the pathway can result in an accumulation of ammonia, which can be toxic to the nervous system. Infants with a complete enzyme deficiency typically appear normal at birth, but present in the neonatal period as ammonia levels rise with lethargy, seizures, hyper- or hypoventilation, and ultimately coma or death. Individuals with partial enzyme deficiency may present later in life, typically following an acute illness or other stressor. Symptoms may be less severe and may present with episodes of psychosis, lethargy, cyclical vomiting, and behavioral abnormalities. All of the UCDs are inherited as autosomal recessive disorders, with the exception of OTC deficiency, which is X-linked. UCDs may be suspected with elevated ammonia, normal anion gap, and a normal glucose. Plasma amino acids can be used to aid in the diagnosis of a UCD. Measurement of urinary orotic acid, enzyme activity (CPS I, OTC, or NAGS), and molecular genetic testing can help to distinguish the conditions and allows for diagnostic confirmation. Acute treatment for UCDs consists of dialysis and administration of nitrogen scavenger drugs to reduce ammonia concentration. Chronic management typically involves restriction of dietary protein with essential amino acid supplementation. More recently, orthotopic liver transplantation has been used with success in treating some patients.

Useful For: Differential diagnosis and follow-up of patients with urea cycle disorders Interpretation: The quantitative results of glutamine, ornithine, citrulline, arginine, and argininosuccinic acid with age-dependent reference values are reported without added interpretation. When applicable, reports of abnormal results may contain an interpretation based on available clinical interpretation.

Reference Values: GLUTAMINE < or =23 months: 316-1020 nmol/mL 2-17 years: 329-976 nmol/mL > or =18 years: 371-957 nmol/mL ORNITHINE < or =23 months: 20-130 nmol/mL 2-17 years: 22-97 nmol/mL > or =18 years: 38-130 nmol/mL CITRULLINE < or =23 months: 9-38 nmol/mL 2-17 years: 11-45 nmol/mL > or =18 years: 17-46 nmol/mL ARGININE < or =23 months: 29-134 nmol/mL 2-17 years: 31-132 nmol/mL > or =18 years: 32-120 nmol/mL ARGININOSUCCINIC ACID or =100 Strongly positive Reference values apply to all ages.


AMPD

AMP Deaminase ST

82049 Current as of August 23, 2017 7:11 am CDT


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FAMP

Amphetamine, Serum or Plasma

91171

Reference Values: Reference Range: 10 â€“ 100 ng/mL

AMPMX 62712

Amphetamine-Type Stimulants Confirmation, Chain of Custody, Meconium Clinical Information: Several stimulants and hallucinogens chemically related to phenylethylamine are referred to collectively as the amphetamine-type stimulants (amphetamines). Generally, this refers to the prescription and illicit amphetamines including amphetamine; methamphetamine; 3,4-methylenedioxymethamphetamine ( MDMA, Ecstasy); 3,4-methylenedioxyamphetamine (MDA); and 3,4-methylenedioxyethylamphetamine (MDEA).(1) Methamphetamine has become a drug of choice among stimulant abusers because of its availability and ease to synthesize. The metabolism of amphetamine consists of hydroxylation and deamination followed by conjugation with glucuronic acid. Methamphetamine is metabolized to amphetamine; both should be present in urine after methamphetamine use. Both MDMA and MDEA are metabolized to MDA.(1) The disposition of drug in meconium, the first fecal material passed by the neonate, is not well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium either by direct deposition from bile or through swallowing of amniotic fluid.(2) The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly moves to the colon by the 16th week of gestation.(3) Therefore, the presence of drugs in meconium has been proposed to be indicative of in utero drug exposure up to 5 months before birth, a longer historical measure than is possible by urinalysis.(2) Intrauterine drug exposure to amphetamines has been associated with maternal abruption, prematurity, and decreased growth parameters such as low-birth weight.(4) Some intrauterine amphetamine-exposed infants may develop hypertonia, tremors, and poor feeding and abnormal sleep patterns.(5) Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection of in utero drug exposure up to 5 months before birth Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited. Since the evidence of illicit drug use during pregnancy can be cause for separating the baby from the mother, a complete chain of custody ensures that the test results are appropriate for legal proceedings.

Interpretation: The presence of any 1 of the following: amphetamine; methamphetamine; 3,4-methylenedioxyamphetamine; 3,4-methylenedioxymethamphetamine; or 3,4-methylenedioxyethylamphetamine at >50 ng/g is indicative of in utero exposure up to 5 months before birth.

Reference Values: Negative Positives are reported with a quantitative LC-MS/MS result. Cutoff concentrations: Amphetamine by LC-MS/MS: 50 ng/g Methamphetamine by LC-MS/MS: 50 ng/g Current as of August 23, 2017 7:11 am CDT


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3,4-Methylenedioxyamphetamine by LC-MS/MS: 50 ng/g 3,4-Methylenedioxyethylamphetamine by LC-MS/MS: 50 ng/g 3,4-Methylenedioxymethamphetamine by LC-MS/MS: 50 ng/g

Clinical References: 1. Disposition of Toxic Drugs and Chemical in Man. Edited by RC Baselt. Foster City, CA, Biochemical Publications, 2008 pp 83-86; 947-952; 993-999 2. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an alternative to urine testing. J Pediatr 1989;115:474-477 3. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005;60:45-56 4. Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of Clinical Biochemistry. Clin Chem 1997;43:235-242 5. Dixon SD: Effects of transplacental exposure to cocaine and methamphetamine on the neonate. West J Med 1989;150:436-442

AMPHM

Amphetamine-Type Stimulants, Confirmation, Meconium

84371

Clinical Information: Several stimulants and hallucinogens chemically related to phenylethylamine are referred to collectively as the amphetamine-type stimulants (amphetamines). Generally, this refers to the prescription and illicit amphetamines including amphetamine; methamphetamine; 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy); 3,4-methylenedioxyamphetamine (MDA); and 3,4-methylenedioxyethylamphetamine (MDEA).(1) Methamphetamine has become a drug of choice among stimulant abusers because of its availability and ease to synthesize. The metabolism of amphetamine consists of hydroxylation and deamination followed by conjugation with glucuronic acid. Methamphetamine is metabolized to amphetamine; both should be present in urine after methamphetamine use. Both MDMA and MDEA are metabolized to MDA.(1) The disposition of drug in meconium is not well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium either by direct deposit from bile or through swallowing of amniotic fluid.(2) The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly moves into the colon by the 16th week of gestation.(3) Therefore, the presence of drugs in meconium has been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.(2) Intrauterine drug exposure to amphetamines has been associated with maternal abruption, prematurity, and decreased growth parameters such as low-birth weight.(4) Some intrauterine amphetamine-exposed infants may develop hypertonia, tremors, and poor feeding and abnormal sleep patterns.(5)

Useful For: Detection of in utero drug exposure up to 5 months before birth Interpretation: The presence of any 1 of the following: amphetamine; methamphetamine; 3,4-methylenedioxyamphetamine; 3,4-methylenedioxymethamphetamine; or 3,4-methylenedioxyethylamphetamine at >50 ng/g is indicative of in utero exposure up to 5 months before birth.

Reference Values: Negative Positives are reported with a quantitative LC-MS/MS result. Cutoff concentrations: AMPHETAMINE BY LC-MS/MS 50 ng/g METHAMPHETAMINE BY LC-MS/MS 50 ng/g 3,4-METHYLENEDIOXYAMPHETAMINE BY LC-MS/MS 50 ng/g 3,4-METHYLENEDIOXYMETHAMPHETAMINE BY LC-MS/MS 50 ng/g Current as of August 23, 2017 7:11 am CDT


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3,4-METHYLENEDIOXYMETHAMPHETAMINE BY LC-MS/MS 50 ng/g

Clinical References: 1. Disposition of Toxic Drugs and Chemical in Man. Edited by RC Baselt. Foster City, CA, Biochemical Publications, 2008 pp 83-86; 947-952; 993-999 2. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: and alternative to urine testing. J Pediatr 1989;115:474-477 3. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005;60:45-56 4. Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of Clinical Biochemistry. Clin Chem 1997;43:235-242 5. Dixon SD: Effects of transplacental exposure to cocaine and methamphetamine on the neonate. West J Med 1989;150:436-442

FASCC

Amphetamines Analysis, Serum

75109

Reference Values: Reference Range: Amphetamines: Cutoff: 50 Confirmation Threshold: 10 mg/mL

AMPHX

Amphetamines Confirmation, Chain of Custody, Urine

62711

Clinical Information: Amphetamines are sympathomimetic amines that stimulate the central nervous system activity and, in part, suppress the appetite. Phentermine, amphetamine, and methamphetamine are prescription drugs for weight loss. All of the other amphetamines are Class I (distribution prohibited) compounds. In addition to their medical use as anorectic drugs, they are used in the treatment of narcolepsy, attention-deficit disorder/attention-deficit hyperactivity disorder, and minimal brain dysfunction. Because of their stimulant effects, the drugs are commonly sold illicitly and abused. Physiological symptoms associated with very high amounts of ingested amphetamine or methamphetamine include elevated blood pressure, dilated pupils, hyperthermia, convulsions, and acute amphetamine psychosis. Chain-of-custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Confirming drug exposure involving amphetamines such as amphetamine and methamphetamine, phentermine, methylenedioxyamphetamine (MDA: a metabolite of MDMA and MDEA), methylenedioxymethamphetamine (MDMA), and methylenediaoxyethylamphetamine (MDEA) Chain-of-custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: The presence of amphetamines in urine at concentrations >500 ng/mL is a strong indicator that the patient has used these drugs within the past 3 days. This test will produce true-positive results for urine specimens collected from patients who are administered Adderall and Benzedrine (contain amphetamine); Desoxyn and Vicks Inhaler (contain methamphetamine); Selegiline (metabolized to methamphetamine and amphetamine); and clobenzorex, famprofazone, fenethylline, fenproporex, and mefenorex, which are amphetamine pro-drugs.

Reference Values: Negative Cutoff concentrations: IMMUNOASSAY SCREEN 550 U/L has been reported as 62% sensitive and 97% specific for acute pancreatitis (3), while a value > 2000 U/L has been reported as 62% sensitive and 97% specific for acute pancreatitis (4). Quantitation of urinary amylase excretion is also useful in monitoring for rejection following pancreas transplantation. The duodenal cuffs of donor pancreases are often surgically anastomosed to the recipient's bladder at the time of pancreas transplantation, allowing for drainage of exocrine pancreas fluid into the bladder. In pancreatic rejection, urinary amylase excretion decreases. In patients with pancreas transplants that drain into the urinary system, a drop in urinary amylase of more than 25% from that patientâ€™s baseline value can indicate acute rejection (5). In this situation, collecting a timed urine sample and expressing the urinary amylase level as Units excreted/hr might reduce variability and improve test performance (6).

Useful For: Assessment of acute rejection of bladder-drained pancreas transplants Diagnoses of acute pancreatitis

Interpretation: Decreases in urinary amylase excretion of greater than 30% to 50%, relative to baseline values, may be associated with acute pancreas allograft rejection. Because there is large day-to-day variability in urinary amylase excretion following pancreas transplantation, if a significant decrease is noted, it should be confirmed by a second collection. There is also large inter-individual Current as of August 23, 2017 7:11 am CDT


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variability in urinary amylase excretion among pancreas transplant recipients. Acute rejection is usually not established solely by changes in urinary amylase excretion, but by tissue biopsy. Levels are elevated in acute pancreatitis (but with poor sensitivity and specificity).

Reference Values: No established reference values

Clinical References: 1. Tietz Textbook of Clinical Chemistry. Third edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Co., 1999, pp 689-698 2. Munn SR, Engen DE, Barr D, et al: Differential diagnosis of hypo-amylasuria in pancreas allograft recipients with urinary exocrine drainage. Transplantation 1990;49:359-362 3. Kemppainen EA, Hedstrom JI, Puolakkainen PA, et al: Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis. N Engl J Med 1997;336:1788-1793 4. Treacy J, Williams A, Bais R, et al: Evaluation of amylase and lipase in the diagnosis of acute pancreatitis. ANZ Journal of Surgery 2001;71:577-582 5. Klassen DK, Hoen-Saric EW, Weir MR, et al: Isolated pancreas rejection in combined kidney pancreas transplantation. Transplantation 1996;61:974-977 6. Benedetti E, Najaran JS, Gruessener AC, et al: Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-drained pancreas transplants. Surgery 1995;118:864-872

AMSU

Amylase, Timed Collection, Urine

8356

Clinical Information: Amylases are enzymes that hydrolyze complex carbohydrates. They are produced by a number of organs and tissues, predominantly the exocrine pancreas (P-type amylase) and salivary glands (S-type amylase). Plasma amylases are of relatively low molecular weight for an enzyme (55,000-60,000 daltons) and enter the urine through glomerular filtration. Conditions that cause increased entry of amylase into plasma (eg, acute pancreatitis) will thus result in increased urinary excretion of amylase. Therefore, urinary amylase is sometimes used in the diagnosis of acute pancreatitis. However, the rate of urinary amylase excretion appears to be less sensitive than plasma markers, and is not specific for the diagnosis of acute pancreatitis. Similar to other low-molecular-weight proteins filtered by glomeruli, amylases are reabsorbed to an extent by the proximal tubule. Thus, conditions associated with increased production and glomerular filtration of other low-molecular-weight proteins that compete with tubular reabsorption of amylase or conditions of proximal tubular injury may increase urinary amylase excretion. Also, a number of disorders other than acute pancreatitis may cause increases in plasma amylase concentrations and consequent increases in urinary amylase excretion. These conditions include burns, ketoacidosis, myeloma, light-chain proteinuria, march hemoglobinuria, acute appendicitis, intestinal perforation, and following extracorporeal circulation. Quantitation of urinary amylase excretion is also useful in monitoring for rejection following pancreas transplantation. The duodenal cuffs of donor pancreases are often surgically anastomosed to the recipient's bladder at the time of pancreas transplantation, allowing for drainage of exocrine pancreas fluid into the bladder. In pancreatic rejection, urinary amylase excretion decreases.

Useful For: Assessment of acute rejection of bladder-drained pancreas transplants As an aid in the diagnosis of acute pancreatitis

Interpretation: Decreases in urinary amylase excretion of greater than 30% to 50%, relative to baseline values, may be associated with acute pancreas allograft rejection. Because there is large day-to-day variability in urinary amylase excretion following pancreas transplantation, if a significant decrease is noted, it should be confirmed by a second collection. There is also large inter-individual variability in urinary amylase excretion among pancreas transplant recipients. Collecting a timed urine specimen and expressing the urinary amylase level as Units excreted/hour might reduce variability and improve test performance. However, acute rejection is usually not established solely by changes in urinary amylase excretion, but by tissue biopsy. Urinary amylase is elevated in acute pancreatitis, but the test has poor sensitivity and specificity.

Reference Values: 3-26 U/hour

Clinical References: 1. Tietz Textbook of Clinical Chemistry. 3rd edition. Edited by CA Burtis, ER Current as of August 23, 2017 7:11 am CDT


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Ashwood. Philadelphia, WB Saunders Co., 1999, pp 689-698 2. Munn SR, Engen DE, Barr D, et al: Differential diagnosis of hypo-amylasuria in pancreas allograft recipients with urinary exocrine drainage. Transplantation 1990;49:359-362 3. Klassen DK, Hoen-Saric EW, Weir MR, et al: Isolated pancreas rejection in combined kidney pancreas transplantation. Transplantation 1996;61:974-977 4. Benedetti E, Najaran JS, Gruessener AC, et al: Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-drained pancreas transplants. Surgery 1995;118:864-872

AMS

Amylase, Total, Serum

8352

Clinical Information: Amylases are a group of hydrolases that degrade complex carbohydrates into fragments. Amylase is produced primarily by the exocrine pancreas where the enzyme is synthesized by the acinar cells and then secreted into the intestinal tract by way of the pancreatic duct system. Amylases also are produced by the salivary glands, small intestine mucosa, ovaries, placenta, liver, and fallopian tubes. Pancreatic and salivary isoenzymes are found in serum.

Useful For: Diagnosis and management of pancreatitis Evaluation of pancreatic function Interpretation: In acute pancreatitis, a transient rise in serum amylase activity occurs within 2 to 12 hours of onset; levels return to normal by the third or fourth day. A 4- to 6-fold elevation of amylase activity above the reference limit is usual with the maximal levels obtained in 12 to 72 hours. However, a significant number of subjects show lesser elevations and sometimes none. The magnitude of the elevation of serum enzyme activity is not related to the severity of pancreatic involvement. Normalization is not necessarily a sign of resolution. In acute pancreatitis associated with hyperlipidemia, serum amylase activity may be spuriously normal; the amylasemia may be unmasked either by serial dilution of the serum or ultracentrifugation. A significant amount of serum amylase is excreted in the urine and, therefore, elevation of serum activity is reflected in the rise of urinary amylase activity. Urine amylase, as compared to serum amylase, appears to be more frequently elevated, reaches higher levels, and persists for longer periods. However, the receiver operator curves (ROC) of various serum and urine amylase assays demonstrated that all urine assays had poorer diagnostic utility than all serum assays. In quiescent chronic pancreatitis, both serum and urine activities are usually subnormal. Because it is produced by several organs, amylase is not a specific indicator of pancreatic function. Elevated levels also may be seen in a number of nonpancreatic disease processes including mumps, salivary duct obstruction, ectopic pregnancy, and intestinal obstruction/infarction.

Reference Values: 0-30 days: 0-6 U/L 31-182 days: 1-17 U/L 183-365 days: 6-44 U/L 1-3 years: 8-79 U/L 4-17 years: 21-110 U/L > or =18 years: 26-102 U/L

Clinical References: 1. Soldin SJ: Pediatric Reference Ranges, AACC Press, Washington DC, Second edition. 1997 2. Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. WB Saunders Company, Philadelphia, 1999 3. Swaroop VS, Chari ST, Clain JE: Acute pancreatitis. JAMA 2004;291:2865-2868

62487

Amyloid A (Hepatic), Immunostain Without Interpretation Clinical Information: Amyloid A (AA), also called serum amyloid A (SAA), is an acute-phase protein. In the liver, AA is expressed on hepatocytes, although expression has been observed in adipocytes. AA can be used with a panel of immunohistochemical markers (beta-catenin, liver fatty acid binding protein, C-reactive protein, and glutamine synthetase) to distinguish hepatic adenoma from focal nodular hyperplasia and non-neoplastic liver. AA, along with C-reactive protein is overexpressed in inflammatory (type 3) hepatic adenoma and is not detectable in normal liver or in other adenoma types.

Useful For: Classification of hepatic adenomas Current as of August 23, 2017 7:11 am CDT


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Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. van Aalten SM, Verheij J, Terkivatan T, et al: Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol 2011;55(1):120-125 2. Bioulac-Sage P, Cubel G, Balabaud C, et al: Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011;31(1):91-103 3. Bioulac-Sage P, Rebouissou S, Thomas C, et al: Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 2007;46(3):740-748

60804

Amyloid A (SAA), Immunostain Without Interpretation Clinical Information: Immunohistochemical staining for amyloid A (SAA) produces diffuse, extracellular staining in positive tissues and colocalizes with Congo Red applegreen birefringence. SAA-type amyloid is associated with chronic inflammatory conditions, such as tuberculosis and rheumatoid arthritis. Immunohistochemical classification of amyloid has been largely replaced by subtyping using tandem mass spectrometry analysis on formalin-fixed paraffin-embedded specimens, due to its superior sensitivity and specificity.

Useful For: Identification and classification of amyloid subtypes in tissue Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Jang B, Koh Y, Seo JW: Immunohistochemical Classification of Amyloid Deposits in Surgical Pathology. Basic and Applied Pathology 2009;2:1-8 2. Leung N, Nasr SH, Sethi S: How I Treat Amyloidosis: The Importance of Accurate Diagnosis and Amyloid Typing. Blood. 2012;120(16):3206-3213 3. Sen S, Sarsik B, Nazan O, et al: Problems in Diagnosis of NonAA Renal Amyloidosis. Turkish Journal of Pathology 2010;26(1):14-24 4. Schonland SO, Hegenbart U, Bochtler T, et al: Immunohistochemistry in the Classification of Systemic Forms of Amyloidosis: A Systematic Investigation of 117 patients. Blood. 2012;119(2):488-493

FABP

Amyloid Beta-Protein

91408

Reference Values: Adult Reference Range(s): 20-80 pg/ml This test was developed and its performance characteristics determined by Inter Science Institute. It has not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.

60805

Amyloid P (SAP), Immunostain Without Interpretation Clinical Information: Amyloid P (SAP) is a serum protein that is generally incorporated into the extracellular deposits of all amyloid types. Immunohistochemical staining for SAP produces diffuse, extracellular staining in positive tissues and colocalizes with Congo Red applegreen birefringence. All



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types of amyloid should be positive for SAP. Immunohistochemical classification of amyloid has been largely replaced by subtyping using tandem mass spectrometry analysis on formalin-fixed paraffin-embedded specimens, due to its superior sensitivity and specificity.

Useful For: Identification of amyloid deposits in tissue Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Jang B, Koh Y, Seo JW: Immunohistochemical classification of amyloid deposits in surgical pathology. Basic and Applied Pathology 2009;2:1-8 2. Schonland SO, Hegenbart U, Bochtler T, et al: Immunohistochemistry in the classification of systemic forms of amyloidosis: a systematic investigation of 117 patients. Blood 2012;119(2):488-493 3. Stewart CR, Haw A 3rd, Lopez R, et al: Serum amyloid P colocalizes with apolipoproteins in human atheroma: functional implications. J Lipid Res 2007;48:2162-2171

APPI 70357

Amyloid Precursor Protein (APP) Immunostain, Technical Component Only Clinical Information: Amyloid precursor protein (APP) is present in Alzheimer disease-associated plaques, large pyramidal cells as well as smaller neurons, astrocytes, and microglia. Histologic features of Alzheimer disease include the presence of abundant neurofibrillary, tangles, neuropil threads, and neuritic ("senile") plaques. The main component of senile plaque amyloid is a 39- to 42-amino acid segment referred to as beta amyloid, which is derived from APP.

Useful For: Aids in the identification of amyloid precursor protein present in Alzheimer disease Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order PATHC / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ahlgren S, Li GL, Olsson Y: Accumulation of beta-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material. Acta Neuropathol 1996;92(1):49-55 2. Craggs LJ, Yamamoto Y, Ihara M, et al: White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neuropathol Appl Neurobiol 2014;40:591-602 3. Dermaut B, Kumar-Singh S, De Jonghe C, et al: Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation. Brain 2001;124:2383-2392 4. Reichard RR, White CL 3rd, Hogan RN, et al: Beta-amyloid precursor protein immunohistochemistry in the evaluation of pediatric traumatic optic nerve injury. Ophthalmology 2004;111(4):822-827 5. Sawaguchi T, Franco P, Kadhim H, et al: Investigation into the correlation in SIDS victims between Alzheimer precursor protein A4 in the brainstem and sleep apnea. 2004;10:161-166

60806

Amyloid Precursor Protein (APP), Immunostain Without Interpretation Clinical Information: Amyloid precursor protein (APP) is present in Alzheimer disease-associated plaques, large pyramidal cells as well as smaller neurons, astrocytes, and microglia. Histologic features of Alzheimer disease include the presence of abundant neurofibrillary, tangles, neuropil threads, and neuritic (â€œsenile") plaques. The main component of senile plaque amyloid is a 39 to 42 amino acid segment



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referred to as beta amyloid, which is derived from APP.

Useful For: An aid in the identification of amyloid precursor protein present in Alzheimer disease Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ahlgren S, Li GL, Olsson Y: Accumulation of beta-amyloid precursor protein and ubiquitin in axons after spinal cord trauma in humans: immunohistochemical observations on autopsy material. Acta Neuropathol 1996;92(1):49-55 2. Craggs LJ, Yamamoto Y, Ihara M, et al: White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Neuropathol Appl Neurobiol 2014;40:591-602 3. Dermaut B, Kumar-Singh S, De Jonghe C, et al: Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimerâ€™s disease due to a novel presenilin 1 mutation. Brain 2001;124:2383-2392 4. Reichard RR, White CL 3rd, Hogan RN, et al: Beta-amyloid precursor protein immunohistochemistry in the evaluation of pediatric traumatic optic nerve injury. Ophthalmology 2004;111(4):822-827 5. Sawaguchi T, Franco P, Kadhim H, et al: Investigation into the correlation in SIDS victims between Alzheimer precursor protein A4 in the brainstem and sleep apnea. 2004;10:161-166

82091

Amyloid Protein Identification, Paraffin, LC-MS/MS Clinical Information: Amyloidosis is a group of hereditary and acquired diseases that are unified by extracellular tissue deposition of misfolded proteins resulting in end organ damage. Amyloidosis can be a systemic or localized disease. Although many cases of amyloidosis are hereditary, most are acquired as the result of an underlying monoclonal B-cell/plasma cell malignancy, as a phenomenon of aging, or as the result of long-standing chronic inflammation. Specific amyloid-related diseases are therefore associated with specific amyloid proteins. These include kappa or lambda immunoglobulin light chains (AL amyloid), transthyretin (ATTR amyloid), serum amyloid A (SAA amyloid), and other uncommon subtypes. Because treatment of amyloidosis patients differs radically for the different amyloid subtypes, it is critically important to accurately identify the proteins that constitute the amyloid deposits. The basic diagnosis of amyloidosis is typically achieved by Congo red staining of paraffin-embedded tissue biopsy specimens obtained from diverse anatomic sites and demonstrating Congo red-positive, apple-green birefringent, amyloid deposits in the tissues. The next step is to definitively subtype the amyloid deposits. This test fulfills that need. It relies on laser microdissection of Congo red-positive amyloid deposits followed by analysis by liquid chromatography-tandem mass spectrometry to accurately determine the identity of the proteins that constitute the amyloid.

Useful For: Definitive identification of amyloid proteins Interpretation: An interpretation will be provided. Clinical References: 1. Theis JD, Dasari S, Vrana JA, et al: Shotgun-proteomics-based clinical testing for diagnosis and classification of amyloidosis. J Mass Spectrom 2013;48(10):1067-1077 2. Said SM, Sethi S, Valeri AM, et al: Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases. Clin J Am Soc Nephrol 2013 Sep;8(9):1515-1523 3. Dogan A: Chapter 21: Classification of amyloidosis by mass spectrometry-based proteomics. In Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations. Edited by MM Picken, A Dogan, GA Herrera. First edition. New York, Springer Science, 2012, pp 261-272 4. Klein CJ, Vrana JA, Theis JD, et al: Amyloid neuropathy type is distinguished by mass spectrometric based proteomic analysis of nerve tissue. Arch Neurol 2011:68(2):195-199 5. Vrana JA, Gamez JD, Madden BJ, et al: Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood 2009;114(24):4957-4959



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TTRX

Amyloidosis, Transthyretin-Associated Familial, Reflex, Blood

83674

Clinical Information: The systemic amyloidoses are a group of diseases that result from the abnormal deposition of amyloid in various tissues of the body. They have been classified into 3 major types: primary, secondary, and hereditary. The most common form of amyloidosis (AL) is a disease of the bone marrow called primary systemic AL (immunoglobulin light chain). Secondary AL usually occurs in tandem with chronic infectious or inflammatory diseases, such as rheumatoid arthritis, tuberculosis, or osteomyelitis. Familial or hereditary AL is the least common form. Determining the specific type of AL is imperative in order to provide both an accurate prognosis and appropriate therapies. Familial or hereditary transthyretin AL is an autosomal dominant disorder caused by mutations in the transthyretin gene (TTR). The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic transthyretin (TTR) protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Affected individuals may present with a variety of symptoms including sensorimotor and autonomic neuropathy, vitreous opacities, cardiomyopathy, nephropathy, and gastrointestinal dysfunction. TTR-associated AL is progressive over a course of 5 to 15 years and usually ends in death from cardiac or renal failure or malnutrition. Orthotopic liver transplantation is a treatment option for some patients who are diagnosed in early stages of the disease. Mayo Medical Laboratories recommends a testing strategy that includes both protein analysis by mass spectrometry (MS) and TTR gene analysis by DNA sequencing (ATTRZ / TTR Gene, Full Gene Analysis) for patients in whom TTR-associated familial AL is suspected. The structure of TTR protein in plasma is first determined by MS. The presence of a pathogenic variant in the TTR gene leads to conformational changes in the TTR protein. This ultimately disrupts the stability of the mature TTR protein tetramer, leading to increased amounts of pro-amyloidogenic TTR monomers in the plasma of affected individuals. MS is able to identify mass difference between wild type TTR and variant TTR protein. Only the transthyretin (also known as prealbumin) is analyzed for amino acid substitutions. Other proteins involved in other less common forms of familial amyloidosis are not examined. If no alterations are detected, gene analysis will not be performed unless requested by the provider (ie, when the diagnosis is still strongly suspected; to rule out the possibility of a false-negative by MS). In all cases demonstrating a structural change by MS, the entire TTR gene will be analyzed by DNA sequence analysis to identify and characterize the observed alteration (gene mutation or benign polymorphism). More than 90 mutations that cause TTR-associated familial AL have now been identified within the TTR gene. Most of the mutations described to date are single base pair changes that result in an amino acid substitution. Some of these mutations correlate with the clinical presentation of AL. For predictive testing in cases where a familial mutation is known, testing for the specific mutation by DNA sequence analysis (FMTT / Familial Mutation, Targeted Testing) is recommended. These assays do not detect mutations associated with non-TTR forms of familial AL. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific mutation in the family before testing at risk individuals.

Useful For: Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis

Interpretation: The presence of a structural change in transthyretin (TTR) is suggestive of a gene mutation that requires confirmation by DNA sequence analysis. A negative result by mass spectrometry does not rule out a TTR mutation. Mass spectrometric (MS) results are falsely negative if the amino acid substitution does not produce a measurable mass shift for the mutation transthyretin. Approximately 90% of the TTR mutations are positive by MS (see Cautions). After identification of the mutation at the DNA level, predictive testing for at-risk family members can be performed by molecular analysis (FMTT / Familial Mutation, Targeted Testing).


Clinical References: 1. Shimizu A, Nakanishi T, Kishikawa M, et al: Detection and identification of protein variants and adducts in blood and tissues: an application of soft ionization mass spectrometry to clinical diagnosis. J Chromatogr B Analyt Technol Biomed Life Sci 2002 Aug 25;776(1):15-30 2. Lim A, Prokaeva T, McComb ME, et al: Characterization of transthyretin variants in familial transthyretin amyloidosis by mass spectrometric peptide mapping and DNA sequence analysis. Anal Chem 2002 Feb 15;74(4):741-751 3. Sekjima Y, Yoshida K, Tokuda T, Ikeda S: Familial Transthyretin Amyloidosis In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: Retrieved February 6, 2017.Available Current as of August 23, 2017 7:11 am CDT


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at https://www.ncbi.nlm.nih.gov/books/NBK1194/ 4. Theberge R, Connors LH, Skinner M, Costello CE: Detection of transthyretin variants using immunoprecipitation and matrixassisted laser desorption/ionization bioreactive probes: a clinical application of mass spectrometry. J Am Soc Mass Spectrom. 2000,11:172-175

ANAID

Anaerobe Ident (Bill Only)

45010

Reference Values: This test is for Billing Purposes Only. This is not an orderable test.

ISAN

Anaerobe Identification by Sequencing (Bill Only)

45255

Reference Values: This test is for billing purposes only. This is not an orderable test.

BATTA

Anaerobe Suscep Battery (Bill Only)

80931

Reference Values: This test is for Billing Purposes Only. This is not an orderable test.

ANAP 81157

Anaplasma phagocytophilum (Human Granulocytic Ehrlichiosis) Antibody, Serum Clinical Information: Human granulocyte ehrlichiosis (HGE) is a zoonotic infection caused by a rickettsia-like agent. The infection is acquired by contact with Ixodes ticks carrying the HGE agent. The deer mouse is the animal reservoir and, overall, the epidemiology is very much like that of Lyme disease and babesiosis. HGE is most prevalent in the upper Midwest and in other areas of the United States that are endemic for Lyme disease. Since its first description in 1994, there have been approximately 50 cases of HGE described in the upper Midwest. The cellular target in HGE cases is the neutrophil. The organisms exist in membrane-lined vacuoles within the cytoplasm of infected host cells. Ehrlichial inclusions, called morulae, contain variable numbers of organisms. Single organisms, wrapped in vacuolar membranes have also been observed in the cytoplasm. Ehrlichia species occur in small electron-dense and large electron-lucent forms, but a clear life cycle has not been elucidated. Diagnosis of human ehrlichiosis has been difficult because the patient's clinical course is often mild and nonspecific, including fever, myalgias, arthralgias, and nausea. This is easily confused with other illnesses such as influenza or other tickborne zoonoses such as Lyme disease, babesiosis, and Rocky Mountain spotted fever. Clues to the diagnosis of ehrlichiosis in a patient with an acute febrile illness after tick exposure include laboratory findings of leukopenia or thrombocytopenia and elevated serum aminotransferase levels. However, these findings may also be present in patients with Lyme disease or babesiosis.

Useful For: As an adjunct in the diagnosis of human granulocytic ehrlichiosis Interpretation: A positive result of an immunoflourescence assay (IFA) test (titer > or =1:64) suggests current or previous infection with human granulocytic ehrlichiosis. In general, the higher the titer, the more likely it is that the patient has an active infection. Seroconversion may also be demonstrated by a significant increase in IFA titers. During the acute phase of the infection, serologic tests are often nonreactive, PCR testing is available to aid in the diagnosis of these cases (see EHRL / Ehrlichia/Anaplasma, Molecular Detection, PCR, Blood).

Reference Values: or =100 Strongly positive Reference values apply to all ages.

Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and Current as of August 23, 2017 7:11 am CDT


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Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB Saunders Company, New York, 2007, Part VI, pp 961-971

60808

Androgen Receptor (AR), Immunostain Without Interpretation Clinical Information: Androgen receptor binds testosterone and 5 alpha-dihydrotestosterone and mediates the biologic action of these sex hormones. It is normally expressed in a wide variety of tissues, including the epithelium and stromal cells of the prostate, endometrium, ovary and breast. Cells of meningiomas and the pituitary gland may also be positive.

Useful For: Identification of tumors that express androgen receptor Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Chen C, Yuan JP, Wei W, et al: Subtype classification for prediction of prognosis of breast cancer from a biomarker panel: correlations and indications. Int J Nanomedicine 2014;9:1039-1048 2. Hobisch A, Culig Z, Radmayr C, et al: Androgen receptor status of lymph node metastases from prostate cancer. Prostate 1996;28:129-135 3. Park S, Koo J, Park HS, et al: Expression of androgen receptors in primary breast cancer. Ann Oncol 2010;21:488-492

FANGL

Androstanediol Glucuronide

75001

Reference Values: Age

Range

Prepubertal Children

Not Established

Adult Males

112 â€“ 1046 ng/dL

Adult Females

11 â€“ 249 ng/dL Occasionally, normal females with no evidence of hirsutism may have levels well beyond the normal range.

ANST

Androstenedione, Serum

9709

Clinical Information: Androstenedione is secreted predominately by the adrenal gland and production is at least partly controlled by adrenocorticotropic hormone (ACTH). It is also produced ACTH-independent in the testes and ovaries from adrenal-secreted dehydroepiandrosterone sulfate (DHEA-S). Androstenedione is a crucial sex-steroid precursor. It lies at the convergence of the 2 biosynthetic pathways that lead from the progestins to the sex-steroids, being derived either via: -C3-dehydrogenation of dehydroepiandrosterone (DHEA) -Catalyzed by 3-beta-hydroxysteroid dehydrogenase-2 (adrenals and gonads) -17,20-lyase (CYP17A1)-mediated side-chain cleavage of 17-alpha-hydroxyprogesterone (OHPG) Androstenedione production during life mimics the pattern of other androgen precursors. Fetal serum concentrations increase throughout embryonal development and peak near birth at approximately young adult levels. Levels then fall rapidly during the first year of life to low prepubertal values. With the onset of adrenarche, androstenedione rises gradually, a process that accelerates with the onset of puberty, reaching adult levels around age 18. Adrenarche is a poorly understood phenomenon peculiar to higher primates that is characterized by a gradual rise in adrenal androgen production. It precedes puberty, but is not causally linked to it. Early adrenarche is not associated with early puberty, or with any reduction in final height, or overt androgenization, and is generally regarded as a benign condition not requiring intervention. However, girls with early adrenarche



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may be at increased risk of polycystic ovarian syndrome as adults, and some boys may develop early penile enlargement. Elevated androstenedione levels can cause symptoms or signs of hyperandrogenism in women. Men are usually asymptomatic, but through peripheral conversion of androgens to estrogens can occasionally experience mild symptoms of estrogen excess, such as gynecomastia. Most mild-to-moderate elevations in androstenedione are idiopathic. However, pronounced elevations of androstenedione may be indicative of androgen-producing adrenal or gonadal tumors. In children, adrenal and gonadal tumors are uncommon, but many forms of congenital adrenal hyperplasia can increase serum androstenedione concentrations. Diagnosis always requires measurement of other androgen precursors (eg, OHPG, 17-alpha-hydroxypregnenolone, and DHEA-S) and cortisol, in addition to androstenedione. See Steroid Pathways in Special Instructions.

Useful For: Diagnosis and differential diagnosis of hyperandrogenism (in conjunction with measurements of other sex-steroids). An initial workup in adults might also include total and bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) measurements. Depending on results, this may be supplemented with measurements of sex hormone-binding globulin (SHBG / Sex Hormone Binding Globulin [SHBG], Serum) and other androgenic steroids (eg, dehydroepiandrosterone sulfate [DHEA-S]). Diagnosis of congenital adrenal hyperplasia (CAH), in conjunction with measurement of other androgenic precursors, particularly, 17-alpha-hydroxyprogesterone (OHPG) (OHPG / 17-Hydroxyprogesterone, Serum), 17 alpha-hydroxypregnenolone, DHEA-S (DHES / Dehydroepiandrosterone Sulfate [DHEA-S], Serum), and cortisol (CORT / Cortisol, Serum). Monitoring CAH treatment, in conjunction with testosterone (TTST / Testosterone, Total, Serum), OHPG (OHPG / 17-Hydroxyprogesterone, Serum), DHEA-S (DHES / Dehydroepiandrosterone Sulfate [DHEA-S], Serum), and DHEA (DHEA_ / Dehydroepiandrosterone [DHEA], Serum). Diagnosis of premature adrenarche, in conjunction with gonadotropins (FSH / Follicle-Stimulating Hormone [FSH], Serum; LH / Luteinizing Hormone [LH], Serum) and other adrenal and gonadal sex-steroids and their precursors (TTBS / Testosterone, Total and Bioavailable, Serum or TGRP / Testosterone, Total and Free, Serum; EEST / Estradiol, Serum; DHES / Dehydroepiandrosterone Sulfate [DHEA-S], Serum; DHEA_ / Dehydroepiandrosterone [DHEA], Serum; SHBG / Sex Hormone Binding Globulin [SHBG], Serum; OHPG / 17-Hydroxyprogesterone, Serum).

Interpretation: Elevated androstenedione levels indicate increased adrenal or gonadal androgen production. Mild elevations in adults are usually idiopathic, or related to conditions such as polycystic ovarian syndrome (PCOS) in women, or use of androstenedione supplements in men and women. However, levels greater than or equal to 500 ng/dL can suggest the presence of an androgen-secreting adrenal, or less commonly, a gonadal, tumor. Androstenedione levels are elevated in more than 90% of patients with benign androgen-producing adrenal tumors, usually well above 500 ng/dL. Most androgen-secreting adrenal carcinomas also exhibit elevated androstenedione levels, but more typically show relatively larger elevations in 17-alpha-hydroxyprogesterone (OHPG) and dehydroepiandrosterone sulfate (DHEA-S) than in androstenedione, as they have often lost the ability to produce downstream androgens. Most androgen-secreting gonadal tumors also overproduce androstenedione, but often to lesser degrees than adrenal tumors. They also overproduce testosterone. In men and in women with high baseline androgen levels (eg, PCOS), the respective elevations of androstenedione and testosterone may not be high enough to allow unequivocal diagnosis of androgen-producing gonadal tumors. In these cases, an elevation of the usual ratio of testosterone to androstenedione of 1, to a ratio of >1.5, is a strong indicator of neoplastic androgen production. Diagnosis and differential diagnosis of congenital adrenal hyperplasia (CAH) always requires the measurement of several steroids. Patients with CAH due to 21-hydroxylase gene (CYP21A2) mutations the most common cause of CAH (>90% of cases), usually have very high levels of androstenedione, often 5- to 10-fold elevations. OHPG levels are usually even higher, while cortisol levels are low or undetectable. All 3 analytes should be tested. In the much less common CYP11A1 mutation, androstenedione levels are elevated to a similar extend as in CYP21A2 mutation, and cortisol is also low, but OHPG is only mildly, if at all, elevated. Also less common, 3 beta HSD-2 deficiency is characterized by low cortisol and substantial elevations in DHEA-S and 17alpha-hydroxypregnenolone, while androstenedione is either low, normal, or, rarely, very mildly elevated (as a consequence of peripheral tissue androstenedione production by 3 beta HSD-1). In the very rare STAR (steroidogenic acute regulatory protein) deficiency, all steroid hormone levels are low and cholesterol is elevated. In the also very rare 17-alpha-hydroxylase deficiency, androstenedione, all other androgen-precursors (17-alpha-hydroxypregnenolone, OHPG, DHEA-S), androgens (testosterone, estrone, estradiol), and cortisol are low, while production of mineral corticoid and their precursors, in Current as of August 23, 2017 7:11 am CDT


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particular progesterone, 11-deoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, are increased. The goal of CAH treatment is normalization of cortisol levels and, ideally, also of sex-steroid levels. Traditionally, OHPG and urinary pregnanetriol or total ketosteroid excretion are measured to guide treatment, but these tests correlate only modestly with androgen levels. Therefore, androstenedione and testosterone should also be measured and used for treatment modifications. Normal prepubertal levels may be difficult to achieve, but if testosterone levels are within the reference range, androstenedione levels up to 100 ng/dL are usually regarded as acceptable. Girls below the age of 7 to 8 and boys before age 8 to 9 who present with early development of pubic hair or, in boys, penile enlargement, may be suffering from either premature adrenarche or premature puberty, or both. Measurement of DHEA-S, DHEA, and androstenedione, alongside determination of sensitive estradiol, total and bioavailable or free testosterone, sex hormone binding globulin (SHBG), and luteinizing hormone/follicle-stimulating hormone levels will allow correct diagnosis in most cases. In premature adrenarche, only the adrenal androgens, chiefly DHEA-S, and to a lesser degree, androstenedione, will be above prepubertal levels, whereas early puberty will also show a fall in SHBG levels and variable elevations of gonadotropins and gonadal sex-steroids above the prepuberty reference range. See Steroid Pathways in Special Instructions.

Reference Values: Tanner Stages

Age (Years) Reference Range (ng/dL)

Stage I (prepubertal) Stage II

9.8-14.5

31-65

Stage III

10.7-15.4

50-100

Stage IV

11.8-16.2

48-140

Stage V

12.8-17.3

65-210 Females*

Tanner Stages

Age (Years)

Reference Range (ng/dL)

Stage II

9.2-13.7

42-100

Stage III

10.0-14.4

80-190

Stage IV

10.7-15.6

77-225

Stage V

11.8-18.6

80-240 *Source: Androstenedione. In Pediatric Reference Ranges. Fourth edition. Edited by SJ Soldin, C Brugnara, EC Wong. Washington, DC, AACC Press, 2003, pp 32-34 ADULTS Males: 40-150 ng/dL Females: 30-200 ng/dL

Stage I (prepubertal)

Clinical References: 1. Von Schnakenburg K, Bidlingmaier F, Knorr D: 17-hydroxyprogesterone, androstenedione, and testosterone in normal children and in prepubertal patients with congenital adrenal hyperplasia. Eur J Pediatr 1980;133:259-267 2. Sciarra F, Tosti-Croce C, Toscano V: Androgen-secreting adrenal tumors. Minerva Endocrinol 1995;20:63-68 3. Young WF Jr: Management approaches to adrenal incidentalomas-a view from Rochester, Minnesota. Endocrinol Metab Clin North Am 2000;29:159-185 4. Ibanez L, DiMartino-Nardi J, Potau N, Saenger P: Premature adrenarche-normal variant or forerunner of adult disease? Endocr Rev 2000;21:671-696 5. Collett-Solberg P: Congenital adrenal hyperplasia: from genetics and biochemistry to clinical practice, part I. Clin Pediatr 2001;40:1-16 6. Allolio B, Arlt W: DHEA treatment: myth or reality? Trends Endocrinol Metab 2002;13:288-294

MASF

Angiosarcoma, MYC (8q24) Amplification, FISH, Tissue

35859

Clinical Information: Postradiation cutaneous angiosarcoma is a malignancy associated with very poor outcome and is consequently treated aggressively. Conversely, atypical vascular lesions are also associated with radiation therapy, but are considered to be benign and do not require aggressive management. Therefore, the differentiation of these neoplasms is of considerable clinical importance.



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Postradiation cutaneous angiosarcomas are characterized by high-level amplification of MYC, whereas reactive and benign vascular lesions do not show amplification of MYC. Similar diagnostic difficulties arise in the setting of primary cutaneous vascular lesions. A subset of primary cutaneous angiosarcomas also shows high-level MYC amplification, which can be useful in the differentiation from benign primary cutaneous vascular lesions.

Useful For: Identifying MYC amplification to aid in the differentiation of cutaneous angiosarcomas from atypical vascular lesions after radiotherapy An aid in the diagnosis of primary cutaneous angiosarcoma

Interpretation: The MYC locus is reported as amplified when the MYC:D8Z2 ratio of 2.0 or greater and demonstrates 6 or more copies of the MYC locus. A lesion with a MYC:D8Z2 ratio or =18 years: 8-53 U/L The reference interval for pediatric patients may be up to 50% higher than that of adults. Current as of August 23, 2017 7:11 am CDT


Page 156

Clinical References: 1. Liebermann J: Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med 1975;59:365-372 2. Rodriguez GE, Shin BC, Abernathy RS, Kendig EL Jr: Serum angiotensin-converting enzyme activity in normal children and in those with sarcoidosis. J Pediatr 1981;99:68-72 3. Personal observations from a Mayo pediatric normal range study using a manual method (Hana) 4. Maguire GA, Price CP: A continuous monitoring spectrophotometric method for the measurement of angiotensin-converting enzyme in human serum. Ann Clin Biochem 1985;22:204-210

FANGI

Angiotensin I, Plasma

90429

Clinical Information: Angiotensin I is a ten amino acid peptide formed by Renin cleavage of Angiotensinogen (Renin Substrate). Angiotensin I has little biological activity except that high levels can stimulate Catecholamine production. It is metabolized to its biologically active byproduct Angiotensin II by Angiotensin Converting Enzyme (ACE). The formation of Angiotensin I is controlled by negative feedback of Angiotensin II and II on Renin release and by Aldosterone concentration. Levels of Angiotensin I are increased in many types of hypertension. Angiotensin I levels are used to determine Renin activity. Angiotensin I is excreted directly into the urine.

Reference Values: Up to 25 pg/mL This test was performed using a kit that has not been cleared or approved by the FDA and is designated as research use only. The analytic performance characteristics of this test have been determined by Inter Science Institute. This test is not intended for diagnosis or patient management decisions without confirmation by other medically established means.

FANG

Angiotensin II, Plasma

90428

Clinical Information: Angiotensin II is a eight amino acid peptide formed by Angiotensin Converting Enzyme (ACE) cleavage of Angiotensin I. Angiotensin II is metabolized further to Angiotensin III. Angiotensin II release is controlled by Renin, blood pressure, blood volume, sodium balance and by Aldosterone concentration. Levels of Angiotensin II are increased in many types of hypertension. Angiotensin II stimulates the release of Anti-Diuretic Hormone, ACTH, Prolactin, Luteinizing Hormone, Oxytocin and Aldosterone. Angiotensin II increases vasoconstriction and inhibits tubular resorption of sodium, and can increase endothelial cell growth.

Reference Values: 10 - 60 pg/mL This test was performed using a kit that has not been cleared or approved by the FDA and is designated as research use only. The analytic performance characteristics of this test have been determined by Inter Science Institute. This test is not intended for diagnosis or patient management decisions without confirmation by other medically established means.

ANISP

Anisakis, Parasite, IgE

82857

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergens that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease, the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat



Page 157

proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).


Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



ANSE

Anise, IgE

82487



Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L. Current as of August 23, 2017 7:11 am CDT


Page 158


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FANSE

Annatto Seed (Bixa orellana) IgE

57520

Interpretation: Class IgE (kU/L) Comment 0 99.99 Very Strong Positive

Reference Values: Cys; E4: Cys112->Arg). The allele frequencies for most Caucasian populations are as follows: -e2=8% to 12% -e3=74% to 78% -e4=14% to 15% E2 and E4 are both associated with higher plasma triglyceride concentrations. Over 90% of individuals with type III hyperlipoproteinemia are homozygous for the e2 allele. However, or =100 Strongly positive Reference values apply to all ages.


ARBOP

Arbovirus Antibody Panel, IgG and IgM, Serum

83267

Clinical Information: California (LaCrosse) Virus: California (LaCrosse) virus is a member of bunyaviridae and is 1 of the arthropod-borne encephalitides. It is transmitted by various Aedes and Culex mosquitoes and is found in such intermediate hosts as the rabbit, squirrel, chipmunk, and field mouse. California meningoencephalitis is usually mild and occurs in late summer. Ninety percent of infections are seen in children less than 15 years of age, usually from rural areas. The incubation period is estimated to be 7 days and acute illness lasts 10 days or less in most instances. Typically, the first symptoms are nonspecific, last 1 to 3 days, and are followed by the appearance of central nervous system (CNS) signs and symptoms such as stiff neck, lethargy, and seizures, which usually abate within 1 week. Symptomatic infection is almost never recognized in those over 18 years old. The most important sequelae of California virus encephalitis is epilepsy, which occurs in about 10% of children; almost always in patients who have had seizures during the acute illness. A few patients (estimated 2%) have persistent paresis. Learning disabilities or other objective cognitive deficits have been reported in a small proportion (no more than 2%) of patients. Learning performance and behavior of most recovered patients are not distinguishable from comparison groups in these same areas. Eastern Equine Encephalitis (EEE): EEE is within the alphavirus group. It is a low prevalence cause of human disease in the eastern and Gulf Coast states. EEE is maintained by a cycle of mosquito/wild bird transmission, peaking in the summer and early fall, when man may become an adventitious host. The most common clinically apparent manifestation is a mild undifferentiated febrile illness, usually with headache. CNS involvement is demonstrated in only a minority of infected individuals, it is more abrupt and more severe than with other arboviruses, with children being more susceptible to severe disease. Fatality rates are approximately 70%. St. Louis Encephalitis (SLE): Areas of outbreaks of SLE since 1933 have involved the western United States, Texas, the Ohio-Mississippi Valley, and Florida. The vector of transmission is the mosquito. Peak



Page 188

incidence occurs in summer and early autumn. Disease onset is characterized by generalized malaise, fever, chills, headache, drowsiness, nausea, and sore throat or cough followed in 1 to 4 days by meningeal and neurologic signs. The severity of illness increases with advancing age; persons over 60 years have the highest frequency of encephalitis. Symptoms of irritability, sleeplessness, depression, memory loss, and headaches can last up to 3 years. Western Equine Encephalitis (WEE): The virus that causes WEE is widely distributed throughout the United States and Canada; disease occurs almost exclusively in the western states and Canadian provinces. The relative absence of the disease in the eastern United States probably reflects a paucity of the vector mosquito species, Culex tarsalis, and possibly a lower pathogenicity of local virus strains. The disease usually begins suddenly with malaise, fever, and headache, often with nausea and vomiting. Vertigo, photophobia, sore throat, respiratory symptoms, abdominal pain, and myalgia are also common. Over a few days, the headache intensifies; drowsiness and restlessness may merge into a coma in severe cases. In infants and children, the onset may be more abrupt than for adults. WEE should be suspected in any case of febrile CNS disease from an endemic area. Infants are highly susceptible to CNS disease and about 20% of cases are under 1 year of age. There is an excess of males with WEE clinical encephalitis, averaging about twice the number of infections detected in females. After recovery from the acute disease, patients may require from several months to 2 years to overcome the fatigue, headache, and irritability. Infants and children are at higher risk of permanent brain damage after recovery than adults. Infections with arboviruses can occur at any age. The age distribution depends on the degree of exposure to the particular transmitting arthropod relating to age, sex, and occupational, vocational, and recreational habits of the individuals. Once humans have been infected, the severity of the host response may be influenced by age. WEE tends to produce the most severe clinical infections in young persons and SLE in older persons. Serious California (LaCrosse) virus infections primarily involve children, especially boys. Adult males exposed to California viruses have high prevalence rates of antibody but usually show no serious illness. Infection among males is primarily due to working conditions and sports activities taking place where the vector is present.

Useful For: Aiding the diagnosis of arboviral (California [LaCrosse], St. Louis encephalitis, Eastern equine encephalitis, and Western equine encephalitis virus) encephalitis

Interpretation: In patients infected with these or related viruses, IgG antibody is generally detectable with in 1 to 3 weeks of onset, peaking within 1 to 2 months, and declining slowly thereafter. IgM class antibody is also reliably detected within 1 to 3 weeks of onset, peaking and rapidly declining within 3 months. A single serum specimen IgG > or =1:10 indicates exposure to the virus. Results from a single serum specimen can differentiate early (acute) infection from past infection with immunity if IgM is positive (suggests acute infection). A 4-fold or greater rise in IgG antibody titer in acute and convalescent sera indicate recent infection. In the United States, it is unusual for any patient to show positive reactions to more than 1 of the arboviral antigens, although Western equine encephalitis and Eastern equine encephalitis antigens will show a noticeable cross-reactivity.

Reference Values: CALIFORNIA VIRUS (La CROSSE) ENCEPHALITIS ANTIBODY IgG: 1.00 mcg/g dry weight indicates excessive exposure. It is normal for some arsenic to be present in nails, as everybody is exposed to trace amounts of arsenic from the normal diet. The highest hair or nail arsenic observed at Mayo Clinic was 210 mcg/g dry weight in a case of chronic exposure that was the cause of death.

Reference Values: 0-15 years: not established > or =16 years: 0.0-0.9 mcg/g of nails

Clinical References: Hindmarsh JT, McCurdy RF: Clinical and environmental aspects of arsenic toxicity. Crit Rev Clin Lab Sci 1986;23:315-347

ASRU

Arsenic, Random, Urine

89889

Clinical Information: Arsenic is perhaps the best known of the metal toxins, having gained notoriety from its extensive use by Renaissance nobility as an antisyphilitic agent and, paradoxically, as an antidote against acute arsenic poisoning. Even today, arsenic is still 1 of the more common toxicants found in insecticides, and leaching from bedrock to contaminate groundwater. The toxicity of arsenic is due to 3 different mechanisms, 2 of them related to energy transfer. Arsenic covalently and avidly binds to dihydrolipoic acid, a necessary cofactor for pyruvate dehydrogenase. Absence of the cofactor inhibits the conversion of pyruvate to acetyl coenzyme A, the first step in gluconeogenesis. This results in loss of energy supply to anaerobic cells, the predominant mechanism of action of arsenic on neural cells that rely on anaerobic respiration for energy. Neuron cell destruction that occurs after long-term energy loss results in bilateral peripheral neuropathy. Arsenic also competes with phosphate for binding to adenosine triphosphate during its synthesis by mitochondria via oxidative phosphorylation, causing formation of the lower energy adenosine diphosphate monoarsine. This results in loss of energy supply to aerobic cells. Cardiac cells are particularly sensitive to this form of energy loss; fatigue due to poor cardiac output is a common symptom of arsenic exposure. Arsenic furthermore binds avidly with any hydrated sulfhydryl group on protein, distorting the 3-dimensional configuration of that protein, causing it to lose activity. Interaction of arsenic with epithelial cell protein at the sites of highest physiologic concentration, the small intestine and proximal tubule of the kidney, results in cellular degeneration. Epithelial cell erosion in the gastrointestinal tract and proximal tubule are characteristic of arsenic toxicity. Arsenic is also a known carcinogen, but the mechanism of this effect is not definitively known. A wide range of signs and symptoms may be seen in acute arsenic poisoning including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension, fever, hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called arseniasis, are mostly insidious and nonspecific. The gastrointestinal tract, skin, and central nervous system are usually involved. Nausea, epigastric pain, colic abdominal pain, diarrhea, and paresthesias of the hands and feet can occur. Arsenic exists in a number of different forms; organic forms are nontoxic, inorganic forms are toxic. See ASFRU / Arsenic Fractionation, Random, Urine for details about arsenic forms. Because arsenic is excreted predominantly by glomerular filtration, analysis for arsenic in urine is the best screening test to detect arsenic exposure.

Useful For: Preferred screening test for detection of arsenic exposure Interpretation: Normally, humans consume 5 to 25 mcg of arsenic each day as part of their normal diet; therefore, normal urine arsenic output is 1,000 mcg/L indicates significant exposure. The highest level observed at Mayo Clinic was 450,000 mcg/L in a patient with severe symptoms of gastrointestinal distress, shallow breathing with classic "garlic breath," intermittent seizure activity, cardiac arrhythmias, and later onset of peripheral neuropathy.



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Reference Values: 0-35 mcg/L Reference values apply to all ages.

Clinical References: 1. Fillol CC, Dor F, Labat L, et al: Urinary arsenic concentrations and speciation in residents living in an area with naturally contaminated soils. Sci Total Environ 2010 Feb 1;408(5):1190-1194 2. Caldwell K, Jones R, Verdon C, et al: Levels of urinary total and speciated arsenic in the US population: National Health and Nutrition Examination Survey 2003-2004. J Expo Sci Environ Epidemiol 2009 Jan;19(1):59-68

ASCRU

Arsenic/Creatinine Ratio, Random, Urine

89890

Clinical Information: Arsenic is perhaps the best known of the metal toxins, having gained notoriety from its extensive use by Renaissance nobility as an antisyphilitic agent and, paradoxically, as an antidote against acute arsenic poisoning. Even today, arsenic is still one of the more common toxicants found in insecticides and leaching from bedrock to contaminate groundwater. The toxicity of arsenic is due to 3 different mechanisms, 2 of them related to energy transfer. Arsenic covalently and avidly binds to dihydrolipoic acid, a necessary cofactor for pyruvate dehydrogenase. Absence of the cofactor inhibits the conversion of pyruvate to acetyl coenzyme A, the first step in gluconeogenesis. This results in loss of energy supply to anaerobic cells, the predominant mechanism of action of arsenic on neural cells that rely on anaerobic respiration for energy. Neuron cell destruction that occurs after long-term energy loss results in bilateral peripheral neuropathy. Arsenic also competes with phosphate for binding to adenosine triphosphate during its synthesis by mitochondria via oxidative phosphorylation, causing formation of the lower energy adenosine diphosphate monoarsine. This results in loss of energy supply to aerobic cells. Cardiac cells are particularly sensitive to this form of energy loss; fatigue due to poor cardiac output is a common symptom of arsenic exposure. Arsenic furthermore binds avidly with any hydrated sulfhydryl group on protein, distorting the 3-dimensional configuration of that protein, causing it to lose activity. Interaction of arsenic with epithelial cell protein at the sites of highest physiologic concentration, the small intestine and proximal tubule of the kidney, results in cellular degeneration. Epithelial cell erosion in the gastrointestinal tract and proximal tubule are characteristic of arsenic toxicity. Arsenic is also a known carcinogen, but the mechanism of this effect is not definitively known. A wide range of signs and symptoms may be seen in acute arsenic poisoning including headache, nausea, vomiting, diarrhea, abdominal pain, hypotension, fever, hemolysis, seizures, and mental status changes. Symptoms of chronic poisoning, also called arseniasis, are mostly insidious and nonspecific. The gastrointestinal tract, skin, and central nervous system are usually involved. Nausea, epigastric pain, colic abdominal pain, diarrhea, and paresthesias of the hands and feet can occur. Arsenic exists in a number of different forms; organic forms are nontoxic, inorganic forms are toxic. See ASFRU / Arsenic Fractionation, Random, Urine for details about arsenic forms. Because arsenic is excreted predominantly by glomerular filtration, analysis for arsenic in urine is the best screening test to detect arsenic exposure.

Useful For: Preferred screening test for detection of arsenic exposure Interpretation: Normally, humans consume 5 to 25 mcg of arsenic each day as part of their normal diet; therefore, normal urine arsenic output is less than 35 mcg arsenic per gram creatinine ( or =62 nmol/h/mg Note: Results from this assay may not reflect carrier status because of individual variation of arylsulfatase A enzyme levels. Low normal values may be due to the presence of pseudodeficiency gene or carrier gene. Patients with these depressed levels may be phenotypically normal.

Clinical References: 1. Gieselmann V, Ingeborg KGieselmann V, e: Metachromatic Leukodystrophy. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill; 2014. Accessed March 14, 2017. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62644361 2. Fluharty AL: Arylsulfatase A Deficiency. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. Updated 2014 Feb 6. Available at www.ncbi.nlm.nih.gov/books/NBK1130/ 3. Mahmood A, Berry J, Wenger D, et al: Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol 2010;25(5):572-580 4. van Rappard DF, Boelens JJ, Wolf NI: Metachromatic leukodystrophy: Disease spectrum and approaches for treatment. Best Pract Res Clin Endocrinol Metab 2015 Mar;29(2):261-273 doi: 10.1016/j.beem.2014.10.001

ARSB

Arylsulfatase B, Fibroblasts

8151

Clinical Information: Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine 4-sulfatase, also known as arylsulfatase B (ARSB). The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of complex macromolecules called glycosaminoglycans (GAGs) including dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. Accumulation of GAGs (also called mucopolysaccharides) in lysosomes interferes with normal functioning of cells, tissues, and organs. Clinical features and severity of symptoms are widely variable, but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, hepatosplenomegaly, corneal clouding, and cardiac disease. Intelligence is usually normal. Rapidly progressing forms have an early onset of symptoms, significantly elevated GAGs, and can lead to death before the second or third decades. A more slowly progressing form has a later onset, milder skeletal manifestations, smaller elevations of GAGs, and typically a longer lifespan. Estimates of the incidence of MPS VI range from 1 in 250,000 to 1 in 300,000. Treatment options include hematopoietic stem cell transplantation and/or enzyme replacement therapy. A diagnostic workup in an individual with MPS VI typically demonstrates elevated levels of urinary GAGs and increased dermatan sulfate detected on thin-layer chromatography. Reduced or absent activity of ARSB in leukocytes and/or fibroblasts is suggestive of a diagnosis of MPS VI. Sequencing of the ARSB gene allows for detection of disease-causing mutations in affected patients and identification of familial mutations allows for testing of at-risk family members (MPS6Z / Mucopolysaccharidosis VI, Full Gene Analysis). Currently, no clear genotype-phenotype correlations have been established. ARSB activity is also reduced in 2 other rare autosomal recessive disorders, multiple sulfatase deficiency (MSD) and mucolipidosis II (I-cell disease). Both of these conditions present with developmental delays that make them clinically different from MPS VI. The symptoms of MSD mimic metachromatic leukodystrophy (MLD) as well as the



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mucopolysaccharidoses and can include developmental delay, neurologic regression, dysmorphic facies, dysostosis multiplex, organomegaly, ichthyosis, and chondroplasia punctata. If MSD is suspected, testing of an additional sulfatase enzyme, such as arylsulfatase A in MLD, can help determine if multiple sulfatases are deficient. I-cell disease is characterized by congenital or early infantile manifestations including coarse facial features, short stature, skeletal anomalies, cardio- and hepatomegaly, and developmental delays. This is a progressive disorder and death typically occurs in the first decade of life. Additional testing including hydrolase enzymes in serum, such as hexosaminidase A in Tay-Sach disease, is recommended if a diagnosis of I-cell is suspected.

Useful For: Diagnosis of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) Interpretation: Arylsulfatase B is deficient in mucopolysaccharidosis VI, multiple sulfatase deficiency, and mucolipidosis II.


Clinical References: 1. Valayannopoulos V, Nicely H, Harmatz P, Turbeville S: Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010 Apr 12;5:5 2. Neufeld EF, Muenzer J: Chapter 136: In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 04/07/2017. Available at www.ommbid.com 3. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. New York, McGraw-Hill Medical Division, 2009, pp 733-735 4. Wood T, Bodamer OA, Burin MG et al: Expert recommendations for the laboratory diagnosis of MPS VI. Mol Genet Metab 2012;106(1):73-82

ASCRI

Ascaris, IgE

82764





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive



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3

3.50-17.4 Positive

4


5


6



VITC

Ascorbic Acid (Vitamin C), Plasma

42362

Clinical Information: Vitamin C, also known as L-ascorbic acid or simply ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component. Vitamin C is required for the enzymatic amidation of neuropeptides, production of adrenal cortical steroid hormones, promotion of the conversion of tropocollagen to collagen, and metabolism of tyrosine and folate. It also plays a role in lipid and vitamin metabolism and is a powerful reducing agent or antioxidant. Specific actions include: activation of detoxifying enzymes in the liver, antioxidation, interception and destruction of free radicals, preservation and restoration of the antioxidant potential of vitamin E, and blockage of the formation of carcinogenic nitrosamines. In addition, vitamin C appears to function in a variety of other metabolic processes in which its role has not been well characterized. Prolonged deficiency of vitamin C leads to the development of scurvy, a disease characterized by an inability to form adequate intercellular substance in connective tissues. This results in the formation of swollen, ulcerative lesions in the gums, mouth, and other tissues that are structurally weakened. Early symptoms may include weakness, easy fatigue and listlessness, as well as shortness of breath, and aching joints, bones, and muscles. The need for vitamin C can be increased by the use of aspirin, oral contraceptives, tetracycline, and a variety of other medications. Psychological stress and advancing age also tend to increase the need for vitamin C. Among the elderly, lack of fresh fruit and vegetables often adds vitamin C depletion to the inherently increased need, with development of near-scurvy status

Useful For: Diagnosing vitamin C deficiency As an aid to deter excessive intake Interpretation: Values below 0.2 mg/dL indicate significant deficiency. Values greater than or equal to 0.2 mg/dL and less than 0.4 mg/dL are consistent with a moderate risk of deficiency due to inadequate tissue stores. Values of 0.4 to 2.0 mg/dL indicate adequate supply. The actual level at which vitamin C is excessive has not been defined. Values above 3.0 mg/dL are suggestive of excess intake. Whether vitamin C in excess is indeed toxic continues to be uncertain. However, limited observations suggest that this condition may induce uricosuria and, in individuals with glucose-6-phosphate dehydrogenase deficiency, may induce increased red blood cell fragility.

Reference Values: 0.4-2.0 mg/dL

Clinical References: 1. Anonymous: Vitamin C toxicity. Nutr Rev 1976;34:236-237 2. Moser U, Bendich A: Vitamin C. In Handbook of Vitamins. Second edition. Edited by LJ Machlin. New York, Marcel Dekker, 1991, pp 195-232 3. Ball GFM: Vitamins: Their Role in the Human Body. London, Blackwell Publishing LTD, 2004, pp 393-420 4. Zlatuse DC, Frank EL: Development and implementation of an HPLC-ECD method for analysis of vitamin C in plasma using single column and automatic alternating dual column regeneration. Prac Lab Med 2016 Dec 1;6:25-37

AJPO

Ashkenazi Jewish Mutation Analysis Panel Without Cystic



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Fibrosis (CF) Clinical Information: Certain genetic diseases are more common in individuals of Ashkenazi Jewish heritage (Jewish individuals of Eastern European ancestry) compared to the non-Jewish population. The majority of these conditions are inherited in an autosomal recessive manner. This group of diseases includes Gaucher, Tay-Sachs, familial dysautonomia, Canavan, mucolipidosis IV, Niemann-Pick Type A and B, FANCC-related Fanconi anemia, and Bloom syndrome. While these conditions are observed outside of the Ashkenazi Jewish population, they occur at a lower frequency. It is estimated that an individual of Ashkenazi Jewish ancestry has a 20% to 25% chance of being a carrier of 1 of these diseases. Gaucher Disease: Gaucher disease is a relatively rare lysosomal storage disorder resulting from a deficiency of acid beta-glucocerebrosidase. Mutations in the beta-glucocerebrosidase gene, GBA, cause the clinical manifestations of Gaucher disease. There are 3 major types of Gaucher disease: nonneuropathic (type 1), acute neuropathic (type 2), and subacute neuropathic (type 3). Type 1 accounts for over 95% of all cases of Gaucher disease and is the presentation commonly found among Ashkenazi Jewish patients. Type 1 disease does not involve nervous system dysfunction; patients display anemia, low blood platelet levels, massively enlarged livers and spleens, lung infiltration, and extensive skeletal disease. There is a broad spectrum of disease in type 1, with some patients exhibiting severe symptoms and others very mild disease. Types 2 and 3 are associated with neurological disease of variable onset and progression, though type 2 tends to be more severe. Eight common GBA mutations, including the N370S mutation most commonly found in the Ashkenazi Jewish population, are included in this test: delta55bp, V394L, N370S, IVS2+1G->A, 84G->GG, R496H, L444P, and D409H. Tay-Sachs: Tay-Sachs disease is caused by an absence of hexosaminidase (HexA) enzyme activity, which results in the accumulation of the sphingolipid GM2 ganglioside. Mutations in the HEXA gene cause the clinical manifestations of Tay-Sachs disease (TSD). The most common form of TSD becomes apparent in infancy when mild motor weakness is noted along with impaired visual acuity and the presence of a "startle response." Other manifestations of this condition include progressive neurodegeneration, seizures, and blindness, leading to total incapacitation and death. This panel tests for the 3 common mutations in the Ashkenazi Jewish population: 1278insTATC, G269S, and IVS12+1G->C. Also included in this assay are the mutations IVS9+1G->A and delta7.6kb mutations along with the R247W and R249W polymorphisms associated with pseudodeficiency. Familial Dysautonomia: Familial dysautonomia affects sensory, parasympathetic, and sympathetic neurons. Patients experience gastrointestinal dysfunction, pneumonia, vomiting episodes, altered sensitivity to pain and temperature, and cardiovascular problems. Progressive neuronal degeneration continues throughout the lifespan. Mutations in the IKBKAP gene cause the clinical manifestations of familial dysautonomia. Two mutations in the IKBKAP gene are common in the Ashkenazi Jewish population: IVS20(+6)T->C and R696P. Canavan Disease: Canavan disease is a severe leukodystrophy resulting from a deficiency of the enzyme aspartoacylase. Mutations in the ASPA gene cause the clinical manifestations of Canavan disease. The deficiency of aspartoacylase leads to spongy degeneration of the brain, and the disease is characterized by delayed development beginning at age 3 to 6 months, head lag, macrocephaly, and hypotonia. Death usually occurs in the first decade of life. Four ASPA mutations are included in this test: 433(-2)A->G, A305E, E285A, and Y231X. Mucolipidosis IV: Mucolipidosis IV is a lysosomal storage disease characterized by mental retardation, hypotonia, corneal clouding, and retinal degeneration. Mutations in the MCOLN1 gene are responsible for the clinical manifestations of mucolipidosis IV. Two mutations in the MCOLN1 gene account for the majority of mutations in the Ashkenazi Jewish population: IVS3(-2)A->G and delta6.4kb. Niemann-Pick Disease Types A and B: Niemann-Pick disease (types A and B) is a lysosomal storage disease caused by a deficiency of the enzyme acid sphingomyelinase. The clinical presentation of type A disease is characterized by jaundice, progressive loss of motor skills, feeding difficulties, learning disabilities, and hepatosplenomegaly. Death usually occurs by age 3. Type B disease is milder, though variable in its clinical presentation. Most individuals with type B do not have neurologic involvement and survive to adulthood. Mutations in the SMPD1 gene are known to cause Niemann-Pick disease types A and B. There are 3 common mutations causing Niemann-Pick type A in the Ashkenazi Jewish population: L302P, R496L, and fsP330. The deltaR608 mutation accounts for approximately 90% of the type B mutant alleles in individuals from the Maghreb region of North Africa and 100% of the mutation alleles in Gran Canaria Island. Fanconi Anemia: Fanconi anemia is an aplastic anemia that leads to bone marrow failure and myelodysplasia or acute myelogenous leukemia. Physical findings include short stature; upper limb, lower limb, and skeletal malformations; and abnormalities of the eyes and genitourinary tract. Mutations in several genes have been associated with Fanconi anemia, although 1 mutation, IVS4(+4)A->T, in the FANCC gene is common in the Ashkenazi Jewish population. A second mutation, 322delG, is over Current as of August 23, 2017 7:11 am CDT


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represented in FANCC patients of Northern European ancestry. Bloom Syndrome: Bloom syndrome is characterized by short stature, sun sensitivity, susceptibility to infections, and a predisposition to cancer. Mutations in the BLM gene lead to genetic instability (increased chromosomal breakage and sister chromatid exchange) and cause the clinical manifestations of Bloom syndrome. The protein encoded by the BLM gene is a helicase involved in maintaining DNA integrity. There is a common mutation in the Ashkenazi Jewish population: 2281delATCTGAinsTAGATTC (2281del6/ins7). Because of the high sensitivity of carrier testing in the Ashkenazi Jewish population, the American College of Medical Genetics and Genomics (ACMG) recommends that carrier screening for cystic fibrosis (CF), Canavan, Tay-Sachs, familial dysautonomia, Niemann-Pick type A, Fanconi anemia (FANCC), Bloom syndrome, mucolipidosis IV, and Gaucher disease be offered to individuals of Ashkenazi Jewish ancestry. The mutation detection rates and carrier frequencies for the diseases included in this panel are listed below. Of note, testing for CF is not included in this panel. If testing for this disorder is desired, please see details and ordering information under CFP / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel. Disease Carrier Rate in the AJ Population Mutation Detection Rate Gaucher 1/18 95% Tay-Sachs 1/31 *99% Familial dysautonomia 1/31 99% Canavan 1/41 98% Mucolipidosis IV 1/127 95% Niemann-Pick type A/B 1/90 97% FANCC-related Fanconi anemia 1/89 >99% Bloom syndrome 1/107 >99% *with biochemical testing The Ashkenazi Jewish panel is useful for identifying carriers of these 8 conditions in an at-risk population. Because the diseases included in the panel are inherited in an autosomal recessive manner, the presence of a family history is not a prerequisite for testing consideration. The identification of disease-causing mutations allows for carrier testing of at-risk family members and prenatal diagnosis for pregnancies in which both parents are known carriers. Refer to Carrier Testing for Tay-Sachs Disease and Other GM2 Gangliosidosis Variants: Supplementing Traditional Biochemical Testing with Molecular Methods, Mayo Medical Laboratories Communique 2004 Jul;29(7) for more information regarding diagnostic strategy. Of note, approximately 1 in 25 individuals of Ashkenazi Jewish ancestry are also carriers of cystic fibrosis (CF). Therefore, the American College of Medical Genetics also recommends that carrier screening for CF be offered to individuals of Ashkenazi Jewish ancestry who are pregnant or considering pregnancy. Carrier screening for CF is available by ordering CFP / Cystic Fibrosis Mutation Analysis, 106-Mutation Panel.

Useful For: Carrier screening in individuals of Ashkenazi Jewish ancestry for Bloom syndrome, Canavan disease, FANCC-related Fanconi anemia, familial dysautonomia, Gaucher disease, mucolipidosis IV, Niemann-Pick disease types A and B, and Tay-Sachs disease


Clinical References: Gross SJ, Pletcher BA, Monaghan KG: Carrier screening individuals of Ashkenazi Jewish descent. Genet Med 2008:10(1):54-56

ASPAR

Asparagus, IgE

82478


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm Current as of August 23, 2017 7:11 am CDT


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sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



AST

Aspartate Aminotransferase (AST) (GOT), Serum

8360

Clinical Information: Aspartate aminotransferase (AST) is found in high concentrations in liver, heart, skeletal muscle, and kidney. AST is present in both cytoplasm and mitochondria of cells. In cases involving mild tissue injury, the predominant form of AST is that from the cytoplasm. Severe tissue damage results in more of the mitochondrial enzyme being released. High levels of AST can be found in cases such as myocardial infarction, acute liver cell damage, viral hepatitis, and carbon tetrachloride poisoning. Slight to moderate elevation of AST is seen in muscular dystrophy, dermatomyositis, acute pancreatitis, and crushed muscle injuries.

Useful For: Diagnosing and monitoring liver disease, particularly diseases resulting in a destruction of hepatocytes

Interpretation: Elevated aspartate aminotransferase (AST) values are seen in parenchymal liver diseases characterized by a destruction of hepatocytes. Values are typically at least 10 times above the normal range. Levels may reach values as high as 100 times the upper reference limit, although 20- to 50-fold elevations are most frequently encountered. In infectious hepatitis and other inflammatory conditions affecting the liver, alanine aminotransferase (ALT) is characteristically as high as or higher than AST, and the ALT:AST ratio, which normally and in other condition is less than 1, becomes greater than unity. AST levels are usually elevated before clinical signs and symptoms of disease appear. Five- to 10-fold elevations of both AST and ALT occur in patients with primary or metastatic carcinoma of the liver, with AST usually being higher than ALT, but levels are often normal in the early stages of malignant infiltration of the liver. Elevations of ALT activity persist longer than do those of AST activity. Elevated AST values may also be seen in disorders affecting the heart, skeletal muscle, and kidney.

Reference Values: Males 0-11 months: not established 1-13 years: 8-60 U/L > or =14 years: 8-48 U/L Females Current as of August 23, 2017 7:11 am CDT


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0-11 months: not established 1-13 years: 8-50 U/L > or =14 years: 8-43 U/L

Clinical References: Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1994

FASPE

Aspen (Populus tremuloides) IgE

57947


Reference Values: or =46% normal COMPLEMENT, TOTAL > or =16 years: 30-75 U/mL Reference values have not been established for patients who are or =100 Strongly positive Reference values apply to all ages.


APIN

Australian Pine, IgE

82803





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





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DYS1

Autoimmune Dysautonomia Evaluation, Serum

37428

Clinical Information: Autoimmune dysautonomia encompasses disorders of peripheral autonomic synapses, ganglionic neurons, autonomic nerve fibers, and central autonomic pathways mediated by neural-specific IgG or effector T cells. These disorders may be idiopathic or paraneoplastic, subacute or insidious in onset, and may present as a limited disorder or generalized pandysautonomia. Pandysautonomia is usually subacute in onset and severe, and includes impaired pupillary light reflex, anhidrosis, orthostatic hypotension, cardiac arrhythmias, gastrointestinal dysmotility, sicca manifestations, and bladder dysfunction. Limited dysautonomia is confined to 1 or just a few domains, is often mild and may include sicca manifestations, postural orthostatism and cardiac arrhythmias, bladder dysfunction, or gastrointestinal dysmotilities. Diagnosis of limited dysautonomia requires documentation of objective abnormalities by autonomic reflex testing, thermoregulatory sweat test, or gastrointestinal motility studies. The most commonly encountered autoantibody marker of autoimmune dysautonomia is the neuronal ganglionic alpha-3-(acetylcholine receptor: AChR) autoantibody. This autoantibody to date is the only proven effector of autoimmune dysautonomia. A direct relationship has been demonstrated between antibody titer and severity of dysautonomia in both alpha-3-AChR-immunized animals and patients with autoimmune dysautonomia. Patients with high alpha-3-AChR autoantibody values (>1.0 nmol/L) generally have profound pandysautonomia. Dysautonomic patients with lower alpha-3-AChR autoantibody values (0.03-0.99 nmol/L) have limited dysautonomia. Importantly, cancer is detected in 30% of patients with alpha-3-AChR autoantibody. Cancers recognized most commonly include small-cell lung carcinomas, thymoma, adenocarcinomas of breast, lung, prostate, and gastrointestinal tract, and lymphoma. Cancer risk factors include a past or family history of cancer, history of smoking, or social or environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favors neurologic improvement and lessens morbidity. Autoantibodies to other onconeural proteins shared by neurons, glia or muscle (eg, antineuronal nuclear antibody-type 1: ANNA-1, CRMP-5-IgG, N-type voltage-gated calcium channel, muscle AChR, and sarcomeric [striational antigens]) serve as additional markers of paraneoplastic or idiopathic dysautonomia. A specific neoplasm is often predictable by the individual patient's autoantibody profile.

Useful For: Investigating idiopathic dysautonomic symptoms Directing a focused search for cancer in patients with idiopathic dysautonomia Investigating autonomic symptoms that appear in the course or wake of cancer therapy and are not explainable by recurrent cancer or metastasis (detection of autoantibodies in this profile helps differentiate autoimmune dysautonomia from the effects of chemotherapy)

Interpretation: Antibodies directed at onconeural proteins shared by neurons, muscle, and glia are valuable serological markers of a patient's immune response to cancer. These autoantibodies are not found in healthy subjects, and are usually accompanied by subacute neurological symptoms and signs. It is not uncommon for more than 1 autoantibody to be detected in patients with autoimmune dysautonomia. These include: -Plasma membrane cation channel antibodies (neuronal ganglionic [alpha-3] and muscle [alpha-1] acetylcholine receptor; neuronal calcium channel N-type or P/Q-type, and neuronal voltage-gated potassium channel antibodies). All of these autoantibodies are potential effectors of autonomic dysfunction. -Antineuronal nuclear autoantibody-type 1 -Neuronal and muscle cytoplasmic antibodies (CRMP-5 IgG, glutamic acid decarboxylase and striational) A rising autoantibody titer in previously seropositive patients suggests cancer recurrence.

Reference Values: CATION CHANNEL ANTIBODIES N-Type Calcium Channel Antibody < or =0.03 nmol/L P/Q-Type Calcium Channel Antibody < or =0.02 nmol/L AChR Ganglionic Neuronal Antibody < or =0.02 nmol/L Neuronal VGKC Autoantibody < or =0.02 nmol/L Glutamic Acid Decarboxylase (GAD65) Antibody < or =0.02 nmol/L Current as of August 23, 2017 7:11 am CDT


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NEURONAL NUCLEAR ANTIBODIES Antineuronal Nuclear Antibody-Type 1 (ANNA-1) or =100 Strongly positive Reference values apply to all ages.


BYST

Baker's Yeast, IgE

82759






Page 242

Class IgE kU/L Interpretation 0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



BCYP

Bald Cypress, IgE

82722





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




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BAMB

Bamboo Shoot, IgE

82879





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FBANG

Banana IgG

57635

Interpretation: mcg/mL of IgG Lower Limit of Quantitation 2.0 Upper Limit of Quantitation 200 Reference Values: or =100 Strongly positive Reference values apply to all ages.


64984

BAP1, Immunostain Without Interpretation Clinical Information: BRCA1-asssociated protein 1 (BAP1) is a deubiquitinating enzyme that is a member of the polycomb group proteins of transcriptional repressors and exhibits tumor suppressive activity. BAP1 is located on chromosome 3p21 where loss of one copy of the gene and inactivating



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mutations are associated with the increased risk and development of various tumors such as malignant mesotheliomas, uveal melanomas, clear cell renal cell carcinoma, and esophageal squamous carcinomas. In some of these cases, loss of nuclear staining for BAP1 has been reported.

Useful For: As part of a panel of immunostains where loss of staining can be used as a marker of various neoplasms

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Carbone M, Ferris LK, Baumann F, et al: BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITS. J Transl Med 2012;10:179-185 2. Koopmans AE, Verdijk RM, Brouwer RWW, et al: Clinical significance of immunohistochemistry for detection of BAP1 mutations in uveal melanoma. Mod Path 2014;27:1321-1330 3. Joseph RW, Kapur P, Serie DJ, et al: Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 Expression. Jl of Urology 2015;195:1-8 4. Klebe S, Driml J, Nasu M, et al: BAP1 hereditary cancer predisposition syndrome: a case report and review of literature. Biomark Res 2015;3:14-20 5. Mori T, Sumii M, Fujishima F, et al: Somatic alteration and depleted nuclear expression of BAP1 in human esophageal squamous cell carcinoma. Cancer Sci 2015;106:1118-1129 6. Churg A, Sheffield BS, Galateau-Salle F: New markers for Separating Benign from Malignant Mesothelials: Are we there yet? Arch Pathol Lab Med 2016;140(4):318-321

BARBX

Barbiturates Confirmation, Chain of Custody, Urine

62713

Clinical Information: Barbiturates represent a class of drugs that were originally introduced as sleep inducers. Butalbital is also used to control severe headaches. Mephobarbital and phenobarbital are frequently used to control major motor (grand mal) seizures. These drugs are commonly abused as "downers" to induce sleep after an amphetamine- or cocaine-induced "high." Chain-of-custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detecting drug abuse involving barbiturates such as amobarbital, butalbital, pentobarbital, phenobarbital, and secobarbital Chain-of-custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: The presence of a barbiturate in urine at >200 ng/mL indicates use of 1 of these drugs. Most of the barbiturates are fast acting; their presence indicates use within the past 3 days. Phenobarbital, commonly used to control epilepsy, has a very long half-life. The presence of phenobarbital in urine indicates that the patient has used the drug sometime within the past 30 days.

Reference Values: Negative Cutoff concentrations: IMMUNOASSAY SCREEN 99.5% of BCR-ABL1 events. Therefore, it is recommended that for diagnosis, RT-PCR plus a second method (eg, BCR-ABL1 FISH or cytogenetics) should be used. However, this RT-PCR assay is invaluable at



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diagnosis for identifying the precise BCR-ABL1 mRNA type (eg, for future quantitative assay disease monitoring), which complementary methods cannot. This assay is intended as a qualitative method, providing information on the presence (and specific mRNA type) or absence of the BCR-ABL1 mRNA. Results from this test can be used to determine the correct subsequent assay for monitoring of transcript levels following therapy (eg, BCRAB, BA190). Because the assay is analytically sensitive, it compensates for situations such as partially degraded RNA quality, or low cell number but it is not intended for quantitative or monitoring purposes.

Useful For: Diagnostic workup of patients with high probability of BCR-ABL1-positive hematopoietic neoplasms, predominantly chronic myelogenous leukemia and acute lymphoblastic leukemia When positive, the test identifies which specific mRNA fusion variant is present to guide selection of an appropriate monitoring assay. If a quantitative monitoring assay is not available for a rare fusion variant, this assay may be of some value for monitoring.

Interpretation: An interpretive report will be provided. Reference Values: A qualitative result is provided that indicates the presence or absence of BCR/ABL mRNA. When positive, the fusion variant is also reported.

Clinical References: 1. Burmeister T, Reinhardt R: A multiplex PCR for improved detection of typical and atypical BCR-ABL fusion transcripts. Leuk Res 2008 Apr;32(4):579-585 2. Melo JV: The diversity of BCR-ABL fusion proteins and their relationship to leukemia phenotype. Blood 1996;88(7):2375-2384 3. Melo JV: BCR-ABL gene variants. Baillieres Clin Haematol 1997;10(2):203-222

BAKDM 89609

BCR/ABL1, Tyrosine Kinase Inhibitor Resistance, Kinase Domain Mutation Screen, Sanger Sequencing Clinical Information: Chronic myelogenous leukemia (CML) is characterized by the presence of the t(9:22) BCR-ABL1 abnormality, resulting in formation of a fusion BCR-ABL1 mRNA and protein. The ABL1 component of this oncoprotein contains tyrosine kinase activity and is thought to play a central role in the proliferative phenotype of this leukemia. Recent advances have resulted in a number of therapeutic drugs that inhibit the ABL1 tyrosine kinase, as well as other protein tyrosine kinases. Imatinib mesylate (Gleevec, Novartis) is the prototype of these tyrosine kinase inhibitors (TKIs), which are capable of inducing durable hematologic and (in most patients) cytogenetic remissions. Unfortunately, a significant subset of patients can develop functional resistance to TKIs, due in a large number of cases (approximately 50%) to the acquisition of point mutations in the kinase domain (KD) of the chimeric ABL1 gene. To date, over 50 distinct mutations have been described, although a smaller subset of these ( or =5.0 nmol/hour/mL) are not consistent with beta-galactosidase deficiency.

Reference Values: > or =5.0 nmol/hour/mL An interpretive report will be provided.

Clinical References: 1. Suzuki Y, Nanba E, Matsuda J, et al: Beta-Galactosidase Deficiency (Beta-Galactosidosis): GM1 Gangliosidosis and Morquio B Disease. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL BeaudetL, B Vogelstein, KW Kinzler et al. New York, McGraw-Hill; 2014. Accessed January 27, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62645114 2. Chamoles NA, Blanco M, Gaggioli D, Casentini C: Hurler-like phenotype: enzymatic diagnosis in dried blood spots on filter paper. Clin Chem 2001;47:2098-2102 3. Regier DS, Tifft CJ: GLB1-Related Disorders. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger et al. Accessed January 30, 2017. Available at www.ncbi.nlm.nih.gov/books/NBK164500/ 4. Fernandes, Saudubray, van den Berghe, Walter. Inborn Metabolic Diseases: Diagnosis and Treatment. Fourth edition. Edited by J Fernandes, J-M Saudubray, G van den Berghe, JH Walter. Springer Science. 2006

BGAT

Beta-Galactosidase, Fibroblasts

8008

Clinical Information: Beta-galactosidase is a lysosomal enzyme responsible for catalyzing the hydrolysis of beta-galactosides. A deficiency of this enzyme is implicated in the following conditions: GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis. Enzymatic testing is not reliable for carrier testing of these conditions. GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by reduced or absent beta-galactosidase activity. Absent or reduced activity leads to the accumulation of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified into 3 subtypes that vary with regard to age of onset and clinical presentation. Type 1, or infantile onset, typically presents between birth and 6 months with a very rapid progression of hypotonia, dysostosis multiplex, hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to 2 years. Type 2 is generally classified as late infantile or juvenile with onset between 7 months and 3 years and presenting with developmental delays or regression and a slower clinical course. Type 3 is an adult or chronic variant with onset between 3 and 30 years and is typically characterized by slowly progressive dementia with Parkinsonian features and dystonia. The incidence has been estimated to be 1 in 100,000 to 200,000 live births. Morquio B (MPS IVB) is an autosomal recessive mucopolysaccharidosis caused by reduced or absent beta-galactosidase activity resulting in the accumulation of keratan sulfate in the lysosomes. The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAG). Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs. MPS IVB typically manifests as a systemic skeletal disorder with variable severity ranging from early severe disease to a later onset attenuated form. Virtually all patients have dysostosis multiplex and short stature along with other symptoms that may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no neurological involvement. Galactosialidosis is an autosomal recessive lysosomal storage disease (LSD) associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a defect in the cathepsin A protein. Clinical features are those typically associated with LSDs including coarse facial features, cherry-red spots, and skeletal dysplasia. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. The early infantile form is associated with fetal hydrops, visceromegaly, skeletal and ophthalmologic disorders, and early death. The late infantile form typically presents with short stature, dysostosis multiplex, coarse facial features, hepatosplenomegaly, and heart valve problems. The juvenile/adult form is characterized by progressive neurologic degeneration, ataxia, cognitive disability, and angiokeratomas. Most of the juvenile/adult form cases have been found in individuals with Japanese ancestry. Patients with mucolipidosis II/III (I-cell disease) may also



Page 285

demonstrate deficiency of beta-galactosidase in leukocytes, in addition to deficiency of other hydrolases. I-cell disease is an autosomal recessive lysosomal storage disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay. Measurement of beta-galactosidase activity is not the preferred diagnostic test for I-cell disease but may be included in the testing strategy. A diagnostic workup in an individual with GM1 gangliosidosis, Morquio B, or galactosialidosis typically demonstrates decreased beta-galactosidase enzyme activity in leukocytes and/or fibroblasts, however, individuals with galactosialidosis would also have decreased neuraminidase activity in leukocytes and/or fibroblasts. Enzymatic testing is not reliable to detect carriers. Molecular sequence analysis of GLB1 allows for detection of the disease-causing mutations in affected patients with GM1 gangliosidosis or Morquio B, and sequencing of CTSA allows for detection of disease-causing mutations in patients with galactosialidosis.

Useful For: Diagnosis of GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis Interpretation: Beta-galactosidase is deficient in GM1 gangliosidosis and Morquio syndrome B. Clinical findings must be used to differentiate between those 2 diseases. The deficiency of beta-galactosidase combined with neuraminidase deficiency (see NEURF / Neuraminidase, Fibroblasts) is characteristic of galactosialidosis.


Clinical References: 1. Suzuki Y, Nanba E, Matsuda J, et al: BetaSuzuki Y, Nanba E, Matsuda J, Higaki K, Oshima A Suzuki, Yoshiyuki, et al.-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In The Online Metabolic and Molecular Bases of Inherited Disease. 2014. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, Accessed January 27, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62645114 2. d'Azzo A, Andria G, Bonten E, Annunziata I: Galactosialidosis. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein B, et al: New York, McGraw-Hill, 2014. Accessed May 04, 2015. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62645512 3. Brunetti-Pierri N, Scaglia F: GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab 2008 Aug;94(4):391-396 4. Caciotti A, Garman SC, Rivera-Colon Y, et al: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 2011 Jul;1812(7):782-790

BGA

Beta-Galactosidase, Leukocytes

8486

Clinical Information: Beta-galactosidase is a lysosomal enzyme responsible for catalyzing the hydrolysis of gangliosides. The deficiency of this enzyme can lead to 1 of the following conditions: GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis. Enzymatic testing is not reliable for carrier detection of these conditions. GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by reduced or absent beta-galactosidase activity. Absent or reduced activity leads to the accumulation of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified into 3 subtypes that vary with regard to age of onset and clinical presentation. Type 1, or infantile onset, typically presents between birth and 6 months with a very rapid progression of hypotonia, dysostosis multiplex, hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to 2 years. Type 2 is generally classified as late infantile or juvenile with onset between 7 months and 3 years and presenting with developmental delays or regression and a slower clinical course. Type 3 is an adult or chronic variant with onset between 3 and 30 years and is typically characterized by slowly progressive dementia with Parkinsonian features and dystonia. The incidence has been estimated to be 1 in 100,000 to 200,000 live births. Morquio B (MPS IVB) is an autosomal recessive mucopolysaccharidosis caused by reduced or absent beta-galactosidase activity resulting in the accumulation of keratan sulfate in the lysosomes. The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or



Page 286

chondroitin sulfate (glycosaminoglycans: GAG). Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs. MPS IVB typically manifests as a systemic skeletal disorder with variable severity ranging from early severe disease to a later onset attenuated form. Virtually all patients have dysostosis multiplex and short stature along with other symptoms that may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no neurological involvement. Galactosialidosis is an autosomal recessive lysosomal storage disease (LSD) associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a defect in the cathepsin A protein. Clinical features are those typically associated with LSDs including coarse facial features, cherry-red spots, or skeletal dysplasia. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. The early infantile form is associated with fetal hydrops, visceromegaly, skeletal and ophthalmologic disorders, and early death. The late infantile form typically presents with short stature, dysostosis multiplex, coarse facial features, hepatosplenomegaly, and/or heart valve problems. The juvenile/adult form is characterized by progressive neurologic degeneration, ataxia, cognitive disability, and/or angiokeratomas. Most of the juvenile/adult form cases have been found in individuals with Japanese ancestry. Patients with mucolipidosis II/III (I-cell disease) may also demonstrate deficiency of beta-galactosidase in leukocytes, in addition to deficiency of other hydrolases. I-cell disease is an autosomal recessive lysosomal storage disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay. Measurement of beta-galactosidase activity is not the preferred diagnostic test for I-cell disease, but may be included in the testing strategy. A diagnostic workup in an individual with GM1 gangliosidosis, Morquio B, or galactosialidosis typically demonstrates decreased beta-galactosidase enzyme activity in leukocytes and/or fibroblasts; however, additional testing and consideration of the patient's clinical findings are necessary to differentiate between these conditions. Individuals with GM1 gangliosidosis can have characteristic abnormalities on urine oligosaccharides and have elevated keratan sulfate in urine (however, to a lesser degree than seen in patients with Morquio B). Individuals with Morquio B can have increased keratan sulfate in urine. Molecular sequence analysis of the GLB1 gene allows for detection of the disease-causing mutations in affected patients with GM1 gangliosidosis and Morquio B. Individuals with galactosialidosis also demonstrate abnormalities on urine oligosaccharides as well as decreased neuraminidase activity in fibroblasts. Enzymatic testing is not reliable to detect carriers. Sequencing of the CTSA gene allows for detection of disease-causing mutations in patients with galactosialidosis.

Useful For: Diagnosis of GM1 gangliosidosis, Morquio B disease, and galactosialidosis Interpretation: Very-low enzyme activity levels are consistent with GM1 gangliosidosis and Morquio B disease. Clinical findings must be used to differentiate between those 2 diseases. The deficiency of beta-galactosidase combined with neuraminidase deficiency (see NEURF / Neuraminidase, Fibroblasts) is characteristic of galactosialidosis.

Reference Values: > or =1.56 nmol/min/mg

Clinical References: 1. Suzuki Y, Nanba E, Matsuda J: Galactosidase Deficiency (Beta-Galactosidosis): GM1 Gangliosidosis and Morquio B Disease. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill; 2014. Accessed January 27, 2017. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62645114 2. d'Azzo A, Andria G, Bonten E, Annunziata I: Chapter 152: Galactosialidosis. In The Metabolic Basis of Inherited Disease. 2014. Edited by D Valle, AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 01/16/2015. Available at www.ommbid.com 3. Brunetti-Pierri N, Scaglia F: GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab 2008 Aug;94(4):391-396 4. Caciotti A, Garman SC, Rivera-Colon Y, et al: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 2011 Jul;1812(7):782-790

BGLT

Beta-Glucosidase, Fibroblasts

8787

Clinical Information: Gaucher disease is an autosomal recessive lysosomal storage disorder caused



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by reduced or absent acid beta-glucosidase (glucocerebrosidase) enzyme activity. Absent or reduced activity of this enzyme results in the accumulation of undigested materials (primarily in the lysosomes) and interferes with the normal functioning of cells. Clinical features and severity of symptoms are widely variable within Gaucher disease, but in general, the disorder is characterized by bone disease, hepatosplenomegaly, and may have central nervous system (CNS) involvement. There are 3 clinical subtypes of the disorder that vary with respect to age of onset and clinical presentation. Type 1 is the most common type, representing 95% of all cases, and is generally characterized by bone disease, hepatosplenomegaly, anemia and thrombocytopenia, coagulation abnormalities, lung disease, and no CNS involvement. Type 2 typically has a very severe progression with onset prior to 2 years, with neurologic disease, hepatosplenomegaly, and lung disease, with death usually between 2 and 4 years due to lung failure. Individuals with type 3 may have onset prior to 2 years of age, but the progression is not as severe and they may survive into the third and fourth decade. In addition, there is a perinatal lethal form associated with skin abnormalities and nonimmune hydrops fetalis, and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild splenomegaly, and corneal opacities. Treatment is available in the form of enzyme replacement therapy and/or substrate reduction therapy for types 1 and 3. Individuals with type 3 may benefit from bone marrow transplantation. Currently, only supportive therapy is available for type 2. The incidence of type 1 ranges from 1 in 20,000 to 1 in 200,000 in the general population, but is much more frequent among Ashkenazi Jews with an incidence ranging from 1 in 400 to 1 in 900. Types 2 and 3 both have an incidence of approximately 1 in 100,000 in the general population. A diagnostic work up for Gaucher disease may demonstrate the characteristic finding of "Gaucher cells" on bone marrow examination. Reduced or absent enzyme activity of acid beta-glucosidase is diagnostic. A targeted mutation panel may allow for detection of disease-causing mutations in affected patients (GAUP / Gaucher Disease, Mutation Analysis, GBA). In addition, full sequencing of GBA (GBAZ / Gaucher Disease, Full Gene Analysis) allows for detection of disease-causing mutations in affected patients for whom a targeted mutation panel identifies a single or no mutation.

Useful For: Diagnosis of Gaucher disease Interpretation: Marked deficiency of acid beta-glucosidase is consistent with a diagnosis of Gaucher disease.


Clinical References: 1. Martins AM, Valadares ER, Porta G, et al: Recommendations on diagnosis, treatment, and monitoring for Gaucher disease. J Pediatr 2009 Oct;155(4 Suppl):S10-S18 2. Grabowski GA, Petsko GA, Kolodny EH: Gaucher Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, 2014. Accessed April 7, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62643884 3. Pastores GM, Hughes DA: Gaucher disease. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 2007.1993-2015. Accessed 4/07/2017. Available at www.ncbi.nlm.nih.gov/books/NBK1269/ 4. Weinreb NJ, Andersson HC, Banikazemi M, et al: Prevalence of type 1 Gaucher disease in the United States. Arch Intern Med 2008 Feb 11;168(3):326-327

BGL

Beta-Glucosidase, Leukocytes

8788

Clinical Information: Gaucher disease is an autosomal recessive lysosomal storage disorder caused by reduced or absent acid beta-glucosidase (glucocerebrosidase) enzyme activity. Absent or reduced activity of this enzyme results in accumulation of glucocerebroside in the lysosomes and interferes with the normal functioning of cells. Clinical features and severity of symptoms are widely variable within Gaucher disease, but in general, the disorder is characterized by abnormal blood parameters such as decreased red blood cells (anemia) and/or platelets (thrombocytopenia), bone disease, and hepatosplenomegaly. Individuals with more severe types of Gaucher disease may have central nervous system (CNS) involvement. There are 3 clinical subtypes of the disorder that vary with respect to age of onset and clinical presentation. Type 1 is the most common type, representing 95% of all cases, and is generally characterized by bone disease, hepatosplenomegaly, anemia and thrombocytopenia, coagulation abnormalities, lung disease, and no CNS involvement. Type 2 typically has a very severe progression with onset in the first 2 years of life including neurologic disease, hepatosplenomegaly, and lung disease, with



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death usually between 2 and 4 years due to lung failure. Individuals with type 3 may have onset prior to 2 years of age, but the progression is not as severe and they may survive into the third and fourth decade. Finally, there is a perinatal lethal form associated with skin abnormalities and nonimmune hydrops fetalis, and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild splenomegaly, and corneal opacities. Treatment is available in the form of enzyme replacement therapy, substrate reduction therapy, and/or chaperone therapy for types 1 and 3. Individuals with type 3 may benefit from bone marrow transplantation. Currently, only supportive therapy is available for type 2. The incidence of type 1 ranges from 1 in 20,000 to 200,000 in the general population, but is much more frequent among Ashkenazi Jews with an incidence between 1 in 400 and 900. Types 2 and 3 both have an incidence of approximately 1 in 100,000 in the general population. A diagnostic workup for Gaucher disease may demonstrate the characteristic finding of "Gaucher cells" on bone marrow examination. Significantly reduced or absent enzyme activity of acid beta-glucosidase is diagnostic. Additionally, the biomarker, glucopsychosine is elevated in symptomatic patients and supports a diagnosis of Gaucher disease (GPSY / Glucopsychosine, Blood Spot). A targeted mutation panel may allow for detection of disease-causing mutations in affected patients (GAUP / Gaucher Disease, Mutation Analysis, GBA). In addition, full sequencing of the GBA gene allows for detection of disease-causing mutations in affected patients in whom a targeted mutation panel identifies no mutations or only a single mutation (GBAZ / Gaucher Disease, Full Gene Analysis).

Useful For: Diagnosis of Gaucher disease Interpretation: Individuals affected with Gaucher disease will have enzyme levels less than 8.7 nmol/h/mg protein. In our experience some carriers will also have less than 8.7 nmol/h/mg protein activity.

Reference Values: > or =8.7 nmol/h/mg protein Note: Results from this assay do not reflect carrier status because of individual variation of beta-glucosidase enzyme levels. For carrier testing, order molecular test GAUP / Gaucher Disease, Mutation Analysis, GBA.

Clinical References: 1. Martins AM, Valadares ER, Porta G, et al: Recommendations on diagnosis, treatment, and monitoring for Gaucher disease. J Pediatr 2009 Oct;155(4 Suppl):S10-S18 2. Grabowski GA, Petsko GA, Kolodny EH: Chapter 146: Gaucher Disease. In Scriver's The Online Metabolic and Molecular Basis of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Medical Division. Accessed 3/17/2015. Available at www.ommbid.com 3. Pastores GM, Hughes DA: Gaucher disease. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington. Accessed 3/17/2015. Available at www.ncbi.nlm.nih.gov/books/NBK1269/ 4. Weinreb NJ, Andersson HC, Banikazemi M, et al: Prevalence of type 1 Gaucher disease in the United States. Arch Intern Med 2008;168:326-328

BHCG

Beta-Human Chorionic Gonadotropin, Quantitative, Serum

61718

Clinical Information: Human chorionic gonadotropin (hCG) is a glycoprotein hormone (molecular weight [MW] approximately 36,000 Dalton [Da]) consisting of 2 noncovalently bound subunits. The alpha subunit (92-amino acids; "naked" protein MW 10,205 Da) is essentially identical to that of luteinizing hormone (LH), follicle-stimulating hormone, and thyroid-stimulating hormone (TSH). The alpha subunit is essential for receptor transactivation. The different beta subunits of the above hormones are transcribed from separate genes, show less homology, and convey the receptor-specificity of the dimeric hormones. The chorionic gonadotropin, beta gene (coding for a 145-amino acid, "naked" protein MW 15,531 Da, glycosylated subunit MW approximately 22,500 Da) is highly homologous to the beta subunit of LH and acts through the same receptor. However, while LH is a classical tropic pituitary hormone, hCG does not usually circulate in significant concentrations. In pregnant primates (including humans) it is synthesized in the placenta and maintains the corpus luteum and, hence, progesterone production, during the first trimester. Thereafter, the placenta produces steroid hormones, diminishing the role of hCG. hCG concentrations fall, leveling off around week 20, significantly above prepregnancy levels. After delivery, miscarriage, or pregnancy termination, hCG falls with a half-life of 24 to 36 hours, until prepregnancy levels are reached. Outside of pregnancy, hCG may be secreted by abnormal germ



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cell, placental, or embryonal tissues, in particular seminomatous and nonseminomatous testicular tumors; ovarian germ cell tumors; gestational trophoblastic disease (GTD: hydatidiform mole and choriocarcinoma); and benign or malignant nontesticular teratomas. Rarely, other tumors including hepatic, neuroendocrine, breast, ovarian, pancreatic, cervical, and gastric cancers may secrete hCG, usually in relatively modest quantities. During pathological hCG production, the highly coordinated secretion of alpha and beta subunits of hCG may be disturbed. In addition to secreting intact hCG, tumors may produce disproportionate quantities of free alpha-subunits or, more commonly, free beta-subunits. Assays that detect both intact hCG and free beta-hCG, including this assay, tend to be more sensitive in detecting hCG-producing tumors. With successful treatment of hCG-producing tumors, hCG levels should fall with a half-life of 24 to 36 hours, and eventually return to the reference range.

Useful For: Monitoring patients for retained products of conception An aid in the diagnosis of gestational trophoblastic disease (GTD), testicular tumors, ovarian germ cell tumors, teratomas, and, rarely, other human chorionic gonadotropin (hCG)-secreting tumors Serial measurement of hCG following treatment to: -Monitor therapeutic response in GTD or in hCG-secreting tumors -Detect persistent or recurrent GTD or hCG-secreting tumors

Interpretation: After delivery, miscarriage, or pregnancy termination, human chorionic gonadotropin (hCG) falls with a half-life of 24 to 36 hours, until prepregnancy levels are reached. An absent or significantly slower decline is seen in patients with retained products of conception. Gestational trophoblastic disease (GTD) is associated with very considerable elevations of hCG, usually above 2 multiples of the medians for gestational age persisting or even rising beyond the first trimester. Serum hCG levels are elevated in approximately 40% to 50% of patients with nonseminomatous testicular cancer and 20% to 40% of patients with seminoma. Markedly elevated levels of hCG (>5,000 IU/L) are uncommon in patients with pure seminoma and indicate the presence of a mixed testicular cancer. Ovarian germ cell tumors (approximately 10% of ovarian tumors) display elevated hCG levels in 20% to 50% of cases. Teratomas in children may overproduce hCG, even when benign, resulting in precocious pseudopuberty. Levels may be elevated to similar levels as seen in testicular cancer. Among nonreproductive tumors, hepatobiliary tumors (hepatoblastomas, hepatocellular carcinomas, and cholangiocarcinomas) and neuroendocrine tumors (eg, islet cell tumors and carcinoids) are those most commonly associated with hCG production. Many hCG-producing tumors also produce other embryonic proteins or antigens, in particular alpha fetoprotein (AFP). AFP should, therefore, also be measured in the diagnostic workup of such neoplasms. Complete therapeutic response in hCG-secreting tumors is characterized by a decline in hCG levels with an apparent half-life of 24 to 36 hours and eventual return to concentrations within the reference range. GTD and some tumors may produce hyperglycoslated hCG with a longer half-life, but an apparent half-life of >3 days suggests the presence of residual hCG-producing tumor tissue. A rise in hCG levels above the reference range in patients with hCG-producing tumors that had previously been treated successfully, suggests possible local or distant metastatic recurrence.

Reference Values: Children(1,2) Males Birth-3 months: < or =50 IU/L* >3 months-0.5, pleural/serum lactate dehydrogenase ratio >0.6, and serum lactate dehydrogenase >200 U/L).

Useful For: May aid in the distinction between a transudative and an exudative body fluid, when used in conjunction with other testing including serum bilirubin analysis, body fluid; serum protein ratio, body fluids; serum lactate dehydrogenase ratio, and serum lactate dehydrogenase Current as of August 23, 2017 7:11 am CDT


Page 300

Interpretation: Elevated body fluid bilirubin is suggestive of an exudative fluid. This testing should be performed in conjunction with other testing including serum bilirubin analysis, body fluid:serum protein ratio, body fluids:serum lactate dehydrogenase ratio, and serum lactate dehydrogenase.

Reference Values: Not applicable The reference range has not been established for bilirubin in body fluids. The test result should be integrated into the clinical context for interpretation.

Clinical References: 1. Elis A, Meisel S, Tishler T, et al: Ascitic fluid to serum bilirubin concentration ratio for the classification of transudates or exudates. Am J Gastroenterol 1998 Mar;93(3):401-403 2. Runyon BA: Ascitic fluid bilirubin concentration as a key to choleperitoneum. J Clin Gastroenterol 1987 Oct;9(5):543-545 3. Darwin P, Goldberg E, Uradomo L: Jackson Pratt drain fluid-to-serum bilirubin concentration ratio for the diagnosis of bile leaks. Gastrointest Endosc 2010 Jan;71(1):99-104 Epub 2009, Nov 27 4. Burgess LJ: Biochemical analysis of pleural, peritoneal and pericardial effusions. Clin Chim Acta 2004 May;343(1-2):61-84 5. Clinical and Laboratory Standards Institute: Analysis of Body Fluids in Clinical Chemistry; Approved Guideline. Clinical and Laboratory Standards Institute, Wayne, PA, 2007, CLSI document C49-A (ISBN 1-56238-638-7)

BILI3

Bilirubin, Serum

8452

Clinical Information: Bilirubin is one of the most commonly used tests to assess liver function. Approximately 85% of the total bilirubin produced is derived from the heme moiety of hemoglobin, while the remaining 15% is produced from RBC precursors destroyed in the bone marrow and from the catabolism of other heme-containing proteins. After production in peripheral tissues, bilirubin is rapidly taken up by hepatocytes where it is conjugated with glucuronic acid to produce bilirubin mono- and diglucuronide, which are then excreted in the bile. A number of inherited and acquired diseases affect 1 or more of the steps involved in the production, uptake, storage, metabolism, and excretion of bilirubin. Bilirubinemia is frequently a direct result of these disturbances. The most commonly occurring form of unconjugated hyperbilirubinemia is that seen in newborns and referred to as physiological jaundice. The increased production of bilirubin, that accompanies the premature breakdown of erythrocytes and ineffective erythropoiesis, results in hyperbilirubinemia in the absence of any liver abnormality. The rare genetic disorders, Crigler-Najjar syndromes type I and type II, are caused by a low or absent activity of bilirubin UDP-glucuronyl-transferase. In type I, the enzyme activity is totally absent, the excretion rate of bilirubin is greatly reduced and the serum concentration of unconjugated bilirubin is greatly increased. Patients with this disease may die in infancy owing to the development of kernicterus. In hepatobiliary diseases of various causes, bilirubin uptake, storage, and excretion are impaired to varying degrees. Thus, both conjugated and unconjugated bilirubin are retained and a wide range of abnormal serum concentrations of each form of bilirubin may be observed. Both conjugated and unconjugated bilirubins are increased in hepatitis and space-occupying lesions of the liver; and obstructive lesions such as carcinoma of the head of the pancreas, common bile duct, or ampulla of Vater.

Useful For: Assessing liver function Evaluating a wide range of diseases affecting the production, uptake, storage, metabolism, or excretion of bilirubin Monitoring the efficacy of neonatal phototherapy

Interpretation: The level of bilirubinemia that results in kernicterus in a given infant is unknown. In preterm infants, the risk of a handicap increases by 30% for each 2.9 mg/dL increase of maximal total bilirubin concentration. While central nervous system damage is rare when total serum bilirubin (TSB) is less than 20 mg/dL, premature infants may be affected at lower levels. The decision to institute therapy is based on a number of factors including TSB, age, clinical history, physical examination, and coexisting conditions. Phototherapy typically is discontinued when TSB level reaches 14 to 15 mg/dL. Physiologic jaundice should resolve in 5 to 10 days in full-term infants and by 14 days in preterm infants. When any portion of the biliary tree becomes blocked, bilirubin levels will increase.

Reference Values: Direct Bilirubin > or =12 months: 0.0-0.3 mg/dL Current as of August 23, 2017 7:11 am CDT


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Reference values have not been established for patients who are 100,000 copies/mL in urine may also indicate a risk for BKVAN.

Useful For: A prospective and diagnostic marker for the development of BK virus nephropathy in renal transplant recipients

Interpretation: Increasing copy levels of BK virus (BKV) DNA in serial specimens may indicate possible BKV-associated nephropathy (BKVAN) in kidney transplant patients. Viral loads of >100,000 copies/mL in urine may also indicate a risk for BKVAN. This assay does not cross react with other Current as of August 23, 2017 7:11 am CDT


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polyomaviruses, including JC virus and SV-40.

Reference Values: None detected

Clinical References: 1. Kazory A, Ducloux D: Renal transplantation and polyomavirus infection: recent clinical facts and controversies. Transplant Infect Dis 2003;5(2):65 2. Vilchez RA, Arrington AS, Butel JS: Polyomaviruses in kidney transplant recipients. Am J Transplantation 2002;2(5):481 3. Hirsch HH: Polyomavirus BK Nephropathy: A (Re-)emerging complication in renal transplantation. Am J Transplantation 2002;2(1):25-30 4. Randhawa PS, Demetris AJ: Nephropathy due to polyomavirus type BK. N Engl J Med 2000;342:1361-1363 5. Volker NT, Klimkait IF, Binet P, et al: Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 2000;342:1309-1315 6. Hariharan S: BK virus nephritis after renal transplantation. Kidney Int 2006;69:655-662 7. Blanckaert K, De Vriese AS: Current recommendations for diagnosis and management of polyoma BK virus nephropathy in renal transplant recipients. Nephrol Dial Transplant 2006;21(12):3364-3367 8. Viscount HB, Eid AJ, Espy MJ, et al: Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus-associated nephropathy. Transplantation 2007;84(3):340-345

BLPEP

Black/White Pepper, IgE

82814





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




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BLACK

Blackberry, IgE

82361





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



BLAST

Blastomyces Antibody by EIA, Serum

35793

Clinical Information: The dimorphic fungus, Blastomyces dermatitidis, causes blastomycosis. When the organism is inhaled, it causes pulmonary disease-cough, pain, and hemoptysis, along with fever and night sweats. It commonly spreads to the skin, bone, or internal genitalia where suppuration and granulomas are typical. Occasionally, primary cutaneous lesions after trauma are encountered; however, this type of infection is uncommon.



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Useful For: Detection of antibodies in patients having blastomycosis Interpretation: A positive result indicates that IgG and/or IgM antibodies to Blastomyces were detected. The presence of antibodies is presumptive evidence that the patient was or is currently infected with (or exposed to) Blastomyces. A negative result indicates that antibodies to Blastomyces were not detected. The absence of antibodies is presumptive evidence that the patient was not infected with Blastomyces. However, the specimen may have been obtained before antibodies were detectable or the patient may be immunosuppressed. If infection is suspected, another specimen should be drawn 7 to 14 days later and submitted for testing. All specimens testing equivocal will be repeated. Specimens testing equivocal after repeat testing should be submitted for further testing by another conventional serologic test (eg, SBL / Blastomyces Antibody by Immunodiffusion, Serum).

Reference Values: Negative

Clinical References: Kaufman L, Kovacs JA, Reiss E: Clinical immunomycology. In Manual of Clinical and Laboratory Immunology. Edited by NR Rose, EC De Macario, JD Folds, et al. Washington DC, ASM Press, 1997, pp 588-589

CBLAS

Blastomyces Antibody by EIA, Spinal Fluid

89986

Clinical Information: The dimorphic fungus, Blastomyces dermatitidis, causes blastomycosis. When the organism is inhaled, it causes pulmonary disease-cough, pain, and hemoptysis, along with fever and night sweats. It commonly spreads to the skin, bone, or internal genitalia where suppuration and granulomas are typical. Occasionally, primary cutaneous lesions after trauma are encountered; however, this type of infection is uncommon. Central nervous system disease is uncommon.

Useful For: Detection of antibodies in patients having blastomycosis Interpretation: A positive result indicates that IgG and/or IgM antibodies to Blastomyces were detected. The presence of antibodies is presumptive evidence that the patient was or is currently infected with (or exposed to) Blastomyces. A negative result indicates that antibodies to Blastomyces were not detected, but does not rule out infection. All specimens testing equivocal will be repeated. Specimens testing equivocal after repeat testing should be submitted for further testing by another conventional serologic test (eg, CBL / Blastomyces Antibody by Immunodiffusion, Spinal Fluid).


Clinical References: Kaufman L, Kovacs JA, Reiss E: Clinical immunomycology. In Manual of Clinical and Laboratory Immunology. Edited by NL Rose, E Conway-de Macario, JD Folds, et al. Washington, DC, ASM Press, 1997, pp 588-589

SBL

Blastomyces Antibody by Immunodiffusion, Serum

8237

Clinical Information: The dimorphic fungus, Blastomyces dermatitidis, causes blastomycosis. When the organism is inhaled, it causes pulmonary disease - cough, pain, and hemoptysis, along with fever and night sweats. It commonly spreads to the skin, bone, or internal genitalia where suppuration and granulomas are typical. Occasionally, primary cutaneous lesions after trauma are encountered; however, this type of infection is uncommon.

Useful For: Detection of antibodies in patients having blastomycosis Interpretation: A positive result is suggestive of infection, but the results cannot distinguish between active disease and prior exposure. Routine culture of clinical specimens (eg, respiratory specimen) is recommended in cases of suspected, active blastomycosis.

Reference Values: Negative Current as of August 23, 2017 7:11 am CDT


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Clinical References: Kaufman L, Kovacs JA, Reiss E: Clinical Immunomycology. In Manual of Clinical and Laboratory Immunology. Edited by NL Rose, E Conway-de Macario, JD Folds, et al. Washington, DC, ASM Press, 1997, pp 588-589

CBL

Blastomyces Antibody by Immunodiffusion, Spinal Fluid

81541

Clinical Information: The dimorphic fungus, Blastomyces dermatitidis, causes blastomycosis. When the organism is inhaled, it causes pulmonary disease-cough, pain, and hemoptysis, along with fever and night sweats. It commonly spreads to the skin, bone, or internal genitalia where suppuration and granulomas are typical. Occasionally, primary cutaneous lesions after trauma are encountered; however, this type of infection is uncommon. Central nervous system disease is uncommon.

Useful For: Detection of antibodies in patients having blastomycosis Interpretation: A positive result is suggestive of infection, but the results cannot distinguish between active disease and prior exposure. Furthermore, detection of antibodies in cerebrospinal fluid (CSF) may reflect intrathecal antibody production, or may occur due to passive transfer or introduction of antibodies from the blood during lumbar puncture. Routine fungal culture of clinical specimens (eg, CSF) is recommended in cases of suspected blastomycosis involving the central nervous system.


Clinical References: Kaufman L, Kovacs JA, Reiss E: Clinical Immunomycology. In Manual of Clinical and Laboratory Immunology. Edited by NL Rose, E Conway-de Macario, JD Folds, et al. Washington, DC, American Society for Microbiology, 1997, pp 588-589

BDIAL

Bleeding Diathesis Profile, Limited

83094

Clinical Information: Bleeding problems may be associated with a wide variety of coagulation abnormalities or may be due to problems not associated with coagulation (trauma and surgery as obvious examples). A partial listing of causes follows. -Deficiency or functional abnormality (congenital or acquired) of any of the following coagulation proteins: fibrinogen (factor I), factor II (prothrombin), factor V, factor VII, factor VIII (hemophilia A), factor IX (hemophilia B), factor X, factor XI (hemophilia C; bleeding severity not always proportionate to factor level), factor XIII (fibrin-stabilizing factor), von Willebrand factor (VWF antigen and activity), and alpha-2 plasmin inhibitor and plasminogen activator inhibitor (PAI-I; severe deficiency in rare cases). Neither alpha-2 plasmin inhibitor nor PAI-I are included as a routine bleeding diathesis assay component, but either can be performed if indicated or requested. -Deficiency (thrombocytopenia) or functional abnormality of platelets such as congenital (Glanzmann thrombasthenia, Bernard-Soulier syndrome, storage pool disorders, etc) and acquired (myeloproliferative disorders, uremia, drugs, etc) disorders. Platelet function abnormalities cannot be studied on mailed-in specimens. -Specific factor inhibitors (most commonly directed against factor VIII); factor inhibitors occur in 10% to15% of the hemophilia population and are more commonly associated with severe deficiencies of factor VIII or IX (antigen or =100 Strongly positive Reference values apply to all ages.


BUN

Blood Urea Nitrogen (BUN), Serum

81793

Clinical Information: Urea is the final degradation product of protein and amino acid metabolism. In protein catabolism, the proteins are broken down to amino acids and deaminated. The ammonia formed in this process is synthesized to urea in the liver. This is the most important catabolic pathway for eliminating excess nitrogen in the human body. Increased blood urea nitrogen (BUN) may be due to prerenal causes (cardiac decompensation, water depletion due to decreased intake and excessive loss,



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increased protein catabolism, and high protein diet), renal causes (acute glomerulonephritis, chronic nephritis, polycystic kidney disease, nephrosclerosis, and tubular necrosis), and postrenal causes (eg, all types of obstruction of the urinary tract, such as stones, enlarged prostate gland, tumors). The determination of serum BUN currently is the most widely used screening test for the evaluation of kidney function. The test is frequently requested along with the serum creatinine test since simultaneous determination of these 2 compounds appears to aid in the differential diagnosis of prerenal, renal and postrenal hyperuremia.

Useful For: Screening test for evaluation of kidney function Interpretation: Serum blood urea nitrogen (BUN) determinations are considerably less sensitive than BUN clearance (and creatinine clearance) tests, and levels may not be abnormal until the BUN clearance has diminished to less than 50%. Clinicians frequently calculate a convenient relationship, the urea nitrogen:creatinine ratio-serum bun in mg/dL/serum creatinine in mg/dL. For a normal individual on a normal diet, the reference interval for the ratio ranges between 12 and 20, with most individuals being between 12 and 16. Significantly lower ratios denote acute tubular necrosis, low protein intake, starvation, or severe liver disease. High ratios with normal creatinine levels may be noted with catabolic states of tissue breakdown, prerenal azotemia, high protein intake, etc. High ratios associated with high creatinine concentrations may denote either postrenal obstruction or prerenal azotemia superimposed on renal disease. Because of the variability of both the BUN and creatinine assays, the ratio is only a rough guide to the nature of the underlying abnormality. Its magnitude is not tightly regulated in health or disease and should not be considered an exact quantity.

Reference Values: Males 1-17 years: 7-20 mg/dL > or =18 years: 8-24 mg/dL Reference values have not been established for patients who are or =18 years: 6-21 mg/dL Reference values have not been established for patients who are or =100 Strongly positive Reference values apply to all ages.




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BLOMP 35366

Bloom Syndrome, Mutation Analysis, 2281 delATCTGAinsTAGATTC (2281del6/ins7) Clinical Information: Bloom syndrome is characterized by short stature, sun sensitivity, susceptibility to infections, and a predisposition to cancer. Mutations in the BLM gene lead to genetic instability (increased chromosomal breakage and sister chromatid exchange) and cause the clinical manifestations of the syndrome. The protein encoded by the BLM gene is a helicase involved in maintaining DNA integrity. The carrier rate in the Ashkenazi Jewish population is 1 in 107. There is a common mutation in the Ashkenazi Jewish population: 2281delATCTGAins TAGATTC (2281del6/ins7). The carrier detection rate for this mutation is above 99%.

Useful For: Carrier screening for Bloom syndrome in individuals of Ashkenazi Jewish ancestry Confirmation of suspected clinical diagnosis of Bloom syndrome in individuals of Ashkenazi Jewish ancestry Prenatal diagnosis for Bloom syndrome in at-risk pregnancies


Clinical References: 1. Gross SJ, Pletcher BA, Monaghan KG: Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med 2008 Jan;10(1):54-6 2. Hickson ID: RecQ helicases: Caretakers of the genome. Nat Rev Cancer 2003;3(3):169-178

MUSS

Blue Mussel, IgE

82548

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive



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4


5


6



FBLUG

Blueberry IgG

57658



BMPRZ

BMPR1A Gene, Full Gene Analysis

35368

Clinical Information: Juvenile polyposis syndrome (JPS) is a rare hereditary cancer predisposition syndrome caused by mutations in the SMAD4 or BMPR1A genes. JPS is characterized by the presence of multiple histologically defined juvenile polyps in the upper and/or lower gastrointestinal (GI) tract and an increased risk for GI cancers. Age of onset for cancer development is typically in the second or third decade of life, although some patients present with a more severe infantile-onset form of the disease. JPS is inherited in an autosomal dominant fashion, although a significant proportion of probands have no family history. Approximately 50% of patients with JPS have an identifiable mutation in the SMAD4 or BMPR1A genes.

Useful For: Confirmation of juvenile polyposis syndrome for patients with clinical features This test should be ordered only for individuals with symptoms suggestive of juvenile polyposis syndrome. Asymptomatic patients with a family history of juvenile polyposis syndrome should not be tested until a mutation has been identified in an affected family member.



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008:10(4):294-300 2. Lammi L, Arte S, Somer M, et al: Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer. Am J Hum Genet 2004;74:1043-1050 3. Liu W, Dong X, Mai M, et al: Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signaling. Nat Genet 2000;26:146-147 4. Mai M, Qian C, Yokomizo A, et al: Cloning of the human homolog of conductin (AXIN2), a gene mapping to chromosome 17q23-q24. Genomics 1998;55:341-344 5. Dong X, Seelan RS, Qian C, et al: Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet Cell Genet 2001;93:26-28

60814

BOB-1, Immunostain Without Interpretation Clinical Information: BOB.1/OBF.1 is a transcriptional co-activator that interacts with the transcription factors Oct1 or Oct2 in regulating transcription of immunoglobulin genes. In normal tonsil, the germinal center B cells all express BOB.1, while only scattered cells in the mantle zone express this protein. On immunohistochemistry, there is strong nuclear staining and weak cytoplasmic staining. Expression of BOB.1/OBF.1, Oct2, and PU.1 transcription factors are often down-regulated in classical Hodgkin lymphomas in contrast to many cases of nodular lymphocyte-predominant Hodgkin lymphoma. This property can be useful in the diagnosis of lymphoma.

Useful For: Classification of lymphomas Current as of August 23, 2017 7:11 am CDT


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Clinical References: 1. McCune RC, Syrbu SE, Vasef MA: Expression profiling of transcription factors Pax-5, Oct-1, Oct-2, BOB.1, and PU.1 in Hodgkin's and non-Hodgkin's lymphomas: a comparative study using high throughput tissue microarrays. Mod Pathol 2006;19:1010-1018 2. Abd El All HS: BOB-1 is expressed in classic Hodgkin lymphoma. Diagn Pathol 2007 Mar 8;2:1-10 3. Loddenkemper C, Anagnostopoulos I, Hummell M, et al: Differential Eu enhancer activity and expression of BOB.1/OBF.1, Oct 2, PU.1, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas and Hodgkin lymphomas. J Pathol 2004 Jan;202(1):60-69 4. Marafioti T, Ascani S, Pulford K, et al: Expression of B-lymphocyte-associated transcription factors in human T-cell neoplasms. Am J Pathol 2003 Mar;162(3):861-871

BAP

Bone Alkaline Phosphatase, Serum

82985

Clinical Information: Bone alkaline phosphatase (BAP) is the bone-specific isoform of alkaline phosphatase. A glycoprotein that is found on the surface of osteoblasts, BAP reflects the biosynthetic activity of these bone-forming cells. BAP has been shown to be a sensitive and reliable indicator of bone metabolism.(1) Normal bone is constantly undergoing remodeling in which bone degradation or resorption is balanced by bone formation. This process is necessary for maintaining bone health. If the process becomes uncoupled and the rate of resorption exceeds the rate of formation, the resulting bone loss can lead to osteoporosis and, consequently, a higher susceptibility to fractures. Osteoporosis is a metabolic bone disease characterized by low bone mass and abnormal bone microarchitecture. It can result from a number of clinical conditions including states of high bone turnover, endocrine disorders (primary and secondary hyperparathyroidism and thyrotoxicosis), osteomalacia, renal failure, gastrointestinal diseases, long-term corticosteroid therapy, multiple myeloma, and cancer metastatic to the bones. Paget disease is another common metabolic bone disease caused by excessive rates of bone remodeling resulting in local lesions of abnormal bone matrix. These lesions can result in fractures or neurological involvement. Antiresorptive therapies are used to restore the normal bone structure.

Useful For: Diagnosis and assessment of severity of metabolic bone disease including Paget disease, osteomalacia, and other states of high bone turnover Monitoring efficacy of antiresorptive therapies including postmenopausal osteoporosis treatment

Interpretation: Bone alkaline phosphatase (BAP) concentration is high in Paget disease and osteomalacia. Antiresorptive therapies lower BAP from baseline measurements in Paget disease, osteomalacia, and osteoporosis. Several studies have shown that antiresorptive therapies for management of osteoporosis patients should result in at least a 25% decrease in BAP within 3 to 6 months of initiating therapy.(2,3) BAP also decreases following antiresorptive therapy in Paget disease.(4) When used as a marker for monitoring purposes, it is important to determine the critical difference (or least significant change). The critical difference is defined as the difference between 2 determinations that may be considered to have clinical significance. The critical difference for this method was calculated to be 25% with a 95% confidence level.(1)

Reference Values: Males or =100 Strongly positive Reference values apply to all ages.


BRCAZ

BRCA1/BRCA2 Genes, Full Gene Analysis

64283

Clinical Information: Hereditary breast and ovarian cancer (HBOC) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the BRCA1 or BRCA2 genes. Mutations within these 2 genes account for the majority of hereditary breast and ovarian cancer families. HBOC is predominantly characterized by young-onset breast cancer and ovarian cancer. However, HBOC is also associated with increased risks for prostate cancer, pancreatic cancer, fallopian tube cancer, and male breast cancer. HBOC is highly penetrant; the risk for developing an invasive breast cancer is about 60% to 65% and the risk for developing ovarian cancer is about 40% by age 70. Some individuals develop multiple primary or bilateral cancers. The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with HBOC. There are founder mutations in BRCA1 and BRCA2 described in several populations including the Dutch, Icelandic, and Ashkenazi Jewish populations. The 3 common founder mutations in the Ashkenazi Jewish population are c.185delAG and c.5385insC in BRCA1, and c.6174delT in BRCA2.

Useful For: Establishing a diagnosis of hereditary breast and ovarian cancer (HBOC) Identification of familial BRCA1 or BRCA2 mutation to allow for predictive testing in family members

Interpretation: All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(2) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Petrij-Bosch A, Peelen T, van Vliet M, et al: BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 1997 Nov;17(3):341-345 2. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 3. Lindor NM, McMaster ML, Lindor CJ, et al: Concise Handbook of Familial Cancer Susceptibility Syndromes. Second Edition. J Natl Cancer Inst Monogr 2008;(38):1-93 4. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer-GeneReviews-NCBI Bookshelf. Accessed 6/1/2015. Available at Current as of August 23, 2017 7:11 am CDT


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http://www.ncbi.nlm.nih.gov/books/NBK1247/ 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1.2015. Accessed 6/1/2015. Available at www.nccn.org 6. Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007 Apr 10;25(11):1329-1333 7. Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 2007 Mar-Apr;57(2):75-89

C2729

Breast Carcinoma-Associated Antigen (CA 27.29), Serum

81413

Clinical Information: Carcinoma of the breast is the most prevalent form of cancer in women. These tumors often produce mucinous antigens that are large-molecular-weight glycoproteins with O-linked oligosaccharide chains. Monoclonal antibodies directed against these antigens have been developed, and several immunoassays are available to quantitate the levels of tumor-associated mucinous antigens in serum. The antibodies recognize epitopes of a breast cancer-associated antigen encoded by the human mucin 1 (MUC-1) gene, which is known by several names including MAM6, milk mucin antigen, CA 27.29, and cancer antigen 15-3 (CA 15-3). While CA 27.29 is expressed at the apical surface of normal epithelial cells, it is present throughout malignant epithelial cells of the breast, lung, ovary, pancreas, and other sites. The cancer-associated form of the antigen is less extensively glycosylated than the normal form and more specific for tumor cells.

Useful For: FDA-approved cancer-associated antigen (CA 27.29) for serial testing in women with prior stage II or III breast cancer who are clinically free of disease Predicting early recurrence of disease in women with treated carcinoma of the breast As an indication that additional tests or procedures should be performed to confirm recurrence of breast cancer

Interpretation: Increased levels of cancer-associated antigen (CA 27.29) (>38 U/mL) may indicate recurrent disease in a woman with treated breast carcinoma.

Reference Values: Males > or =18 years: < or =38.0 U/mL (use not defined) Females > or =18 years: < or =38.0 U/mL Reference values have not been established for patients who are or =10 mcg/mL is toxic Reference Values: 1, because of the prolonged half-life of autoantibody-bound insulin. Dynamic testing may be necessary in the workup of hypoglycemia; the C-peptide suppression test is most commonly employed. C-peptide levels are measured following induction of hypoglycemia through exogenous insulin administration. The test relies on the demonstration of the lack of suppression of serum C-peptide levels within 2 hours following insulin-induced hypoglycemia in patients with insulinoma. Reference intervals have not been formally verified in-house for pediatric patients. The published literature indicates that reference intervals for adult and pediatric patients are comparable.

Reference Values: 1.1-4.4 ng/mL Reference intervals have not been formally verified in-house for pediatric patients. The published literature indicates that reference intervals for adult and pediatric patients are comparable.

Clinical References: 1. Service FJ, O'Brien PC, Kao PC, Young WF Jr: C-peptide suppression test: effects of gender, age, and body mass index; implications for the diagnosis of insulinoma. J Clin Endocrinol Metab 1992;74:204-210 2. Lebowitz MR, Blumenthal SA: The molar ratio of insulin to C-peptide. An aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin administration. Arch Int Med 1993 Mar 8;153(5):650-655 3. Service FJ: Hypoglycemic disorders. N Engl Current as of August 23, 2017 7:11 am CDT


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J Med 1995 Apr 27;332(17):1144-1152 4. Wahren J, Ekberg K, Johansson J, et al: Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab 2000 May;278(5):E759-E768 5. Young DS, Huth EJ: SI Units for Clinical Measurement. First edition. American College of Physicians. Philadelphia, PA, 1998

62483

C-Reactive Protein (CRP), Immunostain Without Interpretation Clinical Information: C-reactive protein (CRP) is an acute-phase reactant associated with host defense which promotes agglutination and -complement fixation. CRP can be used with a panel of immunohistochemical markers (beta-catenin, liver fatty acid binding protein, glutamine synthetase, and amyloid A) to distinguish hepatic adenoma from focal nodular hyperplasia and non-neoplastic liver. CRP, along with amyloid A, is markedly overexpressed in inflammatory (type 3) hepatic adenoma and does not display strong staining in normal liver or in other adenoma types.

Useful For: Classification of hepatic adenomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. van Aalten SM, Verheij J, Terkivatan T, et al: Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol 2011;55(1):120-125 2. Bioulac-Sage P, Cubel G, Balabaud C, et al: Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011; 31(1):91-103 3. Bioulac-Sage P, Rebouissou S, Thomas C, et al: Hepatocellular adenoma subype classification using molecular markers and immunohistochemistry. Hepatology 2007; 46(3):740-748

CRP

C-Reactive Protein (CRP), Serum

9731

Clinical Information: C-reactive protein (CRP) is one of the most sensitive acute-phase reactants for inflammation. CRP is synthesized by the liver and consists of 5 identical polypeptide chains that form a 5-membered ring with a molecular weight of 105,000 daltons. Complexed CRP activates the classical complement pathway. The CRP response frequently precedes clinical symptoms, including fever. CRP elevations are nonspecific and may be useful for the detection of systemic inflammatory processes; to assess treatment of bacterial infections with antibiotics; to detect intrauterine infections with concomitant premature amniorrhexis; to differentiate between active and inactive forms of disease with concurrent infection, eg, in patients suffering from systemic lupus erythematosus or colitis ulcerosa; to therapeutically monitor rheumatic disease and assess anti-inflammatory therapy; to determine the presence of postoperative complications at an early stage, such as infected wounds, thrombosis, and pneumonia; and to distinguish between infection and bone marrow rejection. Postoperative monitoring of CRP levels of patients can aid in the recognition of unexpected complications (persisting high or increasing levels). Measuring changes in the concentration of CRP provides useful diagnostic information about the level of acuity and severity of a disease. It also allows judgments about the disease genesis. Persistence of a high serum CRP concentration is usually a grave prognostic sign that generally indicates the presence of an uncontrolled infection.

Useful For: Detecting systemic inflammatory processes Detecting infection and assessing response to antibiotic treatment of bacterial infections Differentiating between active and inactive disease forms with concurrent infection

Interpretation: In normal healthy individuals, C-reactive protein (CRP) is a trace protein (10.0 mg/L

Clinical References: 1. European Association for Cardiovascular Prevention and Rehabilitation, Reiner Z, Catapano AL, et al: ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-1818 2. Goff DC, Lloyd-Jones DM, Bennett G, et al: 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Circulation 2014;129:S49-S73 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 2014;8:473-488 Ridker PM, Danielson E, Fonseca FA, et al: Reduction in C-reactive protein and LDL-cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175-1182

C1ES

C1 Esterase (C1ES) Inhibitor Antigen, Serum

8198

Clinical Information: C1 esterase inhibitor blocks the activation of C1 (first component of the complement cascade) to its active form. The deficiency of C1 esterase inhibitor results in the inappropriate activation of C1 and the subsequent release of an activation peptide from C2 with kinin-like activity. This kinin-like peptide enhances vascular permeability. C1 esterase inhibitor deficiency results in hereditary or acquired angioedema. This disease is an autosomal dominant inherited condition, in which exhaustion of the abnormally low levels of C1 esterase inhibitor results in C1 activation, breakdown of C2 and C4, and subsequent acute edema of subcutaneous tissue, the gastrointestinal tract, or the upper respiratory tract. The disease responds to attenuated androgens. Because 15% of C1 inhibitor deficiencies have nonfunctional protein, some patients will have abnormal functional results (FC1EQ / C1 Esterase Inhibitor, Functional Assay, Serum) in the presence of normal (or elevated) antigen levels.

Useful For: Diagnosis of hereditary angioedema Monitoring levels of C1 esterase inhibitor in response to therapy

Interpretation: Abnormally low results are consistent with a heterozygous C1 esterase inhibitor Current as of August 23, 2017 7:11 am CDT


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deficiency and hereditary angioedema. Fifteen percent of hereditary angioedema patients have a normal or elevated level but nonfunctional C1 esterase inhibitor protein. Detection of these patients requires a functional measurement of C1 esterase inhibitor; FC1EQ / C1 Esterase Inhibitor, Functional Assay, Serum. Measurement of C1q antigen levels; C1Q / Complement C1q, Serum, is key to the differential diagnoses of acquired or hereditary angioedema. Those patients with the hereditary form of the disease will have normal levels of C1q, while those with the acquired form of the disease will have low levels. Studies in children show that adult levels of C1 inhibitor are reached by 6 months of age.

Reference Values: 19-37 mg/dL

Clinical References: 1. Frank MM: Complement deficiencies. Pediatr Clin North Am 2000;47(6):1339-1354 2. Gelfand JA, Boss GR, Conley CL, et al: Acquired C1 esterase inhibitor deficiency and angioedema: a review. Medicine 1979;58(4):321-328 3. Rosen FS, Alper CA, Pensky J, et al: Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest 1971;50(10):2143-2149 4. Frigas E: Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes. Mayo Clin Proc 1989;64:1269-1275 5. Soldin SJ, Hicks JM, Bailey J, et al: Pediatric reference ranges for estradiol and C1 esterase inhibitor. Clin Chem 1998;44(6s):A17

FC1EQ

C1 Esterase Inhibitor, Functional Assay, Serum

81493

Clinical Information: C1 inhibitor (C1-INH) is a multispecific protease inhibitor that is present in normal human plasma and serum, and which regulates enzymes of the complement, coagulation, fibrinolytic, and kinin-forming systems. The enzymes (proteases) regulated by this protein include the C1r and C1s subunits of the activated first component of complement, activated Hageman factor (factor XIa), kallikrein (Fletcher factor), and plasmin. A deficiency of functionally active C1-INH may lead to life-threatening angioedema. Two major forms of C1-INH deficiency have been reported: the congenital form, termed hereditary angioedema (HAE), and the acquired form that is associated with a variety of diseases, including lymphoid malignancies. HAE is characterized by transient but recurrent attacks of nonpruritic swelling of various tissues throughout the body. The symptomatology depends upon the organs involved. Intestinal attacks lead to a diversity of symptoms including pain, cramps, vomiting, and diarrhea. The most frequent cause of death in this disease is airway obstruction secondary to laryngeal edema occurring during an attack. There are 2 types of HAE that can be distinguished biochemically. Patients with the more common type (85% of HAE patients) have low levels of functional C1-INH and C1-INH antigen. Patients with the second form (15% of HAE patients) have low levels of functional C1-INH but normal or increased levels of C1-INH antigen that is dysfunctional. The variable nature of the symptoms at different time periods during the course of the disease makes it difficult to make a definitive diagnosis based solely on clinical observation.

Useful For: Diagnosing hereditary angioedema and for monitoring response to therapy Interpretation: Hereditary angioedema (HAE) can be definitely diagnosed by laboratory tests demonstrating a marked reduction in C1 inhibitor (C1-INH) antigen or abnormally low functional C1-INH levels in a patient's plasma or serum that has normal or elevated antigen. Nonfunctional results are consistent with HAE. Patients with current attacks will also have low C2 and C4 levels due to C1 activation and complement consumption. Patients with acquired C1-INH deficiency have a low C1q in addition to low C1-INH.

Reference Values: >67% normal (normal) 41-67% normal (equivocal) 20.0 mcg/mL.

Reference Values: Therapeutic: 8.0-20.0 mcg/mL Critical value: > or =30.0 mcg/mL

Clinical References: Ou CN, Frawley VL: Concurrent measurement of theophylline and caffeine in neonates by an interference-free liquid-chromatographic method. Clin Chem 1983;29:1934-1936

60816

Calcitonin (CALCI), Immunostain Without Interpretation Clinical Information: Calcitonin is a hormone involved in calcium metabolism. Staining for calcitonin produces fine granular, cytoplasmic staining of C cells of thyroid, medullary thyroid carcinomas, many atypical laryngeal carcinoids, and other neuroendocrine tumors. Amyloid deposits within medullary thyroid carcinoma may also exhibit varying degrees of calcitonin immunoreactivity.

Useful For: An aid in the identification of C cells of thyroid, medullary thyroid carcinomas, many atypical laryngeal carcinoids, and other neuroendocrine tumors


Clinical References: 1. Hayashida CY, Alves VA, Kanamura CT, et al: Immuhohistochemistry of medullary thyroid carcinoma and C-cell hyperplasia by an affinity-purified anti-human calcitonin antiserum. Cancer 1993;72:1356-1363 2. Hirsch MS, Faquin WC, Krane JF: Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid. Mod Pathol 2004;17:631-636 3. Thomas RM, Baybick JH, Eldayed AM, et al: Gastric carcinoids. An immunohistochemical and clinicopathologic study of 104 patients. Cancer 1994;73(8):2053-2058

CATLN

Calcitonin, Fine-Needle Aspiration Biopsy (FNAB)-Needle Wash,

Current 61527 as of August 23, 2017 7:11 am CDT


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Lymph Node Clinical Information: Calcitonin is a polypeptide hormone secreted by the parafollicular cells (also referred to as calcitonin cells or C-cells) of the thyroid gland. Malignant tumors arising from thyroid C-cells (medullary thyroid carcinoma: MTC) usually produce elevated levels of calcitonin. MTC is an uncommon malignant thyroid tumor, comprising less than 5% of all thyroid malignancies. Measurement of serum calcitonin is used in the follow-up of patients who underwent surgical removal of the thyroid gland. Studies have reported that the measurement of calcitonin in fine-needle aspiration biopsy (FNAB)-needle washes improves the evaluation of suspicious lymph nodes in patients with a history of MTC when used in combination with cytology. Comparing the results of calcitonin in the needle rinse with serum calcitonin is highly recommended. An elevated calcitonin in the serum could falsely elevate calcitonin in the washings, if the rinse is contaminated with blood. In these cases only calcitonin values significantly higher than the serum should be considered as true-positives. Cytologic examination and measurement of calcitonin can be performed on the same specimen. To measure calcitonin, the FNA needle is rinsed with a small volume of normal saline solution immediately after a specimen for cytological examination (for a smear or CytoTrap preparation) has been expelled from the needle. Calcitonin levels are measured in the needle wash.

Useful For: As an adjunct to cytologic examination of fine-needle aspiration specimens in athyrotic individuals treated for medullary thyroid carcinoma to confirm or exclude metastases in enlarged or ultrasonographically suspicious lymph nodes

Interpretation: In athyrotic patients with a history of medullary thyroid carcinoma (MTC), a fine-needle aspiration calcitonin value of 5.0 pg/mL and greater is suggestive of the presence of metastatic MTC in the biopsied lymph node. Calcitonin values less than 5.0 pg/mL suggest the lymph node does not contain medullary thyroid carcinoma. This result is dependent on accurate sampling and a total needle wash volume of less than or equal to 1.5 mL. This test should be interpreted in the context of the clinical presentation, imaging and cytology findings. If the results are discordant with the clinical presentation, a sampling error at the time of biopsy should be considered.


Clinical References: 1. Trimboli P, Rossi F, Baldelli R, et al: Measuring calcitonin in washout of the needle in patients undergoing fine needle aspiration with suspicious medullary thyroid cancer. Diagn Cytopathol 2012 May;40(5):394-398 2. Boi F, Maurelli I, Pinna G, et al: Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 2007 Jun;92(6):2115-2118 3. Kudo T, Miyauchi A, Ito Y, et al: Diagnosis of medullary thyroid carcinoma by calcitonin measurement in fine-needle aspiration biopsy specimens. Thyroid 2007 Jul;17(7):635-638

CATN

Calcitonin, Serum

9160

Clinical Information: Calcitonin is a polypeptide hormone secreted by the parafollicular cells (also referred to as calcitonin cells or C cells) of the thyroid gland. The main action of calcitonin is the inhibition of bone resorption by regulating the number and activity of osteoclasts. Calcitonin is secreted in direct response to serum hypercalcemia and may prevent large oscillations in serum calcium levels and excessive loss of body calcium. However, in comparison to parathyroid hormone and 1,25-dihydroxyvitamin D, the role of calcitonin in the regulation of serum calcium in humans is minor. Measurements of serum calcitonin levels are, therefore, not useful in the diagnosis of disorders of calcium homeostasis. Malignant tumors arising from thyroid C cells (medullary thyroid carcinoma: MTC) usually produce elevated levels of calcitonin. MTC is an uncommon malignant thyroid tumor, comprising less than 5% of all thyroid malignancies. Approximately 25% of these cases are familial, usually appearing as a component of multiple endocrine neoplasia type II (MENII, Sipple syndrome). MTC may also occur in families without other associated endocrine dysfunction, with similar autosomal dominant transmission as MENII, which is then called familial medullary thyroid carcinoma (FMTC). Mutations in the RET proto-oncogene are associated with MENII and FMTC. Serum calcitonin concentrations are high in infants, decline rapidly, and are relatively stable from childhood through adult life. In general, calcitonin



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serum concentrations are higher in men than in women due to the larger C-cell mass in men. Serum calcitonin concentrations may be increased in patients with chronic renal failure, and other conditions such as hyperparathyroidism, leukemic and myeloproliferative disorders, Zollinger-Ellison syndrome, autoimmune thyroiditis, small cell and large cell lung cancers, breast and prostate cancer, mastocytosis, and various neuroendocrine tumors, in particular, islet cell tumors.

Useful For: Aids in the diagnosis and follow-up of medullary thyroid carcinoma Aids in the evaluation of multiple endocrine neoplasia type II and familial medullary thyroid carcinoma

Interpretation: Although most patients with sporadic medullary thyroid carcinoma (MTC) have high basal serum calcitonin concentrations, 30% of those with familial MTC or multiple endocrine neoplasia type II (MENII) have normal basal levels. In completely cured cases following surgical therapy for MTC, serum calcitonin levels fall into the undetectable range over a variable period of several weeks. Persistently elevated postoperative serum calcitonin levels usually indicate incomplete cure. The reasons for this can be locoregional lymph node spread or distant metastases. In most of these cases, imaging procedures are required for further workup. Those individuals who are then found to suffer only locoregional spread may benefit from additional surgical procedures. However, the survival benefits derived from such approaches are still debated. A rise in previously undetectable or very low postoperative serum calcitonin levels is highly suggestive of disease recurrence or spread, and should trigger further diagnostic evaluations.

Reference Values: Pediatric 1 month: < or =34 2 months: < or =31 3 months: < or =28 4 months: < or =26 5 months: < or =24 6 months: < or =22 7 months: < or =20 8 months: < or =19.0 9 months: < or =17.0 10 months: < or =16.0 11 months: < or =15.0 12-14 months: < or =14.0 15-17 months: < or =12.0 18-20 months: < or =10.0 21-23 months: < or =9.0 2 years: < or =8.0 3-9 years: < or =7.0 10-15 years: < or =6.0 16 years: < or =5.0 Adults 17 years and older: Males: < or =14.3 Females: < or =7.6

Clinical References: 1. Wells SA Jr, Asa SL, Dralle H, et al: Medullary Thyroid Carcinoma: management guidelines of the American Thyroid Association. American Thyroid Association Guidelines Task Force 2015 Jun;25(6):567-610 2. Griebeler ML, Gharib H, Thompson GB: Medullary thyroid carcinoma. Endocr Pract 2013 Jul-Aug;19(4):703-11 3. Richards ML: Familial syndromes associated with thyroid cancer in the era of personalized medicine. Thyroid 2010 Jul;20(7):707-13

CALU

Calcium, 24 Hour, Urine

36891

Clinical Information: Calcium is the fifth most common element in the body. It is a fundamental element necessary to form electrical gradients across membranes, an essential cofactor for many enzymes,



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and the main constituent in bone. Under normal physiologic conditions, the concentration of calcium in serum and in cells is tightly controlled. Calcium is excreted in both urine and feces. Ordinarily about 20% to 25% of dietary calcium is absorbed and 98% of filtered calcium is reabsorbed in the kidney. Traffic of calcium between the gastrointestinal tract, bone, and kidney is tightly controlled by a complex regulatory system that includes vitamin D and parathyroid hormone. Sufficient bioavailable calcium is essential for bone health. Excessive excretion of calcium in the urine is a common contributor to kidney stone risk.

Useful For: Evaluation of calcium oxalate and calcium phosphate kidney stone risk, and calculation of urinary supersaturations Evaluation of bone diseases, including osteoporosis and osteomalacia

Interpretation: Increased urinary calcium excretion (hypercalciuria) is a known contributor to kidney stone disease and osteoporosis. Many cases are genetic (often termed "idiopathic"). Previously such patients were often divided into fasting versus absorptive hypercalciuria depending on the level of urine calcium in a fasting versus fed state, but the clinical utility of this approach is now in question. Overall, the risk of stone disease appears increased when 24-hour urine calcium is >250 mg in men and >200 mg in women. Thiazide diuretics are often used to reduce urinary calcium excretion, and repeat urine collections can be performed to monitor the effectiveness of therapy. Known secondary causes of hypercalciuria include hyperparathyroidism, Paget disease, prolonged immobilization, vitamin D intoxication, and diseases that destroy bone (such as metastatic cancer or multiple myeloma). Urine calcium excretion can be used to gauge the adequacy of calcium and vitamin D supplementation, for example in states of gastrointestinal fat malabsorption that are associated with decreased bone mineralization (osteomalacia).

Reference Values: Males: or =22 years: 8.9-10.1 mg/dL Reference values have not been established for patients who are or =19 years: 8.9-10.1 mg/dL Reference values have not been established for patients who are or =120.1 mcg/g are suggestive of an active inflammatory process within the gastrointestinal system. Further diagnostic testing to determine the etiology of the inflammation is suggested.



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< or =50.0 mcg/g (Normal) 50.1-120.0 mcg/g (Borderline) > or =120.1 mcg/g (Abnormal) Reference values apply to all ages.

Clinical References: 1. Gisbert JP, McNicholl AG, Golmollon F: Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Digest Liver Dis 2009;41:56-66 2. Campeotto F, Butel MJ, Kalach N, et al: High faecal calprotectin concentrations in newborn infants. Arch Dis Child-Fetal 2004;89:F353-F355 3. Dabritz J, Musci J, Foell D: Diagnostic utility of faecal biomarkers in patients with irritable bowel syndrome. World J Gastroentero 2014;20(2):363-375 4. Fagerberg, UL, Loof L, Merzoug RD, et al: Fecal calprotectin levels in healthy children studied with an improved assay. J Pediatr Gastr Nutr 2003;37:438-472

CALR

CALR Mutation Analysis, Myeloproliferative Neoplasm (MPN)

62912

Clinical Information: The most frequent genetic mutation in BCR-ABL1-negative myeloproliferative neoplasm (MPN), essential thrombocythemia (ET), and primary myelofibrosis (PMF) is the JAK2V617F mutation, which is present in approximately 50% to 60% of patients. It serves as a confirmatory molecular marker of these diseases. Mutations in the MPL gene are found in an additional 5% to 10% of ET and PMF cases. It was recently discovered that somatic mutation (insertions and deletions) in exon 9 of the CALR gene is the second most frequent somatic mutation after JAK2 in ET and PMF patients, and it is mutually exclusive of JAK2 and MPL mutations.(1,2) It has a frequency of approximately 49% to 88% in JAK2 and MPL-wild type (WT) ET and PMF, and is not found in polycythemia vera (PV) patients.(1-4) Therefore, CALR mutation serves as an important diagnostic molecular marker in ET and PMF. The CALR gene encodes for calreticulin, a multifunctional protein with a C-terminus rich in acidic amino acids and a KDEL ER-retention motif. All the pathologic CALR mutations reported to date are out-of-frame insertion and/or deletions (indel) in exon 9, generating a 1 base-pair (bp) frame shift and a mutant protein with a novel C-terminus rich in basic amino acids and loss of the KDEL ER-retention signal. The most common mutation types are 52-bp deletion (c.1092_1143del, L367fs*46) and 5-bp insertion (c.1154_1155insTTGCC, K385fs*47), and they comprise approximately 85% of CALR mutations in MPN.(1,2) CALR mutations have been found in hematopoietic stem and progenitor cells in MPN patients(2) and may activate the STAT5 signaling pathway.(1) They are associated with decreased risk of thrombosis in ET (1,3-5), and better survival in PMF compared to JAK2 mutations.(5)

Useful For: Rapid and sensitive detection of insertion and deletion-type mutations in exon 9 of CALR An aid in distinction between reactive thrombocytosis and leukocytosis versus a myeloproliferative neoplasm (MPN), especially essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is highly informative in cases in which JAK2 and MPL testing are negative Especially helpful to the pathologist in those bone marrow cases with ambiguous etiology of thrombocytosis, equivocal bone marrow morphologic findings of MPN, and unexplained reticulin fibrosis An aid in prognostication of PMF and thrombosis risk assessment in ET

Interpretation: An interpretive report will be issued. The results will be reported as 1 of the 3 states if DNA amplification is successful (see Cautions): -Positive. A deletion/insertion-type mutation was detected in CALR, exon 9. -Negative. No deletion or insertion was detected in CALR, exon 9. -Equivocal. A small amplicon suspicious for a deletion/insertion type mutation was detected in CALR, exon 9. Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical and other laboratory and morphologic features for definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative neoplasm or other neoplastic disorders.

Reference Values: An interpretive report will be provided

Clinical References: 1. Klampfl T, Gisslinger H, Harutyunyan AS, et al: Somatic mutation of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-90 2. Nangalia J, Massie CE, Baxter EJ, et al: Somatic CALR mutation in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-2405 3. Rumi E, Pietra D, Ferretti V, et al: JAK2 or CALR mutation status Current as of August 23, 2017 7:11 am CDT


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defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood Published online before print 2014 Mar 6;123(10):1544-1551 4. Rotunno G, Mannarelli C, Guglielmelli P, et al: Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552-1555 5. Tefferi A, Lasho TL, Finke CM, et al: CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014 Jul;28(7):1472-1477

CALX 36997

CALR Mutation Analysis, Myeloproliferative Neoplasm (MPN), Reflex Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg, STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as c.G1849T; p. Val617Phe (V617F). The JAK2 V617F is present in 95% to 98% of polycythemia vera (PV), and 50% to 60% of primary myelofibrosis (PMF) and essential thrombocythemia (ET). It has also been described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia and myelodysplastic syndrome. Detection of the JAK2 V617F is useful to help establish the diagnosis of MPN. However, a negative JAK2 V617F result does not indicate the absence of MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30% of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2, CALR, and MPL are essentially mutually exclusive. A CALR mutation is associated with decreased risk of thrombosis in both ET and PMF, and confers a favorable clinical outcome in PMF patients. A triple negative (JAK2 V617F, CALR, and MPL-negative) genotype is considered a high-risk molecular signature in PMF.

Useful For: Aiding in the distinction between a reactive cytosis and a chronic myeloproliferative disorder Evaluates for mutations in CALR in an algorithmic process for the MPNR / Myeloproliverative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL

Interpretation: An interpretation will be provided under the MPNR / Myeloproliferative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL.

Reference Values: Only orderable as a reflex. For more information see MPNR / Myeloproliferative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL. An interpretive report will be provided.

65017

Calreticulin ex9mut, Immunostain Without Interpretation Clinical Information: The detection of calreticulin exon 9 frameshift mutations can assist in the diagnosis and prognostication of myeloproliferative diseases. Although these mutations are heterogeneous they all result in a protein with a novel 36 amino acid C terminus the anticalreticulin CAL2 clone specifically identifies. Most patients with essential thrombocythemia or primary myelofibrosis not associated with Janus kinase 2 (JAK2) or MPL mutations are associated with CALR exon 9 mutations and primary myelofibrosis patients carrying CALR mutations have a more indolent clinical course.

Useful For: Identifying the presence of calreticulin exon 9 frameshift mutations in myeloproliferative neoplasms

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is Current as of August 23, 2017 7:11 am CDT


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available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Vannucchi AM, Rotunno G, Bartalucci N, et al: Calreticulin mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic value. Leukemia 2014 Sep;28(9):1811-1818 2. Stein H, Bob R, Durkop H, et al: A new monoclonal antibody (CAL2) detects CALRETICULIN mutations in formalin-fixed and paraffin-embedded bone marrow biopsies. Leukemia 2016 Jan;30(1):131-135 3. Klampfl T, Gisslinger H, Harutyunyan AS, etal: Somatic mutations of Calreticulin in myeloproliferative neoplasms. N Engl J Med 2013 Dec 19;369(25):2379-2390

60819

Calretinin, Immunostain Without Interpretation Clinical Information: Calretinin is expressed in benign and malignant mesothelial cells, and strongly expressed in Leydig cells of the testis.

Useful For: Marker of mesothelial cells and Leydig cells of the testis Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Abutaily AS, Addis BJ, Roche WR: Immunohistochemistry in the distinction between malignant mesothelioma and pulmonary adenocarcinoma: a critical evaluation of new antibodies. J Clin Pathol 2002;55:662-668 2. Ordonez NG: The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol 2003;27(8):1031-1051 3. Terracciano LM, Mhawech P, Suess K, et al: Calretinin as a marker for cardiac myxoma. Diagnostic and histogenetic considerations. Am J Clin Pathol 2000;114:754-759

FCAMP

Campylobacter jejuni Antibody, ELISA

91224

Reference Values: Reference Range:

or =100 Strongly positive Reference values apply to all ages.


CAGR

Canary Grass, IgE

82829



Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased Current as of August 23, 2017 7:11 am CDT


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likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CANP

Canavan Disease, Mutation Analysis, ASPA

35380

Clinical Information: Canavan disease is a severe leukodystrophy resulting from a deficiency of the enzyme aspartoacylase. Mutations in the ASPA gene cause the clinical manifestations of Canavan disease. The deficiency of aspartoacylase leads to spongy degeneration of the brain, and the disease is characterized by delayed development beginning at age 3 to 6 months, head lag, macrocephaly, and hypotonia. Death usually occurs within the first decade of life. The carrier rate in the Ashkenazi Jewish population is 1 in 41. Four ASPA mutations are included in this test: 433(-2)A->G, A305E, E285A, and Y231X. The E285A and Y231X mutations account for approximately 98% of the mutations in the Ashkenazi Jewish population. The A305E mutation accounts for approximately 50% of the mutations in the non-Ashkenazi Jewish population.

Useful For: Carrier testing for Canavan disease in individuals of Ashkenazi Jewish ancestry Prenatal diagnosis of Canavan disease in at-risk pregnancies Confirmation of a suspected clinical diagnosis of Canavan disease in individuals of Ashkenazi Jewish ancestry

Interpretation: An interpretative report will be provided. Reference Values: An interpretive report will be provided.

Clinical References: 1. Gross SJ, Pletcher BA, Monaghan KG: Carrier screening individuals of Ashkenazi Jewish descent. Genet Med 2008;10(1):54-56 2. ACOG Committee on Genetics: ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol 2009;Oct;114(4):950-953 3. Matalon R: Canavan disease: diagnosis and molecular analysis. Genet Testing 1997;1:21-25

CA25

Cancer Antigen 125 (CA 125), Serum

9289

Clinical Information: Cancer antigen 125 (CA 125) is a glycoprotein antigen normally expressed in tissues derived from coelomic epithelia (ovary, fallopian tube, peritoneum, pleura, pericardium, colon, kidney, stomach). Serum CA 125 is elevated in approximately 80% of women with advanced epithelial ovarian cancer, but assay sensitivity is suboptimal in early disease stages. The average reported sensitivities are 50% for stage I and 90% for stage II or greater. Elevated serum CA 125 levels have been



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reported in individuals with a variety of nonovarian malignancies including cervical, liver, pancreatic, lung, colon, stomach, biliary tract, uterine, fallopian tube, breast, and endometrial carcinomas. Elevated serum CA 125 levels have been reported in individuals with a variety of benign conditions including: cirrhosis, hepatitis, endometriosis, first trimester pregnancy, ovarian cysts, and pelvic inflammatory disease. Elevated levels during the menstrual cycle also have been reported.

Useful For: Evaluating patients' response to ovarian cancer therapy Predicting recurrent ovarian cancer Interpretation: In monitoring studies, elevations of cancer antigen 125 (CA 125) above the reference interval after debulking surgery and chemotherapy indicate that residual disease is likely (>95% accuracy). However, normal levels do not rule-out recurrence. A persistently rising CA 125 value suggests progressive malignant disease and poor therapeutic response. Physiologic half-life of CA 125 is approximately 5 days. In patients with advanced disease who have undergone cytoreductive surgery and are on chemotherapy, a prolonged half-life (>20 days) may be associated with a shortened disease-free survival.

Reference Values: Females: or =4.0 mcg/mL

Clinical References: 1. Svinarov DA, Pippenger CE: Relationships between carbamazepine-diol, carbamazepine-epoxide, and carbamazepine total and free steady-state concentrations in epileptic patients: the influence of age, sex, and comedication. Ther Drug Monit 1996;18:660-665 2. Bernus I, Dickinson RG, Hooper WD, Eadie MJ: The mechanism of the carbamazepine-valproate interactions in humans. Br J Clin Phamacol 1997;44:21-27 3. Dasgupta A, Volk A: Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit 1996;18:284-287 4 Patsalos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239-1276

CARTA

Carbamazepine, Total, Serum

37035

Clinical Information: Carbamazepine (Tegretol) is used in the control of partial seizures with both temporal lobe and psychomotor symptoms, and for generalized tonic-clonic seizures. It is also used for analgesia in trigeminal neuralgia. Carbamazepine exhibits a volume of distribution of 1.4 L/kg with an elimination half-life of 15 hours. Protein binding averages 75%. Carbamazepine-10,11-epoxide (CBZ10-11) is an active metabolite that represents the predominant form of the drug in children. The



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volume of distribution of CBZ10-11 is 1.1 L/kg, and the half-life is 8 hours. Aplastic anemia and agranulocytosis are rare side effects of treatment with carbamazepine; baseline hematologic data should be documented before treatment is initiated. Toxicity associated with carbamazepine overdose occurs when the total carbamazepine serum concentration is at or above 15.0 mcg/mL and is typified by irregular breathing, muscle irritability, and hyperreflexia; followed by hyporeflexia, tachycardia, hypotension, and impaired consciousness with coma in severe toxicity; the higher the blood level, the more severe the symptoms.

Useful For: Monitoring therapy Determining compliance Assessing toxicity Interpretation: Dosage adjustments are usually guided by monitoring serum levels. Most patients respond well when the total carbamazepine serum concentration is in the range of 4.0 to 12.0 mcg/mL. Toxicity often occurs when levels are at or above 15.0 mcg/mL.


Clinical References: 1. Cereghino JJ, Meter JC, Brock JT, et al: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology 1973;23:357-366 2. Patsalos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239-1276

CARBG

Carbamazepine-10,11-Epoxide, Serum

37036

Clinical Information: Carbamazepine is a common antiepileptic drug. It is a first-line drug for treatment of partial seizures and trigeminal neuralgia. Carbamazepine is metabolized by the liver to carbamazepine-10,11-epoxide (CBZ10-11) which is pharmacologically active and potentially toxic. CBZ10-11 is, in turn, inactivated by hepatic conversion to a transdiol derivative. CBZ10-11 may be responsible for the congenital abnormalities that are sometimes associated with the use of carbamazepine during early pregnancy. There have been cases of severe seizures exacerbation when serum epoxide levels were increased. Toxic levels of CBZ10-11 can occur during: -Concomitant administration of other drugs that induce hepatic oxidizing enzymes (eg, most antiepileptic drugs [with the exception of valproic acid and the benzodiazepines], propoxyphene) -Concomitant administration of drugs that inhibit its breakdown such as valproic acid, felbamate, and lamotrigine -High-dose carbamazepine therapy, especially in combination with the above conditions

Useful For: Monitoring patients exhibiting symptoms of carbamazepine toxicity whose serum carbamazepine concentration is within the therapeutic range, but who may be producing significant levels of the active metabolite epoxide

Interpretation: The clinically acceptable serum concentration of carbamazepine-10,11-epoxide (CBZ10-11) is not well established, but 4.0 mcg/mL has often been used as an upper limit for its therapeutic range. The ratio of CBZ10-11 to carbamazepine is usually < or =0.2 mcg/mL in symptomatic adults and < or =0.3 mcg/mL in children. Clinical correlation is aided by comparing values obtained when the patient is symptomatic with those obtained when the patient has improved.

Reference Values: CARBAMAZEPINE, TOTAL Therapeutic: 4.0-12.0 mcg/mL Critical value: > or =15.0 mcg/mL CARBAMAZEPINE-10,11-EPOXIDE Therapeutic concentration: 0.4-4.0 mcg/mL Toxic concentration: > or =8.0 mcg/mL

Clinical References: 1. Theodore WH, Narang PK, Holmes MD, et al: Carbamazepine and its epoxide: relation of plasma levels to toxicity and seizure control. Ann Neurol 1989;25:194-196 2. Tomson T, Almkvist O, Nilsson BY, et al: Carbamazepine-10, 11-epoxide in epilepsy. A pilot study. Arch Neurol 1990;47:888-892 3. McKauge L, Tyrer JH, Eadie MI: Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma. Ther Drug Monit 1981;3:63-70 4. Brodie MJ, Forrest G, Rapeport WG: Carbamazepine-10,11-epoxide concentrations in epileptics of carbamazepine alone and in Current as of August 23, 2017 7:11 am CDT


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combination with other anticonvulsants. Br J Clin Pharmacol 1983;16:747-749 5. Shoeman JF, Elyas AA, Brett EM, Lascelles PT: Correlation between plasma carbamazepine-10,11-epoxide concentration and drug side-effects in children with epilepsy. Dev Med Child Neurol 1984;26:756-764

CARNP

Carbapenemase Detection-Carba NP Test

62606

Clinical Information: Gram-negative bacilli (GNB) with acquired carbapenemases have disseminated worldwide, rendering them a global threat. The therapeutic armamentarium for infections caused by carbapenem-resistant Enterobacteriaceae (CRE) is limited, and CRE infections have been associated with significant mortality. Enterobacteriaceae harboring Klebsiella pneumoniae carbapenemase are endemic in some regions of the United States, and although still sporadic, GNB harboring New Delhi metallo-beta-lactamase have been reported from several states. Timely detection of these carbapenemases (along with emerging carbapenemases such as OXA-48 and VIM) is important. Detection is challenging since isolates may have only borderline reductions in susceptibility to carbapenems, and carbapenem resistance may be mediated by mechanisms other than carbapenemases (eg, AmpC or extended-spectrum beta-lactamase with decreased membrane permeability). While molecular methods are confirmatory, testing may not be immediately available and may be limited by the number of targets assayed. The modified Hodge test suffers from lack of specificity, a long turnaround time, and poor sensitivity for metallo-beta-lactamase detection. The Carba NP test is preferred over the modified Hodge test due to improved specificity and faster turnaround time. The Carba NP test is more specific than and as sensitive as the carbapenemase-modified Hodge test. If an isolate is suspected to possess KPC or NDM carbapenemase (eg, due to local epidemiology), KPC and NDM PCR (KPNRP / KPC (blaKPC) and NDM (blaNDM) in Gram-Negative Bacilli, Molecular Detection, PCR) may be preferred over the Carba NP test.

Useful For: Confirmation of carbapenemase production from pure isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species

Interpretation: A positive result indicates production of a carbapenemase by the isolate submitted for testing. A negative result indicates lack of production of a carbapenemase by the isolate submitted for testing.


Clinical References: 1. Vasoo S, Cunningham SA, Kohner P, et al: Comparison of a novel, rapid chromogenic biochemical assay, the Carba NP test, with the modified Hodge test for detection of carbapenemase-producing Gram-negative bacilli. J Clin Microbiol 2013;51(9):3097-3101 2. Nordmann P, Poirel L, Dortet L: Rapid detection of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 2012;18:1503-1507

CARNB

Carbapenemase Detection-Carba NP Test (Bill Only)

35953


199PC

Carbohydrate Antigen 19-9 (CA 19-9), Pancreatic Cyst Fluid

89508

Clinical Information: Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen, and has been used as a tumor marker. Serum CA 19-9 concentrations may be elevated in patients with gastrointestinal malignancies such as cholangiocarcinoma, colon cancer, or pancreatic cancer. While serum CA 19-9 is neither sensitive nor specific for pancreatic cancer, concentrations of CA 19-9 in pancreatic cyst fluid may help determine whether a pancreatic cyst is benign. Cystic lesions of the pancreas are of various types: -Benign cysts: - Inflammatory cysts (pseudocysts) - Serous cysts (serous cystadenoma) -Mucinous cysts: - Premalignant (mucinous cystadenoma) - Malignant



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(cystadenocarcinoma, intrapapillary mucinous neoplasia) Pancreatic cyst fluid CA 19-9 results should be used in conjunction with imaging studies, cytology, and other cyst-fluid tumor markers, such as carcinoembryonic antigen and amylase.

Useful For: As an adjunct in the assessment of pancreatic cysts, when used in conjunction with carcinoembryonic antigen, amylase, imaging studies and cytology

Interpretation: Cyst fluid carbohydrate antigen 19-9 (CA19-9) concentrations < or =37 U/mL indicate a low risk for a mucinous cyst, and are more consistent with serous cystadenoma or pseudocyst. The sensitivity and specificity are approximately 19% and 98%, respectively, at this concentration. Correlation of these test results with cytology and imaging is recommended.


Clinical References: 1. Snozek CL, Jenkins SM, Bryant SC, et al: Analysis of CEA, CA19-9 and amylase in pancreatic cyst fluid for diagnosis of pancreatic lesions. Clin Chem 2008;54(6 Suppl S):A126-127 2. van der Waaij LA, van Dullemen HM, Porte RJ: Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a polled analysis. Gastrointest Endosc 2005;62:383-389 3. Khalid A, Brugge W: ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol. 2007 Oct;102(10):2339-2349

199PT

Carbohydrate Antigen 19-9 (CA 19-9), Peritoneal Fluid

61530

Clinical Information: Malignancy accounts for approximately 7% of cases of ascites formation. Malignant disease can cause ascites by various mechanisms including: peritoneal carcinomatosis (53%), massive liver metastasis causing portal hypertension (13%), peritoneal carcinomatosis plus massive liver metastasis (13%), hepatocellular carcinoma plus cirrhosis (7%), and chylous ascites due to lymphoma (7%). The evaluation and diagnosis of malignancy-related ascites is based on the patient clinical history, ascites fluid analysis, and imaging tests. The overall sensitivity of cytology for the detection of malignancy-related ascites ranges from 58% to 75%. Cytology examination is most successful in patients with ascites related to peritoneal carcinomatosis as viable malignant cells are exfoliated into the ascitic fluid. However, only approximately 53% of patients with malignancy-related ascites have peritoneal carcinomatosis. Patients with other causes of malignancy-related ascites almost always have a negative cytology. Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen. CA 19-9 may be elevated in the serum patients with gastrointestinal malignancies such as cholangiocarcinoma, pancreatic cancer, or colon cancer. Measurement of CA 19-9 in ascitic fluid is sometimes used in combination with cytology for detecting malignancy-related ascites.

Useful For: An adjunct to cytology to differentiate between malignancy-related ascites and benign causes of ascites formation

Interpretation: A peritoneal fluid carbohydrate antigen 19-9 (CA 19-9) concentration >32 U/mL is suspicious, but not diagnostic, of a malignancy-related ascites. This clinical decision limit cutoff yielded 44% sensitivity and 93% specificity in a study of 137 patients presenting with ascites. However, ascites caused by malignancies not associated with increase serum CA 19-9 concentrations, including lymphoma, mesothelioma, leukemia, and melanoma, routinely had CA 19-9 concentrations or =20.0 U/mL is suspicious, but not diagnostic, of a malignant source of the effusion. This cutoff yielded a sensitivity of 35%, specificity of 95%, and positive predictive value of 88% in a study of 200 patients presenting with effusion. CA 19-9 concentrations were significantly higher in effusions caused by CA 19-9-secreting malignancies, including cholangiocarcinoma, colorectal, stomach, bile duct, lung, ovarian, and pancreatic cancers. However, effusions caused by non-CA 19-9-secreting malignancies, including lymphoma, mesothelioma, leukemia, and melanoma, routinely had CA 19-9 concentrations or =0.13

Apo CIII-1/Apo CIII-2 Ratio

< or =2.91 2.92-3.68

> or =3.69

Apo CIII-0/Apo CIII-2 Ratio

< or =0.48 0.49-0.68

> or =0.69

Clinical References: 1. Freeze HH: Congenital disorders of glycosylation: CDG-I, CDG II, and beyond. Curr Mol Med 2007;7:389-396 2. Freeze HH, Eklund EA, Ng BG, Patterson MC: Neurology of inherited glycosylation disorders. Lancet Neurol 2012;11:453-466 3. Hennet T, Cabalzar J: Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction. Trends Biochem Sci 2015 Jul;40(7):377-384 4. Freeze HH, Chong JX, Bamshad MJ, Ng BG: Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet 2014 Feb 6;94(2):161-175

CDTA

Carbohydrate Deficient Transferrin, Adult, Serum

82425

Clinical Information: Chronic alcoholism causes a transient change in the glycosylation pattern of transferrin where the relative amounts of disialo- and asialotransferrin (carbohydrate deficient transferrin: CDT) are increased over the amount of normally glycosylated tetrasialotransferrin. This recognition led to the use of CDT in serum as marker for chronic alcohol abuse. CDT typically normalizes within several weeks of abstinence of alcohol use. However, it is important to recognize that there are other causes of abnormal CDT levels, which include congenital disorders of glycosylation and other genetic and nongenetic causes of acute or chronic liver disease. CDT testing alone is not recommended for general screening for alcoholism; however, when combined with other methods (ie, gamma-glutamyltransferase, mean corpuscular volume, patient self-reporting, ethylglucuronide analysis) clinicians can expect to identify the majority of patients who consume a large amount of alcohol.

Useful For: An indicator of chronic alcohol abuse Interpretation: Patients with chronic alcoholism may develop abnormally glycosylated transferrin isoforms (ie, carbohydrate deficient transferring: CDT >0.12). CDT results from 0.11 to 0.12 are considered indeterminate. Patients with liver disease due to genetic or nongenetic causes may also have abnormal results.

Reference Values: < or =0.10 0.11-0.12 (indeterminate)

Clinical References: 1. De Giovanni N, Cittadini F, Martello S: The usefulness of biomarkers of Current as of August 23, 2017 7:11 am CDT


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alcohol abuse in hair and serum carbohydrate-deficient transferrin: a case report. Drug Test Anal 2015 Aug;7(8):703-707 2. Fleming MF, Anton RF, Spies CD: A review of genetic, biological, pharmacological, and clinical factors that affect carbohydrate-deficient transferrin levels. Alcohol Clin Exp Res 2004;28(9):1347-1355 3. Gough G, Heathers L, Puckett D, et al: The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. Alcohol Clin Exp Res 2015 Aug;39(8):1493-1500 4. Stibler H: Carbohydrate-deficient transferring in serum: a new marker of potentially harmful alcohol consumption reviewed. Clin Chem 1991;37:2029-2037 5. Torrente MP, Freeman WM, Vrana KE: Protein biomarkers of alcohol abuse. Expert Rev Proteomics 2012;9(4):425-436

CHOU

Carbohydrate, Urine

9255

Clinical Information: Saccharides (also called carbohydrates) are a group of mono-, di-, and oligosaccharides of endogenous and exogenous sources. Their presence frequently reflects dietary consumption, but can indicate specific pathology if either a particular saccharide or a particular excretory pattern is present. Most saccharides (except glucose) have low renal thresholds and are readily excreted in the urine. The presence of saccharides in urine is seen in some inborn errors of metabolism. Urine tests for reducing substances (eg, copper reduction test) are often used to screen for those disorders. However, in addition to sugars, a number of other substances present in biological fluids (eg, salicylates, uric acid, hippuric acid, ascorbic acid) have reducing properties. Conversely, some saccharides such as sucrose and trehalose do not have reducing properties. Other saccharides present at low concentrations may not be identified by reducing tests. Substances in urine may inhibit glucose oxidase-based tests and, also, other saccharides of diagnostic importance may be present along with glucose in urine. Chromatography of urinary saccharides is, therefore, required in many instances to identify the particular species of saccharide present. Any specimen tested for urinary carbohydrates is concurrently tested for the presence of succinyl nucleosides to screen for inborn errors of purine synthesis.

Useful For: Screening for disorders with increased excretion of fructose, glucose, galactose, disaccharides, oligosaccharides, and succinylpurines

Interpretation: The saccharide(s) present is named, identification of the probable source, and an interpretive comment is provided.

Reference Values: Negative If positive, carbohydrate is identified.

Clinical References: 1. Steinmann B, Gitzelmann R, Van den Berghe G: Disorders of fructose metabolism. OMMBID. OMMBID.Accessed 10 Nov 2015. Available from URL: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62671933 2. Race V, Marie S, Vincent M, et al: Clinical, biochemical and molecular genetic correlations in adenylosuccinate lyase deficiency. Hum Mol Genet 2000 Sep 1;9(14):2159-2165

COHBB

Carbon Monoxide, Blood

8649

Clinical Information: Carbon monoxide (CO) poisoning causes anoxia, because CO binds to hemoglobin with an affinity 240 times greater than that of oxygen, thus preventing delivery of oxygen to the tissues. Twenty percent saturation of hemoglobin induces symptoms (headache, fatigue, dizziness, confusion, nausea, vomiting, increased pulse, and respiratory rate). Sixty percent saturation is usually fatal. This concentration is reached when there is 1 part CO per 1,000 parts air. Carboxyhemoglobin diminishes at a rate of about 15% per hour when the patient is removed from the contaminated environment. The most common cause of CO toxicity is exposure to automobile exhaust fumes. Significant levels of carboxyhemoglobin can also be observed in heavy smokers. Victims of fires often show elevated levels from inhaling CO generated during combustion. Susceptibility to CO poisoning is increased in anemic persons.

Useful For: Verifying carbon monoxide toxicity in cases of suspected exposure Current as of August 23, 2017 7:11 am CDT


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Interpretation: The toxic effects of carbon monoxide can be seen above 20% carboxyhemoglobin. It must be emphasized that the carboxyhemoglobin concentration, although helpful in diagnosis, does not always correlate with the clinical findings or prognosis. Factors other than carboxyhemoglobin concentration that contribute to toxicity include length of exposure, metabolic activity, and underlying disease, especially cardiac or cerebrovascular disease. Moreover, low carboxyhemoglobin concentrations relative to the severity of poisoning may be observed if the patient was removed from the carbon monoxide-contaminated environment a significant amount of time before blood sampling.

Reference Values: Normal Concentration Non-Smokers: 0-2% Smokers: < or =9% Toxic concentration: > or =20%

Clinical References: 1. Langman LJ, Bechtel L, Holstege CP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. 5th edition. Elsevier Saunders, St. Louis, MO. 2012 pp 1109-1188 2. Disposition of Toxic Drugs and Chemicals in Man. 10th edition. Edited by RC Baselt. South Beach CA, Biomedical Publications, 2014 3. Instruction Manual: ABL80 FLEX CO-OX analyzer-OSM version, Radiometer Medical ApS, Denmark, 2016

THCX 62743

Carboxy-Tetrahydrocannabinol (THC) Confirmation, Chain of Custody, Urine Clinical Information: Delta-9-tetrahydrocannabinol is the active agent of the popularly abused street drug, marijuana. Following consumption of the drug, either by inhalation or ingestion, it is metabolized to a variety of inactive chemicals, 1 of them being delta-9-tetrahydrocannabinol carboxylic acid. The immunochemical procedure used to screen for tetrahydrocannabinol (THC) as part of IDOAU / Drug Abuse Survey, Urine is designed to cross-react with THC carboxylic acid. In almost all medico-legal cases and in screening of employees, or when the patient adamantly denies THC use and the immunochemical test is positive, confirmation of the result by gas chromatography-mass spectrometry and EIA are required. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection and confirmation of drug abuse involving delta-9-tetrahydrocannabinol (marijuana) Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: The presence of tetrahydrocannabinol carboxylic acid (THC-COOH), a major metabolite of delta-9-tetrahydrocannabinol, in urine at concentrations >15 ng/mL is a strong indicator that the patient has used marijuana. The metabolite of marijuana (THC-COOH) has a long half-life and can be detected in urine for more than 7 days after a single use. The presence of THC-COOH in urine >100 ng/mL indicates relatively recent use, probably within the past 7 days. Levels >500 ng/mL suggest chronic and recent use. Chronic use causes accumulation of THC and THC-COOH in adipose tissue such that it is excreted into the urine for as long as 30 to 60 days from the time chronic use is halted.

Reference Values: Negative Positives are reported with a quantitative GC-MS result. Cutoff concentrations: IMMUNOASSAY SCREEN 100.0 ng/mL indicates relatively recent use, probably within the past 7 days. Levels >500.0 ng/mL suggest chronic and recent use. Chronic use causes accumulation of THC and THC-COOH in adipose tissue such that it is excreted into the urine for as long as 30 to 60 days from the time chronic use is halted.

Reference Values: Negative Cutoff concentration: Carboxy-THC- by GC/MS or =200 ng/mL are highly suspicious for mucinous cysts. The greater the CEA concentration, the greater the likelihood that the mucinous cyst is malignant. However, CEA testing does not reliably distinguish between benign, premalignant, or malignant mucinous cysts. CEA test results should be correlated with the results of imaging studies, cytology, other cyst fluid tumor markers (ie, amylase and CA 19-9), and clinical findings for diagnosis.

Useful For: When used in conjunction with imaging studies, cytology, and other pancreatic cyst fluid tumor markers: -Distinguishing between mucinous and nonmucinous pancreatic cysts -Determining the likely type of malignant pancreatic cyst Current as of August 23, 2017 7:11 am CDT


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Interpretation: A pancreatic cyst fluid carcinoembryonic antigen (CEA) concentration of > or =200 ng/mL is very suggestive for a mucinous cyst but is not diagnostic. The sensitivity and specificity for mucinous lesions are approximately 62% and 93%, respectively, at this concentration. Cyst fluid CEA concentrations of < or =5 ng/mL indicate a low risk for a mucinous cyst, and are more consistent with serous cystadenoma, fluid collections complicating pancreatitis, cystic neuroendocrine tumor, or metastatic lesions. CEA values between these extremes have limited diagnostic value.


Clinical References: 1. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al: Diagnosis of pancreatic cystic neoplasms: a report of cooperative pancreatic cyst study. Gastroenterology 2004 May;126:1330-1336 2. Snozek CL, Jenkins SM, Bryant SC, et al: Analysis of CEA, CA 19-9, and amylase in pancreatic cyst fluid for diagnosis of pancreatic lesions. Clin Chem 2008;54(Suppl S):A126-127 3. Khalid A, Brugge W: ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol 2007 Oct;102(10):2339-2349

CEAPT

Carcinoembryonic Antigen (CEA), Peritoneal Fluid

61528

Clinical Information: Malignancy accounts for approximately 7% of cases of ascites formation. Malignant disease can cause ascites by various mechanisms including: peritoneal carcinomatosis (53%), massive liver metastasis causing portal hypertension (13%), peritoneal carcinomatosis plus massive liver metastasis (13%), hepatocellular carcinoma plus cirrhosis (7%), and chylous ascites due to lymphoma (7%). The evaluation and diagnosis of malignancy-related ascites is based on the patient clinical history, ascites fluid analysis, and imaging tests. The overall sensitivity of cytology for the detection of malignancy-related ascites ranges from 58% to 75%. Cytology examination is most successful in patients with ascites related to peritoneal carcinomatosis as viable malignant cells are exfoliated into the ascitic fluid. However, only approximately 53% of patients with malignancy-related ascites have peritoneal carcinomatosis. Patients with other causes of malignancy-related ascites almost always have a negative cytology. Carcinoembryonic antigen (CEA) is a glycoprotein that is shed from the surface of malignant cells. Measurement of CEA in ascitic fluid has been proposed as a helpful test in detecting malignancy-related ascites given the limited sensitivity of cytology.

Useful For: An adjunct to cytology to differentiate between malignancy-related and benign causes of ascites formation

Interpretation: A peritoneal fluid carcinoembryonic antigen (CEA) concentration >6.0 ng/mL is suspicious but not diagnostic of malignancy-related ascites. This clinical decision limit cutoff yielded 48% sensitivity and 99% specificity in a study of 137 patients presenting with ascites. CEA concentrations were significantly higher in ascites caused by malignancies known to be associated with elevated serum CEA levels including lung, breast, ovarian, gastrointestinal, and colorectal cancers. However, ascites caused by other malignancies such as lymphoma, mesothelioma, leukemia, and melanoma and hepatocellular carcinoma, routinely had CEA concentrations or =3.5 ng/mL is suspicious but not diagnostic of a malignant source of the effusion. This cutoff yielded a sensitivity of 52%, specificity of 95%, and part per volume of 93% in a study of 200 patients presenting with effusion. CEA concentrations were significantly higher in effusions caused by CEA-secreting malignancies, including lung, breast, ovarian, gastrointestinal, and colorectal cancers. However, effusions caused by non-CEA-secreting malignancies, including lymphoma, mesothelioma, leukemia, and melanoma, routinely had CEA concentrations 20 ng/mL) in a Current as of August 23, 2017 7:11 am CDT


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patient with compatible symptoms are strongly suggestive of the presence of cancer and also suggest metastasis. Most healthy subjects (97%) have values < or =3.0 ng/mL. After removal of a colorectal tumor, the serum CEA concentration should return to normal by 6 weeks, unless there is residual tumor. Increases in test values over time in a patient with a history of cancer suggest tumor recurrence.

Reference Values: Nonsmokers: < or =3.0 ng/mL Some smokers may have elevated CEA, usually or =100 Strongly positive Reference values apply to all ages.


CFIBR

Cardiac Fibrinogen, Plasma

83724

Clinical Information: Elevated plasma fibrinogen is a risk factor for cardiovascular disease.(1) Fibrinogen contributes to cardiovascular disease risk through a variety of mechanisms. Plasma viscosity is strongly influenced by fibrinogen concentrations. Fibrinogen is an acute-phase reactant indicative of chronic inflammatory status. Most importantly, fibrinogen and its enzymatic degradation product fibrin bind specifically to activated platelets to promote platelet aggregation and blood clotting. Carotid intimamedia thickness, a radiological measure of atherosclerosis, is significantly correlated with plasma fibrinogen concentrations.(2) Addition of plasma fibrinogen measurement to a prognostic model for cardiovascular disease that includes age, gender, tobacco use, blood pressure, history of diabetes, high density lipoprotein, and total cholesterol significantly improves 10-year risk classification. Fibrinogen assessment in patients at intermediate risk according to conventional biomarkers significantly improves classification.(3) Plasma fibrinogen concentrations can be significantly lowered by smoking cessation and increased physical activity.(4,5)

Useful For: Evaluating risk of atherosclerosis and adverse events related to atherosclerotic disease Interpretation: Elevated plasma fibrinogen confers increased risk of atherosclerosis, acute myocardial infarction, and stroke.

Reference Values: 450 mg/dL 4th quartile (high risk)

Clinical References: 1. Stec JJ, Silbershatz H, Tofler GH, et al: Association of fibrinogen with cardiovascular risk factors and cardiovascular disease in the Framingham offspring population. Circulation 2000;102:1634-1638 2. Antonini-Canterin F, Carrubba S, Gullace G, et al: Association between carotid atherosclerosis and metabolic syndrome: Results from the ISMIR study. Angiology 2010;61:443-448 3. Kaptoge S, Di Angelantonio E, Pennells L, et al: C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012;367:1310-1320 4. Blankengerg S, Luc G, Ducimetiere P, et al: The Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2003;108:2453-2459 5. Jarvie J, Whooley M, Regan M, et al: Effect of physical activity on biomarkers of inflammation and insulin resistance over years in outpatients with coronary heart disease. Current as of August 23, 2017 7:11 am CDT


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Am J Cardiol 2014;114:1192-1197

5361

Cardiovascular or Cardiopulmonary Consultation, Autopsy Clinical Information: Difficult cardiovascular and cardiopulmonary abnormalities, including congenital anomalies, sometimes require the assistance of a cardiac pathologist. This evaluation is offered to provide the careful dissection and diagnostic experience that may be needed for unusual or rare cardiovascular or cardiopulmonary cases.

Useful For: Evaluation of congenital heart disease Evaluation of pulmonary hypertension Evaluation of complex ischemic or valvular heart disease Evaluation of cardiomyopathies Evaluation of sudden unexplained death Not for cases under litigation

Interpretation: This request will be processed as a consultation. Appropriate stain(s) will be performed and a diagnostic interpretation provided.

Reference Values: Abnormalities will be compared to reported reference values.

Clinical References: 1. Edwards WD: Congenital heart disease. In Anderson's Pathology. Edited by J Linder, I Damjanov. St. Louis, MO, Mosby-Year Book, Inc., 1996, pp 1339-1396 2. Edwards WD: Pathology of myocardial infarction and reperfusion. In Acute Myocardial Infarction. Edited by BJ Gersh, S Rahimtoola. New York, Chapman and Hall, 1997, pp 16-50 3. Edwards WD: Cardiomyopathies. Major Prob Path 1991;23:257-309

CVRMP

Cardiovascular Risk Marker Panel, Serum

37002

Clinical Information: Cardiovascular disease is the number 1 cause of death in the United States with an estimated 1.5 million heart attacks and 0.5 million strokes occurring annually. Many of these events occur in individuals who have no prior symptoms. Standard risk factors, including age, smoking status, hypertension, diabetes, cholesterol, and HDL cholesterol, predict only about 65% of individuals who will go on to have a cardiovascular event. Therefore, identification of patients with residual risk is important to target lifestyle and pharmaceutical intervention to those at higher risk of future events. Many additional risk markers have been identified for cardiovascular disease but few have emerged as independent risk markers. Two of these additional risk markers, high-sensitivity C-reactive protein (hsCRP) and lipoprotein (a) (Lp[a]), are clearly shown to be independently associated with increased risk of future cardiovascular events. Several recent guidelines have suggested that clinicians utilize hsCRP and Lp(a) in selected persons to augment risk classification, guide intensity of risk-reduction therapy and modulate clinical judgment when making therapeutic decision.(1-3) Prospective studies assessing these risk factors individually have determined them to be independently associated with increased risk for the development of ischemic events. Guidelines recommend measurement of additional risk markers in individuals who are at intermediate risk for developing cardiovascular disease, those with early atherosclerosis without explanation by abnormalities of traditional risk factors, and those with a strong family history of cardiovascular disease without the presence of traditional risk factors.

Useful For: Assessment for risk of developing cardiovascular disease, major adverse cardiovascular events, or ischemic cerebrovascular events

Interpretation: Specific interpretations are provided based on lipid results according to Mayo Clinic care process models. Mayo Clinic has adopted the National Lipid Association classifications, which are included as reference values on Mayo Clinic and Mayo Medical Laboratories reports (see Reference Values). More aggressive treatment strategies may be pursued in patients determined to be at increased risk.

Reference Values: Age


2-17 years

>18 years


Page 408

Non-HDL Cholesterol (mg/dL)

** Acceptable: high: 120-144 High: > * Desirable: Above Desirable: 130-159 or =145 mg/dL Borderline high: 160-189 mg/dL High: 190-219 mg/dL Very high: > or =220 mg/dL

LDL Cholesterol (mg/dL)

** Acceptable: high: 110-129 High: > *** Desirable: Desirable: 100-129 or =130 Borderline high: 130-159 High: 160-189 Very high: > or =190

HDL Cholesterol (mg/dL)

** Low: low: 40-45 Acceptable: > 45 *** Males: > or =40 Females: > or =50

Total Cholesterol (mg/dL)

** Acceptable: high: 170-199 High: > * Desirable: < 200 Borderline high: or =200 200 - 239 High: > or = 240

LIPOPROTEIN (a) (mg/dL)

< or =30 mg/dL Values >30 mg/dL may suggest increased risk of coronary heart disease.

C-REACTIVE PROTEIN HIGH SENSITIVITY

* Lower risk: Higher risk: >=2.0 mg/L * Lower risk: Higher risk: >=2.0 mg/L Acute inflammation: >10.0 mg/L Acute inflammation: >10.0 mg/L 10-17 years

< or =30 mg/dL Values >30 mg/dL may suggest increased risk of coronary heart disease.

Age

2-9 years

>18 years

Triglycerides (mg/dL)

** Acceptable: high: 75-99 ** Acceptable: high: 90-129 * Normal: high: 150-199 High: High: > or =100 High: > or =130 200-499 Very high: > or =500 *National Lipid Association 2014 **Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents ***National Cholesterol Education Program (NCEP)

Clinical References: 1. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 - executive summary. J Clin Lipidol 2014 Sep-Oct;8(5):473-488 2. Perk J, DeBacker G, Gohlke H, et al: European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2012;33:1635-1701 3. Goff DC, Lloyd-Jones DM, Gennett G, et al: 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk. Circulation 2014;129:S49-S73 4. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents; National Heart, Lung, and Blood Institute: Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents. Pediatrics 2011;128;S213-S256 5. Ridker PM, Rifai N, Rose L, et al: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002 Nov 14;347(20):1557-1565 6. Ridker PM, Danielson E, Fonseca FA, et al: Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009;373:1175â€“1182

FCRDE 57524

Carmine Dye/Red Dye Cochineal (Dactylopius coccus) IgE (Red # 4) Interpretation: Class IgE (kU/L) Comment 0 or = 100 Very High Positive

Reference Values: or =18 years

34-78

25-54

5-30

0.1-0.8 *Values expressed as nmol/mL Schmidt-Sommerfeld E, Werner E, Penn D: Carnitine plasma concentrations in 353 metabolically healthy children. Eur J Pediatr 1988;147:356-360 Used with permission of European Journal of Pediatrics, Springer-Verlag, New York, Inc., Secaucus, NJ

Clinical References: 1. Magoulas PL, El-Hattab AW: Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet Journal of Rare Diseases 2012,7:68 Available from URL: http://www.ojrd.com/content/7/1/68. Accessed 1/22/15 2. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C(2):77-85 3. Zammit VA, Ramsay RR, Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev 2009;61(14):1353-1362

CARNS

Carnitine, Serum

60449

Clinical Information: Carnitine and its esters are required for normal energy metabolism and serve 4 primary functions: -Importing long-chain fatty acids into the mitochondria -Exporting naturally-occurring short-chain acyl-CoA groups from the mitochondria -Buffering the ratio of free CoA to esterified CoA -Removing potentially toxic acyl-CoA groups from the cells and tissues Evaluation of carnitine in serum, plasma, tissue, and urine screens patients for suspected primary disorders of the carnitine cycle, or secondary disturbances in carnitine levels as a result of organic acidemias and fatty acid oxidation disorders. In the latter disorders, acyl-CoA groups accumulate and are excreted into the urine and bile as carnitine derivatives, resulting in a secondary carnitine deficiency. More than 100 such primary and secondary disorders have been described. Individually, the incidence of these disorders varies from 1 in 1,000,000 live births. Collectively, their incidence is approximately 1 in 1,000 live births. Primary carnitine deficiency has an incidence of approximately 1 in 21,000 live births based on Minnesota newborn screening data. Other conditions which could cause an abnormal carnitine level are neuromuscular diseases, gastrointestinal disorders, familial cardiomyopathy, renal tubulopathies and chronic renal failure (dialysis), and prolonged treatment with steroids, antibiotics (pivalic acid), anticonvulsants (valproic acid), and total parenteral nutrition. Follow-up testing is required to differentiate primary and secondary carnitine deficiencies and to elucidate the exact cause.

Useful For: Evaluation of patients with a clinical suspicion of a wide range of conditions including organic acidemias, fatty acid oxidation disorders, and primary carnitine deficiency

Interpretation: When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.



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Reference Values: Total Carnitine (TC)Free Carnitine (FC) Acylcarnitine (AC)

AC/FC Ratio

Age Group

Range*

Range*

Range*

Range

1 day

23-68

12-36

7-37

0.4-1.7

2-7 days

17-41

10-21

3-24

0.2-1.4

8-31 days

19-59

12-46

4-15

0.1-0.7

32 days-12 months 38-68

27-49

7-19

0.2-0.5

13 months-6 years 35-84

24-63

4-28

0.1-0.8

7-10 years

28-83

22-66

3-32

0.1-0.9

11-17 years

34-77

22-65

4-29

0.1-0.9

> or =18 years

34-78

25-54

5-30

0.1-0.8 *Values expressed as nmol/mL Schmidt-Sommerfeld E, Werner E, Penn D: Carnitine plasma concentrations in 353 metabolically healthy children. Eur J Pediatr 1988;147:356-360 Used with permission of European Journal of Pediatrics, Springer-Verlag, New York, Inc., Secaucus, NJ

Clinical References: 1. Magoulas PL, El-Hattab AW: Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet Journal of Rare Diseases 2012,7:68 Available from URL: http://www.ojrd.com/content/7/1/68. Accessed 1/22/15 2. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C(2):77-85 3. Zammit VA, Ramsay RR, Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev 2009;61(14):1353-1362

CARNU

Carnitine, Urine

81123

Clinical Information: Carnitine and its esters are required for normal energy metabolism and serve 4 primary functions: -Importing long-chain fatty acids into the mitochondria -Exporting naturally occurring short-chain acyl-CoA groups from the mitochondria -Buffering the ratio of free CoA to esterified CoA -Removing potentially toxic acyl-CoA groups from the cells and tissues Evaluation of carnitine in serum, plasma, tissue, and urine screens patients for suspected primary disorders of the carnitine cycle, or secondary disturbances in carnitine levels as a result of organic acidemias and fatty acid oxidation disorders. In the latter, acyl-CoA groups accumulate and are excreted into the urine and bile as carnitine derivatives, resulting in a secondary carnitine deficiency. More than 100 such primary and secondary disorders have been described. Individually, the incidence of these disorders varies from 1 in 1,000,000 live births. Collectively, their incidence is approximately 1 in 1,000 live births. Primary carnitine deficiency has an incidence of approximately 1 in 21,000 live births based on Minnesota newborn screening data. Other conditions which could cause an abnormal carnitine level include neuromuscular diseases, gastrointestinal disorders, familial cardiomyopathy, renal tubulopathies and chronic renal failure (dialysis), and prolonged treatment with steroids, antibiotics (pivalic acid), anticonvulsants (valproic acid), and total parenteral nutrition. Follow-up testing is required to differentiate primary and secondary carnitine deficiencies and to elucidate the exact cause.

Useful For: Evaluation of patients with a clinical suspicion of a wide range of conditions including organic acidemias and fatty acid oxidation disorders Monitoring carnitine treatment

Interpretation: When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing and a phone number to Current as of August 23, 2017 7:11 am CDT


Page 412

reach one of the laboratory directors in case the referring physician has additional questions.

Reference Values: FREE 77-214 nmol/mg of creatinine TOTAL 180-412 nmol/mg of creatinine RATIO Acyl to free: 0.7-3.4

Clinical References: 1. Chalmers RA, Roe CR, Stacey TE, et al: Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine. Ped Res 1984;18:1325-1328 2. Magoulas PL, El-Hattab AW: Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet Journal of Rare Diseases 2012,7:68 Available from URL: http://www.ojrd.com/content/7/1/68. Accessed 1/22/15 3. Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C(2):77-85 4. Zammit VA, Ramsay RR, Bonomini M, Arduini A: Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev 2009;61(14):1353-1362

CACTZ 35379

Carnitine-Acylcarnitine Translocase Deficiency, Full Gene Analysis Clinical Information: Carnitine-acylcarnitine translocase (CACT) deficiency is a rare autosomal recessive disorder of fatty acid oxidation. The disease typically presents in the neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, hepatic dysfunction, skeletal muscle weakness, encephalopathy, and early death. However, presentations at a later age with a milder phenotype have also been reported. Initial screening can be done with plasma acylcarnitines. Definitive diagnosis can be made by detection of reduced CACT enzyme activity. Mutations in the SLC25A20 gene are responsible for CACT deficiency, and sequencing of this gene is recommended after positive biochemical analysis.

Useful For: Confirmation of diagnosis of carnitine-acylcarnitine translocase (CACT) deficiency Carrier screening in cases where there is a family history of CACT deficiency, but disease-causing mutations have not been identified in an affected individual


Clinical References: 1. Wang GL, Wang J, Douglas G, et al: Expanded molecular features of carnitine acyl-carnitine translocase (CACT) deficiency by comprehensive molecular analysis. Mol Genet Metab 2011 Aug;103(4):349-357 2. Rubio-Gozalbo ME, Bakker, JA, Waterham, HR, Wanders RJA: Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Mol Aspects Med 2004 Oct-Dec;25(5-6):521-532

CAROB

Carob, IgE

82368

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat



Page 413





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FCARO

Carotene, Beta

75178

Useful For: Confirm the diagnosis of carotenoderma; detect fat malabsorption; depressed carotene levels may be found in cases of steatorrhea.

Interpretation: High levels are useful to rule out steatorrhea but lower values lack specificity. There is poor sensitivity. High in the serum of those ingesting large amounts of vegetables.

Reference Values: 3 - 91 ug/dL

FCRTG

Carrot IgG

57630



FCASG

Casein IgG

57555

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: < 2 mcg/mL The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG tests has not been established. These tests can be used in special clinical situations to select foods for evaluation by diet elimination and challenge in patients who have food-related complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as



Page 415

evidence of food allergy and only indicates immunologic sensitization by the food allergen in question. This test should only be ordered by physicians who recognize the limitations of the test.

CASE

Casein, IgE

82895





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FCASH

Cashew IgG

57687

Interpretation: mcg/mL of IgG Lower Limit of Quantitation 2.0 Upper Limit of Quantitation 200 Reference Values: < 2 mcg/mL The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG tests has not been established. These tests can be used in special clinical situations to



Page 416

select foods for evaluation by diet elimination and challenge in patients who have food-related complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as evidence of food allergy and only indicates immunologic sensitization by the food allergen in question. This test should only be ordered by physicians who recognize the limitations of the test.

CASH

Cashew, IgE

82881





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CASRZ

CASR Gene, Full Gene Analysis

37439

Clinical Information: The extracellular G-protein-coupled calcium-sensing receptor (CASR) is an essential component of calcium homeostasis. CASR is expressed at particularly high levels in the parathyroid glands and kidneys. It forms stable homodimeric cell-membrane complexes, which signal upon binding of extracellular calcium ions (Ca[++]). In the parathyroid glands, this results in downregulation of gene expression of the main short-term regulator of calcium homeostasis, parathyroid



Page 417

hormone (PTH), as well as diminished secretion of already synthesized PTH. At the same time, renal calcium excretion is upregulated and sodium chloride excretion is downregulated. Ca(++) binding to CASR is highly cooperative within the physiological Ca(++) concentration range, leading to a steep dose-response curve, which results in tight control of serum calcium levels. To date, over 100 different alterations in the CASR gene have been described. Many of these cause diseases of abnormal serum calcium regulation. Inactivating mutations result in undersensing of Ca(++) concentrations and consequent PTH overproduction and secretion. This leads to either familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSPHT), depending on the severity of the functional impairment. Except for a very small percentage of cases with no apparent CASR mutations, FHH is due to heterozygous inactivating CASR mutations. Serum calcium levels are mildly-to-moderately elevated. PTH is within the reference range or modestly elevated, phosphate is normal or slightly low, and urinary calcium excretion is low for the degree of hypercalcemia. Unlike patients with primary hyperparathyroidism (PHT), which can be difficult to distinguish from FHH, the majority of FHH patients do not seem to suffer any adverse long-term effects from hypercalcemia and elevated PTH levels. They should, therefore, generally not undergo parathyroidectomy. NSPHT is usually due to homozygous or compound heterozygous inactivating CASR mutations, but can occasionally be caused by dominant-negative heterozygous mutations. The condition presents at birth, or shortly thereafter, with severe hypercalcemia requiring urgent parathyroidectomy. Activating mutations lead to oversensing of Ca(++), resulting in suppression of PTH secretion and consequently hypoparathyroidism. All activating mutations described are functionally dominant and disease inheritance is therefore autosomal dominant. However, sporadic cases also occur. Autosomal dominant hypoparathyroidism caused by CASR mutations may account for many cases of idiopathic hypoparathyroidism. Disease severity depends on the degree of gain of function, spanning the spectrum from mild hypoparathyroidism, which is diagnosed incidentally, to severe and early onset disease. In addition, while the majority of patients suffer only from hypoparathyroidism, a small subgroup with extreme gain of function mutations suffer from concomitant inhibition of renal sodium chloride transport. These individuals may present with additional symptoms of hypokalemic metabolic alkalosis, hyperreninemia, hyperaldosteronism, and hypomagnesemia, consistent with type V Bartter syndrome.

Useful For: Establishing a diagnosis of familial hypocalciuric hypercalcemia As part of the workup of some patients with primary hyperparathyroidism Establishing a diagnosis of neonatal severe primary hyperparathyroidism Establishing a diagnosis of autosomal dominant hypoparathyroidism As part of the workup of idiopathic hypoparathyroidism As part of the workup of patients with Bartter syndrome

Interpretation: Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Reference Values: An interpretive report will be provided

Clinical References: 1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-423 2. Hendy GN, D'Souza-Li L, Yang B, et al: Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hypocalciuric hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 2000 Oct;16(4):281-296. The authors maintain a CASR polymorphism/mutation database available at www.casrdb.mcgill.ca/ 3. Lienhardt A, Bai M, Lgarde JP, et al: Activating mutations of the calcium-sensing receptor: management of hypocalcemia. J Clin Endocrinol Metab 2001 Nov;86(1):5313-5323 4. Hu J, Spiegel AM: Naturally occurring mutations of the extracellular Ca2+ -sensing receptor: implications for its structure and function. Trends Endocrinol Metab 2003 Aug;14(6):282-288 5. Naesens M, Steels P, Verberckmoes R, et al: Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol 2004;96(3):65-78 6. Egbuna OI, Brown EM: Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations. Best Pract Res Current as of August 23, 2017 7:11 am CDT


Page 418

Clin Rheumatol 2008;22:129-148

CBN

Castor Bean, IgE

82770





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CAT

Cat Epithelium, IgE

82665

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and



Page 419

bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



COMT

Catechol-O-Methyltransferase (COMT) Genotype

83301

Clinical Information: Catechol-O-methyltransferase (COMT) is involved in phase II (conjugative) metabolism of catecholamines and catechol drugs, such as dopamine, as well as the catechol-estrogens. COMT transfers a donor methyl-group from S-adenosylmethionine to acceptor hydroxy groups on catechol structures (aromatic ring structures with vicinal hydroxy-groups).(1) Bioactive catecholamine metabolites are metabolized by COMT in conjunction with monoamine oxidase (MAO): -Norepinephrine is methylated by COMT forming normetanephrine. -Epinephrine is methylated by COMT forming metanephrine. -Dopamine is converted to homovanillic acid through the combined action of MAO and COMT. Parkinsonism patients receiving levodopa (L-DOPA) therapy are frequently also prescribed a COMT inhibitor to minimize metabolism of L-DOPA by COMT, thereby prolonging L-DOPA action. COMT is also involved in the inactivation of estrogens. Estradiol can be hydroxylated forming the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol.(2) These hydroxylated estradiols are methylated by COMT, forming the corresponding methoxyestradiols. Several studies have indicated the increased risk of breast cancer due to low activity COMT.(3) The gene encoding COMT is transcribed from alternative promoters to produce 2 forms of the enzyme, a soluble short form of the enzyme and a membrane-bound long form. Variants in the COMT gene are therefore designated in the literature by the position of the amino acid change in both the short and long form of the enzyme. A single nucleotide polymorphism in exon 4 of the gene produces an amino acid change from valine to methionine (Val108/158Met). This polymorphism, COMT*2, reduces the maximum activity of the variant enzyme by 25% and also results in significantly less immunoreactive COMT protein, resulting in a 3-fold to 4-fold decrease in activity compared to wild type COMT*1. The COMT*2 polymorphism has been linked to prefrontal cortex cognitive response to antipsychotic medications. Schizophrenia patients homozygous for



Page 420

the *2 polymorphism displayed improved cognition following drug treatment. Patients homozygous for *1 did not have improved cognition following treatment.(4) A second polymorphism has been identified in exon 4 that results in a threonine substitution for alanine (Ala52/102Thr). This polymorphism, COMT*3, does not reduce enzyme activity and is predicted to be a normally functioning allele.

Useful For: Early identification of patients who may show cognitive improvement with treatment for schizophrenia, this is associated with the COMT*2/ COMT*2 genotype Investigation of inhibitor dosing for decreasing L-DOPA metabolism Research use for assessing estrogen metabolism

Interpretation: An interpretive report will be provided. The normal genotype (wild type) for COMT is *1/*1. COMT*2 (Val108/158Met) leads to a reduced activity allele. COMT*3 (Ala52/102Thr) is a normal activity allele. The following information outlines the relationship between polymorphisms detected in this assay and the effect on the activity of the enzyme produced by that allele: COMT Allele Amino Acid Change Effect on Enzyme Activity/Metabolism *1 None (wild-type) Normal/Extensive *2 Val108/158Met Reduced/Poor *3 Ala52/102Thr Normal/Extensive


Clinical References: 1. Weinshilboum RM, Otterness DM, Szumlanski CL: Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Ann Rev Pharmacol Toxicol 1999;39:19-52 2. Zhu BT, Conney AH: Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998;19:1-27 3. Worda C, Sator MO, Schneeberger C, et al: Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reproduct 2003 Feb 18(2):262-266 4. Shield AJ, Thomae BA, Eckloff BW, et al: Human catechol-O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 2004 February;9(2):151-160 5. van Duursen MBM, Sanderson JT, de Jong PC, et al: Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues; Implications for catechol estrogen-induced DNA damage. Toxicol Sci 2004;81:316-324 6. Weickert TW, Goldberg TE, Mishara A, et al: Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Psychiatry 2004 Nov 1;56(9):677-682

COMTO

Catechol-O-Methyltransferase (COMT) Genotype, Saliva

60336

Clinical Information: Catechol-O-methyltransferase (COMT) is involved in phase II (conjugative) metabolism of catecholamines and catechol drugs, such as dopamine, as well as the catechol-estrogens. COMT transfers a donor methyl-group from S-adenosylmethionine to acceptor hydroxy groups on catechol structures (aromatic ring structures with vicinal hydroxy-groups).(1) Bioactive catecholamine metabolites are metabolized by COMT in conjunction with monoamine oxidase (MAO): -Norepinephrine is methylated by COMT-forming normetanephrine. -Epinephrine is methylated by COMT-forming metanephrine. -Dopamine is converted to homovanillic acid through the combined action of MAO and COMT. Parkinsonism patients receiving levodopa (L-dopa) therapy are frequently also prescribed a COMT inhibitor to minimize metabolism of L-dopa by COMT, thereby prolonging L-dopa action. COMT is also involved in the inactivation of estrogens. Estradiol can be hydroxylated forming the catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol.(2) These hydroxylated estradiols are methylated by COMT, forming the corresponding methoxyestradiols. Several studies have indicated the increased risk of breast cancer due to low-activity COMT.(3) The gene encoding COMT is transcribed from alternative promoters to produce 2 forms of the enzyme, a soluble short form of the enzyme and a membrane-bound long form. Variants in the COMT gene are therefore designated in the literature by the position of the amino acid change in both the short and long form of the enzyme. A single nucleotide polymorphism in exon 4 of the gene produces an amino acid change from valine to methionine (Val108/158Met). This polymorphism, COMT*2, reduces the maximum activity of the variant enzyme by 25% and also results in significantly less immunoreactive COMT protein, resulting in a 3- to 4-fold decrease in activity compared to wild type COMT*1. The COMT*2 polymorphism has been linked to prefrontal cortex cognitive response to antipsychotic medications. Schizophrenia patients homozygous for the *2 polymorphism displayed improved cognition following drug treatment. Patients homozygous for *1 did not have improved cognition following treatment.(4) A second polymorphism has been identified in exon 4 that



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results in a threonine substitution for alanine (Ala52/102Thr). This polymorphism, COMT*3, does not reduce enzyme activity and is predicted to be a normally functioning allele.

Useful For: Early identification of patients who may show cognitive improvement with treatment for schizophrenia; this is associated with the COMT*2/ COMT*2 genotype Investigation of inhibitor dosing for decreasing L-dopa metabolism Research use for assessing estrogen metabolism Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided. The normal genotype (wild type) for COMT is *1/*1. COMT*2 (Val108/158Met) leads to a reduced activity allele. COMT*3 (Ala52/102Thr) is a normal activity allele. The following information outlines the relationship between polymorphisms detected in this assay and the effect on the activity of the enzyme produced by that allele: COMT Allele Amino Acid Change Effect on Enzyme Activity/Metabolism *1 None (wild-type) Normal/Extensive *2 Val108/158Met Reduced/Poor *3 Ala52/102Thr Normal/Extensive


Clinical References: 1. Weinshilboum RM, Otterness DM, Szumlanski CL: Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Ann Rev Pharmacol Toxicol 1999;39:19-52 2. Zhu BT, Conney, AH: Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998;19:1-27 3. Worda C, Sator MO, Schneeberger C, et al: Influence of the catechol-O-methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reproduct 2003 Feb;18(2):262-266 4. Shield AJ, Thomae BA, Eckloff BW, et al: Human catechol-O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 2004 February;9(2):151-160 5. van Duursen MBM, Sanderson JT, de Jong PC, et al: Phytochemicals inhibit catechol-O-methyltransferase activity in cytosolic fractions from healthy human mammary tissues; Implications for catechol estrogen-induced DNA damage. Toxicol Sci 2004;81:316-324 6. Weickert TW, Goldberg TE, Mishara A, et al: Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Psychiatry 2004 Nov 1;56(9):677-682

CATU

Catecholamine Fractionation, Free, 24 Hour, Urine

9276

Clinical Information: The catecholamines (dopamine, epinephrine, and norepinephrine) are derived from tyrosine via a series of enzymatic conversions. All 3 catecholamines are important neurotransmitters in the central nervous system and play crucial roles in the autonomic regulation of many homeostatic functions, namely, vascular tone, intestinal and bronchial smooth muscle tone, cardiac rate and contractility, and glucose metabolism. Their actions are mediated via alpha and beta adrenergic receptors and dopamine receptors, all existing in several subforms. The 3 catecholamines overlap but also differ in their receptor activation profile and consequent biological actions. The systemically circulating fraction of the catecholamines is derived almost exclusively from the adrenal medulla, with small contributions from sympathetic ganglia. They are normally present in the plasma in minute amounts, but levels can increase dramatically and rapidly in response to change in posture, environmental temperature, physical and emotional stress, hypovolemia, blood loss, hypotension, hypoglycemia, and exercise. In patients with pheochromocytoma, a potentially curable tumor of catecholamine producing cells of the adrenal medulla, or less commonly of sympathetic ganglia (paraganglioma), urine catecholamine levels may be elevated. This results in episodic or sustained hypertension and often in intermittent attacks of palpitations, cardiac arrhythmias, headache, sweating, pallor, anxiety, tremor, and nausea ("spells"). Elevations of the urine levels of 1 or several of the catecholamines also may be observed in patients with neuroblastoma and related tumors (ganglioneuroblastomas and ganglioneuromas) and, very occasionally, in other neuroectodermal tumors. At the other end of the spectrum, inherited and acquired syndromes of autonomic dysfunction/failure and autonomic neuropathies are characterized by either inadequate production of 1 or several of the catecholamines, or by insufficient release of catecholamines upon appropriate physiological stimuli (eg, change in posture from supine to standing, cold exposure, exercise, stress).

Useful For: An auxiliary test to fractionated plasma and urine metanephrine measurements in the Current as of August 23, 2017 7:11 am CDT


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diagnosis of pheochromocytoma and paraganglioma An auxiliary test to urine vanillylmandelic acid and homovanillic acid determination in the diagnosis and follow-up of patients with neuroblastoma and related tumors

Interpretation: Diagnosis of Pheochromocytoma: This test should not be used as the first-line test for pheochromocytoma. PMET / Metanephrines, Fractionated, Free, Plasma (the most sensitive assay) and/or METAF / Metanephrines, Fractionated, 24 Hour, Urine (almost as sensitive and highly specific) are the recommended first-line laboratory tests for pheochromocytoma. However, urine catecholamine measurements can still be useful in patients whose plasma metanephrines or urine metanephrines measurements do not completely exclude the diagnosis. In such cases, urine catecholamine specimens have an 86% diagnostic sensitivity when cut-offs of >80 mg/24 hour for norepinephrine and >20 mg/24 hour for epinephrine are employed. Unfortunately, the specificity of these cut-off levels for separating tumor patients from other patients with similar symptoms is only 88%. When more specific (98%) decision levels of >170 mg/24 hours for norepinephrine or >35 mg/24 hours for epinephrine are used, the assayâ€™s sensitivity falls to about 77%. Diagnosis of Neuroblastoma: Vanillylmandelic acid, homovanillic acid, and sometimes urine catecholamine measurements on spot urine or 24-hour urine are the mainstay of biochemical diagnosis and follow-up of neuroblastoma; 1 or more of these tests may be elevated.

Reference Values: NOREPINEPHRINE or =19 years: 4.6-22.1% CD19 ABSOLUTE > or =19 years: 56.6-417.4 cells/mcL %CD20 B CELLS > or =19 years: 5.0-22.3% CD20 ABSOLUTE > or =19 years: 74.4-441.1 cells/mcL CD45 ABSOLUTE 18-55 years: 0.99-3.15 thou/mcL >55 years: 1.00-3.33 thou/mcL

Clinical References: 1. Nadler LM, Ritz J, Hardy R, et al: A unique cell-surface antigen identifying lymphoid malignancies of B-cell origin. J Clin Invest 1981;67:134 2. Robillard N, Avet-Loiseau H, Garand R, et al: CD20 is associated with a small mature plasma cell morphology and t(11;14) in multiple myeloma. Blood 2003;102(3):1070-1071 3. Pescovitz MD: Rituximab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 2006;6:859-866 4. van Zelm MC, Reisli I, van der Burg M, et al: An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006;354:1901-1912 5. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 6. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009 May 21;113(21):5134-5143 7. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 8. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis Current as of August 23, 2017 7:11 am CDT


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hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 9. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 10. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516

88583

CD20, Immunostain Without Interpretation Clinical Information: CD20 is a phosphorylated protein preferentially expressed by mature B lymphocytes. CD20 is not expressed by most normal plasma cells. It is one of the most specific B-cell lineage-associated antigens used in the diagnosis of B-cell lymphomas.

Useful For: Classification of lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Cartun RW, Coles FB, Pastuszak WT: Utilization of monoclonal antibody L26 in the identification and confirmation of B-cell lymphomas. A sensitive and specific marker applicable to formalin- and B5-fixed, paraffin-embedded tissues. Am J Pathol 1987;129(3):415-421 2 Kurtin PJ, Hobday KS, Ziesmer S, Caron BL: Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol 1999;112(3):319-329 3. de Leon ED, Alkan S, Huang JC, Hsi ED: Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkinâ€™s lymphomas of small lymphocytes. Mod Pathol 1998;11(11):1046-1051 4. Martinez AE, Lin L, Dunphy CH: Grading of follicular lymphoma: comparison of routine histology with immunohistochemistry. Arch Pathol Lab Med 2007;131(7):1084-1088

60832

CD21, Immunostain Without Interpretation Clinical Information: CD21 strongly stains the cytoplasm and membranes of the follicular dendritic cells and the membranes of a subset of the mantle zone lymphocytes. Follicular dendritic cells form a basket-weave meshwork in the germinal centers of lymphoid follicles, where they present antigens to B cells. Diagnostically, CD21 may be useful to support a diagnosis of follicular dendritic cell sarcoma, or to confirm the presence of lymphoid follicles.

Useful For: Identification of follicular dendritic cells and a subset of mantle zone lymphocytes Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is no included on the slide, the scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patientâ€™s clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. de Leval L, Harris NL, Longtine J, et al: Cutaneous B-cell lymphomas of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 in differential diagnosis and classification. Am J Surg Pathol 2001;25(6):732-741 2. Maeda K, Matsuda M, Suzuki H, et al: Immunohistochemical recognition of human follicular dendritic cells (FDCâ€™s) in routinely processed paraffin sections. J Histochem Cytochem 2002;50(11):1475-1485. 3. Mesquita RA, de Araujo VC, Paes RAP, et al: Immunohistochemical analysis for CD21, CD35, caldesmon and S100 protein on dendritic cells types in oral lymphomas. J Appl Oral Sci 2009;17(3):248-253 4. Nakamura S, Nagahama M, Kagami Y, et al: Hodgkinâ€™s disease expressing follicular dendritic cell marker CD21 without any Current as of August 23, 2017 7:11 am CDT


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other B-cell marker: a clinicopathologic study of nine cases. Am J Surg Pathol 1999;23(4):363-376

60833

CD22, Immunostain Without Interpretation Clinical Information: CD22 is expressed on B lymphocytes. It can be used as an alternative B-cell marker to CD20 or CD79a. Diagnostically, CD22 is useful to confirm B-cell lineage in malignant lymphomas.

Useful For: Determining B-cell lineage Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Agis H, Krauth MT, Mosberger I, et al: Enumeration and immunohistochemical characterization of bone marrow basophils in myeloproliferative disorders using the basophil specific monoclonal antibody 2D7. J Clin Pathol 2006;59(4):396-402 2. Browne P, Petrosyan K, Hernandez A, Chan JA: The B-cell transcription factors BSAP, Oct-2, and BOB.1 and the pan-B-cell markers CD20, CD22, and CD79a are useful in the differential diagnosis of classic Hodgkin lymphoma. Am J Clin Pathol 2003;120:767-777 3. Garcia CF, Swerdlow SH: Best practices in contemporary diagnostic immunohistochemistry: panel approach to hematolymphoid proliferations. Arch Pathol Lab Med 2009;133(5):756-765

60896

CD23, Immunostain Without Interpretation Clinical Information: CD23 strongly stains the cytoplasm and membranes of follicular dendritic cells and the membranes of a subset of follicular mantle zone B-lymphocytes. Typically, B-cell small lymphocytic lymphoma/chronic lymphocytic leukemias are CD5 positive and CD23 positive, while mantle cell lymphoma is CD5 positive and CD23 negative. Antibodies to CD23 are diagnostically useful in the classification of low-grade B-cell lymphomas.

Useful For: Identification of follicular dendritic cells and useful in the classification of low-grade B-cell lymphomas


Clinical References: 1. Higgins RA, Blankenship JE, Kinney MC: Application of immunohistochemistry in the diagnosis of non-Hodgkin and Hodgkin lymphoma. Arch Pathol Lab Med 2008;132(3):441-461 2. Kurtin PJ, Hobday KS, Ziesmer S, Caron BL: Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol 1999;112(3):319-329 3. Linderoth J, Jerkeman M, Cavallin-Stahl E, et al: Immunohistochemical expression of CD23 and CD40 may identify prognostically favorable subgroups of diffuse large B-cell lymphoma: a Nordic lymphoma group study. Clin Cancer Res 2003;9:722-728

60834

CD25, Immunostain Without Interpretation Clinical Information: CD25 is the receptor for IL2 and is expressed on activated T cells, B cells, and macrophages. It will stain only scattered cells in normal tonsil. CD25 is expressed in certain types of



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B-cell lymphoma (hairy cell leukemia) and T-cell lymphoma (adult T-cell lymphoma/leukemia [ATLL]). An anti-CD25 therapy can be used in patients who have lymphomas that express CD25.

Useful For: Classification of lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Hahn H, Hornick JL: Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol 2007;31(11):1669-1676. 2. Sotlar K, Horny HP, Simonitsch I, et al: CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol 2004;28(10):1319-1325 3. Talpur R, Jones DM, Alencar AJ, et al: CD25 expression is correlated with histological grade and response to denileukin difitox in cutaneous T-cell lymphoma. J Invest Dermatol 2006;126:575-583

60835

CD279 (PD-1), Immunostain Without Interpretation Clinical Information: CD279 (PD-1) is an immunoregulatory receptor highly expressed by follicular T helper cells, and its expression has also been shown in the neoplastic counterpart of this T-cell subset, angioimmunoblastic T-cell lymphoma. This molecule interacts with PD-L1 (B7H1) expressed on follicular dendritic cells and other cell types, which serves to attenuate T-cell activation. In the appropriate histologic context, a background rich in CD279-positive T cells can support a diagnosis of nodular lymphocyte-predominant Hodgkin lymphoma.

Useful For: Identification of follicular T helper cells and phenotyping of angioimmunoblastic T-cell lymphoma


Clinical References: 1. Dorfman DM, Brown JA, Shahsafaie A, Freeman G: Programmed death-1 (PD-1) is a marker of geminal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2006 Jul;30(7):802-810 2. Roncador G, GarcÃ-a Verdes-Montenegro JF, Tedoldi S, et al: Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica 2007 Aug;92(8):1059-1066 3. Kobayashi M, Kawano S, Hatachi S, et al: Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjogren's Syndrome. J Rheumatol 2005 Nov;32(11):2156-2163

88577

CD3, Immunostain Without Interpretation Clinical Information: CD3 is part of the T-cell antigen receptor complex found on the surface of T lymphocytes. In paraffin sections, antibodies to CD3 will also react with a subset of natural killer cells that express the cytoplasmic epsilon chain of CD3. In normal tonsil, the T cells predominate in the interfollicular regions. Diagnostically, antibodies to CD3 are useful in demonstrating T-cell lineage of malignant lymphomas.

Useful For: Demonstrating T-cell lineage Interpretation: This test includes only technical performance of the stain (no pathologist interpretation Current as of August 23, 2017 7:11 am CDT


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is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Oudejans JJ, van der Valk P: Immunohistochemical classification of T cell and NK cell neoplasms. J Clin Pathol 2002;55(2):892 2. Steward M, Bishop R, Piggott NH, et al: Production and characterization of a new monoclonal antibody effective in recognizing the CD3 T-cell associated antigen in formalin-fixed embedded tissue. Histopathology 1997;30(1):16-22 3. Went P, Agostinelli C, Gallamini A, et al: Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006;24(16):2472-2479

60836

CD30, Immunostain Without Interpretation Clinical Information: CD30 is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Expression of CD30 can also be seen in embryonal carcinomas, malignant melanomas, mesenchymal tumors, and activated T and B lymphocytes and plasma cells. Reed-Sternberg cells of classical Hodgkin lymphoma, as well as the neoplastic cells of anaplastic large cell lymphoma express CD30.

Useful For: Identification of CD30 expression in a variety of neoplasms Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Barry T, Jaffe ES, Sorbara L. et al: Peripheral T-cell lymphomas expressing CD30 and CD15. Am J Surg Pathol 2003;27(12):1513-1522 2. Jaffe ES: Anaplastic large cell lymphoma: the shifting sands of diagnostic hematopathology. Mod Pathol 2001;14(3):219-228 3. Sabattini E, Pizzi M, Tabanelli V, et al: CD30 expression in peripheral T-cell lymphomas. Haematologica 2013;98(8):e81-e82

60837

CD31, Immunostain Without Interpretation Clinical Information: CD31 is expressed on endothelial cells, showing some membrane and occasional cytoplasmic staining. It is not expressed on discontinuous endothelium (eg, splenic red pulp). It is also expressed on megakaryocytes, histiocytes, plasma cells, and T-cell subsets. Tonsil sections will exhibit endothelial positivity in vessels primarily located in connective tissue areas around follicles and near the epithelial borders. Diagnostically, CD31 expression can confirm a diagnosis of angiosarcoma, a neoplasm of endothelial cells.

Useful For: Marker of endothelial cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required; order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's.

Clinical References: 1. Gill, R, Oâ€™Donnell RJ, Horval A: Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hemangioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med 2009;133(6):967-972 2. McKenney JK, Weiss SW, Folpe AL: CD31 expression in intratumoral macrophages: a potential diagnostic pitfall 2001. Am J Surg Pathol 25(9):1167-1173 3. Miettinen M, Lindenmayer AE, Chaubal A: Endothelial cell markers CD31, CD34, Current as of August 23, 2017 7:11 am CDT


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and BNH9 antibody to H- and Y- antigens-evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol 1994;7(1):82-90 4. Pusztaszeri MP, Seelentag W, Bosman FT: Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 2006;54(4):385-395

60838

CD33, Immunostain Without Interpretation Clinical Information: CD33 is a transmembrane protein that is a member of the sialic acid-binding immunoglobulin-like lactic (Siglec) family. The exact function of CD33 is not known but it may be involved in cell to cell adhesion. It is not expressed on hematopoietic stem cells, but is expressed on maturing myelomonocytic cells. As granulocytes mature, there is progressive down regulation of CD33. Monocytes and macrophage/histiocytic cells maintain strong expression of CD33. In normal bone marrow, weak to moderate CD33 staining is seen on granulocytic and monocytic precursors, with strong staining in scattered mast cells. CD33 staining is useful for diagnosis of myeloid neoplasms and classification of acute leukemias. A therapeutic antibody targeting CD33 (gemtuzumab/Myelotarg) is available.

Useful For: Classification of myeloid neoplasms and acute leukemias Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Jilani I, Estey E, Huh Y, et al: Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol 2002 Oct;118(4):560-566 2. Thalhammer-Scherrer R, Mitterbauer G, Simonitsch I, et al: The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination. Am J Clin Pathol 2002 Mar;117(3):380-389

60839

CD34, Immunostain Without Interpretation Clinical Information: CD34 is 115 kD membrane associated antigen found on human hematopoietic progenitor cells and vascular endothelial cells. In normal tonsil sections, antibodies to CD34 strongly stain vascular endothelial cells. Diagnostically, CD34 is used as a marker of immaturity in the setting of acute myeloid leukemia or B lymphoblastic leukemia. It is also useful in the classification of spindle cell neoplasms (gastrointestinal stromal tumors, solitary fibrous tumors, and angiosarcomas are often positive).

Useful For: A marker of hematopoietic progenitor cells and vascular endothelial cells Classification of spindle cell neoplasms


Clinical References: 1. Gill, R, Oâ€™Donnell RJ, Horval A: Utility of immunohistochemistry for endothelial markers in distinguishing epithelioid hemangioendothelioma from carcinoma metastatic to bone. Arch Pathol Lab Med 2009;133(6):967-972 2. Miettinen M, Lindenmayer AE, Chaubal A: Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y- antigens-evaluation of their Current as of August 23, 2017 7:11 am CDT


Page 441

specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol 1994;7(1):82-90 3. Pusztaszeri MP, Seelentag W, Bosman FT: Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 2006;54(4):385-395

60840

CD35, Immunostain Without Interpretation Clinical Information: CD35 stains the membrane and cytoplasm of follicular dendritic cells and granulocytes. Follicular dendritic cells form a basketweave meshwork in the germinal centers of lymphoid follicles, where they present antigens to B cells. CD35 is useful in the diagnosis of follicular dendritic-cell sarcoma.

Useful For: Identification of follicular dendritic cells and granulocytes Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Biddle DA, Jae YR, Yoon GS, et al: Extranodal follicular dendritic cell sarcoma of the head and neck region: three new cases, with a review of the literature. Mod Pathol 2002 Jan;15(1):50-58 2. Maeda K, Matsuda M, Suzuki H, et al: Immunohistochemical recognition of human follicular dendritic cells (FDCâ€™s) in routinely processed paraffin sections. J Histochem Cytochem 2002;50(11):1475-1485 3. Mesquita RA, de Araujo VC, Paes RA, et al: Immunohistochemical analysis for CD21, CD35, Caldesmon and S100 protein on dendritic cells types in oral lymphomas. J Appl Oral Sci 2009;17(3):248-253

60841

CD38, Immunostain Without Interpretation Clinical Information: CD38 is a transmembrane protein that shows enzymatic activity involved in the production of calcium mobilizing compounds and receptor activity involved in cellular adhesion and signaling in leukocytes. It is expressed in a variety of cell types including hematopoietic precursors, plasma cells, germinal center B cells (weakly), a subset of T and natural killer cells, erythrocytes, platelets, prostatic epithelium, and smooth and striated muscle cells. In some cases it may be a marker of activation. CD38 expression may be useful in the diagnosis of lymphoproliferative and plasma cell proliferative disorders. Determination of CD38 expression by flow cytometry has been used as a prognostic marker on chronic lymphocytic leukemia.

Useful For: Classification of lymphoproliferative and plasma cell proliferative disorders Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Zupo S, Rugari E, Dono M, et al: CD38 signaling by agonistic monoclonal antibody prevents apoptosis of human germinal center B cells. Eur J Immunol 1994;24:1218-1222 2. Rodig SJ, Vergilio JA, Shahsafaei A, et al: Characteristic expression patterns of TCL1, CD38, and CD44 identify aggressive lymphomas harboring a MYC translocation. Am J Surg Pathol 2008 Jan;32(1):113-122 3. Soma LA, Craig FE, Swerdlow SH: The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol 2006 Feb;37(2):152-159



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TCD4

CD4 Count for Immune Monitoring, Blood

84348

Clinical Information: Lymphocytes in peripheral blood (circulation) are heterogeneous and can be broadly classified into T cells, B cells, and natural killer cells. There are various subsets of each of these individual populations with specific cell-surface markers and function. This assay provides absolute (cells/mcL) and relative (%) quantitation for total T cells and CD4+ and CD8+ T-cell subsets, in addition to a total lymphocyte count (CD45+). Each of these lymphocyte subpopulations have distinct effector and regulatory functions and are maintained in homeostasis under normal physiological conditions. Each of these lymphocyte subsets can be identified by a combination of 1 or more cell surface markers. The CD3 antigen is a pan-T cell marker, and T cells can be further divided into 2 broad categories, based on the expression of CD4 or CD8 co-receptors. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells increase between 8:30 a.m. and noon with no change between noon and afternoon.(1) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(2-4) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(2) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the evening(5) and during summer compared to winter.(6) These data, therefore, indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets. Abnormalities in the number and percent of CD3, CD4, and CD8 T cells have been described in a number of different disease conditions. In patients who are infected with HIV, the CD4 count is measured for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of CD4 T-lymphocytes in patients infected with HIV is associated with increased infections and complications. The Public Health Service has recommended that all HIV-positive patients be tested every 3 to 6 months for the level of CD4 T-lymphocytes. Basic T-cell subset quantitation is also very useful in the evaluation of patients with primary cellular immunodeficiencies of all ages, including follow-up for newborn screening for severe combined immunodeficiency and immune monitoring following immunosuppressive therapy for transplantation, autoimmunity, or any other relevant clinical condition where immunomodulatory treatment is used, and the T-cell compartment is specifically affected. It is also helpful as a preliminary screening assay for gross quantitative anomalies in T cells, whether related to malignancies or infection.

Useful For: Serial monitoring of CD4 T cell count in HIV-positive patients Useful for follow-up and diagnostic evaluation of primary cellular immunodeficiencies, including severe combined immunodeficiency T-cell immune monitoring following immunosuppressive therapy for transplantation, autoimmunity, and other immunological conditions where such treatment is utilized Assessment of T-cell immune reconstitution post hematopoietic cell transplantation Early screening of gross quantitative anomalies in T cells in infection or malignancies

Interpretation: HIV treatment guidelines from the US Department of Health and Human Services and the International Antiviral Society USA Panel recommend antiviral treatment in all patients with HIV infection, regardless of CD4 T-cell count.(7,8) Additionally, antibiotic prophylaxis for Pneumocystis jiroveci infection and other opportunistic infections is recommended for patients with CD4 counts below 200 cells/mcL.

Reference Values: The appropriate age-related reference values will be provided on the report.

Clinical References: 1. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 2. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009;113:5134-5143 3. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 4. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Pyschosom Med 1997;59:42-50 5. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 6. Paglieroni TG, Current as of August 23, 2017 7:11 am CDT


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Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516 7. US Department of Health and Human Services: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://aidsinfo.nih.gov/guidelines 8. Thompson MA, Aberg JA, Hoy JF, et al: Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012;308:387-402

CD4NY

CD4 Count for Monitoring, New York, Blood

28334

Clinical Information: Lymphocytes in peripheral blood (circulation) are heterogeneous and can be broadly classified into T cells, B cells, and natural killer (NK) cells. There are various subsets of each of these individual populations with specific cell-surface markers and function. This assay provides absolute (cells/mcL) and relative (%) quantitation for total T cells and CD4+ and CD8+ T-cell subsets, in addition to a total lymphocyte count (CD45+). Each of these lymphocyte subpopulations have distinct effector and regulatory functions and are maintained in homeostasis under normal physiological conditions. Each of these lymphocyte subsets can be identified by a combination of 1 or more cell surface markers. The CD3 antigen is a pan T-cell marker, and T cells can be further divided into 2 broad categories, based on the expression of CD4 or CD8 coreceptors. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells increase between 8:30 a.m. and noon with no change between noon and afternoon.(1) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(2-4) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(2) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the evening(5) and during summer compared to winter.(6) These data therefore indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets. Abnormalities in the number and percent of CD3, CD4, and CD8 T cells have been described in a number of different disease conditions. In patients who are infected with HIV, the CD4 count is measured for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of CD4 T lymphocytes in patients infected with HIV is associated with increased infections and complications. The Public Health Service has recommended that all HIV-positive patients be tested every 3 to 6 months for the level of CD4 T lymphocytes. Basic T-cell subset quantitation is also very useful in the evaluation of patients with primary cellular immunodeficiencies of all ages, including follow-up for newborn screening for severe combined immunodeficiency and immune monitoring following immunosuppressive therapy for transplantation, autoimmunity, or any other relevant clinical condition where immunomodulatory treatment is used, and the T-cell compartment is specifically affected. It is also helpful as a preliminary screening assay for gross quantitative anomalies in T cells, whether related to malignancies or infection.

Useful For: Serial monitoring of CD4 T-cell count in HIV-positive patients Follow-up and diagnostic evaluation of primary cellular immunodeficiencies, including severe combined immunodeficiency T-cell immune monitoring following immunosuppressive therapy for transplantation, autoimmunity, and other immunological conditions where such treatment is utilized Assessment of T-cell immune reconstitution post hematopoietic cell transplantation Early screening of gross quantitative anomalies in T cells in infection or malignancies

Interpretation: HIV treatment guidelines from the US Department of Health and Human Services and the International Antiviral Society-USA Panel recommend antiviral treatment in all patients with HIV infection, regardless of CD4 T-cell count.(7,8) Additionally, antibiotic prophylaxis for Pneumocystis jiroveci infection and other opportunistic infections is recommended for patients with a CD4 count below 200 cells/mcL.


Clinical References: 1. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract # B11052 2. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009 May Current as of August 23, 2017 7:11 am CDT


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21;113(21):5134-5143 3. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 4. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 5. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J Acquir Immune Defic Syndr 1990;3(2):144-151 6. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516 7. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://aidsinfo.nih.gov/guidelines 8. Thompson MA, Aberg JA, Hoy JF, et al: Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA Panel. JAMA 2012;308:387-402

CD4RT

CD4 T-Cell Recent Thymic Emigrants (RTE)

89504

Clinical Information: Naive T-cells are generated in the thymus and exported to peripheral blood to form the peripheral T-cell repertoire. There is a decrease in naive T cells derived from the thymus with age due to age-related decline in thymic output. Recent thymic emigrants (RTEs) typically refers to those populations of naive T cells that have not diluted their TREC copies (T-cell receptor excision circles) by homeostatic or antigen-driven cell division. Naive T cells can be long-lived in the periphery and postpuberty, and in adults, peripheral T-cell homeostasis is maintained by a balance of thymic output and peripheral T-cell expansion and this proportion changes with age. In infants and prepubertal children, the T-cell repertoire is largely maintained by thymic-derived naive T cells. RTEs express TRECs indicative of naive T cells derived from the thymus.(1) In the CD4 T-cell compartment it has been shown that naive CD45RA+ T cells coexpressing CD31 had a higher frequency of TREC compared to T cells lacking CD31.(2) The higher proportion of TREC+ naive T cells indicate a more recent thymic ontogeny since TRECs can be diluted by cell division (since they are extrachromosomal). It has been shown that CD31+CD4+ T cells continue to possess a relatively higher proportion of TREC despite an age-related 10-fold reduction after the neonatal period.(3) CD4 RTEs (CD31+CD4+CD45RA+) have longer telomeres and higher telomerase activity, which, along with the increased frequency of TREC positivity suggests a population of T cells with low replicative history.(3) The same study has also shown that CD31+ CD4+ T cells are an appropriate cell population to evaluate thymic reconstitution in lymphopenic children posthematopoietic cell transplant.(3) A Mayo study (unpublished) shows that the CD31 marker correlates with TREC-enriched T cells across the spectrum of age and correlates with thymic recovery in adults after autologous hematopoietic cell transplantation.(4) CD31+ CD4 RTEs have also been used to evaluate T-cell homeostatic anomalies in patients with relapsing-remitting multiple sclerosis.(5) For patients with DiGeorge syndrome (DGS)--a cellular immunodeficiency associated with other congenital problems including cardiac defects, facial dysmorphism, hypoparathyroidism, and secondary hypocalcemia, and chromosome 22q11.2 deletion (in a significant proportion of patients)--measurement of thymic function provides valuable information on the functional phenotype, ie, complete DGS (associated with thymic aplasia in a minority of patients) or partial DGS (generally well-preserved thymic function seen the in the majority of patients). Thymus transplants have been performed in patients with complete DGS, but are typically not required in partial DGS. There can be change in peripheral T-cell counts in DGS patients with age.

Useful For: Evaluating thymic reconstitution in patients following hematopoietic cell transplantation, chemotherapy, immunomodulatory therapy, and immunosuppression Evaluating thymic recovery in HIV-positive patients on highly active antiretroviral therapy Evaluating thymic output in patients with DiGeorge syndrome or other cellular immunodeficiencies Assessing the naive T-cell compartment in a variety of immunological contexts (autoimmunity, cancer, immunodeficiency, and transplantation) Identification of thymic remnants postthymectomy for malignant thymoma or as an indicator of relapse of disease (malignant thymoma) or other contexts of thymectomy

Interpretation: The absence or reduction of CD31+CD4 recent thymic emigrants (RTEs) generally correlates with loss or reduced thymic output and changes in the naive CD4 T-cell compartment, especially in infancy and prepubertal children. The CD4RTE result has to be interpreted more cautiously in adults due to age-related decline in thymic function and correlated with total CD4 T cell count and Current as of August 23, 2017 7:11 am CDT


Page 445

other relevant immunological data. CD4 RTEs measured along with TREC (TREC / T-Cell Receptor Excision Circles (TREC) Analysis, Blood) provides a comprehensive assessment of thymopoiesis, but should not be used in adults over the sixth decade of life as clinically meaningful information on thymic function is limited in the older population due to a physiological decline in thymic activity. To evaluate immune reconstitution or recovery of thymopoiesis post-T-cell depletion due to posthematopoietic cell transplant, immunotherapy, or other clinical conditions, it is helpful to systematically (serially) measure CD4RTE, and TREC copies in the appropriate age groups.

Reference Values: CD4 ABSOLUTE Males 1 month-17 years: 153-1,745 cells/mcL 18-70 years: 290-1,175 cells/mcL Reference values have not been established for patients that are 70 years of age. Females 1 month-17 years: 582-1,630 cells/mcL 18-70 years: 457-1,766 cells/mcL Reference values have not been established for patients that are 70 years of age. CD4 RTE % Males 1 month-17 years: 19.4-60.9% 18-25 years: 6.4-51.0% 26-55 years: 6.4-41.7% > or =56 years: 6.4-27.7% Reference values have not been established for patients that are 70 years of age. Females 1 month-17 years: 25.8-68.0% 18-25 years: 6.4-51.0% 26-55 years: 6.4-41.7% > or =56 years: 6.4-27.7% Reference values have not been established for patients that are 70 years of age. CD4 RTE ABSOLUTE Males 1 month-17 years: 50.0-926.0 cells/mcL 18-70 years: 42.0-399.0 cells/mcL Reference values have not been established for patients that are 70 years of age. Females 1 month-17 years: 170.0-1,007.0 cells/mcL 18-70 years: 42.0-832.0 cells/mcL Reference values have not been established for patients that are 70 years of age.

Clinical References: 1. Hassan J, Reen DJ: Human recent thymic emigrants-identification, expansion, and survival characteristics. J Immunol 2001;167:1970-1976 2. Kimmig S, Przybylski GK, Schmidt CA, et al: Two subsets of naive T-helper cells with distinct T-cell receptor excision circle content in human adult peripheral blood. J Exp Med 2002;195(6):789-794 3. Junge S, Kloeckener-Gruissem B, Zufferey R, et al: Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4 T-cells in normal individuals during aging and in lymphopenic children. Eur J Immunol 2007;37:3270-3280 4. Dong X, Hoeltzle MV, Abraham RS: Evaluation of CD4 and CD8 recent thymic emigrants in healthy adults and children. Unpublished data 2008 5. Duszczyszyn DA, Beck JD, Antel J, et al: Altered naiveCD4 and CD8 T-cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic Current as of August 23, 2017 7:11 am CDT


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versus peripheral (non-thymic) mechanisms. Clin Exp Immunol 2005;143:305-313

88578

CD4, Immunostain Without Interpretation Clinical Information: CD4 is expressed on a subset of T cells (T helper cells), histiocytes and monocytes. In normal tonsil, the T cells predominate in interfollicular regions. This immunostain is also used to support T cell or histiocytic lineage in hematolymphoid neoplasms.

Useful For: Identification of T helper cells, histiocytes and monocytes Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Grogg KL, Jung S, Erickson LA, et al: Primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma: a clonal T-cell lymphoproliferative disorder with indolent behavior. Mod Pathol 2008;21:708-715 2. Hans CP, Weisenburger DD, Greiner TC, et al: Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103(1):275-282 3. Oudejans JJ, van der Valk P: Immunohistochemical classification of T cell and NK cell neoplasms. J Clin Pathol 2002;55(2):892 4. Went P, Agostinelli C, Gallamini A, et al: Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006;24(16):2472-2479

60842

CD43, Immunostain Without Interpretation Clinical Information: CD43 is expressed by normal T lymphocytes, granulocytes and granulocyte precursors, monocytes, macrophages, plasma cells, and megakaryocytes. In normal tonsil, CD43 will mainly show staining in T lymphocytes and plasma cells in interfollicular areas.

Useful For: Identification of T lymphocytes, monocytes, macrophages, granulocytes, plasma cells and a subset of B lymphocytes


Clinical References: 1. de Leon ED, Alkan S, Huang JC, Hsi ED: Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkinâ€™s lymphomas of small lymphocytes. Mod Pathol 1998;11(11):1046-1051 2. Kurtin PJ, Hobday KS, Ziesmer S, Caron BL: Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol 1999;112(3):319-329 3. Lai R, Weiss LM, Chang KL, Arber DA: Frequency of CD43 expression in non-Hodgkin lymphoma. A survey of 742 cases and further characterization of rare CD43+ follicular lymphomas. Am J Clin Pathol 1999;111(4):488-494

60843

CD45 Leukocyte Common Antigen (LCA), Immunostain Without Interpretation Clinical Information: CD45 is also called leukocyte common antigen given its shared expression in the vast majority of cells of hematolymphoid lineage. The CD45 antibody used is a cocktail of 2 clones,



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PD7/26 (detects the CD45RB isoform), and 2B11 (detects a common CD45 protein). CD45 expression is very specific and quite sensitive for cells of hematolymphoid lineage, thus distinguishing lymphoma/leukemia from other neoplasms. The main exception is classical Hodgkin Lymphoma, in which CD45 expression is absent.

Useful For: An aid in distinguishing lymphoma/leukemia from other neoplasms Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Carbone A, Gloghini A, Volpe R: Paraffin section immunohistochemistry in the diagnosis of Hodgkinâ€™s disease and anaplastic large cell (CD30+) lymphomas. Virchows Arch A Pathol Anat Histopathol 1992;420(6):527-532 2. Davey FR, Elghetany MT, Kurec AS: Immunophenotyping of hematologic neoplasms in paraffin-embedded tissue sections. Am J Clin Pathol 1990;93(4 Suppl 1):S17-S26 3. Higgins RA, Blankenship JE, Kinney MC: Application of immunohistochemistry in the diagnosis of non-Hodgkin and Hodgkin lymphoma. Arch Pathol Lab Med 2008;132(3):441-461 4. Kurtin PJ, Pinkus GS: Leukocyte common antigen - a diagnostic discriminant between hematopoietic and nonhematopoietic neoplasms in paraffin sections using monoclonal antibodies: correlation with immunologic studies and ultrastructural localization. Hum Pathol 1985;16(4):353-365

88579

CD5, Immunostain Without Interpretation Clinical Information: CD5 is expressed normally on all T cells (one of the panT-cell antigens). It can be aberrantly expressed by B-cell lymphomas (most commonly mantle cell lymphoma, B-cell small lymphocytic lymphoma). Expression of CD5 is useful to support T-cell lineage in T-cell lymphomas, or to help subclassify B-cell lymphomas.

Useful For: Marker of T-cell lineage Phenotyping B-cell lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Baseggio L, Traverse-Glehen A, Petinataud F, et al: CD5 expression identifies a subset of splenic marginal zone lymphomas with higher lymphocytosis: a clinico-pathological, cytogenetic and molecular study of 24 cases. Haematologica 2010;95(4):604-612 2. de Leon ED, Alkan S, Huang JC, Hsi ED: Usefulness of an immunohistochemical panel in paraffin-embedded tissues for the differentiation of B-cell non-Hodgkinâ€™s lymphomas of small lymphocytes. Mod Pathol 1998;11(11):1046-1051 3. Higgins RA, Blankenship JE, Kinney MC: Application of immunohistochemistry in the diagnosis of non-Hodgkin and Hodgkin lymphoma. Arch Pathol Lab Med 2008;132(3):441-461

60845

CD56, Immunostain Without Interpretation Clinical Information: CD56 is an adhesion molecule mediating homophilic and heterophilic adhesion in neurons, natural killer cells, and a small subset of CD4- and CD8-positive T cells. It is expressed in tumors with neuroendocrine differentiation (small cell lung carcinoma and neural-derived tumors) or natural killer cell lineage (subset of lymphomas). In normal small intestine, the ganglion cells in the muscle wall and nerves will show strong staining. Scattered lymphocytes may also be positive.



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Useful For: An aid in the identification of tumors with neuroendocrine differentiation An aid in the identification of natural killer cell lineage in a subset of lymphomas


Clinical References: 1. Chu PG, Arber DA, Weiss LM: Expression of T/NK-cell and plasma cell antigens in nonhematopoietic epithelioid neoplasms. An immunohistochemical study of 447 cases. Am J Clin Pathol 2003;120:64-70 2. EL Demellawy D, Nasr AL, Babay S, Alowami S: Diagnostic utility of CD56 immunohistochemistry in papillary carcinoma of the thyroid. Pathol Res Pract 2009;205:303-309 3. Kaufmann O, Georgi T, Dietel M: Utility of 123C3 monoclonal antibody against CD56 (NCAM) for the diagnosis of small cell carcinomas on paraffin sections. Hum Pathol 1997;28(12):1373-1378 4. Tsang WY, Chan JK, Ng CS, Pau MY: Utility of a paraffin section-reactive CD56 antibody (123C3) for characterization and diagnosis of lymphomas. Am J Surg Pathol 1996;20(2):202-210

60846

CD57, Immunostain Without Interpretation Clinical Information: CD57 is a 110 kD glycoprotein that is selectively expressed on natural killer cells and a subset of follicular T helper cells. Antibodies to CD57 also stain the myelin sheaths of central and peripheral nervous system cells. In normal tonsil, CD57 will stain a minor population of lymphocytes in the germinal centers. It is immunoreactive in tumors of neuroectodermal origins such as small cell carcinoma of the lung and carcinoid tumors, and is positive in adenocarcinomas of the prostate as well as normal and hyperplastic prostatic epithelium. Increased numbers of CD57-positive T cells are present in the background of lymphocyte-predominant Hodgkin lymphoma.

Useful For: Marker of natural killer cells and a subset of follicular T helper cells An aid in the identification of tumors of neuroectodermal origin


Clinical References: 1. Boudova L, Torlakovic E, Delabie J, et al: Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 2003;102(10):3753-3758 2. Khan A, Baker SP, Patwardhan NA, Pullman JM: CD57 (Leu-7) expression is helpful in diagnosis of the follicular variant of papillary thyroid carcinoma. Virchows Arch 1998;432(5):427-432 3. Khoury T, Chandrasekhar R, Wilding G, et al: Tumour eosinophilia combined with an immunohistochemistry panel is useful in the differentiation of type B3 thymoma from thymic carcinoma. Int J Exp Pathol 2011;92(2):87-96 4. Wick MR: Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol 2000;17(3):194-203

60847

CD61, Immunostain Without Interpretation Clinical Information: CD61 shows cytoplasmic staining of normal and abnormal megakaryocytes and occasional endothelial cells. Antibodies to CD61 are most useful in recognizing micromegakaryocytes, cytologically abnormal megakaryocytes, and megakaryoblasts in cases of acute megakaryoblastic leukemia, myeloproliferative disorders, and myelodysplastic syndromes.



Page 449

Useful For: An aid in identification of micromegakaryocytes, cytologically abnormal megkaryocytes, and megakaryoblasts


Clinical References: 1. Dolan MM, Singleton TP, Neglia J, Cioc A: Aplastic anemia and monosomy 7-associated dysmegakoaryocytopoiesis. Am J Clin Pathol 2006;126:925-930 2. Goldman BL, Wurzel J: Hematopoiesis/erythropoiesis in myocardial infarcts. Mod Pathol 2001;14(6):589-594 3. Thiele J, von Ammers E, Wanger S, et al: Megakaryocytopoiesis in idiopathic thrombocytopenic purpura: a morphometric and immunohistochemical study on bone marrow biopsies with special emphasis on precursor cells. Hematol Pathol 1991;5(2):75-82

60848

CD68 (KP1), Immunostain Without Interpretation Clinical Information: In normal tissues, CD68 KP-1 stains the cytoplasm of the granulocytes and myeloid progenitors in the bone marrow, monocytes and macrophages, and osteoclasts. KP-1 reacts against a carbohydrate moiety of CD68. Although CD68 KP-1 is primarily used as a histiocytic marker, it is not specific for histiocytes. It can also be expressed in malignant melanoma, granular cell tumors, peripheral nerve sheath tumors, malignant fibrous histiocytoma, and other mesenchymal neoplasms, and rare carcinomas.

Useful For: An aid in the identification of histocytic and myeloid lineage cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Kunisch E, Fuhrmann R, Roth A, et al: Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM1, and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis 2004;63:774-784 2. Kurtin PJ, Bonin DM: Immunohistochemical demonstration of the lysosome-associated glycoprotein CD68 (KP-1) in granular cell tumors and schwannomas. Human Pathology 1994;25(11):1172-1178 3. Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al: Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkinâ€™s lymphoma. Haematologica 2012;97:1080-1084 4. Tan KL, Scott DW, Hong F, et al: Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma. A Correlative Study from the E2496 Intergroup Trial. Blood 2012;120(18):3280-3287

60849

CD68 (PG-M1), Immunostain Without Interpretation Clinical Information: In normal tissues, CD68 PG-M1 stains monocytes and macrophages and, to a lesser extent, neutrophils in a cytoplasmic granular staining pattern. It has greater specificity for monocytes and macrophages than does KP-1, but its immunohistochemical staining pattern in non hematolymphoid tumors has not been studied as extensively as CD68 KP-1. Diagnostically, CD68 PG-M1 is usually applied to cases of acute leukemia to demonstrate monocytic differentiation and to cases of hematolymphoid neoplasms that are suspected to represent histiocytic sarcomas.

Useful For: An aid in the identification of monocytic differentiation An aid in phenotyping hematolymphoid neoplasms that are suspected to represent histiocytic sarcomas

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation Current as of August 23, 2017 7:11 am CDT


Page 450

is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Kunisch E, Fuhrmann R, Roth A, et al: Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM1, and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis 2004;63:774-784 2. Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al: Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma. Haematologica 2012;97:1080-1084 3. Tan KL, Scott DW, Hong F, et al: Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma. A Correlative Study from the E2496 Intergroup Trial. Blood 2012;120(18):3280-3287

88580

CD7, Immunostain Without Interpretation Clinical Information: CD7 is expressed normally on all T cells (one of the panT-cell antigens) and natural killer cells. Expression of CD7 can be aberrantly lost in T-cell lymphomas, providing support for a diagnosis of T-cell lymphoma. In normal tonsil, the T cells predominate in interfollicular regions.

Useful For: An aid in the identification of T cells and natural killer cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Chu PG, Arber DA, Weiss LM: Expression of T/NK-cell and plasma cell antigens in non hematopoietic epithelioid neoplasms. An Immunohistochemical Study of 447 Cases. Am J Clin Pathol 2003;120:64-70 2. Dunphy CH: Applications of flow cytometry and immunohistochemistry to diagnostic hematopathology. Arch Pathol Lab Med 2004;128:1004-1022 3. Higgins RA, Blankenship JE, Kinney MC: Application of immunohistochemistry in the diagnosis of non-Hodgkin and Hodgkin lymphoma. Archives of Pathology and Laboratory Medicine 2008;132(3):441-461

61778

CD71, Immunostain Without Interpretation Clinical Information: The transferrin receptor (CD71) is highly expressed on the surface of cells of the erythroid lineage and mediates the uptake of transferrin-iron complexes. Transferrin receptor expression levels are highest in early erythroid precursors through the intermediate normoblast phase, then expression decreases through the reticulocyte phase.

Useful For: Assessment of erythroid lineage Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Dong HY, Wilkes S, Yang H: CD71 is selectively and ubiquitously expressed at high levels in erythroid precursors of all maturation stages: A comparative immunochemical study with glycophorin A and hemoglobin A. Am J Surg Pathol 2011 May;35(5):723-732 2. Marsee DK, Pinkus GS, Yu H: CD71 (transferrin receptor): an effective marker for erythroid precursors in bone marrow biopsy specimens. Am J Clin Pathol 2010;134:429-435 3. Sokmensuer LK, Muftuoglu S, Asan E: Immunohistochemical analysis of CD71, CD98 and CD99 activation antigens in human palatine and Current as of August 23, 2017 7:11 am CDT


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nasopharyngeal tonsils. Saudi Med J 2005;26(3):385-389

60850

CD79a, Immunostain Without Interpretation Clinical Information: CD79a stains the cytoplasm and membrane of B lymphocytes and megakaryocytes. CD79a is a protein expressed on the surface of B lymphocytes at all stages of maturation, from B-lymphocyte precursors through plasma cells. Its function is to transduce the signal of antigen binding to immunoglobulin into the cytoplasm of the B lymphocyte initiating intracellular signaling. Antibodies to CD79a are diagnostically useful to demonstrate B cell lineage of acute lymphoblastic leukemia, malignant lymphomas and chronic lymphoproliferative disorders.

Useful For: Phenotyping leukemias and lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Adams H, Liebisch P, Schmid P, et al: Diagnositc utility of B-cell lineage markers CD20, CD791, PAX5, and CD19 in paraffin-embedded tissues From lymphoid neoplasms. Applied Immunohistochemistry and Molecular Morphology 2009;17(2):96-101 2. Hashimoto M, Yamashita Y, Mori N: Immunohistochemical detection of CD79a expression in precursor T cell lymphoblastic lymphoma/leukaemias. Journal of Pathology 2002;197:341-347 3. Kurtin PJ, Hobday KS, Ziesmer S, Caron BL: Demonstration of distinct antigenic profiles of small B-cell lymphomas by paraffin section immunohistochemistry. Am J Clin Pathol 1999;112(3):319-329

GLICP

CD8 T-Cell Immune Competence Panel, Global

89369

Clinical Information: CD8 T cells play an important role in the immune response to viral or intracellular infectious agents, as well as antitumor immunity and immune surveillance. Upon activation, CD8 T cells mediate a variety of effector functions, including cytokine secretion and cytotoxicity. Interferon-gamma (IFN-gamma) is one of the early cytokines produced by CD8 T cells; it is released within a few hours of activation.(1) The cytotoxic function is mediated by the contents of the cytolytic granules.(1) Cell-surface mobilization of the cytolytic granule components, CD107a and CD107b, also known as lysosome-associated membrane proteins LAMP-1 and LAMP-2, occurs when CD8 T cells mediate their cytolytic function and degranulate.(2) CD8 T-cell activation occurs either through the T cell receptor peptide major histocompatibility complex (MHC) or by use of a mitogen (eg, phorbol myristate acetate and the calcium ionophore ionomycin). Mitogen-mediated activation is antigen nonspecific. Impairment of global CD8 T-cell activation (due to inherent cellular immunodeficiency or as a consequence of over-immunosuppression by therapeutic agents) results in reduced production of IFN-gamma and other cytokines, reduced cytotoxic function, and increased risk for developing infectious complications. Agents associated with over-immunosuppression include the calcineurin inhibitors (eg, cyclosporine A, FK506 [Prograf/tacrolimus], and rapamycin [sirolimus]), antimetabolites (eg, mycophenolate mofetil), and thymoglobulin. Immunosuppression is most commonly used for allograft maintenance in solid-organ transplant recipients, to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant patients and, to treat patients with autoimmune diseases. In these settings, reducing the risk for developing infectious complications as a result of over-immunosuppression is a clinical challenge. Therapeutic drug monitoring is routinely used in the transplant practice to avoid overtreatment and to determine patient compliance. But, the levels of drugs measured in blood do not directly correlate with the administered dose due to individual pharmacokinetic differences.(3) Furthermore, drug levels may not necessarily correlate with biological activity of the drug. Consequently, it may be beneficial to consider modification of the immunosuppression regimen based on the patient's level of functional immune competence. This assay provides a means to evaluate over-immunosuppression within the CD8 T-cell compartment (global CD8 T-cell function). Intracellular



Page 452

IFN-gamma expression is a marker for CD8 T-cell activation. Surface CD107a and CD107b are markers for cytotoxic function. This test may be most useful when ordered at the end of induction immunosuppression and 2 to 3 months after maintenance immunosuppression to ensure that global CD8 T-cell function is not compromised. The test may also provide value when immunosuppression is increased to halt or prevent graft rejection, to provide information on a balance between over-immunosuppression with subsequent infectious comorbidities and, under-immunosuppression with resultant graft rejection. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8.30 a.m. and noon with no change between noon and afternoon. Natural killer-cell counts, on the other hand, are constant throughout the day.(4) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(5-7) In fact, cortisol and catecholamine concentrations control distribution and therefore, numbers of naive versus effector CD4 and CD8 T cells.(5) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the evening(8) and during summer compared to winter.(9) These data therefore indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Determining over immunosuppression within the CD8 T-cell compartment, when used on transplant recipients and patients with autoimmune disorders receiving therapy with immunosuppressant agents

Interpretation: Interferon-gamma (IFN-gamma) and CD107a and CD107b expression below the defined reference range are consistent with a global impairment in CD8 T-cell function, most likely due to over immunosuppression. IFN-gamma and CD107a and CD107b levels greater than the defined reference range are unlikely to have any clinical significance.


Clinical References: 1. Betts MR, Casaza JP, Patterson BA, et al: Putative immunodominant human immunodeficiency virus-specific CD8 T-cell responses cannot be predicted by MHC class I haplotype. J Virol 2000;74:9144-9151 2. Peters PJ, Borst J, Oorschot V, et al: Cytotoxic T-lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med 1991;173:1099-1109 3. Venkataramanan R, Shaw LM, Sarkozi L, et al: Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001;41:542-551 4. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract # B11052 5. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009;113:5134-5143 6. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 7. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Pyschosom Med 1997;59:42-50 8. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 9. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516

GLIC

CD8 T-Cell Immune Competence, Global, Blood

89317

Clinical Information: CD8 T cells play an important role in the immune response to viral or intracellular infectious agents, as well as antitumor immunity and immune surveillance. Upon activation, CD8 T cells mediate a variety of effector functions, including cytokine secretion and cytotoxicity. Interferon-gamma (IFN-gamma) is one of the early cytokines produced by CD8 T cells; it is released within a few hours of activation.(1) The cytotoxic function is mediated by the contents of the cytolytic granules.(1) Cell-surface mobilization of the cytolytic granule components, CD107a and CD107b, also known as lysosome-associated membrane proteins LAMP-1 and LAMP-2, occurs when CD8 T cells mediate their cytolytic function and degranulate.(2) CD8 T-cell activation occurs either through the T-cell



Page 453

receptor (TCR)-peptide-major histocompatibility complex (MHC) or by use of a mitogen (eg, phorbol myristate acetate and the calcium ionophore ionomycin). Mitogen-mediated activation is antigen nonspecific. Impairment of global CD8 T-cell activation (due to inherent cellular immunodeficiency or as a consequence of overimmunosuppression by therapeutic agents) results in reduced production of IFN-gamma and other cytokines, reduced cytotoxic function, and increased risk for developing infectious complications. Agents associated with overimmunosuppression include the calcineurin inhibitors (eg, cyclosporine A, FK506 [Prograf/tacrolimus], and rapamycin [sirolimus]), antimetabolites (eg, mycophenolate mofetil), and thymoglobulin. Immunosuppression is most commonly used for allograft maintenance in solid organ transplant recipients, to prevent graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant patients and to treat patients with autoimmune diseases. In these settings, reducing the risk for developing infectious complications as a result of overimmunosuppression is a clinical challenge. Therapeutic drug monitoring (TDM) is routinely used in the transplant practice to avoid overtreatment and to determine patient compliance. But, the levels of drugs measured in blood do not directly correlate with the administered dose due to individual pharmacokinetic differences.(3) Furthermore, drug levels may not necessarily correlate with biological activity of the drug. Consequently, it may be beneficial to consider modification of the immunosuppression regimen based on the patient's level of functional immune competence. This assay provides a means to evaluate overimmunosuppression within the CD8 T-cell compartment (global CD8 T-cell function). Intracellular IFN-gamma expression is a marker for CD8 T-cell activation. Surface CD107a and CD107b are markers for cytotoxic function. This test may be most useful when ordered at the end of induction immunosuppression and 2 to 3 months after maintenance immunosuppression to ensure that global CD8 T-cell function is not compromised. The test may also provide value when immunosuppression is increased to halt or prevent graft rejection, to provide information on a balance between overimmunosuppression with subsequent infectious comorbidities and underimmunosuppression with resultant graft rejection. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon with no change between noon and afternoon. Natural Killer (NK) cell counts, on the other hand, are constant throughout the day.(4) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(5,6,7) In fact, cortisol and catecholamine concentrations control distribution and therefore, numbers of naive versus effector CD4 and CD8 T cells.(5) It is generally accepted that lower CD4 T cell counts are seen in the morning compared to the evening(8) and during summer compared to winter.(9) These data therefore indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Determining overimmunosuppression within the CD8 T-cell compartment, when used on transplant recipients and patients with autoimmune disorders receiving therapy with immunosuppressant agents

Interpretation: Interferon-gamma (IFN-gamma) and CD107a and CD107b expression below the defined reference range are consistent with a global impairment in CD8 T-cell function, most likely due to overimmunosuppression. IFN-gamma and CD107a and CD107b levels greater than the defined reference range are unlikely to have any clinical significance.

Reference Values: Interferon-gamma (IFN-gamma) expression (as % CD8 T cells): 10.3-56.0% CD107a/b expression (as % CD8 T cells): 8.5-49.1% Reference values have not been established for patients who are or =100 Strongly positive Reference values apply to all ages.


CTSA

Ceramide Trihexosides and Sulfatides, Urine

81979

Clinical Information: Urinary excretion of ceramide trihexosides can be suggestive of Fabry disease, while excretion of sulfatide with or without ceramide trihexosides can be suggestive of metachromatic leukodystrophy, multiple sulfatase deficiency, mucolipidosis II (I-cell disease), or saposin B deficiency. Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A (alpha-Gal A). Reduced enzyme activity results in accumulation of glycosphingolipids in the lysosomes throughout the body, in particular, the kidney, heart, and brain. Severity and onset of symptoms are dependent on the residual enzyme activity. Symptoms may include acroparesthesias (pain crises), multiple angiokeratomas, reduced or absent sweating, corneal opacity, renal insufficiency leading to end-stage renal disease, and cardiac and cerebrovascular disease. There are renal and cardiac variant forms of Fabry disease that may be underdiagnosed. Females who are carriers of Fabry disease can have clinical presentations ranging from asymptomatic to severely affected, and they may have alpha-Gal A activity in the normal range. Individuals with Fabry disease, regardless of the severity of symptoms, may show an increased excretion of ceramide trihexoside in urine. Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the arylsulfatase A enzyme, which leads to the accumulation of various sulfatides in the brain, nervous



Page 469

system, and visceral organs, including the kidney and gallbladder. The 3 clinical forms of MLD are late-infantile, juvenile, and adult, depending on age of onset. All result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Symptoms may include hypotonia, clumsiness, diminished reflexes, slurred speech, behavioral problems, and personality changes. Individuals with MLD typically show an increased excretion of sulfatides in urine. Low arylsulfatase A activity has been found in some clinically normal parents and other relatives of MLD patients. These individuals do not have metachromatic deposits in peripheral nerve tissues, and their urine content of sulfatides is normal. Individuals with this "pseudodeficiency" have been recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population. This has been associated with a fairly common polymorphism in the arylsulfatase A gene, which leads to low expression of the enzyme (5%-20% of normal). Saposin B deficiency is a rare autosomal recessive disorder with symptoms that mimic MLD. Age of onset dictates the clinical subtypes of saposin B deficiency. Individuals with saposin B deficiency have normal arylsulfatase A activity. In urine, individuals with saposin B deficiency have an increased excretion of sulfatides and may also show increased excretion of ceramide trihexosides. Multiple sulfatase deficiency (MSD) is another rare autosomal recessive disorder that mimics the symptoms of MLD. In addition, individuals with MSD also may have clinical manifestations that resemble mucopolysaccharidoses. MSD results in deficiencies in all sulfatases including arylsulfatase A and B. Individuals with MSD have an increased excretion of sulfatides in their urine. Mucolipidosis II, also known as I-cell disease, is a rare autosomal recessive disorder with features of both mucopolysaccharidoses and sphingolipidoses. It is characterized by congenital or early infantile manifestations including coarse facial features, short stature, skeletal anomalies, cardio- and hepatomegaly, and developmental delays. This is a progressive disorder and death typically occurs in the first decade of life. Individuals with I-cell disease typically show an increased excretion of ceramide trihexosides and sulfatides in urine.

Useful For: Identifying patients with Fabry disease Identifying patients with metachromatic leukodystrophy Identifying patients with saposin B deficiency Identifying patients with multiple sulfatase deficiency Identifying patients with mucolipidosis II (I-cell disease)

Interpretation: No evidence of ceramide trihexosides or sulfatide accumulation suggests normal enzyme activities. Evidence of ceramide trihexoside accumulation suggests decreased or deficient alpha-galactosidase activity. Follow-up testing with the specific enzyme assay is recommended: -AGA / Alpha-Galactosidase, Leukocytes -AGABS / Alpha-Galactosidase, Blood Spot -AGAS / Alpha-Galactosidase, Serum Evidence of sulfatide accumulation suggests decreased or deficient arylsulfatase A activity. Follow-up with the specific enzyme assay is recommended: -ARSAW / Arylsulfatase A, Leukocytes -ARSU / Arylsulfatase A, 24 Hour, Urine To exclude multiple sulfatase deficiency (MSD), simultaneous determination of ARSB / Arylsulfatase B, Fibroblasts and I2SW / Iduronate-2-sulfatase, Whole Blood (or I2SBS / Iduronate-2-Sulfatase, Blood Spot) is recommended. Evidence of both ceramide trihexoside and sulfatide accumulation suggests a diagnosis of mucolipidosis II (I-cell disease) or saposin B deficiency. Follow-up testing to rule-out I-cell disease may include: -NAGS / Hexosaminidase A and Total Hexosaminidase, Serum -AGAS / Alpha-Galactosidase, Serum or ANAS / Alpha-N-Acetylglucosaminidase, Serum Molecular genetic testing is required to confirm saposin B deficiency. See Fabry Disease Testing Algorithm in Special Instructions.


Clinical References: 1. Desnick RJ, Ioannou YA, Eng CM: Alpha-galactosidase A deficiency: Fabry disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Book Company. Accessed 3/16/2016. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62644837 2. Kuchar L, Ledvinova J, Hrebicek M, et al: Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients detected by analysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am J Med Genet A 2009 Feb 15;149A(4):613-621 3. Mehta A, Hughes DA: Fabry disease. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle; 1993-2016. Updated 2013 Oct 17. Available at (http://www.ncbi.nlm.nih.gov/books/NBK1828) 4. Schlotawa L, Ennemann EC, Radhakrishnan K, et al: SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet 2011;19:253-261 5. Gieselmann V, Ingeborg K: Metachromatic leukodystrophy. Edited by D Current as of August 23, 2017 7:11 am CDT


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Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Book Company. Accessed 3/16/2016. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62644361 6. Leroy JG, Cathey S, Friez MJ: Mucolipidosis II. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle; 1993-2016. Updated 2012 May 10. Available at (http://www.ncbi.nlm.nih.gov/books/NBK1828)

CTSNR

Ceramide Trihexosides and Sulfatides, Urine

37998

Clinical Information: This test measures urinary excretion of ceramide trihexosides and sulfatides which are elevated in patients with Fabry disease, metachromatic leukodystrophy, multiple sulfatase deficiency, mucolipidosis II (I-cell disease), or saposin B deficiency.

Useful For: Identifying patients with Fabry disease Identifying patients with metachromatic leukodystrophy Identifying patients with saposin B deficiency Identifying patients with multiple sulfatase deficiency Identifying patients with mucolipidosis II (I-cell disease)

Interpretation: No evidence of ceramide trihexosides or sulfatide accumulation suggests normal enzyme activities. See Fabry Disease Testing Algorithm in Special Instructions

Reference Values: Only orderable as part of a profile. See LYSDU / Lysosomal Storage Disorders Screen, Urine. For more information regarding ceramide trihexosides and sulfatides, see CTSA / Ceramide Trihexosides and Sulfatides, Urine.

CERAM

Ceramides, Plasma

65054

Clinical Information: Plasma ceramides are predictors of adverse cardiovascular events resulting from unstable atherosclerotic plaque. Ceramides are complex lipids that play a central role in cell membrane integrity, cellular stress response, inflammatory signaling, and apoptosis. Synthesis of ceramides from saturated fats and sphingosine occurs in all tissues. Metabolic dysfunction and dyslipidemia results in accumulation of ceramides in tissues not suited for lipid storage. Elevated concentrations of circulating ceramides are associated with atherosclerotic plaque formation,(1) ischemic heart disease, myocardial infarction,(2,3) hypertension,(4) stroke,(5) type 2 diabetes mellitus, insulin resistance and obesity.(6) Three specific ceramides have been identified as highly linked to cardiovascular disease and insulin resistance: Cer16:0, Cer18:0, and Cer24:1. Individuals with elevated plasma ceramides are at higher risk of major adverse cardiovascular events even after adjusting for age, gender, smoking status, and serum biomarkers such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, c-reactive protein (CRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2). Direct interventional studies have not yet been reported; however, ceramide concentrations are reduced by current cardiovascular therapies including statins, ezetimibe, and Proprotein convertase subtilisin/kexin type 9 (PCSK9) activity.(3,7)

Useful For: Evaluation for risk of major adverse events due to cardiovascular disease within the next 1 to 5 years

Interpretation: Elevated plasma ceramides are associated with increased risk of myocardial infarction, acute coronary syndromes, and mortality within 1 to 5 years. Ceramide Score Relative Risk Risk Category 0-2 1.0 Lower 3-6 1.8 Moderate 7-9 2.3 Increased 10-12 5.1 Higher Score is based on trial data including >4,000 subjects.

Reference Values: Ceramide (16:0): 0.19-0.36 mcmol/L Ceramide (18:0): 0.05-0.14 mcmol/L Ceramide (24:1): 0.65-1.65 mcmol/L Ceramide (16:0)/(24:0): or =100 Strongly positive Reference values apply to all ages.


FAMCE

Cheese American IgE

57914




CNUT

Chestnut, Sweet, IgE

82870




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Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CHICF

CHIC2 (4q12) Deletion (FIP1L1 and PDGFRA Fusion), FISH

35264

Clinical Information: Imatinib mesylate, a small molecule tyrosine kinase inhibitor from the 2-phenylaminopyrimidine class of compounds, has shown activity in the treatment of malignancies that are associated with the constitutive activation of a specific subgroup of tyrosine kinases. A novel tyrosine kinase, generated from fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRA gene, was identified in 9 of 16 patients (56%) with hypereosinophilic syndrome (HES). This fusion results from an approximate 800 kb interstitial chromosomal deletion that includes the cysteine-rich hydrophobic domain 2 (CHIC2) locus at 4q12. FIP1L1-PDGFRA is a constitutively activated tyrosine kinase that transforms hematopoietic cells, and is a therapeutic target for imatinib in a subset of HES patients. Mast cell disease (MCD) is a clinically heterogeneous disorder wherein accumulation of mast cells (MC) may be limited to the skin (cutaneous mastocytosis) or involve 1 or more extra-cutaneous organs (systemic MCD [SMCD]). SMCD is often associated with eosinophilia (SMCD-eos). We recently tested the therapeutic activity of imatinib in 12 adults with SMCD-eos. In this study, we demonstrated that FIP1L1-PDGFRA is the therapeutic target of imatinib in the specific subset of patients with SMCD-eos. Furthermore, we provided evidence that the CHIC2 deletion is a surrogate marker for the FIP1L1-PDGFRA fusion.

Useful For: Providing genetic information for patients with hypereosinophilic syndrome (HES) and systemic mast cell disease (SMCD) involving CHIC2 deletion Identifying and tracking chromosome abnormalities and response to therapy

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range. Detection of an abnormal clone is usually associated with hypereosinophilic syndrome or systemic mastocytosis associated with eosinophilia. The absence of an abnormal clone does not rule out the presence of neoplastic disorder. Current as of August 23, 2017 7:11 am CDT


Page 482


Clinical References: 1. Pardanani A, Ketterling RP, Brockman SR, et al: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood Nov 1 2003;102(9):3093-3096 2. Pardanani A, Brockman SR, Paternoster SF, et al: F1P1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosiniphilia. Blood 2004;104:3038-3045 3. Cools J, DeAngelo DJ, Gotlib J, et al: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med Mar 2003;348(13):1201-1214

CHXP

Chick Pea, IgE

82494




Reference Values: Class IgE KU/L Interpretation 0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





Page 483

CDROP

Chicken Droppings, IgE

82142





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CHCK

Chicken Feathers, IgE

82713

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to



Page 484

sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FCHXG

Chicken IgG

57625



CHIC

Chicken, IgE

82703





Page 486


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CHIKG

Chikungunya IgG, Antibody, Serum

63868

Reference Values: Only orderable as part of a profile. For more information see CHIKV / Chikungunya IgM and IgG, Antibody, Serum.

CHIKV

Chikungunya IgM and IgG, Antibody, Serum

64173

Clinical Information: Chikungunya virus (ChikV) is a single-stranded RNA alphavirus and a member of the Togaviridae family of viruses. The name Chikungunya is derived from the language of the Makonde ethnic groups in southeast Africa and means "that which bends" or "stooped walk." This is in reference to the hunched-over appearance of infected individuals due to the characteristically painful and incapacitating arthralgia caused by the virus. ChikV is endemic throughout Africa, India, and more recently the Caribbean islands. In 2014, the first case of autochthonous or local transmission in the United States occurred in Florida. Humans are the primary reservoir for ChikV and Aedes species mosquitos are the primary vectors for transmission. Unlike other mosquito-borne viruses such as West Nile virus (WNV) and Dengue, the majority of individuals who are exposed to ChikV become symptomatic, with the most severe manifestations observed at the extremes of age and in those with suppressed immunity. Once exposed to ChikV virus, individuals develop lasting immunity and protection from reinfection. The incubation period, prior to development of symptoms, ranges on average from 3 to 7 days. Infected patients typically present with sudden onset high fever, incapacitating joint pain, and often a maculopapular rash lasting anywhere from 3 to 10 days. Notably, symptom relapse can occur in some individuals 2 to 3 months following resolution of initial symptoms. Currently, there are no licensed vaccines and treatment is strictly supportive care.

Useful For: Aiding in the diagnosis of recent infection with Chikungunya virus in patients with recent travel to endemic areas and a compatible clinical syndrome

Interpretation: IgM and IgG Negative: -No serologic evidence of exposure to Chikungunya virus. Repeat testing on a new specimen collected in 5 to 10 days is recommended if clinical suspicion persists. IgM and IgG Positive: -IgM and IgG antibodies to Chikungunya virus detected, suggesting recent or past infection. IgM antibodies to Chikungunya virus may remain detectable for 3 to 4 months postinfection. IgM Positive, IgG Negative: -IgM antibodies to Chikungunya virus detected, suggesting recent infection. Repeat testing in 5 to 10 days is recommended to demonstrate anti-Chikungunya virus IgG seroconversion to confirm current infection. IgM Negative, IgG Positive: -IgG antibodies to Chikungunya virus detected, suggesting past infection. IgM and/or IgG Borderline: -Repeat testing in 10 to 14 days is Current as of August 23, 2017 7:11 am CDT


Page 487

recommended.

Reference Values: IgM: Negative IgG: Negative Reference values apply to all ages.

Clinical References: Pan American Health Organization. Preparedness and Response for Chikungunya virus. Introduction into the Americas. Washington, DC, PAHO 2011

CHIKM

Chikungunya IgM, Antibody, Serum

63867


CHIKI

Chikungunya Interpretation

37102


FCVRQ

Chikungunya Virus RNA, Qualitative Real-Time PCR

58028

Reference Values: Not Detected

CHILI

Chili Pepper, IgE

82499




Reference Values: Class IgE kU/L Interpretation Current as of August 23, 2017 7:11 am CDT


Page 488

0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CHIMU

Chimerism Transplant No Cell Sort

62983

Clinical Information: Patients who have had donor hematopoietic cells infused for the purpose of engraftment (ie, bone marrow transplant recipients) may have their blood or bone marrow monitored for an estimate of the percentage of donor and recipient cells present. This can be done by first identifying unique features of the donor's and the recipient's DNA prior to transplantation and then examining the recipient's blood or bone marrow after the transplantation procedure has occurred. The presence of both donor and recipient cells (chimerism) and the percentage of donor cells are indicators of transplant success. Short tandem repeat (STR) sequences are used as identity markers. STRs are di-, tri-, or tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability in STR length among people and the STR lengths remain stable throughout life, making them useful as identity markers. PCR is used to amplify selected STR regions from germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the proportions of donor and recipient cells in the specimen.

Useful For: Determining the relative amounts of donor and recipient cells in a specimen An indicator of bone marrow transplant success

Interpretation: An interpretive report is provided, which defines unique features of the donor's cells. It is most useful to observe a trend in chimerism levels. Clinically critical results should be confirmed with 1 or more subsequent specimens.


Clinical References: Antin JH, Childs R, Filipovich AH, et al: Establishment of complete and mixed donor chimerism after allogenic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings. Biol Blood Marrow Transplant 2001;7:473-485

CHIMS

Chimerism Transplant Sorted Cells

62984

Clinical Information: Patients who have had donor hematopoietic cells infused for the purpose of engraftment (ie, bone marrow transplant recipients) may have their blood or bone marrow monitored for an estimate of the percentage of donor and recipient cells present. This can be done by first identifying unique features of the donor's and the recipient's DNA prior to transplantation and then examining the recipient's blood or bone marrow after the transplantation procedure has occurred. The presence of both donor and recipient cells (chimerism) and the percentage of donor cells are indicators of transplant success. Short tandem repeat (STR) sequences are used as identity markers. STRs are di-, tri-, or



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tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability in STR length among people and the STR lengths remain stable throughout life, making them useful as identity markers. PCR is used to amplify selected STR regions from germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the proportions of donor and recipient cells in the specimen.

Useful For: Determining the relative amounts of donor and recipient cells in a specimen in sorted cell fractions An indicator of bone marrow transplant success

Interpretation: An interpretive report is provided, which includes whether chimerism is detected or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell analysis permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which can be helpful in clinical management. It is most useful to observe a trend in chimerism levels. Clinically critical results should be confirmed with 1 or more subsequent specimens.



CHIDB

Chimerism-Donor

83182

Clinical Information: Patients who have had donor hematopoietic cells infused for the purpose of engraftment (ie, bone marrow transplant recipients) may have their blood or bone marrow monitored for an estimate of the percentage of donor and recipient cells present. This can be done by first identifying unique features of the donor's and the recipient's DNA prior to transplantation and then examining the recipient's blood or bone marrow after the transplantation procedure has occurred. The presence of both donor and recipient cells (chimerism) and the percentage of donor cells are indicators of transplant success. Short tandem repeat (STR) sequences are used as identity markers. STRs are di-, tri-, or tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability in STR length among people and the STR lengths remain stable throughout life, making them useful as identity markers. PCR is used to amplify selected STR regions from germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the proportions of donor and recipient cells in the specimen. This test evaluates the donor specimen prior to the recipient bone marrow transplant.

Useful For: Evaluating the donor cells prior to bone marrow transplant Determining the relative amounts of donor and recipient cells in a specimen. An indicator of bone marrow transplant success

Interpretation: An interpretive report is provided, which includes whether chimerism is detected or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell analysis permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which can be helpful in clinical management. It is most useful to observe a trend in chimerism levels. Clinically critical results should be confirmed with 1 or more subsequent specimens.





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CHRGB

Chimerism-Recipient Germline (Pre)

83186

Clinical Information: Patients who have had donor hematopoietic cells infused for the purpose of engraftment (ie, bone marrow transplant recipients) may have their blood or bone marrow monitored for an estimate of the percentage of donor and recipient cells present. This can be done by first identifying unique features of the donor's and the recipient's DNA prior to transplantation and then examining the recipient's blood or bone marrow after the transplantation procedure has occurred. The presence of both donor and recipient cells (chimerism) and the percentage of donor cells are indicators of transplant success. Short tandem repeat (STR) sequences are used as identity markers. STRs are di-, tri-, or tetra-nucleotide repeat sequences interspersed throughout the genome at specific sites. There is variability in STR length among people and the STR lengths remain stable throughout life, making them useful as identity markers. PCR is used to amplify selected STR regions from germline DNA of both donor and recipient. The lengths of the amplified fragment are evaluated for differences (informative markers). Following allogeneic hematopoietic cell infusion, the recipient blood or bone marrow can again be evaluated for the informative STR regions to identify chimerism and estimate the proportions of donor and recipient cells in the specimen. This CHRGB / Chimerism-Recipient Germline (Pre) orderable evaluates the recipient specimen prior to bone marrow transplant.

Useful For: Evaluating the recipient cells prior to bone marrow transplant Interpretation: An interpretive report is provided, which includes whether chimerism is detected or not and, if detected, the approximate percentage of donor and recipient cells. Sorted cell analysis permits more detailed evaluation of chimeric status in T-cell and myeloid cell fractions, which can be helpful in clinical management. It is most useful to observe a trend in chimerism levels. Clinically critical results should be confirmed with 1 or more subsequent specimens.



FCPP

Chlamydia Pneumoniae PCR

57339

Reference Values: Not detected = Negative, no virus detected Detected = Positive, virus detected This test employs PCR amplification and agarose gel electrophoresis detection of a Chlamydia pneumoniae-specific conserved genetic target. A positive result should be coupled with clinical indicators for diagnosis. A "Not detected" result for this assay does not exclude Chlamydia pneumoniae involvement in a disease process.

SCLAM

Chlamydia Serology, Serum

8142

Clinical Information: Members of the family Chlamydiaceae are small, nonmotile, gram-negative, obligate intracellular organisms that grow in the cytoplasm of host cells. Two genera of clinical importance are Chlamydia, which includes Chlamydia trachomatis, and Chlamydophila, which includes Chlamydophila pneumoniae and Chlamydophila psittaci. These organisms share many features of bacteria and are susceptible to antibiotic therapy. They are also similar to viruses, requiring living cells for multiplication. The chlamydial life cycle can be divided into 2 distinct phases: an extracellular, nonreplicating, infectious stage and an obligate intracellular, replicating, noninfectious stage. The infectious form, or elementary body (EB), attaches to the target cell membrane and enters the cell via a phagosome. After cell entry, the EB reorganizes into reticulate particles (forming inclusion bodies) and binary fission begins. After 18 to 24 hours, reticulate particles condense to form EBs. These new EBs are released, beginning another infection cycle. Chlamydophila psittaci is the causative agent of psittacosis, a



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disease characterized by pneumonia, headache, altered mentation, and hepatosplenomegaly. Psittacosis is acquired by airborne transmission from infected birds. Chlamydophila pneumoniae (formerly known as TWAR and, more recently, as Chlamydia pneumoniae) causes pneumonia in humans. It is unique because it is a primary pathogen of humans, is spread from human to human, and apparently has no animal or bird host. Chlamydophila pneumoniae is responsible for approximately 10% of pneumonia cases. Chlamydia trachomatis has been implicated in a wide variety of infections in humans. It is a common cause of nongonococcal urethritis and cervicitis, and many systemic complications of chlamydial infections have been described. In females, this organism is a cause of pelvic inflammatory disease, salpingitis, and endometritis. In males, epididymitis and Reiter syndrome occur. Lymphogranuloma venereum is a sexually transmitted infection caused by Chlamydia trachomatis. It presents with a transient primary genital lesion followed by suppurative regional lymphadenopathy. Occasionally, severe proctitis or proctocolitis may develop. Chlamydia trachomatis also causes ophthalmologic infections, such as trachoma (rare in the United States), adult inclusion conjunctivitis and inclusion conjunctivitis in neonates. These disorders have traditionally been diagnosed by cytologic detection or culture. However, molecular detection methods (CTRNA / Chlamydia trachomatis by Nucleic Acid Amplification [GEN-PROBE]) may now represent a more sensitive diagnostic approach. Fitz-Hugh-Curtis syndrome (perihepatitis) has been associated with chlamydiae.

Useful For: Aids in the clinical diagnosis of chlamydial infections Interpretation: IgG: Chlamydophila pneumoniae > or =1:512 IgG endpoint titers of > or =1:512 are considered presumptive evidence of current infection. or =1:64 A single specimen endpoint titer of > or =1:64 and or =1:512 or a 4-fold increase over that of the initial specimen, current (acute) infection is indicated. Unchanging titers >1:64 and 50% protein). Total cholesterol levels have long been known to be related to coronary heart disease (CHD). HDL cholesterol is also an important tool used to assess an individual's risk of developing CHD since a strong negative relationship between HDL cholesterol concentration and the incidence of CHD has been reported. In some individuals, exercise increases the HDL cholesterol level; those with more physical activity have higher HDL cholesterol values.

Useful For: Cardiovascular risk assessment Interpretation: Low high-density lipoprotein (HDL) cholesterol correlates with increased risk for coronary heart disease (CHD). Values > or =80 to 100 mg/dL may indicate metabolic response to certain medications such as hormone replacement therapy, chronic liver disease, or some form of chronic intoxication, such as with alcohol, heavy metals, or industrial chemicals including pesticides. HDL values < or =5 mg/dL occur in Tangier disease, in association with cholestatic liver disease, and in association with diminished hepatocyte function.

Reference Values: The National Lipid Association and the National Cholesterol Education Program (NCEP) have set the following guidelines for lipids (total cholesterol, triglycerides, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and non-HDL cholesterol) in adults ages 18 and Current as of August 23, 2017 7:11 am CDT


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up: HDL CHOLESTEROL Males > or =40 mg/dL Females > or =50 mg/dL The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents has set the following guidelines for lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and non-HDL cholesterol) in children ages 2-17: HDL CHOLESTEROL Low HDL: 45 mg/dL

Clinical References: 1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis, MO: Elsevier Saunders, 2012 2. Rifai N, Warnick GR: Laboratory Measurement of Lipids, Lipoproteins, and Apolipoproteins. AACC Press, Washington DC, 1994 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 - executive summary. J Clin Lipidol 2014 Sep-Oct;8(5):473-488 4. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011 Dec;128 Suppl 5:S213-S256

CHOL

Cholesterol, Total, Serum

8320

Clinical Information: Cholesterol is a steroid with a secondary hydroxyl group in the C3 position. It is synthesized in many types of tissue, but particularly in the liver and intestinal wall. Approximately 75% of cholesterol is newly synthesized and 25% originates from dietary intake. Normally, the cholesterol in the plasma or serum is 60% to 80% esterified. Approximately 50% to 75% of the plasma cholesterol is transported by low-density lipoproteins (LDL) and 15% to 40% by high-density lipoproteins (HDL). Serum cholesterol is elevated in the hereditary hyperlipoproteinemias and in various other metabolic diseases. Moderate-to-markedly elevated values are also seen in cholestatic liver disease. Hypercholesterolemia reflects an increase of lipoproteins of 1 or more specific classes (eg, beta-LDL, alpha-1 HDL, alpha-2 HDL, or LP-X). Hypercholesterolemia is a risk factor for cardiovascular disease. Low levels of cholesterol can be seen in disorders that include hyperthyroidism, malabsorption, and deficiencies of apolipoproteins.

Useful For: Evaluation of cardiovascular risk Interpretation: The National Lipid Association and the National Cholesterol Education Program (NCEP) have set the following guidelines for total cholesterol: Desirable: or =240 mg/dL Values above the normal range indicate a need for quantitative analysis of the lipoprotein profile. Values in hyperthyroidism usually are in the lower normal range; malabsorption values may be below 100 mg/dL, while beta-lipoprotein or apolipoprotein B deficiency values usually are below 80 mg/dL. See Lipids and Lipoproteins in Blood Plasma (Serum) in Special Instructions.

Reference Values: The National Lipid Association and the National Cholesterol Education Program (NCEP) have set the following guidelines for lipids (total cholesterol, triglycerides, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, and non-HDL cholesterol) in adults ages 18 and up: TOTAL CHOLESTEROL Desirable: or =240 mg/dL The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children Current as of August 23, 2017 7:11 am CDT


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and Adolescents has set the following guidelines for lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and non-HDL cholesterol) in children 2 to 17 years of age: TOTAL CHOLESTEROL Acceptable: or =200 mg/dL

Clinical References: 1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood. St. Louis, MO: Elsevier Saunders, 2012 2. National Institute of Health (NIH) Publication: Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. NIH Publication 93-3096. 1993 Sep;93:3096 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol 2014;8(5):473-488 4. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Pediatrics. 2011;128;S213

CHLE

Cholesteryl Esters, Serum

8324

Clinical Information: Cholesterol in the blood serum normally is 60% to 80% esterified with fatty acids, largely as a result of the action of the enzyme lecithin-cholesterol acyltransferase (LCAT), which circulates in the blood in association with the high-density lipoproteins. LCAT transfers an acyl group for lecithin to cholesterol. Familial deficiency of LCAT is uncommon, usually occurring individuals of northern Europe descent, and is associated with erythrocyte abnormalities (target cells) and decreased (20% or less) esterification of plasma cholesterol. This is associated with early atherosclerosis, corneal opacification, hyperlipidemia, and mild hemolytic anemia. Persons with liver disease may have impaired formation of LCAT and, therefore, a secondary deficiency of this enzyme and of esterified plasma cholesterol.

Useful For: Establishing a diagnosis of lecithin-cholesterol acyltransferase deficiency Evaluating the extent of metabolic disturbance by bile stasis or liver disease

Interpretation: In patients with lecithin-cholesterol acyltransferase deficiency, the concentration of unesterified cholesterol in serum may increase 2 to 5 times the normal value, resulting in a decrease in esterified serum cholesterol to 20% or less of the total serum cholesterol.

Reference Values: 60-80% of total cholesterol Reference values have not been established for patients that are 20 mcg/L in a patient with chromium-based implant suggest significant prosthesis wear. Increased urine trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure. The National Institute for Occupational Safety and Health (NIOSH) draft document on occupational exposure reviews the data supporting use of urine to assess chromium exposure. They recommend a Biological Exposure Index of 10 mcg/g creatinine and 30 mcg/g creatinine for the increase in urinary chromium concentrations during a work shift and at the end of shift at the end of the workweek, respectively. A test for this specific purpose (CHROMU / Chromium for Occupational Monitoring, Urine) is available.


Clinical References: 1. Vincent JB: Elucidating a biological role for chromium at a molecular level. Acc Chem Res 2000;33(7):503-510 2. NIOSH Hexavalent Chromium Criteria Document Update, September 2008; Available from URL: http://www.cdc.gov/niosh/topics/hexchrom/ 3. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium exposures from industry and surgical implants. Crit Rev Toxicol 2008;38:645-674

CRS

Chromium, Serum

8638

Clinical Information: Chromium (Cr) exists in valence states ranging from 2(-) to 6(+). Hexavalent chromium (Cr[+6]) and trivalent chromium (Cr[+3]) are the 2 most prevalent forms. Cr(+6) is used in industry to make chromium alloys including stainless steel, pigments, and electroplated coatings. Cr(+6), a known carcinogen, is immediately converted to Cr(+3) upon exposure to biological tissues. Cr(+3) is the only chromium species found in biological specimens. Serum Cr concentrations are likely to be increased above the reference range in patients with metallic joint prosthesis. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis product information for each device for composition details.

Useful For: Screening for occupational exposure Monitoring metallic prosthetic implant wear Interpretation: Results greater than the flagged value indicate clinically significant exposure to chromium (Cr) (see Cautions about specimen collection). Prosthesis wear is known to result in increased circulating concentration of metal ions. Modest increase (0.3-0.6 ng/mL) in serum Cr concentration is likely to be associated with a prosthetic device in good condition. Serum concentrations >1 ng/mL in a patient with Cr-based implant suggest significant prosthesis wear. Increased serum trace element concentrations in the absence of corroborating clinical information do not independently predict Current as of August 23, 2017 7:11 am CDT


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prosthesis wear or failure.

Reference Values: 1000 cases and review of the literature. Prenat Diagn 2012;32:351-361 5. South ST, Lee C, Lamb AN, et al: ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med 2013;15:903-909

CMAPT 35901

Chromosomal Microarray, Tumor, Formalin-Fixed Paraffin-Embedded Clinical Information: The importance of identifying chromosome abnormalities in malignant neoplasms is well established, and often provides important diagnostic, prognostic, and therapeutic information critical to proper patient management. Although many chromosomal abnormalities are large enough to be detected with conventional chromosome analysis, many others are below its limits of resolution, and conventional chromosome analysis does not detect copy-neutral loss of heterozygosity. Chromosomal microarray (CMA) improves the diagnostic yield to identify genetic changes that are not detected by conventional chromosome analysis or FISH studies. CMA utilizes copy number probes and single nucleotide polymorphism probes to detect copy number changes and regions of copy-neutral loss of heterozygosity. CMA analysis is appropriate to identify gain or loss of chromosome material throughout the genome at a resolution of 50 to 100 kilobases. CMA can: -Define the size, precise breakpoints, and gene content of copy number changes to demonstrate the complexity of abnormalities -Characterize unidentified chromosome material, marker chromosomes, and DNA amplification detected by conventional chromosome and FISH studies -Determine if apparently balanced chromosome rearrangements identified by conventional chromosome studies have cryptic imbalances -Assess regions of copy-neutral loss of heterozygosity, which is common in neoplasia and often masks homozygous mutations involving tumor suppressor genes The limit of detection is dependent on size of the abnormality, type of abnormality (deletion or duplication) and DNA quality. When a deletion or duplication exceeds the reporting limits, mosaicism can confidently be detected as low as 25% and may be lower if the abnormality is large and DNA quality is good.

Useful For: Genomic characterization of tumor for copy number imbalances and loss of heterozygosity Assisting in the diagnosis and classification of malignant neoplasms Evaluating the prognosis for patients with malignant tumors

Interpretation: The interpretive report describes copy number changes and any loss of heterozygosity that may be associated with the neoplastic process. Abnormal clones with subclonal cytogenetic evolution will be discussed if identified. The continual discovery of novel copy number variation and published clinical reports means that the interpretation of any given copy number change may evolve with increased scientific understanding. Although the presence of a clonal abnormality usually indicates a neoplasia, in some situations it may reflect a benign or constitutional genetic change. If a genetic change is identified Current as of August 23, 2017 7:11 am CDT


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that is likely constitutional and clearly pathogenic (eg, XYY), follow-up with a medical genetics consultation may be suggested. The absence of an abnormal clone may be the result of specimen collection from a site that is not involved in the neoplasm, or may indicate that the disorder is caused by a point mutation that is not detectable by chromosomal microarray (CMA). CMA, FISH, and conventional cytogenetics are to some extent complementary methods. In some instances, additional FISH or conventional cytogenetic studies will be recommended to clarify interpretive uncertainties. See Cytogenetic Analysis of Glioma in Special Instructions for common questions and answers.


Clinical References: 1. Cooley L, Lebo M, Li M, et al: American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders. Genet Med 2013;15:484-494 2. Ciriello G, Miller ML, Aksoy BA, et al: Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013 Sep 26;45(10):1127-1133 3. Wang Y, Cottman M, Schiffman JD. Molecular inversion probes: a novel microarray technology and its application in cancer research. Cancer Genet 2012 Jul-Aug;205(7-8):341-355

CMAT 35900

Chromosomal Microarray, Tumor, Fresh or Frozen using Affymetrix Cytoscan HD Clinical Information: The importance of identifying chromosome abnormalities in malignant neoplasms is well established, and often provides important diagnostic, prognostic, and therapeutic information critical to proper patient management. Although many chromosomal abnormalities are large enough to be detected with conventional chromosome analysis, many others are below its limits of resolution, and conventional chromosome analysis does not detect copy-neutral loss of heterozygosity. Chromosomal microarray (CMA) improves the diagnostic yield to identify genetic changes that are not detected by conventional chromosome analysis or FISH studies. CMA utilizes >1.9 million copy number probes and approximately 750,000 single nucleotide polymorphism probes to detect copy number changes and regions of copy-neutral loss of heterozygosity. CMA analysis is appropriate to identify gain or loss of chromosome material throughout the genome at a resolution of 30 to 60 kilobases. CMA can: -Define the size, precise breakpoints, and gene content of copy number changes to demonstrate the complexity of abnormalities -Characterize unidentified chromosome material, marker chromosomes, and DNA amplification detected by conventional chromosome and FISH studies -Determine if apparently balanced chromosome rearrangements identified by conventional chromosome studies have cryptic imbalances -Assess regions of copy-neutral loss of heterozygosity, which is common in neoplasia and often masks homozygous mutations involving tumor suppressor genes The limit of detection is dependent on size of the abnormality, type of abnormality (deletion or duplication) and DNA quality. When a deletion or duplication exceeds the reporting limits, mosaicism can confidently be detected as low as 25% and may be lower if the abnormality is large and DNA quality is good.

Useful For: Genomic characterization of tumor for copy number imbalances and loss of heterozygosity Assisting in the diagnosis and classification of malignant neoplasms, including hematolymphoid malignancies Evaluating the prognosis for patients with malignant tumors

Interpretation: The interpretive report describes copy number changes and any loss of heterozygosity that may be associated with the neoplastic process. Abnormal clones with subclonal cytogenetic evolution will be discussed if identified. The continual discovery of novel copy number variation and published clinical reports means that the interpretation of any given copy number change may evolve with increased scientific understanding. Although the presence of a clonal abnormality usually indicates a neoplasia, in some situations it may reflect a benign or constitutional genetic change. If a genetic change is identified that is likely constitutional and clearly pathogenic (eg, XYY), follow-up with a medical genetics consultation may be suggested. The absence of an abnormal clone may be the result of specimen collection from a site that is not involved in the neoplasm, or may indicate that the disorder is caused by a point mutation that is not detectable by chromosomal microarray (CMA). CMA, FISH, and conventional cytogenetics are to some extent complementary methods. In some instances, additional FISH or conventional cytogenetic studies will be recommended to clarify interpretive uncertainties. Current as of August 23, 2017 7:11 am CDT


Page 515


Clinical References: 1. Cooley L, Lebo M, Li M, et al: American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders. Genet Med 2013;15:484-494 2. Ciriello G, Miller ML, Aksoy BA, et al: Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013 Sep 26;45(10):1127-1133

CHRAF

Chromosome Analysis, Amniotic Fluid

35243

Clinical Information: Chromosome analysis for prenatal diagnosis is appropriate in pregnancies with abnormal maternal screening, advanced maternal age, and features suggestive of or concerns for aneuploidy syndromes, including Down syndrome, Turner syndrome, Klinefelter syndrome, trisomy 13 syndrome, and trisomy 18 syndrome. Chromosomal abnormalities are the cause of a wide range of disorders associated with birth defects and congenital diseases. Many of these disorders can be diagnosed prenatally by analysis of amniocytes. This method permits diagnosis of chromosome abnormalities during the second trimester of pregnancy or later. A chromosomal microarray (CMAP / Chromosomal Microarray, Prenatal, Amniotic Fluid/Chorionic Villus Sampling) is recommended, rather than chromosomal analysis, to detect clinically relevant gains or losses of chromosomal material in pregnancies with 1 or more major structural abnormalities. Chromosomal microarray can also be considered, rather than chromosome analysis, for patients undergoing invasive prenatal diagnostic testing with a structurally normal fetus.

Useful For: Prenatal diagnosis of chromosome abnormalities, including aneuploidy (ie, trisomy or monosomy) and balanced rearrangements

Interpretation: Cytogenetic studies on amniotic fluid are considered nearly 100% accurate for the detection of large fetal chromosome abnormalities. However, subtle or cryptic abnormalities involving microdeletions usually can be detected only with the use of targeted FISH testing. Approximately 3% of amniotic fluid specimens analyzed are found to have chromosome abnormalities. Some of these chromosome abnormalities are balanced and may not be associated with birth defects. A normal karyotype does not rule out the possibility of birth defects, such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and other environmental factors (ie, teratogen exposure). For these reasons, clinicians should inform their patients of the technical limitations of chromosome analysis prior to performing the amniocentesis. It is recommended that a qualified professional in Medical Genetics communicate all results to the patient.

Reference Values: An interpretative report will be provided.

Clinical References: 1. American College of Obstetricians and Gynecologists Committee on Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013;122:1374-1377 2. Society for Maternal-Fetal Medicine (SMFM): The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2-B9 3. Committee Opinion, 640: Cell-free DNA screening for fetal aneuploidy. American College of Obstetricians and Gynecologists Committee on Genetics. Obstet Gynecol 2015;123:e31-e37 4. Wilson KL, Czerwinski JL, Hoskovec JM, et al: NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Couns 2013;22:4-15

CHRPC 35315

Chromosome Analysis, Autopsy, Products of Conception, or Stillbirth Clinical Information: Chromosome analysis of products of conception, spontaneous abortions, stillborn infants, or neonates is appropriate when previous losses have occurred and features suggestive of or concerns for aneuploidy syndromes, including Down syndrome, Turner syndrome, Klinefelter syndrome, trisomy 13 syndrome and trisomy 18 syndrome. Chromosomal abnormalities may result in malformed fetuses, spontaneous abortions, or neonatal deaths. Estimates of the frequency of chromosome



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abnormalities in spontaneous abortuses range from 15% to 60%. Chromosome studies of products of conception (POC) may provide useful information concerning the cause of miscarriage and, thus, the recurrence risk for pregnancy loss and risk for having subsequent children with chromosome anomalies. Chromosome analysis of the stillborn infant or neonate (autopsy) may be desirable, particularly if there is a family history of 2 or more miscarriages or when malformations are evident. For neonatal cases, peripheral blood is the preferred specimen for chromosome analysis (CHRCB / Chromosome Analysis, Congenital Disorders, Blood). Some of the chromosome abnormalities that are detected in these specimens are balanced (no apparent gain or loss of genetic material) and may not be associated with birth defects, miscarriage, or stillbirth. For balanced chromosome rearrangements, it is sometimes difficult to determine whether the chromosome abnormality is the direct cause of a miscarriage or stillbirth. In these situations, chromosome studies of the parents' peripheral blood may be useful to determine if an abnormality is familial or de novo. De novo, balanced rearrangements can cause miscarriages or stillbirth by producing submicroscopic deletions, duplications, or gene mutations at the site of chromosome breakage. A normal karyotype does not rule out the possibility of birth defects, such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). -Subtle structural chromosomal abnormalities can occasionally be missed -Culturing of maternal cells rather than fetal cells -Chromosome mosaicism may be missed due to statistical sampling error (rare) A chromosomal microarray (CMAP / Chromosomal Microarray, Prenatal, Amniotic Fluid/Chorionic Villus Sampling) is recommended, rather than chromosomal analysis, to detect clinically relevant gains or losses of chromosomal material in instances of intrauterine fetal demise or stillbirth.

Useful For: Diagnosis of congenital chromosome abnormalities in products of conception, including aneuploidy (ie, trisomy or monosomy)

Interpretation: A normal result is a karyotype of 46,XX or 46,XY. A chromosome abnormality known to be pathogenic will be reported as abnormal. Apparently balanced rearrangements will be reported. On rare occasions, structural changes with unknown clinical significance will be identified and reported. Due to bacterial contamination or nonviable cells, we are unable to establish a viable culture 20% of the time. In these cases, the specimen cannot be used for chromosome analysis, and the FISH aneuploidy test (POCRF / Products of Conception (POC) Aneuploidy Detection, FISH, Fresh Tissue) is automatically initiated. While the FISH test is not as comprehensive as a chromosome analysis, it can provide information with regard to the most common numeric abnormalities in spontaneous miscarriage and stillbirth. A FISH signal pattern with 2 signals for 13, 15, 16, 18, 21, 22 and either 2 signals for chromosome X or one signal for chromosome X and one signal for chromosome Y in each interphase will be reported as normal. A FISH signal pattern indicating an additional signal (3 signals) in each interphase will be reported as having a trisomy of the chromosome identified. A FISH signal pattern indicating loss of a signal (1 signal) will be reported as having a monosomy of the chromosome identified. A FISH signal pattern indicating an additional signal for every chromosome (3 signals for X and/or Y and 3 signals for chromosomes 13, 15, 16, 18, 21, 22) will be reported as having triploidy.


Clinical References: 1. Laurino MY, Bennett RL, Saraiya DS, et al: Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors. J Genet Couns 2005;14,165-181 2. American College of Obstetricians and Gynecologists Committee on Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013;122:1374-1377 3. Society for Maternal-Fetal Medicine (SMFM): The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2-B9

CHRBF

Chromosome Analysis, Body Fluid

35314

Clinical Information: Cytogenetic studies on body fluids (eg, pleural effusions, ascites, and pericardial, cerebrospinal, and synovial fluids) may be helpful to diagnose or to rule-out metastases or relapses in patients with lymphoma or other malignancies. Chromosome analysis serves as a useful adjunct to cytology. In pleural fluids, lymphomas are often more readily diagnosed by cytogenetic techniques than by standard cytologic examination.



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Useful For: Assisting in the diagnosis of certain malignancies Interpretation: The observation of a chromosomally abnormal clone is evidence of a clonal neoplastic process. A normal karyotype does not eliminate the possibility of a neoplastic process. On rare occasions, the presence of an abnormality may be associated with a congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical genetics consultation is recommended.


Clinical References: Dewald GW, Dines DE, Weiland LH, Gordon H: The usefulness of chromosome examination in the diagnosis of malignant pleural effusions. N Engl J Med 1976;295:1494-1500

CHRCV

Chromosome Analysis, Chorionic Villus Sampling

35251

Clinical Information: Although not used as widely as amniocentesis, the use of chorionic villus sampling (CVS) for chromosome analysis is an important procedure for the prenatal diagnosis of chromosome abnormalities. CVS can be collected by either transcervical or transabdominal techniques. The medical indications for performing chromosome studies on CVS are similar to amniocentesis, and may include advanced maternal age, abnormal first-trimester screen, and family history of a chromosome abnormality. A chromosomal microarray (CMAP / Chromosomal Microarray, Prenatal) is recommended, rather than chromosomal analysis, to detect clinically relevant gains or losses of chromosomal material in pregnancies with one or more major structural abnormalities. Chromosomal microarray can also be considered, rather than chromosome analysis, for patients undergoing invasive prenatal diagnostic testing with a structurally normal fetus.

Useful For: Prenatal diagnosis of chromosome abnormalities, including aneuploidy (ie, trisomy or monosomy) and balanced rearrangements This test is not appropriate as a first-tier test for detecting gains or losses of chromosomal material in pregnancies with 1 or more major structural abnormalities.

Interpretation: Cytogenetic studies on chorionic villus specimen (CVS) are considered more than 99% reliable for the detection of most fetal chromosome abnormalities. However, subtle or cryptic abnormalities involving microdeletions usually can be detected only with the use of targeted FISH testing. Approximately 3% of CSVs analyzed are found to have chromosome abnormalities. Some of these chromosome abnormalities are balanced and may not be associated with birth defects. A normal karyotype does not rule out the possibility of birth defects, such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). For these reasons, clinicians should inform their patients of the technical limitations of chromosome analysis before the procedure is performed, so that patients may make an informed decision about pursuing the procedure. Limitations: -False-chromosome mosaicism may occur due to artifact of culture -True mosaicism may be missed due to statistical sampling error -Presence of chromosome abnormalities in placental cells that do not occur in the cells of the fetus (confined placental mosaicism) -Subtle structural chromosome abnormalities can occasionally be missed It is recommended that a qualified professional in Medical Genetics communicate all results to the patient.


Clinical References: 1. American College of Obstetricians and Gynecologists Committee on Genetics: Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol 2013;122:1374-1377 2. Society for Maternal-Fetal Medicine (SMFM): The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016;215:B2-B9 3. Committee Opinion, 640: Cell-free DNA screening for fetal aneuploidy. American College of Obstetricians and Gynecologists Committee on Genetics. Obstet Gynecol 2015;123:e31-e37 4. Wilson KL, Czerwinski JL, Hoskovec JM, et al: NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Couns 2013;22:4-15



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CHRCB

Chromosome Analysis, Congenital Disorders, Blood

35248

Clinical Information: Chromosome analysis is appropriate for individuals with clinical features including infertility, multiple miscarriages, delayed puberty, ambiguous genitalia, amenorrhea, or individuals with clinical features suggestive of an aneuploidy syndrome, including Down syndrome, Turner syndrome, Klinefelter syndrome, Trisomy 13 syndrome, and Trisomy 18 syndrome. A chromosomal microarray study (CMACB / Chromosomal Microarray, Congenital, Blood) is recommended as the first-tier test (rather than a congenital chromosome study) to detect clinically relevant gains or losses of chromosomal material for individuals with multiple anomalies not specific to well-delineated genetic syndromes, individuals with apparently nonsyndromic developmental delay or intellectual disability, and individuals with autism spectrum disorders. Chromosome analysis may be appropriate for this patient population if microarray has been performed with normal results. Some chromosome rearrangements are balanced (no gain or loss of material) and, therefore, not detectable by chromosomal microarray. In rare situations these rearrangements may interrupt gene functioning and have the potential to cause abnormal clinical features. Limitations: A normal karyotype (46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of abnormal clinical features such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). Chromosomal mosaicism may be missed due to statistical sampling error (rare) and subtle structural chromosome abnormalities can occasionally be missed.

Useful For: Diagnosis of congenital chromosome abnormalities, including aneuploidy, structural abnormalities, and balanced rearrangements

Interpretation: When interpreting results, the following factors need to be considered: -Some chromosome abnormalities are balanced (no apparent gain or loss of genetic material) and may not be associated with birth defects. However, balanced abnormalities often cause infertility and, when inherited in an unbalanced fashion, may result in birth defects in the offspring. -A normal karyotype (46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of birth defects such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). It is recommended that a qualified professional in Medical Genetics communicate all abnormal results to the patient.


Clinical References: 1. Manning M, Hudgins L, Professional Practice and Guidelines Committee: Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010;12(11):742-745 2. Laurino MY, Bennett RL, Saraiya DS, et al: Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors. J Genet Couns 2005;14:165-181 3. Sheets KB, Crissman BG, Feist CD, et al: Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet Couns 2011;20:432-441

CHFXC

Chromosome Analysis, Congenital Disorders, Fixed Cells

64921

Clinical Information: Chromosome analysis is appropriate for individuals with clinical features including infertility, multiple miscarriages, delayed puberty, ambiguous genitalia, amenorrhea, or individuals with clinical features suggestive of an aneuploidy syndrome, including Down syndrome, Turner syndrome, Klinefelter syndrome, trisomy 13 syndrome, and trisomy 18 syndrome. A chromosomal microarray study (CMACB / Chromosomal Microarray, Congenital, Blood) is recommended as the first-tier test (rather than a congenital chromosome study) to detect clinically relevant gains or losses of chromosomal material for individuals with multiple anomalies not specific to well-delineated genetic syndromes, individuals with apparently nonsyndromic developmental delay or intellectual disability, and individuals with autism spectrum disorders. Chromosome analysis may be appropriate for this patient population if microarray has been performed with normal results. Some chromosome rearrangements are balanced (no gain or loss of material) and therefore not detectable by chromosomal microarray. In rare



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situations, these rearrangements may interrupt gene functioning and have the potential to cause abnormal clinical features. Limitations: A normal karyotype (46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of abnormal clinical features such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). Chromosomal mosaicism may be missed due to statistical sampling error (rare) and subtle structural chromosome abnormalities can occasionally be missed.

Useful For: Diagnosis of congenital chromosome abnormalities, including aneuploidy, structural abnormalities, and balanced rearrangements

Interpretation: When interpreting results, the following factors need to be considered: -Some chromosome abnormalities are balanced (no apparent gain or loss of genetic material) and may not be associated with birth defects. However, balanced abnormalities often cause infertility and, when inherited in an unbalanced fashion, may result in birth defects in the offspring. -A normal karyotype (46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of birth defects such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). -Chromosomal mosaicism may be missed due to statistical sampling error (rare) -Subtle structural chromosome abnormalities can occasionally be missed -It is recommended that a qualified professional in Medical Genetics communicate all abnormal results to the patient.


Clinical References: 1. Manning M, Hudgins L: Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med 2010;12(11):742-745 2. Laurino MY, Bennett RL, Saraiya DS, et al: Genetic evaluation and counseling of couples with recurrent miscarriage: recommendations of the National Society of Genetic Counselors. J Genet Couns 2005;14:165-181 3. Sheets KB, Crissman BG, Feist CD, et al: Practice guidelines for communicating a prenatal or postnatal diagnosis of Down syndrome: recommendations of the national society of genetic counselors. J Genet Couns 2011;20:432-444

CHRHB

Chromosome Analysis, Hematologic Disorders, Blood

35308

Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis, and monitoring of treatment of many hematologic disorders. Whenever possible, it is best to do chromosome studies for neoplastic hematologic disorders on bone marrow. Bone marrow studies are more sensitive and the chances of finding metaphases are about 95%, compared with only a 60% chance for blood studies. When it is not possible to collect bone marrow, chromosome studies on blood may be useful. When blood cells are cultured in a medium without mitogens, the observation of any chromosomally abnormal clone may be consistent with a neoplastic process. See Laboratory Screening Tests for Suspected Multiple Myeloma in Special Instructions. Conventional chromosome studies of B-cell disorders are not always successful because B-lymphocytes do not proliferate well in cell culture. The agent CpG 7909 (CpG) is a synthetic oligodeoxynucleotide that binds to the Toll-like receptor 9 (TLR9) present on B cells, causing B-cell activation. In the laboratory setting, CpG may be used as a mitogen to stimulate B-cells in patient specimens, thus allowing identification of chromosome abnormalities. CpG stimulation reveals an abnormal karyotype in approximately 80% of patients with of chronic lymphocytic leukemia (CLL), and the karyotype is complex in 20% to 25% of cases. Several studies have reported that increased genetic complexity revealed by CpG-stimulated chromosome studies confers a less favorable time to first treatment, treatment response, and overall survival.

Useful For: Assisting in the classification and follow-up of certain malignant hematological disorders when bone marrow is not available

Interpretation: The presence of an abnormal clone usually indicates a malignant neoplastic process. The absence of an apparent abnormal clone in blood may result from a lack of circulating abnormal cells and not from an absence of disease. On rare occasions, the presence of an abnormality may be associated with a congenital abnormality and, thus, not related to a malignant process. When this situation is Current as of August 23, 2017 7:11 am CDT


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suspected, follow-up with a medical genetics consultation is recommended.


Clinical References: 1. Dewald GW, Ketterling RP, Wyatt WA, Stupca PJ: Cytogenetic studies in neoplastic hematologic disorders. In Clinical Laboratory Medicine, Second edition. Edited by KD McClatchey. Baltimore, Williams and Wilkens, 2002, pp 658-685 2. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood 2012 Mar 8;119(10):2310-2313

CHRBM

Chromosome Analysis, Hematologic Disorders, Bone Marrow

35245

Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis, and treatment monitoring of many hematologic disorders. Cytogenetic studies on bone marrow may be helpful in many malignant hematologic disorders as the observation of a chromosomally abnormal clone may be consistent with a neoplastic process. Certain chromosome abnormalities may help classify a malignancy. As examples, the Philadelphia (Ph) chromosome, also referred to as der(22)t(9;22)(q34;q11.2), is usually indicative of chronic myeloid leukemia (CML) or acute leukemia; t(8;21)(q22;q22) defines a specific subset of patients with acute myeloid leukemia; and t(8;14)(q24.1;q32) is associated with Burkitt lymphoma. Cytogenetic studies are also used to monitor patients with hematologic neoplasia and may identify disease progression, such as the onset of blast crisis in CML, which is often characterized by trisomy 8, isochromosome 17q, and multiple Ph chromosomes. Conventional chromosome studies of B-cell disorders are not always successful because B lymphocytes do not proliferate well in cell culture. The agent CpG 7909 (CpG) is a synthetic oligodeoxynucleotide that binds to the Toll-like receptor 9 (TLR9) present on B cells, causing B-cell activation. In the laboratory setting, CpG may be used as a mitogen to stimulate B cells in patient specimens, thus allowing identification of chromosome abnormalities. CpG stimulation reveals an abnormal karyotype in approximately 80% of patients with chronic lymphocytic leukemia, and the karyotype is complex in 20% to 25% of cases. Several studies have reported that increased genetic complexity revealed by CpG-stimulated chromosome studies confers a less favorable time to first treatment, treatment response, and overall survival. See Diagnosis and Monitoring of Multiple Myeloma in Publications.

Useful For: Assisting in the diagnosis and classification of certain malignant hematological disorders Evaluation of prognosis in patients with certain malignant hematologic disorders Monitoring effects of treatment Monitoring patients in remission

Interpretation: To ensure the best interpretation, it is important to provide some clinical information to verify the appropriate type of cytogenetic study is performed. The following factors are important when interpreting the results: -Although the presence of an abnormal clone usually indicates a malignant neoplastic process, in rare situations, the clone may reflect a benign condition. -The absence of an abnormal clone may be the result of specimen collection from a site that is not involved in the neoplasm or may indicate that the disorder is caused by submicroscopic abnormalities that cannot be identified by chromosome analysis. -On rare occasions, the presence of an abnormality may be associated with a congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical genetics consultation is recommended. -On occasion, bone marrow chromosome studies are unsuccessful. If clinical information has been provided, we may have a FISH study option that could be performed.


Clinical References: 1. Dewald GW, Ketterling RP, Wyatt WA, Stupca PJ: Cytogenetic studies in neoplastic hematologic disorders. In Clinical Laboratory Medicine. Second edition. Edited by KD McClatchey. Baltimore, Williams and Wilkens, 2002, pp 658-685 2. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood 2012 Mar 8;119(10):2310-2313 Current as of August 23, 2017 7:11 am CDT


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CHFXH

Chromosome Analysis, Hematologic Disorders, Fixed Cells

64922

Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis, and treatment monitoring of many hematologic disorders. Cytogenetic studies on bone marrow may be helpful in many malignant hematologic disorders as the observation of a chromosomally abnormal clone may be consistent with a neoplastic process. Certain chromosome abnormalities may help classify a malignancy. As examples, the Philadelphia (Ph) chromosome, also referred to as der(22)t(9;22)(q34;q11.2), is usually indicative of chronic myeloid leukemia (CML) or acute leukemia, t(8;21)(q22;q22) defines a specific subset of patients with acute myeloid leukemia, and t(8;14)(q24.1;q32) is associated with Burkitt lymphoma. Cytogenetic studies are also used to monitor patients with hematologic neoplasia and may identify disease progression, such as the onset of blast crisis in CML, which is often characterized by trisomy 8, isochromosome 17q, and multiple Ph chromosomes.

Useful For: Assisting in the diagnosis and classification of certain malignant hematological disorders Evaluating the prognosis of patients with certain malignant hematologic disorders Monitoring effects of treatment Monitoring patients in remission

Interpretation: To ensure the best interpretation, it is important to provide some clinical information to verify the appropriate type of cytogenetic study is performed. The following factors are important when interpreting the results: -Although the presence of an abnormal clone usually indicates a malignant neoplastic process, in rare situations, the clone may reflect a benign condition. -The absence of an abnormal clone may be the result of specimen collection from a site that is not involved in the neoplasm or may indicate that the disorder is caused by submicroscopic abnormalities that cannot be identified by chromosome analysis. -On rare occasions, the presence of an abnormality may be associated with a congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical genetics consultation is recommended. -On occasion, bone marrow chromosome studies are unsuccessful. If clinical information has been provided, we may have a FISH study option that could be performed.


Clinical References: 1. Dewald GW, Ketterling RP, Wyatt WA, Stupca PJ: Cytogenetic studies in neoplastic hematologic disorders. In Clinical Laboratory Medicine. Second edition. Edited by KD McClatchey. Baltimore, Williams and Wilkens, 2002, pp 658-685 2. Rigolin GM, Cibien F, Martinelli S, et al: Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with "normal" FISH: correlations with clinicobiological parameters. Blood 2012 Mar 8;119(10):2310-2313

CHRLN

Chromosome Analysis, Lymphoid Tissue

35309

Clinical Information: Chromosomal abnormalities play a central role in the pathogenesis, diagnosis, and monitoring of treatment of many hematologic disorders. The observation of a chromosomally abnormal clone is consistent with a clonal neoplastic process. Certain chromosome abnormalities can help classify the type of lymphoma. For example, t(14;18)(q32;q21.3) involving the IGH and BCL2 genes is usually indicative of a follicular lymphoma. A translocation between MYC and IGH genes or a t(8;14)(q24.1;q32) are both associated with Burkitt lymphoma. Cytogenetic studies often can help distinguish between B-cell and T-cell disorders. Structural abnormalities involving breakpoints at any immunoglobulin locus is consistent with a B-cell disorder; structural abnormalities involving breakpoints at a T-cell receptor site are usually associated with a T-cell disorder.

Useful For: Assisting in the classification of certain cases of lymphoma Interpretation: The observation of a chromosomally abnormal clone is evidence of a clonal neoplastic process. Certain chromosome abnormalities also may be associated with certain morphologic classifications. However, a normal karyotype does not eliminate the possibility of a neoplastic process. On rare occasions, the presence of an abnormality may be associated with a congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical genetics consultation is Current as of August 23, 2017 7:11 am CDT


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recommended.


Clinical References: 1. Pierre RV, Dewald GW, Banks PM: Cytogenetic studies in malignant lymphoma: possible role in staging studies. Cancer Genet Cytogenet 1980;1:257-261 2. Dewald GW, Jenkins RB: Cytogenetic and molecular genetic studies of patients with monoclonal gammopathies. In Neoplastic Diseases of Blood. Second edition. Edited by PH Wiernik, GP Canello, RA Kyle, CA Schiffer. New York, Churchill Livingstone, 1991, pp 427-438

CRAT 35316

Chromosome Analysis, Rearrangement in Ataxia Telangiectasia, Blood Clinical Information: Chromosomal instability syndromes are autosomal recessive disorders characterized by defects in DNA repair mechanisms or genetic instability. Patients with these disorders have an increased risk of developing malignant disorders. When blood from affected individuals is cultured and chromosome analysis is performed, elevated rates of chromosomal rearrangements are observed. These disorders include ataxia telangiectasia (AT) and Nijmegen breakage syndrome (NBS). An increased frequency of chromosome rearrangements, including involvement at 7p13, 7q34, 14q11.2, or 14q32, signals a positive result. NBS usually has a higher frequency of cells with chromosome rearrangements than AT and generally does not include the clinical features of ataxia or increased serum alpha-fetoprotein. A normal result does not rule out a diagnosis of AT, NBS, or other chromosome instability syndromes.

Useful For: Evaluating patients for chromosome instability syndromes, including ataxia telangiectasia and Nijmegen breakage syndrome

Interpretation: The pattern of chromosome breakage and the number of breaks are compared to a normal control and an interpretive report is provided.


Clinical References: 1. Gatti R, Perlman S: Ataxia-Telangiectasia. Accessed December 27, 2016, Available at http://www.ncbi.nlm.nih.gov/books/NBK26468/ 2. Concanon P, Gatti R: Nijmegen Breakage Syndrome. Accessed February 16, 2012, Available at http://www.ncbi.nlm.nih.gov/books/nbk1176/ 3. Dewald GW, Noonan KJ, Spurbeck JL, Johnson DD: T-lymphocytes with 7;14 translocations: frequency of occurrence, breakpoints, and clinical and biological significance. Am J Hum Genet 1986 Apr;38(4):520-532 4. Digweed M, Sperling K: Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair 2004;3:1207-1217 5. van der Burgt I, Chrzanowska KH, Smeets D, et al: Nijmegen breakage syndrome. J Med Genet 1996;33:153-156

BLOOM 35317

Chromosome Analysis, Sister Chromatid Exchange (SCE) for Bloom Syndrome, Blood Clinical Information: Sister chromatid exchange analysis is appropriate in individuals with clinical features suggestive of Bloom syndrome. Bloom syndrome is a genetic disorder associated with various congenital defects and predisposition to acute leukemia, pulmonary fibrosis, and Hodgkin lymphomas. Carcinoma also is commonly seen in these patients. Approximately one-fourth to one-half of patients develop some type of cancer with a mean age of 25 years at onset. The severity and age of onset of cancer varies among patients. These patients often have prenatal or postnatal growth retardation, short stature, malar hypoplasia, telangiectatic erythema of the face and other regions, hypo- and hyperpigmentation, immune deficiencies, occasional mild mental retardation, infertility, and high-pitched voices. Bloom syndrome is an autosomal recessive disorder caused by mutations in the BLM gene located at 15q26.1. While multiple mutations have been detected, the use of molecular testing to diagnose Bloom syndrome is limited in many ethnic groups. Patients with Bloom syndrome demonstrate a high frequency of



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chromosome abnormalities when their cells are cultured. Thus, cytogenetic studies can be helpful to establish a diagnosis. Bloom syndrome results in 2 characteristic cytogenetic abnormalities. First, the cells are at increased risk for random breaks leading to fragments or exchanges between nonhomologous chromosomes. Second, cells in these patients have an increased frequency of sister chromatid exchanges (SCE: exchange of material between homologous chromosomes) of approximately 10-fold to 20-fold higher than average. This test is diagnostic for Bloom syndrome. This test cannot be used to identify heterozygote carriers for Bloom syndrome and is not appropriate as part of a prenatal screening panel. A normal result does not rule out the possibility of birth defects, such as those caused by chromosomal abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). The test does not rule out other numeric or structural abnormalities. If a constitutional chromosome abnormality is suspected, a separate conventional cytogenetic study, CHRCB / Chromosome Analysis, for Congenital Disorders, Blood should be requested.

Useful For: Establishing a diagnosis of Bloom syndrome Interpretation: A frequency of sister chromatid exchange comparable to a control specimen and historical reference values will be reported as normal. A 10-fold or more increase in sister chromatid exchange relative to a control specimen and historical reference values will be reported as abnormal. This is consistent with a diagnosis of Bloom syndrome.


Clinical References: 1. Dicken CH, Dewald G, Gordon H: Sister chromatid exchanges in Bloom's syndrome. Arch Dermatol 1978:114;755-760 2. Sanz MM, German J. Bloom's Syndrome. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle; 1993-2014. 2006 Mar 22 (Updated 2013 Mar 28). Accessed 05/22/2013 Available at: http://www.ncbi.nlm.nih.gov/books/NBK1398/

CHRTI

Chromosome Analysis, Skin Biopsy

35250

Clinical Information: Chromosomal abnormalities cause a wide range of disorders associated with birth defects and congenital diseases. Usually, the abnormalities can be demonstrated in peripheral blood, which is readily available. Chromosome analysis on skin fibroblasts may be indicated when the results from peripheral blood are inconclusive or in clinical circumstances such as suspected cases of chromosome mosaicism, confirmation of new chromosome disorders, or some dermatological disorders. Subtle structural chromosomal anomalies can occasionally be missed. Chromosomal mosaicism may be missed due to statistical sampling error (rare).

Useful For: Diagnosis of mosaic congenital chromosome abnormalities, including mosaic aneuploidy and mosaic structural abnormalities Subsequent chromosome analysis when results from peripheral blood are inconclusive

Interpretation: When interpreting results, the following factors need to be considered: -Some chromosome abnormalities are balanced (no apparent gain or loss of genetic material) and may not be associated with birth defects. However, balanced abnormalities often cause infertility and, when inherited in an unbalanced fashion, may result in birth defects in the offspring. -A normal karyotype (46,XX or 46,XY with no apparent chromosome abnormality) does not eliminate the possibility of birth defects such as those caused by submicroscopic cytogenetic abnormalities, molecular mutations, and environmental factors (ie, teratogen exposure). It is recommended that a qualified professional in Medical Genetics communicate all results to the patient.


Clinical References: 1. The Principals of Clinical Cytogenetics. Second edition. Edited by SL Gerson, MB Keagle. Totowa, NJ, Humana Press 2005 pp 210 2. Azcona C, Bareille P, Stanhop R: Lesson of the week: Turner's syndrome mosaicisim in patients with a normal blood lymphocyte karyotype. BMJ 1999;318:856-857 3. Woods CG, Bankier A, Curry J, et al: Asymmetry and skin pigmentary anomalies in Current as of August 23, 2017 7:11 am CDT


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chromosome mosaicism. J Med Genet 1994;31:694-701 4. Ribeiro Noce T, de Pina-Neto JM, Happle R: Phylloid pattern of pigmentary disturbance in a case of complex mosaicism. Am J Med Genet 2001;98:145-147

CHRST

Chromosome Analysis, Solid Tumors

35320

Clinical Information: Most malignant neoplasms are associated with clonal genetic abnormalities and the observation of an abnormal cytogenetic clone is consistent with a neoplasm. In many instances, these abnormalities can be demonstrated by cytogenetic analysis. Some physicians now consider cytogenetic analysis a useful laboratory test to determine the neoplastic potential of solid tumors. For some tumors, cytogenetic analysis can help classify solid tumors. For example, an X;18 translocation has been specifically associated with synovial sarcoma, many alveolar rhabdomyosarcomas have an associated 2;13 translocation, and nearly every myxoid liposarcoma has a 12;16 translocation. A complete summary of the correlation between tumor histology and specific chromosome anomalies is too extensive to summarize here. The reader is referred to the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. 2014 Available at URL: http://cgap.nci.nih.gov/Chromosomes/Mitelman

Useful For: Assisting in the classification of malignant tumors associated with chromosomal abnormalities

Interpretation: The observation of a chromosomally abnormal clone is evidence of a clonal neoplastic process. Certain chromosome abnormalities may also be specifically associated with certain morphologic classifications. In many tumors, the cytogenetic interpretation may be complicated by the observation of numerous complex chromosome anomalies. Nevertheless, the presence of certain chromosome abnormalities within a complex karyotype may still aid in classifying the tumor. However, a normal karyotype does not eliminate the possibility of a neoplastic process. Additionally, FISH testing or other strategies may be more appropriate for certain tumor types. On rare occasions, the presence of an abnormality may be associated with a congenital abnormality that is not related to a malignant neoplastic process. Follow-up with a medical genetics consultation is recommended.


Clinical References: 1. Sandberg AA, Turc-Carel C, Gemmell RM: Chromosomes in solid tumors and beyond. Cancer Res 1988;48:1049-1059 2. Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. Edited by F Mitelman, B Johansson, F Mertens. 2014, Available from URL: http://cgap.nci.nih.gov/Chromosomes/Mitelman

CHSUM

Chronic Hepatitis (Unknown Type)

81385

Clinical Information: Hepatitis B: Hepatitis B virus (HBV) is a DNA virus that is endemic throughout the world. The infection is spread primarily through percutaneous contact with infected blood products, eg, blood transfusion, sharing of needles by drug addicts. The virus is also found in virtually every type of human body fluid and is known to be spread through oral and genital contact. HBV can be transmitted from mother to child during delivery through contact with blood and vaginal secretions; it is not commonly transmitted transplacentally. After a course of acute illness, HBV persists in approximately 10% of patients. Some of these carriers are asymptomatic, others develop chronic liver disease including cirrhosis and hepatocellular carcinoma. Hepatitis C: Hepatitis C virus (HCV) is an RNA virus that is a significant cause of morbidity and mortality worldwide. HCV is transmitted through contaminated blood or blood products or through other close, personal contacts. It is recognized as the cause of most cases of posttransfusion hepatitis. HCV shows a high rate of progression (>50%) to chronic disease. In the United States, HCV infection is quite common, with an estimated 3.5 to 4 million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of chronic HCV. The following algorithms are available in Special Instructions: -Testing Algorithm for the Screening and Diagnosis of Hepatitis C -Chronic Hepatitis C Treatment and Monitoring Algorithm: Interferon-Free Combination Therapy -Viral Hepatitis Serologic Profiles



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Useful For: The diagnosis and evaluation of patients with symptoms of hepatitis with a duration >6 months Distinguishing between chronic hepatitis B and chronic hepatitis C

Interpretation: Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profile in Special Instructions. Chronic Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the serum 6 to 16 weeks following hepatitis B viral infection. In acute cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms. Persistence of HBsAg for more than 6 months indicates development of either a chronic carrier state or chronic liver disease. Anti-hepatitis B core (anti-HBc) appears shortly after the onset of symptoms. The IgM subclass usually falls to undetectable levels within 6 months, and the IgG subclass may remain for many years. Hepatitis B surface antibody (anti-HBs) usually appears with the resolution of hepatitis B virus infection after the disappearance of HBsAg. If HBsAg and anti-HBc (total antibody) are positive and patient's condition warrants, consider testing for hepatitis Be antigen (HBeAg), anti-HBe, hepatitis B virus DNA (HBV-DNA) or anti-hepatitis D virus (anti-HDV). Chronic Hepatitis C Virus (HCV): Anti-HCV is almost always detectable by the late convalescent and chronic stage of infection. The serologic tests currently available do not differentiate between acute and chronic hepatitis C infections.

Reference Values: HEPATITIS B SURFACE ANTIGEN Negative HEPATITIS B SURFACE ANTIBODY, QUALITATIVE/QUANTITATIVE Hepatitis B Surface Antibody Unvaccinated: negative Vaccinated: positive Hepatitis B Surface Antibody, Quantitative Unvaccinated: or =12.0 mIU/mL HEPATITIS B CORE TOTAL ANTIBODIES Negative HEPATITIS C ANTIBODY Negative Interpretation depends on clinical setting.

Clinical References: 1. Wietzke P, Schott P, Braun F, et al: Clearance of HCV RNA in a chronic hepatitis C virus-infected patient during acute hepatitis B virus superinfection. Liver 1999;19:348-353 2. Villari D, Pernice M, Spinella S, et al: Chronic hepatitis in patients with active hepatitis B virus and hepatitis C virus combined infections: A histological study. Am J Gastroenter 1995;90:955-958 3. Schmilovitz-Weiss H, Levy M, Thompson N, Dusheiko G: Viral markers in the treatment of hepatitis B and C. Gut 1993;34:S26-S35

CHSBP

Chronic Hepatitis Profile (Type B)

9023

Clinical Information: Hepatitis B virus (HBV) is a DNA virus that is endemic throughout the world. The infection is spread primarily through percutaneous contact with infected blood products (eg, blood transfusion and sharing of needles by drug addicts). The virus is also found in virtually every type of human body fluid and is known to be spread through oral and genital contact. HBV can be transmitted from mother to child during delivery through contact with blood and vaginal secretions; it is not commonly transmitted transplacentally. After a course of acute illness, HBV persists in approximately 10% of patients. Some of these carriers are asymptomatic; others develop chronic liver disease including cirrhosis and hepatocellular carcinoma. See HBV Infection-Diagnostic Approach and Management Algorithm and Viral Hepatitis Serologic Profile in Special Instructions.

Useful For: Evaluating patients with suspected or confirmed chronic hepatitis B Monitoring hepatitis B viral infectivity Current as of August 23, 2017 7:11 am CDT


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Interpretation: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the serum 6 to 16 weeks following hepatitis B viral (HBV) infection. In acute cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms. Persistence of HBsAg for more than 6 months indicates development of either chronic carrier state or chronic liver disease. Hepatitis B surface antibody (anti-HBs) appears with the resolution of HBV infection after the disappearance of HBsAg. Anti-HBs also appears as the immune response following a course of inoculation with the hepatitis B vaccine. Hepatitis B core antibody (anti-HBc) appears shortly after the onset of symptoms of HBV infection and may be the only serologic marker remaining years after exposure to hepatitis B. The presence of hepatitis B envelope antigen (HBeAg) correlates with infectivity, the number of viral Dane particles, the presence of core antigen in the nucleus of the hepatocyte, and the presence of viral DNA polymerase in serum. Hepatitis B envelope antibody (anti-HBe) positivity in a carrier is often associated with chronic asymptomatic infection. If the patient has a sudden exacerbation of disease, consider ordering hepatitis C virus antibody (anti-HCV) and hepatitis delta virus antibody (anti-HDV). If HBsAg converts to negative and patient's condition warrants, consider testing for anti-HBs. If HBsAg is positive, consider testing for anti-HDV. See HBV Infection-Diagnostic Approach and Management Algorithm and Viral Hepatitis Serologic Profiles in Special Instructions.

Reference Values: HEPATITIS B SURFACE ANTIGEN Negative HEPATITIS Be ANTIGEN Negative HEPATITIS Be ANTIBODY Negative Interpretation depends on clinical setting. See Viral Hepatitis Serologic Profiles in Special Instructions.

Clinical References: 1. Bonino F, Piratvisuth T, Brunetto MR, et al: Diagnostic markers of chronic hepatitis B infection and disease. Antiviral Therapy 2010;15(3):35-44 2. Servoss JC, Friedman LS: Serologic and molecular diagnosis of hepatitis B virus. Clin Liver Dis 2004;8:267-281 3. Badur S, Akgun A: Diagnosis of hepatitis B infections and monitoring of treatment. J Clin Virol 2001;21:229-237

CLLMV 65175

Chronic Lymphocytic Leukemia (CLL) Monitoring Minimal Residual Disease (MRD) Detection, Varies Clinical Information: Chronic lymphocytic leukemia (CLL) is a low-grade, B-cell neoplasm that is the most common leukemia detected in the western world. It is a disease primarily of adults and may present as a lymphocytosis, be detected as part of a lymphadenopathy evaluation, or be found incidentally in an otherwise asymptomatic patient. The diagnosis of CLL is based on a combination of morphologic features showing primarily small lymphoid cells with coarse chromatin and scant cytoplasm and an immunophenotype of clonal B-cells with dim immunoglobulin, dim CD20, and coexpression of CD5 and CD23. New therapeutic approaches in CLL have been increasingly successful with some patients showing no or only very minimal residual disease (MRD) in their peripheral blood or bone marrow specimens following a therapeutic course. Immunophenotyping studies are necessary as morphologic features are not sufficient to detect MRD. The absence of MRD is an important prognostic indicator in these patients.

Useful For: Confirming the presence or absence of minimal residual disease in patients with known chronic lymphocytic leukemia who are either postchemotherapy or post-bone marrow transplantation

Interpretation: An interpretive report for presence or absence of minimal residual disease (MRD) for chronic lymphocytic leukemia (CLL) is provided. Individuals without CLL should not have detectable clonal B cells in the peripheral blood or bone marrow. Patients who have detectable MRD by this assay are considered to have residual CLL disease.

Reference Values: An interpretive report will be provided. Current as of August 23, 2017 7:11 am CDT


Page 527

This test will be processed as a laboratory consultation. An interpretation of the immunophenotypic findings and correlation with the morphologic features will be provided by a hematopathologist for every case.

Clinical References: 1. Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on chronic lymphocytic leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111:5446-5456 2. Varghese AM, Rawstron AC, Hillmen P: Eradicating minimal residual disease in chronic lymphocytic leukemia: should this be the goal of treatment? Curr Hematol Malig Rep 2010;5:35-44 3. Shanafelt TD: Predicting clinical outcome in CLL: how and why. Hematology Am Soc Hematol Educ Program 2009;421-429 4. Sayala HA, Rawstron AC, Hillmen P: Minimal residual disease assessment in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol 2007;20:499-512 5. Rawstron AC, Villamor N, Ritgen M, et al: International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007;21:956-964 6. Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005;23:2971-2979

CLLF

Chronic Lymphocytic Leukemia (CLL), FISH

35266

Clinical Information: Chronic lymphocytic leukemia (CLL) is the most common leukemia in North America. The most common cytogenetic abnormalities in CLL involve chromosomes 6, 11, 12, 13, and 17. These are detected and quantified using the CLL FISH panel. Use of CpG-oligonucleotide mitogen will identify an abnormal CLL karyotype in at least 80% of cases. This mitogen is added to cultures when chromosome analysis is ordered and the reason for referral is a B-cell disorder (CHRBM / Chromosome Analysis, Hematologic Disorders, Bone Marrow and CHRHB / Chromosome Analysis, Hematologic Disorders, Blood). This FISH test detects an abnormal clone in approximately 70% of patients with indolent disease and >80% of patients who require treatment. At least 5% of patients referred for CLL FISH testing have translocations involving the IGH locus; approximately 66% of these patients have translocations that result in fusion of IGH/CCND1, IGH/BCL2, or IGH/BCL3. Fusion of IGH and CCND1 is associated with t(11;14)(q13;q32), IGH and BCL2 with t(14;18)(q32;q21), and IGH and BCL3 with t(14;19)(q32;q13.3). Patients with t(11;14)(q13;q32) usually have the leukemic phase of mantle cell lymphoma. Patients with t(14;18) or t(14;19) may have an atypical form of B-CLL or the leukemic phase of a lymphoma. The prognostic associations for chromosome abnormalities detected by this FISH assay are, from best to worst: 13q-, normal, +12, 6q-, 11q-, and 17p-.

Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen in patients with chronic lymphocytic leukemia (CLL) Identifying and tracking known chromosome abnormalities in patients with CLL and tracking response to therapy Distinguishing patients with 11;14 translocations who have leukemic phase of mantle cell lymphoma from patients who have CLL Detecting patients with atypical CLL or other forms of lymphoma associated with translocations between IGH and BCL2, BCL3, MYC, or other partner genes

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe set. The absence of an abnormal clone does not rule out the presence of a neoplastic disorder.


Clinical References: 1. Dewald GW, Brockman SR, Paternoster SF, et al: Chromosome anomalies detected by interphase FISH: correlation with significant biological features of B-cell chronic lymphocytic leukemia. Br J Haematol 2003;121:287-295 2. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000 Dec;343(26):1910-1916 3. Van Dyke DL, Shanafelt TD, Call TG, et al: A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol 2010;148:544-550 4. Shanafelt TD: Predicting clinical outcome in CLL: how and why. Hematology Am Soc Hematol Educ Program 2009;421-429 5. Van Dyke DL, Werner L, Rassenti LZ, et Current as of August 23, 2017 7:11 am CDT


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al: The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol 2016 Apr;173(1):105-113

CHUB

Chub Mackerel, IgE

82822





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CSU

Chyluria Screen

81980

Clinical Information: Chyle is lymphatic fluid that contains emulsified fats (chylomicrons). Chyle in the urine (chyluria) is the result of obstruction of lymph flow and rupture of lymphatic vessels into the renal tubules. Chyluria, also called galacturia, imparts a milky appearance to urine.

Useful For: Diagnosis of chyluria (galacturia) Interpretation: This assay provides information regarding the fat content in urine fluid. Urinary cholesterol and triglyceride values are normally or =100 Strongly positive Reference values apply to all ages.


FCHYS

Chymotrypsin, Stool

57806

Reference Values: 2.3 â€“ 51.4 U/g



Page 530

FCING

Cinnamon IgG

57676




Page 531


FCIC

Circulating Immune Complexes (CIC)

91497

Interpretation: Circulating immune complexes (CICs) are detectable in a variety of systemic disorders such as rheumatological, autoimmune, allergic diseases; viral, bacterial infections and malignancies. Although detection of CICs is neither essential nor specific for any disease, anti-C1q assay is likely to provide information regarding disease activity in lupus nephritis.

Reference Values: Negative 25 EU/mL

CTCBC 35323

Circulating Tumor Cells (CTC) for Breast Cancer by CellSearch, Blood Clinical Information: In patients with metastatic cancer, tumor cells may be present in the bloodstream (circulating tumor cells: CTCs). Studies suggest that the number of CTCs is associated with progression-free and overall survival in patients with metastatic breast cancer.(1,2) Serial testing for CTCs, in conjunction with other clinical methods for monitoring breast cancer, can assist physicians in the management of these patients.(3)

Useful For: Aids in monitoring patients with metastatic breast cancer Interpretation: Results are reported as favorable or unfavorable. In patients with metastatic breast cancer, unfavorable results (> or =5 circulating tumor cells/7.5 mL of blood) are predictive of shorter progression-free survival and shorter overall survival.(1)


Clinical References: 1. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004;351:781-791 2. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004 Oct 15;10:6897-6904 3. Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2006 Mar 1;23:1420-1430

CTCCC 26176

Circulating Tumor Cells (CTC) for Colorectal Cancer by CellSearch, Blood Clinical Information: According to the American Cancer Society, colorectal cancer claims approximately 50,000 lives each year, the vast majority of which are a result of metastatic disease. Although there are many options for the treatment of metastatic colorectal cancer, oncologists often have to wait several months before they can determine if a specific treatment is beneficial to the patient. The CellSearch System identifies and enumerates the number of circulating tumor cells (CTCs) in a blood specimen.(1) Studies suggest that the number of CTCs is associated with progression-free and overall survival in patients with metastatic colorectal cancer.(2,3)

Useful For: Aids in monitoring patients with metastatic colon cancer Interpretation: Results are reported as favorable or unfavorable. In patients with metastatic colon cancer, the finding of > or =3 circulating tumor cells/7.5 mL of blood is predictive of shorter progression-free survival and overall survival.(2) Current as of August 23, 2017 7:11 am CDT


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Clinical References: 1. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004 Oct;10:6897-6904 2. Cohen SJ, Punt CJ, Iannotti N, et al: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008 Jul;26(19):3213-3221 3. Cohen SJ, Punt CJ, Iannotti N, et al: Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 2009;20(7):1223-1229

CTCPC 35325

Circulating Tumor Cells (CTC) for Prostate Cancer by CellSearch, Blood Clinical Information: According to the American Cancer Society, prostate cancer claims approximately 28,000 lives each year, the vast majority of which are a result of metastatic disease. Although there are many options for the treatment of metastatic prostate cancer, oncologists often have to wait several months after initiation of treatment before they can determine if the treatment is beneficial to the patient. The CellSearch System identifies and enumerates the number of circulating tumor cells (CTCs) in a blood specimen.(1) Studies suggest that the number of CTCs is associated with progression-free and overall survival in patients with metastatic prostate cancer.(2,3)

Useful For: Aids in monitoring patients with metastatic prostate cancer Interpretation: Results are reported as favorable or unfavorable. In patients with metastatic prostate cancer, the finding of > or =5 circulating tumor cells/7.5 mL of blood is predictive of shorter progression-free survival and overall survival.(2)


Clinical References: 1. Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004 Oct;10:6897-6904 2. deBono JS, Scher HI, Montgomery RB, et al: Circulating tumor cells predict survival benefit from treatment in the metastatic castration-resistant prostate cancer. Clin Cancer Res 2008 October 1;14(19):6302-6309 3. Danila DC, Heller G, Gignac GA, et al: Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 2007 December 1;13(23):7053-7058

CITAL

Citalopram, Serum

83730

Clinical Information: Citalopram (Celexa) and S-citalopram (escitalopram, Lexapro) are approved for treatment of depression. Celexa is a racemic mixture containing equal amounts of R- and S-enantiomer. Metabolites of citalopram (N-desmethylcitalopram) are less active than citalopram and do not accumulate in serum to clinically significant concentration. Citalopram metabolism is carried out by cytochrome P450 (CYP) 2C19 and 3A4-5. CYP 2D6 may play a minor role in citalopram metabolism. Citalopram is known to reduce CYP 2D6 activity. Citalopram clearance is significantly affected by reduced hepatic function, but only slightly by reduced renal function. A typical Celexa dose administered to an adult is 40-mg per day. A typical Lexapro dose is 20-mg per day. Citalopram is 80% protein bound, and the apparent volume of distribution is 12 L/Kg. Bioavailability is 80% and protein binding is 56% for either form of the drug. Time to peak serum concentration is 4 hours, and the elimination half-life is 35 hours. Half-life is increased in the elderly. Dosage reductions may be necessary for patients who are elderly or have reduced hepatic function.

Useful For: Monitoring citalopram therapy Identifying noncompliance, although regular blood level monitoring is not indicated in most patients Identifying states of altered drug metabolism when used in Current as of August 23, 2017 7:11 am CDT


Page 533

conjunction with CYP2C19 and CYP3A4-5 genotyping

Interpretation: Steady-state serum concentrations associated with optimal response to citalopram are in the range of 50 to 100 ng/mL when the patient is administered the R,S-enantiomeric mixture (Celexa). The most common toxicities associated with excessive serum concentration are fatigue, impotence, insomnia, and anticholinergic effects. The toxic range for citalopram is >220 ng/mL.

Reference Values: 50-110 ng/mL

Clinical References: 1. Hiemke C, Baumann P, Bergemann N, et al: AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011;44:195-235 2. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. Elsevier, Mosby, Saunders, 2011

CITR

Citrate Excretion, 24 Hour, Urine

9329

Clinical Information: Urinary citrate is a major inhibitor of kidney stone formation due in part to binding of calcium in urine. Low urine citrate levels are considered a risk for kidney stone formation. Several metabolic disorders are associated with low urine citrate. Any condition that lowers renal tubular pH or intracellular pH may decrease citrate (eg, metabolic acidosis, increased acid ingestion, hypokalemia, or hypomagnesemia). Low urinary citrate promotes kidney stone formation and growth, and is subject to therapy by correcting acidosis, hypokalemia, or hypomagnesemia by altering diet or using drugs such as citrate and potassium.

Useful For: Diagnosing risk factors for patients with calcium kidney stones Monitoring results of therapy in patients with calcium stones or renal tubular acidosis

Interpretation: Any value less than the mean for 24 hours represents a potential risk for kidney stone formation and growth. Patients with low urinary citrate, and new or growing stone formation, may benefit from adjustments in therapy known to increase urinary citrate excretion. (See Clinical Information) Very low levels (60 years: not established

Clinical References: Hosking DH, Wilson JW, Liedtke RR, et al: The urinary excretion of citrate in normal persons and patients with idiopathic calcium urolithiasis (abstract). Urol Res 1984;12:26

RCITR

Citrate Excretion, Pediatric, Random, Urine

84773

Clinical Information: Urinary citrate is a major inhibitor of kidney stone formation due in part to binding of calcium in urine. Low urine citrate levels are considered a risk for kidney stone formation. Several metabolic disorders are associated with low urine citrate. Any condition which lowers renal tubular pH or intracellular pH may decrease citrate (eg, metabolic acidosis, increased acid ingestion, hypokalemia, or hypomagnesemia). Low urinary citrate is subject to therapy by correcting acidosis, hypokalemia, or hypomagnesemia by altering diet or using drugs such as citrate and potassium.

Useful For: Diagnosing risk factors for patients with calcium kidney stones. Monitoring results of therapy in patients with calcium stones or renal tubular acidosis. A timed 24-hour urine collection is the preferred specimen for measuring and interpreting this urinary analyte. Random collections normalized to urinary creatinine may be of some clinical use in patients who cannot collect a 24-hour specimen, typically small children. Therefore, this random test is offered for children or =100 Strongly positive Reference values apply to all ages.


60855

Claudin-1, Immunostain Without Interpretation Clinical Information: Claudins are a family of tight junction-associated proteins that prevent leakage of ions, water, etc, between cells. Differential expression of claudin proteins is seen in various epithelial cell types. Strong expression of claudin-1 is seen on squamous epithelial cells of the skin. Claudin-1 may have reduced expression in invasive versus benign breast lesions. In the diagnostic setting, 30% to 50% of soft tissue and intramucosal intestinal perineuriomas are positive for claudin-1. Gastric intestinal-type adenocarcinoma shows more frequent claudin-1 expression than diffuse gastric carcinomas.

Useful For: An aid in the identification of a number of different soft tissue and epithelial neoplasms Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. Current as of August 23, 2017 7:11 am CDT


Page 537

Clinical References: 1. Morita K, Furuse M, Fujimoto K, et al: Claudin multigene family encoding fourtransmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 1999;96:511-516 2. Tokes AM, Kulka J, Paku S, et al: Claudin 1, 3 and 4 proteins and mRNA expression in benign and malignant breast lesions; a research study. Breast Cancer Res 2005;7(2):296-305 3. Flope AL, Billings SD, McKenny JK, et al: Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol 2002;26(12):1620-1626

FCLBZ

Clobazam, Serum/Plasma

57709

Reference Values: Clobazam: 30 - 300 ng/mL Desmethylclobazam: 300 - 3000 ng/mL

CLOM

Clomipramine, Serum

80902

Clinical Information: Clomipramine (chlorimipramine, Anafranil) is a tricyclic antidepressant drug used primarily to treat obsessive-compulsive disorder (OCD). Clomipramine is also used to treat panic disorder and treatment-resistant depression. Clomipramine preferentially blocks synaptic reuptake of serotonin; its pharmacologically active metabolite, norclomipramine (desmethylchlorimipramine) preferentially blocks synaptic reuptake of norepinephrine. Clomipramine undergoes significant first-pass hepatic metabolism (up to 50%) which probably explains the high degree of interindividual variability observed between administered dose and steady-state serum concentrations of the drug and its metabolite. The serum ratio of clomipramine to norclomipramine is typically 1:2-2.5. The elimination half-lives of clomipramine and norclomipramine are 19-37 hours and 54-77 hours, respectively. One to two weeks are required to achieve steady-state when a patient is started on clomipramine or following an alteration in the dose. Anticholinergic side effects (ie, dry mouth, excessive sweating, blurred vision, urinary retention, constipation) frequently accompany treatment. Other side effects may include tremor, nausea, orthostatic hypotension, dizziness, sexual dysfunction, and sleep disturbances. Signs and symptoms following overdose are similar to other tricyclic antidepressant drugs: cardiac toxicity (eg, tachycardia, arrhythmia, impaired conduction, congestive heart failure) is the major concern.

Useful For: Determining whether a poor therapeutic response is attributable to noncompliance Monitoring serum concentration of clomipramine and norclomipramine to assist in optimizing the administered dose

Interpretation: Studies investigating the relationship between serum concentrations of clomipramine and norclomipramine and therapeutic response have yielded conflicting results. However, the probability of therapeutic failure seems to increase if the sum of the clomipramine and norclomipramine serum concentrations is 65 years, gastric acid suppression, etc. Clostridium difficile infection is the



Page 539

most common cause of diarrhea in hospitalized patients and may lead to serious complications, including sepsis, bowel perforation, and increased overall mortality (especially in elderly patients). The incidence of Clostridium difficile infection has risen in the community and in healthcare settings. While culture is not the preferred means to diagnose Clostridium difficile-associated diarrhea, culture for Clostridium difficile provides an isolate suitable for antimicrobial susceptibility testing. Note that this test does not differentiate between toxin-producing and nontoxigenic strains of Clostridium difficile.

Useful For: Clostridium difficile culture provides an isolate suitable for antimicrobial susceptibility testing.

Interpretation: A positive result indicates the presence of viable Clostridium difficile in stool. A positive culture may be found with asymptomatic Clostridium difficile colonization with a toxin-producing or non-toxin-producing strain, or with Clostridium difficile-associated diarrhea. A negative result indicates the absence of Clostridium difficile growth in culture. Isolation of Clostridium difficile does not differentiate between toxin-producing and non-toxin-producing strains.

Reference Values: No growth after 1 day of incubation.

Clinical References: Cohen SH, Gerding DN, Johnson S, et al: Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010;31(5):431-455

CDFRP

Clostridium difficile Toxin, Molecular Detection, PCR, Feces

35149

Clinical Information: Clostridium difficile is the cause of C difficile-associated diarrhea (CDAD), an antibiotic-associated diarrhea, and pseudomembranous colitis (PMC). In these disorders bacterial overgrowth of C difficile develops in the colon, typically as a consequence of antibiotic usage. Clindamycin and broad-spectrum cephalosporins have been most frequently associated with CDAD and PMC, but almost all antimicrobials may be responsible. Disease is related to production of toxin A and B. Treatment typically involves withdrawal of the associated antimicrobials and, if symptoms persist, orally administered and intraluminally active metronidazole, vancomycin, or fidaxomicin. Intravenous metronidazole may be used if an oral agent cannot be administered. In recent years, a more severe form of CDAD with increased morbidity and mortality has been recognized as being caused by an epidemic toxin-hyperproducing strain of C difficile (NAP1 strain). Many toxin-hyperproducing isolates also contain the binary toxin gene and are resistant quinolones. This test does not differentiate between toxin-hyperproducing and nontoxin-hyperproducing strains. Traditionally, diagnosis relied upon 1) clinical and epidemiologic features, 2) culture (which is labor intensive and time consuming), 3) cytotoxicity assays, which are labor intensive and time consuming, and 4) toxin detection immunoassays (which are insensitive). The described PCR assay detects the regulatory gene (tcdC) responsible for production of toxins A and B. This test is used for rapid diagnosis of CDAD and PMC enabling prompt treatment that may reduce hospital stays for inpatients with CDAD.

Useful For: Sensitive, specific, and rapid diagnosis of Clostridium difficile-associated diarrhea and pseudomembranous colitis

Interpretation: A positive PCR result for the presence of the gene regulating toxin production (tcdC) indicates the presence of Clostridium difficile and toxin A and/or B. A negative result indicates the absence of detectable C difficile tcdC DNA in the specimen, but does not rule-out C difficile infection. False-negative results may occur due to inhibition of PCR, sequence variability underlying the primers or probes, or the presence of C difficile in quantities less than the limit of detection of the assay.

Reference Values: Not applicable

Clinical References: 1. Aichinger E, Schleck CD, Harmsen WS, et al: Nonutility of repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J Clin Microbiol 2008;46:3795-3797 2. Sloan LM, Duresko BJ, Gustafson DR, et al: Comparison of real-time Current as of August 23, 2017 7:11 am CDT


Page 540

PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection. J Clin Microbiol 2008;46:1996-2001 3. Verdoorn BP, Orenstein R, Rosenblatt JE, et al: High prevalence of tcdC deletion-carrying Clostridium difficile and lack of association with disease severity. Diagn Microbiol Infect Dis 2010;66:24-28 4. Karre T, Sloan L, Patel R, et al: Comparison of two commercial molecular assays to a laboratory-developed molecular assay for diagnosis of Clostridium difficile infection. J Clin Microbiol 2011;49:725-727

CLOV

Clove, IgE

82490





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CLZ

Clozapine, Serum

42366

Clinical Information: Clozapine (Clozaril), a tricyclic dibenzodiazepine, is used for the symptomatic management of psychotic disorders and is considered an atypical antipsychotic drug. It is currently used primarily for the treatment of patients with schizophrenia or schizoaffective disorders who are at risk for



Page 541

recurrent suicidal behavior and who have encountered nonresponse or adverse, intolerable extrapyramidal side effects with more classical antipsychotics (chlorpromazine, haloperidol). Although clozapine was developed about 30 years ago and the initial results were promising, the development of several fatal cases of agranulocytosis resulted in the discontinued use of this agent. Seizures, an increased risk of fatal myocarditis, and orthostatic hypotension have also been associated with the use of clozapine. The use of clozapine has regained interest for several reasons. Patients who did not respond to treatment with other antipsychotics improved when clozapine was administered. Also, the agranulocytosis that occurs in approximately 1% to 2% of patients can be controlled with close hematologic monitoring. However, because of the significant risk of agranulocytosis and seizure associated with its use, clozapine should only be used in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments, either because of insufficient effectiveness or the inability to achieve an effective dose because of intolerable adverse reactions from those drugs. Treatment is usually started with dosages of 25 to 75 mg/day with a gradual increase to reach a final dose of 300 to 450 mg/day within approximately 2 weeks of the initiation of treatment. Once the desired effect is achieved, the dose may be gradually decreased to keep the patient on the lowest possible effective dose. Patients being treated with clozapine should be closely monitored during treatment for adverse reactions. Treatment must include monitoring of white blood cell count and absolute neutrophil count. Clozapine treatment should be discontinued in patients failing to show an acceptable clinical response. In addition, in patients exhibiting beneficial clinical responses, the need for continuing treatment should be periodically reevaluated. Clozapine is metabolized to desmethylated and N-oxide derivatives. The desmethyl metabolite (norclozapine) has only limited activity, and N-oxide metabolite is inactive.

Useful For: Monitoring patient compliance An aid to achieving desired plasma levels Interpretation: The effectiveness of clozapine treatment should be based on clinical response and treatment should be discontinued in patients failing to show an acceptable clinical response.

Reference Values: CLOZAPINE Therapeutic range: >350 ng/mL CLOZAPINE + NORCLOZAPINE Therapeutic range: >450 ng/mL

Clinical References: 1. Volpicelli SA, Centorrino F, Puopolo PR, et al: Determination of clozapine, norclozapine, and clozapine-N-oxide in serum by liquid chromatography. ClinChem 1993;39(8):1656-1659 2. Chung MC, Lin SK, Chang WH, Jann MW: Determination of clozapine and desmethylclozapine in human plasma by high performance liquid chromatography with ultraviolet detection. J Chromatogr 1993;613:168-173 3. Perry PJ, Miller DD, Arndt SV, Cadoret RJ: Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenia patients. Am J Psychiatry 1991;40(5);722-747 4. Physiciansâ€™ Desk Reference (PDR) 2007 5. Fitton A, Heel RC: Clozapine. A review of its pharmacological properties, and therapeutic use in schizophrenia. Drugs 1991;40(5);722-747 6. Package insert: Clozaril. East Hanover, NJ: Novartis Pharmaceuticals; May 2005 7. Mitchell PB: Therapeutic drug monitoring of psychotropic medications. Br J Clin Pharmacol 2001;52(Suppl 1):45S-54S

60856

Clusterin, Immunostain Without Interpretation Clinical Information: In lymph nodes, tonsils, and spleen, clusterin stains the follicular dendritic cell meshworks. B cells, T cells, and histiocytes are negative. Clusterin is often positive in the tumor cells of systemic anaplastic large-cell lymphoma and is usually negative in Reed Sternberg cells in classical Hodgkin lymphoma. It is a sensitive marker for follicular dendritic cell sarcomas.

Useful For: A marker of follicular dendritic cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If Current as of August 23, 2017 7:11 am CDT


Page 542

a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Grogg KL, Lae ME, Kurtin PJ, Macon WR: Clusterin expression distinguishes follicular dendritic cell tumors from other dendritic cell neoplasms. Am J Surg Pathol 2004;28(8):988-998 2. Grogg KL, Macon WR, Kurtin PJ, Nascimento AG: A survey of clusterin and fascin expression in sarcomas and spindle cell neoplasms: Strong Clusterin Immunostaining is Highly Specific for Follicular Dendritic Cell Tumor. Modern Pathology 2005;18:260-266 3. Saffer H, Wahed A, Rassidakis GZ, Medieros J: Clusterin expression in malignant lymphomas: A Survey of 266 Cases. Modern Pathology 2002;15(11):1221-1226

62335

cMET, Immunostain Without Interpretation Clinical Information: c-Met, a cell surface receptor tyrosine kinase, regulates cellular proliferation, migration, and differentiation during development. Increased expression of c-Met has been shown to correlate with poor prognosis in nonsmall cell carcinomas of the lung.

Useful For: Aids in the identification of normal and neoplastic c-Met expressing cells Clinical References: 1. Knudsen BS, Zhao P, Resau J, et al: A Novel Multipurpose Monoclonal Antibody for Evaluating Human c-Met Expression in Preclinical and Clinical Settings. Appl Immunohistochem Mol Morphol 2009;17(1):57-67 2. Nakamura Y, Niki T, Goto A, et al: c-Met activation in lung adenocarcinoma tissues: An immunohistochemical analysis. Cancer Sci 2007;98(7):1006-1013 3. Christensen JG, Burrows J, Salgia R: c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Letters 2005;225:1-26

FCMVQ

CMV by PCR

91734

Reference Values: Not detected = Negative, no virus detected Detected = Positive, virus detected 1,000,000 copies/mL = Positive. Virus detected above maximum quantitative range. This test employs real-time PCR amplification of a Cytomegalovirus-specific conserved genetic target. A positive result should be coupled with clinical indicators for diagnosis. A â€œNot detected" result for this assay does not exclude Cytomegalovirus involvement in a disease process.

F_2

Coagulation Factor II Activity Assay, Plasma

9121

Clinical Information: Factor II (prothrombin) is a vitamin K-dependent serine protease synthesized in liver. It participates in the final common pathway of coagulation, as the substrate for the prothrombinase enzyme complex. Prothrombin is the precursor of thrombin (IIa) which converts fibrinogen to fibrin. Plasma biological half-life is about 3 days. Deficiency of factor II may cause prolonged prothrombin time and activated partial thromboplastin time. Deficiency may result in a bleeding diathesis.

Useful For: Diagnosing a congenital deficiency (rare) of coagulation factor II Evaluating acquired deficiencies associated with liver disease or vitamin K deficiency, oral anticoagulant therapy, and antibody-induced deficiencies (eg, in association with lupus-like anticoagulant) Determining warfarin treatment stabilization in patients with nonspecific inhibitors (ie, lupus anticoagulant) Determining degree of anticoagulation with warfarin to correlate with level of protein S Investigation of prolonged prothrombin time or activated partial thromboplastin time Current as of August 23, 2017 7:11 am CDT


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Interpretation: Liver disease, vitamin K deficiency, or warfarin anticoagulation can cause decreased factor II activity. Homozygotes generally have levels of or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. Lancellotti S, De Cristofaro R: Congenital prothrombin deficiency. Semin Thromb Hemost 2009 Jun;35(4):367-381 2. Peyvandi F, Bolton-Maggs PH, Batorova A, De Moerloose P: Rare bleeding disorders. Haemophilia 2012 Jul;18 Suppl 4:148-153 3. Girolami A, Scandellari R, Scapin M, Vettore S: Congenital bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm 2008;78:281-374 4. Brenner B, Kuperman AA, Watzka M, Oldenburg J: Vitamin K-dependent coagulation factors deficiency. Semin Thromb Hemost 2009 Jun;35(4):439-446

F2IS

Coagulation Factor II Inhibitor Screen, Plasma

7805

Clinical Information: Coagulation factor inhibitors arise in patients who are congenitally deficient in a specific factor in response to factor replacement therapy, or can occur spontaneously without known cause or in response to a variety of medical conditions including the postpartum state, immunologic disorders, certain antibiotic therapies, some malignancies, and old age. Inhibitors of factor VIII coagulant activity are the most commonly occurring of the specific factor inhibitors.

Useful For: Detection and quantitation of inhibitor to factor II Interpretation: Normally, there is no inhibitor, ie, negative. If the screening assays indicate the presence of an inhibitor, it will be quantitated and reported in Bethesda (or equivalent) units.

Reference Values: FACTOR II ACTIVITY ASSAY Adults: 75-145% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =25%) which may remain below adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. FACTOR II INHIBITOR SCREEN Negative

Clinical References: 1. Feinstein DI: Acquired inhibitors of blood coagulation. In Hematology: Basic Principles and Practice. Edited by R Hoffman, EJ Benz Jr, SJ Shattil, et al. New York, Livingstone Press, 1991, pp 1380-1394 2. Kasper CK: Treatment of factor VIII inhibitors. Prog Hemost Thromb 1989;9:57-86

F_9

Coagulation Factor IX Activity Assay, Plasma

9065

Clinical Information: Factor IX is a vitamin K-dependent serine protease synthesized in the liver and participates in the intrinsic coagulation pathway. Its biological half-life is 18 to 24 hours. Congenital deficiency inherited as an X-linked recessive bleeding disorder (hemophilia B). Severe deficiency ( or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. Barrowcliffe TW, Raut S, Sands D, Hubbard AR: Coagulation and chromogenic assays of factor VIII activity: general aspects, standardization, and recommendations. Semin Thromb Hemost 2002 Jun;28(3):247-256 2. Franchini M, Lippi G, Favaloro EJ: Acquired inhibitors of coagulation factors: part II. Semin Thromb Hemost 2012 Jul;38(5):447-453 3. Carcao MD: The diagnosis and management of congenital hemophilia. Semin Thromb Hemost 2012 Oct;38(7):727-734

FACTV

Coagulation Factor V Activity Assay, Plasma

9054

Clinical Information: Factor V is a vitamin K-independent protein synthesized in the liver and in other tissues (endothelium, megakaryocytes/platelets). In its thrombin-activated form (factor Va), it serves as an essential cofactor in the prothrombinase enzyme complex which converts prothrombin to thrombin (the prothrombinase complex consists of the enzyme, activated factor X, factor Va cofactor, a phospholipid surface, and calcium). Deficiency of factor V may cause prolonged prothrombin time and activated partial thromboplastin time. Deficiency may result in a bleeding diathesis. Plasma biological half-life varies from 12 to 36 hours. Platelets contain 20% to 25% of the factor V in blood. Factor V (also known as labile factor) is highly susceptible to proteolytic inactivation, with the potential for spuriously decreased assay results.

Useful For: Diagnosing congenital deficiencies (rare) of coagulation factor V Evaluating acquired deficiencies associated with liver disease, factor V inhibitors, myeloproliferative disorders, and intravascular coagulation and fibrinolysis Investigation of prolonged prothrombin time or activated partial thromboplastin time

Interpretation: See Cautions Acquired deficiencies are much more common than congenital (see Useful For). Congenitally deficient homozygotes generally have levels < or =10% to 20%. Congenitally deficient heterozygotes generally have levels < or =50%. Congenital deficiency may occur in combined association with factor VIII deficiency.

Reference Values: Adults: 70-165% Normal, full-term newborn infants may have borderline low or mildly decreased levels (> or =30% to 35%) which reach adult levels within 21 days postnatal. Healthy premature infants (30-36 weeks gestation) may have borderline low or mildly decreased levels.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. Girolami A, Scandellari R, Scapin M, Vettore S: Congenital bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm 2008;78:281-374 2. Brenner B, Kuperman AA, Watzka M, Oldenburg J: Vitamin K-dependent coagulation factors deficiency. Semin Thromb Hemost 2009 Jun;35(4):439-446 3. Asselta R, Peyvandi F: Factor V deficiency. Semin Thromb Hemost 2009 Jun;35(4):382-389 4. Lippi G, Favaloro EJ, Montagnana M, et al: Inherited and acquired factor V deficiency. Blood Coagul Fibrinolysis 2011;22(3):160-166 5. Spreafico M, Peyvandi F: Combined FV and FVIII deficiency. Haemophilia 2008 Nov;14(6):1201-1208

F5IS

Coagulation Factor V Inhibitor Screen, Plasma

7807

Clinical Information: Factor V inhibitors can occur in patients with congenital factor V deficiency after transfusion of fresh frozen plasma, however, more commonly, they occur spontaneously in previously healthy older patients who have no underlying diseases. Topical bovine thrombin or fibrin glue, which contain bovine thrombin and factor V, are commonly used in surgery for topical hemostasis,



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can result in development of anti-bovine thrombin/factor V inhibitors that cross-react with human thrombin and factor V. Other associations include antibiotics, transfusions and malignancies.

Useful For: Detection and quantitation of inhibitors against coagulation factor V Interpretation: Normally, there is no inhibitor, ie, negative. If the screening assays indicate the presence of an inhibitor, it will be quantitated and reported in Bethesda (or equivalent) units.

Reference Values: FACTOR V ACTIVITY ASSAY Adults: 75-165% Normal, full-term newborn infants may have borderline low or mildly decreased levels (> or =30-35%) which reach adult levels within 21 days postnatal.* Healthy premature infants (30-36 weeks gestation) may have borderline low or mildly decreased levels.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. FACTOR V INHIBITOR SCREEN Negative


F_7

Coagulation Factor VII Activity Assay, Plasma

9055

Clinical Information: Factor VII is a vitamin K-dependent serine protease synthesized in the liver. It is a component of the extrinsic coagulation scheme, measured by the prothrombin time. Plasma biological half-life is about 3 to 6 hours. Deficiency may result in a bleeding diathesis.

Useful For: Diagnosing congenital deficiency of coagulation factor VII Evaluating acquired deficiencies associated with liver disease, oral anticoagulant therapy, and vitamin K deficiency Determining degree of anticoagulation with warfarin to correlate with level of protein C Investigation of a prolonged prothrombin time

Interpretation: Liver disease, vitamin K deficiency, or warfarin anticoagulation can cause decreased factor VII activity. Heterozygotes generally have levels of < or =50%. Homozygotes have levels usually or =25%.

Reference Values: Adults: 65-180% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =20%) which increase within the first postnatal week but may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. Girolami A, Scandellari R, Scapin M, Vettore S: Congenital bleeding disorders of the vitamin K-dependent clotting factors. Vitam Horm 2008;78:281-374 2. Brenner B, Kuperman AA, Watzka M, Oldenburg J: Vitamin K-dependent coagulation factors deficiency. Semin Thromb Hemost 2009 Jun;35(4):439-446 3. Mariani G, Bernardi F: Factor VII deficiency. Semin Thromb Hemost 2009 Jun;35(4):400-406

F7IS

Coagulation Factor VII Inhibitor Screen, Plasma

7809

Clinical Information: Coagulation factor inhibitors arise in patients who are congenitally deficient in a specific factor in response to factor replacement therapy, or can occur spontaneously without known cause or in response to a variety of medical conditions including the postpartum state, immunologic



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disorders, certain antibiotic therapies, some malignancies, and old age. Inhibitors of factor VIII coagulant activity are the most commonly occurring of the specific factor inhibitors.

Useful For: Detection and quantitation of inhibitor to coagulation factor VII Interpretation: Normally, there is no inhibitor, ie, negative. If the screening assays indicate the presence of an inhibitor, it will be quantitated and reported in Bethesda (or equivalent) units.

Reference Values: FACTOR VII ACTIVITY ASSAY Adults: 65-180% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =20%) which increase within the first postnatal week but may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. FACTOR VII INHIBITOR SCREEN Negative


F8A

Coagulation Factor VIII Activity Assay, Plasma

9070

Clinical Information: Factor VIII is synthesized in the liver, and perhaps in other tissues. It is a coagulation cofactor which circulates bound to von Willebrand factor and is part of the intrinsic coagulation pathway. The biological half-life is 9 to 18 hours (average is 12 hours). Congenital factor VIII decrease is the cause of hemophilia A which has an incidence of 1 in 10,000 and is inherited in a recessive sex-linked manner on the X chromosome. Severe deficiency ( or =18 years of age: 60%-140% Chromogenic Factor X activity generally correlates with the one-stage factor X activity. In full term or premature neonates, infants, and children, the one-stage factor X activity* is lower than adult reference range and progressively rises to the adult reference range by adolescence. However, no similar data for the chromogenic factor X activity have been published. *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. Austin JH, Stearns CR, Winkler AM, et al: Use of the chromogenic factor X assay in patients transitioning from Argatroban to warfarin therapy. Pharmacotherapy 2012;32(6):493-501 2. McGlasson DL, Romick BG, Rubal BJ: Comparison of a chromogenic factor x assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagul Fibrinolysis 2008;19:513-517 3. Moll S, Ortel TL: Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997;127:177-185 4. Robert A, Le Querrec A, Delahousse B, et al: Control of oral anticoagulation in patients with antiphospholipid syndrome--influence of the lupus anticoagulant on International Normalized Ratio. Thromb Haemost 1998;80:99-103

F10IS

Coagulation Factor X Inhibitor Screen, Plasma

7811

Clinical Information: Coagulation factor inhibitors arise in patients who are congenitally deficient in a specific factor in response to factor replacement therapy, or can occur spontaneously without known cause or in response to a variety of medical conditions including the postpartum state, immunologic disorders, certain antibiotic therapies, some malignancies, and old age. Inhibitors of factor VIII coagulant activity are the most commonly occurring of the specific factor inhibitors.

Useful For: Detection and quantitation of inhibitor to coagulation factor X Interpretation: Normally, there is no inhibitor, ie, negative. If the screening assays indicate the presence of an inhibitor, it will be quantitated and reported in Bethesda (or equivalent) units.

Reference Values: FACTOR X ACTIVITY ASSAY Adults: 70-150% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =15-20%) which may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. FACTOR X INHIBITOR SCREEN Negative

Clinical References: 1. Feinstein DI: Acquired inhibitors of blood coagulation. In Hematology: Basic Principles and Practice. Edited by R Hoffman, EJ Benz Jr, SJ Shattil, et al. New York, NY, Livingstone Press, 1991, pp 1380-1394 2. Kasper CK: Treatment of factor VIII inhibitors. Prog Hemost Thromb 1989;9:57-86

F_11

Coagulation Factor XI Activity Assay, Plasma

9067

Clinical Information: Factor XI is synthesized in the liver. Its biological half-life is 60 to 80 hours. Factor XI is a component of intrinsic coagulation pathway which, when activated, activates factor IX to IXa. Factor XI deficiency may cause prolonged partial thromboplastin time. Deficiency associated with mild bleeding diathesis, but there is poor correlation between activity level and clinical bleeding. A



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relatively high incidence of congenital deficiency occurs among Ashkenazi Jewish descent (hemophilia C).

Useful For: Diagnosing deficiency of coagulation factor XI Investigation of prolonged activated partial thromboplastin time

Interpretation: Acquired deficiency is associated with liver disease and rarely inhibitors. Homozygotes: or =10%) which may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: 1. He R, Chen D, He S: Factor XI: hemostasis, thrombosis, and antithrombosis. Thromb Res 2012 May;129(5):541-550 2. Martin-Salces M, Jimenez-Yuste V, Alvarez MT, et al: Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost 2010;16 (2):209-213 3. Seligsohn U. Factor XI in haemostasis and thrombosis: past, present and future. Thromb Haemost 2007;98(1):84-89 4. Santoro R, Prejano S, Iannaccaro P. Factor XI deficiency: a description of 34 cases and literature review. Blood Coagul Fibrinolysis 2011Jul;22(5):431-435

F11IS

Coagulation Factor XI Inhibitor Screen, Plasma

7803

Clinical Information: Factor XI inhibitors typically arise in patients with congenital XI deficiency (hemophilia C), after infusion of fresh frozen plasma or factor XI concentrates. Acquired factor XI inhibitors rarely occur spontaneously.

Useful For: Detection and quantitation of inhibitor to coagulation factor XI Interpretation: Normally, there is no inhibitor, ie, negative. If the screening assays indicate the presence of an inhibitor, it will be quantitated and reported in Bethesda (or equivalent) units.

Reference Values: FACTOR XI ACTIVITY ASSAY Adults: 55-150% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =10%) which may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. FACTOR XI INHIBITOR SCREEN Negative


F_12

Coagulation Factor XII Activity Assay, Plasma

9069

Clinical Information: Factor XII is synthesized in the liver. Its biological half-life is 40 to 50 hours. Factor XII is a component of the contact activation system and is involved in both intrinsic pathway and fibrinolytic system Factor XII deficiency is often discovered when activated partial thromboplastin time is found to be unexpectedly long. The deficiency causes no known bleeding disorder. An association between severe factor XII deficiency and thrombosis risk has been proposed, but not proven.

Useful For: Diagnosing deficiency of coagulation factor XII Determining cause of prolonged activated partial thromboplastin time Current as of August 23, 2017 7:11 am CDT


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Interpretation: Acquired deficiency is associated with liver disease, nephritic syndrome, and chronic granulocytic leukemia. Congenital homozygous deficiency: 20% Congenital heterozygous deficiency: 20% to 50%

Reference Values: Adults: 55-180% Normal, full-term newborn infants or healthy premature infants may have decreased levels (> or =15% to 20%) which may not reach adult levels for > or =180 days postnatal.* *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.

Clinical References: Renne T, Schmaier AH, Nickel KF, et al: In vivo roles of factor XII. Blood 2012 Nov 22;120(22):4296-4303

COU

Cobalt, 24 Hour, Urine

80083

Clinical Information: Cobalt is rare but widely distributed in the environment. It is an essential cofactor in vitamin B12. While cobalt is an essential element, cobalt deficiency has not been reported in humans. Cobalt is used in the manufacture of hard alloys with high melting points and resistance to oxidation. Cobalt salts are also used in the glass and pigment industry. Previously, cobalt salts were sometimes used as foam stabilizers in the brewing industry; this practice was banned due to the cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma emitter in experimental biology, cancer therapy, and industrial radiography. Cobalt is not highly toxic, but large doses will produce adverse clinical manifestations. Acute symptoms are pulmonary edema, allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic symptoms include pulmonary syndrome, skin disorders, and thyroid abnormalities. The inhalation of dust during machining of cobalt alloyed metals can lead to interstitial lung disease. Improperly handled (60)Co can cause radiation poisoning from exposure to gamma radiation. Urine cobalt concentrations are likely to be increased above the reference value in patients with metallic joint prosthesis. Prosthetic devices produced by Zimmer Company and Johnson and Johnson typically are made of aluminum, vanadium, and titanium. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis product information for each device for composition details.

Useful For: Detecting cobalt exposure Monitoring metallic prosthetic implant wear Interpretation: Concentrations > or =2.0 mcg/specimen indicate excess exposure. There are no Occupational Safety and Health Administration (OSHA) blood or urine criteria for occupational exposure to cobalt. Prosthesis wear is known to result in increased circulating concentration of metal ions. In a patient with a cobalt-based implant, modest increase (2-4 mcg/specimen) in urine cobalt concentration is likely to be associated with a prosthetic device in good condition. Excessive exposure is indicated when urine cobalt concentration is >5 mcg/specimen, consistent with prosthesis wear. Urine concentrations >20 mcg/specimen in a patient with a cobalt-based implant suggest significant prosthesis wear. Increased urine trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure.

Reference Values: 0.0-1.9 mcg/specimen Reference values apply to all ages.

Clinical References: 1. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium from industry and surgical implants. Crit Rev Toxicol 2008;38:645-674 2. Lhotka C, Szekes T, Stefan I, et al: Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003;21:189-195 3. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders M: Update on the genotoxicity and carcinogenicity of cobalt ompounds. Occup Environ Med 2001;58(10):619-625



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CORU

Cobalt, Random, Urine

60354

Clinical Information: Cobalt is rare but widely distributed in the environment. It is an essential cofactor in vitamin B12. While cobalt is an essential element, cobalt deficiency has not been reported in humans. Cobalt is used in the manufacture of hard alloys with high melting points and resistance to oxidation. Cobalt salts are also used in the glass and pigment industry. Previously, cobalt salts were sometimes used as foam stabilizers in the brewing industry; this practice was banned due to the cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma emitter in experimental biology, cancer therapy, and industrial radiography. Cobalt is not highly toxic, but large doses will produce adverse clinical manifestations. Acute symptoms are pulmonary edema, allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic symptoms include pulmonary syndrome, skin disorders, and thyroid abnormalities. The inhalation of dust during machining of cobalt alloyed metals can lead to interstitial lung disease. Improperly handled (60)Co can cause radiation poisoning from exposure to gamma radiation. Urine cobalt concentrations are likely to be increased above the reference value in patients with metallic joint prosthesis. Prosthetic devices produced by Zimmer Company and Johnson and Johnson typically are made of aluminum, vanadium, and titanium. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis product information for each device for composition details.

Useful For: Detecting cobalt exposure Monitoring metallic prosthetic implant wear Interpretation: Concentrations > or =2.0 mcg/L indicate excess exposure. There are no Occupational Safety and Health Administration (OSHA) blood or urine criteria for occupational exposure to cobalt. Prosthesis wear is known to result in increased circulating concentration of metal ions. In a patient with a cobalt-based implant, modest increase (2-4 mcg/L) in urine cobalt concentration is likely to be associated with a prosthetic device in good condition. Excessive exposure is indicated when urine cobalt concentration is >5 mcg/L, consistent with prosthesis wear. Urine concentrations >20 mcg/L in a patient with a cobalt-based implant suggest significant prosthesis wear. Increased urine trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure.

Reference Values: 0.0-1.9 mcg/L Reference values apply to all ages.

Clinical References: 1. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium from industry and surgical implants. Crit Rev Toxicol 2008;38:645-674 2. Lhotka C, Szekes T, Stefan I, et al: Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003;21:189-195 3. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders M: Update on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med 2001;58(10):619-625

COS

Cobalt, Serum

80084

Clinical Information: Cobalt is rare but widely distributed in the environment, used in the manufacture of hard alloys with high melting points and resistance to oxidation; cobalt alloys are used in manufacture of some artificial joint prosthesis devices. Cobalt salts are used in the glass and pigment industry. Previously, cobalt salts were sometimes used as foam stabilizers in the brewing industry; this practice was banned due to the cardiovascular diseases it induced. The radioactive isotope of cobalt, (60)Co, is used as a gamma emitter in experimental biology, cancer therapy, and industrial radiography. Cobalt is an essential cofactor in vitamin B12 metabolism. Cobalt deficiency has not been reported in humans. Cobalt is not highly toxic, but large doses will produce adverse clinical manifestations. Acute symptoms are pulmonary edema, allergy, nausea, vomiting, hemorrhage, and renal failure. Chronic symptoms include pulmonary syndrome, skin disorders, and thyroid abnormalities. The inhalation of dust during machining of cobalt alloyed metals can lead to interstitial lung disease. Serum cobalt concentrations are likely to be increased above the reference range in patients with joint prosthesis



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containing cobalt. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside are typically made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis product information for each device for composition details.

Useful For: Detecting cobalt toxicity Monitoring metallic prosthetic implant wear Interpretation: Concentrations > or =1.0 ng/mL indicate possible environmental or occupational exposure. Cobalt concentrations associated with toxicity must be interpreted in the context of the source of exposure. If cobalt is ingested, concentrations > 5 ng/mL suggest major exposure and likely toxicity. If cobalt exposure is due to orthopedic implant wear, there are no large case number reports associating high circulating serum cobalt with toxicity. There are no Occupational Health and Safety Administration (OSHA) blood or urine criteria for occupational exposure to cobalt. Prosthesis wear is known to result in increased circulating concentration of metal ions. Modest increase (4-10 ng/mL) in serum cobalt concentration is likely to be associated with a prosthetic device in good condition. Serum concentrations >10 ng/mL in a patient with cobalt-based implant suggest significant prosthesis wear. Increased serum trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure.

Reference Values: 0.0-0.9 ng/mL or =2.0 mcg/g creatinine indicate excess exposure. There are no Occupational Safety and Health Administration (OSHA) blood or urine criteria for occupational exposure to cobalt. Prosthesis wear is known to result in increased circulating concentration of metal ions. In a Current as of August 23, 2017 7:11 am CDT


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patient with a cobalt-based implant, modest increase (2-4 mcg/g creatinine) in urine cobalt concentration is likely to be associated with a prosthetic device in good condition. Excessive exposure is indicated when urine cobalt concentration is >5 mcg/g creatinine, consistent with prosthesis wear. Urine concentrations >20 mcg/g creatinine in a patient with a cobalt-based implant suggest significant prosthesis wear. Increased urine trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure.

Reference Values: 0.0-1.9 mcg/g Creatinine Reference values apply to all ages.

Clinical References: 1. Keegan GM, Learmonth ID, Case CP: A systematic comparison of the actual, potential, and theoretical health effects of cobalt and chromium from industry and surgical implants. Crit Rev Toxicol 2008;38:645-674 2. Lhotka C, Szekes T, Stefan I, et al: Four-year study of cobalt and chromium blood levels in patients managed with two different metal-on-metal total hip replacements. J Orthop Res 2003;21:189-195 3. Lison D, De Boeck M, Verougstraete V, Kirsch-Volders M: Update on the genotoxicity and carcinogenicity of cobalt compounds. Occup Environ Med 2001;58(10):619-625

FCOKE

Cocaine Analysis - Whole Blood

75174

Reference Values: Cocaine Screen: Cocaine and Metabolite, UA â€“ Negative; Cutoff: 25 ng/mL Cocaine Confirmation: Cocaine Benzoylecgonine Confirmation threshold: 10 ng/mL

COKMX 62720

Cocaine and Metabolite Confirmation, Chain of Custody, Meconium Clinical Information: Cocaine is an alkaloid found in Erythroxylon coca, which grows principally in the northern South American Andes and to a lesser extent in India, Africa, and Java.(1) Cocaine is a powerfully addictive stimulant drug. Cocaine abuse has a long history and is rooted into the drug culture in the United States,(2) and is one of the most common illicit drugs of abuse.(3,4) Cocaine is rapidly metabolized primarily to benzoylecgonine, which is further metabolized to m-hydroxybenzoylecgonine (m-HOBE).(1,5) Cocaine is frequently used with other drugs, most commonly ethanol, and the simultaneous use of both drugs can be determined by the presence of the unique metabolite cocaethylene.(4) Intrauterine drug exposure to cocaine has been associated with placental abruption, premature labor, small for gestational age status, microcephaly, and congenital anomalies (eg, cardiac and genitourinary abnormalities, necrotizing enterocolitis, and central nervous system stroke or hemorrhage).(6) The disposition of drug in meconium, the first fecal material passed by the neonate, is not well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium either by direct deposition from bile or through swallowing of amniotic fluid.(7) The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly moves into the colon by the 16th week of gestation.(8) Therefore, the presence of drugs in meconium has been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.(7) Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection of in utero drug exposure up to 5 months before birth Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel Current as of August 23, 2017 7:11 am CDT


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involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited. Since the evidence of illicit drug use during pregnancy can be cause for separating the baby from the mother, a complete chain of custody ensures that the test results are appropriate for legal proceedings.

Interpretation: The presence of any of the following: cocaine, benzoylecgonine, cocaethylene, or m-hydroxybenzoylecgonine, at > or =50 ng/g is indicative of in utero drug exposure up to 5 months before birth.

Reference Values: Negative Positives are reported with a quantitative LC-MS/MS result. Cutoff concentrations Cocaine by LC-MS/MS: 50 ng/g Benzoylecgonine by LC-MS/MS: 50 ng/g Cocaethylene by LC-MS/MS: 50 ng/g m-Hydroxybenzoylecgonine by LC-MS/MS: 50 ng/g

Clinical References: 1. Isenschmid DS: Cocaine. In Principles of Forensic Toxicology. Second edition. Edited by B Levine. Washington DC, AACC Press, 2003 pp 207-228 2. US Drug Enforcement Administration: Cocaine. Retrieved 9/3/09. Available at URL: www.usdoj.gov/dea/concern/cocaine.html 3. National Institute on Drug Abuse: NIDA InfoFacts: Crack and Cocaine. Retrieved 9/3/09. Available at URL: www.nida.nih.gov/InfoFacts/cocaine.html 4. Isenschmid DS: Cocaine-effects on human performance and behavior. Forsensic Sci Rev 2002;14:61 5. Kolbrich EA, Barnes AJ, Gorelick DA, et al: Major and minor metabolites of cocaine in human plasma following controlled subcutaneous cocaine administration. J Anal Toxicol 2006;30:501-510 6. Kwong TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of Clinical Biochemistry. Clin Chem 1997;43:235-242 7. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers; an alternative to urine testing. J Pediatr 1989;115:474-477 8. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005;60:45-56

COKEX

Cocaine and Metabolite Confirmation, Chain of Custody, Urine

62719

Clinical Information: Cocaine is a drug of current health concern because of its proliferation among recreational drug abusers. Freebase and crack increase the potential for major cocaine toxicity. Cocaine use is declining across the nation according to the National Institute of Drug Abuse. Increasingly, laboratory results are disputed or there are medical/legal overtones. Therefore, physicians are finding an increased need to confirm positive results before informing or confronting the patients. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detecting and confirming drug abuse involving cocaine Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: Reports will specifically indicate the presence or absence of cocaine and benzoylecgonine. The presence of cocaine, or its major metabolite, benzoylecgonine, indicates use within the past 4 days. Cocaine has a 6-hour half-life, so it will be present in urine for 1 day after last use. Benzoylecgonine has a half-life of 12 hours, so it will be detected in urine up to 72 hours after last use. There is no correlation between concentration and pharmacologic or toxic effects.

Reference Values: Negative Positives are reported with a quantitative GC-MS result. Current as of August 23, 2017 7:11 am CDT


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Cutoff concentrations: IMMUNOASSAY SCREEN or =100 Strongly positive Reference values apply to all ages.


REED

Common Reed, IgE

82902


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens. Current as of August 23, 2017 7:11 am CDT


Page 570



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



CVID

Common Variable Immunodeficiency Confirmation Flow Panel

87993

Clinical Information: Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency with a prevalence of CVID of 1:25,000 to 1:50,000.(1) It has a bimodal presentation with a subset presenting in early childhood and a second set presenting between 15 and 40 years of age or even later. CVID is characterized by hypogammaglobulinemia usually involving most or all of the immunoglobulin (Ig) classes (IgG, IgA, IgM, and IgE), impaired functional antibody responses, and recurrent sinopulmonary infections.(1) B cell numbers are usually normal, although a minority of patients (5%-10%) have very low B cell counts (3.4% %CD19+BAFF-R+: >90.2% Reference values apply to all ages.

Clinical References: 1. Warnatz K, Denz A, Drager R, et al: Severe deficiency of switched memory B cells (CD27+ IgM-IgD-) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 2002;99:1544-1551 2. Grimbacher B, Hutloff A, Schlesier M, et al: Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003;4(3):261-268 3. Salzer U, Chapel HM, Webster AD, et al: Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37(8):820-828 4. van Zelm M, Reisli I, van der Burg M, et al: An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006;354:1901-1912 5. Warnatz K, Salzer U, Gutenberger S, et al: Finally found: human BAFF-R deficiency causes hypogammaglobulinemia. Clin Immunol 2005;115(Suppl 1):820

60858

Complement 4d (C4d, Comp 4d), Immunostain Without Interpretation Clinical Information: Complement 4d (C4d) is a split product resulting from complement activation. The deposition of C4d on the walls of peritubular capillaries in kidney allografts or capillaries in cardiac allografts has been associated with antibody-mediated transplant rejection.

Useful For: An aid in the identification of antibody-mediated transplant rejection Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Fedson SE, Daniel SS, Husain AN: Immunohistochemistry staining of C4d to diagnose antibody-mediated rejection in cardiac transplantation. The Journal of Heart and Lung Transplantation 2008;27(4):372-379 2. Magro CM, Dyrsen ME: The use of C3d and C4d Current as of August 23, 2017 7:11 am CDT


Page 572

immunohistochemistry on formalin-fixed tissue as a diagnostic adjunct in the assessment of inflammatory skin disease. J AM Acad Dermatol 2008;59(5):822-833 3. Roden AC, Scott JP, Jenkins SM, Aubry MC: C4d by immunofluorescence and immunohistochemistry in routine lung allograft biopsies. The Journal of Heart and Lung Transplantation 2013;32(45):519-520

C1Q

Complement C1q, Serum

8851

Clinical Information: The first component of complement (C1) is composed of 3 subunits designated as C1q, C1r, and C1s. C1q recognizes and binds to immunoglobulin complexed to antigen and initiates the complement cascade. Congenital deficiencies of any of the early complement components (C1, C2, C4) results in an inability to clear immune complexes. Inherited deficiency of C1 is rare. Like the more common C2 deficiency, C1 deficiency is associated with increased incidence of immune complex disease (systemic lupus erythematosus, polymyositis, glomerulonephritis, and Henoch-Schonlein purpura). Low C1 levels have also been reported in patients with abnormal immunoglobulin levels (Bruton's and common variable hypogammaglobulinemia and severe combined immunodeficiency), and this is most likely due to increased catabolism. The measurement of C1q is an indicator of the amount of C1 present.

Useful For: Assessment of an undetectable total complement (CH50) level Diagnosing congenital C1 (first component of complement) deficiency Diagnosing acquired deficiency of C1 inhibitor

Interpretation: An undetectable C1q in the presence of an absent total complement (CH50) and normal C2, C3, and C4 suggests a congenital C1 (first component of complement) deficiency. A low C1q in combination with a low C1 inhibitor and low C4 suggests an acquired C1 inhibitor deficiency.


Clinical References: 1. Frank MM: Complement in the pathophysiology of human disease. N Engl J Med 1987 June 11;316(24):1525-1530 2. Frank MM: Complement deficiencies. Pediatr Clin North Am 2000 December;47(6):1339-1354 3. Frigas E: Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes. Mayo Clin Proc 1989 October;64(10):1269-1275

C3

Complement C3, Serum

8174

Clinical Information: The complement system is an integral part of the body's immune defenses. The primary complement pathway consists of recognition (Clq, Clr, Cls), activation (C4, C2, C3), and attack (C5, C6, C7, C8, C9) mechanisms with respect to their role in antibody-mediated cytolysis. The complement system can be activated via immune complexes, and the alternative pathway (properdin pathway), which is activated primarily by foreign bodies such as microorganisms. C3 activation involves cleavage by C3 convertase into C3a and C3b. When immune complexes are not involved, the alternate method of complement activation initiates the reactant sequence at C3, bypassing C1, C4, and C2. Severe recurrent bacterial infections occur in patients with homozygous C3 deficiency and in those patients with low levels of C3 secondary to the absence of C3b activator. Decreased C3 may be associated with acute glomerulonephritis, membranoproliferative glomerulonephritis, immune complex disease, active systemic lupus erythematosus, septic shock, and end-stage liver disease.

Useful For: Assessing disease activity in systemic lupus erythematosus (SLE) Investigating an undetectable total complement (CH50) level

Interpretation: A decrease in C3 levels to the abnormal range is consistent with disease activation in systemic lupus erythematosus (SLE).


Clinical References: 1. Ross SC, Densen P: Complement deficiency states and infection: epidemiology, pathogenesis, and consequences of neisserial and other infections in an immune deficiency. Medicine 1984;63:243-273 2. Frank MM: Complement in the pathophysiology of human disease. N Engl Current as of August 23, 2017 7:11 am CDT


Page 573

J Med 1987;316:1525-1530

C4

Complement C4, Serum

8171

Clinical Information: The complement system is an integral part of the immune defenses. It can be activated via immune complexes (classic pathway) or by bacterial polysaccharides (alternative pathway). The classic complement pathway consists of recognition, (C1q, C1r, C1s), activation (C2, C3, C4), and attack (C5, C6, C7, C8, C9) mechanisms with respect to their role in antibody-mediated cytolysis. C4 is one of the activation proteins of the classic pathway. In the absence of C4, immune complexes will not be cleared by C3 activation peptides, but bacterial infections can still be defended via the alternative pathway. C4 may be decreased in systemic lupus erythematosus, early glomerulonephritis, immune complex disease, cryoglobulinemia, hereditary angioedema, and congenital C4 deficiency.

Useful For: Investigating an undetectable total complement (CH50) Confirming hereditary angioedema (with low C1 inhibitor) Assessing disease activity in systemic lupus erythematosus, proliferative glomerulonephritis, rheumatoid arthritis, and autoimmune hemolytic anemia

Interpretation: C4 levels will be decreased in acquired autoimmune disorders, in active phase of lupus erythematosus, and in rheumatoid arthritis An undetectable C4 level (with normal C3) suggests a congenital C4 deficiency Levels will be increased in patients with autoimmune hemolytic anemia


Clinical References: 1. Ross SC, Densen P: Complement deficiency states and infection: epidemiology, pathogenesis, and consequences of neisserial and other infections in an immune deficiency. Medicine 1984;63:243-273 2. Frank MM: Complement in the pathophysiology of human disease. N Engl J Med 1987;316:1525-1530 3. Tiffany TO: Fluorometry, nephelometry, and turbidimetry. In Textbook of Clinical Chemistry. Edited by NW Tietz. Philadelphia, WB Saunders Company, 1986, pp 79-97

AH50

Complement, Alternate Pathway (AH50), Functional, Serum

88676

Clinical Information: Complement proteins are components of the innate immune system. There are 3 pathways to complement activation: the classic pathway, the alternative (or properdin) pathway, and the lectin activation (or mannose-binding protein: MBP) pathway. The total hemolytic complement (CH50) assay (COM / Complement, Total, Serum) is the best screening assay for most complement abnormalities. It assesses the classical complement pathway including early components that activate the pathway in response to immune complexes, as well as the late components involved in the membrane attack complex. The CH50 assay will be abnormal if there are specific hereditary or acquired C1-C9 complement component deficiencies or if there is consumption of complement due to immune (or autoimmune) complexes. The complement alternate pathway (AH50) assay is a screening test for complement abnormalities in the alternative pathway. The alternate pathway shares C3 and C5-C9 components, but has unique early complement components designated factors D, B, and P, as well as regulatory factors H and I. This pathway is activated by microbial polysaccharides and does not require immune complex formation. Patients with disseminated infections with pyogenic bacteria in the presence of a normal CH50 may have an absent AH50 due to hereditary or acquired deficiencies of the alternate pathway. Patients with deficiencies in the alternate pathway factors (D, B, P, H, and I) or late complement components (C3, C5-C9) are unusually susceptible to recurrent neisserial meningitis. The use of the CH50 and AH50 assays allow identification of the specific pathway abnormality. Unregulated alternative pathway can also result in disease. The majority of these diseases present with renal function impairment such as atypical hemolytic uremic syndrome (a-HUS), dense deposit disease (DDD), and C3 glomeulonephritis (C3GN).

Useful For: Investigation of suspected alternative pathway complement deficiency, atypical hemolytic uremic syndrome, C3 glomerulonephritis, dense-deposit disease

Interpretation: Absent complement alternate pathway (AH50) in the presence of a normal total hemolytic complement (CH50) suggests an alternate pathway component deficiency. Normal AH50 with Current as of August 23, 2017 7:11 am CDT


Page 574

absent CH50 suggests an early (C1, C2, C4) classic pathway deficiency. Absent AH50 and CH50 suggests a late (C3, C5, C6, C7, C8, C9) component deficiency or complement consumption. Absent AH50 and CH50 in the presence of a normal C3 and C4 suggests a late (C5, C6, C7, C8, C9) component deficiency.

Reference Values: > or =46% normal

Clinical References: 1. Frank MM: Medical intelligence current concepts: complement in the pathophysiology of human disease. N Engl J Med 1987;316:1525-1530 2. Thurman JM, Holers VM: Brief reviews: the central role of the alternative complement pathway in human disease. J Immunol 2006;176:1305-1310 3. Frank MM: Complement deficiencies. Pediatr Clin North Am 2000;47(6):1339-54

COM

Complement, Total, Serum

8167

Clinical Information: Complement proteins are components of the innate immune system. There are 3 pathways to complement activation: (1) the classic pathway, (2) the alternative (or properdin) pathway, and (3) the lectin activation (or mannan-binding protein) pathway. The classic pathway of the complement system is composed of a series of proteins that are activated in response to the presence of immune complexes. The activation process results in the generation of peptides that are chemotactic for neutrophils and that bind to immune complexes and complement receptors. The end result of the complement activation cascade is the formation of the lytic membrane attack complex (MAC). The absence of early components (C1, C2, C3, C4) of the complement cascade results in the inability of immune complexes to activate the cascade. Patients with deficiencies of the early complement proteins are unable to generate the peptides that are necessary to clear immune complexes and to attract neutrophils or to generate lytic activity. These patients have increased susceptibility to infections with encapsulated microorganisms. They may also have symptoms that suggest autoimmune disease, and complement deficiency may be an etiologic factor in the development of autoimmune disease. Patients with deficiencies of the late complement proteins (C5, C6, C7, C8, and C9) are unable to form the MAC, and may have increased susceptibility to neisserial infections. Undetectable complement levels are found in patients with specific component deficiencies. Decreased complement levels are found in infectious and autoimmune diseases due to fixation and consumption of complement.

Useful For: Detection of individuals with an ongoing immune process First-order screening test for congenital complement deficiencies

Interpretation: Low levels of total complement (total hemolytic complement CH50) may occur during infections, disease exacerbation in patients with systemic lupus erythematosus, and in patients with immune complex diseases such as glomerulonephritis. Undetectable levels suggest the possibility of a complement component deficiency. Individual complement component assays are useful to identify the specific deficiency.

Reference Values: > or =16 years: 30-75 U/mL Reference values have not been established for patients that are 250 mcg/g dry weight. >1,000 mcg/g dry weight: VERY HIGH. This finding is virtually diagnostic of WD; such patients should be showing all the signs and symptoms of WD. 250 mcg/g dry weight to 1,000 mcg/g dry weight: HIGH. This finding is suggestive of WD unless signs and symptoms, supporting histology, and other biochemical results (low serum ceruloplasmin, low serum copper, and high urine copper) are not evident. 35 mcg/g dry weight to 250 mcg/g dry weight: HIGH. Excessive copper at this level can be associated with cholestatic liver disease, such as primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and familial cholestatic syndrome. The heterozygous carriers for WD occasionally have modestly elevated values, but rarely higher than 125 mcg/g of dry weight. In general, the liver copper content is higher than 250 mcg/g dried tissue in WD patients. In patients with elevated levels of copper without supporting histology and other biochemical test results, contamination during collection, handling, or processing should be considered. Fresh tissue would be appropriate for copper measurement. Genetic test for WD (WDMS / Wilson Disease Mutation Screen, ATP7B DNA Sequencing) is available at Mayo Clinic.

Reference Values: 10-35 mcg/g dry weight >1,000 mcg/g dry weight: VERY HIGH This finding is strongly suggestive of Wilson disease. If this finding is without supporting histology and other biochemical test results, contamination during collection, handling, or processing should be considered. Fresh tissue would be appropriate for copper measurement. Genetic test for Wilson disease (WDMS / Wilson Disease Mutation Screen, ATP7B DNA Sequencing) is also available at Mayo Clinic. Please call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 if you need further assistance. 250-1,000 mcg/g dry weight: HIGH This finding is suggestive of possible Wilson disease. If this finding is without supporting histology and other biochemical test results, contamination during collection, handling, or processing should be considered. Fresh tissue would be appropriate for copper measurement. Genetic test for Wilson disease (WDMS / Wilson Disease Mutation Screen, ATP7B DNA Sequencing) is also available at Mayo Clinic. Please call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 if you need further assistance. Current as of August 23, 2017 7:11 am CDT


Page 588

35-250 mcg/g dry weight: HIGH Excessive copper at this level can be associated with cholestatic liver disease, such as primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and familial cholestatic syndrome. Heterozygous carriers for Wilson disease occasionally have modestly elevated values, but rarely higher than 125 mcg/g of dry weight. In general, the liver copper content is higher than 250 mcg/g dried tissue in patients with Wilson disease. If this finding is without supporting histology and other biochemical test results, contamination during collection, handling, or processing should be considered. Fresh tissue would be appropriate for copper measurement. Genetic test for Wilson disease (WDMS / Wilson Disease Mutation Screen, ATP7B DNA Sequencing) is also available at Mayo Clinic. Please call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 if you need further assistance.

Clinical References: 1. Korman J, Volenberg I, Balko J, et al: Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008 Oct;48(4):1167-1174 2. Roberts EA, Schlisky ML: Diagnosis and Treatment of Wilson Disease: AASLD Practice Guidelines. Hepatology 2008;47:2089-2111 3. de Bie P, Muller P, Wijmenga C, Klomp LW: Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 2007 November;44(11):673-688 4. Merle U, Schaefer M, Ferenci P, Stremmel W: Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007;56:115-120

CUS

Copper, Serum

8612

Clinical Information: In serum from normal, healthy humans, more than 95% of the copper is incorporated into ceruloplasmin; the remaining copper is loosely bound to albumin. Low serum copper, most often due to excess iron or zinc ingestion and infrequently due to dietary copper deficit, results in severe derangement in growth and impaired erythropoiesis. Low serum copper is also observed in hepatolenticular degeneration (Wilson disease) due to a decrease in the synthesis of ceruloplasmin and allelic variances in cellular metal ion transporters. In Wilson disease, the albumin-bound copper may actually be increased, but ceruloplasmin copper is low, resulting in low serum copper. However, during the acute phase of Wilson disease (fulminant hepatic failure), ceruloplasmin and copper may be normal; in this circumstance, hepatic inflammation causes increased release of ceruloplasmin. It is useful to relate the degree of liver inflammation to the ceruloplasmin and copper-see discussion on hypercupremia below. Significant hepatic inflammation with normal ceruloplasmin and copper suggest acute Wilson disease. Other disorders associated with decreased serum copper concentrations include malnutrition, hypoproteinemia, malabsorption, nephrotic syndrome, Menkes disease, copper toxicity, and megadosing of zinc-containing vitamins (zinc interferes with normal copper absorption from the gastrointestinal tract). Hypercupremia is found in primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, malignant diseases (including leukemia), thyrotoxicosis, and various infections. Serum copper concentrations are also elevated in patients taking contraceptives or estrogens and during pregnancy. Since the gastrointestinal (GI) tract effectively excludes excess copper, it is the GI tract that is most affected by copper ingestion. Increased serum concentration does not, by itself, indicate copper toxicity.

Useful For: Diagnosis of: -Wilson disease -Primary biliary cirrhosis -Primary sclerosing cholangitis Interpretation: Serum copper below the normal range is associated with Wilson disease, as well as a variety of other clinical situations (see Clinical Information). Excess use of denture cream containing zinc can cause hypocupremia. Serum concentrations above the normal range are seen in primary biliary cirrhosis and primary sclerosing cholangitis, as well as a variety of other clinical situations (see Clinical Information).

Reference Values: 0-2 months: 0.40-1.40 mcg/mL 3-6 months: 0.40-1.60 mcg/mL 7-9 months: 0.40-1.70 mcg/mL 10-12 months: 0.80-1.70 mcg/mL 13 months-10 years: 0.80-1.80 mcg/mL > or =11 years: 0.75-1.45 mcg/mL

Clinical References: 1. McCullough AJ, Fleming CR, Thistle JL, et al: Diagnosis of Wilson's Current as of August 23, 2017 7:11 am CDT


Page 589

disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:161-167 2. Wiesner RH, LaRusso NF, Ludwig J, Dickson ER: Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985;88:108-114 3. Spain RI, Leist TP, De Sousa EA: When metals compete: a case of copper-deficiency myeloneuropathy and anemia. Nat Clin Pract Neurol 2009 Feb;5(2):106-111 4. Kale, SG, Holmes CS, Goldstein DS, et al: Neonatal Diagnosis and Treatment of Menkes Disease. N Engl J Med 2008 Feb 7;358(6):605-614 5. Nations SP, Boyer PJ, Love LA, et al: Denture cream: An unusual source of excess zinc, leading to hypocupremia and neurologic disease. Neurology 2008;71;639-643

CUCRU

Copper/Creatinine Ratio, Random, Urine

60427

Clinical Information: The biliary system is the major pathway of copper excretion. Biliary excretion of copper requires an adenosine triphosphate (ATP)-dependent transporter protein. Mutations in the gene for the transporter protein cause hepatolenticular degeneration (Wilson disease). Ceruloplasmin, the primary copper-carrying protein in the blood, is also reduced in Wilson disease. Urine copper excretion is increased in Wilson disease due to a decreased serum binding of copper to ceruloplasmin, or due to allelic variances in cellular metal ion transporters. Hypercupriuria is also found in hemochromatosis, biliary cirrhosis, thyrotoxicosis, various infections, and a variety of other acute, chronic, and malignant diseases (including leukemia). Urine copper concentrations are also elevated in patients taking contraceptives or estrogens and during pregnancy. Low urine copper levels are seen in malnutrition, hypoproteinemias, malabsorption, and nephrotic syndrome. Increased zinc consumption interferes with normal copper absorption from the gastrointestinal tract causing hypocupremia.

Useful For: Investigation of Wilson disease and obstructive liver disease using a random urine specimen

Interpretation: Humans normally excrete less than 60 mcg/24 hour in the urine. Urinary copper excretion greater than 60 mcg/24 hour may be seen in: -Wilson disease -Obstructive biliary disease (eg, primary biliary cirrhosis, primary sclerosing cholangitis) -Nephrotic syndrome (due to leakage through the kidney) -Chelation therapy -Estrogen therapy -Mega-dosing of zinc-containing vitamins Because ceruloplasmin is an acute phase reactant, urine copper is elevated during acute inflammation. During the recovery phase, urine copper is usually below normal, reflecting the expected physiologic response to replace the copper that was depleted during inflammation.

Reference Values: 0-17 years: not established Male > or =18 years: 9-43 mcg/g creatinine Female > or =18 years: 7-72 mcg/g creatinine

Clinical References: 1. Zorbas YG, Kakuris KK, Deogenov VA, Yerullis KB: Copper homeostasis during hypokinesia in healthy subjects with higher and lower copper consumption. Trace Elements and Electrolytes 2008;25:169-178 2. Lech T. Sadlik JK: Contribution to the data on copper concentration in blood and urine in patients with Wilson's disease and in normal subjects. Biol Trace Elem Res 2007 Jul;118(1):16-20

CORI

Coriander, IgE

82476




Page 590





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FCORG

Corn IgG

57526

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: or =100 Strongly positive Reference values apply to all ages.


CORTC

Corticosterone, Serum

88221

Clinical Information: Corticosterone is a steroid hormone and a precursor molecule for aldosterone. It is produced from deoxycorticosterone, further converted to 18-hydroxy corticosterone and, finally, to aldosterone in the mineralocorticoid pathway. The adrenal glands, ovaries, testes, and placenta produce steroid hormones, which can be subdivided into 3 major groups: mineral corticoids, glucocorticoids, and sex steroids. Synthesis proceeds from cholesterol along 3 parallel pathways, corresponding to these 3 major groups of steroids, through successive side-chain cleavage and hydroxylation reactions. At various levels of each pathway, intermediate products can move into the respective adjacent pathways via additional, enzymatically catalyzed reactions (see Steroid Pathways in Special Instructions). Corticosterone is the first intermediate in the corticoid pathway with significant mineral corticoid activity. Its synthesis from 11-deoxycorticosterone is catalyzed by 11 beta-hydroxylase 2 (CYP11B2) or by 11 beta-hydroxylase 1 (CYP11B1). Corticosterone is in turn converted to 18-hydroxycorticosterone and finally to aldosterone, the most active mineral corticoid. Both of these reactions are catalyzed by CYP11B2, which, unlike its sister enzyme CYP11B1, also possesses 18-hydroxylase and 18-methyloxidase (also known as aldosterone synthase) activity. The major diagnostic utility of measurements of steroid synthesis intermediates lies in the diagnosis of disorders of steroid synthesis, in particular congenital adrenal hyperplasia (CAH). All types of CAH are associated with cortisol deficiency with the exception of CYP11B2 deficiency and isolated impairments of the 17-lyase activity of CYP17A1 (this enzyme also has 17 alpha-hydroxylase activity). In cases of severe illness or trauma, CAH predisposes patients to poor recovery or death. Patients with the most common form of CAH (21-hydroxylase deficiency, >90% of cases), with the third most common form of CAH (3-beta-steroid



Page 593

dehydrogenase deficiency, or =18 years: 1.0-119 mcg/g creatinine Females 0-2 years: 3.0-120 mcg/g creatinine Current as of August 23, 2017 7:11 am CDT


Page 597

3-8 years: 2.2-89 mcg/g creatinine 9-12 years: 1.4-56 mcg/g creatinine 13-17 years: 1.0-42 mcg/g creatinine > or =18 years: 0.7-85 mcg/g creatinine Use the conversion factors below to convert each analyte from mcg/g creatinine to nmol/mol creatinine. Conversion factor Cortisol: mcg/g creatinine x 413=nmol/mol creatinine Cortisol molecular weight=362.5 Creatinine molecular weight=149.59

Clinical References: 1. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing's syndrome. Endocrinol Metab Clin North Am 2001;30:729-747 2. Boscaro M, Barzon L, Fallo F, Sonino N: Cushing's syndrome. Lancet 2001;357:783-791 3. Taylor RL, Machacek D, Singh RJ: Validation of a high-throughput liquid chromatography-tandem mass spectrometry method for urinary cortisol and cortisone. Clin Chem 2002;48:1511-1519

CIVC

Cortisol, Inferior Vena Cava, Serum

6347


CLAV

Cortisol, Left Adrenal Vein, Serum

6346


CRAV

Cortisol, Right Adrenal Vein, Serum

6345


SALCT

Cortisol, Saliva

84225

Clinical Information: Cortisol levels are regulated by adrenocorticotropic hormone (ACTH), which is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). Cushing syndrome results from overproduction of glucocorticoids as a result of either primary adrenal disease (adenoma, carcinoma, or nodular hyperplasia) or an excess of ACTH (from a pituitary tumor or an ectopic source). ACTH-dependent Cushing syndrome due to a pituitary corticotroph adenoma is the most frequently diagnosed subtype; most commonly seen in women in the third through fifth decades of life. CRH is released in a cyclic fashion by the hypothalamus, resulting in diurnal peaks (elevated in the morning) and nadirs (low in the evening) for plasma ACTH and cortisol levels. The diurnal variation is lost in patients with Cushing syndrome and these patients have elevated levels of evening plasma cortisol. The measurement of late-night salivary cortisol is an effective and convenient screening test for Cushing syndrome.(1) In a recent study from the National Institute of Health, nighttime salivary cortisol measurement was superior to plasma and urine free cortisol assessments in detecting patients with mild Cushing syndrome.(2) The sensitivity of nighttime salivary cortisol measurements remained superior to all other measures. The distinction between Cushing syndrome and pseudo-Cushing states is most difficult in the setting of mild-to-moderate hypercortisolism. Subtle increases in salivary cortisol at the midnight cortisol (cortisol of nadir) appear to be one of the earliest abnormalities in Cushing syndrome.

Useful For: Screening for Cushing syndrome Diagnosis of Cushing syndrome in patients presenting Current as of August 23, 2017 7:11 am CDT


Page 598

with symptoms or signs suggestive of the disease

Interpretation: Cushing syndrome is characterized by increased salivary cortisol levels, and late-night saliva cortisol measurements may be the optimum test for the diagnosis of Cushing syndrome. It is standard practice to confirm elevated results at least once. This can be done by repeat late-night salivary cortisol measurements, midnight blood sampling for cortisol (CORT / Cortisol, Serum), 24-hour urinary free cortisol collection (CORTU / Cortisol, Free, 24 Hour, Urine), or overnight dexamethasone suppression testing. Upon confirmation of the diagnosis, the cause of hypercortisolism, adrenal versus pituitary versus ectopic adrenocorticotropic hormone production, needs to be established. This is typically a complex undertaking, requiring dynamic testing of the pituitary adrenal axis and imaging procedures. Referral to specialized centers or in-depth consultation with experts is strongly recommended.

Reference Values: 7 a.m.-9 a.m.: 100-750 ng/dL 3 p.m.-5 p.m.: 10) with the CU index have an autoimmune basis for their disease. A positive result does not indicate which autoantibody (anti-IgE, anti-FceRI or anti-FCERII) is present.

Reference Values: < 10.0 The CU Index test is the second generation Functional Anti-FceR test. Patient with a CU Index greater than or equal to 10 have basophil reactive factors in their serum which supports an autoimmune basis for disease.

FCUIP

CU Index Panel

57590

Reference Values: Anti-Thyroid Peroxidase IgG: Anti-Thyroglobulin IgG: TSH (Thyrotropin): CU Index:


or =100 Strongly positive Reference values apply to all ages.


FUNID

Culture Referred for Identification, Fungus

8223

Clinical Information: Organisms are referred for identification or to confirm an identification made elsewhere. This may provide helpful information regarding the significance of the organism, its role in the disease process, and its possible origin.

Useful For: Identification of pure isolates of filamentous fungi and yeast Interpretation: Genus and species are reported on fungal isolates whenever possible. Reference Values: Not applicable

Clinical References: Shea YR: General approaches for detection and identification of fungi. In Manual of Clinical Microbiology. 10th edition. Edited by J Versalovic, KC Carroll, et al: Washington, DC. ASM Press, 2011, pp 1776-1792

CTBID 80278

Culture Referred for Identification, Mycobacterium and Nocardia Clinical Information: There are over 170 recognized species of mycobacteria and more than 100 Nocardia species. Many of these species are human pathogens and, therefore, identification to the species level is important to help guide patient care. In addition, there are other aerobic actinomycete genera that can be human pathogens including, but not limited to, Tsukamurella, Rhodococcus, and Gordonia species. Nucleic acid hybridization probes are utilized that identify specific ribosomal RNA sequences of Mycobacterium tuberculosis complex, Mycobacterium avium complex, and Mycobacterium gordonae. Other Mycobacteria species, Nocardia species and other aerobic actinomycete genera are identified using MALDI-TOF mass spectrometry or nucleic acid sequencing of a 500-base pair region of the 16S ribosomal RNA gene.

Useful For: Rapid identification to the species level for Mycobacterium species, Nocardia species, and other aerobic actinomycete genera and species from pure culture isolates Current as of August 23, 2017 7:11 am CDT


Page 635

Interpretation: Organisms growing in pure culture are identified to the species level whenever possible.


Clinical References: 1. Pfyffer GE, Palicova F: Mycobacterium: general characteristics; laboratory detection, and staining procedures. In Manual of Clinical Microbiology. 10th edition, Vol 1. Edited by J Versalovic, KC Carroll, G Funke, et al. Washington DC, ASM Press. 2011 pp 472-502 2. Halse TA, Escuyer, VE, Musser, KA: Evaluation of a single tube multiplex real-time PCR for differentiation of the Mycobacterium tuberculosis complex in clinical specimens. J Clin Microbiol 2011 July;49(7):2562-2567, doi: 10.1128/JCM.00467-11

VRID2

Culture Referred for Identification, Virus

5190

Clinical Information: See specific virus Useful For: Viral identification and confirmation Interpretation: See specific virus Reference Values: Not applicable

Clinical References: Depends upon specific virus

CURR

Curry, IgE

82498





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive



Page 636

3

3.50-17.4 Positive

4


5


6



CURL

Curvularia lunata, IgE

82852





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





Page 637

FCURV

Curvularia spicifera/Bipolaris IgE

57898

Interpretation: Class IgE (kU/L) Comment 0 99.99 Very High Positive

Reference Values: G), which results in a splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele (functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from 0.14 among sub-Saharan Africans to 0.95 in European populations. In general, most drugs metabolized by CYP3A5 are also metabolized by CYP3A4, with few exceptions. For this reason, substrates of these 2 enzymes are listed together in most publications and genotyping of both genes might be needed to fully understand the metabolism of these drugs and predict phenotype. The clinical relevance of CYP3A4 and CYP3A5 activity on drug metabolism has not been fully explored in many cases. Tacrolimus is an immunosuppressive calcineurin inhibitor used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice. Tacrolimus dose requirements are closely associated with CYP3A5 genotype. According to existing literature and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, individuals with at least 1 copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) typically require a higher dose of tacrolimus to reach the targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie, *3/*3). CYP3A5*3 genotyping may predict dose requirements for tacrolimus but does not replace the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended.

Useful For: Aids in optimizing treatment with tacrolimus and potentially other drugs metabolized by CYP3A5

Interpretation: Absence of the *3 allele does not rule out the possibility that a patient harbors another variant that can impact the function of this enzyme, drug response, or drug side effects. CYP3A5 genotype is only one factor that should be taken into consideration for drug dosing. CYP3A5*1/*1 Extensive (normal) metabolizer: The CYP3A5*3 allele was not detected. Therefore, this patient is expected to be an extensive (normal) metabolizer. This phenotype is also known as CYP3A5 expresser. Rapid metabolism of drugs that are inactivated or activated by CYP3A5 is expected. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended. CYP3A5*1/*3 Intermediate metabolizer: One copy of the CYP3A5*3 allele was detected. Therefore, this patient is expected to be an intermediate metabolizer. This phenotype is also known as CYP3A5 expresser. Reduced metabolism of drugs that are inactivated or activated by CYP3A5 is expected when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended. CYP3A5*3/*3 Poor metabolizer: Two copies of the CYP3A5*3 allele were detected. Therefore, this patient is expected to be a poor metabolizer. This phenotype is also known as CYP3A5 nonexpresser. Drugs that are inactivated or activated by CYP3A5 are metabolized at greatly reduced rate when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature supports normal dosing, presumably because original dosing guidelines were determined on patients who were poor metabolizers like this patient. Therapeutic drug monitoring is recommended. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.



Page 645

Clinical References: 1. Birdwell K, Decker B, Barbrino J, et al: Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmaco Ther 2015:98(1):19-24 doi: 10.1002/cpt.113 2. Thervet E, Loriot MA, Barbier S, et al: Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin PharmacolTher 2010;87:721-726 3. Lamba J, Hebert J, Schuetz E, et al: PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics 2012 Jul; 22(7):555-558

3A5O

CYP3A5 Genotype, Saliva

63039

Clinical Information: CYP3A5 is 1 of the 4 CYP3 genes localized in tandem on chromosome 7 that encode the CYP3A subfamily of enzymes responsible for the metabolism of more than 50% of medications. CYP3A5 is expressed in liver, as well as extrahepatic tissue such as small intestine, lung, kidney, breast, and prostate. The CYP3A5 expression level and enzymatic activity can be modulated by genetic variation. CYP3A5 allelic frequency depends upon ethnicity. For example, in individuals of European descent the most common allele is the CYP3A5*3 allele (c.219-237A>G), which results in a splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele (functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from 0.14 among sub-Saharan Africans to 0.95 in European populations. In general, most drugs metabolized by CYP3A5 are also metabolized by CYP3A4, with few exceptions. For this reason, substrates of these 2 enzymes are listed together in most publications and genotyping of both genes might be needed to fully understand the metabolism of these drugs and predict phenotype. The clinical relevance of CYP3A4 and CYP3A5 activity on drug metabolism has not been fully explored in many cases. Tacrolimus is an immunosuppressive calcineurin inhibitor used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice. Tacrolimus dose requirements are closely associated with CYP3A5 genotype. Broadly accepted dosing algorithms for use of genotype in dosing of tacrolimus have not been published, although the results of research conducted by Thervet et al(1) provide some guidance on initial dosing. According to existing literature, individuals with at least 1 copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) typically require a higher dose of tacrolimus to reach the targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie, *3/*3). CYP3A5*3 genotyping may predict dose requirements for tacrolimus but does not replace the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended.

Useful For: An aid to optimizing treatment with tacrolimus and potentially other drugs metabolized by CYP3A5 Genotyping patients who prefer not to have venipuncture done

Interpretation: Absence of the *3 allele does not rule out the possibility that a patient harbors another variant that can impact the function of this enzyme, drug response, or drug side effects. CYP3A5 genotype is only one factor that should be taken into consideration for drug dosing. CYP3A5*1/*1 Extensive (normal) metabolizer: The CYP3A5*3 allele was not detected. Therefore, this patient is expected to be an extensive (normal) metabolizer. This phenotype is also known as CYP3A5 expresser. Rapid metabolism of drugs that are inactivated or activated by CYP3A5 is expected. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended. CYP3A5*1/*3 Intermediate metabolizer: One copy of the CYP3A5*3 allele was detected. Therefore, this patient is expected to be an intermediate metabolizer. This phenotype is also known as CYP3A5 expresser. Reduced metabolism of drugs that are inactivated or activated by CYP3A5 is expected when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature indicates that higher doses may be required, presumably because original dosing guidelines were determined on patients who were poor metabolizers. Therapeutic drug monitoring is recommended. CYP3A5*3/*3 Poor metabolizer: Two copies of the CYP3A5*3 allele were detected. Therefore, this Current as of August 23, 2017 7:11 am CDT


Page 646

patient is expected to be a poor metabolizer. This phenotype is also known as CYP3A5 nonexpresser. Drugs that are inactivated or activated by CYP3A5 are metabolized at greatly reduced rate when compared to patients who are *1/*1. Patients with this phenotype should not be coadministered CYP3A5 inhibitors due to an increased risk of toxicity or lack of efficacy, respectively. For patients taking tacrolimus with this genotype, the literature supports normal dosing, presumably because original dosing guidelines were determined on patients who were poor metabolizers like this patient. Therapeutic drug monitoring is recommended. For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Birdwell K, Decker B, Barbrino J, et al: Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmaco Ther 2015:98(1):19-24 doi: 10.1002/cpt.113 2. Thervet E, Loriot MA, Barbier S, et al: Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin PharmacolTher 2010;87:721-726 3. Lamba J, Hebert J, Schuetz E, et al: PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics 2012 Jul; 22(7):555-558

CYSTC

Cystatin C with Estimated GFR, Serum

35038

Clinical Information: Cystatin C: Cystatin C is a low molecular weight (13,250 kD) cysteine proteinase inhibitor that is produced by all nucleated cells and found in body fluids, including serum. Since it is formed at a constant rate and freely filtered by the kidneys, its serum concentration is inversely correlated with the glomerular filtration rate (GFR); that is, high values indicate low GFRs while lower values indicate higher GFRs, similar to creatinine. The renal handling of cystatin C differs from creatinine. While both are freely filtered by glomeruli, once it is filtered, cystatin C, unlike creatinine, is reabsorbed and metabolized by proximal renal tubules. Thus, under normal conditions, cystatin C does not enter the final excreted urine to any significant degree. The serum concentration of cystatin C remains unchanged with infections, inflammatory or neoplastic states, and is not affected by body mass, diet, or drugs. Thus, cystatin C may be a more reliable marker of renal function (GFR) than creatinine. Estimated Glomerular Filtration Rate (GFR): GFR can be estimated (eGFR) from serum cystatin C utilizing an equation which includes the age and gender of the patient. The CKD-EPI cystatin C equation was developed by Inker et al:(1) and demonstrated good correlation with measured iothalamate clearance in patients with all common causes of kidney disease, including kidney transplant recipients. Cystatin C eGFR may have advantages over creatinine eGFR in certain patient groups in whom muscle mass is abnormally high or low (for example quadriplegics, very elderly, or malnourished individuals). Blood levels of cystatin C also equilibrate more quickly than creatinine, and therefore, serum cystatin C may be more accurate than serum creatinine when kidney function is rapidly changing (for example amongst hospitalized individuals).

Useful For: Cystatin C: An index of glomerular filtration rate, especially in patients where serum creatinine may be misleading (eg, very obese, elderly, or malnourished patients) Assessing renal function in patients suspected of having kidney disease Monitoring treatment response in patients with kidney disease Estimated Glomerular Filtration Rate (eGFR): An index of GFR, especially in patients where serum creatinine may be misleading (eg, very obese, elderly, or malnourished patients); for such patients, use of CKD-EPI cystatin C equation is recommended to estimate GFR Assessing renal function in patients suspected of having kidney disease Monitoring treatment response in patients with kidney disease

Interpretation: Cystatin C: Cystatin C inversely correlates with the glomerular filtration rate (GFR), that is elevated levels of cystatin C indicate decreased GFR. Cystatin C may provide more accurate assessment of GFR for very obese, elderly, or malnourished patients than creatinine. Cystatin C equation does not require patient ethnic data, and can be used for those patients with this information unavailable. Due to immaturity of renal function, cystatin C levels are higher in neonates 86 years: no reference values established eGFR >60 mL/min/BSA eGFR will not be calculated for patients under 18 years.

Clinical References: 1. Inker LA, Schmid CH, Tighiouart H, et al: Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012 Jul;367(1):20-29 2. Buehrig CK, Larson TS, Bergert JH, et al: Cystatin C is superior to serum creatinine for the assessment of renal function. J Am Soc Nephrol 2001;12:194A 3. Grubb AO: Cystatin C - properties and use as a diagnostic marker. Adv Clin Chem 2000;35:63-99 4. Coll E, Botey A, Alvarez L, et al: Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis 2000 Jul;36(1):29-34 5. Flodin M, Jonsson AS, Hansson LO, et al: Evaluation of Gentian cystatin C reagent on Abbott Ci8200 and calculation of glomerular filtration rate expressed in mL/min/1.73 m(2) from the cystatin C values in mg/L. Scand J Clin Lab Invest 2007;67:560-567 6. Larsson A, Hansson LO, Flodin M, et al: Calibration of the Siemens cystatin C immunoassay has changed over time. Clin Chem 2011;57:777-778 7. Voskoboev NV, Larson TS, Rule AD, Lieske JC: Importance of cystatin C assay standardization. Clin Chem 2011 Aug;57(8):1209-1211 8. Nitsch D, Sandling JK, Byberg L et al: Fetal, developmental, and parental influences on cystatin C in childhood: the Uppsala Family Study. Am J Kidney Dis 2011 Jun;57(6):863-872 9. Voskoboev NV, Larson TS, Rule AD, Lieske JC: Analytic and clinical validation of a standardized cystatin C particle enhanced turbidimetric assay (PETIA) to estimate glomerular filtration rate. Clin Chem Lab Med 2012 Mar;50(9):1591-1596 10. Finney H, Newman DJ, Thakkar H, et al: Reference ranges for the plasma cystatin C and creatinine measurements in premature infants, neonates, and older children. Arch Dis Child 2000 Jan;82(1):71-75

CFP

Cystic Fibrosis Mutation Analysis, 106-Mutation Panel

35386

Clinical Information: Cystic fibrosis (CF), in the classic form, is a severe autosomal recessive disorder characterized by a varied degree of chronic obstructive lung disease and pancreatic enzyme insufficiency. The incidence of CF varies markedly among different populations, as does the mutation



Page 648

detection rate for the mutation screening assay. To date, over 1,500 mutations have been described within the CF gene, named cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, deltaF508, accounts for approximately 67% of the mutations worldwide and approximately 70% to 75% in a North American Caucasian population. Most of the remaining mutations are rather rare, although some show a relatively higher prevalence in certain ethnic groups or in some atypical presentations of CF such as congenital bilateral absence of the vas deferens (CBAVD). Mutations detected by the assay performed in the Mayo Clinic Molecular Genetics Laboratory include the 23 mutations recommended by the American College of Medical Genetics as well as 83 other mutations. Of note, CFTR potentiator therapies may improve clinical outcomes for patients with a clinical diagnosis of CF and at least 1 copy of the G178R, G551S, G551D, S549N, S549R, G1244E, S1251N, S1255P, or G1349D mutation. The G178R, S549N, S549R, S551D, and S1251N mutations are included in this test. These 106 mutations account for approximately 91% of CF chromosomes in a Northern European Caucasian population. Detection rates for several ethnic and racial groups are listed in the table below. Note that interpretation of test results and risk calculations are also dependent on clinical information and family history. Racial or Ethnic Group Carrier Frequency Mutation Detection Rate* African American 1/65 81% Ashkenazi Jewish 1/25 97% Asian American (excluding individuals of Japanese ancestry) 1/90 54% Mixed European 1/25 82% Eastern European 1/25 77% French Canadian 1/25 91% Hispanic American 1/46 82% Northern European 1/25 91% Southern European 1/25 79% *Rates are for classical CF. Rates are lower for atypical forms of CF and for CBAVD. CFTR mutations listed below are included in this panel. Deletion exons 2-3 Exon 11: R553X Intron 2: 296+2 T->A Exon 11: A559T Exon 3: E60X Exon 11: R560T Exon 3: R75X Intron 11: 1811+1.6kb A->G Exon 3: G85E Intron 11: 1812-1 G->A Exon 3: 394_395delTT Intron 12: 1898+1 G->A Intron 3: 405+1 G->A Intron 12: 1898+1 G->T Intron 3: 406-1 G->A Intron 12: 1898+1 G->C Exon 4: E92X Intron 12: 1898+5 G->T Exon 4: 444delA Exon 12: P574H Exon 4: 457TAT->G Exon 13: 1949del84 Exon 4: R117H Exon 13: 2043delG Exon 4: R117C Exon 13: 2055del9->A Exon 4: Y122X Exon 13: 2105del13ins5 Exon 4: 574delA Exon 13: 2108delA Intron 4: 621+1 G->T Exon 13: 2143delT Exon 5: 663delT Exon 13: 2183_2184delAAinsG Exon 5: G178R Exon 13: 2184delA Intron 5: 711+1 G->T Exon 13: 2184insA Intron 5: 711+5 G->A Exon 13: R709X Intron 5: 712-1 G->T Exon 13: K710X Exon 6a: H199Y Exon 13: 2307insA Exon 6a: P205S Exon 13: R764X Exon 6a: L206W Intron 14b: 2789+5 G->A Exon 6a: 852del22 Exon 15: 2869insG Exon 6b: 935delA Exon 15: Q890X Exon 6b: 936delTA Intron 16: 3120+1 G->A Exon 7: deltaF311 Exon 17a: 3171delC Exon 7: 1078delT Exon 17a: 3199del6 Exon 7: G330X Exon 17b: R1066C Exon 7: R334W Exon 17b: W1089X (TGG->TAG) Exon 7: T338I Exon 17b: Y1092X (C->G) Exon 7: R347P Exon 17b: Y1092X (C->A) Exon 7: R347H Exon 17b: M1101K Exon 7: R352Q Exon 17b: M1101R Exon 7: Q359K Exon 18: D1152H Exon 7: T360K Exon 19: R1158X Exon 8: 1288insTA Exon 19: R1162X Exon 9: A455E Exon 19: 3659delC Exon 10: S466X (C->A) Exon 19: 3667del4 Exon 10: S466X (C->G) Exon 19: S1196X Exon 10: G480C Exon 19: W1204X (TGG->TAG) Exon 10: Q493X Exon 19: 3791delC Exon 10: deltaI507 Exon 19: Q1238X Exon 10: deltaF508 Intron 19: 3849+10kb C->T Exon 10: 1677delTA Exon 20: 3876delA Exon 10: C524X Exon 20: S1251N Intron 10: 1717-1 G->A Exon 20: S1255X Exon 11: G542X Exon 20: 3905insT Exon 11: S549N Exon 20: W1282X (TGG->TGA) Exon 11: S549R (T->G) Exon 21: 4016insT Exon 11: G551D Exon 21: N1303K (C->A) Exon 11:Q552X Exon 21: N1303K (C->G) See Cystic Fibrosis Molecular Diagnostic Testing Algorithm in Special Instructions for additional information.

Useful For: Confirmation of a clinical diagnosis of cystic fibrosis Risk refinement via carrier screening for individuals in the general population Prenatal diagnosis or familial mutation testing when the familial mutations are included in the 106-mutation panel listed above (if familial mutations are not included in the 106-mutation panel, order FMTT / Familial Mutation, Targeted Testing) Risk refinement via carrier screening for individuals with a family history when familial mutations are not available Identification of patients who may respond to CFTR potentiator therapy


Clinical References: 1. Quint A, Lerer I, Sagi M, Abeliovich D: Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am J Med Genet A 2005;136(3):246-248 2. Bobadilla JL, Macek M, Fine FP, Farrell PM: Cystic fibrosis: a worldwide analysis of CFTR mutations-correlation with incidence data and application to screening. Hum Mutat 2002;19(6):575-606 3. Current as of August 23, 2017 7:11 am CDT


Page 649

Sugarman EA, Rohlfs EM, Silverman LM, Alitto BA: CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med 2004;6(5):392-399 4. Watson MS, Cutting GR, Desnick RJ, et al: Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med 2004;6(5):387-391 5. Heim RA, Sugarman EA, Allitto BA: Improved detection of cystic fibrosis mutations in the heterozygous U.S. population using an expanded, pan-ethnic mutation panel. Genet Med 2001;3(3):168-176 6. De Boeck K, Munck A, Walker S, et al: Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J Cyst Fibros. 2014 Sep 26 [Epub ahead of print]

FCAI

Cysticercosis Antibody, IgG by ELISA

75097

Interpretation: Seroconversion between acute and convalescent sera is considered strong evidence of recent infection. The best evidence for infection is a significant change on two appropriately timed specimens where both tests are done in the same laboratory at the same time. Patients with collagen vascular diseases, hepatic cirrhosis, schistosomiasis, and other parasitic infections can produce false-positive results. There is a strong cross-reaction between cysticercosis and echinococcosis positive sera. Confirmation of positive ELISA results by the cysticercosis antibody, IgG by Western blot is recommended.

Reference Values: Reference Interval: or =16 years: 32-290 mcmol/24 hours ORNITHINE 3-15 years: 3-16 mcmol/24 hours > or =16 years: 5-70 mcmol/24 hours ARGININE 3-15 years: 10-25 mcmol/24 hours > or =16 years: 13-64 mcmol/24 hours Conversion Formulas: Result in mcmol/24 hours x 0.24=result in mg/24 hours Result in mg/24 hours x 4.17=result in mcmol/24 hours

Clinical References: 1. Saravakos P, Kokkinou V, Giannatos E: Cystinuria. Current Diagnosis and Management. Urology April 2014;4(83):693-699 2. Palacin, M, Goodyer, P, Nunes V, Gasparini P: Cystinuria. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, 2014. Accessed 6 July 2016. Available at http://ommbid.mhmedical.com/content.aspx?sectionid=62653976&bookid=971&Resultclick=2

CYSR

Cystinuria Profile, Quantitative, Random, Urine

81067

Clinical Information: Cystinuria is an inborn error of metabolism resulting from poor absorption and reabsorption of the amino acid cystine in the intestine and in the kidney. This leads to an accumulation of poorly soluble cystine in the urine and results in the production of kidney stones (urolithiasis). Symptoms may include acute episodes of abdominal or lower back pain, presence of blood in the urine (hematuria), and recurrent episodes of kidney stones may result in frequent urinary tract infections, which may ultimately result in renal insufficiency. The combined incidence of cystinuria has been estimated to be 1



Page 651

in 7,000. Cystinuria can be classified into 3 subtypes based on the excretion of amino acids in the urine of heterozygotes (parents or children of affected individuals). Heterozygotes of type I excrete normal amounts of cystine, while those with types II and III present with slight-to-moderate excretion of cystine and other amino acids (lysine, arginine, and ornithine). All 3 subtypes are caused by mutations in only 2 genes, SLC3A1 on chromosome 2p and SLC7A9 on chromosome 19q. A new classification system has been proposed to distinguish the various forms of cystinuria: type A, due to mutations in the SLC3A1 gene; type B, due to mutations in the SLC7A9 gene; and type AB, due to 1 mutation in each SLC3A1 and SLC7A9.

Useful For: Biochemical diagnosis and monitoring of cystinuria Interpretation: Homozygotes or compound heterozygotes with cystinuria excrete large amounts of cystine in urine, but the amount varies markedly. Urinary excretion of other dibasic amino acids (arginine, lysine, and ornithine) is also typically elevated. Plasma concentrations are generally normal or slightly decreased. Individuals who are homozygous and heterozygous for non-type I cystinuria can be distinguished by the pattern of urinary amino acids excretion: homozygous individuals secrete large amounts of cystine and all 3 dibasic amino acids, whereas heterozygous individuals secrete more lysine and cystine than arginine and ornithine.

Reference Values: Urine Amino Acid Age Groups Reference Values (nmol/mg < or =12 creatinine) Months

13-35 Months 3-6 Years

7-8 Years

9-17 Years

> or =18 Years

(n=36)

(n=45)

(n=39)

(n=10)

(n=40)

(n=145)

10-560

20-395

14-240

Arginine

Arg

Ornithine

Orn

Cystine

Cys

12-504

11-133

Lysine

Lys

19-1988

25-743

10-98 14-307

17-276

10-240

15-271

Clinical References: 1. Saravakos P, Kokkinou V, Giannatos E: Cystinuria. Current Diagnosis and Management. Urology April 2014;4(83):693-699 2. Palacin, M, Goodyer, P, Nunes V, Gasparini P: Cystinuria. Edited by D Valle, AL Beaudet, B Vogelstein, et al: New York, NY: McGraw-Hill; 2014. Accessed 6 July 2016. Available at http://ommbid.mhmedical.com/content.aspx?sectionid=62653976&bookid=971&Resultclick=2

CYOXS

Cytochrome Oxidase Stain (Bill Only)

80873


1A2

Cytochrome P450 1A2 Genotype

89401

Clinical Information: The cytochrome P450 (CYP) family is involved in the primary metabolism of many drugs. The CYPs are a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP enzymes, CYP1A2, is wholly or partially responsible for the hydroxylation or dealkylation of many commonly prescribed drugs. CYP1A2-mediated drug metabolism is highly variable. A number of variants have been identified in the CYP1A2 gene that result in increased, diminished, or abolished catalytic activity and substrate



Page 652

metabolism. Dosing of drugs that are metabolized through CYP1A2 may require adjustment based on the CYP1A2 genotype. Individuals who are poor metabolizers may require lower than usual doses to achieve optimal response, whereas individuals who are ultrarapid metabolizers may benefit from increased doses. CYP1A2 phenotype is predicted based upon the number of functional, partially functional, nonfunctional, and inducible alleles present in a sample. In the absence of clear guidance on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism also may benefit by switching to another comparable drug that is not primarily metabolized by CYP1A2 or by therapeutic drug monitoring where applicable. The following table outlines the relationship between the variations (star alleles) detected in this assay and the effect on the activity of the enzyme produced by that allele. CYP1A2 Allele Nucleotide Change* (Legacy nomenclature)* cDNA Nucleotide Change Effect on Enzyme Metabolism** *1 None (wild type) None (wild type) Extensive (normal) metabolizer *1K -729C->T c.-10+113C->T Decreased activity and decreased inducibility *1F -163C->A c.-9-154C->A Increased inducibility *4 2499A->T c.1156A->T Greatly reduced activity *5 3497G->A c.1217G->A Decreased activity *6 5090C->T c.1291C->T No activity *7 3533G->A c.1253+1G->A No activity *8 5166G->A c.1367G->A No activity *11 558C->A c.558C->A No activity *15 125C->G c.125C->G No activity *16 2473G->A c.1130G->A No activity **The frequency of these variants varies by ethnicity. *Effect of a specific allele on the activity of the CYP1A2 enzyme can only be estimated since the literature does not provide precise data. A complicating factor in correlating CYP1A2 genotype to CYP1A2 phenotype is that some drugs or their metabolites are inhibitors of CYP1A2 catalytic activity. These drugs may reduce CYP1A2 catalytic activity. Consequently, an individual may require a dose decrease greater than predicted based upon genotype alone. Another complicating factor is that CYP1A2 is inducible by several drugs and environmental agents (eg, cigarette smoke) and the degree of inducibility is under genetic control. It is important to interpret the results of testing in the context of other coadministered drugs and environmental factors.

Useful For: Identifying individuals who are poor, intermediate, extensive, or ultrarapid metabolizers of drugs metabolized by CYP1A2 to assist drug therapy decision making

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating whether results are consistent with a poor, intermediate, extensive, or ultrarapid metabolizer phenotype. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) CYP1A2 activity is also dependent upon hepatic function status, as well as age. Renal function may be important for drugs that are also excreted in urine. Patients may develop drug toxicity if hepatic or renal function is decreased. Drug metabolism is known to decrease with age. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and age. For additional information regarding pharmacogenomic genes and their associated drugs, see Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 9/21/15. Available at: http://www.cypalleles.ki.se/cyp1a2.htm 2. Ito M, Katono Y, Oda A, et al: Functional characterization of 20 allelic variants of CYP1A2. Drug Metab Pharmacokinet 2015 Jun;30(3):247-252 3. Zhou H, Josephy PD, Kim D, Guengerick FP: Functional characterization of four allelic variants of human cytochrome P450 1A2. Arch Biochem Biophys 2004 Feb;422(1):23-30 4. Murayama N, Soyama A, Saito Y, et al: Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes. J Pharmacol Exp Ther 2004 Jan;308(1):300-306 5. Saito Y, Hanioka N, Maekawa K, et al: Functional analysis of three CYP1A2 variants found in a Japanese population. Drug Metab Dispos 2005 Dec;33(12):1905-1910

1A2O

Cytochrome P450 1A2 Genotype, Saliva

60346

Clinical Information: The cytochrome P450 (CYP) family is involved in the primary metabolism of many drugs. The CYPs are a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP enzymes, CYP1A2, is wholly or



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partially responsible for the hydroxylation or dealkylation of many commonly prescribed drugs. CYP1A2-mediated drug metabolism is highly variable. A number of variants have been identified in the CYP1A2 gene that results in increased, diminished, or abolished catalytic activity and substrate metabolism. Dosing of drugs that are metabolized through CYP1A2 may require adjustment based on the CYP1A2 genotype. Individuals who are poor metabolizers may require lower than usual doses to achieve optimal response, whereas individuals who are ultrarapid metabolizers may benefit from increased doses. CYP1A2 phenotype is predicted based upon the number of functional, partially functional, nonfunctional, and inducible alleles present in a sample. In the absence of clear guidance on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism also may benefit by switching to another comparable drug that is not primarily metabolized by CYP1A2 or by therapeutic drug monitoring where applicable. The following table outlines the relationship between the variations (star alleles) detected in this assay and the effect on the activity of the enzyme produced by that allele. CYP1A2 Allele Nucleotide Change* (Legacy nomenclature)* cDNA Nucleotide Change Effect on Enzyme Metabolism** *1 None (wild type) None (wild type) Extensive (normal) metabolizer *1K -729C->T c.-10+113C->T Decreased activity and decreased inducibility *1F -163C->A c.-9-154C->A Increased inducibility *4 2499A->T c.1156A->T Greatly reduced activity *5 3497G->A c.1217G->A Decreased activity *6 5090C->T c.1291C->T No activity *7 3533G->A c.1253+1G->A No activity *8 5166G->A c.1367G->A No activity *11 558C->A c.558C->A No activity *15 125C->G c.125C->G No activity *16 2473G->A c.1130G->A No activity **The frequency of these variants varies by ethnicity. *Effect of a specific allele on the activity of the CYP1A2 enzyme can only be estimated since the literature does not provide precise data. A complicating factor in correlating CYP1A2 genotype to CYP1A2 phenotype is that some drugs or their metabolites are inhibitors of CYP1A2 catalytic activity. These drugs may reduce CYP1A2 catalytic activity. Consequently, an individual may require a dose decrease greater than predicted based upon genotype alone. Another complicating factor is that CYP1A2 is inducible by several drugs and environmental agents (eg, cigarette smoke) and the degree of inducibility is under genetic control. It is important to interpret the results of testing in the context of other coadministered drugs and environmental factors.

Useful For: Identifying individuals who are poor, intermediate, extensive, or ultrarapid metabolizers of drugs metabolized by CYP1A2 to assist drug therapy decision making Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating whether results are consistent with a poor, intermediate, extensive, or ultra-rapid metabolizer phenotype. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) CYP1A2 activity is also dependent upon hepatic function status, as well as age. Renal function may be important for drugs that are also excreted in urine. Patients may develop drug toxicity if hepatic or renal function is decreased. Drug metabolism is known to decrease with age. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and age. For additional information regarding pharmacogenomic genes and their associated drugs, see Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 9/21/15. Available at: http://www.cypalleles.ki.se/cyp1a2.htm 2. Ito M, Katono Y, Oda A, et al: Functional characterization of 20 allelic variants of CYP1A2. Drug Metab Pharmacokinet 2015 Jun;30(3):247-252 3. Zhou H, Josephy PD, Kim D, Guengerick FP: Functional characterization of four allelic variants of human cytochrome P450 1A2. Arch Biochem Biophys 2004 Feb;422(1):23-30 4. Murayama N, Soyama A, Saito Y, et al: Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes. J Pharmacol Exp Ther 2004 Jan;308(1):300-306 5. Saito Y, Hanioka N, Maekawa K, et al: Functional analysis of three CYP1A2 variants found in a Japanese population. Drug Metab Dispos 2005 Dec;33(12):1905-1910



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2C19B

Cytochrome P450 2C19 Genotype, Blood

62996

Clinical Information: Primary metabolism of many drugs is performed by cytochrome P450 (CYP450) enzymes, a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP450 enzymes, CYP2C19, participates in the metabolism of a wide variety of drugs, including the activation of the anticoagulant clopidogrel, and the inactivation of citalopram. CYP2C19 drug metabolism is variable among individuals. Some individuals have CYP2C19 genetic variants that lead to severely diminished or absent CYP2C19 catalytic activity (ie, poor metabolizers). The frequency of CYP2C19 variants (also referred to as polymorphisms) depends on ethnicity. CYP2C19 variants that produce poor metabolizers are found with frequencies of 2% to 5% in Caucasians, 4% in African Americans, 13% to 23% in Asians, and 38% to 79% in Polynesians and Micronesians. The following table displays the CYP2C19 variants detected by this assay, the corresponding star allele, and the effect on CYP2C19 enzyme activity: CYP2C19 Allele Nucleotide Change Effect on Enzyme Activity *1 None (wild type) Extensive metabolizer (normal) *2 c.681G>A No activity *3 c.636G>A No activity *4 c.1A>G No activity *5 c.1297C>T No activity *6 c.395G>A No activity *7 c.819+2T>A No activity *8 c.358T>C Severely decreased *9 c.431G>A Decreased *10 c.680C>T Severely decreased *17 c.-806C>T Enhanced activity CYP2C19 drug metabolism is dependent on the specific genotype detected, and also on the number and type of drugs administered to the patient. Individuals without a detectable CYP2C19 variant will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C19*1/*1. If an individual is homozygous or compound heterozygous for an alleles with no activity, the individual is predicted to be a poor metabolizer. If an individual is heterozygous for an allele with no activity, the individual is predicted to be an intermediate metabolizer. Individuals with the CYP2C19*17 allele (in the absence of any inactive or decreased activity alleles) may have enhanced metabolism of drugs. In some cases, a range of potential phenotypes may be given, depending on the combination of alleles identified. Patients who are poor metabolizers may benefit from dose alteration or selection of a comparable drug that is not primarily metabolized by CYP2C19. It is important to interpret the results of testing in the context of other coadministered drugs.

Useful For: Identifying patients who may be at risk for altered metabolism of drugs that are modified by CYP2C19 Predicting anticoagulation response to clopidogrel

Interpretation: A report will be provided that includes CYP2C19 genotype, predicted CYP2C19 phenotype, and assay information. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and drug-metabolite inhibition must be considered when treating intermediate metabolizers. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed Sept 21, 2015. Available at www.cypalleles.ki.se/cyp1a2.htm 2. Blaisdell J, Mohrenweiser H, Jackson J, et al: Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 2002 Dec;12(9):703-711 3. Hicks J, Bishop J, Sangkuhl K, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther 2015;98(2):27-34 4. Hicks J, Swen J, Thorn C, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93(5):402-408 5. Mega J, Close S, Wiviott D, et al: Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362

2C19C

Cytochrome P450 2C19 Genotype, Saliva

62997

Clinical Information: Primary metabolism of many drugs is performed by cytochrome P450



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(CYP450) enzymes, a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP450 enzymes, CYP2C19, participates in the metabolism of a wide variety of drugs, including the activation of the anticoagulant clopidogrel, and the inactivation of citalopram. CYP2C19 drug metabolism is variable among individuals. Some individuals have CYP2C19 genetic variants that lead to severely diminished or absent CYP2C19 catalytic activity (ie, poor metabolizers). The frequency of CYP2C19 variants (also referred to as polymorphisms) depends on ethnicity. CYP2C19 variants that produce poor metabolizers are found with frequencies of 2% to 5% in Caucasians, 4% in African Americans, 13% to 23% in Asians, and 38% to 79% in Polynesians and Micronesians. The following table displays the CYP2C19 variants detected by this assay, the corresponding star allele, and the effect on CYP2C19 enzyme activity: CYP2C19 Allele Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive metabolizer (normal) *2 c.681G->A No activity *3 c.636G->A No activity *4 c.1A->G No activity *5 c.1297C->T No activity *6 c.395G->A No activity *7 c.819+2T->A No activity *8 c.358T->C Severely decreased *9 c.431G->A Decreased *10 c.680C>TG Severely decreased *17 c.-806C->T Enhanced activity CYP2C19 drug metabolism is dependent on the specific genotype detected, and also on the number and type of drugs administered to the patient. Individuals without a detectable CYP2C19 variant will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C19*1/*1. If an individual is homozygous or compound heterozygous for an allele with no activity, the individual is predicted to be a poor metabolizer. If an individual is heterozygous for an allele with no activity, the individual is predicted to be an intermediate metabolizer. Individuals with the CYP2C19*17 allele (in the absence of any inactive or decreased activity alleles) may have enhanced metabolism of drugs. In some cases, a range of potential phenotypes may be given, depending on the combination of alleles identified. Patients who are poor metabolizers may benefit from dose alteration or selection of a comparable drug that is not primarily metabolized by CYP2C19. It is important to interpret the results of testing in the context of other coadministered drugs.

Useful For: Identifying patients who may be at risk for altered metabolism of drugs that are modified by CYP2C19 Predicting anticoagulation response to clopidogrel Genotyping patients who prefer not to have venipuncture done

Interpretation: A report will be provided that includes CYP2C19 genotype, predicted CYP2C19 phenotype, and assay information. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and drug-metabolite inhibition must be considered when treating intermediate metabolizers. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed Sept 21, 2015. Available at www.cypalleles.ki.se/cyp1a2.htm 2. Blaisdell J, Mohrenweiser H, Jackson J, et al: Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 2002 Dec;12(9):703-711 3. Hicks J, Bishop J, Sangkuhl K, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther 2015;98(2):127-34 4. Hicks J, Swen J, Thorn C, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013;93(5):402-408 5. Mega J, Close S, Wiviott D, et al: Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354-362

2C9B

Cytochrome P450 2C9 Genotype by Sequence Analysis, Blood

36441

Clinical Information: Primary metabolism of many drugs is performed by cytochrome P450 (CYP450), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues



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including the intestines and liver. One of these CYP450 enzymes, CYP2C9, participates in the metabolism of a wide variety of drugs including warfarin and phenytoin. CYP2C9-mediated drug metabolism is variable among individuals. Some individuals have CYP2C9 genetic variants that lead to severely diminished or absent CYP2C9 catalytic activity (ie, poor metabolizers). These individuals may metabolize various drugs at a slower rate than normal and may require dosing adjustments to prevent adverse drug reactions. A number of specific CYP2C9 variants have been identified that result in enzymatic deficiencies. The following information outlines the relationship between the variants detected in the assay and their effect on enzyme activity: CYP2C9 Allele cDNA Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive metabolizer (normal) *2 430C->T Reduced activity *3 1075A->C No activity *4 1076T->C Reduced activity *5 1080C->G Reduced activity *6 818delA No activity *8 449G->A Substrate specific *9 752A->G Reduced activity *11 1003C->T Reduced activity CYP2C9 drug metabolism is dependent on the specific genotype detected, and also on the number and type of drugs administered to the patient. Individuals without a detectable CYP2C9 variant will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C9 *1/*1. If an individual is homozygous or compound heterozygous for an allele with no activity, the individual is predicted to be a poor metabolizer. If an individual is heterozygous for an allele with no activity, the individual is predicted to be an intermediate metabolizer. In some cases, a range of potential phenotypes may be given, depending on the combination of alleles identified. Patients who are poor metabolizers may benefit from dose alteration or selection of a comparable drug that is not primarily metabolized by CYP2C9. It is important to interpret the results of testing in the context of other coadministered drugs.

Useful For: Identifying individuals who may be at risk for altered metabolism of drugs that are modified by CYP2C9

Interpretation: A report will be provided that includes CYP2C9 genotype, predicted CYP2C9 phenotype, and assay information. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and drug/metabolite inhibition must be considered in the case of intermediate metabolism. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 9/21/15. Available at www.cypalleles.ki.se/cyp1a2.htm/ 2. Caudle KE, Rettie AE, Whirl-Carrillo M, et al: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther 2014;96(5):542-548 3. Niemi M, Cascorbi I, Timm R, et al: Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 2002;72:326-332 4. Johnson JA, Gong L, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90(4):625-629 5. Blaisdell J, Jorge-Nebert LF, Coulter S, et al: Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 2004;14(8):527-537

2C9C

Cytochrome P450 2C9 Genotype by Sequence Analysis, Saliva

36446

Clinical Information: Primary metabolism of many drugs is performed by cytochrome P450 (CYP450), a group of oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP450 enzymes, CYP2C9, participates in the metabolism of a wide variety of drugs including warfarin and phenytoin. CYP2C9-mediated drug metabolism is variable among individuals. Some individuals have CYP2C9 genetic variants that lead to a severely diminished or absent CYP2C9 catalytic activity (ie, poor metabolizers). These individuals may



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metabolize various drugs at a slower rate than normal and may require dosing adjustments to prevent adverse drug reactions. A number of specific CYP2C9 variants have been identified that result in enzymatic deficiencies. The following information outlines the relationship between the variants detected in the assay and their effect on enzyme activity: CYP2C9 Allele cDNA Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive metabolizer (normal) *2 430C->T Reduced activity *3 1075A->C No activity *4 1076T->C Reduced activity *5 1080C->G Reduced activity *6 818delA No activity *8 449G->A Substrate specific *9 752A->G Reduced activity *11 1003C->T Reduced activity CYP2C9 drug metabolism is dependent on the specific genotype detected, and also on the number and type of drugs administered to the patient. Individuals without a detectable CYP2C9 variant will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C9 *1/*1. If an individual is homozygous or compound heterozygous for an allele with no activity, the individual is predicted to be a poor metabolizer. If an individual is heterozygous for an allele with no activity, the individual is predicted to be an intermediate metabolizer. In some cases, a range of potential phenotypes may be given, depending on the combination of alleles identified. Patients who are poor metabolizers may benefit from dose alteration or selection of a comparable drug that is not primarily metabolized by CYP2C9. It is important to interpret the results of testing in the context of other coadministered drugs.

Useful For: Identifying individuals who may be at risk for altered metabolism of drugs that are modified by CYP2C9 Genotyping patients who prefer not to have venipuncture done

Interpretation: A report will be provided that includes CYP2C9 genotype, predicted CYP2C9 phenotype, and assay information. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Drug-drug interactions and drug-metabolite inhibition must be considered in the case of intermediate metabolism. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 9/21/15. Available at: http://www.cypalleles.ki.se/cyp1a2.htm/ 2. Caudle KE, Rettie AE, Whirl-Carrillo M, et al: Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther 2014;96(5):542-548 3. Niemi M, Cascorbi I, Timm R, et al: Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 2002;72:326-332 4. Johnson JA, Gong L, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90(4):625-629 5. Blaisdell J, Jorge-Nebert LF, Coulter S, et al: Discovery of new potentially defective alleles of human CYP2C9. Pharmacogenetics 2004;14(8):527-537

2D6CB 62429

Cytochrome P450 2D6 (CYP2D6) Comprehensive Cascade, Blood Clinical Information: The cytochrome P450 (CYP) family of enzymes is responsible for primary metabolism of many drugs. CYP450s are oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism of many commonly prescribed drugs such as some analgesics, anticonvulsants, antidepressants, antipsychotics, antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, sympathomimetic and other drug classes. The CYP2D6 gene is highly variable with over 100 named alleles. The gene may be deleted, duplicated, and multiplied, and can have multiple



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sequence variations. In addition, some individuals have genes that are hybrids of CYP2D6 and the CYP2D7 pseudogene. Some individuals have altered CYP2D6 variants that result in synthesis of enzyme devoid of catalytic activity, or an enzyme with diminished catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly depending upon the gene variant found on each chromosome. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict ultrarapid, ultrarapid to extensive (normal), extensive (normal), extensive (normal) to intermediate, intermediate, intermediate to poor, and poor metabolizer phenotypes. (see Table 1) Table 1. Enzyme Activity of Individual Star Alleles Enzyme Activity Examples of CYP2D6 star alleles Extensive metabolism (normal) *1, *35 Increased activity *2A Decreased activity *2, *9, *10, *14B, *17, *29 and *41 Negligible activity *36 No or null activity *3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *14A, *15, *68 CYP2D6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample. (see Table 2) Table 2. Phenotype Assignment of CYP2D6 Predicted Drug Metabolizer Phenotype** Without Gene Duplication With Gene Duplication UM 2 increased activity alleles 3 normal and/or increased activity alleles EM to UM A combination of 1 normal activity allele with 1 increased activity allele A combination of 2 normal alleles with one decreased activity allele EM 2 normal activity alleles; a combination of one increased activity allele with one decreased allele A combination of 2 normal alleles with 1 null allele; a combination of 1 normal allele with 2 decreased activity alleles IM to EM A combination of 1 normal activity allele with 1 decreased activity allele; a combination of 1 increased activity with 1 null allele 1 increased activity allele with 2 null alleles, 3 decreased activity alleles IM 1 normal activity allele with 1 null activity allele; 2 decreased activity alleles 1 normal allele with 2 or more null alleles, 2 decreased activity alleles with 1 null allele. PM to IM A combination of 1 decreased activity allele with 1 null allele 1 decreased activity allele with 2 null allele PM Only null alleles detected * Phenotyping was derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Committee website and the PharmGKB website for the related Clinical Pharmacogenetics Implementation Consortium guidelines. **Ultra-Rapid Metabolizer, UM; Extensive Metabolizer, EM; Intermediate Metabolizer, IM; Poor Metabolizer, PM There are instances where a phenotype prediction is not categorical and, in these instances, a range of possible phenotypes will be given. It should be noted that other laboratories may use different phenotype prediction methods as there is no consensus on this at this time. However, the method used here represents the findings of the majority of literature available at this time. Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6 *1/*1. Dosing drugs that are metabolized through CYP2D6 may require adjustment based on the individual patient's genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2D6 enzyme and higher than usual doses in the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6 enzyme and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit by switching to another comparable drugs that is not primarily metabolized by CYP2D6 or by therapeutic drug monitoring where applicable. Overall, this test provides a comprehensive CYP2D6 genotype result for patients, ensuring a more accurate phenotype prediction. This assay has clinical significance for patients taking or considering medications activated (eg, codeine, tramadol, and tamoxifen) or inactivated (eg, antidepressants and antipsychotics) by the CYP2D6 enzyme. The different tiers associated with the CYP2D6 Cascade will be sequentially initiated until a complete genotype is determined.

Useful For: Providing information relevant to tamoxifen codeine, and tramadol, as well as other medications metabolized by CYP2D6 Determining the exact genotype when other methods fail to generate this information or if genotype-phenotype discord is encountered clinically Identifying exact genotyping when required (eg, drug trials, research protocols) Identifying novel variants that may interfere with drug metabolism

Interpretation: A comprehensive interpretive report will be provided that combines the results of all tier testing utilized to obtain the final genotype. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(1) For the CYP2D6 Copy Number Variation assay, the reportable copy number range is 0 to 4 copies for each of the CYP2D6 region assessed. Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive Current as of August 23, 2017 7:11 am CDT


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comments detailing their potential or known significance. For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Reference Values: A comprehensive interpretive report will be provided.

Clinical References: 1. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Available at www.cypalleles.ki.se/cyp2d6.htm 2. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 3. Black JL 3rd, Walker DL, O'Kane DJ, Harmandayan M: Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction. Drug Metab Dispos 2012;40(1):111-119 4. Goetz MP, Rae M, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318 5. Kircheiner J, Nickchen K, Bauer M, et al: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004;9:442-473 6. Crews KR, Gaedigk A, Dunnenberger HM, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2011 Feb;91(2):321-326 7. Hicks JK, Swen JJ, Thorn CF, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013 May:93(5):402-408

2D6O

Cytochrome P450 2D6 Genotype, Saliva

60334

Clinical Information: The cytochrome P450 (CYP) family of enzymes is responsible for primary metabolism of many drugs. CYP450s are oxidative/dealkylating enzymes localized in the microsomes of many tissues including the intestines and liver. One of the CYP enzymes, CYP2D6, is wholly or partially responsible for the metabolism of many commonly prescribed drugs such as some analgesics, anticonvulsants, antidepressants, antipsychotics, antiemetics, antihypertensives, antiestrogens, antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants, sympathomimetic and other drug classes. The CYP2D6 gene is highly variable with over 100 named alleles. The gene may be deleted, duplicated, and multiplied, and can have multiple sequence variations. In addition, some individuals have genes that are hybrids of CYP2D6 and the CYP2D7 pseudogene. Some individuals have altered CYP2D6 variants that result in synthesis of enzyme devoid of catalytic activity, or an enzyme with diminished catalytic activity. These individuals may process CYP2D6-metabolized medications more slowly depending upon the gene variant found on each chromosome. CYP2D6 duplications and multiplications involving active alleles may result in ultrarapid metabolism of CYP2D6-metabolized drugs. CYP2D6 genotype results are used to predict ultrarapid, ultrarapid to extensive (normal), extensive (normal), extensive (normal) to intermediate, intermediate, intermediate to poor, and poor metabolizer phenotypes for a sample.(see Table 1) Table 1. Enzyme Activity of Individual Star Alleles Enzyme Activity Examples of CYP2D6* alleles Extensive metabolism (normal) *1, *35 Increased activity *2A Decreased activity *2, *9, *10, *14B, *17, *29, *41 No or null activity *3, *4, *4N, *5, *6, *7, *8, *11, *12, *13, *14A, *15 CYP2D6 phenotype is predicted based upon the number of functional, partially functional, and nonfunctional alleles present in a sample.(see Table 2) Table 2. Phenotype Assignment of CYP2D6 Predicted Drug Metabolizer Phenotype** Without Gene Duplication With Gene Duplication UM 2 increased activity alleles 3 normal and/or increased activity alleles EM to UM A combination of 1 normal activity allele with 1 increased activity allele A combination of 2 normal alleles with 1 decreased activity allele EM 2 normal activity alleles; a combination of one increased activity allele with one decreased allele A combination of 2 normal alleles with 1 null allele; a combination of 1 normal allele with 2 decreased activity alleles IM to EM A combination of 1 normal activity allele with 1 decreased activity allele; a combination of 1 increased activity with 1 null allele 1 increased activity allele with 2 null alleles, 3 decreased activity alleles IM 1 normal activity allele with 1 null activity allele; 2 decreased activity alleles 1 normal allele with 2 or more null alleles, 2 decreased activity alleles with 1 null allele. PM to IM A combination of 1 decreased activity allele with 1 null allele 1 decreased activity allele with 2 null allele PM Only null alleles detected * Phenotyping was derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Committee



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website and the PharmGKB website for the related Clinical Pharmacogenetics Implementation Consortium guidelines. **Ultra-Rapid Metabolizer, UM; Extensive Metabolizer, EM; Intermediate Metabolizer, IM; Poor Metabolizer, PM There are instances where a phenotype prediction is not categorical and, in these instances, a range of possible phenotypes will be given. It should be noted that other laboratories may use different phenotype prediction methods as there is no consensus on this at this time. However, the method used here represents the findings of the majority of literature available at this time. Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2D6 *1/*1. Dosing drugs that are metabolized by CYP2D6 may require adjustment based on the individual patient's genotype. Patients who are poor metabolizers may require lower than usual doses to achieve optimal response in the case of drugs that are inactivated by the CYP2D6 enzyme, and higher than usual doses in the case of drugs that are activated by CYP2D6 enzyme. Alternatively, patients who are ultrarapid metabolizers may benefit from increased doses in the case of drugs that are inactivated by CYP2D6 enzyme, and lower doses in the case of drugs that are activated by CYP2D6. In the absence of clear guidance from FDA on dosing for various metabolizer phenotypes, patients with either ultrarapid or poor metabolism may benefit from therapeutic drug monitoring or switching to another comparable drug that is not primarily metabolized by CYP2D6.

Useful For: Determining the CYP2D6 genotype of patients considered for treatment with tamoxifen, codeine, and tramadol, as well as other medications metabolized by CYP2D6 Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided. All alterations detected will be reported with standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee (www.cypalleles.ki.se/CYP2D6.htm). Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance. For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 2. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed September 21, 2015. Available at www.cypalleles.ki.se/cyp2d6.htm 3. Black JL 3rd, Walker DL, O'Kane DJ, Harmandayan M: Frequency of undetected CYP2D6 hybrid genes in clinical samples: impact on phenotype prediction. Drug Metab Dispos 2012;40(1):111-119 4. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 2005;23:9312-9318 5. Kirchheiner J, Nickchen K, Bauer M, et al: Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004;9:442-473 6. Crews KR, Gaedigk A, Dunnenberger HM, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther 2012 Feb;91(2):321-326 7. Hicks JK, Swen JJ, Thorn CF, et al: Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013 May:93(5):402-408

3A4B

Cytochrome P450 3A4 Genotype, Blood

61241

Clinical Information: The cytochrome P450 (CYP) 3A4 enzyme is responsible for the metabolism of approximately 50% of drugs that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells, including lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli, and genetic variation.(1) A CYP3A4 intron 6 variant, CYP3A4*22 (c.522-191C->T), affects hepatic expression of CYP3A4 and response to statin drugs. The CYP3A4*22



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allele is associated with reduced CYP3A4 activity, which may result in a better response to lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. However, reduced CYP3A4 activity may also be associated with statin-induced myopathy, especially for simvastatin. Studies show that in livers with the wild-type genotype (homozygous C or CC) the CYP3A4 mRNA level and enzyme activity were 1.7- and 2.5-fold greater than in heterozygous CYP3A4*22 (CT) and homozygous CYP3A4*22 (TT) carriers, respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele required significantly lower statin doses for optimal lipid control than did non-T carriers.(2) These results indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 in Caucasians is 5% to 8%. The allele frequency is 4.3% in African Americans and in Chinese. Individuals without a detectable CYP3A4*22 variant, will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP3A4*1/*1.

Useful For: Aids in determining therapeutic strategies for drugs that are metabolized by CYP3A4, including atorvastatin, simvastatin, and lovastatin

Interpretation: Extensive metabolizer: The CYP3A4*22 allele was not detected. Therefore, this patient is expected to be an extensive metabolizer. Rapid metabolism of drugs that are inactivated or activated by CYP3A4 is expected. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Intermediate to extensive metabolizer: One copy of the CYP3A4*22 allele was detected. Therefore, this patient is expected to be an intermediate to extensive metabolizer. Reduced metabolism of drugs that are inactivated or activated by CYP3A4 is expected when compared to patients who are *1/*1. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Intermediate metabolizer: Two copies of the CYP3A4*22 allele were detected. Therefore, this patient is expected to be an intermediate metabolizer. Drugs that are inactivated or activated by CYP3A4 are metabolized at reduced rate when compared to patients who are *1/*1. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Absence of the *22 allele does not rule out the possibility that a patient harbors another variant that can impact the function of this enzyme, drug response, or drug side effects. The CYP3A4 genotype is only one factor that should be taken into consideration for drug dosing. For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Evans WE, Relling RV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;486:487-491 2. Wang D, Guo Y, Wrighton SA, et al: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274-286 3. Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002;18:1271-1294 4. Elens L, Becker ML, Haufroid V, et al: Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam study. Pharmacogenet Genomics 2011;21(12):861-866 5. Elens L, Van Schaik RH, Panin N, et al: Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitor' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 2011;12(10):1383-1396

3A4O

Cytochrome P450 3A4 Genotype, Saliva

61242

Clinical Information: The cytochrome P450 (CYP) 3A4 enzyme is responsible for the metabolism of approximately 50% of drugs that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells, including lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli, and genetic variation.(1) A CYP3A4 intron 6 variant, CYP3A4*22



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(c.522-191C->T), affects hepatic expression of CYP3A4 and response to statin drugs. The CYP3A4*22 allele is associated with reduced CYP3A4 activity, which may result in a better response to lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. However, reduced CYP3A4 activity may also be associated with statin-induced myopathy, especially for simvastatin. Studies show that in livers with the wild-type genotype (homozygous C or CC) the CYP3A4 mRNA level and enzyme activity were 1.7- and 2.5-fold greater than in heterozygous CYP3A4*22 (CT) and homozygous CYP3A4*22 (TT) carriers, respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele required significantly lower statin doses for optimal lipid control than did non-T carriers.(2) These results indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 in Caucasians was 5% to 8%. The allele frequency is 4.3% in African Americans and in Chinese.

Useful For: Aids in determining therapeutic strategies for drugs that are metabolized by CYP3A4, including atorvastatin, simvastatin and lovastatin Genotyping patients who prefer not to have venipuncture done

Interpretation: Extensive metabolizer: The CYP3A4*22 allele was not detected. Therefore, this patient is expected to be an extensive metabolizer. Rapid metabolism of drugs that are inactivated or activated by CYP3A4 is expected. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Intermediate to extensive metabolizer: One copy of the CYP3A4*22 allele was detected. Therefore, this patient is expected to be an intermediate to extensive metabolizer. Reduced metabolism of drugs that are inactivated or activated by CYP3A4 is expected when compared to patients who are *1/*1. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Intermediate metabolizer: Two copies of the CYP3A4*22 allele were detected. Therefore, this patient is expected to be an intermediate metabolizer. Drugs that are inactivated or activated by CYP3A4 are metabolized at reduced rate when compared to patients who are *1/*1. Coadministration of CYP3A4 inhibitors may increase the risk of toxicity for drugs inactivated by CYP3A4, or may cause lack of efficacy for drugs activated by CYP3A4. Absence of the *22 allele does not rule out the possibility that a patient harbors another variant that can impact the function of this enzyme, drug response, or drug side effects. The CYP3A4 genotype is only one factor that should be taken into consideration for drug dosing. For additional information regarding pharmacogenomic genes and their associated drugs, please see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Evans WE, Relling RV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;486:487-491 2. Wang D, Guo Y, Wrighton SA, et al: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274-286 3. Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002;18:1271-1294 4. Elens L, Becker ML, Haufroid V, et al: Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam study. Pharmacogenet Genomics 2011;21(12):861-866 5. Elens L, Van Schaik RH, Panin N, et al: Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitor' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 2011;12(10):1383-1396

FCYTP

Cytokine Panel

75139

Interpretation: Results are used to understand the pathophysiology of immune, infectious, or inflammatory disorders, or may be used for research purposes.

Reference Values: Tumor Necrosis Factor â€“ alpha



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Interleukin 2 Interleukin 2 Receptor CD25 Soluble Interleukin 12 Interferon gamma Interleukin 4 Interleukin 5 Interleukin 10 Interleukin 13 Interleukin 17 Interleukin 1 beta Interleukin 6 Interleukin 8

CMVG

Cytomegalovirus (CMV) Antibodies, IgG, Serum

34970

Clinical Information: Cytomegalovirus (CMV) is a member of the Herpesviridae family of viruses and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone marrow derived cells.(1) Primary CMV infection in immunocompetent individuals may also manifest as a mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise, and lymphadenopathy. CMV is a significant cause of morbidity and mortality among bone marrow or solid organ transplant recipients, individuals with AIDS and other immunosuppressed patients due to virus reactivation or from a newly acquired infection.(2,3) Infection in these patient populations can affect almost any organ and lead to multiorgan failure. CMV is also responsible for congenital disease among newborns and is 1 of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and herpes simplex virus). CMV seroprevalence increases with age. In the United States the prevalence of CMV specific antibodies increases from approximately 36% to over 91% in adolescents between the ages of 6 to 11 and adults over 80 years old, respectively.(4)

Useful For: Determining whether a patient (especially transplant recipients, organ and blood donors) has had a recent infection or previous exposure to cytomegalovirus

Interpretation: Positive cytomegalovirus (CMV) IgG results indicate past or recent CMV infection. These individuals may transmit CMV to susceptible individuals through blood and tissue products. Equivocal CMV IgG results may occur during acute infection or may be due to nonspecific binding reactions. Submit an additional sample for testing if clinically indicated. Individuals with negative CMV IgG results are presumed to not have had prior exposure or infection with CMV, and are therefore considered susceptible to primary infection.

Reference Values: Negative (reported as positive, negative, or equivocal)

Clinical References: 1. Soderberg-Naucler C, Khanna R, et al: Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 1997;91:119 2. Kusne S, Shapiro R, Fung J: Prevention and treatment of cytomegalovirus infection in organ transplant recipients. Transpl Infect Dis 1999;1(3):187-203 3. Rubin RH: Importance of CMV in the transplant population. Transpl Infect Dis 1999;1(1):3-7 4. Staras SA, Dollard SC, Radford KW, et al: Seroprevalence of cytomegalovirus infection in the United States, 1998-1994. Clin Infect Dis 2006;43(9):1143



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CMVP

Cytomegalovirus (CMV) Antibodies, IgM and IgG, Serum

62067

Clinical Information: Cytomegalovirus (CMV) is a member of the Herpesviridae family of viruses and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone marrow derived cells.(1) Primary CMV infection in immunocompetent individuals may also manifest as a mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise and lymphadenopathy. CMV is a significant cause of morbidity and mortality among bone marrow or solid organ transplant recipients, individuals with AIDS and other immunosuppressed patients due to virus reactivation or from a newly acquired infection.(2,3) Infection in these patient populations can affect almost any organ and lead to multi-organ failure. CMV is also responsible for congenital disease among newborns and is 1 of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and herpes simplex virus). CMV seroprevalence increases with age. In the United States the prevalence of CMV specific antibodies increases from approximately 36% to over 91% in adolescents between the ages of 6 to 11 and adults over 80 years old, respectively.(4)

Useful For: Diagnosis of primary, acute phase infection with cytomegalovirus (CMV), especially in patients with infectious mononucleosis and pregnant women who, based on clinical signs or exposure, may have primary CMV infection Determining whether a patient (especially transplant recipients, organ and blood donors) has had a recent infection or previous exposure to CMV

Interpretation: IgM: A negative cytomegalovirus (CMV) IgM results suggest that the patient is not experiencing a recent infection. However, a negative result does not rule out primary CMV infection. It has been reported that CMV-specific IgM antibodies were not detectable in 10% to 30% of cord blood sera from infants demonstrating infection in the first week of life. In addition, up to 23% (3/13) of pregnant women with primary CMV infection did not demonstrate detectable CMV IgM responses within 8 weeks post-infection. In cases of primary infection where the time of seroconversion is not well defined as high as 28% (10/36) of pregnant women did not demonstrate CMV IgM antibody. Positive CMV IgM results indicate a recent infection (primary, reactivation, or reinfection). IgM antibody responses in secondary (reactivation) CMV infections have been demonstrated in some CMV mononucleosis patients, in a few pregnant women, and in renal and cardiac transplant patients. Levels of antibody may be lower in transplant patients with secondary rather than primary infections. IgG: Positive CMV IgG results indicate past or recent CMV infection. These individuals may transmit CMV to susceptible individuals through blood and tissue products. Individuals with negative CMV IgG results are presumed to not have had prior exposure or infection with CMV, and are therefore considered susceptible to primary infection. Equivocal CMV IgM or IgG results may occur during acute infection or may be due to non-specific binding reactions. Submit an additional sample for testing if clinically indicated.

Reference Values: CMV IgM: Negative (reported as positive, negative, or equivocal) CMV IgG: Negative (reported as positive, negative, or equivocal)


CMVM

Cytomegalovirus (CMV) Antibodies, IgM, Serum

34971

Clinical Information: Cytomegalovirus (CMV) is a member of the Herpesviridae family of viruses and usually causes asymptomatic infection after which it remains latent in patients, primarily within bone marrow derived cells.(1) Primary CMV infection in immunocompetent individuals may also manifest as a mononucleosis-type syndrome, similar to primary Epstein-Barr virus infection, with fever, malaise, and



Page 665

lymphadenopathy. CMV is a significant cause of morbidity and mortality among bone marrow or solid organ transplant recipients, individuals with AIDS and other immunosuppressed patients due to virus reactivation or from a newly acquired infection.(2,3) Infection in these patient populations can affect almost any organ and lead to multiorgan failure. CMV is also responsible for congenital disease among newborns and is 1 of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and herpes simplex virus). CMV seroprevalence increases with age. In the United States the prevalence of CMV specific antibodies increases from approximately 36% to over 91% in adolescents between the ages of 6 to 11 and adults over 80 years old, respectively.(4)

Useful For: Diagnosis of primary, acute phase infection with cytomegalovirus (CMV), especially in patients with infectious mononucleosis and pregnant women who, based on clinical signs or exposure, may have primary CMV infection

Interpretation: A negative cytomegalovirus (CMV) IgM results suggest that the patient is not experiencing a recent infection. However, a negative result does not rule-out primary CMV infection. It has been reported that CMV-specific IgM antibodies were not detectable in 10% to 30% of cord blood sera from infants demonstrating infection in the first week of life. In addition, up to 23% (3/13) of pregnant women with primary CMV infection did not demonstrate detectable CMV IgM responses within 8 weeks postinfection. In cases of primary infection where the time of seroconversion is not well defined as high as 28% (10/36) of pregnant women did not demonstrate CMV-IgM antibody. Positive CMV IgM results indicate a recent infection (primary, reactivation, or reinfection). IgM antibody responses in secondary (reactivation) CMV infections have been demonstrated in some CMV mononucleosis patients, in a few pregnant women, and in renal and cardiac transplant patients. Levels of antibody may be lower in transplant patients with secondary, rather than primary, infections. Equivocal CMV IgM results may occur during acute infection or may be due to nonspecific binding reactions. Submit an additional sample for testing if clinically indicated.

Reference Values: Negative (Reported as positive, negative, or equivocal)


CMVC8 88826

Cytomegalovirus (CMV) CD8 T-Cell Immune Competence, Quantitative Assessment by Flow Cytometry Clinical Information: Cytomegalovirus (CMV), a double-stranded DNA virus, belongs to the Herpesviridae family of viruses and is structurally similar to other herpes viruses. Although many human strains of CMV exist, there is little genetic homology between human CMV and CMV of other species. The reported seroprevalence rates of CMV range from 40% to 100% in the general population. In the urban United States, the seroprevalence of CMV has been reported to be 60% to 70%.(1) However, data from Mayo Clinic's laboratory indicate that the seroprevalence in the Midwestern US population is closer to 30% (unpublished observations). Once CMV infection occurs, the virus spreads hematogenously to almost every organ. After acute infection, the virus enters a latent phase. Activation from this phase can be seen after acute illness, immunosuppression in allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation, or use of chemotherapy agents. CMV infection or reactivation has been implicated in allograft rejection in renal(2) and cardiac transplantation.(1) In cardiac transplants, CMV infection has been shown to contribute to accelerated development of transplant atherosclerosis (cardiac allograft vasculopathy). CMV remains a significant cause of morbidity and mortality after HSCT. Of allogeneic HSCT patients who are CMV-seropositive, 60% to 70% will experience reactivation and, without ganciclovir or other preemptive therapy, 20% to 30% will develop end-organ disease.(3) CD8 T cells play a critical role in viral immunity, and CD8 T-cell effector functions include cytotoxicity and



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cytokine production. Cytotoxicity occurs after CD8 T-cell activation, causing target cell apoptosis. Cytotoxic T-cell responses mediate killing of target cells via 2 major pathways, granule-dependent (perforin and granzymes) and granule-independent (Fas and Fas ligand [FasL]) mechanisms. The granule-dependent pathway does not require the de novo synthesis of proteins by effector CD8 T cells, but rather it utilizes preformed lytic granules located within the cytoplasm. Among the proteins in these preformed lytic granules are the lysosomal-associated membrane proteins (LAMP), including LAMP-1 (CD107a) and LAMP-2 (CD107b). These proteins are not normally found on the surface of T cells. Degranulation of activated CD8 T cells occurs rapidly after T-cell receptor (TCR) stimulation, exposing CD107a and CD107b. The cytokines produced by activated T cells include interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), macrophage inflammatory protein 1 alpha (MIP-1 alpha), macrophage inflammatory protein 1 beta (MIP-1 beta), and interleukin-2 (IL-2). Several studies have shown the importance of cytotoxic T-cell responses to CMV in conferring protection from subsequent CMV disease. Antiviral drugs have helped reduce the incidence of early CMV infection, and acyclovir and ganciclovir have been the mainstay of antiviral treatment for a number of years, although these drugs have poor bioavailability.(4) The development of the new antiviral drugs valacyclovir and valganciclovir (by the addition of a valine ester) has increased the bioavailability of these drugs by 10-fold.(4) There is some data to suggest valganciclovir prophylaxis may be considered for HSCT patients who are at high risk for infection and disease, though there is a need for further study in this area.(5) Two main strategies have been used for the prevention of early CMV infection and disease in CMV-seropositive patients and in seronegative recipients who receive a seropositive graft-preemptive therapy: -Patient monitoring for CMV infection and treatment only when CMV viremia is present. -Prophylactic management-where all patients receive treatment after transplantation with the goal of preventing CMV disease.(5) The disadvantage of prophylactic therapy is that it requires monitoring for myelosuppression and infections-side effects of antiviral drug therapy. Despite this disadvantage, there are several reasons to consider prophylaxis, including the fact that the incidence of recurrent infections after treatment is 30% to 40%,(5) patients receiving preemptive therapy have a 5% CMV disease break-through, and prophylaxis reduces the risk of viral reactivation. Late CMV infection occurs 3 months after transplantation and is now recognized as a significant cause of morbidity after allogeneic HSCT. These complications usually occur in the setting of continued immunosuppression for chronic graft-versus-host disease (GVHD). The clinical manifestations of late CMV disease differ slightly from those seen early after transplantation. Within the first 100 days after HSCT, almost all patients with CMV disease have CMV pneumonia or gastrointestinal disease. In late CMV disease, the more unusual manifestations of CMV infection (eg, CMV retinitis, CMV-associated bone marrow failure, or CMV encephalitis) tend to occur.(6) These late manifestations occur in a setting of continued CMV-specific T-cell immunodeficiency. Therefore, it is necessary to monitor CMV-specific CD8 T-cell responses, in addition to viral load, to effectively identify patients at higher risk of CMV disease. It has been shown that ganciclovir may delay the recovery of the protective CMV-specific T-cell response, which may contribute to the occurrence of late CMV disease.(7) The use of ganciclovir as early treatment after detection of CMV in blood or other body fluid and as a prophylaxis for CMV infection in bone marrow transplant (BMT) and heart transplant recipients has dramatically reduced the incidence of CMV in these immunocompromised hosts. Yet, early treatment and prophylaxis have not been uniformly successful, with up to 15% of BMT recipients developing CMV disease after discontinuation of antiviral therapy. Similarly, patients undergoing lung transplantation have been shown to be only transiently protected with antiviral agents. These data suggest that the CMV-specific responses necessary for protection may not recover during the time the host is receiving antiviral therapy. Ganciclovir exerts its antiviral effects at the stage of viral DNA replication and, therefore, in the presence of the drug, infected cells may express some of the immediate early and early gene products, but not the full complement of CMV genes required for replication and virion formation. In latently infected CMV-seropositive individuals, the HLA class I-restricted cytotoxic T lymphocyte response to CMV is predominantly specific for epitopes derived from structural virion proteins. Therefore, in patients receiving ganciclovir, the viral antigens may be inadequate to activate host T-cell responses, resulting in the failure to reconstitute CMV-specific immunity. In fact, a prospective, randomized placebo-controlled study of ganciclovir prophylaxis revealed that when ganciclovir therapy is discontinued, a larger fraction of patients (who received the drug) are deficient in CMV-specific T-cell immunity at day 100 than in the placebo group.(7) That study also showed that bone marrow donor serology has an important influence on the early detection of virus-specific T-cell responses.(7) Not all medical centers use ganciclovir for prophylaxis; some use acyclovir and the same findings may apply in this case as well. In a more recent study, it was shown that impaired CD8 function was associated with the use of high-dose steroids, bone marrow as a source of Current as of August 23, 2017 7:11 am CDT


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stem cells, and CD8 T-cell lymphopenia.(3) In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4 and CD8 functional recovery in recipients of ganciclovir prophylaxis, suggesting that subclinical CMV reactivation while on antiviral therapy can be a potent stimulator of T-cell function.(3) Regardless of antiviral therapy, immunologic reconstitution remains the key element in protection from late-onset CMV disease. This test assesses the number of CMV-specific CD8 T cells and their function (activation via production of the cytokine IFN-gamma and cytotoxic potential via CD107a and CD107b as markers of degranulation) using a panel of 5 major histocompatibility complex (MHC) class I alleles (HLA A1, A2, B7, B8, and B35) along with their respective immunodominant CMV epitopes. This 3-part assay allows a comprehensive assessment of CMV-specific CD8 T cell immunity and, when combined with evaluation of viremia using molecular analyses, provides a more accurate picture of the nature of CMV reactivation and the corresponding immune response than evaluating viremia alone. Assessment of Global CD8 T-Cell Function: CD8 T cell activation occurs either through the TCR-peptide-MHC or by use of a mitogen (eg, phorbol myristate acetate and the calcium ionophore ionomycin). Mitogen-mediated activation is antigen nonspecific. Impairment of global CD8 T cell activation (due to inherent cellular immunodeficiency or as a consequence over immunosuppression by therapeutic agents) results in reduced production of IFN-gamma and other cytokines, reduced cytotoxic function, and increased risk for developing infectious complications. Agents associated with over-immunosuppression include the calcineurin inhibitors (eg, cyclosporine A, FK506 [Prograf/tacrolimus], and rapamycin [sirolimus]), antimetabolites (eg, mycophenolate mofetil), and thymoglobulin. The incorporation of global CD8 T cell function in this assay is helpful in determining if the lack of CMV-specific (antigen-specific) response is due to a global impairment in CD8 T cell function, due to immunosuppression or other causes, or whether the lack of CMV CD8 T cell immunity is unrelated to overall CD8 T cell function. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon, with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant throughout the day.(8) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(9-11) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(9) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening (12), and during summer compared to winter.(13) These data, therefore, indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Assessing cytomegalovirus (CMV)-specific immune competence in allo-hematopoietic stem cell transplantation patients who are at risk for developing late CMV disease (beyond day 100 after transplant) Assessing CMV-specific immune competence in solid organ transplant patients who are at high risk for CMV reactivation posttransplant Monitoring immune competence in patients post-primary CMV infection after transplant who are at risk for CMV reactivation after the cessation of antiviral prophylaxis Identifying individuals who are likely to be protected from posttransplant CMV infection and those who are at higher risk of CMV reactivation The global CD8 T cell immune competence assay is useful for determining over immunosuppression within the CD8 T cell compartment, when used on transplant recipients and patients with autoimmune disorders receiving therapy with immunosuppressant agents

Interpretation: For allogeneic hematopoietic stem cell transplantation (HSCT) and solid organ transplant patients who are cytomegalovirus (CMV)-seropositive and at risk for CMV reactivation, posttransplant results should be compared to pretransplant (preconditioning/baseline) results. The report includes absolute CD3 and CD8 T-cell counts as well as a derived CMV-specific CD8 T-cell count (derived from CD3 and CD8 T-cell counts). The absolute count of CMV-CD8 T cells that are activated and have cytotoxic function in response to specific CMV peptide is also provided. The data from the 3 components of this assay should be interpreted together and not individually. In the setting of CMV viremia, frequent monitoring of CMV-immune competence helps define the evolution of the CMV-immune response. In this clinical context, CMV-immune competence should be measured as frequently as viral load to determine correlation between the 2 parameters. CMV-specific CD8 T-cell counts may show a decline in numbers over time in the absence of active infection or antigenemia. The absence of CMV-specific CD8 T cells may be a risk factor in the immune-compromised or Current as of August 23, 2017 7:11 am CDT


Page 668

immune-incompetent transplant patient, who is at risk for CMV reactivation. The presence of CMV-specific CD8 T cells may not be protective in itself. If the CMV-specific CD8 T cells do not show appropriate cytotoxic function (due to the fact that they recognize CMV epitopes that do not effectively induce a cytotoxic response), these patients may be at higher risk of an inadequate immune response to CMV infection. While the reference values provide a guideline of CMV-specific CD8 T-cell numbers and function in a cohort of healthy individuals, baseline (pretransplant/preconditioning) assessments should be taken into consideration when determining CMV-specific immune competence posttransplant. Correlation between data from multiple post-transplant specimens (if available) and the presence or absence of viremia (or active CMV disease) also are useful in the interpretation of results. CD8 T cell counts are elevated when the immune system is initially reconstituted post-HSCT, and the CD4 to CD8 ratio can be inverted for about 12 months post-HSCT. Interferon-gamma (IFN-gamma) and CD107a/b expression below the defined reference range are consistent with a global impairment in CD8 T cell function, most likely due to over-immunosuppression. IFN-gamma and CD107a/b levels greater than the defined reference range are unlikely to have any clinical significance.

Reference Values: Total CD3 T cells: 884-5,830 x 10(3)/mL Total CD8 T cells: 168-1,847 x 10(3)/mL Total CMV CD8 T cells: 0-115 x 10(3)/mL The adult reference values were determined for healthy adult controls ages 20 to 80 years (n=94), for HLA A1, A2, B7, B8, and B35 alleles. Reference values for CMV-specific T cells that are functional (interferon-gamma+, IFN-g+) and have cytotoxic activity (CD107a and CD107b expression, CD107 a/b+): Total CMV CD8 T-cells IFN-g: 0.028-52.200 x 10(3)/mL Total CMV CD8 T-cells CD107a/b: 0.252-50.760 x 10(3)/mL The 95% confidence interval reference values were determined from 102 healthy adult donors: Interferon-gamma (IFN-gamma) expression (as % CD8 T cells): 10.3-56.0% CD107a/b expression (as % CD8 T cells): 8.5-49.1% The reference values were developed for each of the following 4 major histocompatibility complex class I alleles: A1, A2, B7, and B8 (n=45). We were unable to develop ranges for the B35 allele due to a lack of matching donors. The data is expressed as the absolute number of CMV-specific CD8 T cells that are IFN-gamma+ or CD107a/b+.

Clinical References: 1. Melnick JL, Adam E, Debakey ME: Cytomegalovirus and atherosclerosis. Eur Heart J 1993;14:30-38 2. von Willebrand E, Petterson E, Ahnonen J, et al: CMV infection, class II antigen expression, and human kidney allograft rejection. Transplantation 1986;42:364-367 3. Hakki M, Riddell SR, Storek J, et al: Immune reconstitution to CMV after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 2003;102:3060-3067 4. Baden LR: Pharmacokinetics of valganciclovir in HSCT patients with gastrointestinal GVHD. Biol Blood Marrow Transplant 2005;15(2):5-7 5. Bachier CR: Prevention of early CMV infection in HSCT. Biol Blood Marrow Transplant 2005;15(2):8-9 6. Boeckh M: Prevention of late CMV infection in HSCT. Biol Blood Marrow Transplant 2005;15(2):9-11 7. Li CR, Greenberg PD, Gilbert MJ, et al: Recovery of HLA-restricted CMV-specific T cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994;83(7):1971-1979 8. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment.15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 9. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009;113:5134-5143 10. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 11. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Pyschosomatic Medicine 1997;59:42-50 12. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 13. Current as of August 23, 2017 7:11 am CDT


Page 669

Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516

FCYTO

Cytomegalovirus (CMV) Genotypic Drug Resistance

58006

Reference Values: Not Detected

FCMIG

Cytomegalovirus (CMV) IgG Avidity (AviDx), ELISA

75226

Clinical Information: Discrimination between recent (primary) and past cytomegalovirus (CMV) infection can be an important tool in the clinical management of transplant recipients and pregnant women. Although nearly all individuals with recent CMV infection are positive for CMV IgM, individuals with past CMV may also express CMV IgM following viral reactivation; thus, detection of CMV IgM is not a reliable indicator of recent CMV infection. Measurement of CMV IgG avidity can assist in discriminating recent from past CMV infection. Although a low avidity index is a reliable indicator of CMV infection within the previous 6 months, a high avidity index is more meaningful from a clinical standpoint; a high avidity index essentially excludes the possibility that infection occurred within the previous 4 months. Avidity index values should be considered within the context of other laboratory findings and clinical signs.

Interpretation: < or = 0.50 Low Avidity Index 0.51 â€“ 0.59 Intermediate Avidity Index > or = 0.60 High Avidity Index

Reference Values: > or = 0.60

LCMV

Cytomegalovirus (CMV), Molecular Detection, PCR

81240

Clinical Information: Infection with cytomegalovirus (CMV) is a significant cause of morbidity and mortality in transplant recipients and other immunocompromised hosts. Specific neurologic syndromes associated with CMV infection include subacute radiculomyelopathy, peripheral neuropathy, and encephalitis. CMV-associated central nervous system (CNS) disease occurs most commonly in immunocompromised patients. Histologic evidence of CMV infections in autopsy brain tissue was identified in 20% to 40% of AIDS patients. In 2 separate studies, CMV (DNA) was the most common herpesvirus (29/181, 16/49) detected from cerebrospinal fluid of patients with AIDS. CNS infections with CMV can also occur in immunocompetent patients. CMV is a leading cause of congenital viral infections worldwide, and laboratory testing by real-time PCR is useful in the diagnosis of neonatal CMV disease.

Useful For: Rapid qualitative detection of cytomegalovirus (CMV) DNA This test is not intended for the monitoring of cytomegalovirus (CMV) disease progression.

Interpretation: Detection of cytomegalovirus (CMV) DNA in a specimen supports the clinical diagnosis of infection due to this virus. Studies indicate that CMV DNA is not detected by PCR in cerebrospinal fluid from patients without central nervous system disease caused by this virus.


Clinical References: 1. Espy M, Binnicker MJ: Comparison of six real-time PCR assays for the qualitative detection of cytomegalovirus in clinical specimens. J Clin Microbiol 2013:51(11):3749-3752 2. Petito CK, Cho ES, Lemann W, et al: Neuropathy of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol 1986 November;45(6):635-646 3. Cinque P, Vago L, Dahl H, et al: Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996 August;10(9):951-958 4. Broccolo F, Iulioano R, Careddu AM, et al: Detection of lymphotropic herpesvirus DNA by polymerase Current as of August 23, 2017 7:11 am CDT


Page 670

chain reaction in cerebrospinal fluid of AIDS patients with neurological disease. Acta Virol 2000 June-August;44(3):137-143 5. Prosch S, Schielke E, Reip A, et al: Human cytomegalovirus (HCMV) encephalitis in an immunocompetent young person and diagnostic reliability of HCMV DNA PCR using cerebrospinal fluid of nonimmunosuppressed patients. J Clin Microbiol 1998 December;36(12):3636-3640 6. Sia IG, Patel R: New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev 2000;13:83-121

CMVQU

Cytomegalovirus DNA Detection and Quantification, Plasma

61861

Clinical Information: Cytomegalovirus (CMV) is a common and major cause of opportunistic infection in organ transplant recipients, causing significant morbidity and mortality. CMV infection and disease typically occur during the first year after organ transplantation after cessation of antiviral prophylaxis. Such infection usually manifests as fever, leukopenia, hepatitis, colitis, or retinitis. Other manifestations of CMV infection in this population may be more subtle and include allograft injury and loss, increased susceptibility to infections with other organisms, and decreased patient survival (ie, indirect effects). The risk of CMV disease is highest among organ recipients who are CMV seronegative prior to transplantation and receive allografts from CMV-seropositive donors (ie, CMV D+/R- mismatch). The infection is transmitted via latent CMV present in the transplanted organ donor and the virus subsequently reactivates, causing a primary CMV infection in the recipient. CMV disease may also occur from reactivation of the virus already present within the recipients. Factors, such as the type of organ transplanted, intensity of the antirejection immunosuppressive therapy, advanced age, and presence of comorbidities in the recipient, are also associated with increased risk for CMV disease after allograft transplantation. Lung, heart, small intestine, pancreas, and kidney-pancreas transplant recipients are at greater risk for CMV infection than kidney and liver transplant recipients. Among the various clinical laboratory diagnostic tests currently available to detect CMV infection, nucleic acid amplification tests (eg, PCR) are the most sensitive and specific detection methods. In addition, quantification of CMV DNA level in peripheral blood (ie, CMV viral load) is used routinely to determine when to initiate preemptive antiviral therapy, diagnose active CMV disease, and monitor response to antiviral therapy. A number of factors can affect CMV viral load results, including the specimen type (whole blood versus plasma), biologic properties of CMV, performance characteristics of the quantitative assay (eg, limit of detection, limits of quantification, linearity, and reproducibility), degree of immunosuppression, and intensity of antiviral therapy. In general, higher CMV viral loads are associated with tissue-invasive disease, while lower levels are associated with asymptomatic infection. However, the viral load in the peripheral blood compartment may be low or not detectable in some cases of tissue invasive disease. Since wide degree of overlap exists in CMV viral load and disease, rise in viral load over time is more important in predicting CMV disease than a single viral load result at a given time point. Therefore, serial monitoring (eg, weekly intervals) of organ transplant recipients with quantitative CMV PCR is recommended in such patients at risk for CMV disease. Since changes in viral load may be delayed by several days in response to antiviral therapy and immunosuppression, viral load should not be monitored more frequently than a weekly basis. Typically, CMV viral load changes of >0.5 log IU/mL are considered biologically significant changes in viral replication. Patients with suppression of CMV replication (ie, viral load of or =2 serial dilutions are considered significant.(3) In patients with very low levels of cANCA, the immunofluorescent staining pattern may mimic the pANCA pattern. In patients with MPA, monitoring of disease activity may be performed by measuring MPO ANCA (MPO / Myeloperoxidase Antibodies, IgG, Serum).

Reference Values: Negative If positive for cANCA, results are titered.

Clinical References: 1. Russell KA, Wiegert E, Schroeder DR, et al: Detection of anti-neutrophil cytoplasmic antibodies under actual clinical testing conditions. Clin Immunol 2002:103;196-203 2. Savige J, Gillis D, Benson E, et al: International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 1999:111;507-513 3. Specks U, Homburger HA, DeRemee RA: Implications of cANCA testing for the classification of Wegenerâ€™s Granulomatosis: performance of different detection systems. Adv Exp Med Biol 1993:336;65-70

DDITT

D-Dimer, Plasma

40936

Clinical Information: The specific degradation of fibrin (ie, fibrinolysis) is the reactive mechanism responding to the formation of fibrin. Plasmin is the fibrinolytic enzyme derived from inactive plasminogen. Plasminogen is converted into plasmin by plasminogen activators. The main plasminogen activators are tissue plasminogen activator (tPA) and pro-urokinase, which is activated into urokinase (UK) by, among others, the contact system of coagulation. In the bloodstream, plasmin is rapidly and specifically neutralized by alpha 2-antiplasmin, thereby restricting its fibrinogenolytic activity and localizes the fibrinolysis on the fibrin clot. On the fibrin clot, plasmin degrades fibrin into various products (ie, D-dimers). Antibodies specific for these products, which do not recognize fibrinogen, have been developed. The presence of these various fibrin degradation products, among which D-dimer is the terminal product, is the proof that the fibrinolytic system is in action in response to coagulation activation. Elevated D-dimer levels are found in association with disseminated intravascular coagulation (DIC), pulmonary embolism (PE), deep vein thrombosis (DVT), trauma, and bleeding. D-dimer may also be increased in association with pregnancy, liver disease, malignancy, inflammation, or a chronic hypercoagulable state.

Useful For: Excluding the diagnosis of acute pulmonary embolism or deep vein thrombosis, particularly when results of a sensitive D-dimer assay are combined with clinical information, including pretest disease probability(1-4) Diagnosis of intravascular coagulation and fibrinolysis, also known as disseminated intravascular coagulation, especially when combined with clinical information and other laboratory test data (eg, platelet count, assays of clottable fibrinogen and soluble fibrin monomer complex, and clotting time assays-prothrombin time and activated partial thromboplastin time)(5)

Interpretation: A normal D-dimer result less than or equal to 500 ng/mL fibrinogen equivalent units (FEU) on the IL D-Dimer HS500 kit has a negative predictive value of approximately 100% (range 97%-100%) and is FDA approved for the exclusion of acute pulmonary embolism (PE) and deep vein thrombosis (DVT) when there is low or moderate pretest probability for PE or DVT. D-dimer concentrations increase with age and, thus, the specificity for DVT and PE exclusion decreases with age. For DVT or PE exclusion, in addition to clinical pretest probability, age-adjusted D-dimer cutoffs are suggested for patients more than 50 years of age. Recent evidence suggests using clinical pretest probability and age-adjusted cutoffs to improve the performance of D-dimer testing in patients greater than 50 years of age. In recent studies, when compared to a fixed D-dimer cutoff, age adjusted D-dimer cutoff values (calculated as follows: age [years] x 10 ng/mL) resulted in equivalent outcomes and no additional false negative findings.(7-8) Increased D-dimer values are abnormal but do not indicate a Current as of August 23, 2017 7:11 am CDT


Page 673

specific disease state. D-dimer values may be increased as a result of: -Clinical or subclinical disseminated intravascular coagulation/intravascular coagulation and fibrinolysis -Other conditions associated with increased activation of the procoagulant and fibrinolytic mechanisms such as recent surgery, active or recent bleeding, hematomas, trauma, or thromboembolism -Association with pregnancy, liver disease, inflammation, malignancy, or hypercoagulable (procoagulant) states The degree of D-dimer increase does not definitely correlate with the clinical severity of associated disease states.

Reference Values: < or =500 ng/mL Fibrinogen Equivalent Units (FEU) D-dimer values < or =500 ng/mL FEU may be used in conjunction with clinical pretest probability to exclude deep vein thrombosis (DVT) and pulmonary embolism (PE).

Clinical References: 1. Brill-Edward P, Lee A: D-dimer testing in the diagnosis of acute venous thromboembolism. Thromb Haemost 1999 August;82(2):688-694 2. Heit JA, Minor TA, Andrews JC, et al: Determinants of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med 1999 March;123(3):235-240 3. Heit JA, Meyers BJ, Plumhoff EA, et al: Operating characteristics of automated latex immunoassay tests in the diagnosis of angiographically-defined acute pulmonary embolism. Thromb Haemost 2000 June;83(6):970 4. Bates SM, Grand'Maison A, Johnston M, et al: A latex D-dimer reliably excludes venous thromboembolism. Arch Intern Med 2001 February;161(3):447-453 5. Levi M, ten Cate H: Disseminated intravascular coagulation. N Engl J Med 1999 August;341(8):586-592 6. Feinstein DI, Marder VJ, Colman RW: Consumptive thrombohemorrhagic disorders. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Third edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, PA, JB Lippincott Co., 2001, pp 1197-1234 7. Righini M, Van Es J, Den Exter PL, et al: Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135 8. Schouten HJ, Geersing GJ, Koek HL, et al: Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ 2013;346:f2492

DLAC

D-Lactate, Plasma

8878

Clinical Information: D-lactate is produced by bacteria residing in the colon when carbohydrates are not completely absorbed in the small intestine. When large amounts of D-lactate are present, individuals can experience metabolic acidosis, altered mental status (from drowsiness to coma), and a variety of other neurologic symptoms, particularly dysarthria and ataxia. D-lactic acidosis is typically observed in patients with a malabsorptive disorder, such as short-bowel syndrome, or, following a jejunoileal bypass. In addition, healthy children presenting with gastroenteritis may also develop the critical presentation of D-lactic acidosis. Routine lactic acid determinations in blood will not reveal abnormalities because most lactic acid assays measure only L-lactate. Accordingly, D-lactate analysis must be specifically requested (eg, DLAC / D-Lactate, Plasma). However, as D-lactate is readily excreted in urine, DLAU / D-Lactate, Urine is the preferred specimen for D-lactate determinations.

Useful For: An adjunct to urine D-lactate (preferred), in the diagnosis of D-lactate acidosis Interpretation: Increased levels are consistent with D-lactic acidosis. However, because D-lactate is readily excreted, urine determinations are preferred.

Reference Values: 0.0-0.25 mmol/L

Clinical References: 1. Brandt RB, Siegel SA, Waters MG, Bloch MH: Spectrophotometric assay for D-(-)-lactate in plasma. Anal Biochem1980;102(1):39-46 2. Petersen C: D-lactic acidosis. Nutr Clin Pract 2005;20(6):634-645

DLAU

D-Lactate, Urine

8873

Clinical Information: D-lactate is produced by bacteria residing in the colon when carbohydrates are



Page 674

not completely absorbed in the small intestine. When large amounts are absorbed it can cause metabolic acidosis, altered mental status (from drowsiness to coma) and a variety of other neurologic symptoms, in particular dysarthria and ataxia. Although a temporal relationship has been described between elevations of plasma and urine D-lactate and the accompanying encephalopathy, the mechanism of neurologic manifestations has not been elucidated. D-lactic acidosis is typically observed in patients with short-bowel syndrome and following jejunoileal bypass resulting in carbohydrate malabsorption. In addition, healthy children presenting with gastroenteritis may also develop the critical presentation of D-lactic acidosis. Routine lactic acid determinations in blood will not reveal abnormalities because most lactic acid assays measure only L-lactate. Accordingly, D-lactate analysis must be specifically requested (eg, DLAC / D-Lactate, Plasma). However, as D-lactate is readily excreted in urine, this is the preferred specimen for D-lactate determinations.

Useful For: Preferred test for diagnosing D-lactate acidosis, especially in patients with jejunoileal bypass and short-bowel syndrome

Interpretation: Increased levels are diagnostic. Reference Values: 0.0-0.25 mmol/L

Clinical References: 1. Brandt RB, Siegel SA, Waters MG, Bloch MH: Spectrophotometric assay for D-(-)-lactate in plasma. Anal Biochem 1980;102(1):39-46 2. Petersen C: D-lactic acidosis. Nutr Clin Pract 2005 Dec;20(6):634-645

DAGR

Dairy and Grain Allergen Profile

31768


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens responsible for anaphylaxis, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens.

Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4




Page 675

5


6



DAND

Dandelion, IgE

82694





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FDANT

Dantrolene, Serum/Plasma



Page 676

Reference Values: Reporting limit determined each analysis Synonym(s): Dantrium Usual therapeutic range: 0.2 - 3.5 mcg/mL

DATE

Date, Fruit, IgE

82358





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



DATRE

Date, Tree, IgE

82481

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE



Page 677

antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



DEEP

Deer Epithelium, IgE

82144


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of Current as of August 23, 2017 7:11 am CDT


Page 678

allergic reactions to insect venom allergens, drugs, or chemical allergens.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



DHEA_

Dehydroepiandrosterone (DHEA), Serum

81405

Clinical Information: Dehydroepiandrosterone (DHEA) is the principal human C-19 steroid. DHEA has very low androgenic potency, but serves as the major direct or indirect precursor for most sex steroids. DHEA is secreted by the adrenal gland and production is at least partly controlled by adrenocorticotropic hormone (ACTH). The bulk of DHEA is secreted as a 3-sulfoconjugate dehydroepiandrosterone sulfate (DHEAS). Both hormones are albumin bound, but DHEAS binding is much tighter. As a result, circulating concentrations of DHEAS are much higher (>100-fold) compared to DHEA. In most clinical situations, DHEA and DHEAS results can be used interchangeably. In gonads and several other tissues, most notably skin, steroid sulfatases can convert DHEAS back to DHEA, which can then be metabolized to stronger androgens and to estrogens. During pregnancy, DHEA/DHEAS and their 16-hydroxylated metabolites are secreted by the fetal adrenal gland in large quantities. They serve as precursors for placental production of the dominant pregnancy estrogen, estriol. Within weeks after birth, DHEA/DHEAS levels fall by 80% or more and remain low until the onset of adrenarche at age 7 or 8 in girls and age 8 or 9 in boys. Adrenarche is a poorly understood phenomenon, peculiar to higher primates, that is characterized by a gradual rise in adrenal androgen production. It precedes puberty, but is not casually linked to it. Early adrenarche is not associated with early puberty or with any reduction in final height or overt androgenization. However, girls with early adrenarche may be at increased risk of polycystic ovarian syndrome as adults and some boys may develop early penile enlargement. Following adrenarche, DHEA/DHEAS levels increase until the age of 20 to a maximum roughly comparable to that observed at birth. Levels then decline over the next 40 to 60 years to around 20% of peak levels. The clinical significance of this age-related drop is unknown and trials of DHEA/DHEAS replacement in the elderly have not produced convincing benefits. However, in young and old patients with primary adrenal failure, the addition of DHEA/DHEAS to corticosteroid replacement has been shown in some studies to improve mood, energy, and sex drive. Elevated DHEA/DHEAS levels can cause symptoms or signs of hyperandrogenism in women. Men are usually asymptomatic, but through peripheral conversion of androgens to estrogens can occasionally experience mild estrogen excess. Most mild-to-moderate elevations in DHEAS levels are idiopathic. However, pronounced elevations of DHEA/DHEAS may be indicative of androgen-producing adrenal tumors. In small children, congenital adrenal hyperplasia (CAH) due to 3 beta-hydroxysteroid dehydrogenase deficiency is associated with excessive DHEA/DHEAS production. Lesser elevations may be observed in 21-hydroxylase deficiency (the most common form of



Page 679

CAH) and 11 beta-hydroxylase deficiency. By contrast, steroidogenic acute regulatory protein (STAR) or 17 alpha-hydroxylase deficiency is characterized by low DHEA/DHEAS levels. See Steroid Pathways in Special Instructions.

Useful For: Diagnosing and differential diagnosis of hyperandrogenism (in conjunction with measurements of other sex steroids) An initial screen in adults might include dehydroepiandrosterone (DHEA)/dehydroepiandrosterone sulfate (DHEAS) and bioavailable testosterone measurement. Depending on results, this may be supplemented with measurements of sex hormone-binding globulin and occasionally other androgenic steroids (eg, 17-hydroxyprogesterone). An adjunct in the diagnosis of congenital adrenal hyperplasia (CAH); DHEA/DHEAS measurements play a secondary role to the measurements of cortisol/cortisone, 17 alpha-hydroxyprogesterone, and androstenedione. Diagnosing and differential diagnosis of premature adrenarche

Interpretation: Elevated dehydroepiandrosterone (DHEA)/dehydroepiandrosterone sulfate (DHEAS) levels indicate increased adrenal androgen production. Mild elevations in adults are usually idiopathic, but levels >5-fold or more of the upper limit of normal can suggest the presence of an androgen-secreting adrenal tumor. DHEA/DHEAS levels are elevated in >90% of patients with such tumors. This is particularly true for androgen-secreting adrenal carcinomas, as they have typically lost the ability to produce downstream androgens, such as testosterone. By contrast, androgen-secreting adrenal adenomas may also produce excess testosterone and secrete lesser amounts of DHEA/DHEAS. Patients with congenital adrenal hyperplasia (CAH) may show very high levels of DHEA/DHEAS, often 5-fold to 10-fold elevations. However, with the possible exception of 3 beta-hydroxysteroid dehydrogenase deficiency, other steroid analytes offer better diagnostic accuracy than DHEA/DHEAS measurements. Consequently, DHEA/DHEAS testing should not be used as the primary tool for CAH diagnosis. Similarly, discovering a high DHEA/DHEAS level in an infant or child with symptoms or signs of possible CAH should prompt additional testing, as should the discovery of very high DHEA/DHEAS levels in an adult. In the latter case, adrenal tumors need to be excluded and additional adrenal steroid profile testing may assist in diagnosing nonclassical CAH. See Steroid Pathways in Special Instructions.

Reference Values: Premature: or =16 years: 0.4-0.9 ng/mL Toxic concentration: > or =3.0 ng/ mL

Clinical References: 1. Jortani SA, Pinar A, Johnson NA, Valdes R Jr: Validity of unbound digoxin measurements by immunoassays in presence of antidote (Digibind). Clin Chim Acta 1999;283:159-169 2. Package insert: DIGIBIND Digoxin Immune FAB (Ovine). GlaxoSmithKline, Research Triangle Park NC, 2003 3. Applied Therapeutic Drug Monitoring. Vol 2. Edited by TP Moyer, RL Boeckx. Washington DC, American Association for Clinical Chemistry, 1984 4. Jortani SA, Voldes R Jr: Digoxin and its related endogenous factors. Crit Rev Clin Lab Sci 1997;34:225-274 5. Datta P, Hinz V, Klee G: Comparison four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors. Clin Biochem 1996;29(6):541-547 6. Soldin SJ: Free drug measurements. When and why? An overview. Arch Pathol Lab Med 1999;123:822-823 7. Dickstein K, Cohen-Solal A, Filippatos G, et al: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur Heart J 2008;29:2388-2442

DIG

Digoxin, Serum

8674

Clinical Information: Compounds in the digitalis family of glycosides consist of a steroid nucleus, a lactone ring, and a sugar. Digoxin is widely prescribed for the treatment of congestive heart failure and various disturbances of cardiac rhythm. Digoxin improves the strength of myocardial contraction and results in the beneficial effects of increased cardiac output, decreased heart size, decreased venous pressure, and decreased blood volume. Digoxin therapy also results in stabilized and slowed ventricular pulse rate. These therapeutic effects are produced through a network of direct and indirect interactions upon the myocardium, blood vessels, and the autonomic nervous system. Digoxin is well absorbed after oral administration and is widely distributed to tissues, especially the heart, kidney, and liver. A number of factors can alter normal absorption, distribution, and bioavailability of the drug, including naturally occurring enteric bacteria in the bowel, presence of food in the gut, strenuous physical activity, ingestion of quinine or quinidine, and concomitant use of a wide range of drugs. Children generally require higher concentrations of digoxin. After oral administration, there is an early rise in serum concentration. Equilibration of serum and tissue levels occurs at approximately 6 to 8 hours. For this reason, blood



Page 698

specimens for digoxin analysis should be drawn at least 6 to 8 hours after drug administration. Digoxin is excreted primarily in the urine. The average elimination half-life is 36 to 40 hours, but may be considerably prolonged in those with renal disease, causing digoxin accumulation and toxicity. Symptoms of digoxin toxicity often mimic the cardiac arrhythmia's for which the drug was originally prescribed (eg, heart block and heart failure). Other typical symptoms of toxicity include gastrointestinal effects, including anorexia, nausea, vomiting, abdominal pain and diarrhea, and neuropsychologic symptoms, such as fatigue, malaise, dizziness, clouded or blurred vision, visual and auditory hallucination, paranoid ideation, and depression. Toxicity of digoxin may reflect several factors: the drug has a narrow therapeutic window (a very small difference exists between therapeutic and toxic tissue levels); individuals vary in their ability to metabolize and respond to digoxin; absorption of various oral forms of digoxin may vary over a 2-fold range; susceptibility to digitalis toxicity apparently increases with age.

Useful For: Monitoring digoxin therapy Interpretation: The therapeutic range is 0.6 to 1.2 ng/mL. Levels of 4.0 ng/mL and above may be potentially life-threatening.

Reference Values: or =4.0 ng/mL > =16 years 0.6-1.2 ng/mL Toxic concentration: > or =4.0 ng/mL

Clinical References: 1. Datta P, Hinz V, Klee G: Comparison four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors. Clin Biochem 1996;29(6):541-547 2. Applied Therapeutic Drug Monitoring. Vol 2. Edited by TP Moyer, RL Boeckx. Washington, DC, American Association for Clinical Chemistry, 1984 3. Jortani SA, Voldew R Jr: Digoxin and its related endogenous factors. Crit Rev Clin Lab Sci 1997;34:225-274 4. Dickstein K, Cohen-Solal A, Filippatos G, et al: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur Heart J 2008;29:2388-2442

DPYDG 65213

Dihydropyrimidine Dehydrogenase (DPYD) Full Gene Sequencing Clinical Information: 5-Fluorouracil (5-FU) and its orally administered prodrug, capecitabine, are fluoropyrimidine-based chemotherapeutic agents that are widely used for the treatment of colorectal cancer and other solid tumors. The dihydropyrimidine dehydrogenase (DPYD) gene encodes the rate-limiting enzyme for fluoropyrimidine catabolism and eliminates over 80% of administered 5-FU. Dihydropyrimidine dehydrogenase (DPYD) activity is subject to wide variability, mainly due to genetic variation (table 1). This results in a broad range of enzymatic deficiency from partial (3%-5% of population) to complete loss (0.2% of population) of enzyme activity.(2,3) Patients who are deficient in DPYD are at an increased risk for side effects and toxicity when undergoing 5-FU treatment.(4) In addition, pathogenic homozygous or compound heterozygous variants within DPYD are associated with dihydropyrimidine dehydrogenase (DPD) deficiency. DPD deficiency shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation. Table 1. Known Genetic Variations Associated with Fluoropyrimidine Treatment Gene cDNA numbering Alternative Name Enzyme Activity Phenotypeâ—• DPYD No Variations Identified *1 c.1905+1G>A *2A No activity or significantly reduced activity High risk for fluoropyrimidine toxicity c.1679T>G *13 c.1898delC *3 c.299_302delTCAT *7 c.1156G>T *12 c.2846A>T rs67376798 Reduced activity Increased risk for fluoropyrimidine toxicity c.1129-5923C>G rs75017182 c.703C>T *8 Probable reduced function Increased risk for fluoropyrimidine toxicity c.2983G>T *10 c.1003G>T *11 c.557A>G rs115232898 c.1601C>T *4 Normal activity** Normal risk for fluoropyrimidine toxicity c.1627A>G *5



Page 699

c.2194C>T *6 c.85T>C *9A *Other or novel variations, besides those listed here, may also impact fluoropyrimidine-related side effects and tumor response and will be reported if detected. **Alleles that are categorized as having normal enzyme activity (eg, *4, *5, *6, *9A) will not be reported if detected because variants with normal enzyme activity are not expected to impact fluoropyrimidine-related side effects and tumor response. The DPYD gene is located on chromosome 1 and contains 2 transcripts. The longer transcript (NM_000110.3) contains 23 exons, and the shorter transcript (NM_001160301.1) contains 6 exons, with exon 6 being unique to this transcript. All exons from the longer transcript (NM_000110.3) and exon-intron boundaries are assessed. Genetic variations involved in the metabolic pathway of fluoropyrimidines have been shown to contribute to the differences in clinical outcomes including toxicity and tumor response.

Useful For: Identifying individuals at increased risk of toxicity when considering 5-fluorouracil (5-FU) and capecitabine chemotherapy treatment For an individual with suspected dihydropyrimidine dehydrogenase (DPD) deficiency, this test may be useful in identifying variants associated with decreased or absent DPD enzyme activity

Interpretation: Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics recommendations as a guideline.(5) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Online Mendelian Inheritance in Man: Dihydropyrimidine dehydrogenase deficiency. #274270. Updated 4/18/2012. Available from http://omim.org/ 2. Caudle KE, Thorn CF, Klein TE, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2013;94(6):640-645 3. Morel A, Boisdron-Celle M, Fey L, et al: Clinical relevance of different dihyropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006 Nov;5(11):2895-2904 4. FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. Available at: http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm 5. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424 6. Offer SM, Fossum CC, Wegner NJ, et al: Comparative functional analysis of DPYD variants of potential clinical relevance to dihydropyrimidine dehydrogenase activity. Cancer Res 2014;74(9):2545-2554

DHRF 62766

Dihydrorhodamine (DHR) Flow Cytometric N-Formyl-Methionyl-Leucyl-Phenylalanine (fMLP) Test, Blood Clinical Information: This assay can be used for the diagnostic evaluation of Rac2 deficiency, which is a neutrophil defect that causes profound neutrophil dysfunction with decreased chemotaxis, polarization, superoxide anion production, azurophilic granule secretion. This disease is caused by inhibitory mutations in the RAC2 gene, which encodes a Rho family GTPase essential to neutrophil activation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function.(1) Patients with Rac2 deficiency have been shown to have normal neutrophil oxidative burst when stimulated with phorbol myristate acetate (PMA), indicating normal NADPH oxidase activity, but abnormal neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP), which is a physiological activator of neutrophils. The defective oxidative burst to fMLP, but not to PMA, indicates a signaling defect in Rac2 deficiency.(2)

Useful For: Diagnosis of Rac2 deficiency Interpretation: An interpretive report will be provided, in addition to the quantitative values described Current as of August 23, 2017 7:11 am CDT


Page 700

in Clinical Information. Interpretation of the results of the quantitative dihydrorhodamine (DHR) flow cytometric assay has to include both the proportion of positive neutrophils for DHR after N-formyl-methionyl-leucyl-phenylalanine stimulation, and the mean fluorescence intensity.

Reference Values: Result Name

Unit

Cutoff for defining normal

% fMLP ox-DHR+

%

> or =10%

MFI fMLP ox-DHR+

MFI

> or =2

Control % fMLP ox-DHR+

%

> or =10%

Control MFI fMLP ox-DHR+

MFI

> or =2 The appropriate age-related reference values for Absolute Neutrophil Count will be provided on the report.

Clinical References: 1. Ambruso DR, Knall C, Abell AN, et al: Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 2000;97:4654-4659 2. Accetta D, Syverson G, Bonacci B, et al: Human phagocyte defect caused by a RAC2 mutation detected by means of neonatal screening for T cell lymphopenia. J Allergy Clin Immunol 2011;127:535-538

DHRP 62765

Dihydrorhodamine (DHR) Flow Cytometric Phorbol Myristate Acetate (PMA) Test, Blood Clinical Information: Chronic granulomatous disease (CGD) is caused by genetic defects in the gene components that encode the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex. These defects result in an inability to produce superoxide anions required for killing of bacterial and fungal organisms. Other clinical features include a predisposition to systemic granulomatous complications and autoimmunity.(1) There are 5 known genetic defects associated with the clinical phenotype of CGD.(2) The gene defects include mutations in the CYBB gene, encoding the gp91phox protein, which is X-linked and accounts for approximately 70% of CGD cases. Other gene defects are autosomal recessive: NCF1 (p47phox), NCF2 (p67phox), CYBA (p22phox), and NCF4 (p40phox). Typically, patients with X-linked CGD have the most severe disease, while patients with p47phox defects tend to have the best outcomes. Mutations in NCF4 encoding the p40phox protein has been the most recently described(3) and appears to be associated with more gastrointestinal disease with fewer infections. There is significant clinical variability even among individuals with similar mutations, in terms of NADPH oxidase function, indicating that there can be several modulating factors including the genetic defect, infection history, and granulomatous and autoimmune complications. There appears to be a correlation between very low NADPH superoxide production and worse outcomes. CGD can be treated with hematopoietic cell transplantation (HCT), which can be effective for the inflammatory and autoimmune manifestations. It has been shown that survival of patients with CGD was strongly associated with residual reactive oxygen intermediate (ROI) production, independent of the specific gene defect.(4) Measurement of NADPH oxidase activity through the dihydrorhodamine (DHR) flow cytometry assay contributed to the assessment of ROI. The diagnostic laboratory assessment for CGD includes evaluation of NADPH oxidase function in neutrophils, using either the nitroblue tetrazolium test (NBT) or the more analytically sensitive DHR test, as described here. Activation of neutrophils with phorbol myristate acetate (PMA) results in oxidation of DHR to a fluorescent compound, rhodamine 123, which can be measured by flow cytometry. Flow cytometry can distinguish between the different genetic forms of CGD.(5, 6) Complete myeloperoxidase (MPO) deficiency can cause a false-positive result for CGD in the DHR flow cytometric assay (7); however, there is a difference between the percent DHR+ neutrophils and the mean fluorescence intensity (MFI) after PMA stimulation that allows discrimination between true X-linked CGD and complete MPO deficiency. Further, the addition of recombinant human MPO enhances the DHR signal in MPO-deficient neutrophils but not in CGD neutrophils.(7) It is important to have quantitative measures in the DHR flow cytometry assay to effectively use the test for diagnosis of the different forms of CGD as well as for monitoring chimerism and NADPH oxidase activity post-HCT. These quantitative measures include assessment of the relative proportion (%) of neutrophils that are



Page 701

positive for DHR fluorescence after PMA stimulation and the relative fluorescence intensity of DHR (MFI) on neutrophils after activation. Female carriers of X-linked CGD can become symptomatic for CGD due to skewed lyonization (X chromosome inactivation).(8) Age-related acquired skewing of lyonization can also cause increased susceptibility to infections in carriers of X-linked CGD.(9) While germline mutations are more common in CGD, there have been reports of de novo, sporadic mutations in the CYBB gene, causing X-linked CGD in male patients whose mothers are not carriers for the affected allele. Additionally, somatic mosaicism has been reported in patients with X-linked CGD who have small populations of normal cells.(10) There are also reports of triple somatic mosaicism in female carriers (11,12) as well as late-onset disease in an adult female who was a somatic mosaic for a novel mutation in the CYBB gene.(13) Therefore, the clinical, genetic, and age spectrum of CGD is varied and laboratory assessment of NADPH oxidase activity after neutrophil stimulation, coupled with appropriate interpretation, is critical to achieving an accurate diagnosis or for monitoring patients posttransplant.

Useful For: Diagnosis of chronic granulomatous disease (CGD), X-linked and autosomal recessive forms, complete myeloperoxidase (MPO) deficiency; monitoring chimerism and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function posthematopoietic cell transplantation Assessing residual NADPH oxidase activity pretransplant Identification of carrier females for X-linked CGD; assessment of changes in lyonization with age in carrier females

Interpretation: An interpretive report will be provided, in addition to the quantitative values described in Clinical Information. Interpretation of the results of the quantitative dihydrorhodamine (DHR) flow cytometric assay has to include both the proportion of positive neutrophils for DHR after phorbol myristate acetate stimulation, and the mean fluorescence intensity. Additionally, visual assessment of the pattern of DHR fluorescence is helpful in discriminating between the various genetic defects associated with chronic granulomatous disease and complete myeloperoxidase deficiency.


Unit

Cutoff for defining normal

% PMA ox-DHR+

%

> or =95%

MFI PMA ox-DHR+

MFI

> or =60

Control % PMA ox-DHR+

%

> or =95%

Control MFI PMA ox-DHR+

MFI


Clinical References: 1. Kang EM, Marciano BE, DeRavin SS, et al: Chronic granulomatous disease: overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol 2011;127:1319-1326 2. Segal BH, DeCarlo ES, Kwon-Chung KJ, et al: Aspergillus nidulans infection in chronic granulomatous disease. Medicine 1998;77:345-354 3. Matute JD, Arias AA, Wright NA, et al: A new genetic subgroup of CGD with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood 2009;114:3309-3315 4. Kuhns DB, Alvord WG, Heller T, et al: Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med 2010;363:2600-2610 5. Vowells SJ, Fleisher TA, Sekhsaria S, et al: Genotype-dependent variability in flow cytometric evaluation of reduced NADPH oxidase function in patients with CGD. J Pediatr 1996;128:104-107 6. Vowells SJ, Sekhsaria S, Malech H, et al: Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol Methods 1995;178:89-97 7. Mauch L, Lun A, Oâ€™Gorman MRG, et al: CGD and complete MPO deficiency both yield strongly reduced DHR 123 test signals but can be easily discerned in routine testing for CGD. Clin Chem 2007;53:890-896 8. Roesler J: Carriers of X-linked CGD at risk. Clin Immunol 2009;130:233 9. Rosen-Wolff A, Soldan W, Heyne K, et al: Increased susceptibility of a carrier of X-linked CGD to Aspergillus fumigatus infection associated with age-related skewing of lyonization. Ann Hematol 2001;80:113-115 10. Yamada M, Okura Y, Suzuki Y, et al: Somatic mosaicism in two unrelated patients with X-linked CGD characterized by the presence of a small population of normal cells. Gene 2012;497:110-115 11. de Boer M, Bakker E, Van Lierde S, et al: Somatic triple mosaicism in a carrier of X-linked CGD. Blood 1998;91:252-257 12. Noack D, Heyworth PG, Kyono W, et al: A second case of somatic triple mosaicism in the CYBB gene causing CGD. Hum Genet 2001;109:234-238 13. Wolach B, Scharf Y, Gavrieli R, et al: Unusual late presentation of X-linked CGD Current as of August 23, 2017 7:11 am CDT


Page 702

in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood 2005;105:61-66

DHR

Dihydrorhodamine (DHR) Flow Cytometric Test, Blood

62764

Clinical Information: Chronic granulomatous disease (CGD) is caused by genetic defects in the gene components that encode the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex. These defects result in an inability to produce superoxide anions required for killing bacterial and fungal organisms. Other clinical features include a predisposition to systemic granulomatous complications and autoimmunity.(1) There are 5 known genetic defects associated with the clinical phenotype of CGD.(2) The gene defects include mutations in the CYBB gene, encoding the gp91phox protein, which is X-linked and accounts for approximately 70% of CGD cases. Other gene defects are autosomal recessive: NCF1 (p47phox), NCF2 (p67phox), CYBA (p22phox), and NCF4 (p40phox). Typically, patients with X-linked CGD have the most severe disease, while patients with p47phox defects tend to have the best outcomes. Mutations in NCF4 encoding the p40phox protein have been the most recently described(3) and appears to be associated with more gastrointestinal disease with fewer infections. There is significant clinical variability even among individuals with similar mutations, in terms of NADPH oxidase function, indicating that there can be several modulating factors including the genetic defect, infection history, and granulomatous and autoimmune complications. There appears to be a correlation between very low NADPH superoxide production and worse outcomes. CGD can be treated with hematopoietic cell transplantation (HCT), which can be effective for the inflammatory and autoimmune manifestations. It has been shown that survival of patients with CGD was strongly associated with residual reactive oxygen intermediate (ROI) production, independent of the specific gene defect.(4) Measurement of NADPH oxidase activity through the dihydrorhodamine (DHR) flow cytometry assay contributed to the assessment of ROI. The diagnostic laboratory assessment for CGD includes evaluation of NADPH oxidase function in neutrophils, using either the nitroblue tetrazolium test (NBT) or the more analytically sensitive DHR test, as described here. Activation of neutrophils with phorbol myristate acetate (PMA) results in oxidation of DHR to a fluorescent compound, rhodamine 123, which can be measured by flow cytometry. Flow cytometry can distinguish between the different genetic forms of CGD.(5, 6) Complete myeloperoxidase (MPO) deficiency can cause a false-positive result for CGD in the DHR flow cytometric assay (7); however, there is a difference between the percent DHR+ neutrophils and the mean fluorescence intensity (MFI) after PMA stimulation that allows discrimination between true X-linked CGD and complete MPO deficiency. Further, the addition of recombinant human MPO enhances the DHR signal in MPO-deficient neutrophils but not in CGD neutrophils.(7) It is important to have quantitative measures in the DHR flow cytometry assay to effectively use the test for diagnosis of the different forms of CGD as well as for monitoring chimerism and NADPH oxidase activity post-HCT. These quantitative measures include assessment of the relative proportion (%) of neutrophils that are positive for DHR fluorescence after PMA stimulation and the relative fluorescence intensity of DHR (MFI) on neutrophils after activation. This assay can also be used for the diagnostic evaluation of Rac2 deficiency, which is a neutrophil defect that causes profound neutrophil dysfunction with decreased chemotaxis, polarization, superoxide anion production, azurophilic granule secretion. This disease is caused by inhibitory mutations in the RAC2 gene, which encodes a Rho family GTPase essential to neutrophil activation and NADPH oxidase function.(8) Patients with Rac2 deficiency have been shown to have normal neutrophil oxidative burst when stimulated with PMA, indicating normal NADPH oxidase activity, but abnormal neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine (fMLP), which is a physiological activator of neutrophils. The defective oxidative burst to fMLP, but not to PMA, indicates a signaling defect in Rac2 deficiency.(9) Female carriers of X-linked CGD can become symptomatic for CGD due to skewed lyonization (X chromosome inactivation).(10) Age-related acquired skewing of lyonization can also cause increased susceptibility to infections in carriers of X-linked CGD.(11) While germline mutations are more common in CGD, there have been reports of de novo, sporadic mutations in the CYBB gene, causing X-linked CGD in male patients whose mothers are not carriers for the affected allele. Additionally, somatic mosaicism has been reported in patients with X-linked CGD who have small populations of normal cells.(12) There are also reports of triple somatic mosaicism in female carriers (13,14) as well as late-onset disease in an adult female who was a somatic mosaic for a novel mutation in the CYBB gene.(15) Therefore, the clinical, genetic, and age spectrum of CGD is varied and laboratory assessment of NADPH oxidase activity after neutrophil stimulation, coupled with appropriate interpretation, is critical to achieving an accurate diagnosis or for monitoring



Page 703

patients posttransplant.

Useful For: Diagnosis of chronic granulomatous disease (CGD), X-linked and autosomal recessive forms, Rac2 deficiency, complete myeloperoxidase (MPO) deficiency; monitoring chimerism and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function posthematopoietic cell transplantation Assessing residual NADPH oxidase activity pretransplant Identification of carrier females for X-linked CGD; assessment of changes in lyonization with age in carrier females

Interpretation: An interpretive report will be provided, in addition to the quantitative values. Interpretation of the results of the quantitative dihydrorhodamine (DHR) flow cytometric assay has to include both the proportion of positive neutrophils for DHR after phorbol myristate acetate (PMA) and/or N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation, and the mean fluorescence intensity (MFI). Additionally, visual assessment of the pattern of DHR fluorescence is helpful in discriminating between the various genetic defects associated with chronic granulomatous disease (CGD) and complete myeloperoxidase (MPO) deficiency.


Unit

Cutoff for Defining Normal

% PMA ox-DHR+

%

> or =95%

MFI PMA ox-DHR+

MFI

> or =60

% fMLP ox-DHR+

%

> or =10%

MFI fMLP ox-DHR+

MFI

> or =2

Control % PMA ox-DHR+

%

> or =95%

Control MFI PMA ox-DHR+

MFI

> or =60

Control % fMLP ox-DHR+

%

> or =10%

Control MFI fMLP ox-DHR+

MFI


Clinical References: 1. Kang EM, Marciano BE, DeRavin SS, et al: Chronic Granulomatous Disease: Overview and hematopoietic stem cell transplantation. J Allergy Clin Immunol 2011;127:1319-1326 2. Segal BH, DeCarlo ES, Kwon-Chung KJ, et al: Aspergillus nidulans infection in chronic granulomatous disease. Medicine 1998;77:345-354 3. Matute JD, Arias AA, Wright NA, et al: A new genetic subgroup of CGD with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood 2009;114:3309-3315 4. Kuhns DB, Alvord WG, Heller T, et al: Residual NADPH oxidase and survival in Chronic Granulomatous Disease. N Engl J Med 2010;363:2600-2610 5. Vowells SJ, Fleisher TA, Sekhsaria S, et al: Genotype-dependent variability in flow cytometric evaluation of reduced NADPH oxidase function in patients with CGD. J Pediatr 1996;128:104-107 6. Vowells SJ, Sekhsaria S, Malech H, et al: Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes. J Immunol Methods 1995;178:89-97 7. Mauch L, Lun A, Oâ€™Gorman MRG, et al: CGD and complete MPO deficiency both yield strongly reduced DHR 123 test signals but can be easily discerned in routine testing for CGD. Clin Chem 2007;53:890-896 8. Ambruso DR, Knall C, Abell AN, et al: Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 2000;97:4654-4659 9. Accetta D, Syverson G, Bonacci B, et al: Human phagocyte defect caused by a RAC2 mutation detected by means of neonatal screening for T cell lymphopenia. J Allergy Clin Immunol 2011;127:535-538 10. Roesler J: Carriers of X-linked CGD at risk. Clin Immunol 2009;130:233 11. Rosen-Wolff A, Soldan W, Heyne K, et al: Increased susceptibility of a carrier of X-linked CGD to Aspergillus fumigatus infection associated with age-related skewing of lyonization. Ann Hematol 2001:80:113-115 12. Yamada M, Okura Y, Suzuki Y, et al: Somatic mosaicism in two unrelated patients with X-linked CGD characterized by the presence of a small population of normal cells. Gene 2012:497:110-115 13. de Boer M, Bakker E, Van Lierde S, et al: Somatic triple mosaicism in a carrier of X-linked CGD. Blood 1998;91:252-257 14. Noack D, Heyworth PG, Kyono W, et al: A second case of somatic triple mosaicism in the CYBB gene causing CGD. Hum Genet 2001;109:234-238 15. Wolach B, Current as of August 23, 2017 7:11 am CDT


Page 704

Scharf Y, Gavrieli R, et al: Unusual late presentation of X-linked CGD in an adult female with a somatic mosaic for a novel mutation in CYBB. Blood 2005;105:61-66

DHTS

Dihydrotestosterone, Serum

81479

Clinical Information: The principal prostatic androgen is dihydrotestosterone (DHT). Levels of DHT remain normal with aging, despite a decrease in the plasma testosterone, and are not elevated in benign prostatic hyperplasia (BPH).(1) DHT is generated by reduction of testosterone by 5 alpha-reductase. Two isoenzymes of 5 alpha-reductase have been discovered. Type 1 is present in most tissues in the body where 5 alpha-reductase is expressed, and is the dominant form in sebaceous glands. Type 2 is the dominant isoenzyme in genital tissues, including the prostate. Androgenetic alopecia (AGA; male-pattern baldness) is a hereditary and androgen-dependent progressive thinning of the scalp hair that follows a defined pattern.(2) While the genetic involvement is pronounced but poorly understood, major advances have been achieved in understanding the principal elements of androgen metabolism that are involved. DHT may be related to baldness. High concentrations of 5 alpha-reductase have been found in frontal scalp and genital skin and androgen-dependent processes are predominantly due to the binding of DHT to the androgen receptor (AR). Since the clinical success of treatment of AGA with modulators of androgen metabolism or hair growth promoters is limited, sustained microscopic follicular inflammation with connective tissue remodeling, eventually resulting in permanent hair loss, is considered a possible cofactor in the complex etiology of AGA. Currently available AGA treatment modalities with proven efficacy are oral finasteride, a competitive inhibitor of 5 alpha-reductase type 2, and topical minoxidil, an adenosine triphosphate-sensitive potassium channel opener that has been reported to stimulate the production of vascular endothelial growth factor in cultured dermal papilla cells. Currently, many patients with prostate disease receive treatment with a 5 alpha-reductase inhibitor such as finasteride (Proscar) to diminish conversion of DHT from testosterone. See Steroid Pathways in Special Instructions.

Useful For: Monitoring patients receiving 5 alpha-reductase inhibitor therapy or chemotherapy Evaluating patients with possible 5 alpha-reductase deficiency

Interpretation: Patients taking 5 alpha-reductase inhibitor have decreased dihydrotestosterone (DHT) serum levels. Patients with genetic 5 alpha-reductase deficiency (a rare disease) also have reduced DHT serum levels. DHT should serve as the primary marker of peripheral androgen production. However, because it is metabolized rapidly and has a very high affinity for sex hormone-binding globulin (SHBG), DHT does not reflect peripheral androgen action. Instead, its distal metabolite, 3 alpha, 17 beta-androstanediol glucuronide, serves as a better marker of peripheral androgen action See Steroid Pathways in Special Instructions.

Reference Values: Mean

Age

Reference Range (pg/mL)

Stage I (>6 months and prepubertal) 7.1 years < or =50 Stage II

12.1 years < or =200

Stage III

13.6 years 80-330

Stage IV

15.1 years 220-520

Stage V

18 years

240-650 >19 years: 112-955 pg/mL Females Cord blood: < or =50 pg/mL < or =6 months: < or =1,200 pg/mL Tanner Stages

Mean

Age

Reference Range (pg/mL)

Stage I (>6 months and prepubertal)

7.1 years

< or =50

Stage II

10.5 years

< or =300

Stage III

11.6 years

< or =300

Stage IV

12.3 years

< or =300



Page 705

Stage V

14.5 years

< or =300 20-55 years: < or =300 pg/mL >55 years: < or =128 pg/mL 1. Pang S, Levine LS, Chow D, et al: Dihydrotestosterone and its relationship to testosterone in infancy and childhood. J Clin Endocrinol Metab 1979;48:821-826 2. Stanczyk FZ: Diagnosis of hyperandrogenism: biochemical criteria. Best Pract Res Clin Endocrinol Metab 2006;20(2):177-191

Clinical References: 1. Bartsch G, Rittmaster RS, Klocker H: Dihydrotestosterone and the concept of 5 alpha-reductase inhibition in human benign prostatic hyperplasia. World J Urol 2002;19(6):413-425 2. Trueb RM: Molecular mechanisms of androgenetic alopecia. Exp Gerontol 2002;37(8-9):981-990 3. Singh SM, Gauthier S, Labrie F: Androgen receptor antagonists (antiandrogens): structure-activity relationships. Curr Med Chem 2000;7(2):211-247 4. Rhodes L, Harper J, Uno H, et al: The effects of finasteride (Proscar) on hair growth, hair cycle stage, and serum testosterone and dihydrotestosterone in adult male and female stumptail macaques (Macaca arctoides). J Clin Endocrinol Metab 1994;79:991-996 5. Gustafsson O, Norming U, Gustafsson S, et al: Dihydrotestosterone and testosterone levels in men screened for prostate cancer: a study of a randomized population. Br J Urol 1996;77:433-440

DCMGP

Dilated Cardiomyopathy Multi-Gene Panel, Blood

63159

Clinical Information: The cardiomyopathies are a group of disorders characterized by disease of the heart muscle. Cardiomyopathy can be caused by inherited, genetic factors, or by nongenetic (acquired) causes such as infection or trauma. When the presence or severity of the cardiomyopathy observed in a patient cannot be explained by acquired causes, genetic testing for the inherited forms of cardiomyopathy may be considered. Overall, the cardiomyopathies are some of the most common genetic disorders. The inherited forms of cardiomyopathy include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and left ventricular noncompaction (LVNC). DCM is established by the presence of left ventricular enlargement and systolic dysfunction. DCM may present with heart failure with symptoms of congestion, arrhythmias, and conduction system disease, or thromboembolic disease (stroke). The most recent estimates of the incidence of DCM suggest that the condition affects approximately 1 in every 250 people. These estimates are higher than originally reported due to subclinical phenotypes and underdiagnosis. After exclusion of nongenetic causes such as ischemic injury, DCM is traditionally referred to as "idiopathic" dilated cardiomyopathy. Approximately 20% to 50% of individuals with idiopathic DCM may have an identifiable genetic cause for their disease. Families with 2 or more affected individuals are diagnosed with familial dilated cardiomyopathy. The majority of familial dilated cardiomyopathy is inherited in an autosomal dominant manner; however, autosomal recessive and X-linked forms have also been reported. At least 28 genes have been reported in association with DCM, including genes encoding the cardiac sarcomere and other proteins involved in proteins responsible for cardiac muscle contraction. Some genes associated with DCM also cause other forms of hereditary cardiomyopathy, cardiac channelopathies, skeletal myopathies, or metabolic defects. See table for details regarding the genes tested by this panel and associated diseases. Genes included in the Dilated Cardiomyopathy Multi-Gene Panel Gene Protein Inheritance Disease Association ABCC9 ATP-Binding cassette, subfamily C, member 9 AD DCM, Cantu syndrome ACTC1 Actin, alpha, cardiac muscle AD CHD, DCM, HCM, LVNC ACTN2 Actinin, alpha-2 AD DCM, HCM ANKRD1 Ankyrin repeat domain-containing protein 1 AD HCM, DCM CRYAB Crystallin, alpha-B AD, AR DCM, myofibrillar myopathy CSRP3 Cysteine-and glycine-rich protein 3 AD HCM, DCM DES Desmin AD, AR DCM, ARVC, myofibrillar myopathy, RCM with AV block, neurogenic scapuloperoneal syndrome Kaeser type, LGMD LAMA4 Laminin, alpha-4 AD DCM LAMP2 Lysosome-associated membrane protein 2 X-linked Danon disease LDB3 LIM domain-binding 3 AD DCM, LVNC, myofibrillar myopathy LMNA Lamin A/C AD, AR DCM, EMD, LGMD, congenital muscular dystrophy (see OMIM for full listing) MYBPC3 Myosin-binding protein-C, cardiac AD HCM, DCM MYH6 Myosin, heavy chain 6, cardiac muscle, alpha HCM, DCM MYH7 Myosin, heavy chain 7, cardiac muscle, beta AD HCM, DCM, LVNC, myopathy MYPN Myopalladin AD HCM, DCM NEXN Nexilin AD HCM, DCM PLN Phospholamban AD HCM, DCM RAF1 V-raf-1 murine leukemia viral oncogene homolog 1 AD



Page 706

Noonan/multiple lentigines syndrome, DCM RBM20 RNA-binding motif protein 20 AD DCM SCN5A Sodium channel, voltage gated, type V, alpha subunit AD Brugada syndrome, DCM, Heart block, LQTS, SSS, SIDS SGCD Sarcoglycan, delta AD, AR DCM, LGMD TAZ Tafazzin X-linked Barth syndrome, LVNC, DCM TCAP Titin-CAP (Telethonin) AD, AR HCM, DCM, LGMD TNNC1 Troponin C, slow AD HCM, DCM TNNI3 Troponin I, cardiac AD, AR DCM, HCM, RCM TNNT2 Troponin T2, cardiac AD HCM, DCM, RCM, LVNC TPM1 Tropomyosin 1 AD HCM, DCM, LVNC TTN Titin AD, AR HCM, DCM, ARVC myopathy TTR Transthyretin AD Transthyretin-related amyloidosis VCL Vinculin AD HCM, DCM Abbreviations: Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular noncompaction cardiomyopathy (LVNC), restrictive cardiomyopathy (RCM), limb-girdle muscular dystrophy (LGMD), Emory muscular dystrophy (EMD), congenital heart defects (CHD), sudden infant death syndrome (SIDS), long QT syndrome (LQTS), sick sinus syndrome (SSS), autosomal dominant (AD), autosomal recessive (AR)

Useful For: Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of hereditary dilated cardiomyopathy (DCM) Establishing a diagnosis of a hereditary DCM, and in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved Identification of a pathogenic variant within a gene known to be associated with disease features that allows for predictive testing of at-risk family members

Interpretation: Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.


Clinical References: 1. Hershberger RE, Kushner JD, Parks SB: Dilated Cardiomyopathy Overview. In GeneReviews. 2007. Available at www.genetests.org 2. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. Circulation 2005;112:e154-e235 3. Callis TE, Jensen BC, Weck KE, Willis MS: Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all. Expert Rev Mol Diagn 2010 April;10:3:329-351 4. Herman DS, Lam L, Taylor MR, et al: Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366(7):619-628 5. Dhandapany PS, Razzaque MA, Muthusami U, et al: RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet 2014;46(6):635-639 6. Hershberger RE, Morales A: Dilated Cardiomyopathy Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. 1993-2014. Updated 2013 May 9. Available at http://www.ncbi.nlm.nih.gov/books/NBK1309/ 7. Ackerman M, Priori SG, Willems S, et al: HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm 2011;8:1308-1339

DILL

Dill, IgE

82602




Page 707





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FDILT

Diltiazem (Cardizem, Dilacor)

91118

Reference Values: Reference Range: 50 - 200 ng/mL

CDRVT

Dilute Russell Viper Venom Time (DRVVT) Confirmation Ratio

63681

Reference Values: Only orderable as part of a profile. For more information see DRVTI / Dilute Russell Viper Venom Time (DRVVT), with Reflex, Plasma and DRVTJ / Dilute Russell Viper Venom Time (DRVVT) Mix and Confirm Reflexes, Plasma. or =1.2) by LA as well as coagulation factor deficiencies, anticoagulant effects, or other types of coagulation factor inhibitors. Specimens with abnormal results (DRVVT screen ratio > or =1.2) are subjected to reflexive testing (DRVVT mix and confirmation ratios) as described in the Testing Algorithm (also see Interpretation). It is advisable to use the DRVVT screen, mix and confirm ratio results in conjunction with other appropriate coagulation tests (reflexive testing panels) to diagnose or exclude LA. Although LA cause prolonged clotting times in vitro, there is a strong association with thrombosis risk. However, not all patients with persisting LA develop thrombosis.

Useful For: Detecting and confirming or helping to exclude the presence of lupus anticoagulants (LA) Identifying LA that do not prolong the activated partial thromboplastin time (APTT) Evaluating unexplained prolongation of the APTT or prothrombin time clotting tests Current as of August 23, 2017 7:11 am CDT


Page 709

Interpretation: Dilute Russell viper venom time (DRVVT) screen ratio ( or =1.2 and DRVVT mix ratio or =1.2 DRVVT confirm ratio or =1.2 and DRVVT mix ratio > or =1.2 DRVVT confirm ratio > or =1.2: The data are consistent with presence of LA, provided anticoagulant effect can be excluded (see Cautions). Because no single coagulation test can identify or exclude all LAs, and because of the complexity of testing LA, a combination or panel of coagulation tests is recommended: LUPPR / Lupus Anticoagulant Profile THRMP / Thrombophilia Profile PROCT / Prolonged Clot Time Profile DRVVT assays ordered as a single, stand-alone test should be interpreted within patient clinical context and close attention to medication use by patient (see Cautions).

Reference Values: Dilute Russell viper venom time screen ratio or =0.01 IU/mL suggest a vaccine response. A diphtheria toxoid booster should be considered for patients with anti-diphtheria toxoid IgG values between 0.01 and or =0.01 IU/mL) Unvaccinated: Negative (G) results in an amino acid coding polymorphism, Ser9Gly, which is associated with variable response to treatment with atypical antipsychotic medications and predisposition to tardive dyskinesia, a side effect of certain antipsychotic drugs. Worldwide, the frequency of the A (DRD3 25A) and G (DRD3 25G) alleles is nearly equal. However, the allele frequencies are markedly different in different populations (see below) and this may impact the risk of tardive dyskinesia within a given population or cohort following treatment with antipsychotic drugs. Population Frequencies for DRD3 25A and DRD3 25G Alleles: -Allele frequency - European: G=35%, A=65% - African American: G=70%, A=30% - Han Chinese Beijing: G=37%, A=63% - Japanese: G=24%, A=76% Other polymorphisms in the 5' promoter region of DRD3 have also been studied, but results are too preliminary to be used in the management or diagnoses of psychiatric illnesses. Tardive dyskinesia: The DRD3 25G polymorphism is associated with the presence and severity of typical neuroleptic-induced tardive dyskinesia in schizophrenic patients. Higher mean movement scores were found in patients homozygous for the DRD3 25G allele as compared to both heterozygous and DRD3 25A homozygous patients.(1,2) The risk for tardive dyskinesia increases with the number of DRD3 25G alleles. Individuals homozygous for the DRD3 25G allele have an odds ratio of 2.8 for developing tardive dyskinesia compared to individuals homozygous for the DRD3 25A allele.(2) Treatment responses: The DRD3 25G allele has been associated with treatment response to clozapine(3) and olanzapine. Among a group of Chinese patients with schizophrenia treated with risperidone, patients homozygous for the DRD3 25A allele had a better response, as measured by improved scores on the Positive and Negative Symptom Scale (PANSS), a questionnaire used to evaluate symptoms associated with schizophrenia, compared to patients homozygous for the DRD3 25G allele.(4) These improved responses included decreased social and emotional withdrawal, improved abstract thinking, and increased spontaneity and flow of conversation. A better response was observed in the heterozygous state (DRD3 25AG) compared to the homozygous groups (DRD3 25GG, P=0.05; DRD3 25AA P=0.06) in another study of patients receiving a variety of typical and atypical antipsychotics.(5)

Useful For: Influencing choice of antipsychotics prior to treatment, especially to ascertain if atypical antipsychotics may be used with low risk of tardive dyskinesia Identifying those patients receiving antipsychotics who are at increased risk of developing tardive dyskinesias. Individuals with the 25G allele should be monitored closely for signs of tardive dyskinesia if a decision is made to treat with antipsychotics Testing may also be considered for individuals who will receive antipsychotic medications, if they are first-degree relatives of patients who have developed tardive dyskinesia. Assessing potential for effective treatment response with clozapine, olanzapine, and risperidone Genotyping patients who prefer not to have venipuncture done


Clinical References: 1. Lerer B, Segman RH, Fangerau H, et al: Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 2002;27:105-119 2. de Leon J, Susce MT, Pan RM, et al: Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness. J Clin Psychopharmacol 2005;25:448-456 3. Scharfetter J, Chaudry HR, Hornik K, et al: Dopamine D3 receptor gene polymorphism and response to clozapine in schizophrenic Pakistani patients. Eur Neuropsychopharmacol 1999;10(1):17-20 4. Lane HY, Hsu SK, Liu YC, et al: Dopamine D3 receptor Ser9Gly polymorphism and risperidone response. J Clin Psychopharmacol 2005;25(1):6-11 5. Reynolds GP, Yao Z, Zhang X, et al: Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms Current as of August 23, 2017 7:11 am CDT


Page 718

separately associate with positive and negative symptom response. Eur Neuropsychopharmacol 2005;15:143-151

DRD4

Dopamine Receptor D4 Genotype (DRD4), Blood

89096

Clinical Information: The dopamine receptor D4 gene (DRD4) is located near the telomeric region of chromosome 11q and is a highly variable gene. A 48-base pair (bp) variable number tandem repeat polymorphism in exon 3 of DRD4, which ranges from 2 to 11 repeats, creates a 32- to 176-amino acid variation in the third intracellular loop on the dopamine receptor. The frequency of these alleles is shown in the table. The DRD4 7-repeat allele (7R) has functional consequences and is associated with lower affinity for dopamine receptor agonists and reduced signal transduction (eg, cAMP levels) compared to the more common DRD4 4-repeat allele (4R). The effect of other copy number repeats is not as well defined to date. Frequency of alleles with various DRD4 exon 3 48-bp repeats: Allele/Number of repeats (R) Allelic Frequency (%) 2R 8.8 3R 2.4 4R 65.1 5R 1.6 6R 2.2 7R 19.2 8R 0.6 9R 3 g/24 hours) that is predominantly albumin is consistent with amyloidosis (AL) or light chain deposition disease (LCDD). Because patients with AL and LCDD may have elevated urinary protein without an identifiable M-spike, urine protein electrophoresis is not considered an adequate screen for these disorders and immunofixation is also recommended.

Reference Values: PROTEIN, TOTAL 3 g/24 hours) that is predominantly albumin is consistent with primary systemic amyloidosis (AL) and light-chain deposition disease (LCDD). Because patients with AL and LCDD may have elevated urinary protein without an identifiable M-spike, urine protein electrophoresis is not considered an adequate screen for these disorders and immunofixation is also recommended.

Reference Values: PROTEIN, TOTAL No reference values apply to random urine. ELECTROPHORESIS, PROTEIN The following fractions, if present, will be reported as a percent of the total protein: Albumin Alpha-1-globulin Alpha-2-globulin Beta-globulin Gamma-globulin No reference values apply to random urines.

Clinical References: 1. Kyle RA, Katzmann JA, Lust JA, Dispenziei A: Clinical indications and applications of electrophoresis and immunofixation. In Manual of Clinical Laboratory Immunology. Sixth edition. Edited by NR Rose, et al. Washington, DC. ASM Press, 2002, pp 66-67 2. Kyle RA, Katzmann JA, Lust JA, Dispernzieri A: Immunochemical characterization of immunoglobulins. In Manual of Current as of August 23, 2017 7:11 am CDT


Page 750

Clinical Laboratory Immunology. Sixth edition. Edited by N.R. Rose, RG Hamilton, B Detrick. Washington, DC, ASM Press, 2002, pp 71-91

PEL

Electrophoresis, Protein, Serum

80085

Clinical Information: Serum proteins can be grouped into 5 fractions by protein electrophoresis: Albumin, which represents almost two-thirds of the total serum protein - Alpha-1, composed primarily of alpha-1-antitrypsin (A1AT), an alpha-1-acid glycoprotein - Alpha-2, composed primarily of alpha-2-macroglobulin and haptoglobin - Beta, composed primarily of transferrin and C3 - Gamma, composed primarily of immunoglobulins The concentration of these fractions and the electrophoretic pattern may be characteristic of diseases such as monoclonal gammopathies, A1AT deficiency disease, nephrotic syndrome, and inflammatory processes associated with infection, liver disease, and autoimmune diseases.

Useful For: Monitoring patients with monoclonal gammopathies Diagnosis of monoclonal gammopathies, when used in conjunction with immunofixation Protein electrophoresis alone is not considered an adequate screen for monoclonal gammopathies

Interpretation: Monoclonal Gammopathies: - A characteristic monoclonal band (M-spike) is often found on protein electrophoresis (PEL) in the gamma-globulin region and more rarely in the beta or alpha-2 regions. The finding of a M-spike, restricted migration, or hypogammaglobulinemic PEL pattern is suggestive of a possible monoclonal protein and should be followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine, which includes immunofixation (IF), to identify the immunoglobulin heavy chain and/or light chain. - A monoclonal IgG or IgA greater than 3 g/dL is consistent with multiple myeloma (MM). - A monoclonal IgG or IgA less than 3 g/dL may be consistent with monoclonal gammopathy of undetermined significance (MGUS), primary systemic amyloidosis, early or treated myeloma, as well as a number of other monoclonal gammopathies. - A monoclonal IgM greater than 3 g/dL is consistent with macroglobulinemia. - The initial identification of a serum M-spike greater than 1.5 g/dL on PEL should be followed by MPSU / Monoclonal Protein Study, 24 Hour, Urine. - The initial identification of an IgM, IgA, or IgG M-spike greater than 4 g/dL, greater than 5 g/dL, and greather than 6 g/dL, respectively, should be followed by VISCS / Viscosity, Serum. - After the initial identification of an M-spike, quantitation of the M-spike on follow-up PEL can be used to monitor the monoclonal gammopathy. However, if the monoclonal protein falls within the beta region (most commonly an IgA or an IgM) quantitative immunoglobulin levels may be more a useful tool to follow the monoclonal protein level than PEL. A decrease or increase of the M-spike that is greather than 0.5 g/dL is considered a significant change. - Patients suspected of having a monoclonal gammopathy may have normal serum PEL patterns. Approximately 11% of patients with MM have a completely normal serum PEL, with the monoclonal protein only identified by IF. Approximately 8% of MM patients have hypogammaglobulinemia without a quantifiable M-spike on PEL but identified by IF. Accordingly, a normal serum PEL does not rule out the disease and should not be used to screen for the disorder. The MPSS / Monoclonal Protein Study, Serum, which includes immunofixation, and FLCP / Immunoglobulin Free Light Chains, Serum should be done to screen if the clinical suspicion is high. Other Abnormal PEL Findings: - A qualitatively normal but elevated gamma fraction (polyclonal hypergammaglobulinemia) is consistent with infection, liver disease, or autoimmune disease. - A depressed gamma fraction (hypogammaglobulinemia) is consistent with immune deficiency and can also be associated with primary amyloidosis or nephrotic syndrome. - A decreased albumin (1.1 g/dL), and decreased gamma fraction ( or =1 year: 6.3-7.9 g/dL Reference values have not been established for patients that are or =100 Strongly positive Reference values apply to all ages.




Page 752

FENC

Encainide (Enkaidr), ODE and MODE

90087

Reference Values: Encainide: Reference Range: 15 - 100 ng/mL O-Demethylencainide (ODE): Reference Range: 100 - 300 ng/mL 3-Methoxy-ODE (MODE): Reference Range: 60 - 300 ng/mL 10% of patients do not form therapeutic concentrations of the active metabolites, ODE and MODE. In these patients the recommended range for the encainide concentration is 300 - 1200 ng/mL.

FENAP

Encephalitis Antibody Panel (CSF)

58099

Reference Values: Encephalitis Antibody Panel (CSF) Lymphocytic Choriomeningitis (LCM) Virus Ab, IFA (CSF) Reference Range:

IgG IgM

18.5 gm/dL, persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and erythromelalgia (dysesthesia and erythema involving the distal extremities). Secondary polycythemias may either be due to an appropriate or an inappropriate increase in red cell mass. Appropriate secondary polycythemias (eg, high-altitude living and pulmonary disease) are characterized by hypoxia and a compensatory increase in red cell mass. EPO production is increased in an attempt to increase the delivery of oxygen by increasing the number of oxygen-carrying RBCs. Some tumors secrete EPO or EPO-like proteins; examples include tumors of the kidney, liver, lung, and brain. Such increases result in inappropriate secondary polycythemias. Abnormal EPO levels also may be seen in renal failure. The majority of EPO production is in the kidneys. Therefore, chronic renal failure may result in decreased renal EPO production and, subsequently, anemia. In addition to the kidneys, the liver also produces a small amount of EPO. Thus, anephric patients have a residual amount of EPO produced by the liver. Chronic renal failure patients, as well as patients with anemia due to a variety of other causes including chemotherapy, HIV/AIDS, and some hematologic disorders may be candidates for treatment with recombinant human EPO. Recombinant EPO compounds used to treat anemia include epoetin alpha and darbepoetin. Epoetin alpha is a 165 amino acid glycoprotein produced in mammalian cells and has an identical amino acid sequence to natural human EPO. It has 3 oligosaccharide chains and a molecular mass of 30.4 kDa. Darbepoetin alpha is a 165 amino acid glycoprotein that is also produced in mammalian cells. It has 2 additional N-linked oligosaccharide chains and a molecular mass of 37 kDa. There are no specific assays for measuring recombinant EPO compounds. Drug levels can only be roughly estimated from the cross reactivity of the compounds in EPO assays. According to in-house studies, epoetin and darbepoetin show approximately 58% and 36% cross-reactivity, respectively, in the EPO assay.

Useful For: An aid in distinguishing between primary and secondary polycythemia Differentiating between appropriate secondary polycythemia (eg, high-altitude living, pulmonary disease, tobacco use) and inappropriate secondary polycythemia (eg, tumors) Identifying candidates for erythropoietin (EPO) replacement therapy (eg, chronic renal failure) Evaluating patients undergoing EPO replacement therapy who demonstrate an inadequate hematopoietic response

Interpretation: In the appropriate clinical setting (eg, confirmed elevation of hemoglobin >18.5 gm/dL, persistent leukocytosis, persistent thrombocytosis, unusual thrombosis, splenomegaly, and erythromelalgia), polycythemia vera is unlikely when erythropoietin (EPO) levels are elevated and polycythemia vera is likely when EPO levels are suppressed. EPO levels are also increased in patients with anemia of bone marrow failure, iron deficiency, or thalassemia. Patients, who have either a poor or no erythropoietic response to EPO therapy, but high-normal or high EPO levels, may have additional, unrecognized cause(s) for their anemia. If no contributing factors can be identified after adequate further study, the possibility that the patient may have developed EPO-antibodies should be considered. This can be a serious clinical situation that can result in red cell aplasia, and should prompt expeditious referral to hematologists or immunologists skilled in diagnosing and treating this disorder.

Reference Values: 2.6-18.5 mIU/mL

Clinical References: 1. Tefferi A: Diagnosing polycythemia vera: a paradigm shift. Mayo Clin Proc 1999;74:159-162 2. Hoagland HC: Myelodysplastic (preleukemia) syndromes: the bone marrow factory failure problem. Mayo Clin Proc 1995;70:673-677 3. Casadeval N: Pure red cell aplasia and Current as of August 23, 2017 7:11 am CDT


Page 781

anti-erythropoietin antibodies in patients treated with epoetin. Nephrol Dial Transplant 2003;18 (Suppl. 8):viii37-viii41 4. Fisher JW: Erythropoietin: physiology and pharmacology update. Exp Biol Med 2003;228:1-14 5. Strippoli GFM, Manno C, Schena FP, Craig JC: Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. The Cochrane Library, 2005, Volume 2

EPOR

Erythropoietin Receptor (EPOR) Gene, Exon 8 Sequencing

61679

Clinical Information: Erythrocytosis (ie, increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera: PV), or secondary, in response to increased serum erythropoietin (EPO) levels. Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other EPO-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected. Unlike polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A small subset of cases is associated with pheochromocytoma and/or paraganglioma formation. It is caused by mutations in several genes and may be inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although it is possible for new mutations to arise in an individual. The genes coding for hemoglobin, beta globin and alpha globin (high-oxygen-affinity hemoglobin variants), hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), and the erythropoietin receptor, EPOR, and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and von Hippel Lindau: VHL) can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL have normal p50 results. The true prevalence of hereditary erythrocytosis-causing mutations is unknown. Genes Associated with Hereditary Erythrocytosis Gene Inheritance Serum EPO p50 JAK2 V617F Acquired Decreased Normal JAK2 exon 12 Acquired Decreased Normal EPOR Dominant Decreased to normal level Normal PHD2/EGLN1 Dominant Normal level Normal BPGM Recessive Normal level Decreased Beta Globin Dominant Normal level to increased Decreased Alpha Globin Dominant Normal level to increased Decreased HIF2A/EPAS1 Dominant Normal level to increased Normal VHL Recessive Markedly Increased Normal The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF), which regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many hypoxia response genes including EPO, VEGF, and GLUT1. HIF-alpha is regulated by von Hippel-Lindau (VHL) protein-mediated ubiquitination and proteosomal degradation, which requires prolyl hydroxylation of HIF proline residues. The HIF-alpha subunit is encoded by the HIF2A (official name EPAS1) gene. Enzymes important in the hydroxylation of HIF-alpha are the prolyl hydroxylase domain proteins, of which the most significant isoform is PHD2, which is encoded by the PHD2 (official name EGLN1) gene. Mutations resulting in altered HIF-alpha, PHD2, and VHL proteins can lead to clinical erythrocytosis. A small subset of mutations, in PHD2 and HIF2A, has also been detected in erythrocytic patients presenting with paragangliomas or pheochromocytomas. Truncating mutations in the EPOR gene coding for the erythropoietin receptor can result in erythrocytosis through loss of the negative regulatory cytoplasmic SHP-1 binding domain leading to EPO hypersensitivity. All currently known mutations have been localized to exon 8, are mainly missense or small deletion and insertions resulting in stop codons, and are heterozygous. EPOR mutations are associated with decreased to normal EPO levels and normal p50 values (see Table).

Useful For: The definitive evaluation of an individual with JAK2-negative erythrocytosis associated with lifelong sustained increased RBC mass, elevated RBC count, hemoglobin, or hematocrit

Interpretation: An interpretive report will be provided as a part of the HEMP / Hereditary Erythrocytosis Mutations, and will include specimen information, assay information, and whether the specimen was positive for any mutations in the gene. If positive, the mutation will be correlated with clinical significance, if known. Current as of August 23, 2017 7:11 am CDT


Page 782

Reference Values: Only orderable as part of a profile. For more information see HEMP / Hereditary Erythrocytosis Mutations. An interpretive report is provided.

Clinical References:

FFES

Estradiol Free, Serum (includes Estradiol and SHBG)

91215

Reference Values: Estradiol, Serum MS Units: pg/mL Age Range Newborn Levels are markedly elevated at birth and fall rapidly during the first week to prepubertal values of or =400 mg/dL (> or =0.4%) may be lethal as normal respiration may be depressed below the level necessary to maintain life. The blood ethanol level is also useful in diagnosis of alcoholism. A patient who chronically consumes ethanol will develop a tolerance to the drug, and requires higher levels than described above to achieve various states of intoxication. An individual who can function in a relatively normal manner with a blood ethanol level >150 mg/dL (>0.15%) is highly likely to have developed a tolerance to the drug achieved by high levels of chronic intake.

Reference Values: Not detected (Positive results are quantified.) Limit of detection: 10 mg/dL (0.01 g/dL) Legal limit of intoxication is 80 mg/dL (0.08 g/dL). Toxic concentration is dependent upon individual usage history. Potentially lethal concentration: > or =400 mg/dL (0.4 g/dL)

Clinical References: Porter WF, Moyer TP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1993, pp 1155-1235

ALCX

Ethanol, Chain of Custody, Blood

62709

Clinical Information: Ethanol is the single most important substance of abuse in the United States. It is the active agent in beer, wine, vodka, whiskey, rum, and other liquors. Ethanol acts on cerebral functions as a depressant similar to general anesthetics. This depression causes most of the typical



Page 796

symptoms such as impaired thought, clouded judgment, and changed behavior. As the level of alcohol increases, the degree of impairment becomes progressively increased. In most jurisdictions in the United States, the level of prima facie evidence of being under the influence of alcohol for purposes of driving a motor vehicle is 80 mg/dL. Chain-of-custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection of ethanol (ethyl alcohol) in blood to document prior consumption or administration of ethanol Quantification of the concentration of ethanol in blood correlates directly with degree of intoxication Chain-of-custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: The presence of ethanol in blood at concentrations greater than 30 mg/dL (>0.03% or g/dL) is generally accepted as a strong indicator of the use of an alcohol-containing beverage. Blood ethanol levels greater than 50 mg/dL (>0.05%) are frequently associated with a state of increased euphoria. Blood ethanol level greater than 80 mg/dL (>0.08%) exceeds Minnesota's legal limit for driving a motor vehicle. These levels are frequently associated with loss of manual dexterity and with sedation. A blood alcohol level greater than or equal to 400 mg/dL (> or =0.4%) may be lethal as normal respiration may be depressed below the level necessary to maintain life. The blood ethanol level is also useful in diagnosis of alcoholism. A patient who chronically consumes ethanol will develop a tolerance to the drug, and requires higher levels than described above to achieve various states of intoxication. An individual who can function in a relatively normal manner with a blood ethanol level greater than 150 mg/dL (>0.15%) is highly likely to have developed a tolerance to the drug achieved by high levels of chronic intake.

Reference Values: Not detected (Positive results are quantified.) Limit of detection: 10 mg/dL (0.01 g/dL) Legal limit of intoxication is 80 mg/dL (0.08 g/dL). Toxic concentration is dependent upon individual usage history. Potentially lethal concentration: > or =400 mg/dL (0.4 g/dL)

Clinical References: Porter WF, Moyer TP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1993, pp 1155-1235

ETHNL

Ethanol, Serum

37040

Clinical Information: Ethanol is the single most important substance of abuse in the United States. It is the active agent in beer, wine, vodka, whiskey, rum, and other liquors. Ethanol acts on cerebral functions as a depressant similar to general anesthetics. This depression causes most of the typical symptoms such as impaired thought, clouded judgment, and changed behavior. As the level of alcohol increases, the degree of impairment becomes progressively increased. In most jurisdictions in the United States, the level of prima facie evidence of being under the influence of alcohol for purposes of driving a motor vehicle is a blood ethanol concentration 80 mg/dL (0.08 g/dL; 0.08%; 800 mcg/dL). In the context of medical/clinical assessment, serum is submitted for analysis. On average, the serum or serum concentration of the alcohols is 1.2-fold higher than blood. The serum would contain approximately 0.10 g/dL of ethanol in a blood specimen that contains 0.08 g/dL ethanol.

Useful For: Detection of ethanol (ethyl alcohol) in serum to document prior consumption or administration of ethanol Quantification of the concentration of ethanol in serum correlates with degree of intoxication.

Interpretation: The presence of ethanol in blood at concentrations greater than 30 mg/dL (>0.03%) is generally accepted as a strong indicator of the use of an alcohol-containing beverage. Blood ethanol levels greater than 50 mg/dL (>0.05%) are frequently associated with a state of increased euphoria. Blood Current as of August 23, 2017 7:11 am CDT


Page 797

ethanol levels greater than or equal to 80 mg/dL (> or =0.08%) exceeds Minnesota's legal limit for driving a motor vehicle. These levels are frequently associated with loss of manual dexterity and with sedation. A blood alcohol level greater than or equal to 400 mg/dL (> or =0.4%) may be lethal as normal respiration may be depressed below the level necessary to maintain life. The blood ethanol level is also useful in diagnosis of alcoholism. A patient who chronically consumes ethanol will develop a tolerance to the drug and requires higher levels than described above to achieve various states of intoxication. An individual who can function in a relatively normal manner with a blood ethanol level greater than150 mg/dL (>0.15%) is highly likely to have developed a tolerance to the drug achieved by high levels of chronic intake.

Reference Values: or =80 mg/dL Critical value: > or =400 mg/dL

Clinical References: 1. Caplan YH: In Forensic Science Handbook. Vol 2. Edited by R Saferstein. Prentice Hall, 1982 2. Goodman, Gilman's: The Pharmacological Basis of Therapeutics. 10th edition. Edited by AG Gilman, JG Hardman, LE LImbird. McGraw-Hill book Company, 2001 3. Porter WF, Moyer TP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1993, pp 1155-1235 4. Levine B: Principles of Forensic Toxicology. AACC Press, 1999

ETHSX

Ethosuximide, Serum

37041

Clinical Information: Ethosuximide (Zarontin) is used in the treatment of absence (petit mal) seizures, although valproic acid and methsuximide are used more frequently for this condition. Ethosuximide is completely absorbed from the gastrointestinal tract, reaching a peak plasma concentration in 1 to 7 hours. Approximately 10% to 20% of the drug is excreted unchanged in the urine; the remainder is metabolized by hepatic microsomal enzymes. The volume of distribution of ethosuximide is 0.7 L/kg, and its half-life is 40 to 50 hours. Little ethosuximide circulating in the blood is bound to protein. Ethosuximide produces a barbiturate-like toxicity, characterized by central nervous system and respiratory depression, nausea, and vomiting when the blood level is >150 mcg/mL.

Useful For: Monitoring therapy Determining compliance Assessing toxicity Interpretation: Dosage is guided by blood levels; the therapeutic range for ethosuximide is 40 to 100 mcg/mL. Toxic concentration: >150 mcg/mL.

Reference Values: Therapeutic: 40-100 mcg/mL Critical value: >150 mcg/mL

Clinical References: 1. Patsalos PN, Berry DJ, Bourgeois BF, et al: Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 2008;49(7):1239-1276 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Third edition. Edited by CA Burtis, ER Ashwood. WB Saunders Company, Philadelphia, 1999, pp 862-905

ETHO

Ethotoin (Peganone)

80449

Reference Values: Reference Range: 8.0 - 20.0 ug/mL Please note: The therapeutic range for ethotoin is not well established. Many patients respond well to ethotoin concentrations up to 60 ug/mL.



Page 798

ETGX

Ethyl Glucuronide Confirmation, Chain of Custody, Urine

63418

Clinical Information: Ethyl glucuronide and ethyl sulfate are minor metabolites of ethanol that are detectable in body fluids following alcohol consumption and, less commonly, following extraneous exposure. Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are direct biomarkers or metabolites of ethanol. EtG and EtS can be detected up to 5 days in urine using a cutoff of 500 ng/mL.(1) Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny. Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Useful For: Monitoring abstinence in clinical and justice system settings using ethyl blucuronide and ethyl sulfate as direct biomarkers or metabolites of ethanol This chain-of-custody test is intended to be used in a setting where the test results can be used definitively to make a diagnosis.

Interpretation: A positive interpretation will be given if either the ethyl glucuronide result is greater than or equal to 250 ng/mL and/or the ethyl sulfate is greater than or equal to 100 ng/mL. A "high" positive (ie, >1,000 ng/mL) may indicate: -Heavy drinking on the same day or previously (ie, previous day or 2). -Light drinking the same day A "low" positive (ie, 500-1,000 ng/mL) may indicate: -Previous heavy drinking (ie, previous 1-3 days). -Recent light drinking (ie, past 24 hours). -Recent intense "extraneous" exposure (ie, within 24 hours or less). A "very low" positive (ie, 100-500 ng/mL) may indicate: -Previous heavy drinking (ie, 1-3 days) -Previous light drinking (ie, 12-36 hours). -Recent "extraneous" exposure.

Reference Values: Negative Cutoff concentrations: Ethyl Glucuronide: 500 ng/mL

Clinical References: 1. Reisfield GM, Goldberger BA, Crews BO, et al: Ethyl glucuronide, ethyl sulfate, and ethanol in urine after sustained exposure to an ethanol-based hand sanitizer. J Anal Toxicol 2011;35:85-91 2. The role of biomarkers in the treatment of alcohol use disorders. 2012 Revision Substance Abuse and Mental Health Services Administration. Spring 2012;11(2):1-7

ETGC

Ethyl Glucuronide Confirmation, Random, Urine

63421

Clinical Information: Ethyl glucuronide and ethyl sulfate are minor metabolites of ethanol which are detectable in body fluids following alcohol consumption and less commonly following extraneous exposure.

Useful For: Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are direct biomarkers or metabolites of ethanol. EtG and EtS can be detected up to 5 days in urine using a cutoff of 500 ng/mL.(1) These biomarkers are often used in monitoring abstinence in clinical and justice system settings.

Interpretation: A positive interpretation will be given if either the ethyl glucuronide result is greater than or equal to 250 ng/mL and/or the ethyl sulfate is greater than or equal to 100 ng/mL. A "high" positive (ie, >1,000 ng/mL) may indicate: -Heavy drinking on the same day or previously (ie, previous day or 2). -Light drinking the same day A "low" positive (ie, 500-1,000 ng/mL) may indicate: -Previous heavy drinking (ie, previous 1-3 days). -Recent light drinking (ie, past 24 hours). -Recent intense "extraneous" exposure (ie, within 24 hours or less). A "very low" positive (ie, 100-500 ng/mL) may indicate: -Previous heavy drinking (ie, 1-3 days) -Previous light drinking (ie, 12-36 hours). -Recent "extraneous" exposure.(2)



Page 799

Clinical References: 1. Reisfield GM, Goldberger BA, Crews BO, et al: Ethyl glucuronide, ethyl sulfate, and ethanol in urine after sustained exposure to an ethanol-based hand sanitizer. J Anal Toxicol 2011;35:85-91 2. The role of biomarkers in the treatment of alcohol use disorders. 2012 Revision Substance Abuse and Mental Health Services Administration. Spring 2012;11(2):1-7

ETGR

Ethyl Glucuronide Screen with Reflex, Urine

63419

Clinical Information: This procedure uses immunoassay reagents that are designed to produce a negative result when no drugs are present in a natural (ie, unadulterated) specimen of urine; the assay is designed to have a high true-negative rate. Like all immunoassays, it can have a false-positive rate due to cross-reactivity with natural chemicals and drugs other than those they were designed to detect. The immunoassay also has a false-negative rate to the antibodyâ€™s ability to cross-react with different drugs in the class being screened for. Ethyl glucuronide is a direct metabolite of ethanol that is formed by enzymatic conjugation of ethanol with glucuronic acid. Alcohol in urine is normally detected for only a few hours, whereas ethyl glucuronide can be detected in the urine for 1 to 3 days.

Useful For: Screening for drug abuse involving alcohol Interpretation: This assay only provides a preliminary analytical test result. A more specific alternative method (ie, liquid chromatography-tandem mass spectrometry; LC-MS/MS) must be used to obtain a confirmed analytical result. A positive result using the ethyl glucuronide screen indicates only the potential presence of ethyl glucuronide and does not necessarily correlate with the extent of physiological and psychological effects.

Reference Values: Negative Screening cutoff concentration: Ethyl Glucuronide: 500 ng/mL

Clinical References: 1. Schmitt G, Aderjan R, Keller T, Wu M: Ethyl glucuronide: an unusual ethanol metabolite in humans. Synthesis, analytical data, and determination in serum and urine. J Anal Toxicol 1995;19:91-94 2. Dahl H, Stephanson N, Beck O, Helander A: Comparison of urinary excretion characteristics of ethanol and ethyl glucuronide. J Anal Toxicol 2002;26:201-104 3. Wurst FM, Skipper GE, Weinmann W: Ethyl glucuronide--the direct ethanol metabolite on the threshold from science to routine use. Addiction 2003;98 (S2):51-61 4. Zimmer H, Schmitt G, Aderjan R: Preliminary immunochemical test for the determination of ethyl glucuronide in serum and urine: comparison of screening method results with gas chromatography-mass spectrometry. J Anal Toxicol 2002;26:11-16 5. Weinmann W, Schaefer P, Thierauf A: Confirmatory analysis of ethyl glucuronide in urine by liquid chromatography/electrospray ionization/tandem mass spectrometry according to forensic guidelines. J Am Soc Mass Spectrom 2004;15(2):188-193

ETGS

Ethyl Glucuronide Screen, Urine

63420

Clinical Information: This procedure uses immunoassay reagents that are designed to produce a negative result when no drugs are present in a natural (ie, unadulterated) specimen of urine; the assay is designed to have a high true-negative rate. Like all immunoassays, it can have a false-positive rate due to cross-reactivity with natural chemicals and drugs other than those they were designed to detect. The immunoassay also has a false-negative rate to the antibodyâ€™s ability to cross-react with different drugs in the class being screened for. Ethyl glucuronide is a direct metabolite of ethanol that is formed by enzymatic conjugation of ethanol with glucuronic acid. Alcohol in urine is normally detected for only a few hours, whereas ethyl glucuronide can be detected in the urine for 1 to 3 days.

Useful For: Screening for drug abuse involving alcohol Interpretation: This assay only provides a preliminary analytical test result. A more specific alternative method (ie, liquid chromatography-tandem mass spectrometry: LC-MS/MS) must be used to obtain a confirmed analytical result. A positive result using the ethyl glucuronide screen indicates only the Current as of August 23, 2017 7:11 am CDT


Page 800

potential presence of ethyl glucuronide and does not necessarily correlate with the extent of physiological and psychological effects.

Reference Values: Negative Screening cutoff concentration: Ethyl Glucuronide: 500 ng/mL

Clinical References: 1. Schmitt G, Aderjan R, Keller T, Wu M: Ethyl glucuronide: an unusual ethanol metabolite in humans. Synthesis, analytical data, and determination in serum and urine. J Anal Toxicol 1995;19:91-94 2. Dahl H, Stephanson N, Beck O, Helander A: Comparison of urinary excretion characteristics of ethanol and ethyl glucuronide. J Anal Toxicol 2002;26:201-104 3. Wurst FM, Skipper GE, Weinmann W: Ethyl glucuronide--the direct ethanol metabolite on the threshold from science to routine use. Addiction 2003;98 (S2):51-61 4. Zimmer H, Schmitt G, Aderjan R: Preliminary immunochemical test for the determination of ethyl glucuronide in serum and urine: comparison of screening method results with gas chromatography-mass spectrometry. J Anal Toxicol 2002;26:11-16 5. Weinmann W, Schaefer P, Thierauf A: Confirmatory analysis of ethyl glucuronide in urine by liquid chromatography/electrospray ionization/tandem mass spectrometry according to forensic guidelines. J Am Soc Mass Spectrom 2004;15(2):188-193

ETGL

Ethylene Glycol, Serum

8749

Clinical Information: Ethylene glycol, present in antifreeze products, may be ingested accidentally or for the purpose of inebriation or suicide. Ethylene glycol itself is relatively nontoxic, and its initial central nervous system (CNS) effects resemble those of ethanol. However, metabolism of ethylene glycol by alcohol dehydrogenase results in the formation of a number of acid metabolites, including oxalic acid and glycolic acid. These acid metabolites are responsible for much of the toxicity of ethylene glycol. Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4 to 12 hours, severe metabolic acidosis develops from accumulation of acid metabolites. Finally, delayed renal insufficiency follows deposition of oxalate in renal tubules. Ethylene glycol toxicity is treated with 4-methylpyrazole (4-MP; fomepizole) or ethanol to saturate the enzyme alcohol dehydrogenase and prevent conversion of ethylene glycol to its toxic metabolites.

Useful For: Confirming and monitoring ethylene glycol toxicity Interpretation: Toxic concentrations greater than or equal to 20 mg/dL may cause intoxication, CNS depression, metabolic acidosis, renal damage and hypocalcemia. Ingestion of ethylene glycol can be fatal if patients do not receive immediate medical treatment.

Reference Values: Toxic concentration: > or =20 mg/dL

Clinical References: 1. Porter W: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, DE Bruns. Vol 4. St. Louis, MO. Elsevier Saunders, 2006, pp 1287-1369 2. O'Brien CP: Drug addiction and drug abuse. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by LL Brunton, JS Lazo, KL Parker. Vol 11. McGraw-Hill Book Company, Inc, 2006. Available at http://www.accessmedicine.com/content.aspx?aID=941547 3. Anderson IB: Ethylene glycol and other glycols. In Poisoning and Drug Overdose. Edited by KR Olson. Fifth edition. Available at http://www.accessmedicine.com/content.aspx?aID=2683943

EOXD

Ethylene Oxide, IgE

82767

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the



Page 801

immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



ETVBF

ETV6 (12p13.2) Rearrangement, FISH

64338

Clinical Information: Rearrangements involving 12p13 are some of the most commonly observed chromosomal abnormalities in hematologic malignancies. The ETV6 gene (ETS variant gene 6) codes for a transcription factor and is involved in deletions and translocations in both myeloid and lymphoid malignancies. Over 30 translocation partners have been identified.

Useful For: Providing diagnostic and prognostic information for patients with various lymphoid and myeloid malignancies

Interpretation: A positive result is detected when the percent of cells with an abnormality exceeds the normal cutoff for the probe set. A positive result suggests rearrangement of the ETV6 locus, which can be useful for diagnosis. A negative result suggests no rearrangement of the ETV6 gene region at 12p13.2.


Clinical References: 1. De Braekeleer E, Douet-Guilber N, Morel F, et al: ETV6 fusion genes in hematological malignancies: A review. Leuk Res 2012;36:945-961 2. Linka Y, Kruger M, Novosel A, et al: The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for Current as of August 23, 2017 7:11 am CDT


Page 802

leukemia using three different genome-wide screening methods. Blood Cancer J 2013;3:1-9 3. Bokemeyer A, Eckert C, Meyr F, et al: Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia. Haematologica 2014;99(4):706-714 4. Agape P, Gerard B, Cave H, et al: Analysis of ETV6 and ETV6-AML1 proteins in acute lymphoblastic leukaemia. Br J Haematol 1997;98:234-239 5. Haferlach C, Bacher U, Schnittger S, et al: ETV6 rearrangements are recurrent in myeloid malignancies and are frequently associated with other genetic events. Genes Chromosomes Cancer. 2012;51:328-337

ETV6F

ETV6 (12p13.2) Rearrangement, FISH, Tissue

63433

Clinical Information: ETV6 rearrangement is a recurrent abnormality in mammary analogue secretory carcinoma, secretory carcinoma of the breast, and infantile fibrosarcoma, but is not observed in tumors that share clinical and pathologic similarities.

Useful For: Providing diagnostic information and guiding treatment primarily for patients with mammary analogue secretory carcinoma, secretory carcinoma of the breast, and infantile fibrosarcoma

Interpretation: A positive result is detected when the percent of cells with an abnormality exceeds the normal cutoff for the probe set. A positive result suggests rearrangement of the ETV6 locus, which can be useful for diagnosis. A negative result suggests no rearrangement of the ETV6 gene region at 12p13.2.


Clinical References: 1. Skalova A: Mammary analogue secretory carcinoma of salivary gland origin: an update and expanded morphologic and immunohistochemical spectrum of recently described entity. Head Neck Pathol 2013 July;7:S30-S36 2. Makretsov N, He M, Hayes M, et al: A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma. Genes Chromosomes Cancer 2004;40:152-157 3. Sheng WQ, Hisaoka M, Okamoto S, et al: Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection pf the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues. Am J Clin Pathol 2001;115:348-355 4. Steelman C, Katzenstein H, Parham D, et al: Unusual presentation of congenital infantile fibrosarcoma in seven infants with molecular-genetic analysis. Fetal Pediatr Pathol 2011;30:329-337 5. Skalova A, Vanecek T, Sima R, et al: Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599-608

EUCL

Eucalyptus, IgE

82758



Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased Current as of August 23, 2017 7:11 am CDT


Page 803

likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FECLT

Euglobulin Clot Lysis Time

57810

Reference Values: >60 min

EMAY

Euroglyphus maynei, IgE

82846




Reference Values: Class IgE kU/L Interpretation



Page 804

0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



EHOR

European Hornet, IgE

82662





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 805


EVROL

Everolimus, Blood

35146

Clinical Information: Everolimus is an immunosuppressive agent derived from sirolimus (rapamycin). Both drugs function via inhibition of mTOR signaling, and share similar pharmacokinetic and toxicity profiles. Everolimus has a shorter half-life than sirolimus, which allows for more rapid achievement of steady-state pharmacokinetics. Everolimus is extensively metabolized, primarily by CYP3A4, thus its use with inducers or inhibitors of that enzyme may require dose adjustment. The most common adverse effects include hyperlipidemia, thrombocytopenia, and nephrotoxicity. Everolimus is useful as adjuvant therapy in renal cell carcinoma and other cancers. It recently gained FDA approval for prophylaxis of graft rejection in solid organ transplant, an application which has been accepted for years in Europe. The utility of therapeutic drug monitoring has not been established for everolimus as an oncology chemotherapy agent; however, measuring blood drug concentrations is common practice for its use in transplant. Therapeutic targets vary depending on the transplant site and institution protocol. Guidelines for heart and kidney transplants suggest that trough (immediately prior to the next scheduled dose) blood concentrations between 3 and 8 ng/mL provide optimal outcomes.

Useful For: Management of everolimus immunosuppression in solid organ transplant Interpretation: Therapeutic targets vary by transplant site and institution protocol. Heart and kidney transplant guidelines suggest a therapeutic range of 3 to 8 ng/mL. Measurement of drug concentrations in oncology chemotherapy is less common, thus no therapeutic range is established for this application.

Reference Values: 3-8 ng/mL Target steady-state trough concentrations vary depending on the type of transplant, concomitant immunosuppression, clinical/institutional protocols, and time post-transplant. Results should be interpreted in conjunction with this clinical information and any physical signs/symptoms of rejection/toxicity.

Clinical References: 1. Eisen HJ, Tuzcu EM, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003;349(9):847-858 2. Kovarik JM, Beyer D, Schmouder RL: Everolimus drug interactions: application of a classification system for clinical decision making. Biopharm Drug Dispos 2006;27(9):421-426 3. Rothenburger M, Zuckermann A, Bara C, et al: Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second German-Austrian Certican Consensus Conference. J Heart Lung Transplant 2007;26(4):305-311 4. Sanchez-Fructuoso AI: Everolimus: an update on the mechanism of action, pharmacokinetics and recent clinical trials. Expert Opin Drug Metab Toxicol 2008;4(6):807-819

EWSF 35268

Ewing Sarcoma (EWS), 22q12 (EWSR1) Rearrangement, FISH, Tissue Clinical Information: Ewing sarcoma (EWS)/primitive neuroectodermal tumors (PNET) are members of the small, round cell group of tumors that are thought to originate in cells of primitive neuroectodermal origin with variable degrees of differentiation. The small, round cell group of tumors also includes rhabdomyosarcomas, desmoplastic small, round cell tumors, and poorly differentiated synovial sarcomas. Although immunohistochemical markers can be helpful in the correct diagnosis of these tumors, recent molecular studies have shown the specificity of molecular markers in differentiating specific subtypes of small, round blue-cell tumors. Accurate diagnosis of each tumor type is important for appropriate clinical management of patients. Ewing tumors are characterized cytogenetically by rearrangements of the EWSR1 gene at 22q12 with FLI1 at 11q24 (t[11;22]) or ERG at 21q22 (t[21;22]) in 85% and 5% to 10% of Ewing tumors, respectively. Less than 1% of cases may have other fusion partners



Page 806

such as ETV1 at 7p22, E1AF at 17q12, or FEV at 2q33. Detection of these transcripts by reverse transcriptase-PCR (RT-PCR) (EWS, Ewing Sarcoma RT-PCR) that allows specific identification of the t(11;22) and the t(21;22), has greatly facilitated the diagnosis of Ewing tumors. However, if the quality of the available RNA is poor, the results are equivocal, or if a rare translocation partner is present, FISH testing has proven to be useful in identifying the 22q12 EWS gene rearrangement in these tumors.

Useful For: Supporting the diagnosis of Ewing sarcoma (EWS)/primitive neuroectodermal tumor (PNET), myxoid chondrosarcoma, desmoplastic small, round cell tumor, clear cell sarcoma, and myxoid liposarcoma when used in conjunction with an anatomic pathology consultation An aid in the diagnosis of EWS when reverse transcriptase-PCR results are equivocal or do not support the clinical picture

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff for the EWSR1 FISH probe set. A positive result is consistent with a diagnosis of Ewing sarcoma (EWS)/primitive neuroectodermal tumors (PNET). A negative result suggests that a EWSR1 rearrangement is not present but does not exclude the diagnosis of EWS/PNET.


Clinical References: 1. World Health Organization Classification of Tumors. Pathology and Genetics Tumours of Soft Tissue and Bone. Edited by CDM Fletcher, KK Unni, F Mertens: IARC Press; Lyon 2002, pp 298-300 2. Burchill SA: Ewing's sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol 2003 February;56(2):96-102 3. Riley RD, Burchill SA, Abrams KR, et al: A systematic review of molecular and biological markers in tumors of the Ewing's sarcoma family. Eur J Cancer 2003 January;39:19-30 4. Romeo S, Dei Tos AP: Soft tissue tumors associated with EWSR1 translocation. Virchows Arch. 2010 Feb;456(2):219-34

EWS

Ewing Sarcoma, by Reverse Transcriptase PCR (RT-PCR)

35331

Clinical Information: Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET), a closely related tumor, are members of the small round-cell tumor group that also includes rhabdomyosarcoma, synovial sarcoma, lymphoma, Wilms tumor, and desmoplastic small round-cell tumor. ES is the second most common malignant tumor of bone in children and young adults. It is an aggressive osteolytic tumor with a high risk of metastasizing. ES can also present as a soft tissue tumor mass. These tumors are usually bland and undifferentiated with relatively low mitotic indexes, which is misleading in light of the rapid growth commonly observed clinically. While treatment and prognosis depend on establishing the correct diagnosis, the diagnosis of sarcomas that form the small round-cell tumor group can be very difficult by light microscopic examination alone, especially true when only small-needle biopsy specimens are available for examination. The use of histochemical and immunohistochemical stains (eg, MIC2 [CD99], desmin, myogenin, myoD1, WT1) can assist in establishing the correct diagnosis, but these markers are not entirely specific for ES/PNET. Expertise in soft tissue and bone pathology are often needed. Studies have shown that some sarcomas have specific recurrent chromosomal translocations. These translocations produce highly specific gene fusions that help define and characterize subtypes of sarcomas that are useful in the diagnosis of these lesions.(1-4) The balanced t(11;22)(q24;q12) chromosomal translocation produces the EWSR1-FLI1 fusion transcript and is present in 95% of ES and PNET. Because the EWSR1-FLI1 fusion transcript is a common finding in ES/PNET, in soft tissues these 2 lesions are essentially identical. Less common are the t(21;22)(p22;q12) or EWSR1-ERG transcript, present in 650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and death from myocardial infarction prior to 20 years of age. Heterozygous FH is prevalent in many different populations, with an approximate average incidence of 1 in 500 individuals, but as high as 1 in 67 to 1 in 100 individuals in some populations in South Africa and 1 in 270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately 1 in 1,000,000. Treatment for FH is aimed at lowering the plasma level of LDL and increasing LDL receptor activity. Identification of LDLR variant(s) in individuals suspected of having FH helps to determine appropriate treatment. FH heterozygotes are often treated with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (ie, statins), either in monotherapy or in combination with other drugs such as nicotinic acid and inhibitors of intestinal cholesterol absorption. Such drugs are generally not effective in FH homozygotes, and treatment in this population may consist of LDL apheresis, portacaval anastomosis, and liver transplantation. The LDLR gene maps to chromosome 19p13 and consists of 18 exons spanning 45 kb. Hundreds of variants have been identified in the LDLR gene, the majority of them occurring in the ligand binding and epidermal growth factor (EGF) precursor homology regions in the 5' region of the gene (type II and III variants, respectively). Although most FH-causing variants are small (eg, point variants), approximately 10% to15% of variants in the LDLR gene are large rearrangements such as exonic deletions and duplications, which are not amenable to sequencing (eg, LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing) but can be detected by this MLPA assay.

Useful For: Aiding in the diagnosis of familial hypercholesterolemia (FH) in individuals with elevated untreated low-density lipoprotein (LDL) cholesterol Distinguishing the diagnosis of FH from other causes of hyperlipidemia, such as familial defective ApoB-100 and familial combined hyperlipidemia Current as of August 23, 2017 7:11 am CDT


Page 816

Comprehensive LDL receptor genetic analysis for suspect FH individuals who test negative for an LDLR point variant by sequencing (LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing)


Clinical References: 1. Hobbs H, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992:1:445-466 2. Goldstein JL, Hobbs H, Brown MS: Familial hypercholesterolemia. In The Metabolic Basis of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al New York, McGraw-Hill Book Company, 2006 pp 2863-2913 3. Van Aalst-Cohen ES, Jansen AC, Tanck MW, et al: Diagnosing familial hypercholesterolemia: the relevance of genetic testing. Eur Heart J 2006;27:2240-2246 4. Soutar AK, Naoumova RP: Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4(4):214-225 5. Schouten JP, McElgunn CJ, Waaijer R, et al: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res, 2002;30(12):e57

ADHP 83375

Familial Hypercholesterolemia/Autosomal Dominant Hypercholesterolemia Genetic Testing Reflex Panel Clinical Information: Autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of low-density lipoprotein (LDL) cholesterol, and associated with premature cardiovascular disease and myocardial infarction. Approximately 1 in 500 individuals worldwide are affected by ADH. Most ADH is caused by genetic variants leading to decreased intracellular uptake of cholesterol. The majority of these cases have familial hypercholesterolemia (FH), which is due to variants in the LDLR gene, which encodes for the LDL receptor. Approximately 15% of ADH cases have familial defective apolipoprotein B-100 (FDB) due to variants in the LDL receptor-binding domain of the APOB gene, which encodes for apolipoprotein B-100. ADH can occur in either the heterozygous or homozygous state, with 1 or 2 variant alleles, respectively. In general, FH heterozygotes have 2-fold elevations in plasma cholesterol and develop coronary atherosclerosis after the age of 30. Homozygous FH individuals have severe hypercholesterolemia (generally greater than 650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and death from myocardial infarction prior to 20 years of age. Heterozygous FH is prevalent among many different populations, with an approximate average worldwide incidence of 1 in 500 individuals, but as high as 1 in 67 to 1 in 100 individuals in some South African populations and 1 in 270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately 1 in 1,000,000. Similar to FH, FDB homozygotes express more severe disease, although not nearly as severe as FH homozygotes. Approximately 40% of males and 20% of females with an APOB variant will develop coronary artery disease. In general, when compared to FH, individuals with FDB have less severe hypercholesterolemia, fewer occurrences of tendinous xanthoma, and a lower incidence of coronary artery disease. Plasma LDL cholesterol levels in patients with homozygous FDB are similar to levels found in patients with heterozygous (rather than homozygous) FH. The LDLR gene maps to chromosome 19p13 and consists of 18 exons spanning 45 kb. Hundreds of variants have been identified in the LDLR gene, the majority of them occurring in the ligand binding and epidermal growth factor (EGF) precursor homology regions in the 5' region of the gene. The majority of variants in the LDLR gene are missense, small insertion or deletion variants, and other point variants, most of which are detected by full gene sequencing. Approximately 10% to 15% of variants in the LDLR gene are large rearrangements, such as large exonic deletions and duplications. The APOB gene maps to chromosome 2p. The vast majority of FDB cases are caused by a single APOB variant at residue 3500, resulting in a glutamine substitution for the arginine residue (R3500Q). This common FDB variant occurs at an estimated frequency of 1 in 500 individuals of European descent. A less frequently occurring variant at that same codon, which results in a tryptophan substitution (R3500W), is more prevalent in individuals of Chinese and Malay descent, and has been identified in the Scottish population as well. The R3500W variant is estimated to occur in approximately 2% of ADH cases. Residue 3500 interacts with other apolipoprotein B-100 residues to induce conformational changes necessary for apolipoprotein B-100 binding to the LDL receptor. Thus, variants at residue 3500 lead to a reduced binding affinity of LDL for its receptor. Identification of 1 or more variants in individuals suspected of having ADH helps to



Page 817

determine appropriate treatment of this disease. Treatment is aimed at lowering plasma LDL levels and increasing LDL receptor activity. FH heterozygotes and FDB homozygotes and heterozygotes are often treated with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (ie, statins), either in monotherapy or in combination with other drugs such as nicotinic acid and inhibitors of intestinal cholesterol absorption. Such drugs are generally not effective in FH homozygotes, and treatment in these individuals may consist of LDL apheresis, portacaval anastomosis, and liver transplantation. Screening of at-risk family members allows for effective primary prevention by instituting statin therapy and dietary modifications at an early stage. This test provides a reflex approach to diagnosing the above disorders. The tests can also be separately ordered: -LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing -LDLM / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis See Familial/Autosomal Dominant Hypercholesterolemia Diagnostic Algorithm in Special Instructions.

Useful For: Aiding in the diagnosis of familial hypercholesterolemia defective apoB-100 in individuals with elevated, untreated low-density lipoprotein cholesterol concentrations Distinguishing the diagnosis of autosomal dominant hypercholesterolemia from other causes of hyperlipidemia, such as familial combined hyperlipidemia Genetic evaluation of hypercholesterolemia utilizing a cost-effective, reflex-testing approach


Clinical References: 1. Hobbs HH, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992;1:445-466 2. Goldstein JL, Hobbs HH, Brown MS: Familial hypercholesterolemia. In The Metabolic Basis of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, WS Sly. New York, McGraw-Hill Book Company, 2006 pp 2863-2913 3. Whitfield AJ, Barrett PH, van Bockxmeer FM, Burnett JR: Lipid disorders and mutations in the APOB gene. Clin Chem 2004;50:1725-1732 4. Innerarity TL, Mahley RW, Weisgraber KH, et al: Familial defective apolipoprotein B100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res 1990;31:1337-1349

FMTT

Familial Mutation, Targeted Testing

63032

Clinical Information: This test is available to test for the presence of 1 or more mutations previously identified in a family member. Targeted testing is used for diagnostic or predictive testing in cases in which mutations have been previously identified in an affected family member. Targeted testing is available for a specific subset of genes only. Genes Available for Testing* ABCD1 ACADM ACADS ACADVL AGXT APC APOA1 APOA2 ARSA ARSB ATP7B AXIN2 BMPR1A BRCA1 BRCA2 BTD CASR CDH1 CDKN1C CFTR CHEK2 CPOX CPT2 CTRC FECH FGA FLCN FTCD GAA GALC GALT GBA GLA GNPTAB GNS GRHPR GRN GSN HEXA HGSNAT HMBS IDS IDUA LYZ MAPT MECP2 MEFV MLH1 MLH3 MLYCD MMACHC MMADHC MSH2 MSH6 MUTYH NAGLU NPC1 NPC2 PKHD1 PMS2 PPOX PRSS1 PSAP PTEN RAI1 RET SCG5 SDHB SDHC SDHD SEPT9 SGSH SLC25A20 SMAD4 SMPD1 SPINK1 STK11 SUMF1 TACSTD1/EPCAM TNFRSF1A TP53 TTR UBE3A VHL * FMTT is available for family members of a patient who had testing performed by the molecular genetics laboratory at Mayo Medical Laboratories. For these individuals, FMTT can be used to detect variants in the genes listed in the table above, in addition to any gene (excluding pharmacogenomics variants) via large panels. Contact the laboratory to determine whether adequate DNA is available in the laboratory or if a new proband sample is required. Refer to the following resources for information regarding the listed gene targets. GeneReviews-NCBI Bookshelf, available at www.ncbi.nlm.nih.gov/books/NBK1116/ or OMIM, available at www.omim.org/. Testing may be delayed if the required documentation is not received (ie, patient information sheet).

Useful For: Diagnostic or predictive testing for specific conditions when 1 or more mutations have been identified in a family member Carrier screening for individuals at risk for having a mutation that was previously identified in a family member

Interpretation: All detected alterations are evaluated according to American College of Medical Current as of August 23, 2017 7:11 am CDT


Page 818

Genetics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300

FANCP 35416

Fanconi Anemia C Mutation Analysis, IVS4(+4)A->T and 322delG Clinical Information: Fanconi anemia is an aplastic anemia that leads to bone marrow failure and myelodysplasia or acute myelogenous leukemia. Physical findings include short stature; upper limb, lower limb, and skeletal malformations; and abnormalities of the eyes and genitourinary tract. The proteins encoded by the genes associated with Fanconi anemia may work together to repair DNA damage. Mutations in several genes have been associated with Fanconi anemia, although 1 mutation, IVS4(+4)A->T in the FANCC gene has been shown to be common in the Ashkenazi Jewish population. The carrier rate in the Ashkenazi Jewish population is 1 in 89 and the detection rate for this mutation using this assay is greater than 99%. A second FANCC mutation, 322delG, is overrepresented in patients of Northern European ancestry.

Useful For: Carrier screening for Fanconi anemia in individuals of Ashkenazi Jewish ancestry Prenatal diagnosis of Fanconi anemia in at-risk pregnancies Confirmation of suspected clinical diagnosis of Fanconi anemia in individuals of Ashkenazi Jewish ancestry


Clinical References: 1. Gross SJ, Pletcher BA, Monaghan KG: Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med 2008 Jan;10(1):54-6 2. Kutler DI, Auerbach AD: Fanconi anemia in Ashkenazi Jews. Fam Cancer 2004;3(3-4):241-248

60874

Fascin, Immunostain Without Interpretation Clinical Information: Fascin is an actin-bundling protein that is present in antigen-presenting cells, and upregulated in Epstein Barr virus-positive lymphocytes and Hodgkin cells. Antibodies to fascin result in distinct cytoplasmic staining of the Langerhans cells, follicular dendritic cells, and interdigitating reticulum cells in normal lymph nodes. Fascin is usually positive in classical Hodgkin lymphoma and negative in lymphocyte predominant Hodgkin lymphoma.

Useful For: Classification of lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Fan G, Kotylo P, Neiman R, Braziel RM: Comparison of fascin expression in anaplastic large cell lymphoma and Hodgkin disease. Am J Clin Pathol 2003;119:199-204 2. Kempf W, Levi E, Kamarashev J, et al: Fascin expression in CD30-positive cutaneous lymphoproliferative disorders. J Cutan Pathol 2002;29:295-300 3. Pinkus GS, Pinkus JL, Langhoff E, et al: Fascin, a sensitive new marker for reed-sternberg cells of Hodgkinâ€™s disease. Evidence for a dendritic or B cell derivation? Current as of August 23, 2017 7:11 am CDT


Page 819

Am J Pathol 1997;150(2):543-562

FATF

Fat, Feces

8310

Clinical Information: Total fecal lipids include glycerides, phospholipids, glycolipids, soaps, sterols, cholesteryl esters, and sphingolipids. Excess fecal fat in stool, (steatorrhea) is indicative of malabsorption disorders, such as pancreatic insufficiency or Whipple disease. Therefore, measurement of the fecal fats can be useful in establishing a diagnosis of such pancreatic diseases as cystic fibrosis, chronic pancreatitis, neoplasia, or stone obstruction, and such intestinal diseases as Whipple disease, regional enteritis, tuberculous enteritis, gluten-induced enteropathy (also called celiac disease or sprue), and the atrophy of malnutrition. Distinguishing free fatty acids from neutral fats, once thought to be helpful in the differential diagnosis of pancreatic disease, has fallen out of favor. Note that the composition of fats in the stool, normally predominately free fatty acids, can change significantly to predominately neutral fatty acids when the patient is on orlistat. This test does not distinguish between free and neutral fatty acids.

Useful For: Diagnosing fat malabsorption due to pancreatic or intestinal disorders Monitoring effectiveness of enzyme supplementation in certain malabsorption disorders

Interpretation: Excretion of more than 7 grams fat/24 hours, when on a diet of 100 to 150 g of fat, is suggestive of a malabsorption defect. Abnormal results from a random specimen should be confirmed by submission of a timed collection. Test values for timed fecal fat collections will be reported in terms of g/24 hours; the duration of the collection may be 24, 48, 72, or 96 hours. Test values for random fecal fat collections will be reported in terms of percent fat. Coefficient of Fat Absorption (CFA) can be calculated as follows: (grams fat consumed â€“ grams of fat excreted) x 100 CFA = -------------------------------------------------------------- grams of fat consumed

Reference Values: TIMED COLLECTION > or =18 years: 2-7 g fat/24 hours Reference values have not been established for patients who are or =18 years: 2,270-3,850 nmol/mL Oleic Acid, C18:1w9 or =18 years: 650-3,500 nmol/mL Stearic Acid, C18:0 or =18 years: 590-1,170 nmol/mL

Clinical References: Rinaldo P, Matern D, Bennett MJ: Fatty acid oxidation disorders. Ann Rev Physiol 2002;64:477-502 Current as of August 23, 2017 7:11 am CDT


Page 838

POXP

Fatty Acid Profile, Peroxisomal (C22-C26), Plasma

60468

Clinical Information: Peroxisomes are organelles present in all human cells except mature erythrocytes. They carry out essential metabolic functions including beta-oxidation of very long-chain fatty acids (VLCFA), alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include disorders of peroxisomal biogenesis with defective assembly of the entire organelle and single peroxisomal enzyme/transporter defects where the organelle is intact but a specific function is disrupted. Peroxisomal beta-oxidation of VLCFA is impaired in all disorders of peroxisomal biogenesis and in selected single enzyme deficiencies, particularly X-linked adrenoleukodystrophy (X-ALD), resulting in elevated concentrations of VLCFA in plasma or serum. Peroxisomal biogenesis disorders (PBD) include the Zellweger syndrome spectrum disorders that are clinically diverse and range in severity from neonatal lethal (Zellweger syndrome) to more variable clinical courses in neonatal adrenoleukodystrophy and infantile Refsum disease. Affected children typically have hypotonia, poor feeding, distinctive facial features, seizures, and liver dysfunction. Other features can include retinal dystrophy, hearing loss, developmental delays, and bleeding episodes. Rhizomelic chondrodysplasia punctata is another PBD. It is characterized by rhizomelic shortening, chondrodysplasia punctata, cataracts, intellectual disability, and seizures, although it can have a milder phenotype with only cataracts and chondrodysplasia. The typical biochemical profile shows normal VLCFA and elevated phytanic acid. X-ALD is a neurologic disorder affecting the white matter and adrenal cortex. It can present between ages 4 and 8 as a childhood cerebral form with behavioral and cognitive changes, associated with neurologic decline. Other forms include an "Addison disease only" phenotype with adrenocortical insufficiency without initial neurologic abnormality and adrenomyeloneuropathy associated with later-onset progressive paraparesis. X-ALD is an X-linked condition that primarily affects males; however, some females who are carriers can develop later-onset neurologic manifestations. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel (RUSP), a list of conditions that are nationally recommended for newborn screening by the Secretaryâ€™s Advisory Committee on Heritable Disorders in Newborns and Children. Refsum disease is a peroxisomal disorder characterized by anosmia, retinitis pigmentosa, neuropathy, deafness, ataxia, ichthyosis, and cardiac abnormalities. The classic biochemical profile of Refsum disease is an elevated plasma or serum phytanic acid level. Biochemical abnormalities in peroxisomal disorders include accumulations of VLCFA, phytanic, and pristanic acid. The differential diagnosis of these disorders is based on recognition of clinical phenotypes combined with a series of biochemical tests to assess peroxisomal function and structure. These include measurements and ratios of VLCFA, pipecolic acid (PIPA / Pipecolic Acid, Serum; PIPU / Pipecolic Acid, Urine), phytanic acid and its metabolite pristanic acid. In addition, confirmatory testing for X-linked adrenoleukodystrophy (XALDZ / X-Linked Adrenoleukodystrophy, Full Gene Analysis) via molecular genetic analysis is available at Mayo Medical Laboratories.

Useful For: Evaluating patients with possible peroxisomal disorders, including peroxisomal biogenesis disorders, X-linked adrenoleukodystrophy, and Refsum disease An aid in the assessment of peroxisomal function

Interpretation: Reports include concentrations of C22:0, C24:0, C26:0 species, phytanic acid and pristanic acid, and calculated C24:0/C22:0, C26:0/C22:0, and phytanic acid:pristanic acid ratios. When no significant abnormalities are detected, a simple descriptive interpretation is provided. A profile of elevated phytanic acid, low-normal pristanic acid, and normal very long-chain fatty acids is suggestive of Refsum disease (phytanic acid oxidase deficiency); however, phytanic acid concentration may also be increased in disorders of peroxisomal biogenesis and should be considered in the differential diagnosis of peroxisomal disorders. If results are suggestive of hemizygosity for X-linked adrenoleukodystrophy, we also include the calculated value of a discriminating function used to more accurately segregate hemizygous individuals from normal controls. Positive test results could be due to a genetic or nongenetic condition. Additional confirmatory testing would be required to differentiate between these causes.

Reference Values: C22:0 < or =96.3 nmol/mL C24:0 < or =91.4 nmol/mL Current as of August 23, 2017 7:11 am CDT


Page 839

C26:0 < or =1.30 nmol/mL C24:0/C22:0 RATIO < or =1.39 C26:0/C22:0 RATIO < or =0.023 PRISTANIC ACID 0-4 months: < or =0.60 nmol/mL 5-8 months: < or =0.84 nmol/mL 9-12 months: < or =0.77 nmol/mL 13-23 months: < or =1.47 nmol/mL > or =24 months: < or =2.98 nmol/mL PHYTANIC ACID 0-4 months: < or =5.28 nmol/mL 5-8 months: < or =5.70 nmol/mL 9-12 months: < or =4.40 nmol/mL 13-23 months: < or =8.62 nmol/mL > or =24 months: < or =9.88 nmol/mL PRISTANIC/PHYTANIC ACID RATIO 0-4 months: < or =0.35 5-8 months: < or =0.28 9-12 months: < or =0.23 13-23 months: < or =0.24 > or =24 months: < or =0.39

Clinical References: 1. Moser AB, Kreiter N, Bezman L, et al: Plasma very long chain fatty acid assay in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999;45:100-110 2. Wanders RJA: Inborn Errors of Peroxisome Biogenesis and Function. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 323-337

POX

Fatty Acid Profile, Peroxisomal (C22-C26), Serum

81369

Clinical Information: Peroxisomes are organelles present in all human cells except mature erythrocytes. They carry out essential metabolic functions including beta-oxidation of very long-chain fatty acids (VLCFA), alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include disorders of peroxisomal biogenesis with defective assembly of the entire organelle and single peroxisomal enzyme/transporter defects where the organelle is intact but a specific function is disrupted. Peroxisomal beta-oxidation of VLCFA is impaired in all disorders of peroxisomal biogenesis and in selected single enzyme deficiencies, particularly X-linked adrenoleukodystrophy (X-ALD), resulting in elevated concentrations of VLCFA in plasma or serum. Peroxisomal biogenesis disorders (PBD) include the Zellweger syndrome spectrum disorders that are clinically diverse and range in severity from neonatal lethal (Zellweger syndrome) to more variable clinical courses in neonatal adrenoleukodystrophy and infantile Refsum disease. Affected children typically have hypotonia, poor feeding, distinctive facial features, seizures, and liver dysfunction. Other features can include retinal dystrophy, hearing loss, developmental delays, and bleeding episodes. Rhizomelic chondrodysplasia punctata is another PBD. It is characterized by rhizomelic shortening, chondrodysplasia punctata, cataracts, intellectual disability, and seizures, although it can have a milder phenotype with only cataracts and chondrodysplasia. The typical biochemical profile shows normal VLCFA and elevated phytanic acid. X-ALD is a neurologic disorder affecting the white matter and adrenal cortex. It can present between ages 4 and 8 as a childhood cerebral form with behavioral and cognitive changes, associated with neurologic



Page 840

decline. Other forms include an "Addison disease only" phenotype with adrenocortical insufficiency without initial neurologic abnormality and adrenomyeloneuropathy associated with later-onset progressive paraparesis. X-ALD is an X-linked condition that primarily affects males; however, some females who are carriers can develop later-onset neurologic manifestations. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel (RUSP), a list of conditions that are nationally recommended for newborn screening by the Secretaryâ€™s Advisory Committee on Heritable Disorders in Newborns and Children. Refsum disease is a peroxisomal disorder characterized by anosmia, retinitis pigmentosa, neuropathy, deafness, ataxia, ichthyosis, and cardiac abnormalities. The classic biochemical profile of Refsum disease is an elevated plasma or serum phytanic acid level. Biochemical abnormalities in peroxisomal disorders include accumulations of VLCFA, phytanic, and pristanic acid. The differential diagnosis of these disorders is based on recognition of clinical phenotypes combined with a series of biochemical tests to assess peroxisomal function and structure. These include measurements and ratios of VLCFA, pipecolic acid (PIPA / Pipecolic Acid, Serum; PIPU / Pipecolic Acid, Urine), phytanic acid and its metabolite pristanic acid. In addition, confirmatory testing for X-linked adrenoleukodystrophy (XALDZ / X-Linked Adrenoleukodystrophy, Full Gene Analysis) via molecular genetic analysis is available at Mayo Medical Laboratories.

Useful For: Evaluating patients with possible peroxisomal disorders, single-enzyme defects of peroxisomal metabolism such as X-linked adrenoleukodystrophy or peroxisomal biogenesis disorders (Zellweger syndrome spectrum) An aid in the assessment of peroxisomal function

Interpretation: Reports include concentrations of C22:0, C24:0, C26:0 species, phytanic acid and pristanic acid, and calculated C24:0/C22:0, C26:0/C22:0, and phytanic acid:pristanic acid ratios. When no significant abnormalities are detected, a simple descriptive interpretation is provided. A profile of elevated phytanic acid, low-normal pristanic acid, and normal very long-chain fatty acids is suggestive of Refsum disease (phytanic acid oxidase deficiency); however, serum phytanic acid concentration may also be increased in disorders of peroxisomal biogenesis and should be considered in the differential diagnosis of peroxisomal disorders. If results are suggestive of hemizygosity for X-linked adrenoleukodystrophy, we also include the calculated value of a discriminating function used to more accurately segregate hemizygous individuals from normal controls. Positive test results could be due to a genetic or nongenetic condition. Additional confirmatory testing would be required to differentiate between these causes.

Reference Values: C22:0 < or =96.3 nmol/mL C24:0 < or =91.4 nmol/mL C26:0 < or =1.30 nmol/mL C24:0/C22:0 RATIO < or =1.39 C26:0/C22:0 RATIO < or =0.023 PRISTANIC ACID 0-4 months: < or =0.60 nmol/mL 5-8 months: < or =0.84 nmol/mL 9-12 months: < or =0.77 nmol/mL 13-23 months: < or =1.47 nmol/mL > or =24 months: < or =2.98 nmol/mL PHYTANIC ACID 0-4 months: < or =5.28 nmol/mL 5-8 months: < or =5.70 nmol/mL 9-12 months: < or =4.40 nmol/mL Current as of August 23, 2017 7:11 am CDT


Page 841

13-23 months: < or =8.62 nmol/mL > or =24 months: < or =9.88 nmol/mL PRISTANIC/PHYTANIC ACID RATIO 0-4 months: < or =0.35 5-8 months: < or =0.28 9-12 months: < or =0.23 13-23 months: < or =0.24 > or =24 months: < or =0.39

Clinical References: 1. Moser AB, Kreiter N, Bezman L, et al: Plasma very long chain fatty acid assay in 3,000 peroxisome disease patients and 29,000 controls. Ann Neurol 1999;45:100-110 2. Wanders RJA: Inborn Errors of Peroxisome Biogenesis and Function. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 323-337

FBN1B

FBN1, Full Gene Sequence

64514

Clinical Information: Fibrillin-1 is a 320-kD cysteine-rich glycoprotein found in the extracellular matrix. Monomers of fibrillin-1 associate to form microfibrils that provide mechanical stability and elastic properties to connective tissues. Fibrillin-1 is encoded by the FBN1 gene, which contains 65 exons and is located at chromosome 15q21. Pathogenic FBN1 variants are most commonly associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder involving the ocular, skeletal, and cardiovascular systems. Ocular MFS manifestations most commonly include myopia and lens displacement. Skeletal manifestations can include arachnodactyly (abnormally long and slender fingers and toes), dolichostenomelia (long limbs), pectus (chest wall) deformity, and scoliosis. Cardiovascular manifestations, which are the major cause of early morbidity and mortality in MFS, include aortic aneurysm and dissection, as well as mitral valve and tricuspid valve prolapse. There is significant interand intrafamilial variability in the MFS phenotype. Pathogenic FBN1 variants have also been reported in several other rare phenotypes with variable overlap with classic MFS. In some cases, MFS may present in the neonatal period with severe, rapidly progressive disease (previously termed "neonatal Marfan syndrome"). Other FBN1-associated conditions include autosomal dominant ectopia lentis (displacement of the lens of the eye), familial thoracic aortic aneurysm and dissection, isolated skeletal features of MFS, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), Shprintzen-Goldberg syndrome (Marfanoid-craniosynostosis; premature ossification and closure of sutures of the skull), and autosomal dominant Weill-Marchesani syndrome (short stature, short fingers, ectopia lentis). Hundreds of pathogenic variants have been identified in FBN1, many of them unique to individual families. There is a wide range of variability, including intrafamilial variability, in expressivity among pathogenic FBN1 variants. Approximately two-thirds of pathogenic FBN1 variants are missense changes, with the majority of these being cysteine substitutions. Approximately 25% to 33% of pathogenic FBN1 variants are de novo, in which an individual has no family history of disease. Pathogenic FBN1 variants have been shown to occur across the gene. Some genotype-phenotype correlations have been observed, including the association with truncating and splicing variants with risk for aortic dissection, cysteine-based variants, and ectopia lentis, and severe, early onset MFS and variants in exons 24 through 32. Marfan syndrome has significant clinical overlap with a condition called Loeys-Dietz syndrome (LDS); however, the vascular phenotype of LDS can be more severe, and LDS is caused by pathogenic variants in different genes (TGFBR1, TGFBR2, SMAD3, and TGFB2). When the diagnosis of MFS, LDS, or a related disorder is suspected, the use of genetic testing is important to verify the diagnosis and provide appropriate clinical management. Confirmation of the genetic diagnosis also allows for preconception, prenatal, and family counseling.

Useful For: An aid in the diagnosis of FBN1-associated Marfan syndrome, autosomal dominant ectopia lentis, isolated ascending aortic aneurysm and dissection, isolated skeletal features of Marfan syndrome, MASS phenotype (mitral valve prolapse, aortic diameter increased, stretch marks, skeletal features of MFS), Shprintzen-Goldberg syndrome, and autosomal dominant Weill-Marchesani syndrome

Interpretation: Evaluation and categorization of variants is performed using American College of Current as of August 23, 2017 7:11 am CDT


Page 842

Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment. Unless reported or predicted to impact splicing, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. A list of common (presumed benign) FBN1 variants identified for this patient is available from the lab upon request.


Clinical References: 1. Baudhuin LM, Kotzer KE, Lagerstedt SA: Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet Med 2015 Mar;17(3):177-187, doi:10.1038/gim.2014.91 2. Baudhuin LM, Kotzer KE, Lagerstedt SA: Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet 2015 May;60(5):241-252, doi: 10.1038/jhg.2015.10 3. Faivre L, Collod-Beroud G, Loeys BL, et al: Effect of mutation type and location on clinical outcome of 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007;81(3):454-466 4. Loeys BL, Dietz HC, Braverman AC, et al: The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485 5. Boileau C, Jondeau G, Mizuguchi T, Matsumoto N: Molecular genetics of Marfan syndrome. Curr Opin Cardiol 2005 May;20(3):194-200 6. Faivre L, Gorlin RJ, Wirtz MK, et al: In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 2003 Jan;40(1):34-36

FETH2

Feather Panel # 2

81880


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and /or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive



Page 843

3

3.50-17.4 Positive

4


5


6


Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. New York, WB Saunders Company, 2007, Part VI, pp 961-971

FFAPL

Febrile Antibodies Panel

57379

Reference Values: Rickettsia (Typhus Fever) Antibodies (IgG, IgM) with Reflex to Titers Reference Range: Not Detected Rickettsia (RMSF) Antibodies (IgG, IgM) with Reflex to Titers Reference Range: Not Detected Salmonella Antibodies, EIA Reference Range: Not Detected Antibodies to Salmonella flagellar (H) and somatic (O) antigens typically peak 3 â€“ 5 weeks after infection. A positive results in this assay is equivalent to a titer of >=1:160 by tube agglutination (Widal). Results should not be considered as diagnostic unless confirmed by culture. Brucella Antibodies (IgG, IgM), EIA with Reflex to Agglutination Reference Range: or = 10/OIF. The greater the number of leukocytes, the greater the likelihood that an invasive pathogen is present. The finding of many fecal leukocytes is a good indicator of the presence of an Current as of August 23, 2017 7:11 am CDT


Page 844

invasive microbiological pathogen such as Salmonella or Shigella. Few or no leukocytes and many erythrocytes suggests amebiasis. Fecal leukocytes are rarely seen in diarrheas caused by other parasites or viruses.

Reference Values: Interpretive report

Clinical References: Pickering LK, DuPont HL, Olarte J, et al: Fecal leukocytes in enteric infections. Am J Clin Pathol 1977;68:562-565

FOBT 60693

Fecal Occult Blood, Colorectal Cancer Screen, Qualitative, Immunochemical Clinical Information: Colorectal cancer (CRC) is 1 of the most commonly diagnosed cancers in the United States (US), and the second leading cause of cancer-related deaths. CRC almost always develops from adenomatous polyps, yet patients remain asymptomatic until the cancer progresses to a fairly advanced stage. Screening for colorectal cancer is strongly advocated for by the US Preventive Services Task Force, the American Cancer Society, the American College of Gastroenterology, and other clinical societies, due to the high incidence of disease and decrease in mortality with medical intervention. Men and women at average risk for colorectal cancer should be screened at regular intervals beginning at age 50, continuing until age 75. Individuals with certain high-risk factors (age, African-American race, inflammatory intestinal disorders, family history of colon cancer, obesity, diabetes, poor diet) may consider earlier screening strategies. Several options are available for CRC screening and includes fecal occult blood testing (FOBT), sigmoidoscopy, and colonoscopy. FOBT historically utilized guaiac-based tests that identify the presence of hemoglobin based on a nonspecific peroxidase reaction. Guaiac-based FOBT is no longer recommended for cancer screening because it does not detect most polyps and cancers. Furthermore, the false-positive rate with guaiac tests is high if patients do not follow the recommended dietary (withholding notably meat, certain vegetables, iron supplements) or pharmaceutical (withholding nonsteroidal anti-inflammatory drugs, vitamin C) restrictions. Finally, multiple stool collections are needed for optimal interpretation of guaiac-based FOBT results. Fecal immunochemical testing (FIT) has evolved as the preferred occult blood test for colorectal cancer screening due to the lack of specificity and sensitivity of guaiac-based methods. FIT specifically detects the presence of human hemoglobin, eliminating the need for dietary and medication restrictions. For colorectal cancer screening only a single collection is required. The specificity of FIT is routinely >95% with reported sensitivities ranging from 40% to 70% based on the patient population. The clinical specificity of FIT is 97% based on internal studies conducted at Mayo. To evaluate occult GI bleeding in patients with anemia or iron deficiency, the HemoQuant test should be used (HQ / HemoQuant, Feces). Neither FIT nor guaiac testing detects upper gastrointestinal (GI) bleeding because globin and heme are degraded during intestinal transit. In contrast, the HemoQuant test detects occult bleeding equally well from all sources within the GI tract. The HemoQuant test utilizes a specific fluorometric method that will detect any hemoglobin or heme-derived porphyrins in the stool, is very sensitive, and provides quantitative results.

Useful For: Colorectal cancer screening Screening for gastrointestinal bleeding Interpretation: This is a quantitative assay but results are reported qualitatively as negative or positive for the presence of fecal occult blood; the cutoff for positivity is 100 ng/mL hemoglobin. The following comments will be reported with the qualitative result for patients >17 years: -Positive results; further testing is recommended if clinically indicated. This test has 97% specificity for detection of lower gastrointestinal bleeding in colorectal cancer. -Negative results; this test will not detect upper gastrointestinal bleeding; HQ / HemoQuant, Feces test should be ordered if clinically indicated.

Reference Values: Negative This test has not been validated in a pediatric population, results should be interpreted in the context of the patient's presentation.

Clinical References: 1. Levin B, Lieberman DA, McFarland B, et al: Screening and Surveillance for Current as of August 23, 2017 7:11 am CDT


Page 845

the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 2008;58:130 2. Whitlock EP, Lin JS, Liles E, et al: Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2008;149:638 3. Hol L, Wilschut JA, van Ballegooijen M, et al: Screening for colorectal cancer: random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels. Br J Cancer 2009;100:1103 4. Levi Z, Rozen P, Hazazi R, et al: A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med 2007;146:244 5. Tannous B, Lee-Lewandrowski E, Sharples C, et al: Comparison of conventional guaiac to four immunochemical methods for fecal occult blood testing: implications for clinical practice in hospital and outpatient settings. Clin Chem Acta 2009;400:120-122

FELBA

Felbamate (Felbatol), Serum

80782

Clinical Information: Felbamate is an anticonvulsant drug approved for treatment of partial seizures with or without secondary generalization in persons >14 years of age. It is also approved for Lennox-Gastout syndrome in children >2 years of age. Felbamate is well absorbed (>90%) and is metabolized by the hepatic cytochrome P450 system. Metabolites lack anticonvulsant activity. The elimination half-life of felbamate ranges from 13 to 23 hours. Optimal response to felbamate is seen with serum concentrations between 30 mcg/mL to 60 mcg/mL. Patients who are elderly or have renal dysfunction may require reduced dosing; felbamate should not be given to individuals with hepatic disease. Toxicity can be severe, including life-threatening aplastic anemia or liver failure, but no defined toxic concentration has been established. Coadministration of felbamate increases the concentration of phenytoin and valproic acid, decreases carbamazepine concentration, and increases carbamazepine-10,11-epoxide (its active metabolite). Conversely, coadministration of phenytoin or carbamazepine causes a decrease in felbamate concentration.

Useful For: Determining whether a poor therapeutic response is attributable to noncompliance or lack of drug effectiveness Monitoring changes in serum concentrations resulting from interactions with coadministered drugs such as barbiturates and phenytoin

Interpretation: Optimal response to felbamate is associated with serum concentrations of 30 mcg/mL to 60 mcg/mL. Toxic serum concentrations for felbamate have not been established.

Reference Values: 30.0-60.0 mcg/mL

Clinical References: 1. Johannessen, SI, Tomson, T: Pharmacokinetic Variability of Newer Antiepileptic Drugs: When is Monitoring Needed? Clin Pharmacokinet 2006; 45 (11): 1061-10752. Schmidt D: Felbamate: successful development of a new compound for the treatment of epilepsy. Epilepsia 1996;34(Suppl 7):S30-S33 2. Patsalos PN: Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008 Jul;49(7): 1239-1276

FESE

Fennel Seed, IgE

82363




Page 846




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FNTSX

Fentanyl and Metabolite, Chain of Custody, Serum

62727

Clinical Information: Fentanyl is an extremely fast acting synthetic opioid related to the phenylpiperidines.(1,2) It is available in injectable as well as transdermal formulations.(1) The analgesic effects of fentanyl is similar to those of morphine and other opioids (1); it interacts predominantly with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues.(1,3) Fentanyl is approximately 80% to 85% protein bound.(1) Fentanyl plasma protein binding capacity decreases with increasing ionization of the drug. Alterations in pH may affect its distribution between plasma and the central nervous system. The average volume of distribution for fentanyl is 6 L/kg (range 3-8).(3,4) In humans, the drug appears to be metabolized primarily by oxidative N-dealkylation to norfentanyl and other inactive metabolites that do not contribute materially to the observed activity of the drug. Within 72 hours of intravenous (IV) administration, approximately 75% of the dose is excreted in urine, mostly as metabolites with 1.0 ng/mL is a strong indicator that the patient has used fentanyl.

Reference Values: Negative Cutoff concentrations: Immunoassay screen C is a variant of the FECH gene associated with reduced gene expression. This variant is found in approximately 10% of the general Caucasian population. Autosomal recessive inheritance (2 pathogenic mutations in trans) is infrequent, accounting for 2.0 or an average of 6 or more copies of the FGFR1 locus are observed per tumor nucleus. A tumor with an FGFR1:D8Z2 ratio < or =2.0 and having an average of 1.0 mcg/mL are associated with a high rate of cardiac adverse experiences such as conduction defects or bradycardia. Therapeutic concentration: 0.2 to 1.0 mcg/mL. Toxic concentration: >1.0 mcg/mL

Reference Values: 0.2-1.0 mcg/mL

Clinical References: 1. Burtis CA, Ashwood ER, Bruns DE, et al: Tietz Textbook of Clinical Chemistry and Molecular Diagnosis (Fifth edition), Elsevier, St. Louis, USA, 2012 2. Josephson ME, Buxton AE, Marchlinski FE: The tachyarrhythmias: tachycardias. In Harrison's Principles of Internal Medicine. 12th edition. Edited by JD Wilson, E Braunwald, KJ Isselbacher, et al: New York, McGraw-Hill Book Company, 1991, p 915

FLG

FLG Gene, Mutation Analysis

35426

Clinical Information: Ichthyosis vulgaris is a common disease with an incidence rate of approximately 1 in 250. It is characterized by palmar hyperlinearity, keratosis pilaris, xerosis, and prominent fine scaling of the extensor surfaces of the extremities, the scalp, central part of the face, and the trunk. The clinical onset typically occurs within the first few years of life. Approximately 37% to 50% of people with ichthyosis vulgaris have atopic diseases and about 8% of patients with atopic diseases have classic features of ichthyosis vulgaris. A large number of epidemiological studies support an increased risk and severity of asthma that occurs in association with atopic disease. Clinical presentation associated with ichthyosis vulgaris can be confirmed by genetic testing. Ichthyosis vulgaris is caused by loss-of-function alterations in the filaggrin (FLG) gene on chromosome 1q21. Filaggrin is a filament aggregating protein that promotes terminal differentiation of the epidermis and skin barrier formation. This prevents epidermal water loss and inhibits entry of allergens, toxic chemicals, and infectious organisms. Loss of filaggrin expression causes cytoskeletal disorganization leading to clinical phenotype associated with ichthyosis vulgaris. FLG mutations are found in about 7.7% of Europeans and 3% of Asians. However, these mutations appear to be less common in dark-skinned ethnicities. The R501X and 2282del4 are complete loss-of-function mutations accounting for approximately 80% of mutations in the Northern European population. However, they are rarer in the Southern European population. These 2 alterations have been shown to be very strong predisposing factors for atopic diseases. FLG mutations in other ethnicities are different than those found in European-origin populations. This disease is inherited in a semidominant manner (ie, heterozygotes have either no symptoms or milder ichthyosis vulgaris and homozygotes/compound heterozygotes show marked ichthyosis vulgaris).

Useful For: Genetic diagnosis of ichthyosis vulgaris for clinical management, risk assessment for atopic diseases and atopic disease-associated asthma, and genetic counseling for family members

Interpretation: All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Current as of August 23, 2017 7:11 am CDT


Page 867

Reference Values: Interpretive report will be provided.

Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Smith FJD, Irvine AD, Terron-Kwiatkowski A, et al: Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006;38:337-342 3. Thyssen JP, Godoy-Gijon E, Elias PM: Ichthyosis vulgaris-the filaggrin mutation disease. Br J Dermatol 2013 Jun;168(6):1155-1166 4. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006 Apr;38(4):441-446

60875

FLI-1, Immunostain Without Interpretation Clinical Information: Friend leukemia virus integration 1 (FLI1) is a member of the erythroblast transformation specific (ETS) family of transcription factors. It has antiapoptotic activity and also interferes with nuclear hormone receptor signaling. A chromosomal translocation between the FLI1 gene and the EWS gene is found in most Ewing sarcomas. In normal tissues, nuclear staining for FLI1 is seen in endothelial cells, a subset of T cells, megakaryocytes, and normal breast epithelium. Studies have shown FLI1 expression in endothelial-derived tumors, Ewing sarcoma, Merkel cell carcinoma, lung adenocarcinoma, melanoma, and erythroleukemia, and lack of expression in rhabdomyosarcoma, desmoplastic round cell tumors, and colon adenocarcinoma.

Useful For: An aid in phenotyping endothelial-derived tumors, Ewing sarcoma, Merkel cell carcinoma, lung adenocarcinoma, melanoma, and erythroleukemia

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Folpe AL, Hill CE, Parham DM, et al: A study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 2000;24(12):1657-1662 2. Pusztaszeri MP, Seelentag W, Bosman FT, et al: Immuno-histochemical expression of endothelial markers CD31, CD34, von Willebrand factor and fli-1 in normal human tissues. J Histochem Cytochem 2006;54:385-395 3. Folpe AL, Chand EM, Goldblum JR, et al: Expression of fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. AM J Surg Pathol 2001;25(8):1061-1066

FLNDR

Flounder (Bothidae/Pleuronectidae Fam) IgE

57895


Reference Values: 4 mcmol/L. Chronic fluorosis may produce osteosclerosis, periostitis, calcification of ligaments and tendons, and crippling deformities. Prolonged exposure to the fluoride-containing antifungal agent voriconazole can produce high plasma fluoride concentrations and bone changes (periostitis).

Useful For: Assessing accidental fluoride ingestion Monitoring patients receiving sodium fluoride for bone disease or patients receiving voriconazole therapy

Interpretation: Humans exposed to fluoride-treated water typically have plasma fluoride in the range of 1 to 4 mcmol/L. Those who are not drinking fluoride-treated water have plasma fluoride 4 mcmol/L indicate excessive exposure and are associated with periostitis.

Reference Values: 0.0-4.0 mcmol/L Current as of August 23, 2017 7:11 am CDT


Page 869

Clinical References: 1. Cardos VES, Whitford GH, Aoyama H, et al: Daily variations in human plasma fluoride concentrations. J Fluorine Chem 2008:129;1193-1198 2. Wermers RA, Cooper K, Razonable RR, et al: Long term use of voriconazole, a fluoride containing medication, is associated with periostitis, fluorosis, and fluoride excess in transplant patients. Clin Infect Dis 2011;52:604-611

FLUOX

Fluoxetine, Serum

80228

Clinical Information: Fluoxetine is a selective serotonin reuptake inhibitor approved for treatment of bulimia, obsessive-compulsive behavior, panic, premenstrual dysphoria, and major depressive disorder, with a variety of off-label uses. Both fluoxetine and its major metabolite, norfluoxetine, are pharmacologically active, and are reported together in this assay. Most individuals respond optimally when combined serum concentrations for both parent and metabolite are in the therapeutic range (120-300 ng/mL) at steady state. Due to the long half-lives of parent and metabolite (1-6 days), it may take several weeks for patients to reach steady-state concentrations. Fluoxetine is a potent inhibitor of the metabolic enzyme CYP2D6, with lesser inhibitory effects on CYP2C19 and CYP3A. Therapy with fluoxetine is therefore subject to numerous drug interactions, which is compounded by wide interindividual variability in fluoxetine pharmacokinetics. Measurement of the drug is useful for managing comedications, dose or formulation changes, and in assessing compliance. Side effects are milder for fluoxetine than for older antidepressants such as the tricyclics. The most common side effects of fluoxetine therapy include nausea, nervousness, anxiety, insomnia, and drowsiness. Anticholinergic and cardiovascular side effects are markedly reduced compared to tricyclic antidepressants. Fatalities from fluoxetine overdose are extremely rare.

Useful For: Monitoring serum concentration of fluoxetine during therapy Evaluating potential toxicity Evaluating patient compliance

Interpretation: Most individuals display optimal response to fluoxetine when combined serum levels of fluoxetine and norfluoxetine are between 120 and 300 ng/mL. Some individuals may respond well outside of this range, or may display toxicity within the therapeutic range, thus interpretation should include clinical evaluation. A toxic range has not been well established.

Reference Values: Fluoxetine + norfluoxetine: 120-300 ng/mL

Clinical References: 1. Wille SM, Cooreman SG, Neels, HM, Lambert WE: Relevant issues in the monitoring and toxicology of antidepressants. Crit Rev Clin Lab Sci 2008;45(1):25-89 2. Baumann P, Hiemke C, Ulrich S, et al: The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004;37:243-265

PROLX

Fluphenazine (Prolixin), Serum

80458

Reference Values: Reference Range: 1.0 - 10 ng/mL

FFLUR

Flurazepam (Dalmane) and Desalkylflurazepam

90091

Reference Values: Flurazepam: Reference Range: 0 - 30 ng/mL Desalkylflurazepam: Reference Range: 30 - 150 ng/mL Flurazepam + Desalkyflurazepam: Reference Range: 30 - 180 ng/mL



Page 870

17BFP

Fluticasone 17-Beta-Carboxylic Acid, Urine

89739

Clinical Information: Inhaled corticosteroids are the single most effective therapy for adult patients with asthma. Even low doses of inhaled corticosteroids have been shown to reduce mortality related to asthma. The September 2007 issue of Pediatrics reported that "Verification of (asthma) treatment adherence by objective measures remains necessary."(1) In this pediatric asthma adherence study, the 104 asthmatic children and their parents grossly overestimated their medication adherence. Over 1 of 3 responses reported full compliance to medications when no medications had been taken. Over 46% of individuals exaggerated their adherence by at least 25%. The authors concluded that "Under the best of conditions in this study, accuracy of self-report was insufficient to provide a stand-alone measure of adherence."(1,2) Fluticasone propionate (FP) is an inhaled corticosteroid with anti-inflammatory and immunosuppressive properties commonly used for the treatment of asthma, airway inflammation, and allergic rhinitis. FP is typically well tolerated and has a low risk for adverse systemic effects when utilized at recommended therapeutic doses. However, noncompliance with recommended FP therapy may result in poorly controlled asthma or misinterpretation of the patient's therapeutic responsiveness. Patients with excessive exposure to FP may present with clinical features of Cushing syndrome, but with evidence of hypothalamus-pituitary-adrenal axis suppression, including suppressed cortisol levels. Conversely, a patient not administering the drug as recommended may have their therapeutic responsiveness interpreted, in error by the patient or clinician, as steroid-resistance. FP has low oral bioavailability and high hepatic first-pass metabolism, which results in low plasma FP concentrations; any systemic levels are believed to occur through adsorption from the lungs. Native FP absorbed by the gastrointestinal tract (40 IU/L) -Primary ovarian hypofunction in females -Primary hypogonadism in males Normal or decreased FSH in: -Polycystic ovary disease in females FSH and LH are both decreased in failure of the pituitary or hypothalamus.

Reference Values: Males 1-7 days: < or =3.0 IU/L 8-14 days: < or =1.4 IU/L 15 days-3 years: < or =2.5 IU/L 4-6 years: < or =6.7 IU/L 7-8 years: < or =4.1 IU/L 9-10 years: < or =4.5 IU/L 11 years: 0.4-8.9 IU/L 12 years: 0.5-10.5 IU/L 13 years: 0.7-10.8 IU/L 14 years: 0.5-10.5 IU/L 15 years: 0.4-18.5 IU/L 16 years: < or =9.7 IU/L 17 years: 2.2-12.3 IU/L > or =18 years: 1.0-18.0 IU/L Current as of August 23, 2017 7:11 am CDT


Page 873

TANNER STAGES* Stage l: < or =3.7 IU/L Stage ll: < or =12.2 IU/L Stage lll: < or =17.4 IU/L Stage lV: 0.3-8.2 IU/L Stage V: 1.1-12.9 IU/L *Puberty onset occurs for boys at a median age of 11.5 (+/- 2) years. For boys there is no proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage V (adult) should be reached by age 18. Females 1-7 days: < or =3.4 IU/L 8-14 days: < or =1.0 IU/L 15 days-6 years: < or =3.3 IU/L 7-8 years: < or =11.1 IU/L 9-10 years: 0.4-6.9 IU/L 11 years: 0.4-9.0 IU/L 12 years: 1.0-17.2 IU/L 13 years: 1.8-9.9 IU/L 14-16 years: 0.9-12.4 IU/L 17 years: 1.2-9.6 IU/L > or =18 years: Premenopausal Follicular: 3.9-8.8 IU/L Midcycle: 4.5-22.5 IU/L Luteal: 1.8-5.1 IU/L Postmenopausal: 16.7-113.6 IU/L TANNER STAGES* Stage l: 0.4-6.7 IU/L Stage ll: 0.5-8.7 IU/L Stage lll: 1.2-11.4 IU/L Stage lV: 0.7-12.8 IU/L Stage V: 1.0-11.6 IU/L *Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for girls at a median age of 10.5 (+/- 2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African American girls. Progression through Tanner stages is variable. Tanner stage V (adult) should be reached by age 18. Pediatric ranges derived for DXI method from analytic comparison to reference method in: Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), cortisol and ferritin in neonates, children and young adults. Clin Chem Lab Med 2002;40(11):1151-1160

Clinical References: 1. Demers LM, Vance ML: Pituitary function. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis: Elsevier Saunders Company, 2006, pp 1984-1989 2. Haymond S, Gronowski AM: Reproductive related disorders. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis: Elsevier Saunders Company, 2006, pp 2101 -2127 3. Instruction manual: UniCel DXI 800 FSH Assay. Beckman Coulter, Inc., Fullerton, CA, 2010

60876

Follicle-Stimulating Hormone, Alpha-Subunit (Alpha FSH), Immunostain Without Interpretation



Page 874

Clinical Information: Follicle-stimulating hormone (FSH), alpha subunit is a component common to all of the glycoprotein hormones produced by the anterior pituitary (luteinizing hormone: LH, thyroid-stimulating hormone: TSH, and FSH). Glycoprotein hormone-producing cells (approximately 30% of the total cell population) in normal pituitary stain in a cytoplasmic pattern. Immunohistochemical detection of alpha-FSH may be useful in the classification of pituitary adenomas.

Useful For: Aids in the classification of pituitary adenomas and neoplasms with ectopic hormone production

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Hamid Z, Mrak RE, Ijaz MT, Faas FH: Sensitivity and specificity of immunohistochemistry in pituitary adenomas. Endocrinologist 2009;19(1):38-43 2. Osamura RY, Kajiya H, Takei M, et al: Pathology of the human pituitary adenomas. Histochem Cell Biol 2008;130(3):495-507 3. Osamura RY, Watanabe K: Immunohistochemical studies of human FSH producing pituitary adenomas. Virchows Archiv A 1988;413(1):61-68 4. Pawlikowski M, Pisarek H, Kubiak R. et al: Immunohistochemical detection of FSH receptors in pituitary adenomas and adrenal tumors. Folia Histochem Cytobiol 2012;50(3):325-330

FOOD6

Food Panel

81874





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4




Page 875

5


6



FDP1

Food Panel # 2

86207





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FFPG4

Food Panel IgG4 (532)



Page 876

Reference Values: Corn IgG4 Egg White IgG4 Egg Yolk IgG4 Milk Cow IgG4 Peanut IgG4 Soybean IgG4 Wheat IgG4 Yeast (Saccharomyces cerevisiae) IgG4

FFPII

Food Panel II IgG

57850

Reference Values:

The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG4 tests has not been clearly established. These tests can be used in special clinical situations to select foods for evaluation by diet elimination and challenge in patients who have food-related complaints, and to evaluate food allergic patients prior to food challenges. The presence of food-specific IgG4 alone cannot be taken as evidence of food allergy and only indicates immunologic sensitization to the food allergen in question.

Barley IgG or =100 Strongly positive Reference values apply to all ages.



Page 885


FXS

Fragile X Syndrome, Molecular Analysis

35428

Clinical Information: Fragile X syndrome is an X-linked disorder with variable expression in males and females. It is caused by an expansion of the CGG trinucleotide repeat in the FMR1 gene, located on the X chromosome. This trinucleotide repeat is polymorphic in the general population, with the number of repeats ranging from 5 to 44. These normal alleles are passed from generation to generation with the number of repeats remaining constant. Small expansions, called premutations, most often range from 59 to 200 CGG repeats. Premutation carriers do not exhibit features of fragile X syndrome, but are at risk for other FMR1-related disorders such as fragile X tremor/ataxia syndrome (FXTAS) and premature ovarian failure (POF). Transmission of a premutation by a male to his daughter usually results in little or no change in the CGG repeat number. Transmission of a premutation by a female to her son or daughter usually results in further expansion, either to a larger premutation or a full mutation. The risk for a female premutation carrier to have a child affected with fragile X syndrome by expansion to a full mutation increases with the number of CGG repeats in the premutation. Full mutations can be 200 to thousands of repeats long, and are associated with abnormal methylation of a region adjacent to the FMR1 gene. This is thought to interfere with normal FMR1 gene expression, resulting in fragile X syndrome. There are multiple clinical phenotypes associated with expansion (premutations and full mutations) in the FMR1 gene. Fragile X Syndrome: Approximately 1/4000 individuals (male and female) are affected with fragile X syndrome. Most affected males exhibit moderate mental retardation, with affected females having milder (if any) cognitive deficiency. Neuropsychiatric diagnoses such as autism spectrum and anxiety disorders are common. Characteristic physical features include a long face with prominent jaw, protruding ears, connective tissue abnormalities, and large testicles in postpubertal males. Fragile X Tremor/Ataxia Syndrome (FXTAS): FXTAS is a neurodegenerative disorder that is clinically distinct from fragile X syndrome. Both male and female premutation carriers are at risk for FXTAS. However, the disorder is much less common, milder in presentation, and shows a later age of onset in females. Clinical hallmarks of the disorder include intention tremor, gait ataxia, dementia, and neuropsychiatric symptoms. The risk for FXTAS increases as the number of CGG repeats increases, and the majority of individuals with FXTAS have CGG repeat expansions of 70 or more. Penetrance of clinical symptoms is associated with increasing age, with the majority of affected males showing symptoms between age 70 and 90. Premature Ovarian Failure (POF): Female premutation carriers are at risk for increased follicular stimulating hormone (FSH) levels, early menopause, and POF. Penetrance and early onset of female reproductive symptoms correlates with increasing size of the CGG repeat, and reaches its highest penetrance at approximately 80 to 90 repeats. Of note, penetrance actually remains stable or may even decrease at approximately 100 repeats. There is no risk for increased penetrance of the POF phenotype due to maternal or paternal inheritance of the expanded CGG repeat.

Useful For: Determination of carrier status for individuals with a family history of fragile X syndrome or X-linked mental retardation Confirmation of a diagnosis of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian failure caused by expansions in the FMR1 gene Prenatal diagnosis of fragile X syndrome when there is a documented FMR1 expansion in the family

Interpretation: An interpretive report will be provided. Reference Values: Normal alleles: 5-44 CGG repeats Intermediate (grey zone) alleles: 45-54 CGG repeats Premutation alleles: 55-200 CGG repeats Full mutation alleles: >200 CGG repeats An interpretive report will be provided.

Clinical References: 1. Jacquemont S, Hagerman RJ, Hagerman PJ, Leehey MA: Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 2007;6(1):45-55 2. Mc-Conkie-Rosell A, Finucane B, Cronister A, et al: Genetic counseling for fragile X Syndrome: updated recommendations of the National Society of Genetic Counselors. J Genet Couns Current as of August 23, 2017 7:11 am CDT


Page 886

2005;14(4):249-270 3. Sherman S, Pletcher BA, Driscoll DA: Fragile X syndrome: diagnostic and carrier testing (ACMG Practice Guideline). Genet Med 2005;7:584-587

FUFXS

Fragile X, Follow up Analysis

35427

Reference Values: This is not an orderable test. This follow-up test is added by the laboratory dependent upon on the result of the PCR analysis (FXS / Fragile X Syndrome, Molecular Analysis).

FRANC

Francisella Tularensis Antibody

91552

Clinical Information: Tularemia antibody titers > or = to 1:40 are of diagnostic significance. However, titers in this range may also indicate previous infection. Antibody begins to appear 2-3 week post-onset and generally peaks at approximately 5 weeks into the disease. With this delay in antibody appearance a second specimen will usually demonstrate a diagnostic four-fold rise in titer for patients with active disease.

Interpretation: Interpretive Criteria: or =1:160 Positive In the presence of compatible symptoms, a Francisella tularensis antibody titer of 1:160 or greater in an acute specimen supports a presumptive diagnosis of tularemia. However, a titer > or =1:160 may also reflect past infection. An equivocal titer may be due to cross-reactive antibodies (Brucella, Yersinia, or Proteus OX19), past infection, or very recent infection. A four-fold rise in titer between acute and convalescent sera is required for definitive serologic diagnosis of tularemia.

Reference Values: Reference Range: or =16 years: 0.00-0.72 mmol/L Reference values have not been established for patients who are 0.5 mcg/g) observed in affected dermal tissue specimens collected more than 48 hours after administration of gadolinium-containing contrast media indicates gadolinium deposition. These patients may have increased risk of nephrogenic systemic fibrosis (NSF). In individuals with NSF, affected tissues are likely to contain gadolinium at concentrations in the range of 4 to 186 mcg/g. Unaffected tissues from gadolinium-exposed subjects exhibit gadolinium concentration of 0.6 to 28 mcg/g. A reportable gadolinium concentration in tissue suggests recent administration of gadolinium-containing contrast media. Patients with increased gadolinium in affected dermal tissue have an increased risk to develop NSF.

Reference Values: 3 ng/mL) observed in serum specimens draw >96 hours after administration of gadolinium-containing contrast media is not typical of most patients with normal renal function, indicating impaired elimination of gadolinium or exposure to anthropogenic sources. Patients with reduced renal function who have been exposed to gadolinium may have an increased risk to develop nephrogenic systemic fibrosis. A normal value is or =0.7 nmol/h/mg of hemoglobin

Clinical References: 1. Li, Y, Ptolemy AS, Harmonay L, et al: Ultra fast and sensitive liquid chromatography tandem mass spectrometry based assay for galactose-1-phosphate uridylyltransferase and galactokinase deficiencies. Mol Gen Metab 2011;102(1):33-40 2. Ko DH, Jun SH, Park HD, et al: Multiplex enzyme assay for galactosemia using ultraperformance liquid chromatography-tandem mass spectrometry. Clin Chem 2010;56:764-771 3. Hennermann JB, Schadewaldt P, Vetter B, et al: Features and outcome of galactokinase deficiency in children diagnosed by newborn screening. J Inherit Metab Dis 2011;34:399-407 4. Walter JH, Fridovich-Keil JL: Galactosemia. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill, New York, 2014, Accessed January 26, 2016. Available at: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62672411

GALP

Galactose, Quantitative, Plasma

83638

Clinical Information: Galactosemia is an autosomal recessive disorder that results from a deficiency of any 1 of the 3 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). GALT deficiency is the most common cause of galactosemia and is often referred to as classic galactosemia. The complete or near-complete deficiency of GALT enzyme is life-threatening if left untreated. Complications in the neonatal period include failure to thrive, liver failure, sepsis, and death; even with survival, long-term intellectual disability can result. Galactosemia is treated by a galactose-restricted diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, individuals with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Females with galactosemia are at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of classic galactosemia in the United States is 1 in 30,000, although literature reports range from 1 in 10,000 to 1 in 60,000 live births. A comparison of plasma and urine galactose and blood galactose-1-phosphate (Gal-1-P) levels may be useful in distinguishing among the 3 forms of galactosemia. See Galactosemia Testing Algorithm in Special Instructions for additional information. Deficiency Galactose (Plasma/Urine) Gal-1-P (Blood) GALK Elevated Normal GALT Elevated Elevated GALE Normal-Elevated Elevated

Useful For: Screening for galactosemia Interpretation: Additional testing is required to investigate the cause of abnormal results. In patients with galactosemia, elevated galactose in plasma or urine may suggest ineffective dietary restriction or compliance; however, the concentration of galactose-1-phosphate in erythrocytes (GAL1P / Galactose-1-Phosphate [Gal-1-P], Erythrocytes) is the most sensitive index of dietary control. Increased concentrations of galactose may also be suggestive of severe hepatitis, biliary atresia of the newborn, and, in rare cases, galactose intolerance. If results are outside the normal range and galactosemia is suspected, additional testing to identify the specific enzymatic defect is required. Results should be correlated with clinical presentation and confirmed by specific enzyme or molecular analysis. See Galactosemia Testing Algorithm in Special Instructions for follow-up of abnormal newborn screening results, comprehensive diagnostic testing, and carrier testing. See GALT / Galactose-1-Phosphate Uridyltransferase (GALT), Current as of August 23, 2017 7:11 am CDT


Page 904

Blood for GALT testing, GALK / Galactokinase, Blood for GALK testing, and GALE / UDP-Galactose-4â€™ Epimerase (GALE), Blood for GALE testing.

Reference Values: 1-7 days: or =24.5 nmol/h/mg of hemoglobin

Clinical References: 1. Berry GT: Classic Galactosemia and Clinical Variant Galactosemia. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Retrieved 03/11/2015. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1518/ 2. Walter JH, Fridovich-Keil JL: Galactosemia. In The Metabolic and Molecular Bases of Inherited Disease. Edited by Valle D, Beaudet AL, Vogelstein B, et al. New York, McGraw-Hill, 2014. Accessed January 26, 2016. Available at http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62672411 Current as of August 23, 2017 7:11 am CDT


Page 907

GALTP 80341

Galactose-1-Phosphate Uridyltransferase Biochemical Phenotyping, Erythrocytes Clinical Information: Galactosemia is an autosomal recessive disorder that results from a deficiency of any 1 of the 3 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). GALT deficiency is the most common cause of galactosemia and is often referred to as classic galactosemia. The complete or near-complete deficiency of GALT enzyme is life-threatening if left untreated. Complications in the neonatal period include failure to thrive, liver failure, sepsis, and death; even with survival, long-term intellectual disability can result. Galactosemia is treated by a galactose-restricted diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, individuals with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Females with galactosemia are at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of classic galactosemia in the United States is approximately 1 in 30,000, although literature reports range from 1 in 10,000 to 1 in 60,000 live births. Duarte-variant galactosemia (compound heterozygosity for the Duarte mutation, N314D, and a classic mutation) is generally associated with higher levels of enzyme activity (5%-20%) than classic galactosemia (22.1 ng/mL had a significant association with mortality and New York Heart Association (NYHA) classification. However, this was an older population and definitive evidence of cardiac disease was not documented.

Reference Values: or =18 years: < or =22.1 ng/mL

Clinical References: 1. Weintraub NL, Collins SP, Pang PS, et al: Acute heart failure syndromes: emergency department presentation, treatment, and disposition: current approaches and future aims: a scientific statement from the American Heart Association. Circulation 2010;122:1975-1996 2. Felker GM, Fiuzat M, Shaw LK, et al: Galectin-3 in ambulatory patients with heart failure: results from the HF-ACTION Study. Circ Heart Fail 2012 Jan;5(1):72-78 3. Lok DJ, Van Der Meer P, de la Porte PW, et al: Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol 2010 May;99(5):323-328 4. de Boer RA, Lok DJ, Jaarsma T, et al: Predictive value of plasma galectin-3 levels in heart failure with reduced and preserved ejection fraction. Ann Med 2011 Feb;43(1):60-68 5. Christenson RH, Duh SH, Wu AH, et al: Multi-center determination of galectin-3 assay performance characteristics: Anatomy of a novel assay for use in heart failure. Clin Biochem 2010 May;43(7-8):683-690 6. Meeusen JW, Johnson JN, Gray A, et al: Soluble ST2 and galectin-3 in pediatric patients without heart failure. Clin Biochem 2015;Dec;48(18):1337-1340

GALTZ

GALT Gene, Full Gene Analysis

35435

Clinical Information: Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The complete or near complete deficiency of the GALT enzyme is life threatening. If left untreated, complications include liver failure, sepsis, mental retardation, and death. Galactosemia is treated by a galactose-free diet, which allows for rapid recovery from the acute symptoms and a generally good prognosis. Despite adequate treatment from an early age, children with galactosemia remain at increased risk for developmental delays, speech problems, and abnormalities of motor function. Females with galactosemia are at increased risk for premature ovarian failure. The prevalence of classic galactosemia is approximately 1 in 30,000. Duarte variant galactosemia (compound heterozygosity for the Duarte variant, N314D, and a classic mutation) is generally associated with higher levels of GALT activity (5%-20%) than classic galactosemia (Asp, GGT>GAT], Hb F-Chori-I [AyT16(A13)Gly->Asp, GGC>GAC] and Hb F-Chori-II [AyI29(B11)Gly->Glu, GGA>GAA]. Hemoglobin 2012;36:305-309 3. Akinsheye I, Alsultan A, Solovieff N, et al: Fetal hemoglobin in sickle cell anemia. Blood 2011;118:19-27 4. Disorders of Hemoglobin Genetics, Pathophysiology, and Clinical Management. Second edition. Edited by M Steinberg, B Forget, D Higgs, D Weatherall. New York, Cambridge University Press, 2009 5. Molecular Hematology. Third edition. Edited by D Provan, J Gribben. Malden, Massachusets, Blackwell Publishing, 2010 6. Color Atlas of Hemoglobin Disorders: A Compendium Based on Proficiency Testing. Edited by JD Hoyer, SH Kroft. Northfield, IL. College of American Pathologists, 2003 7. Merchant S, Oliveira JL, Hoyer JD, Viswanatha DS: Chapter 24. Molecular diagnosis in hematopathology. In Hematopathology: A Volume in the Series: Foundations in Diagnostic Pathology. Second edition. Edited by J Goldblum. E Hsi. Churchill Livingstone. 2012

GGT

Gamma-Glutamyltransferase (GGT), Serum

8677

Clinical Information: Gamma-glutamyltransferase (GGT) is primarily present in kidney, liver, and pancreatic cells. Small amounts are present in other tissues. Even though renal tissue has the highest level of GGT, the enzyme present in the serum appears to originate primarily from the hepatobiliary system, and GGT activity is elevated in any and all forms of liver disease. It is highest in cases of intra- or post-hepatic biliary obstruction, reaching levels some 5 to 30 times normal. It is more sensitive than alkaline phosphatase (ALP), leucine aminopeptidase, aspartate transaminase, and alanine aminotransferase in detecting obstructive jaundice, cholangitis and cholecystitis; its rise occurs earlier than with these other enzymes and persists longer. Only modest elevations (2-5 times normal) occur in infectious hepatitis, and in this condition GGT determinations are less useful diagnostically than are measurements of the transaminases. High elevations of GGT are also observed in patients with either primary or secondary (metastatic) neoplasms. Elevated levels of GGT are noted not only in the sera of patients with alcoholic cirrhosis but also in the majority of sera from persons who are heavy drinkers. Studies have emphasized the value of serum GGT levels in detecting alcohol-induced liver disease. Elevated serum values are also seen in patients receiving drugs such as phenytoin and phenobarbital, and this is thought to reflect induction of new enzyme activity. Normal values are observed in various muscle diseases and in renal failure. Normal values are also seen in cases of skeletal disease, children older than 1 year, and in healthy pregnant women-conditions in which ALP is elevated.

Useful For: Diagnosing and monitoring hepatobiliary disease, it is currently the most sensitive enzymatic indicator of liver disease Ascertaining whether observed elevations of alkaline phosphatase are due to skeletal disease (normal gamma-glutamyltransferase: GGT) or reflect the presence of hepatobiliary disease (elevated GGT) A screening test for occult alcoholism

Interpretation: An elevation of gamma-glutamyltransferase (GGT) activity is seen in any and all forms of liver disease, although the highest elevations are seen in intra- or post-hepatic biliary obstruction. Elevated values can also indicate alcoholic cirrhosis or individuals who are heavy drinkers. The finding of increased GGT and alkaline phosphatase (ALP) activity is consistent with hepatobiliary disease. The finding of normal GGT activity and increased ALP activity is consistent with skeletal disease.

Reference Values: Males 1-6 years: 7-19 U/L 7-9 years: 9-22 U/L 10-13 years: 9-24 U/L 14-15 years: 9-26 U/L 16-17 years: 9-27 U/L 18-35 years: 9-31 U/L 36-40 years: 8-35 U/L Current as of August 23, 2017 7:11 am CDT


Page 914

41-45 years: 9-37 U/L 46-50 years: 10-39 U/L 51-54 years: 10-42 U/L 55 years: 11-45 U/L > or =56 years: 12-48 U/L Reference values have not been established for patients 1 year: 6-29 U/L Reference values have not been established for patients 1:2,000) have been found only in patients with multifocal motor neuropathy and not with motor neuron disease. About 30% to 50% of patients with these clinical syndromes or the pure motor variant of chronic inflammatory demyelinating polyneuropathy have increased antibody titers. Increased antibody titers, therefore, appear to be a specific but not sensitive marker of those related disorders. Borderline elevation of titers against ganglioside epitopes may be seen in patients with motor neuron disease or motor neuropathy For IgG and IgM antibodies directed against monosialo GM1 and disialo GD1b, 99% of 182 age- and sex-stratified normal individuals had titers 1:1,000 IgM monosialo GM1 >1:2,000 IgG asialo GM1

>1:8,000

IgM asialo GM1

>1:4,000

IgG disialo GD1b

>1:1,000

IgM disialo GD1b

>1:1,000

Clinical References: 1. Taylor BV, Gross L, Windebank AJ: The sensitivity and specificity of anti-GM1 antibody testing. Neurology 1996;47:951-955 2. Vernino S,Wolfe GI: Antibody testing in peripheral neuropathies. Neurol Clin 2007;25:29-46 3. Kaida K, Ariga T, Yu RK: Antiganglioside antibodies and their pathophysiological effects on Guillain-Barre syndrome and related disorders-a review. Glycobiology 2009;19:676-692

FGQ1B

Ganglioside GQ1b Antibody (IgG), EIA

57248

Reference Values: Less than 1:100 titer

FGARG

Garlic IgG

57634



GAST

Gastrin, Serum

8512

Clinical Information: Gastrin is a peptide hormone produced by mucosal G cells of the gastric antrum. It is synthesized as preprogastrin, cleaved to progastrin, which undergoes several posttranslational modifications, in particular sulfation, and is finally processed into the mature 34-amino acid, gastrin-34. Gastrin-34 may be cleaved further into the shorter 17-amino acid, gastrin-17. Either may be secreted as a c-terminal amidated or unamidated isoform. A number of additional, smaller gastrin fragments, as well as gastrin molecules with atypical posttranslational modifications (eg, absent sulfation), may also be secreted in small quantities. Gastrin half-life is short, 5 minutes for amidated gastrin-17, and 20 to 25 minutes for amidated gastrin-34. Elimination occurs through peptidase cleavage and renal excretion. Gastrin-17 I (nonsulfated form) and gastrin-17 II (sulfated) appear equipotent. Their biological effects are chiefly associated with the amidated isoforms and consist of promotion of gastric epithelial cell proliferation and



Page 918

differentiation to acid-secreting cells, direct promotion of acid secretion, and indirect stimulation of acid production through histamine release. In addition, gastrin stimulates gastric motility and release of pepsin and intrinsic factor. Most gastrin isoforms with atypical posttranslational modifications and most small gastrin fragments display reduced or absent bioactivity. This assay measures predominately gastrin-17. Larger precursors and smaller fragments have little or no cross-reactivity in the assay. Intraluminal stomach pH is the main factor regulating gastrin production and secretion. Rising gastric pH levels result in increasing serum gastrin levels, while falling pH levels are associated with mounting somatostatin production in gastric D cells. Somatostatin, in turn, downregulates gastrin synthesis and release. Other, weaker factors that stimulate gastrin secretion are gastric distention, protein-rich foods, and elevated secretin or serum calcium levels. Serum gastrin levels may also be elevated in gastric distention due to gastric outlet obstruction, and in a variety of conditions that lead to real or functional gastric hypo- or achlorhydria (gastrin is secreted in an attempted compensatory response to achlorhydria). These include atrophic gastritis with or without pernicious anemia; a disorder characterized by destruction of acid-secreting (parietal) cells of the stomach, gastric dumping syndrome, and surgically excluded gastric antrum. In atrophic gastritis, the chronic cell-proliferative stimulus of the secondary hypergastrinemia may contribute to the increased gastric cancer risk observed in this condition. Gastrin levels are pathologically increased in gastrinoma, a type of neuroendocrine tumor that can occur in the pancreas (20%-40%) or in the duodenum (50%-70%). The triad of nonbeta islet cell tumor of the pancreas (gastrinoma), hypergastrinemia, and severe ulcer disease is referred to as the Zollinger-Ellison syndrome. Over 50% of gastrinomas are malignant and can metastasize to regional lymph nodes and the liver. About 25% of gastrinomas occur as part of the multiple endocrine neoplasia type 1 (MEN 1) syndrome and are associated with hyperparathyroidism and pituitary adenomas. These MEN 1-associated tumors have been observed to occur at an earlier age than sporadic tumors and often follow a more benign course.

Useful For: Investigation of patients with achlorhydria or pernicious anemia Investigation of patients suspected of having Zollinger-Ellison syndrome Diagnosis of gastrinoma; basal and secretin-stimulated serum gastrin measurements are the best laboratory tests for gastrinoma

Interpretation: Achlorhydria is the most common cause of elevated serum gastrin levels. The most common cause for achlorhydria is treatment of gastroduodenal ulcers, nonulcer dyspepsia, or gastroesophageal reflux with proton pump inhibitors (substituted benzimidazoles, eg, omeprazole). Other causes of hypo- and achlorhydria include chronic atrophic gastritis with or without pernicious anemia, gastric ulcer, gastric carcinoma, and previous surgical or traumatic vagotomy. If serum B12 levels are significantly low (400 pg/mL). Levels of >1,000 pg/mL in a gastric- or duodenal-ulcer patient without previous gastric surgery, on no drugs, who has a basal gastric acid output of >15 mmol/hour (>5 mmol/hour in patients with prior acid-reducing surgery) are considered diagnostic of gastrinoma. If there are any doubts about gastric acid output, an infusion of 0.1 N HCl into the stomach reduces the serum gastrin in patients with achlorhydria, but not in those with gastrinoma. Other conditions that may be associated with hypergastrinemia in the face of normal or increased gastric acid secretion include gastric and, rarely, duodenal ulcers, gastric outlet obstruction, bypassed gastric antrum, and gastric dumping. Occasionally, diabetes mellitus, autonomic neuropathy with gastroparesis, pheochromocytoma, rheumatoid arthritis, thyrotoxicosis, and paraneoplastic syndromes can also result in hypergastrinemia with normal acid secretion. None of these conditions tends to be associated with fasting serum gastrin levels >400 pg/mL, and levels >1,000 pg/mL are virtually never observed. Several provocative tests can be used to distinguish these patients from individuals with gastrinomas. Patients with gastrinoma, who have normal or only mildly to modestly increased fasting serum gastrin levels, respond with exaggerated serum gastrin increases to intravenous infusions of secretin or calcium. Because of its greater safety, secretin infusion is preferred. The best validated protocol calls for a baseline fasting gastrin measurement, followed by an injection of 2 clinical units of secretin per kg body weight (0.4 microgram/kg) over 1 minute and further serum gastrin specimens at 5-, 10-, 15-, 20-, and 30-minutes postinjection. A peak-gastrin increase of >200 pg/mL above the baseline value has >85% sensitivity and near 100% specificity for gastrinoma. Secretin or calcium infusion tests are not carried out in the clinical laboratory, but are usually performed at Current as of August 23, 2017 7:11 am CDT


Page 919

gastroenterology or endocrine testing units under the supervision of a physician. They are progressively being replaced (or supplemented) by imaging procedures, particularly duodenal and pancreatic endoscopic ultrasound. All patients with confirmed gastrinoma should be evaluated for possible multiple endocrine neoplasia type 1 (MEN 1), which is the underlying cause in approximately 25% of cases. If clinical, biochemical, or genetic testing confirms MEN 1, other family members need to be screened.

Reference Values: 12.0 mcg/mL

Clinical References: 1. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs. Clin Chem 1998;44(5):1129-1140 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry, Fourth edition. Edited by CA Burtis, ER Ashwood, Philadelphia, WB Saunders Company, 2006 3. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide. Mayo Clinic Scientific Press and Informa Healthcare USA, 2008

GENRA

Gentamicin, Random, Serum



Page 925

Clinical Information: Gentamicin is an antibiotic used to treat life-threatening blood infections caused by gram-negative bacilli, particularly Citrobacter freundii, Acinetobacter species, Enterobacter species, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, and Serratia species. It is often used in combination with beta-lactam therapy. A gentamicin minimal inhibitory concentration (MIC) of less than or equal to 4.0 mcg/mL is considered susceptible for gram-negative bacilli. A MIC of less than or equal to 500 mcg/mL is considered synergistic when combined with appropriate antibiotics for treatment of serious enterococcal infections. Conventional dosing of gentamicin is usually given 2 to 3 times per day by intravenous or intramuscular injections in doses to achieve peak blood concentration between 3.0 to 12.0 mcg/mL depending on the type of infections. Gentamicin also may be administered at higher doses (usually 5-7 mg/kg) once per day to patients with good renal function (known as pulse dosing). Dosing amount or interval must be decreased to accommodate for reduced renal function. Ototoxicity and nephrotoxicity are the primary toxicities associated with gentamicin. This risk is enhanced in presence of other ototoxic or nephrotoxic drugs. Monitoring of serum levels and symptoms consistent with ototoxicity is important. For longer durations of use, audiology/vestibular testing should be considered at baseline and periodically during therapy.

Useful For: Monitoring adequacy of serum concentration during gentamicin therapy in specimens for which no collection timing information is provided

Interpretation: Goal peak concentrations levels depend on the type of infection being treated. Goal trough levels should be less than 2.0 mcg/mL. Peak targets are generally between 3.0 and 12.0 mcg/mL for conventional dosing. Prolonged exposure to either peak levels exceeding 12.0 mcg/mL or to trough levels exceeding 2.0 mcg/mL may lead to toxicity.

Reference Values: Gentamicin, Peak Therapeutic: 3.0-12.0 mcg/mL Toxic: >12.0 mcg/mL Gentamicin, Trough Therapeutic: 2.0 mcg/mL

Clinical References: 1. Hammett-Stabler CA, Johns T: Laboratory Guidelines for Monitoring of Antimicrobial Drugs. Clin Chem 1998;44(5):1129-1140 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood, Philadelphia, WB Saunders Company, 2006 3. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide. Mayo Clinic Scientific Press and Information Healthcare USA, 2008

GENTA

Gentamicin, Trough, Serum

37043

Clinical Information: Gentamicin is an antibiotic used to treat life-threatening blood infections caused by gram-negative bacilli, particularly Citrobacter freundii, Acinetobacter species, Enterobacter species, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, and Serratia species. It is often used in combination with beta-lactam therapy. A gentamicin minimal inhibitory concentration (MIC) of 4.0 mcg/mL or less is considered susceptible for gram-negative bacilli. A MIC of 500 mcg/mL or less is considered synergistic when combined with appropriate antibiotics for treatment of serious enterococcal infections. Conventional dosing of gentamicin is usually given 2 to 3 times per day by intravenous or intramuscular injections in doses to achieve peak blood concentration between 3.0 to 12.0 mcg/mL depending on the type of infection. Gentamicin also may be administered at higher doses (usually 5-7 mg/kg) once per day to patients with good renal function (known as pulse dosing). Dosing amount or interval must be decreased to accommodate for reduced renal function. Ototoxicity and nephrotoxicity are the primary toxicities associated with gentamicin. This risk is enhanced in presence of other ototoxic or nephrotoxic drugs. Monitoring of serum levels and symptoms consistent with ototoxicity is important. For longer durations of use, audiology/vestibular testing should be considered at baseline and periodically during therapy.

Useful For: Monitoring adequacy of drug clearance during gentamicin therapy Current as of August 23, 2017 7:11 am CDT


Page 926

Interpretation: Goal levels depend on the type of infection being treated. Goal trough levels should be less than 2.0 mcg/mL for conventional dosing. Prolonged exposure to trough levels exceeding 2.0 mcg/mL may lead to toxicity.

Reference Values: Therapeutic: 2.0 mcg/mL

Clinical References: 1. Wilson JW, Estes LL: Mayo Clinic Antimicrobial Therapy Quick Guide, 2008 2. Hammett-Stabler CA, Johns T: Laboratory guidelines for monitoring of antimicrobial drugs. Clin Chem 1998 May;44(5):1129-1140 3. Gonzalez LS III, Spencer JP: Aminoglcosides: a practical review. Am Fam Physician 1998 Nov 15;58(8):1811-1820

GERB

Gerbil Epithelium, IgE

82545





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





Page 927

GCTF

Germ Cell Tumor (GCT), Isochromosome 12p, FISH, Tissue

35270

Clinical Information: Germ cell tumors (GCT) comprise a heterogeneous group of solid neoplasms that arise in midline locations including the gonads, retroperitoneum, mediastinum, and central nervous system. GCT are categorized based upon their histologic differentiation and can be separated into 2 classes. Seminomatous GCT include seminoma of the testis, dysgerminoma of the ovaries, and germinoma of the brain. Nonseminomatous GCT include yolk sac tumor, embryonal carcinoma, choriocarcinoma, immature teratoma, and mixed forms. Due to the wide spectrum of histologic features observed in these tumors, distinction from non-GCT can be difficult. GCT are often very responsive to chemotherapy and have a better outcome relative to histologically similar malignancies. Thus, distinguishing GCT from non-GCT is critical to providing the appropriate treatment for the patient. Gain of the short arm of chromosome 12, most commonly as an isochromosome 12p[i(12p)], is a highly nonrandom chromosomal marker seen in a significant percentage of GCT. While i(12p) is not 100% specific for GCT, the literature indicates it has diagnostic and possible therapeutic relevance for patients with these tumors. Testing of i(12p) should be concomitant with histologic evaluation, and positive results may support the diagnosis of GCT.

Useful For: Supporting the diagnosis of germ cell tumors when used in conjunction with an anatomic pathology consultation

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff for the i(12p) probe set. A positive result is consistent with the diagnosis of a germ cell tumors (GCT). A negative result suggests that the i(12p) marker is not present, but does not exclude the diagnosis of a GCT.


Clinical References: 1. Wehle D, Yonescu R, Long PP, et al: Fluorescence in situ hybridization of 12p in germ cell tumors using a bacterial artificial chromosome clone 12p probe on paraffin-embedded tissue: clinical test validation. Cancer Genet Cytogenet 2008 June;183(2):99-104 2. Poulos C, Cheng L, Zhang S, et al: Analysis of ovarian teratomas for Isochromosome 12p: evidence supporting a dual histogenetic pathway for teratomatous elements. Mod Pathology 2006;19:766-771 3. Chaganti RS, Houldsworth J: Genetics and biology of adult human male germ cell tumors. Cancer Res. 2000 Mar 15;60(6):1475-82.

60898

Germinal Center B-cell Expressed Transcript 1 (GCET1), Immunostain Without Interpretation Clinical Information: Germinal center B-cell expressed transcript 1 (GCET1), is also known as Centerin and SERPIN9 (serine protease inhibitor). GCET1 is expressed in B cells in the germinal center of normal lymph node and tonsil tissues. Most follicular lymphomas strongly express GCET1. In addition, a proportion of diffuse large B-cell lymphomas (DLBCL) are positive. In the diagnosis of B-cell lymphomas, GCET1 can be useful in an immunohistochemical panel to assign a germinal center phenotype.


Clinical References: 1. Choi WWL, Weisenburger DD, Greiner TC, et al: A new immunostain algorithm classifies diffuse large b-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009;15(17):5494-5502 2. Paterson MA, Hosking PS, Coughlin PB, et al: Expression of the Current as of August 23, 2017 7:11 am CDT


Page 928

serpin centerin defines a germinal center phenotype in b-cell lymphomas. Am J Clin Pathol 2008;130:117-126 3. Montes-Moreno S, Roncador G, Maestre L, et al: GCET1 (centerin), a highly restricted marker for a subset of germinal center-derived lymphomas. Blood 2008;111(1):351-368

FGHTL

Ghrelin Total, Plasma

57902

Reference Values: GHRELIN (Total): (Plasma) Adult Reference Range(s)

pg/mL

Normal weight/control subjects: 520 - 700 pg/mL Obese subjects prior to diet: 340 - 450 pg/mL Levels: 8:00 am - 12:00 pm: Up to 420 pg/mL 6:00pm: Up to 480 pg/mL Obese subjects post induced weight loss: 450 - 600 pg/mL Levels: 8:00 am - 12:00 pm: Up to 575 pg/mL 6:00 pm: Up to 600 pg/mL Obese subjects post gastric-bypass surgery: Up to 120 pg/mL

GRW

Giant Ragweed, IgE

82685





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive



Page 929

3

3.50-17.4 Positive

4


5


6



GRAB

Giardia Antibody, IFA

80628

Reference Values: REFERENCE RANGE: 250 mg/dL), circulating ketones (beta-hydroxy butyrate), and acidosis (typically with increased anion gap). In diabetic patients, low glucagon levels (undetectable or in the lower quartile of the normal range) in the presence of hypoglycemia indicate impairment of hypoglycemic counter-regulation. These patients may be particularly prone to recurrent hypoglycemia. This can be a permanent problem due to islet alpha-cell destruction or other, less well understood processes (eg, autonomous neuropathy). It can also be functional, most often due to over tight blood-glucose control, and may be reversible after decreasing insulin doses.

Reference Values: < or =6 hours: 100-650 pg/mL 1-2 days: 70-450 pg/mL 2-4 days: 100-650 pg/mL 4-14 days: declining gradually to adult levels >14 days: < or =80 pg/mL (range based on 95% confidence limits) Glucagon levels are inversely related to blood glucose levels at all ages. This is particularly pronounced at birth and shortly thereafter, until regular feeding patterns are established. This explains the higher levels immediately after birth, which then first fall as the glucagon release mobilizes the infant's glucose stores, then rise again as stores are depleted, finally normalizing towards adult levels as regular feeding patterns are established.

Clinical References: 1. Sherwood NM, Krueckl SL, McRory JE: The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocrin Rev 2000 Dec;21(6):619-670 2. Tomassetti P, Migliori M, Lalli S, et al: Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. Ann Oncol 2001;12 Suppl 2:S95-99 3. Cryer PE: Hypoglycemia risk reduction in type 1 diabetes. Exp Clin Endocrinol Diabetes 2001;109 Suppl 2:S412-423 4. Jhiang G, Zhang BB: Glucagon and regulation of glucose metabolism. Am J Physiol Metab 2003;284:E671-E678 5. vanBeek AP, de Haas ER, van Vloten WA, et al: The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eu J Endocrinol 2004;151:531-537

GPSY

Glucopsychosine, Blood Spot

62236

Clinical Information: Gaucher disease is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme, beta-glucosidase. Beta-glucosidase facilitates the lysosomal degradation of glucosylceramide (glucocerebroside) and glucopsychosine (glucosylsphingosine). Gaucher disease is caused by mutations in the GBA gene. There are 3 described types of Gaucher disease with varying clinical presentations and age of onset from a perinatal lethal disorder to an asymptomatic type. Features of all types of Gaucher disease include hepatosplenomegaly and hematological abnormalities. Gaucher disease type I is the most common, representing more than 90% of cases. It is generally characterized by bone disease, hepatosplenomegaly, anemia and thrombocytopenia, coagulation abnormalities, lung disease, but no central nervous system (CNS) involvement. Gaucher disease types II and III are characterized by the presence of primary neurologic disease. In addition, Type II typically presents with limited psychomotor development, hepatosplenomegaly, and lung disease, resulting in death usually between 2 and 4 years of age. Individuals with Gaucher disease type III may present prior to 2 years of age, but the progression is not as rapid and patients may survive into the third and fourth decade. Further subtypes of Gaucher disease include a perinatal lethal form associated with skin abnormalities and nonimmune hydrops fetalis, and a cardiovascular form presenting with calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and gaze impairment. Treatment is available in the form of enzyme replacement therapy and/or substrate reduction therapy for types I and III. These treatment options have generally made bone marrow transplantation obsolete. Currently, only supportive therapy is available for type II because of the inability of enzyme provided by replacement therapy to cross the blood-brain barrier. The incidence of Gaucher disease type I ranges from 1 in 30,000 to 1 in 100,000 in the general population, but is much more frequent among Ashkenazi Jews with an incidence of approximately 1 in 900. Types II and III both have an incidence of approximately 1 in 100,000 in the general population. A diagnostic workup for Gaucher disease may demonstrate the characteristic finding of Gaucher cells on bone marrow examination, other hematologic abnormalities, and hepatosplenomegaly. The diagnosis can be confirmed by the demonstration of reduced or absent acid beta-glucosidase activity in leukocytes (BGL / Beta-Glucosidase, Leukocytes) and molecular genetic



Page 939

analysis of the GBA gene (GAUP / Gaucher Disease, Mutation Analysis, GBA; or GBAZ / Gaucher Disease, Full Gene Analysis). Glucopsychosine is elevated in symptomatic patients and supports a diagnosis of Gaucher disease. It may also be helpful in determining treatment response.

Useful For: Quantification of glucopsychosine (glucosylsphingosine) in dried blood spots supports the biochemical diagnosis of Gaucher disease May aid in monitoring a patientâ€™s response to treatment

Interpretation: An elevation of glucopsychosine is indicative of Gaucher disease. Reference Values: Normal or =12 months: 39.3-57.7 U/g Hb Reference values have not been established for patients who are or =0.03 nmol/L Confirming susceptibility to organ-specific neurological disorders (eg, myasthenia gravis, Lambert-Eaton syndrome); titers generally < or =0.02 nmol/L

Interpretation: High titers (> or =0.02 nmol/L) are found in classic stiff-man syndrome (93% positive) and in related autoimmune neurologic disorders (eg, acquired cerebellar ataxia, some acquired nonparaneoplastic encephalomyelopathies). Diabetic patients with polyendocrine disorders also generally have glutamic acid decarboxylase (GAD65) antibody values > or =0.02 nmol/L. Values in patients who have type 1 diabetes without a polyendocrine or autoimmune neurologic syndrome are usually < or =0.02 nmol/L. Low titers (0.03-19.9 nmol/L) are detectable in the serum of approximately 80% of type 1 diabetic patients. Conversely, low titers are detectable in the serum of or =0.03 nmol/L are consistent with susceptibility to autoimmune (type 1) diabetes and related endocrine disorders (thyroiditis and pernicious anemia).

Reference Values: < or =0.02 nmol/L Reference values apply to all ages.

Clinical References: 1. Walikonis JE, Lennon VA: Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus. Mayo Clin Proc 1998 December;73(12):1161-1166 2. Kawasaki E, Yu L, Gianani R, et al: Evaluation of islet cell antigen (ICA) 512/IA-2 autoantibody radioassays using overlapping ICA512/IA-2 constructs. J Clin Endocrinol Metab 1997 February;82(2):375-380 3. Saiz A, Current as of August 23, 2017 7:11 am CDT


Page 946

Arpa J, Sagasta A, et al: Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus and polyendocrine autoimmunity. Neurology 1997 October;49(4):1026-1030 4. Pittock SJ, Yoshikawa H, Ahlskog JE, et al: Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal and spinal cord dysfunction. Mayo Clin Proc 2006;81:1207-1214

GD65C 84221

Glutamic Acid Decarboxylase (GAD65) Antibody Assay, Spinal Fluid Clinical Information: Glutamic acid decarboxylase (GAD) is a neuronal enzyme involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). Serum antibodies directed against the 65-kd isoform of GAD (GAD65) are detected in heightened frequency in a variety of autoimmune neurologic disorders, including stiff-man (Moersch-Woltman) syndrome, autoimmune cerebellitis, some idiopathically acquired epilepsies, some rare acquired encephalomyelopathies with and without neoplasia, and in myasthenia gravis and Lambert-Eaton myasthenic syndrome. GAD65 antibodies account for the majority of clinically recognized pancreatic islet cell antibodies, and are an important serological marker of predisposition to type 1 (insulin-dependent) diabetes. GAD65 autoantibodies also serve as a marker of predisposition to autoimmune disorders that commonly or sometimes coexist with type 1 diabetes, including autoimmune thyroid disease (eg, thyrotoxicosis, Graves disease, Hashimoto thyroiditis, hypothyroidism), pernicious anemia, premature ovarian failure, Addison disease (idiopathic adrenocortical failure), and vitiligo. GAD65 antibodies are found in the serum of approximately 8% of healthy subjects older than age 50, usually in low titer, but often accompanied by related "thyrogastric" autoantibodies.

Useful For: Possible use in evaluating patients with stiff-man syndrome, autoimmune cerebellitis and other acquired central nervous system disorders affecting gabaminergic neurotransmission

Interpretation: Intrathecal synthesis of GAD65 antibody has been demonstrated in patients with stiff-man syndrome, but cerebrospinal fluid (CSF) values are log orders lower than serum. We have not determined the frequency of GAD65 antibodies in CSF of patients with various diagnoses.

Reference Values: < or =0.02 nmol/L

Clinical References: 1. Saiz A, Arpa J, Sagasta A, et al: Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin-dependent diabetes mellitus and polyendocrine autoimmunity. Neurology 1997 October;49(4):1026-1030 2. Boylan KB, Lennon VA: Cerebellar ataxia with glutamic acid decarboxylase antibody. Ann Neurol 1999;46:457 (abstract) 3. Dalakas MC, Li M, Fujii M, Jacobowitz DM: Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001 September 11;57:780-784

62485

Glutamine Synthetase (GS), Immunostain Without Interpretation Clinical Information: Glutamine synthetase (GS) is an enzyme which catalyzes the ATP-dependent condensation of glutamate with ammonia to form glutamine. GS can be used with a panel of immunohistochemical markers (beta-catenin, liver fatty acid binding protein, C-reactive protein, and amyloid A) to distinguish hepatic adenoma from focal nodular hyperplasia and non-neoplastic liver. GS, a target gene of beta-catenin, is expressed in hepatic adenomas with beta-catenin mutations (type 2), but is not expressed in hepatic adenomas without beta-catenin mutations. GS is expressed in zone 3 of normal liver and has a characteristic map-like pattern in focal nodular hyperplasia.

Useful For: Classification of hepatic adenomas and the identification of focal nodular hyperplasia Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is Current as of August 23, 2017 7:11 am CDT


Page 947

available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. van Aalten SM, Verheij J, Terkivatan T, et al: Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol 2011;55(1):120-125 2. Bioulac-Sage P, Cubel G, Balabaud C, et al: Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011;31(1):91-103 3. Bioulac-Sage P, Rebouissou S, Thomas C, et al: Hepatocellular adenoma subype classification using molecular markers and immunohistochemistry. Hepatology 2007;46(3):740-748

FGLUT

Gluten IgG

57559

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: < 2 mcg/mL The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG tests has not been established. These tests can be used in special clinical situations to select foods for evaluation by diet elimination and challenge in patients who have food-related complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as evidence of food allergy and only indicates immunologic sensitization by the food allergen in question. This test should only be ordered by physicians who recognize the limitations of the test.

GLT

Gluten, IgE

82894





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive



Page 948

4


5


6



TGGB

Glycerol-Corrected Triglycerides, Serum

63445

Clinical Information: Triglycerides are esters of glycerol with 3 long-chain fatty acids. Increased plasma triglyceride concentrations are indicative of a metabolic abnormality and, along with elevated cholesterol, are considered a risk factor for atherosclerotic disease. Hyperlipidemia may be inherited or associated with biliary obstruction, diabetes mellitus, nephrotic syndrome, renal failure, or metabolic disorders related to endocrinopathies. Increased triglycerides may also be medication-induced (eg, prednisone). See Lipids and Lipoproteins in Blood Plasma in Special Instructions. Traditional, nonglycerol-blanked methods for measuring triglycerides break down plasma and serum triglycerides into glycerol and fatty acids. The glycerol is then measured in an enzymatic colorimetric assay. Consequently, patients with elevated free glycerol in circulation will have a falsely elevated triglyceride concentration, pseudohypertriglyceridemia, when using a nonglycerol-blanked triglyceride assay. Glycerol is an intermediate in the conversion of glucose to lipids and serves as the precursor for triglyceride and other glycerolipids. Patients with type 2 diabetes mellitus, hyperthyroidism, those who are obese, or those receiving oral or parenteral supplementation with glycerol may have slightly higher free glycerol in circulation, however this increase is unlikely to affect triglyceride result interpretation. Glycerol kinase deficiency (GKD) is an X-linked genetic condition leading to impaired function of glycerol kinase (GK), the primary regulator of glycerol entry into metabolic pathways. Insufficient GK activity leads to extreme elevations in plasma glycerol concentrations (ie, hyperglycerolemia) and glyceroluria. Patients with GKD may be placed on a glycerol-restricted diet and instructed to avoid prolonged periods of fasting. GKD is divided into 3 clinical forms: -Complex GKD involves mutations in the GK locus and 2 others (adrenal hypoplasia congenital: AHC and Duchenne muscular dystrophy: DMD) on Xp21 and manifests in infants. -Juvenile GKD is associated with metabolic and central nervous system instability and deterioration. Juvenile GKD usually presents in the early years of life as repeated vomiting, acidemia, and central nervous system depression. - Adult GKD is mainly benign with detection usually found incidentally by pseudohypertriglyceridemia.

Useful For: Evaluation of pseudohypertriglyceridemia for possible glycerol kinase deficiency Evaluation of triglyceride as a cardiovascular risk factor in individuals with elevated cholesterol values

Interpretation: Patients with glycerol kinase deficiency typically have serum free glycerol concentrations greater than 10 fold above normal.

Reference Values: TRIGLYCERIDE, TOTAL and CORRECTED The National Cholesterol Education Program (NCEP) has set the following guidelines in adults ages 18 and up: Normal: or =500 mg/dL The National Cholesterol Education Program (NCEP) and National Health and Nutrition Examination Survey (NHANES) has set the following guidelines in children ages or =100 Strongly positive Reference values apply to all ages.


GRAS1

Grass Panel # 1

81706





Negative



Page 963

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



GRAS2

Grass Panel # 2

81707





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6


Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB Saunders Current as of August 23, 2017 7:11 am CDT


Page 964

Company, New York, 2007, Part VI, pp 961-971

GRAS3

Grass Panel # 3

81708





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



62501

GRB2-Associated Binding Protein 1 (GAB1), Immunostain Without Interpretation Clinical Information: GAB1 (growth factor receptor bound protein 2-associated protein 1) is an adapter protein that is involved in growth, transformation, and apoptosis. GAB1 can be used with a panel of immunohistochemical markers in the classification of medulloblastomas into SHH (sonic hedgehog), WNT (wingless-type murine mammary tumor), or non-SHH/WNT subgroups.

Useful For: Identification and differentiation of medulloblastomas Current as of August 23, 2017 7:11 am CDT


Page 965


Clinical References: 1. Ellison DW, Dalton J, Kocak M, et al: Medulloblastoma clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 2011;121:381-396 2. Northcott PA, Korshunov A, Witt H, et al: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011 Apr 10;29(11):1408-1414 3. Thompson MC, Fuller C, Hogg TL, et al: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006;24:1924-931

GRFE

Greek Fennel, IgE

82365





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6


Clinical References: Homburger HA: Chapter 53: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. Edited by RA McPherson, MR Pincus. WB Saunders Company, New York, 2007, Part VI, pp 961-971 Current as of August 23, 2017 7:11 am CDT


Page 966

GCBN

Green Coffee Bean, IgE

82769





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



GPEA

Green Pea, IgE

82887




Page 967





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



GPEP

Green Pepper, IgE

82623





Page 968


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



GSTB

Green String Bean, IgE

82610





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5




Page 969

6



ALDR

Grey Alder, IgE

82671





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



GRHPZ

GRHPR Gene, Full Gene Analysis

35444

Clinical Information: Primary hyperoxaluria type 2 (PH2) is a hereditary disorder of glyoxylate metabolism caused by deficiency of the hepatic enzyme glyoxylate reductase/hydroxypyruvate reductase



Page 970

(GRHPR). Absence of GRHPR activity results in excess oxalate and usually L-glycerate excreted in the urine leading to nephrolithiasis (kidney stones) and sometimes renal failure. Onset of PH2 is typically in childhood or adolescence with symptoms related to kidney stones. In some cases, kidney failure may be the initial presenting feature. Nephrocalcinosis, as seen by renal ultrasound, is observed less frequently in individuals with PH2 than primary hyperoxaluria type 1 (PH1). End-stage renal disease (ESRD) is also less common and of later onset than PH1; however, once ESRD develops, oxalate deposition in other organs such as bone, retina, and myocardium can occur. While the exact prevalence and incidence of PH2 are not known, it is thought that PH2 is less common than PH1, which has an estimated prevalence rate of 1 to 3 per million population and an incidence of 0.1 per million/year. Biochemical testing is indicated in patients with possible primary hyperoxaluria. Measurement of urinary oxalate in a timed, 24-hour urine collection is strongly preferred, with correction to adult body surface area in pediatric patients (HYOX / Hyperoxaluria Panel, Urine; OXU / Oxalate, Urine). In very young children (incapable of performing a timed collection), random urine oxalate to creatinine ratios may be used for determination of oxalate excretion. In patients with reduced kidney function, POXA / Oxalate, Plasma is also recommended. Urinary excretion of oxalate of >1.0 mmol/1.73 m(2)/24 hours is strongly suggestive of, but not diagnostic, for primary hyperoxaluria as there are other forms of inherited hyperoxaluria (PH1 and non-PH1/PH2) and secondary hyperoxaluria that may result in similarly elevated urine oxalate excretion rates. An elevated urine glycerate in the presence of hyperoxaluria is suggestive of PH2. Caution is warranted in interpretation of urine oxalate excretion in patients with reduced kidney function as urine oxalate concentrations may be lower due to reduced glomerular filtration rate. Historically, the diagnosis of PH2 was confirmed by GRHPR enzyme analysis performed on liver biopsy; however, this has been replaced by molecular testing, which forms the basis of confirmatory or carrier testing in most cases. PH2 is inherited as an autosomal recessive disorder caused by mutations in the GRHPR gene, which encodes the enzyme GRHPR. Two common GRHPR mutations have been identified: c.103delG and c.403_404+2delAAGT. These mutations account for about one-third of the mutant alleles described in the Northern European Caucasian population and about 15% in the Asian population. Direct sequencing of the GRHPR gene will identify these 2 mutations as well as other less common or novel mutations associated with PH2.

Useful For: Confirming a diagnosis of primary hyperoxaluria type 2 (PH2) Carrier testing for individuals with a family history of PH2 in the absence of known mutations in the family

Interpretation: All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008:10(4):294-300 2. Primary Hyperoxaluria Type 2-GeneReviews-NCBI Bookshelf. Available from URL: http://www.ncbi.nlm.nih.gov/books/NBK2692/, accessed 8-7-2012 3. Rumsby G, Williams E, Coulter-Mackie M: Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004;66(3):959-963 4. Cregeen DP, Williams EL, Hulton S, Rumsby G: Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2. Hum Mutat 2003;22(6):497 5. Laboratory and molecular diagnosis of primary hyperoxaluria and oxalosis. Mayo Medical Laboratories' Communique, April 2007

CGAS

Group A Streptococcus (Streptococcus pyogenes) Culture

62989

Clinical Information: Streptococcus pyogenes (group A streptococcus) is a common cause of pharyngitis and skin and soft tissue infection. In children, S pyogenes can cause perianal infection. The classic presentation is a well-demarcated rash around the anus with itching, rectal pain, and, occasionally, blood-streaked stools. Untreated, painful defecation, toilet avoidance, and constipation may persist for months, until effective treatment is administered. Anal fissures may ensue. A swab of the affected area may be submitted for S pyogenes culture to confirm the diagnosis. Health care workers may transmit S



Page 971

pyogenes to their patients (eg, in the postsurgical setting) leading to outbreaks of invasive disease. Screening of health care workers or other patients for S pyogenes may be requested by Infection Prevention and Control as part of an investigation of a potential nosocomial case (or cases). Isolates may be typed to assess strain relatedness.

Useful For: Diagnosis of perianal cellulitis Screening patients and health care workers for Streptococcus pyogenes for the purpose of investigating possible nosocomial transmission

Interpretation: Positive cultures are reported out as Streptococcus pyogenes. Reference Values: Negative

Clinical References: 1. Spellerberg B, Brandt C: Streptococcus, In Manual of Clinical Microbiology. 11th edition. Edited by J Jorgensen. Washington DC, ASM Press, 2015, pp 383-402 2. Cohen R, Levy C, Bonacorsi S, et al: Diagnostic Accuracy of Clinical Symptoms and Rapid Diagnostic Test in Group A Streptococcal Perianal Infections in Children. Clin Infect Dis 2015 Jan 15;60:267-270

CGBS

Group B Streptococcus (Streptococcus agalactiae) Culture

87346

Clinical Information: Streptococcus agalactiae (group B streptococcus) is a cause of morbidity and mortality among infants. Infections occurring within the first week of life are considered early-onset; those occurring in infants >1 week of age are considered late-onset. Maternal vaginal or rectal colonization with Streptococcus agalactiae is a risk factor for early-onset disease in infants. Ten to 30% of pregnant women are vaginally or rectally colonized with Streptococcus agalactiae and may transmit the organism to their infant during labor and delivery. The Centers for Disease Control and Prevention recommends screening for colonization with Streptococcus agalactiae at 35 to 37 weeks gestation as a guide for intrapartum antibiotic prophylaxis to decrease the risk of infection with Streptococcus agalactiae in the infant.

Useful For: Screening for maternal colonization with Streptococcus agalactiae at 35 to 37 weeks gestation as a guide for intrapartum antibiotic prophylaxis to decrease the risk of infection by Streptococcus agalactiae in the infant

Interpretation: Positive cultures are reported out as Streptococcus agalactiae. Reference Values: Negative

Clinical References: 1. Prevention of Perinatal Group B Streptococcal Disease: Revised Guidelines from CDC, Recommendations and Reports, Morbidity and Mortality Weekly Report (MMWR) 2010 Nov 19; 59(RR10);1-32 http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm?s_cid=rr5910a1_w 2. Church DL: Group B Streptococcus Cultures. In Clinical Microbiology Procedures Handbook. Edited by AL Leber. Washington DC, ASM Press, 2016, section 3.9.2

FGRPR

Grouper IgE

57943


Reference Values: 50.0 mcg/dL averaged over 3 blood samplings must be removed from workplace exposure. -An employee may not return to work in a lead exposure environment until their whole blood lead level is or =20.0 mcg/dL Adults (> or =16 years): > or =70.0 mcg/dL CADMIUM 0.0-4.9 ng/mL Reference values apply to all ages. MERCURY 0-9 ng/mL Reference values apply to all ages.

Clinical References: Arsenic: Hall M, Chen Y, Ahsan H, et al: Blood arsenic as a biomarker of arsenic exposure: results from a prospective study. Toxicology 2006;225:225-233 Lead: 1. http://www.cdc.gov/exposurereport 2. de Burbure C, Buchet J-P, Leroyer A, et al: Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels. Environ Health Perspect 2006;114:584-590 3. Kosnett MJ, Wedeen RP, Rothenberg SJ, et al: Recommendations for medical management of adult lead exposure. Environ Health Perspect 2007;115:463-471 4. Jusko T, Henderson C, Lanphear B, et al: Blood lead concentrations or =16 years: 0.0-1.3 mcg/specimen MERCURY 0-15 years: not established > or =16 years: 0-9 mcg/specimen Current as of August 23, 2017 7:11 am CDT


Page 989

Toxic concentration: >50 mcg/specimen The concentration at which toxicity is expressed is widely variable between patients. 50 mcg/specimen is the lowest concentration at which toxicity is usually apparent.

HMSRU

Heavy Metals Screen, Random, Urine

60236

Clinical Information: See individual test descriptions for: -ASRU / Arsenic, Random Urine -PBRU / Lead, Random Urine -CDRU / Cadmium, Random Urine -HGRU / Mercury, Random Urine

Reference Values: ARSENIC 0-35 mcg/L Reference values apply to all ages. LEAD 0-4 mcg/L Reference values apply to all ages. CADMIUM 0-15 years: not established > or =16 years: 0.0-1.3 mcg/L MERCURY 0-15 years: not established > or =16 years: 0-9 mcg/L Toxic concentration: >50 mcg/L The concentration at which toxicity is expressed is widely variable between patients. 50 mcg/L is the lowest concentration at which toxicity is usually apparent.

HMHA

Heavy Metals, Hair

45479

Clinical Information: "See Individual Unit Codes" Useful For: "See Individual Unit Codes" Interpretation: "See Individual Unit Codes" Reference Values: ARSENIC 0-15 years: not established > or =16 years: 0.0-0.9 mcg/g of hair LEAD 0.0-3.9 mcg/g of hair Reference values apply to all ages. MERCURY 0-15 years: not established > or =16 years: 0.0-0.9 mcg/g of hair

Clinical References: "See Individual Unit Codes"

HMNA

Heavy Metals, Nails

31070

Clinical Information: "See Individual Unit Codes"



Page 990

Useful For: "See Individual Unit Codes" Interpretation: "See Individual Unit Codes" Reference Values: ARSENIC 0-15 years: not established > or =16 years: 0.0-0.9 mcg/g of nails LEAD 0.0-3.9 mcg/g of nails Reference values apply to all ages. MERCURY 0-15 years: not established > or =16 years: 0.0-0.9 mcg/g of nails

Clinical References: "See Individual Unit Codes"

HPSA

Helicobacter pylori Antigen, Feces

81806

Clinical Information: Helicobacter pylori is well recognized as the cause of chronic active gastritis, duodenal ulcer, and nonulcer dyspepsia. Currently accepted methods for the diagnosis of Helicobacter pylori infection include, the urea breath test (UBT), and culture or histologic examination or direct urease testing (CLO test) of biopsy specimens obtained at the time of gastroduodenoscopy (ENDO). Each of these tests has its drawbacks, including lack of specificity (serology) or high cost, complexity, and inconvenience for the patient (UBT and ENDO). The utility of this test in asymptomatic individuals is not known, but testing for Helicobacter pylori in such individuals is not generally recommended. See Helicobacter pylori Diagnostic Algorithm in Special Instructions.

Useful For: As an aid in the diagnosis of Helicobacter pylori Monitoring the eradication of Helicobacter pylori after therapy (in most situations, confirmation of eradication is not mandatory)

Interpretation: Positive results indicate the presence of Helicobacter pylori antigen in the stool. Negative results indicate the absence of detectable antigen but does not eliminate the possibility of infection due to Helicobacter pylori.


Clinical References: 1. NIH Consensus Development Panel. Helicobacter pylori in peptic ulcer disease. JAMA 1994;272:65-69 2. Report of the Digestive Health Initiative. International Update Conference on H. pylori. Tysons Corner, McLean, VA, Feb 13-16, 1997

UBT

Helicobacter pylori Breath Test

81590

Clinical Information: The causal relationship between the urease-producing bacterium, Helicobacter pylori, and chronic active gastritis, duodenal ulcer, and nonulcer dyspepsia is well established. Conventional methods for the diagnosis of active H pylori infection include evaluation of biopsied gastric tissue by histopathology and culture. Less invasive assays include testing for the presence of H pylori antigen is stool specimens and detection of H pylori urease production by the Urea Breath Test (UBT). Serologic testing for the presence of IgM/IgG/IgA class antibodies to H pylori is also performed; however, this is not recommended by either the American College of Gastroenterologists nor the American Gastroenterological Association (AGA) as an accurate marker for active disease. These serologic markers can remain elevated despite resolution of active disease and may lead to misdiagnosis and/or inappropriate treatment. Recommendations for use of the (13)C-Urea Breath Test (Meretek UBT) were recently provided by the Digestive Health Initiative, a joint committee assembled with representatives from the AGA, the American Society for Gastrointestinal Endoscopy (ASGE), and the



Page 991

American Association for the Study of Liver Diseases (AASLD).(1) These recommendations include the following statements: "When endoscopy is not clinically indicated, the primary diagnosis of H pylori infection can be made serologically or with the UBT. When endoscopy is clinically indicated, the primary diagnosis should be established by biopsy urease testing and/or histology. Available evidence suggests that confirmation of H pylori eradication is not mandatory in most situations because of costs associated with testing. However, for selected patients with complicated ulcer disease, low-grade gastric mucosa-associated lymphoid tissue lymphoma, and following resection of early gastric cancer, it is appropriate to confirm eradication. In other situations, the decision to confirm H pylori eradication should be made on a case-by-case basis." This consensus group further specifies that there is no indication to test asymptomatic people and that testing for H pylori is only recommended if treatment is planned. The (13)C-Urea Breath Test (Meretek UBT) is a highly sensitive and specific noninvasive, nonradioactive test for diagnosing H pylori infection prior to antimicrobial treatment and for assessing whether the organism has been successfully eradicated following antimicrobial therapy. In 2 recent large prospective studies, the (13)C-UBT was shown to be as, or more, sensitive and specific for diagnosing H pylori active infection than culture, PCR, stain, rapid urease testing of biopsy tissue, or serology. When the test is used to assess eradication, it should be performed 4 to 6 weeks after completion of antimicrobial treatment. See Helicobacter pylori Diagnostic Algorithm in Special Instructions.

Useful For: Diagnostic testing for Helicobacter pylori infection in patients suspected to have active H pylori infection or for monitoring response to therapy

Interpretation: The Helicobacter pylori urea breath test can detect very low levels of H pylori and, by assessing the entire gastric mucosa, avoids the risk of sampling errors inherent in biopsy-based methods. In the absence of gastric H pylori, the (13)C-urea does not produce (13)CO2 in the stomach. A negative result does not rule out the possibility of H pylori infection. If clinical signs are suggestive of H pylori infection, retest with a new specimen or by using an alternative method. A false-positive test may occur due to urease associated with other gastric spiral organisms observed in humans such as H heilmannii. A false-positive test could occur in patients who have achlorhydria.


Clinical References: 1. Talley NJ, Vakil NB, Moayyedi P: American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-1780

CAMPY

Helicobacter pylori Culture

9388

Clinical Information: Helicobacter pylori is a spiral-shaped gram-negative bacterium that may cause chronic gastritis, peptic ulcer disease, or gastric neoplasia. In adults of industrialized countries, an estimated 0.5% of the susceptible population becomes infected each year, although the incidence has been decreasing over time. The organism may asymptomatically colonize humans. In suspected Helicobacter pylori-associated disease, the noninvasive stool antigen or urea breath test is recommended. If patients fail to respond to treatment and antimicrobial resistance is suspected, a gastric biopsy, gastric brushings, or gastric aspirate may be cultured to attempt to recover the organism for antimicrobial susceptibility testing to assess for resistance.

Useful For: Recovery of Helicobacter pylori from gastric specimens for antimicrobial susceptibility testing of the organism

Interpretation: A positive result provides definitive evidence of the presence of Helicobacter pylori. Organisms may be detected in asymptomatic (colonized) individuals. False-negative culture results may occur since the organism may die between biopsy collection and laboratory culture.

Reference Values: No growth after 7 days

Clinical References: Theel ES: Helicobacter pylori Infection: Test Utilization Strategies for Diagnosis. Mayo Medical Laboratories Communique 2013;38(6):1-8



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HELIS

Helicobacter pylori Culture with Antimicrobial Susceptibilities

62769

Clinical Information: Helicobacter pylori is a spiral-shaped gram-negative bacterium that may cause chronic gastritis, peptic ulcer disease, or gastric neoplasia. In adults of industrialized countries, an estimated 0.5% of the susceptible population becomes infected each year, although the incidence has been decreasing over time. The organism may asymptomatically colonize humans. In suspected H pylori-associated disease, the noninvasive stool antigen or urea breath test is recommended. If patients fail to respond to treatment and antimicrobial resistance is suspected, gastric biopsy, gastric brushings, or gastric aspirate may be cultured to attempt to recover the organism for antimicrobial susceptibility testing to assess for resistance. Multidrug regimens are required to attain successful cure of H pylori infection. Antimicrobial resistance in H pylori is increasing. Disease caused by H pylori resistant to clarithromycin or metronidazole is associated with a greater incidence of treatment failure than disease caused by a susceptible strain. The Clinical and Laboratory Standards Institute (CLSI) recommends agar dilution for H pylori antimicrobial susceptibility testing. Amoxicillin, ciprofloxacin, clarithromycin, metronidazole and tetracycline are routinely tested. The only antimicrobial for which interpretive breakpoints have been defined by the CLSI is clarithromycin.

Useful For: Recovery of Helicobacter pylori from gastric specimens for antimicrobial susceptibility testing of the organism (amoxicillin, ciprofloxacin, clarithromycin, metronidazole and tetracycline are routinely tested)

Interpretation: A positive result provides definitive evidence of the presence of Helicobacter pylori. Organisms may be detected in asymptomatic (colonized) individuals. False-negative culture results may occur since the organism may die between biopsy collection and laboratory culture.

Reference Values: No growth after 7 days Susceptibility results are reported as minimum inhibitory concentration (MIC) in mcg/mL and as susceptible, intermediate, or resistant according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. In some instances an interpretive category cannot be provided based on available data and the following comment will be included: "There are no established interpretive guidelines for agents reported without interpretations." Susceptible (S): The "susceptible" category implies that isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the dosage recommended to treat the site of infection is used, resulting in likely clinical efficacy. Intermediate (I) The "intermediate" category includes isolates with antimicrobial agent minimum inhibitory concentrations (MICs) that approach usually attainable blood and tissue levels, and for which response rates may be lower than for susceptible isolates. Note: The intermediate category implies clinical efficacy in body sites where the drugs are physiologically concentrated or when a higher than normal dosage of a drug can be used. This category also includes a buffer zone, which should prevent small, uncontrolled, technical factors from causing major discrepancies in interpretations, especially for drugs with narrow pharmacotoxicity margins. Resistant (R) The "resistant" category implies that the isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and/or that demonstrate MIC that fall in the range where specific microbial resistance mechanisms are likely, and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. (Clinical and Laboratory Standards Institute: Performance Standards for Antimicrobial Susceptibility Testing. 26th Informational Supplement. CLSI document M100S. Wayne, PA, 2016)

Clinical References: Theel ES. Helicobacter pylori Infection: Test Utilization Strategies for Diagnosis. Mayo Medical Laboratories Communique 2013;38(6):1-8



Page 993

60890

Helicobactor pylori (H. pylori), Immunostain Without Interpretation Clinical Information: Helicobacter pylori is a bacterium that frequently infects the stomach, colonizing the gastric pits. Helicobacter pylori infection is associated with the development of gastroduodenal ulcers and gastric mucosa-associated lymphoid tissue (MALT) lymphomas.

Useful For: An aid in the identification of Helicobacter pylori infection Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Marzio L, Angelucci D, Grossi L, et al: Anti-Helicobacter pylori specific antibody immunohistochemistry improves the diagnostic accuracy of Helicobacter pylori in biopsy specimen from patients treated with triple therapy. American Journal of Gastroenterology 1998;93(2):223-226 2. Nakamura Sh, Yao t, Aoyagi K, et al: Helicobacter pylori and primary gastric lymphoma. A histopathologic and immunohistochemical analysis of 237 patients. Cancer 1997;79(1):3-11 3. Patnayak R, Reddy V, Jena A, et al: Utility of immunohistochemistry in demonstrating Helicobacter pylori. Onc Gas Hep Rep 2015;4:4-7

HELM

Helminthosporium halodes, IgE

82749

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease, the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children or =100 Strongly positive Reference values apply to all ages.


FHSSE

Helminthosporium sativum/Drecshlera IgE

57532

Interpretation: Class IgG (kU/L) Comment 0 99.99 Very Strong Positive

Reference Values: A). Homozygosity for the C282Y mutation is associated with 60% to 90% of all cases of HH. Additionally, 3% to 8% of individuals affected with HH are heterozygous for this mutation. These frequencies show variability among different populations, with the highest frequency observed in individuals of northern European ancestry. Penetrance for elevated serum iron indices among C282Y homozygotes is relatively high, but not 100%. However, the penetrance for the characteristic clinical end points (such as diabetes mellitus, hepatic cirrhosis, and cardiomyopathy) is quite low. There is no test that can predict whether a C282Y homozygote will develop clinical symptoms. The H63D (exon 2, 187C->G) mutation is associated with HH, but the actual clinical effects of this mutation are uncertain. Homozygosity for H63D is insufficient to cause clinically significant iron overload in the absence of additional modifying factors. However, compound heterozygosity for C282Y/H63D has been associated with increased hepatic iron concentrations. Approximately 1% to 2% of individuals with this genotype will develop clinical evidence of iron overload. While individuals with this genotype may have increased iron indices, most will not develop clinical disease without comorbid factors (steatosis, diabetes, or excess alcohol consumption). The clinical significance of a third HFE mutation, S65C (exon 2, 193A->T), appears to be minimal. This rare variant displays a very low penetrance. Compound heterozygosity for C282Y and S65C may confer a low risk for mild HH. Individuals who are heterozygous for S65C and either the wild-type or H63D alleles do not seem to be at an increased risk for HH. The S65C mutation is only reported when it is part of the C282Y/S65C genotype. See Hereditary Hemochromatosis Algorithm in Special Instructions.

Useful For: Establishing or confirming the clinical diagnosis of hereditary hemochromatosis (HH) in adults HFE genetic testing is NOT recommended for population screening Testing of individuals with increased transferrin-iron saturation in serum and serum ferritin With appropriate genetic counseling, predictive testing of individuals who have a family history of HH

Interpretation: An interpretive report will be provided. For more information about hereditary hemochromatosis testing, see Hereditary Hemochromatosis Algorithm in Special Instructions.


Clinical References: 1. Mura C, Raguenes O, Ferec C: HFE Mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 1999;93(8):2502-2505 2. Beutler E, Felitti VJ, Koziol J, et al: Penetrance of 845G->A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359(9302):211-218 3. Walsh A, Dixon JL, Ramm GA, et al: The clinical relevance of compound heterozygosity for the C282Y and H63D substitutions in hemochromatosis. Clin Gastroenterol Hepatol 2006;4(11):1403-1410 4. Whitlock EP, Garlitz BA, Harris EL, et al: Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145(3):209-223



Page 999

HGB

Hemoglobin

801417

Clinical Information: Hemoglobin transports oxygen and CO2. This activity is decreased in anemia and increased in polycythemia, erythrocytosis, and dehydration. Hemoglobin measurements are used as clinical guides in the diagnosis or monitoring of many diseases.

Useful For: As a screening tool to confirm a hematologic disorder, to establish or rule out a diagnosis, to detect an unsuspected hematologic disorder, or to monitor effects of radiation or chemotherapy

Interpretation: Results outside of normal value ranges may reflect a primary disorder of the cell-producing organs or an underlying disease. Results should be interpreted in conjunction with the patient's clinical picture and appropriate additional testing performed.

Reference Values: HEMOGLOBIN Males: Birth-7 days: 13.5-22.0 g/dL 8-14 days: 12.5-21.0 g/dL 15 days-1 month: 10.0-20.0 g/dL 2-5 months: 10.0-14.0 g/dL 6 months-1 year: 10.5-13.5 g/dL 2 years: 11.0-14.0 g/dL 3-5 years: 11.0-14.5 g/dL 6-11 years: 12.0-14.0 g/dL 12-15 years: 12.8-16.0 g/dL Adults: 13.5-17.5 g/dL Females: Birth-7 days: 13.5-22.0 g/dL 8-14 days: 12.5-21.0 g/dL 15 days-1 month: 10.0-20.0 g/dL 2-5 months: 10.0-14.0 g/dL 6 months-1 year: 10.5-13.5 g/dL 2 years: 11.0-14.0 g/dL 3-5 years: 11.8-14.7 g/dL 6-11 years: 12.0-14.5 g/dL 12-15 years: 12.2-14.8 g/dL Adults: 12.0-15.5 g/dL

Clinical References: 1. CLSI. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. Approved Guideline-Third Edition. CLSI document EP28-A3c. Wayne, PA. Clinical and Laboratory Standards Institute, 2008 2. Klee G: Decision rules for accelerated hematology laboratory investigation. University of Minnesota 1974; PhD thesis 3. McKenzie SB: Textbook of Hematology. Lea and Febiger, Philadelphia 1988 4. Orkin SH, Fisher DE, Ginsburg D, et al: Nathan and Oski's Hematology and Oncology of Infancy and Childhood. Edited by ST Orkin, DE Fisher, AT Look, et al. WB Saunders Co, Philadelphia, 1981 5. Adeli, K, Raizman, J, Chen, Y, et al: Complex Biological Profile of Hematologic Markers Across Pediatric, Adult, and Geriatric Ages: Establishment of Robust Pediatric and Adult Reference Intervals on the Basis of the Canadian Health Measures Survey. Clin Chem 61:8 2015 6. Soldin, J, Brugnara, C, Wong, EC: Pediatric Reference Intervals. In Pediatric References Intervals. Fifth Edition. Edited by SJ Soldin, C Brugnara, EC Wong. AACC Press. Washington DC, 2005. ISBN 1-594250-32-4

60891

Hemoglobin (Hb), Immunostain Without Interpretation Clinical Information: This immunostain uses antibodies to hemoglobin that stain red blood cells and red blood cell precursors in bone marrow and in other sites in a diffuse cytoplasmic staining pattern. This stain may be useful in the diagnosis of erythroleukemia or myelodysplastic neoplasms.



Page 1000

Useful For: An aid in the identification of red blood cells and red blood cell precursors Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Chuang SS, Li CY: Useful panel of antibodies for the classification of acute leukemia by immunohistochemical methods in bone marrow trephine biopsy specimens. Am J Clin Pathol 1997;107(4):410-418 2. Dong HY, Wilkes S, Yang H: CD71 is selectively and ubiquitously expressed at high levels in erythroid precursors of all maturation stages: A comparative immunochemical study with glycophorin A and hemoglobin A. Am J Surg Pathol 2011;35(5): 723-732 3. Oâ€™Malley DP, Young SK, Perkins SL, et al: Morphologic and immunohistochemical evaluation of splenic hematopoietic proliferations in neoplastic and benign disorders. Modern Pathology 2005;18:1550-1561

HBA1C

Hemoglobin A1c, Blood

82080

Clinical Information: Diabetes mellitus is a chronic disorder associated with disturbances in carbohydrate, fat, and protein metabolism characterized by hyperglycemia. It is one of the most prevalent diseases, affecting approximately 24 million individuals in the United States. Long-term treatment of the disease emphasizes control of blood glucose levels to prevent the acute complications of ketosis and hyperglycemia. In addition, long-term complications such as retinopathy, neuropathy, nephropathy, and cardiovascular disease can be minimized if blood glucose levels are effectively controlled. Hemoglobin A1c (HbA1c) is a result of the nonenzymatic attachment of a hexose molecule to the N-terminal amino acid of the hemoglobin molecule. The attachment of the hexose molecule occurs continually over the entire life span of the erythrocyte and is dependent on blood glucose concentration and the duration of exposure of the erythrocyte to blood glucose. Therefore, the HbA1c level reflects the mean glucose concentration over the previous period (approximately 8-12 weeks, depending on the individual) and provides a much better indication of long-term glycemic control than blood and urinary glucose determinations. Diabetic patients with very high blood concentrations of glucose have from 2 to 3 times more HbA1c than normal individuals. Diagnosis of diabetes includes 1 of the following: -Fasting plasma glucose > or =126 mg/dL -Symptoms of hyperglycemia and random plasma glucose >or =200 mg/dL -Two-hour glucose > or =200 mg/dL during oral glucose tolerance test unless there is unequivocal hyperglycemia, confirmatory testing should be repeated on a different day In addition, recommendations from the American Diabetes Association (ADA) include the use of HbA1c to diagnose diabetes, using a cutpoint of 6.5%. The cutpoint was based upon sensitivity and specificity data from several studies. Advantages to using HbA1c for diagnosis include: -HbA1c provides an assessment of chronic hyperglycemia -Assay standardization efforts from the National Glycohemoglobin Standardization Program have been largely successful and the accuracy of HbA1c is closely monitored by manufacturers and laboratories -No fasting is necessary -Intraindividual variability is very low (critical value of 200 mg/dL. Patients who have an HbA1c between 5.7 and 6.4 are considered at increased risk for developing diabetes in the future. (The terms prediabetes, impaired fasting glucose, and impaired glucose tolerance will eventually be phased out by the ADA to eliminate confusion.) The ADA recommends measurement of HbA1c (typically 3-4 times per year for type 1 and poorly controlled type 2 diabetic patients, and 2 times per year for well-controlled type 2 diabetic patients) to determine whether a patient's metabolic control has remained continuously within the target range.

Useful For: Evaluating the long-term control of blood glucose concentrations in diabetic patients Diagnosing diabetes Identifying patients at increased risk for diabetes (prediabetes)

Interpretation: Diagnosing diabetes American Diabetes Association (ADA) -Hemoglobin A1c (HbA1c) > or =6.5% Therapeutic goals for glycemic control (ADA) -Adults: - Goal of therapy: 8.0% HbA1c -Pediatric patients: - Toddlers and preschoolers: 7.5%) - School age (6-12 years): or =24 months: 95.8-98.0% HEMOGLOBIN A2 1-30 days: 0.0-2.1% 1-2 months: 0.0-2.6% 3-5 months: 1.3-3.1% > or =6 months: 2.0-3.3% HEMOGLOBIN F 1-30 days: 22.8-92.0% 1-2 months: 7.6-89.8% 3-5 months: 1.6-42.2% 6-8 months: 0.0-16.7% 9-12 months: 0.0-10.5% 13-17 months: 0.0-7.9% 18-23 months: 0.0-6.3% > or =24 months: 0.0-0.9% VARIANT 1 0.0 VARIANT 2 0.0 VARIANT 3 0.0 Current as of August 23, 2017 7:11 am CDT


Page 1005

Clinical References: 1. The Management of Sickle Cell Disease. Fourth edition. Bethesda, MD: National Institutes of Health. National Heart, Lung, and Body Institute, 2002 2. Rosse WF, Telen M, Ware R: Transfusion Support for Patients with Sickle Cell Disease. Bethesda, MD: American Association of Blood Banks 1998 3. Ferster A, Tahriri P, Vermylen C, et al: Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 2001;97:3268-3632 4. Charache S, Terrin ML, Moore RD, et al: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-1322 5. Sebia CapillaryS Manual: 2014(06) Available at www.iproweb.fr/test/3%20-%20AU%20SOL/SEBIA%20-%20CAPILLARYS%202/MANUAL%202.pdf 6. Keren DF, Shalhoub R, Gulbranson R, et al: Expression of hemoglobin variant migration by capillary electrophoresis relative to hemoglobin A2 improves precision. Am J Clin Pathol 2012 Apr;137(4):660-664

HGB_Q

Hemoglobin, Qualitative, Urine

8581

Clinical Information: Free hemoglobin (Hgb) in urine usually is the result of lysis of RBCs present in the urine due to bleeding into the urinary tract (kidney, ureters, bladder). Less commonly, intravascular hemolysis (eg, transfusion reaction, hemolytic anemia, paroxysmal hemoglobinuria) may result in excretion of free Hgb from blood into urine. Injury to skeletal or cardiac muscle results in the release of myoglobin, which also is detected by this assay. Conditions associated with myoglobinuria include hereditary myoglobinuria, phosphorylase deficiency, sporadic myoglobinuria, exertional myoglobinuria in untrained individuals, crush syndrome, myocardial infarction, myoglobinuria of progressive muscle disease, and heat injury.

Useful For: Screening for hematuria, myoglobinuria, or intravascular hemolysis Interpretation: Free hemoglobin (Hgb), in the presence of RBCs, indicates bleeding into the urinary tract. Free Hgb, in the absence of RBCs, is consistent with intravascular hemolysis. Note: RBCs may be missed if lysis occurred prior to analysis; the absence of RBCs should be confirmed by examining a fresh specimen. The test is equally sensitive to hemoglobin and to myoglobin. The presence of myoglobin may be confirmed by MYOU / Myoglobin, Urine.

Reference Values: Appearance (internal specimens only): normal Hemoglobin: negative RBCs (internal specimens only): 0-2 rbcs/hpf

Clinical References: Fairbanks, V.F. and Klee G.G., Textbook of Clinical Chemistry 1986, Chapter 15, p 1562

HAEVP

Hemolytic Anemia Evaluation

84157

Clinical Information: Hemolytic anemia (HA) is characterized by increased red cell destruction and a decreased red cell life span. Patients usually have decreased hemoglobin concentration, hematocrit, and red blood cell count, but some can have compensated disorders, and symptoms such as reticulocytosis, pigmented gallstones, and decreased haptoglobin are factors that raise clinical suspicion. Blood smear abnormalities may include spherocytes, schistocytes, stomatocytes, polychromasia, basophilic stippling, and target cells. Osmotic fragility can be increased due to the presence of spherocytes. These are all nonspecific features that can be present in both hereditary and acquired hemolytic disorders. Inherited hemolytic disorders may include red cell membrane disorders, red cell enzyme defects, or abnormalities in the hemoglobin molecule in the red cell. This panel assesses for possible causes of congenital/hereditary causes of hemolytic anemia and does not evaluate for acquired causes. Therefore, the anemia should be lifelong or familial in nature. Examples of acquired HA (which should be excluded prior to ordering this panel) include: autoimmune HA, direct Coombs-positive HA, cold agglutinin disease, disseminated intravascular coagulation, and drug-induced HA. This consultative evaluation looks for the cause of increased red cell destruction and includes testing for red cell membrane disorders, such as hereditary spherocytosis, hemoglobinopathies, and red cell enzyme abnormalities. This panel is limited



Page 1006

in use in patients with a history of recent transfusion and should be ordered as remote a date from transfusion as possible in those that are chronically transfused.

Useful For: Evaluation of lifelong or inherited hemolytic anemias, including red cell membrane disorders, unstable or abnormal hemoglobin variants, and red cell enzyme disorders Cold agglutinin disorders and autoimmune disorders should be excluded prior to testing. This evaluation is not suitable for acquired causes of hemolysis.

Interpretation: An interpretive report will be provided. Reference Values: Definitive results and an interpretive report will be provided.

Clinical References: 1. Steiner LA, Gallagher PG. Erythrocyte disorders in the perinatal period. Semin Perinatol 2007 Aug;31(4):254-61. PMID: 17825683 2. Beutler E: Glucose-6-phosphate dehydrogenase deficiency and other enzyme abnormalities. In Hematology. Fifth edition. Edited by E Beutler, MA Lichtman, BS Coller, TJ Kipps. New York, McGraw-Hill Book Company, 1995, pp 564-581 3. Hoyer JD, Hoffman DR: The thalassemia and hemoglobinopathy syndromes. In Clinical Laboratory Medicine. Second edition. Edited by KD McMlatchey. Philadelphia, Lippincott, Williams and Wilkins, 2002, pp 866-895 4. King MJ, GarÃ§on L, Hoyer JD, Iolascon A, et al: International Council for Standardization in Haematology. ICSH guidelines for the laboratory diagnosis of nonimmune hereditary red cell membrane disorders. Int J Lab Hematol 2015 Jun;37(3):304-25. PMID: 25790109 5. Lux SE, IV: Anatomy of the red cell membrane skeleton: unanswered questions. Blood 2016 Jan 14;127(2):187-99 DOI: 10.1182/blood-2014-12-512772. PMID: 26537302 6. Gallagher PG. Abnormalities of the erythrocyte membrane. Pediatr Clin North Am 2013 Dec;60(6):1349-62. PMID: 24237975 7. Bianchi P, Fermo E, Vercellati C, Marcello AP, et al: Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. Haematologica 2012 Apr;97(4):516-23. PMID: 22058213 8. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008;371:64-74 9. Hereditary hemolytic anemias due to red blood cell enzyme disorders. Edited by B Glader. Philadelphia: Wolters Kluwer/Lippincott, Williams and Wilkins; 2014, pp 728

F8INP 66206

Hemophilia A F8 Gene, Intron 1 and 22 Inversion Mutation Analysis, Amniotic Fluid or Chorionic Villus Sampling Clinical Information: Hemophilia A (HA) is due to a deficiency of clotting factor VIII (FVIII). HA is an X-linked recessive bleeding disorder that affects approximately 1 in 5,000 males. Males are typically affected with bleeding symptoms, whereas carrier females generally do not have bleeding symptoms but are at risk of having affected sons. Rarely, approximately 10% of carrier females have FVIII activity levels below 35% and are at risk for bleeding. Bleeding, the most common clinical symptom in individuals with HA, correlates with FVIII activity levels. FVIII activity levels of 3.0 mg total hemoglobin/g feces >4.0 mg total hemoglobin/g feces* *Alternative reference values for persons who have ingested red meat or aspirin during any of the 3 days preceding specimen collection.

Clinical References: 1. Ahlquist DA, McGill DB, Schwartz S, et al: HemoQuant, a new quantitative assay for fecal hemoglobin: comparison with Hemoccult. Ann Intern Med 1984;101:297-302 2. Ahlquist DA, Wieand HS, Moertel CG, et al: Accuracy of fecal occult blood screening for colorectal neoplasia: a prospective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262-1267 3. Harewood GC, McConnell JP, Harrington JJ, et al: Detection of occult upper gastrointestinal bleeding: performance differences in fecal blood tests. Mayo Clin Proc 2002;77(1):23-28

UHSD

Hemosiderin, Urine

8582

Clinical Information: When the plasma hemoglobin level is >50 to 200 mg/dL after hemolysis, the capacity of haptoglobin to bind hemoglobin is exceeded, and hemoglobin readily passes through the glomeruli of the kidney. Part of the hemoglobin is absorbed by the proximal tubular cells where the hemoglobin iron is converted to hemosiderin. When these tubular cells are later shed into the urine, hemosiderinuria results. If all of the hemoglobin cannot be absorbed into the tubular cells, hemoglobinuria results. Hemosiderin is found as yellow-brown granules that are free or in epithelial cells and occasionally in casts in an acidic or neutral urine.

Useful For: Detecting hemosiderinuria, secondary to excess hemolysis, as in incompatible blood transfusions, severe acute hemolytic anemia, or hemochromatosis

Interpretation: A positive hemosiderin indicates excess red cell destruction. Hemosiderinuria may still be detected after hemoglobin has cleared from the urine and hemoglobin dipstick is negative.

Reference Values: Hemosiderin: negative (reported as positive or negative) Hemoglobin (internal specimens only): negative RBC (internal specimens only): 0-2 rbc/hpf

Clinical References: Henry JB: Clinical Diagnosis and Management by Laboratory Methods. 18th edition. Philadelphia, WB Saunders Company, 1991, pp 412-413

FWWE

Hemp Western Water (Acnida tamariscina) IgE

57956


Reference Values: 50%) than expected Not useful for monitoring therapy with the heparinoid "danaparoid"

Interpretation: Results above the therapeutic range may be supratherapeutic suggesting that the heparin dose may need to be decreased. Results below the therapeutic range may be subtherapeutic suggesting that the heparin dose may need to be increased.

Reference Values: Adult Therapeutic Range UFH therapeutic range: 0.30-0.70 IU/mL (6 hours following initiation or dose adjustment) LMWH therapeutic range: 0.50-1.00 IU/mL for twice daily dosing* LMWH therapeutic range: 1.00-2.00 IU/mL for once daily dosing* LMWH prophylactic range: 0.10-0.30 IU/mL (*sample obtained 4-6 hours following subcutaneous injection) Heparin Anti-Xa assay is used to measure heparin concentrations in patients receiving low-molecular-weight heparin or unfractionated heparin.

Clinical References: 1. Marci CD, Prager D: A review of the clinical indications for the plasma heparin assay. Am J Clin Pathol 1993;99:546-550 2. Houbouyan L, Boutiere B, Contant G, et al: Validation of analytical hemostasis systems: measurement of anti-Xa activity of low-molecular-weight-heparins. Clin Chem 1996;42:1223-1230 3. Jeske W, Messmore HL Jr, Fareed J: Pharmacology of heparin and oral anticoagulants. In Thrombosis and Hemorrhage. Second edition. Edited by J Loscalzo, AI Schafer. Baltimore, MA, Williams and Wilkins, 1998, pp 1193-1204 4. Monagle P, Michelson AD, Bovill E, Andrew M: Antithrombotic therapy in children. Chest 2001;119:344-370 5. Fraser G, McKenna J: Monitoring low molecular weight heparins with antiXa activity: house of cards or firm foundation? Hospital Pharmacy 2003;38:202-211 6. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE: Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009;43:1064:1083

FHPCF

Heparin Cofactor II

91658

Reference Values: 65 - 145%

HITIG

Heparin-PF4 IgG Antibody (HIT), Serum

86533

Clinical Information: Thrombocytopenia in patients treated with heparin is relatively common and has diverse, sometimes multifactorial, causes. Among the possible causes of thrombocytopenia in such patients, immune-mediated heparin-dependent thrombocytopenia (HIT) is clinically important because of its frequency and its associated risk of paradoxical new or progressive thrombosis. HIT, also called



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heparin-associated thrombocytopenia (HAT), consists of 2 distinct clinicopathologic syndromes. The first, sometimes designated type I HIT (HIT-I) or nonimmune HAT, is a common benign condition that is not immunologically mediated. Type I HIT is characterized by a mild decrease of the platelet count (typically < or =30% decrease from baseline) occurring early (days) in the course of treatment with heparin, especially intravenous unfractionated heparin (UFH), and which does not progress and may resolve despite continuation of heparin therapy. The second, more serious immune-mediated syndrome, sometimes designated type II heparin-induced thrombocytopenia (HIT-II), occurs in up to 1% to 5% of patients treated with UFH. It is typically characterized by onset of thrombocytopenia between days 5 and 10 of UFH therapy, but thrombocytopenia can arise earlier or later in association with continued heparin exposure. In patients recently exposed to heparin (eg, within the preceding 3-6 months), onset of thrombocytopenia can be rapid (within 24 hours) after heparin reexposure, probably reflecting persistence of heparin-dependent antiplatelet antibodies or anamnestic recall of them. Typically, during the course of HIT-II, the platelet count decreases by at least 40% to 50% from baseline or the postoperative peak (in surgical patients), even though the absolute count may remain normal, and thrombocytopenia resolves within 7 to 14 days of cessation of heparin therapy (unless there is another coexisting cause of thrombocytopenia). The risk of immune-mediated HIT-II is significantly greater with UFH exposure than with exposure to low-molecular-weight heparin (LMWH), although the latter can react with heparin-dependent antibodies induced by UFH. The risk is probably also associated with the dosage and route of heparin administration (eg, intravenous), as well as associated medical and surgical conditions. HIT-II is clinically important, not because of the mild or moderate thrombocytopenia and minimal bleeding risk, but because of the high risk for development of paradoxical thrombosis (arterial or venous) that may be new or progressive. This evolution, termed heparin-induced thrombocytopenia with thrombosis (HITT) syndrome, can occur in up to 30% to 50% of patients with HIT-II, even following discontinuation of heparin therapy. Clinically, it is often difficult to distinguish between HIT-I and HIT-II and among other etiologies of thrombocytopenia occurring in patients receiving heparin. However, the development of new or progressive thrombosis is one defining clinical feature of HIT-II. Recent studies provide evidence that HIT-II is caused, in at least 90% of cases, by antibodies to antigen complexes of heparinoid (heparin or similar glycosaminoglycans) and platelet factor 4 (PF4). PF4 is a platelet-specific heparin-binding (neutralizing) protein that is abundant in platelet alpha granules from which it is secreted following platelet stimulation. A reservoir of PF4 normally accumulates upon vascular endothelium. Following heparin administration, immunogenic complexes of PF4 and heparin can provide an antigenic stimulus for antibody development in some patients. Antibodies bound to platelets that display complexes of PF4/heparin antigen can activate platelets via interaction of the Fc immunoglobulin tail of the IgG antibody with platelet Fc gamma IIA receptors, leading to perpetuation of the pathologic process that can cause platelet-rich thrombi in the microcirculation in some cases (eg, HITT syndrome). Functional assays for HIT-II antibody detection rely on antibody-mediated heparin-dependent platelet activation, as detected by platelet aggregation, or platelet secretion of serotonin or adenosine triphosphate (ATP) or other substances, using patient serum or plasma supplemented with heparin and normal test platelets from carefully selected donors. The sensitivity of functional assays for HIT-II ranges from 50% to 60% for heparin-dependent platelet aggregation (HDPA) assays, to 70% to 80% for serotonin release assays. The specificity of positive functional tests for HIT diagnosis is believed to be high (> or =90%). However, because of their complexity, functional tests for detecting HIT antibodies are not widely available. Enzyme-linked immunosorbent assays (ELISAs) have recently been developed to detect HIT-II antibodies and are based on the detection of human antibodies that react with solid phase antigen complexes of heparinoid and human PF4 (H/PF4 complexes). The ELISA for H/PF4 antibodies is very sensitive for antibody detection, but relatively nonspecific for clinical HIT diagnosis. Routine screening of all patients prior to, during, or following heparin use is currently not recommended. A positive H/PF4 ELISA result has relatively low and uncertain predictive value for the development of clinical HIT-II.

Useful For: Detection of IgG antibodies directed against heparin/platelet factor 4 complexes that are implicated in the pathogenesis of immune-mediated type II heparin-induced thrombocytopenia (HIT-II). Clinical picture of HIT type II: -In patients not previously exposed to heparin -Decrease in platelet count (thrombocytopenia) of 50% or more from baseline or postoperative peak -Onset of thrombocytopenia beginning approximately 5 to 10 days after initiation of heparin this may or may not be associated with new or progressive thrombosis in patients treated with heparin Patients previously exposed to heparin (especially within the preceding 100 days), in addition to the above findings, the onset of thrombocytopenia could occur within 24 to 48 hours after reexposure to heparin Current as of August 23, 2017 7:11 am CDT


Page 1017

Interpretation: Results are reported as: 1) Heparin-induced thrombocytopenia (HIT) enzyme-linked immunosorbent assay (ELISA) OD; 2) Heparin inhibition (%); 3) Interpretation. Typical patterns of results and interpretations are depicted in the following table. Interpretive comments will also accompany test reports, when indicated. HIT ELISA OD Heparin Inhibition Interpretation Normal Range or =0.400 > or =50% Positive Equivocal > or =0.400 500 mIU/mL during the first week after transplantation, >250 mIU/mL during weeks 2 to 12, and >100 mIU/mL after week 12. See HBV Infection-Monitoring Before and After Liver Transplantation in Special Instructions.


Clinical References: 1. Samuel D: Management of hepatitis B in liver transplant patients. Semin Liver Dis 2004;24(suppl 1):55-62 2. Terrault NA, Vyas G: Hepatitis B immune globulin preparations and use in liver transplantation. Clin Liver Dis 2003;7:537-550 3. Lok AS: Prevention of recurrent hepatitis B post-liver transplantation. Liver Transpl 2002;8:S67-S73

HBAB

Hepatitis B Surface Antibody, Qualitative/Quantitative, Serum

8254

Clinical Information: Hepatitis B virus (HBV) infection, also known as serum hepatitis, is endemic throughout the world. The infection is spread primarily through blood transfusion or percutaneous contact with infected blood products, such as sharing of needles among injection drug users. The virus is also found in virtually every type of human body fluid and has been known to be spread through oral and genital contact. HBV can be transmitted from mother to child during delivery through contact with blood and vaginal secretions, but is not commonly transmitted via the transplacental route. The incubation period for HBV infection averages 60 to 90 days (range of 45-180 days). Common symptoms include malaise, fever, gastroenteritis, and jaundice (icterus). After acute infection, HBV infection becomes chronic in 30% to 90% of infected children or =5 years of age. Some of these chronic carriers are asymptomatic, while others progress to chronic liver disease, including cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) is the first serologic marker, appearing in the serum 6 to 16 weeks following HBV infection. In acute cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms with the appearance of hepatitis B surface antibody (anti-HBs). Anti-HBs also appears as the immune response following hepatitis B vaccination. See The Laboratory Approach to the Diagnosis and Monitoring of Hepatitis B Infection in Publications and HBV Infection-Diagnostic Approach and Management Algorithm in Special Instructions.

Useful For: Identifying previous exposure to hepatitis B virus Determining adequate immunity from hepatitis B vaccination

Interpretation: This assay provides both qualitative and quantitative results. A positive result indicates recovery from acute or chronic hepatitis B virus (HBV) infection, or acquired immunity from HBV vaccination. This assay does not differentiate between a vaccine-induced immune response and an immune response induced by infection with HBV. A positive total anti-hepatitis B core (anti-HBc) result would indicate that the hepatitis B surface antibody (anti-HBs) response is due to past HBV infection. Positive results (quantitative hepatitis B surface antibody [anti-HBs] levels of > or =12.0 mIU/mL) indicate adequate immunity to hepatitis B from past hepatitis B or HBV vaccination. After receiving a primary HBV vaccine series, individuals with anti-HBs levels of 12 mIU/mL or greater are considered protected from hepatitis B in accordance with the CDC guideline.(1) A negative result (quantitative anti-HBs level of or =5 to 80%). To determine the duration of treatment and monitor the response to anti-HCV therapy, HCV RNA levels in serum or plasma are typically measured at 0 (baseline), 4 (rapid virologic response, RVR), 8, and 12 (early virologic response: EVR) weeks of therapy, end-of-treatment (24, 28, or 48 weeks depending on HCV genotype and treatment response), and 24 weeks post-treatment (sustained virologic



Page 1034

response: SVR). The following algorithms are available in Special Instructions: -Testing Algorithm for the Screening and Diagnosis of Hepatitis C -Chronic Hepatitis C Treatment and Monitoring Algorithm: Interferon-Free Combination Therapy

Useful For: Detection of acute hepatitis C virus (HCV) infection before the appearance of HCV antibodies in serum (ie, 6 months after onset of acute infection). These antibodies do not neutralize the virus, and they do not provide immunity against this viral infection. Loss of HCV antibodies may occur many years following resolution of infection. Despite the value of serologic tests to screen for HCV infection, several limitations of serologic testing are known: -There may be a long delay (up to 6 months) between exposure to the virus and the development of detectable antibodies. -False-reactive screening test results can occur. -A reactive screening test result does not distinguish between past (resolved) and present HCV infection. -Serologic tests cannot provide information on clinical response to antiviral therapy. Positive screening serologic test results should be followed by a confirmatory or supplemental test, such as line immunoassay (HCVL) for HCV antibodies or a nucleic acid test for HCV RNA. Although nucleic acid tests provide a very sensitive and specific approach to directly detect HCV RNA in a patient's blood, they are not suitable for use in testing cadaveric or hemolyzed serum specimens due to interference of heme with the nucleic acid amplification processes.

Useful For: Screening cadaveric or hemolyzed serum specimens for hepatitis C virus-specific IgG antibodies Note: This test is not intended for screening blood, cell, or tissue donors.

Interpretation: All specimens with signal-to-cutoff ratios of > or =1.0 will be considered reactive and reflexed to the hepatitis C virus (HCV) IgG antibody confirmatory test by line immunoassay (HCVL) at an additional charge. Additional testing is needed to differentiate between past (resolved) and chronic Current as of August 23, 2017 7:11 am CDT


Page 1036

hepatitis C. A negative screening test result does not exclude the possibility of exposure to or infection with HCV. Negative screening test results in individuals with prior exposure to HCV may be due to antibody levels below the limit of detection of this assay or lack of reactivity to the HCV antigens used in this assay. Patients with recent HCV infections (6 months after onset of acute infection). These antibodies do not neutralize the virus, and they do not provide immunity against this viral infection. Loss of HCV antibodies may occur many years following resolution of infection. Despite the value of serologic tests to screen for HCV infection, several limitations of serologic testing are known: -There may be a long delay (up to 6 months) between exposure to the virus and the development of detectable antibodies. -False-reactive screening test results can occur. -A reactive screening test result does not distinguish between past (resolved) and present HCV infection. -Serologic tests cannot provide information on clinical response to antiviral therapy. Positive screening serologic test results should be followed by a confirmatory or supplemental test, such as line immunoassay for HCV antibodies or a nucleic acid test for HCV RNA. Although nucleic acid tests provide a very sensitive and specific approach to directly detect HCV RNA in a patient's blood, they are not suitable for use in testing cadaveric or hemolyzed serum specimens due to interference of heme with the nucleic acid amplification processes.

Useful For: Screening cadaveric or hemolyzed serum specimens for hepatitis C virus infection in nonsymptomatic individuals Note: In accordance with National Coverage Determination guidance, this test is indicated for asymptomatic patients born from 1945 through 1965, those with history of injection drug use, or history of receiving blood transfusion prior to 1992.

Interpretation: All specimens with signal-to-cutoff ratios of > or =1.0 will be considered reactive and reflex to the hepatitis C virus antibody confirmatory test by line immunoassay (HCVL) at an additional charge. Additional testing is needed to differentiate between past (resolved) and chronic hepatitis C. A negative screening test result does not exclude the possibility of exposure to or infection with HCV. Negative screening test results in individuals with prior exposure to HCV may be due to antibody levels below the limit of detection of this assay or lack of reactivity to the HCV antigens used in this assay. Patients with recent HCV infections ( type 1) and the method of antiviral therapy may be different depending on the specific type of HSV causing disease. In addition, the results of HSV type-specific IgG testing is sometimes used during pregnancy to identify risks of congenital HSV disease and allow for focused counseling prior to delivery.(2-3)

Useful For: Supplementing culture or molecular detection of herpes simplex virus (HSV) for the diagnosis of acute infection Determining whether a patient has been previously exposed to HSV types 1 or 2 Distinguishing between infection caused by HSV types 1 and 2, especially in patients with subclinical or unrecognized HSV infection

Interpretation: The presence of IgM herpes simplex virus (HSV) antibodies indicates acute infection with either HSV type 1 or 2. The IgG antibody assay detects IgG-class antibodies to type-specific HSV glycoprotein G (gG), and may allow for the differentiation of infection caused by HSV types 1 and 2. The presence of IgG-class antibodies to HSV types 1 or 2 indicates previous exposure, and does not necessarily indicate that HSV is the causative agent of an acute illness.

Reference Values: HSV TYPE 1 ANTIBODY, IgG Negative (reported as positive, negative, or equivocal) HSV TYPE 2 ANTIBODY, IgG Negative (reported as positive, negative, or equivocal) HSV ANTIBODY SCREEN, IgM, by EIA Negative (reported as reactive or negative)

Clinical References: 1. Ashley RL, Wald A: Genital herpes: review of the epidemic and potential use of type-specific serology. Clin Microbiol Rev 1999;12:1-8 2. Ashley RL, Wu L, Pickering JW, et al: Premarket evaluation of a commercial glycoprotein G-based enzyme immunoassay for herpes simplex virus type-specific antibodies. J Clin Microbiol 1998;36:294-295 3. Brown ZA, Selke S, Zeh J, et al: The acquisition of herpes simplex virus during pregnancy. N Engl J Med 1997;337:509-515 4. Lafferty WE, Coombs RW, Benedetti J, et al: Recurrences after oral and genital herpes simplex infection. N Engl J Med 1987;316:1444-1449 5. Binnicker MJ, Jespersen DJ and Harring JA. Evaluation of three multiplex flow immunoassays to enzyme immunoassay for the detection and differentiation of IgG-class antibodies to Herpes Simplex Virus types 1 and 2. Clin Vac Immunol 2010 Feb;17(2):253-257

VHSV

Herpes Simplex Virus (HSV), Culture From Neonates

62352

Clinical Information: Herpes simplex virus (HSV) types 1 (HSV-1) and 2 (HSV-2) cause various



Page 1065

clinical syndromes. Anatomic sites infected include the skin, oral mucosa, oral cavity, eyes, genital tract, and central nervous system (CNS).(1,2) Systemic involvement may also occur. HSV infections are common, with data suggesting that the seroprevalence of HSV-1 and HSV-2 in the United States (2005-2010) is 53.9% and 15.7%, respectively.(3) Although HSV-1 has historically been believed to cause recurrent oral lesions, it is an increasingly important cause of genital herpes. Both HSV-1 and HSV-2 can cause CNS disease, with infection in neonates being considered a medical emergency. Diagnostic methods for HSV have included routine viral culture, molecular testing by PCR, and serology. It is difficult to recover HSV from cerebrospinal fluid (CSF) specimens using viral culture, and the serologic diagnosis of HSV is limited by the inability to distinguish between primary and reactivated disease. Detection of HSV by real-time PCR is now recognized as the most sensitive approach to diagnose HSV infection, especially CNS-associated HSV disease. However, performing viral culture for HSV in neonates being evaluated for potential congenital herpes is still recommended.(4)

Useful For: An aid in the diagnosis of congenital herpes simplex virus (HSV) infection through the recovery of HSV using viral culture (shell-vial)

Interpretation: Recovery of herpes simplex virus (HSV) from clinical specimens supports the diagnosis of congenital infection due to the virus. A negative result by rapid culture should be interpreted in the context of the patientâ€™s clinical presentation and exposure history. Furthermore, testing by real-time PCR for this virus should be considered prior to ruling out HSV disease.

Reference Values: No virus isolated

Clinical References: 1. Schiffer JT, Corye L: New concepts in understanding genital herpes. Curr Infect Dis Rep Nov 2009;11(6):457-464 2. Sauerbrei A, Eichhorn U, Hottenrott G, Wutzler P: Virological diagnosis of herpes simplex encephalitis. J Clin Virol 2000;17(1):31-36 3. American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. Herpes Simplex. Edited by LK Pickering. 29th edition. Elk Grove Village, IL: American Academy of Pediatrics, 2012 4. Bradley H, Markowitz LE, Gibson T, McQuillan GM: Seroprevalence of Herpes Simplex Virus types 1 and 2-United States, 1999-2010. J Infect Dis 2014 Feb 1;209(3):325-333 5. Stranska R, Schuurman R, de Vos M, van Loon AM: Routine use of a highly automated and internally controlled real-time PCR assay for the diagnosis of herpes simplex and varicella-zoster virus infections. J Clin Virol 2004 May;30(1):39-44 6. Espy MJ, Uhl JR, Mitchell PS, et al: Diagnosis of herpes simplex virus infections in the clinical laboratory by LightCycler PCR. J Clin Microbiol 2000;38(2):795-799

LHSV

Herpes Simplex Virus (HSV), Molecular Detection, PCR

80575

Clinical Information: Herpes simplex virus (HSV) types 1 and 2 are members of the Herpesviridae family, and produce infections that may range from mild stomatitis to disseminated and fatal disease. Clinical conditions associated with HSV infection include gingivostomatitis, keratitis, encephalitis, vesicular skin eruptions, aseptic meningitis, neonatal herpes, genital tract infections, and disseminated primary infection. Infections with HSV types 1 and 2 can differ significantly in their clinical manifestations and severity. HSV type 2 primarily causes urogenital infections and is found almost exclusively in adults. HSV type 1 is closely associated with orolabial infection, although genital infection with this virus can be common in certain populations. The diagnosis of HSV infections is routinely made based on clinical findings and supported by laboratory testing using PCR or viral culture.

Useful For: Aiding in the rapid diagnosis of herpes simplex virus (HSV) infections, including qualitative detection of HSV DNA in nonblood clinical specimens

Interpretation: This is a qualitative assay; results are reported either as negative or positive for herpes simplex virus (HSV) type 1 or HSV type 2, or HSV indeterminate. Detection of HSV DNA in clinical specimens supports the clinical diagnosis of infection due to the virus.


Clinical References: 1. Schiffer JT, Corye L: New concepts in understanding genital herpes. Curr Current as of August 23, 2017 7:11 am CDT


Page 1066

Infect Dis Rep Nov 2009;11(6):457-464 2. Espy MJ, Uhl JR, Svien KA: Laboratory diagnosis of herpes simplex virus infections in the clinical laboratory by LightCycler PCR. J Clin Microbiol 2000;38(2):795-799 3. Espy MJ, Ross TK, Teo R: Evaluation of LightCycler PCR for implementation of laboratory diagnosis of herpes simplex virus infections. J Clin Microbiol 2000;38(8):3116-3118 4. Sauerbrei A, Eichhorn U, Hottenrott G, Wutzler P: Virological diagnosis of herpes simplex encephalitis. J Clin Virol 2000;17(1):31-36 5. Mitchell PS, Espy MJ, Smith TF, et al: Laboratory diagnosis of central nervous system infections with herpes simplex virus by PCR performed with cerebrospinal fluid specimens. J Clin Microbiol 1997;35(11):2873-2877 6. Yi-Wei T, Mitchell PS, Espy MJ, et al: Molecular diagnosis of herpes simplex virus infections in the central nervous system. J Clin Microbiol 1999;37(7):2127-2136

LHSVB

Herpes Simplex Virus (HSV), Molecular Detection, PCR, Blood

62993

Clinical Information: Herpes simplex virus (HSV) types 1 and 2 cause a variety of clinical syndromes. Anatomic sites infected include the skin, lips, oral cavity, eyes, genital tract, and central nervous system (CNS). Systemic disease may also occur, in which the virus may be detectable in the bloodstream. The detection of HSV-1 or HSV-2 from blood specimens may help support the diagnosis of disseminated disease associated with this virus.

Useful For: Aids in the rapid diagnosis of disseminated disease due to herpes simplex virus (HSV) Qualitative detection of HSV DNA

Interpretation: This is a qualitative assay; results are reported either as negative or positive for herpes simplex virus (HSV) type 1 or HSV type 2. In a small number of cases (eg, or =20 nmol/min/mL > or =16 years: 10.4-23.8 nmol/min/mL HEXOSAMINIDASE PERCENT A, S < or =15 years: 20-90% > or =16 years: 56-80%

Clinical References: 1. Delnooz CCS, Lefeber DJ, Langemeijer SMC, et al: New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. J Neurol Neurosurg Current as of August 23, 2017 7:11 am CDT


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Psychiatry 2010;81:968-972 2. Gravel RA, Kaback MM, Proia RL, et al: The GM2 gangliosidoses. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al: New York, NY, McGraw-Hill, 2014. Available from: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62645630. Accessed August 24, 2015 3. Maegawa GH, Stockley T, Tropak M, et al: The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 2006 Nov;118(5):e1550-1562 4. O'Brien JS, Okada S, Chen A, Fillerup DL: Tay-Sachs disease: detection of heterozygotes and homozygotes by hexosaminidase assay. N Engl J Med 1970;283:15-20

NAGR

Hexosaminidase A and Total, Leukocytes/Molecular Reflex

82943

Clinical Information: Tay-Sachs disease and Sandhoff disease are lysosomal storage disorders, also referred to as GM2 gangliosidoses, caused by deficiencies of the enzymes hexosaminidase A and hexosaminidase B, respectively. These isoenzymes are dimers that differ in their subunit composition. Hexosaminidase A is a heterodimer composed of 1 alpha and 1 beta subunit (alpha-beta), while hexosaminidase B is a homodimer composed of 2 beta subunits (beta-beta). The defective lysosomal degradation and the excessive accumulation of GM2 ganglioside and related glycolipids results in the development of the clinical symptomology observed in Tay-Sachs and Sandhoff diseases. Tay-Sachs Disease: Tay-Sachs disease is caused by a deficiency of hexosaminidase A due to a defect in the alpha subunit. This autosomal recessive condition results from 2 mutations in the HEXA gene, which encodes for the alpha subunit of hexosaminidase. Individuals with Tay-Sachs disease have a deficiency in hexosaminidase A; those with higher residual enzyme activity may have a milder clinical presentation with a later age of onset. The acute infantile form typically presents with progressive motor deterioration beginning at 3 to 6 months of age. Patients exhibit weakness, hypotonia, and decreasing attentiveness. Motor skills learned previously, such as crawling or sitting alone, are nearly always lost by age 1. Other symptoms include rapid diminishing of vision, seizures, macroencephaly due to cerebral gliosis, and the characteristic cherry-red spot in the retina. Affected individuals typically do not survive past age 5. The juvenile or subacute form of Tay-Sachs disease often presents between 2 and 10 years with ataxia and clumsiness. Patients develop difficulties with speech and cognition. Neurologic features progressively worsen and death is typically 2 to 4 years later. Disease progression is slower in patients with chronic or adult-onset Tay-Sachs disease. Early signs and symptoms may be subtle and nonspecific, involving muscle and/or neurologic findings, often resulting in initial misdiagnoses. Affected individuals may exhibit abnormalities of gait and posture, spasticity, dysarthria (loss of speech), and progressive muscle wasting and weakness. Cognitive impairment, dementia, or psychiatric findings are observed in some patients. Significant clinical variability exists both between and within families. The carrier frequency of Tay-Sachs disease is increased in certain groups including individuals of Ashkenazi Jewish, Celtic, and French Canadian ancestry. A common cause of false-positive carrier screening by enzyme analysis, particularly among individuals of non-Ashkenazi Jewish descent, is due to the presence of a pseudodeficiency allele. Such sequence variations are not associated with disease, but result in the production of a hexosaminidase A enzyme with decreased activity towards the artificial substrate typically used in the enzyme assay. The recommended testing strategy is to order NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex, which begins with enzyme analysis and when the percent of hexosaminidase A enzyme is low, reflexes to the molecular panel which includes the most common mutations observed in these high-risk populations and 2 common pseudodeficiency alleles. Sandhoff Disease: Sandhoff disease (deficiency of hexosaminidase A and B due to a defect in the beta subunit) is an autosomal recessive condition resulting from 2 mutations in the HEXB gene, which encodes for the beta subunit of hexosaminidase. Individuals with Sandhoff disease have deficiencies in both hexosaminidase A and hexosaminidase B. Phenotypically, patients with Sandhoff disease present with features very similar to Tay-Sachs disease including variability in age of onset and severity. Enzyme analysis is generally required to distinguish between the 2 disorders. Unlike Tay-Sachs disease, Sandhoff disease does not have an increased carrier frequency in any specific population. Diagnostic and Carrier Testing: Testing for Tay-Sachs and Sandhoff diseases occurs by analysis of hexosaminidase A, a heat-labile enzyme, and total hexosaminidase (hexosaminidase A plus hexosaminidase B). When testing the enzyme, an artificial substrate is most commonly used. The total hexosaminidase is quantified. Following this, heat inactivation of hexosaminidase A occurs with a second measurement of the total enzyme level. From this, the percent hexosaminidase A is calculated. Biochemically, Tay-Sachs disease is



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characterized by normal total hexosaminidase with a very low percent hexosaminidase A. Carriers of Tay-Sachs disease are asymptomatic, but have intermediate percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. Follow-up molecular testing is recommended for all individuals with enzyme results in the carrier or possible carrier ranges to differentiate carriers of a pseudodeficiency allele from those with a disease-causing mutation. In addition, this allows for the facilitation of prenatal diagnosis for at-risk pregnancies. A very small group of patients affected with Tay-Sachs disease have the B1 variant. In the presence of an artificial substrate, the B1 variant allows for a heterodimer formation of hexosaminidase A and exhibits activity. However, in vivo the B1 variant hexosaminidase A is inactive on the natural substrate. Thus, with the artificial substrate, these patients appear to be unaffected. Individuals with the B1 variant of Tay-Sachs disease must be distinguished using a natural substrate assay (MUGS / Hexosaminidase A [MUGS], Serum). This testing should be considered if one of the other assays indicates normal, indeterminate, or carrier results and the suspicion of Tay-Sachs disease remains high. Hexosaminidase testing using the artificial substrate provides an indirect assay for Sandhoff disease. Affected individuals exhibit very low total hexosaminidase with a disproportionately high percent hexosaminidase A due to alpha subunit homodimer formation. Carriers of Sandhoff disease are asymptomatic but have intermediate levels of total hexosaminidase with high percent hexosaminidase A in serum, leukocytes, and cultured fibroblasts. However, not all individuals with this pattern are true carriers of Sandhoff disease and follow-up molecular testing is recommended. In addition, molecular analysis allows for the facilitation of prenatal diagnosis for at-risk pregnancies. Testing hexosaminidase using the natural substrate does not identify homozygotes or heterozygotes for Sandhoff disease.

Useful For: Carrier detection and diagnosis of Tay-Sachs disease (see also NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes and NAGS / Hexosaminidase A and Total Hexosaminidase, Serum for additional testing options). Recommended test for carrier detection of Tay-Sachs disease Carrier detection and diagnosis of Sandhoff disease (testing option-not the recommended test)

Interpretation: Interpretation is provided with report. Hexosaminidase A usually composes greater than 62% of the total hexosaminidase activity in leukocytes (normal = 63%-75% A). In leukocytes, the percent Hex A is used in determining whether an individual is a carrier of or affected with Tay-Sachs disease: -63% to 75% hexosaminidase A is normal (noncarrier) -58% to 62% hexosaminidase A is indeterminate (molecular testing recommended to discern carriers from non-carriers and to allow for prenatal diagnosis if desired) -less than 58% hexosaminidase A is a carrier (molecular testing recommended to discern disease-causing mutations from pseudodeficiency alleles and to allow for prenatal diagnosis if desired) -less than 20% hexosaminidase A is consistent with a diagnosis of Tay-Sachs disease. In leukocytes, the total hexosaminidase in combination with the percent hexosaminidase A aids in determining whether an individual is at-risk to be a carrier of or is affected with Sandhoff disease: -greater than or equal to 76% hexosaminidase A is suggestive of a Sandhoff carrier, when the total hexosaminidase is depressed -Total hexosaminidase activity near zero with nearly 100% hexosaminidase A is consistent with Sandhoff disease

Reference Values: HEXOSAMINIDASE TOTAL < or =15 years: > or =20 nmol/min/mg > or =16 years: 16.4-36.2 nmol/min/mg HEXOSAMINIDASE PERCENT A < or =15 years: 20-80% of total > or =16 years: 63-75% of total

Clinical References: 1. Triggs-Raine BL, Feigenbaum ASJ, Natowicz M, et al: Screening for carriers of Tay-Sachs disease among Ashkenazi Jews-A comparison of DNA-based and enzyme-based tests. N Engl J Med 1990;323:6-12 2. Delnooz CCS, Lefeber DJ, Langemeijer SMC, et al: New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. J Neurol Neurosurg Psychiatry 2010;81(9):968-972 3. Vallance H, Morris TJ, Coulter-Mackie M, et al: Common HEXB polymorphisms reduce serum HexA and HexB enzymatic activities, potentially masking Tay-Sachs disease carrier identification. Mol Genet Metab 2006 Feb;87(2):122-127 4. Kaback MM, Desnick RJ. Hexosaminidase A Deficiency. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Seattle, WA, University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1218/ 5. Neudorfer O, Pastores GM, Zeng BJ, et al: Late-onset Current as of August 23, 2017 7:11 am CDT


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Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med 2005 Feb;7(2):119-123 6. Sutton VR: Tay-Sachs disease screening and counseling families at risk for metabolic disease. Obstet Gynecol Clin North Am 2002 Jun;29(2):287-296 7. D'Souza G, McCann CL, Hedrick J, et al: Tay-Sachs disease carrier screening: a 21-year experience. Genet Test 2000;4(3):257-263

FSHAG

Hickory Shagbark (Carya ovata) IgE

57950


Reference Values: 90%) of exposed individuals will remain asymptomatic, individuals seeking medical attention can present with a diverse set of symptoms ranging from a self-limited pulmonary illness to severe, disseminated disease. Individuals at risk for severe infection include those with impaired cellular immunity, patients who have undergone organ transplantation, are HIV positive, or have a hematologic malignancy. The available laboratory methods for the diagnosis of H capsulatum infection include fungal culture, molecular techniques, serologic testing, and antigen detection. While culture remains the gold standard diagnostic test and is highly specific, prolonged incubation is often required and sensitivity decreases (9%-34%) in cases of acute or localized disease. Similarly, molecular methods offer high specificity, but decreased sensitivity. Serologic testing likewise offers high specificity; however, results may be falsely negative in immunosuppressed patients or those who present with acute disease. Also, antibodies may persist for years following disease resolution, thereby limiting the clinical specificity. Detection of H capsulatum antigen from urine samples has improved sensitivity (80%-95%) for the diagnosis of active histoplasmosis compared to both culture and serology. Additionally, urine antigen levels can be followed to monitor patient response to therapy, with declining levels consistent with disease resolution. Notably, however, H capsulatum antigen may persist at low levels following completion of antifungal therapy and clinical improvement.

Useful For: Aids in the diagnosis of Histoplasma capsulatum infection Monitoring Histoplasma antigen titers in urine

Interpretation: Presence of Histoplasma antigen in urine is indicative of current or recent infection with H capsulatum. Declining levels of Histoplasma antigen are indicative of disease regression and can be used to monitor patient response to antifungal therapy. Notably, low-level titers may persist for extended periods of time following appropriate treatment and resolution of infection. Urine samples with "Indeterminate" results are automatically reflexed to MiraVista Diagnostics (Indianapolis, IN) for confirmatory testing. Clinical decisions regarding Histoplasma infection should not be based on an indeterminate result alone. Other laboratory findings, including Histoplasma serology, fungal culture, and molecular tests (eg, RT-PCR) should be considered, alongside clinical presentation and exposure history, to confirm the diagnosis. The absence of detectable Histoplasma antigen in urine is consistent with the absence of infection. Repeat testing on a fresh urine sample if early acute Histoplasma infection is suspected.

Reference Values: HISTOPLASMA ANTIGEN RESULT Negative HISTOPLASMA ANTIGEN VALUE Negative: 0.00-0.10 Indeterminate: 0.11-0.49 Positive: > or =0.50

Clinical References: 1. Theel ES, Harring JA, Dababneh AlS, et al: Re-evaluation of Commercial Reagents for Detection of Histoplasma capsulatum Antigen in Urine. J Clin Micro epub 28 Jan 2015, doi: 10.1128/JCM.03175-14 2. Wheat LJ, Freifeld AG, Kleiman MB, et al: Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of Current as of August 23, 2017 7:11 am CDT


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America. Clin Infect Dis 2007;45:807-825

HBRP 60213

Histoplasma capsulatum/Blastomyces dermatitidis, Molecular Detection, PCR Clinical Information: Infections with Blastomyces dermatitidis and Histoplasma capsulatum cause a variety of clinical manifestations ranging from self-limited, mild pulmonary illness to potentially life-threatening, disseminated disease. Patients at risk for disseminated disease include neonates and immunosuppressed individuals, particularly those with AIDS, hematologic malignancies, or a recent transplant. Primary infections are acquired through inhalation of microconidia that are present in the environment. In the United States, most cases of blastomycosis and histoplasmosis occur along the Ohio and Mississippi River valleys. The gold standard for diagnosis of blastomycosis and histoplasmosis remains isolation of the organisms in culture. Although sensitive, recovery in culture and subsequent identification may require days to weeks. The organisms can be identified after growth in culture using traditional macro- and microscopic morphologic techniques or through the use of nucleic acid hybridization probes. Hybridization probe-based procedures are rapid and demonstrate good sensitivity and specificity from culture, although some cross-reactivity with relatively uncommon fungal organisms has been reported. Additional diagnostic tests that can be utilized for these organisms include stains, histopathology, serology, and antigen detection with each of these methods offering advantages and limitations depending on the stage of the illness and the status of the patient. Fungal stains (eg, calcofluor white) offer a rapid diagnostic approach, but demonstrate poor sensitivity and specificity. Serologic tests such as complement fixation and immunodiffusion are noninvasive, but are laborious, subjective, and may show low sensitivity, especially in immunocompromised hosts. Antigen detection also offers a noninvasive approach, but has been demonstrated to show cross-reactivity with antigens from closely related fungal species. Molecular techniques have been established as sensitive and specific methods for the diagnosis of infectious diseases and have the added advantage of a rapid turnaround time for results. Due to the limitations of conventional diagnostic methods for blastomycosis and histoplasmosis, a single tube, real-time PCR assay was developed and verified for the detection and differentiation of Blastomyces dermatitidis and Histoplasma capsulatum directly from clinical specimens.

Useful For: Rapid detection of Histoplasma capsulatum and Blastomyces dermatitidis DNA An aid in the rapid diagnosis of histoplasmosis and blastomycosis

Interpretation: A positive result for Histoplasma capsulatum indicates presence of Histoplasma DNA; a positive result for Blastomyces dermatitidis indicates presence of Blastomyces DNA. A negative result indicates absence of detectable Histoplasma capsulatum and Blastomyces dermatitidis DNA. Fungal culture has increased sensitivity over this PCR assay and should always be performed when the PCR is negative.


Clinical References: 1. Kauffman CA: Histoplasmosis. Clin Chest Med 2009;30:217-225 2. Wheat LJ, Freifeld AG, Kleiman MB, et al: Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825 3. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al: Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clin Infect Dis 2000;30:679-683

HBRPB 60751

Histoplasma capsulatum/Blastomyces dermatitidis, Molecular Detection, PCR, Blood Clinical Information: Infections with Blastomyces dermatitidis and Histoplasma capsulatum cause a variety of clinical manifestations ranging from self-limited, mild pulmonary illness to potentially life-threatening, disseminated disease. Patients at risk for disseminated disease include neonates and immunosuppressed individuals, particularly those with AIDS, hematologic malignancies, or a recent



Page 1084

transplant. Primary infections are acquired through inhalation of microconidia that are present in the environment. In the United States, most cases of blastomycosis and histoplasmosis occur along the Ohio and Mississippi River valleys. The gold standard for diagnosis of blastomycosis and histoplasmosis remains isolation of the organisms in culture. Although sensitive, recovery in culture and subsequent identification may require days to weeks. The organisms can be identified after growth in culture using traditional macro- and microscopic morphologic techniques or through the use of nucleic acid hybridization probes. Hybridization probe-based procedures are rapid and demonstrate good sensitivity and specificity from culture, although some cross-reactivity with relatively uncommon fungal organisms has been reported. Additional diagnostic tests that can be utilized for these organisms include stains, histopathology, serology, and antigen detection with each of these methods offering advantages and limitations depending on the stage of the illness and the status of the patient. Fungal stains (eg, calcofluor white) offer a rapid diagnostic approach, but demonstrate poor sensitivity and specificity. Serologic tests such as complement fixation and immunodiffusion are noninvasive, but are laborious, subjective, and may show low sensitivity, especially in immunocompromised hosts. Antigen detection also offers a noninvasive approach, but has been demonstrated to show cross-reactivity with antigens from closely related fungal species. Molecular techniques have been established as sensitive and specific methods for the diagnosis of infectious diseases and have the added advantage of a rapid turnaround time for results. Due to the limitations of conventional diagnostic methods for blastomycosis and histoplasmosis, a single tube, real-time PCR assay was developed and verified for the detection and differentiation of Blastomyces dermatitidis and Histoplasma capsulatum directly from clinical specimens.

Useful For: Rapid detection of Histoplasma capsulatum and Blastomyces dermatitidis DNA Interpretation: A positive result for Histoplasma capsulatum indicates presence of Histoplasma DNA; a positive result for Blastomyces dermatitidis indicates presence of Blastomyces DNA. A negative result indicates absence of detectable Histoplasma capsulatum and Blastomyces dermatitidis DNA.


Clinical References: 1. Kauffman CA: Histoplasmosis. Clin Chest Med 2009;30:217-225 2. Wheat LJ, Freifeld AG, Kleiman MB, et al: Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825 3. Chapman SW, Bradsher RW Jr, Campbell GD Jr, et al: Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clin Infect Dis 2000;30:679-683

HIBLC

Histoplasma/Blastomyces Antibody Panel, Spinal Fluid

62612

Clinical Information: Histoplasma: Histoplasma capsulatum is a soil saprophyte that grows well in soil enriched with bird droppings. The usual disease is self-limited, affects the lungs, and is asymptomatic. Chronic cavitary pulmonary disease, disseminated disease, and meningitis may occur and can be fatal, especially in young children and immunosuppressed patients. Blastomyces: The dimorphic fungus, Blastomyces dermatitidis, causes blastomycosis. When the organism is inhaled, it causes pulmonary disease-cough, pain, and hemoptysis, along with fever and night sweats. It commonly spreads to the skin, bone, or internal genitalia where suppuration and granulomas are typical. Occasionally, primary cutaneous lesions after trauma are encountered; however, this type of infection is uncommon. Central nervous system disease is uncommon.

Useful For: Histoplasma: Aiding in the diagnosis of Histoplasma meningitis Blastomyces: Detection of antibodies in patients having blastomycosis

Interpretation: Histoplasma: Any positive serologic result in spinal fluid is significant. Simultaneous appearance of the H and M precipitin bands indicates active histoplasmosis. The M band alone indicates active or chronic disease or a recent skin test for histoplasmosis. Blastomyces: A positive result indicates that IgG and/or IgM antibodies to Blastomyces were detected. The presence of antibodies is presumptive evidence that the patient was or is currently infected with (or exposed to) Blastomyces. A negative result indicates that antibodies to Blastomyces were not detected, but does not rule out infection. All specimens Current as of August 23, 2017 7:11 am CDT


Page 1085

testing equivocal will be repeated. Specimens testing equivocal after repeat testing should be submitted for further testing by another conventional serologic test (eg, CBL / Blastomyces Antibody by Immunodiffusion, Spinal Fluid).

Reference Values: HISTOPLASMA ANTIBODY, SPINAL FLUID Mycelial by complement fixation: Negative Yeast by complement fixation: Negative Antibody by immunodiffusion: Negative BLASTOMYCES ANTIBODY BY EIA, SPINAL FLUID Negative

Clinical References: 1. Kaufman L, Kovacs JA, Reiss E: Clinical immunomycology. In Manual of Clinical Laboratory Immunology. Fifth edition. Edited by NR Rose, EC De Macario, JD Folds, et al. Washington DC, ASM Press, 1997 2. Kaufman L, Kovacs JA, Reiss E: Clinical immunomycology. In Manual of Clinical Laboratory Immunology. Fifth edition. Edited by NR Rose, EC De Macario, JD Folds, et al. Washington DC, ASM Press, 1997, pp 588-589

HV1CD 83628

HIV-1 and HIV-2 Antibodies for Cadaveric or Hemolyzed Specimens, Serum Clinical Information: Epidemiological data indicate that AIDS is caused by at least 2 types of HIV. The first virus, HIV-1, has been isolated from patients with AIDS, AIDS-related complex, and asymptomatic infected individuals at high risk for AIDS. HIV-1 is transmitted by sexual contact, exposure to infected blood or blood products, or from an infected mother to her fetus or infant. A second HIV virus, HIV-2, was isolated from patients in West Africa in 1986. HIV-2 appears to be endemic only in West Africa, but it also has been identified in individuals who have lived in West Africa or had sexual relations with individuals from that geographic region. HIV-2 is similar to HIV-1 in its morphology, overall genomic structure, and its ability to cause AIDS. Antibodies against HIV-1 and HIV-2 are usually not detected until 6 to 12 weeks following exposure and are almost always detected by 12 months. They may fall into undetectable levels in the terminal stage of AIDS. See HIV Testing Algorithm (Fourth Generation Screening Assay) Including Follow-up of Reactive HIV Rapid Serologic Test Results in Special Instructions.

Useful For: Diagnosis of HIV-1 and/or HIV-2 infection in cadaveric or hemolyzed serum specimens from symptomatic patients with or without risk factors for HIV infection This assay kit is FDA-approved for testing cadaveric or hemolyzed blood specimens.

Interpretation: A reactive HIV-1/-2 antibody screen result obtained by EIA suggests the presence of HIV-1 and/or HIV-2 infection. However, it does not differentiate between HIV-1 and HIV-2 antibody reactivity. Diagnosis of HIV infection must be based on results of supplemental tests, such as HIV antibody confirmation/differentiation test (automatically reflexed on all samples with reactive screen test results at an additional charge). All presumptive antibody-positive test results should be verified by submitting a second serum specimen for retesting. A negative HIV-1/-2 antibody EIA screen result usually indicates the absence of HIV-1 or HIV-2 infection. However, for specimens that are reactive by the rapid HIV antibody tests, confirmatory testing is recommended even if the EIA results are negative.

Reference Values: Negative See HIV Serologic Interpretive Guide in Special Instructions for further interpretive information.

Clinical References: 1. Constantine N: HIV antibody assays May 2006. In HIV InSite Knowledge Base (online textbook). Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-02-01 2. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommendations. June 27, 2014. Available from http://stacks.cdc.gov/view/cdc/23447 3. Hariri S, McKenna MT: Epidemiology of human Current as of August 23, 2017 7:11 am CDT


Page 1086

immunodeficiency virus in the United States. Clin Microbiol Rev 2007;20:478-488 4. Owen SM, Yang C, Spira T, et al: Alternative algorithms for human immunodeficiency virus infection diagnosis using tests that are licensed in the United States. J Clin Microbiol 2008;46:1588-1595

HIVDI 62421

HIV-1 and HIV-2 Antibody Confirmation and Differentiation, Serum Clinical Information: AIDS is caused by 2 known types of HIV. HIV type 1 (HIV-1) is found in patients with AIDS, AIDS-related complex, and asymptomatic infected individuals at high risk for AIDS. The virus is transmitted by sexual contact, by exposure to infected blood or blood products, or from an infected mother to her fetus or infant. HIV type 2 (HIV-2) infection is endemic only in West Africa, and it has been identified in individuals who had sexual relations with individuals from that geographic region. HIV-2 is similar to HIV-1 in viral morphology, overall genomic structure, and its ability to cause AIDS. Antibodies against HIV-1 and HIV-2 are usually not detectable until 6 to 12 weeks following exposure and are almost always detectable by 12 months. They may fall to undetectable levels (ie, seroreversion) in the terminal stage of AIDS when the patient's immune system is severely depressed. Routine serologic screening of patients at risk for HIV-1 or HIV-2 infection usually begins with a HIV-1/-2 antigen and/or antibody screening test, which may be performed by various FDA-approved assay methods, including rapid HIV antibody tests, enzyme immunoassays, chemiluminescent immunoassays. In testing algorithms that begin with these methods, supplemental or confirmatory testing should be requested only for specimens that are repeatedly reactive by these methods according to assay manufacturers' instructions for use.

Useful For: Confirmation and differentiation of HIV-1 and HIV-2 antibodies in serum specimens that show reactive results with third- (HIV-1/-2 antibody only) and fourth- (HIV antigen and antibody) generation HIV serologic assays

Interpretation: Negative results for both HIV-1 and HIV-2 antibodies usually indicate the absence of HIV-1 and HIV-2 infection. However, in patients with reactive initial combined HIV-1/-2 antigen and antibody test results, such negative results do not rule-out acute or early HIV infection. If acute or early HIV infection is suspected, detection of HIV-1 RNA (HIVDQ / HIV-1 RNA Detection and Quantification, Plasma) and/or HIV-2 DNA/RNA (FHV2Q / HIV-2 DNA/RNA Qualitative Real-Time PCR) is recommended, based on patientâ€™s clinical and epidemiologic exposure history. Positive HIV-1 antibody, but negative HIV-2 antibody results, indicates the presence of HIV-1 infection. Together with reactive initial combined HIV-1/-2 antigen and antibody test results, individuals with such results are presumed to have HIV-1 infection. Verification of a first-time positive test result is recommended for the diagnosis of HIV-1 infection. Additional testing with a newly submitted plasma specimen for HIV-1 RNA (HIVDQ) is recommended to verify and confirm the diagnosis of HIV-1 infection prior to initiating antiretroviral treatment. Positive HIV-1 antibody, but indeterminate HIV-2 antibody results, indicates the presence of HIV-1 infection, with probable cross-reactivity of HIV-1 antibodies with HIV-2 antigens on the assay strip. Verification of a first-time positive test result is recommended for the diagnosis of HIV-1 infection. Submit a plasma specimen for detection of HIV-1 RNA (HIVDQ). However, such result patterns may rarely indicate early HIV-2 infection (ie, HIV-2 coinfection) in HIV-1-infected individuals. For individuals at risk for HIV-2 infection (based on epidemiologic exposure history), a plasma specimen should be submitted also for HIV-2 DNA/RNA (FHV2Q). Indeterminate HIV-1 antibody, but negative HIV-2 antibody results, suggest either very early HIV-1 infection (in individuals with risk factors) or the presence of nonspecific cross-reactivity between the patients' specimens and HIV-1 antigens on the assay strip. If patient has known risk factors for HIV-1 infection, a new specimen should be submitted for HIV-2 serologic testing (HIV2 / HIV-2 Antibody Evaluation, Serum or HIV2M / HIV-2 Antibody Screen, Serum) or HIV-2 DNA/RNA (FHV2Q). Negative HIV-1 antibody, but indeterminate HIV-2 antibody results, suggests either very early HIV-2 infection (in individuals with risk factors) or presence of nonspecific cross-reactivity between the patients' specimens and HIV-2 antigens on the assay strip. If patient has known risk factors for HIV-2 infection (based on patient's clinical and epidemiologic history), a new specimen should be submitted for HIV-2 serologic testing (HIV2 or HIV2M) or HIV-2 DNA/RNA (FHV2Q). Positive results for both HIV-1 and HIV-2 antibodies suggest probable the presence of HIV-1 and HIV-2 coinfection. However, such results may be rarely due to: a) HIV-1 infection with HIV-2 antibody cross-reactivity; or b) HIV-2 infection with HIV-1 antibody cross-reactivity (eg, absence of Current as of August 23, 2017 7:11 am CDT


Page 1087

HIV-1 p24 and p31 bands). Verification of a first-time positive test result is recommended for the diagnosis of HIV infection. Based on patient's clinical and epidemiologic history, plasma specimens should be submitted for detection of HIV-1 RNA (HIVDQ) and/or HIV-2 DNA/RNA (FHV2Q). Indeterminate results for both HIV-1 and HIV-2 antibodies indicate either very early HIV infection (in individuals with risk factors) or the presence of nonspecific cross-reactivity between the patients' specimens and HIV antigens on the assay strip. Nonspecific cross-reactivity may be due to recent non-HIV infections, hypergammaglobulinemic states, connective tissue disorders, or pregnancy (alloantibodies). For individuals at risk for HIV infection, plasma specimens should be submitted for detection of HIV-1 RNA (HIVDQ) and/or HIV-2 DNA/RNA (FHV2Q), depending on the epidemiologic exposure history. Negative HIV-1 antibody, but positive HIV-2 antibody results, indicates the presence of HIV-2 infection. Together with a reactive initial HIV-1/-2 antigen and antibody screening test results, individuals with such results are presumed to have HIV-2 infection. Additional testing with a newly submitted plasma specimen for HIV-2 DNA/RNA (FHV2Q) is recommended to verify and confirm the diagnosis of HIV-2 infection prior to initiating antiretroviral treatment. Reactive HIV-1 antibody, but positive HIV-2 antibody results, usually indicates the presence of HIV-2 infection with HIV-1 antibody cross-reactivity (eg, presence of only HIV-1 gp41 and/or gp160 band). However, such results may be rarely due to HIV-1 and HIV-2 coinfection. Verification of a first-time positive test result is recommended for the diagnosis of HIV-2 infection, by submitting a new specimen for HIV-2 serologic testing (HIV2 or HIV2M) or a plasma specimen for HIV-2 DNA/RNA (FHV2Q). If the patient is at risk for HIV-1 infection (based on patient's clinical and epidemiologic history), a plasma specimen should be submitted also for detection of HIV-1 RNA (HIVDQ). Indeterminate HIV-1 antibody, but positive HIV-2 antibody results, indicates the presence of HIV-2 infection, with probable cross-reactivity of HIV-2 antibodies with HIV-1 antigens on the assay strip. Verification of a first-time positive test result is recommended for the diagnosis of HIV-2 infection, by submitting a plasma specimen for (FHV2Q). However, such result patterns may rarely indicate early HIV-1 infection (ie, HIV-1 coinfection) in HIV-2-infected individuals. For individuals at risk for HIV-1 infection, (based on epidemiologic exposure history), plasma specimen should be submitted also for detection of HIV-1 RNA (HIVDQ). See HIV Testing Algorithm (Fourth Generation Screening Assay) Including Follow-up of Reactive HIV Rapid Serologic Test Results in Special Instructions.


Clinical References: 1. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommendations. June 27, 2014. Available at: http://stacks.cdc.gov/view/cdc/23447 2. Malloch L, Kadivar K, Putz J, et al: Comparative evaluation of the Bio-Rad Geenius HIV-1/2 confirmatory assay and the Bio-Rad Multispot HIV-1/2 rapid test as an alternative differentiation assay for CLSI M53 algorithm-I. J Clin Virol 2013;58(suppl. 1):e85-e91 3. Montesinos I, Eykmans J, Delforge ML: Evaluation of the Bio-Rad Geenius HIV-1/2 test as confirmatory assay. J Clin Virol 2014;60:399-401 4. Mor O, Milequir F, Michaeli M, et al: Evaluation of the Bio-Rad Geenius HIV 1/2 assay as an alternative to the INNO-LIA HIV 1/2 assay for confirmation of HIV infection. J Clin Microbiol 2014;52:2677-2679 5. Abbate I, Pergola C, Pisciotta M, et al: Evaluation in a clinical setting of the performances of a new rapid confirmatory assay for HIV-1/2 serodiagnosis. J Clin Virol 2014;61:166-169

HV1CM 60357

HIV-1 and HIV-2 Antibody Screen for Hemolyzed Specimens, Serum Clinical Information: Epidemiological data indicate that AIDS is caused by at least 2 types of HIV. The first virus, HIV-1, has been isolated from patients with AIDS, AIDS-related complex, and asymptomatic infected individuals at high risk for AIDS. HIV-1 is transmitted by sexual contact, exposure to infected blood or blood products, or from an infected mother to her fetus or infant. A second HIV virus, HIV-2, was isolated from patients in West Africa in 1986. HIV-2 appears to be endemic only in West Africa, but it also has been identified in individuals who have lived in West Africa or had sexual relations with individuals from that geographic region. HIV-2 is similar to HIV-1 in its morphology, overall



Page 1088

genomic structure, and its ability to cause AIDS. Antibodies against HIV-1 and HIV-2 are usually not detected until 6 to 12 weeks following exposure and are almost always detected by 12 months. They may fall into undetectable levels in the terminal stage of AIDS. See HIV Testing Algorithm (Fourth Generation Screening Assay) Including Follow-up of Reactive HIV Rapid Serologic Test Results in Special Instructions.

Useful For: Diagnosis of HIV-1 and/or HIV-2 infection in cadaveric or hemolyzed serum specimens from asymptomatic patients with or without risk factors for HIV infection (assay kit is FDA-approved for testing cadaveric or hemolyzed blood specimens)

Interpretation: A reactive HIV-1/-2 antibody screen result obtained by EIA suggests the presence of HIV-1 and/or HIV-2 infection. However, it does not differentiate between HIV-1 and HIV-2 antibody reactivity. Diagnosis of HIV infection must be based on results of supplemental tests, such as HIV antibody confirmation/differentiation test (automatically reflexed on all samples with reactive screen test results at an additional charge). All presumptive antibody-positive test results should be verified by submitting a second serum specimen for retesting. A negative HIV-1/-2 antibody EIA screen result usually indicates the absence of HIV-1 or HIV-2 infection. However, for specimens that are reactive by the rapid HIV antibody tests, confirmatory testing is recommended even if the EIA results are negative.


Clinical References: 1. Constantine N: HIV antibody assays May 2006. In HIV InSite Knowledge Base (online textbook). Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-02-01 2. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommendations. June 27, 2014. Available from http://stacks.cdc.gov/view/cdc/23447 3. Hariri S, McKenna MT: Epidemiology of human immunodeficiency virus in the United States. Clin Microbiol Rev 2007;20:478-488 4. Owen SM, Yang C, Spira T, et al: Alternative algorithms for human immunodeficiency virus infection diagnosis using tests that are licensed in the United States. J Clin Microbiol 2008;46:1588-1595

HIVCO

HIV-1 and HIV-2 Antigen and Antibody Evaluation, Serum

62420

Clinical Information: AIDS is caused by 2 known types of HIV. HIV type 1 (HIV-1) is found in patients with AIDS, AIDS-related complex, and asymptomatic infected individuals at high risk for AIDS. The virus is transmitted by sexual contact, by exposure to infected blood or blood products, or from an infected mother to her fetus or infant. HIV type 2 (HIV-2) infection is endemic only in West Africa, and it has been identified in individuals who had sexual relations with individuals from that geographic region. HIV-2 is similar to HIV-1 in viral morphology, overall genomic structure, and its ability to cause AIDS. Antibodies against HIV-1 and HIV-2 are usually not detectable until 6 to 12 weeks following exposure and are almost always detectable by 12 months. They may fall to undetectable levels (ie, seroreversion) in the terminal stage of AIDS when the patient's immune system is severely depressed. Routine serologic screening of patients at risk for HIV-1 or HIV-2 infection usually begins with a HIV-1/-2 antigen and/or antibody screening test, which may be performed by various FDA-approved assay methods, including rapid HIV antibody tests, enzyme immunoassays, and chemiluminescent immunoassays. In testing algorithms that begin with these methods, supplemental or confirmatory testing should be requested only for specimens that are repeatedly reactive by these methods according to assay manufacturers' instructions for use.

Useful For: Screening for HIV-1 and/or HIV-2 infection in asymptomatic patients Diagnosing HIV-1 and/or HIV-2 infection in symptomatic patients Follow-up testing of individuals with reactive results from rapid HIV tests

Interpretation: Negative HIV-1/-2 antigen and antibody screening test results usually indicate absence of HIV-1 and HIV-2 infection. However, such negative results do not rule-out acute HIV infection. If acute HIV-1 infection is suspected, detection of HIV-1 RNA (HIVDQ / HIV-1 RNA Detection and Current as of August 23, 2017 7:11 am CDT


Page 1089

Quantification, Plasma) or HIV-1 DNA and RNA (HIVP / HIV-1 DNA and RNA Qualitative Detection by PCR, Plasma) is recommended. Reactive HIV-1/-2 antigen and antibody screening test results suggest the presence of HIV-1 and/or HIV-2 infection, but it is not diagnostic for HIV infection and should be considered preliminary. Reactive result of this assay does not differentiate among reactivity with HIV-1 p24 antigen, HIV-1 antibody, and HIV-2 antibody. Diagnosis of HIV infection must be based on results of supplemental tests, such as HIVDI / HIV-1 and HIV-2 Antibody Confirmation and Differentiation, Serum (automatically reflexed on all samples with reactive screen test results at an additional charge). All initially positive supplemental or confirmatory HIV test results (by serologic or molecular test methods) should be verified by submitting a second serum specimen for repeat testing. Such positive HIV test results are required under laws in many states in the United States to be reported to the departments of health of the respective states where the patients reside. See HIV Testing Algorithm (Fourth Generation Screening Assay) Including Follow-up of Reactive HIV Rapid Serologic Test Results in Special Instructions.


Clinical References: 1. Bennett B, Branson B, Delaney K, et al: HIV testing algorithms: a status report. A publication from The Association of Public Health Laboratories. April 2009. Available at http://www.aphl.org/aphlprograms/infectious/hiv/Documents/ID_2009April_HIV-Testing-Algorithms-Sta tus-Report.pdf 2. Chavez P, Wesolowski L, Patel P, et al: Evaluation of the performance of the Abbott ARCHITECT HIV Ag/Ab Combo assay. J Clin Virol 2011;52(Suppl 1):S51-S55 3. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommendations. June 27, 2014. Available at http://stacks.cdc.gov/view/cdc/23447

HIVP

HIV-1 DNA and RNA Qualitative Detection by PCR, Plasma

64693

Clinical Information: Human immunodeficiency virus (HIV)-1 infection is usually confirmed by detection of HIV-1-specific antibodies in serum. However, serologic testing may not reliably identify HIV-1 infection in neonates with passively acquired maternal HIV-1 antibodies or with incompletely developed immune systems, individuals with early HIV-1 infection (200 copies/mL, which eliminates most cases of viremia resulting from isolated blips or assay variability. Confirmed viral load rebound (ie, >200 copies/mL) on 2 separate tests obtained at least 2 to 4 weeks apart should prompt a careful evaluation of patient's tolerance of current drug therapy, drug-drug interactions, and patient adherence.

Reference Values: Undetected

Clinical References: 1. Gunthard HF, Aberg JA, Eron JJ, et al: Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International AIDS Society-USA panel. JAMA 2014;312:410-425. Available at http://jama.jamanetwork.com/article.aspx?articleid=1889146 2. Relucio K, Holodniy M: HIV-1 RNA and viral load. Clin Lab Med 2002;22:593-610 3. Centers for Disease Control and Prevention and Association of Public Health Laboratories. Laboratory testing for the diagnosis of HIV infection: Updated recommendations. June 27, 2014. Available at http://stacks.cdc.gov/view/cdc/23447 4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. May 1, 2014. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

HIVQG 36932

HIV-1 RNA Quantification with Reflex to HIV-1 Genotypic Drug Resistance, Plasma Clinical Information: HIV-1 is an RNA virus that infects human host cells and is then converted to complementary DNA (cDNA) by the action of viral reverse transcriptase. HIV-1 is the causative agent of AIDS, a severe, life-threatening condition. Currently, 2 types of HIV: HIV type 1 (HIV-1) and HIV type 2 (HIV-2), are known to infect humans. HIV-1 has been isolated from patients with AIDS, AIDS-related complex, and asymptomatic infected individuals at high-risk for AIDS. Accounting for over 99% of HIV infections in the world, HIV-1 is transmitted by sexual contact, by exposure to infected blood or blood products, from an infected pregnant woman to fetus in utero or during birth, or from an infected mother to infant via breast feeding. HIV-2 has been isolated from infected patients in West Africa and it appears to be endemic only in that region. However, HIV-2 also has been identified in individuals who have lived in West Africa or had sexual relations with individuals from that geographic region. HIV-2 is similar to HIV-1 in its morphology, overall genomic structure, and ability to cause AIDS. Multiple clinical studies of plasma HIV-1 viral load (expressed as HIV-1 RNA copies/mL of plasma) have shown a clear relationship of HIV-1 RNA copy number to stage of HIV-1 disease and efficacy of anti-HIV-1 therapy. Quantitative HIV-1 RNA level in plasma (ie, HIV-1 viral load) is an important surrogate marker in assessing the risk of disease progression and monitoring response to anti-HIV-1 drug therapy in the routine medical care of HIV-1-infected patients. Studies have identified a number of mutations associated with antiviral resistance. Genotypic analysis allows identification of nucleotide changes associated with HIV drug resistance. When combination therapy fails, genotyping for drug resistance mutations may help



Page 1094

direct appropriate changes in antiretroviral therapy and may result in at least a short-term benefit, as evidenced by viral load reduction.

Useful For: Detecting and quantifying plasma HIV-1 RNA levels (viral load) in HIV-1-infected patients, followed by genotypic determination of viral resistance to anti-HIV drugs Guiding initiation or change of antiretroviral treatment regimens

Interpretation: HIV-1 detection and quantification: This assay has a plasma HIV-1 RNA quantification result range of 20 to 10,000,000 copies/mL (1.30-7.00 log copies/mL). An "Undetected" result indicates that the assay was unable to detect HIV-1 RNA within the plasma specimen. A result of "10,000,000" with the result comment of "HIV-1 RNA level is >10,000,000 copies/mL (>7.00 log copies/mL). This assay cannot accurately quantify HIV-1 RNA above this level" indicates that HIV-1 RNA is detected, but the level present is above the upper quantification limit of this assay. For the purpose of monitoring patient's response to antiretroviral therapy, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents defines virologic failure as a confirmed viral load of greater than 200 copies/mL, which eliminates most cases of viremia resulting from isolated blips or assay variability. Confirmed viral load rebound (ie, >200 copies/mL) on 2 separate tests obtained at least 2 to 4 weeks apart should prompt a careful evaluation of patient's tolerance of current drug therapy, drug-to-drug interactions, and patient adherence. If the viral load is 500 copies/mL or above, genotypic anti-HIV-1 drug resistance mutation analysis is performed automatically at an additional charge. Sequence data of the patient's viral strain is compared with those in a database of known drug resistance mutations. Results are provided that highlight those codon changes associated with specific drug resistance. These mutations are categorized and reported. HIV-1 genotypic drug resistance analysis: "Susceptible" indicates that the genotypic mutations present in patient's HIV-1 strain have not been associated with resistance to the specific drug in question. "Resistant" indicates that genotypic mutations detected have been associated with maximum reduction in susceptibility to the specific drug. "Possible resistance" indicates that genotypic mutations detected have been associated with 1 or both of the following outcomes: -Diminished virologic response in some, but not all, patients having virus with these mutations -Intermediate decrease in susceptibility of the virus to the specific drug. "Unable to genotype" indicates that the sequence data obtained are of poor quality to determine the presence or absence of genotypic resistant mutations in the patient's HIV strain. Possible causes of such poor sequence data include polymorphism in the region of the sequencing primers interfering with primer binding and subsequent sequencing reaction. "Inconclusive" indicates inability of the assay to reliably determine antiviral resistance because of either low HIV-1 viral load (ie, 80% of HTLV infections in drug users in the United States are due to HTLV-II. HTLV-II also appears to be endemic in Native American populations, including the Guaymi Indians in Panama and Native Americans in Florida and New Mexico. HTLV-II-infected blood donors most often report either a history of injection drug use or a history of sexual contact with an injection drug user. A smaller percentage of infected individuals report a history of blood transfusion. HTLV-II is transmitted similarly to HTLV-I, but much less is known about the specific modes and efficiency of transmission of HTLV-II. The virus can be transmitted by transfusion of cellular blood products (whole blood, red blood cells, and platelets). HTLV-II infection has been associated with hairy-cell leukemia, but definitive evidence is lacking on a viral etiologic role. HTLV-II has also been linked with



Page 1130

neurodegenerative disorders characterized by spastic paraparesis and variable degrees of ataxia. Infection by these viruses results in the appearance of specific antibodies against the viruses that can be detected by serologic tests such as EIA. For accurate diagnosis of HTLV-I or HTLV-II infection, all initially screening test-reactive results should be verified by a confirmatory test, such as Western blot or line immunoassay.

Useful For: Qualitative detection of human T-cell lymphotropic virus types I and II (HTLV-I and HTLV-II)-specific antibodies with confirmation and differentiation between HTLV-I and HTLV-II infection

Interpretation: Negative screening results indicate the absence of both human T-cell lymphotropic virus types I and II (HTLV-I- and HTLV-II)-specific IgG antibodies in serum. A reactive screening test result is suggestive of infection with either HTLV-I or HTLV-II. However, this result does not confirm infection (eg, low specificity), and it cannot differentiate between HTLV-I and HTLV-II infection. Specimens with reactive screening test results will be tested automatically by the line immunoassay (LIA) confirmatory test. Positive LIA results provide confirmatory evidence of infection with HTLV-I or HTLV-II. A reactive screening result with a negative or indeterminate confirmatory test result suggests either a false-reactive screening test result or a seroconverting HTLV infection. Repeat testing in 1 to 2 months can clarify the final infection status. Persistently indeterminate confirmatory test results indicate absence of HTLV infection.


Clinical References: 1. Araujo A, Hall WW: Human T-lymphotropic virus type II and neurological disease. Ann Neurol 2004;56(1):10-19 2. Mahieux R, Gessain A: Adult T-cell leukemia/lymphoma and HTLV-I. Curr Hematol Malig Rep 2007;2(4):257-264 3. Yamano Y, Sato T: Clinical pathophysiology of human T-lymphotropic virus-type I-associated myelopathy/tropical spastic paraparesis. Front Microbiol 2012;3:1-10 4. Gessain A, Mahieux R: Tropical spastic paraparesis and HTLV-I associated myelopathy: clinical, epidemiological, virological, and therapeutic aspects. Rev Neurol(Paris) 2012;168(3):257-269

MPS2Z

Hunter Syndrome, Full Gene Analysis

35463

Clinical Information: Mucopolysaccharidosis type II (MPS-II), also known as Hunter syndrome, is a rare X-linked condition caused by mutations in the IDS gene. MPS-II is characterized by reduced or absent activity of the iduronate 2-sulfatase enzyme. The clinical features and severity of symptoms of MPS-II are widely variable, ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, joint contractures, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. Female carriers are usually asymptomatic. The IDS gene is located on the X chromosome and has 9 exons. IDS is the only known gene to be associated with MPS-II. The recommended first-tier test for MPS-II is biochemical testing that measures iduronate 2-sulfatase enzyme activity in fibroblasts: IDNS / Iduronate Sulfatase, Fibroblasts. Individuals with decreased or absent enzyme activity are more likely to have a mutation in the IDS gene identifiable by molecular gene testing. However, enzymatic testing is not reliable to detect carriers. This test screens for mutations in all 9 exons of the IDS gene.

Useful For: Confirmation of a diagnosis of mucopolysaccharidosis type II (Hunter syndrome) Carrier testing when there is a family history of mucopolysaccharidosis type II (Hunter syndrome), but disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for Current as of August 23, 2017 7:11 am CDT


Page 1131

standards of interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Lagerstedt K, Karsten SL, Carlberg BM, et al: Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome. Hum Mol Genet 1997;6(4):627-633 3. Martin R, Beck M, Eng C, et al: Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatrics 2008;121(2):e377-386 4. Wraith JE, Scarpa M, Beck M, et al: Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 2008;167(3):267-277

HAD

Huntington Disease, Molecular Analysis

35452

Clinical Information: Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. HD is associated with cognitive impairment leading to dementia and a wide range of neuropsychiatric problems including apathy, depression, anxiety, and other behavioral disturbances. Additionally, affected individuals typically develop extrapyramidal symptoms (eg, dystonia, dysarthria, chorea, gait disturbance, postural instability, oculomotor dysfunction).

Useful For: Molecular confirmation of clinically suspected cases of Huntington disease (HD) Presymptomatic testing for individuals with a family history of HD and a documented expansion in the HTT gene

Interpretation: An interpretive report will be provided. Reference Values: Normal alleles: 39 CAG repeats An interpretive report will be provided.

Clinical References: 1. American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group: Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet 1998;62:1243-1247 2. Potter NT, Spector EB, Prior TW: Technical standards and guidelines for Huntington disease testing. Genet Med 2004;6:61-65

MPS1Z

Hurler Syndrome, Full Gene Analysis

35465

Clinical Information: Mucopolysaccharidosis type I (MPS-I) can be categorized into 3 syndromes, Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome. MPS-I, inherited in an autosomal recessive manner, is caused by mutations in the IDUA gene. Furthermore, MPS-I is characterized by reduced or absent activity of the alpha-L-iduronidase enzyme. Hurler syndrome (severe MPS-I) has early onset and consists of skeletal deformities, coarse facial features, corneal clouding, hepatosplenomegaly, cardiac involvement, hearing loss, and respiratory tract infections. Developmental delay is noticed as early as 12 months with death occurring usually before 10 years of age. Hurler-Scheie syndrome and Scheie syndrome (attenuated MPS-I) have onset between 3 to 10 years of age and consist of corneal clouding, cardiac involvement, moderate-to-severe hearing loss, and progressive pulmonary disease. Typically skeletal and joint involvement is the most significant source of discomfort for attenuated MPS-I. Intellect with attenuated MPS-I is typically normal or nearly normal. The IDUA gene is located on chromosome 4 and has 14 exons. IDUA is the only known gene to be associated with MPS-I, and the 3 syndromes appear to be caused by different combinations of mutations. The recommended first-tier test for MPS-I is biochemical testing that measures alpha-L-iduronidase enzyme activity in blood or fibroblasts: IDSWB / Alpha-L-Iduronidase, Blood or IDST / Alpha-L-Iduronidase, Fibroblasts. Individuals with decreased or absent enzyme activity are more likely to have 2 identifiable mutations in the IDUA gene by molecular genetic testing. However, enzymatic testing is not reliable to detect carriers.

Useful For: Identifying mutations within the IDUA gene Confirmation of a diagnosis of mucopolysaccharidosis type I (MPS-I) Carrier testing when there is a family history of MPS- I, but Current as of August 23, 2017 7:11 am CDT


Page 1132

disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Muenzer J, Wraith JE, Clarke LA: International Consensus Panel on Management and Treatment of Mucopolysaccharidosis I. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics 2009;123(1):19-29 3. Scott HS, Bunge S, Gal A, et al: Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 1995;6:288-302 4. Terlato NJ, Cox GF: Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature. Genet Med 2003;5(4):286-294 5. Vijay S, Wraith JE: Clinical presentation and follow-up of patients with the attenuated phenotype of mucopolysaccharidosis type I. Acta Paediatr 2005;94(7):872-877

FHMTB

Hydrocodone and metabolites

58081

Reference Values: Reference Range: Hydrocodone, unconjugated: 10 â€“ 100 ng/mL Hydromorphone, unconjugated: 1 â€“ 30 ng/mL Dihydrocodeine, unconjugated: Not established ng/mL

HYDCU

Hydrocodone with Metabolite Confirmation, Urine

62614

Clinical Information: Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation, and 6-keto reduction to the 6-beta hydroxymetabolites. Hydromorphone and norhydrocodone are both metabolites of hydrocodone. Dihydrocodeine is also a minor metabolite. Trace amounts of hydrocodone can also be found in the presence of approximately 100-fold higher concentrations of oxycodone or hydromorphone since it can be a pharmaceutical impurity in these medications. The presence of hydrocodone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is metabolized primarily in the liver and is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites. The presence of hydromorphone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is also a metabolite of hydrocodone; therefore, the presence of hydromorphone could also indicate exposure to hydrocodone. The detection interval for the opiates is generally 2 to 3 days after last ingestion.

Useful For: Detection and quantification of hydrocodone, norhydrocodone, and hydromorphone in urine

Interpretation: This procedure reports the total urine concentration; this is the sum of the unconjugated and conjugated forms of the parent drug.

Reference Values: Negative Cutoff concentrations: Hydrocodone-by LC-MS/MS: 25 ng/mL Norhydrocodone-by LC-MS/MS: 25 ng/mL Current as of August 23, 2017 7:11 am CDT


Page 1133

Hydromorphone-by LC-MS/MS: 25 ng/mL

Clinical References: 1. Gutstein HB, Akil H: Opioid Analgesics. In The Pharmacological Basis of Therapeutics. 11th edition. Edited by LL Brunton, JS Lazo, KL Parker. Goodman and Gilman's: McGraw-Hill Companies, Inc. 2006:http://www.accessmedicine.com/content.aspx?aID=940653 2. Baselt, RC: Dispositition of Toxic Drugs and Chemical in Man. Ninth edition. Edited by RC Baselt. Foster City, CA: Biomedical Publications, 2011 3. Hackett LP, Dusci LJ, Ilett KF, Chiswell GM: Optimizing the hydrolysis of codeine and morphine glucuronides in urine. Ther Drug Monit 2002;24(5):652-657

HYDMU

Hydromorphone Confirmation, Urine

62615

Clinical Information: Opiates are the natural or synthetic drugs that have a morphine-like pharmacological action. Medically, opiates are used primarily for relief of pain. Opiates include morphine and drugs structurally similar to morphine (eg, codeine, hydrocodone, hydromorphone, oxycodone). Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation, and 6-keto reduction to the 6-beta hydroxymetabolites. Hydromorphone is a metabolite of hydrocodone. The presence of hydrocodone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is metabolized primarily in the liver and is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites. The presence of hydromorphone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is also a metabolite of hydrocodone; therefore, the presence of hydromorphone could also indicate exposure to hydrocodone.

Useful For: Detection and quantification of hydromorphone in urine Interpretation: This procedure reports the total urine concentration; this is the sum of the unconjugated and conjugated forms of the parent drug.

Reference Values: Negative Cutoff concentrations: Hydromorphone-by LC-MS/MS: 25 ng/mL


HCQ

Hydroxychloroquine, Serum

64947

Clinical Information: Hydroxychloroquine is an antimalarial drug used to treat or prevent malaria. It is highly effective against erythrocytic forms of Plasmodium, but not effective against exoerythrocytic forms of parasites. Hydroxychloroquine is also used to treat symptoms of acute or chronic rheumatoid arthritis and lupus erythematosus. Adult doses range from 400 mg/week for suppressive therapy to 1,200 mg/day for acute malaria attacks. Typical daily doses of 200 to 600 mg are used for lupus and rheumatoid diseases. Hydroxychloroquine has a long terminal elimination half-life in blood (>40 days), which exceed those in plasma. The oral bioavailability averages 79%. Hydroxychloroquine accumulates in several organs, especially melanin-containing retina and skin. Mild to moderate overdose can result in gastrointestinal effects (ie, nausea, vomiting, and abdominal pain), headache, visual and hearing disturbances, and neuromuscular excitability. Acute hepatitis, cardiotoxicity, and retinopathy may occur with therapeutic doses. The effects of overdosage with hydroxychloroquine include headache, drowsiness, visual disturbances, convulsions, cardiovascular collapse, and respiratory arrest. Toxic retinopathy has also been associated with higher doses and longer duration of use.

Useful For: Monitoring serum hydroxychloroquine concentrations, assessing compliance, and Current as of August 23, 2017 7:11 am CDT


Page 1134

adjusting dosage in patients

Interpretation: The serum concentration should be interpreted in the context of the patient's clinical response and may provide useful information in patients showing poor response, noncompliance, or adverse effects.

Reference Values: For suppressive treatment of malaria, suggested plasma or serum concentrations should be >10 ng/mL. For systemic lupus erythematosus, proposed blood target concentrations should be 1,000 ng/mL.

Clinical References: 1. Disposition of Toxic Drugs and Chemicals in Man. 10th edition. Seal Beach, CA: Biomedical Publications; 2014 2. Frances C, Cosnes A, Duhaut P, et al: Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol 2012;148(4):479-484 3. Costedoat-Chalumeau N, Amoura Z, Hulot JS, et al: Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54(10):3284-3290 4. McChesney EW BW, McAuliff JP. Laboratory studies on the 4-aminoquinoline antimalarials: II. Plasma levels of chloroquine and hydroxychloroquine in man after various oral dosage regimens. Antibiot Chemother (Northfield) 1962;12:583-594 5. Tett SE, Cutler DJ, Day RO, Brown KF: A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers. Brit J Clin Pharmaco. 1988;26(3):303-313

HYD18

Hydroxycorticosterone, 18

80744

Reference Values: If no age provided: Age

Range (ng/dL)

Premature (26-28 Weeks) Day 4 10-670 Premature (31-35 Weeks) Day 4 57-410 Full Term Day 3

31-546

31 Days-11 Months

5-220

12-23 Months

18-155

24 Months-9 Years

6-85

10-14 Years

10-72

Adults

9-58

Adults 8:00 AM Supine

4-21

Adults 8:00 AM Upright

5-46

If age is provided: Age

Range (ng/dL)

Premature (26-28 Weeks) Day 4 10-670 Premature (31-35 Weeks) Day 4 57-410 Full Term Day 3

31-546

1-11 Months

5-220

1 year old

18-155

2-9 Years

6-85

10-14 Years

10-72



Page 1135

HGEM 62230

Adults

9-58

Adults 8:00 AM Supine

4-21

Adults 8:00 AM Upright

5-46

Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Blood Spot Clinical Information: Acylcarnitine analysis is included in newborn screening blood testing and is utilized for detection of several inborn errors of metabolism, including fatty acid oxidation disorders (FAOD) and organic acidemias (OA). A limitation of this analytic method is its inability to differentiate between several isomers. Additional testing of 2-hydroxy glutaric acid (2OH-GA), 3-hydroxy glutaric acid (3OH-GA), glutaric acid (GA), methylsuccinic acid (MSA), and ethylmalonic acid (EMA) by LC-MS/MS allows better differentiation among C4-acylcarnitine and glutarylcarnitine/C10-OH isomers. C4-acylcarnitine represents both butyrylcarnitine and isobutyrylcarnitine and is elevated in short-chain acyl Co-A dehydrogenase (SCAD) deficiency, isobutyryl-CoA dehydrogenase (IBDH) deficiency, and ethylmalonic encephalopathy (EE). SCAD deficiency is a condition affecting fatty acid metabolism, with reported symptoms of hypoglycemia, lethargy, developmental delays, and failure to thrive. There is controversy on whether a biochemical diagnosis necessarily confers clinical symptoms. IBDH deficiency is characterized by cardiomyopathy, hypotonia, and developmental delays, although many individuals with IBDH deficiency are asymptomatic. EE is a rare progressive encephalopathy associated with hypotonia, seizures, and abnormal movements. Individuals with SCAD deficiency demonstrate elevated plasma EMA and MSA levels and individuals with EE show only elevations in EMA, while individuals with IBDH deficiency do not typically have elevations in either EMA or MSA. Glutarylcarnitine (C5-DC) is elevated in glutaric acidemia type 1 (GA-1), but is not differentiated from C10-OH acylcarnitine. GA-1, is caused by a deficiency of glutaryl-CoA dehydrogenase and is characterized by bilateral striatal brain injury leading to dystonia, often a result of acute neurologic crises triggered by illness. Individuals with GA-1 typically show elevations of glutaric acid and 3OH-GA, even in those considered to be "low excretors." Glutaric acidemia (GA-2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is caused by defects in either the electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase. This disease can be severe and is often fatal in the first weeks of life, with typical symptoms of hypoglycemia, muscle weakness, metabolic acidosis, dysmorphic features, cardiac defects or arrhythmias, renal cysts, and fatty infiltration of the liver. GA-2 can have a milder presentation, also known as ethylmalonic-adipic aciduria, with Reye-like illnesses in childhood and muscle weakness in childhood and adulthood. In addition to elevations in glutaric acid, individuals with GA-2 can also show increased EMA, MSA, 2OH-GA, and 3OH-GA. The American College of Medical Genetics (ACMG) newborn screening work group published diagnostic algorithms for the follow-up of infants who had a positive newborn screening result. For more information, see http://www.acmg.net.

Useful For: Evaluation of patients with an abnormal newborn screen showing elevations of glutarylcarnitine (C5-DC) Evaluation of patients with abnormal newborn screens showing elevations of C4-acylcarnitine to aid in the differential diagnosis of short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies Diagnosis of glutaric acidemia type 1 Aids in diagnosis of glutaric acidemia type 2

Interpretation: Elevations of ethylmalonic acid (EMA) and methylsuccinic acid (MSA) are consistent with a diagnosis of short-chain acyl Co-A dehydrogenase (SCAD) deficiency. Elevation of EMA is consistent with a diagnosis of ethylmalonic encephalopathy. Normal levels of EMA in the context of elevated C4 is consistent with a diagnosis of isobutyryl-CoA dehydrogenase (IBDH) deficiency. Elevation of glutaric acid (GA) and 3-hydroxy glutaric acid (3OH-GA) are consistent with a diagnosis of glutaric acidemia type 1 (GA-1). Elevation of GA, 2-hydroxy glutaric acid (2OH-GA), 3OH-GA, EMA, and MSA are consistent with a diagnosis of glutaric acidemia (GA-2).

Reference Values: 2-OH Glutaric acid < or =25 nmol/mL 3-OH Glutaric acid < or =1.5 nmol/mL Current as of August 23, 2017 7:11 am CDT


Page 1136

Glutaric acid < or =1.5 nmol/mL Methylsuccinic acid < or =0.45 nmol/mL Ethylmalonic acid < or =3.5 nmol/mL

Clinical References: 1. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. 2008:10(2):151-156 2. Kolker S, Christensen E, Leonar JV, et al: Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis 2011;34:677-694 3. Frerman FE, Goodman SI: Chapter 103: Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: Glutaric Acidemia Type II. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al. Available at http://www.ommbid.com/

HGEMP 62300

Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Plasma Clinical Information: Acylcarnitine analysis is included in newborn screening blood testing and is utilized for detection of several inborn errors of metabolism, including fatty acid oxidation disorders (FAOD) and organic acidemias (OA). A limitation of this analytic method is its inability to differentiate between several isomers. Additional testing of 2-hydroxy glutaric acid (2OH-GA), 3-hydroxy glutaric acid (3OH-GA), glutaric acid (GA), methylsuccinic acid (MSA), and ethylmalonic acid (EMA) by LC-MS/MS allows better differentiation among C4 acylcarnitine and glutarylcarnitine/C10-OH isomers. C4 acylcarnitine represents both butyrylcarnitine and isobutyrylcarnitine and is elevated in short chain acyl Co-A dehydrogenase (SCAD) deficiency, isobutyryl-CoA dehydrogenase (IBDH) deficiency, and ethylmalonic encephalopathy (EE). SCAD deficiency is a condition affecting fatty acid metabolism, with reported symptoms of hypoglycemia, lethargy, developmental delays, and failure to thrive. There is controversy on whether a biochemical diagnosis necessarily confers clinical symptoms. IBDH deficiency is characterized by cardiomyopathy, hypotonia, and developmental delays, although many individuals with IBDH deficiency are asymptomatic. EE is a rare progressive encephalopathy associated with hypotonia, seizures, and abnormal movements. Individuals with SCAD deficiency demonstrate elevated plasma EMA and MSA levels and individuals with EE show only elevations in EMA, while individuals with IBDH deficiency do not typically have elevations in either EMA or MSA. Glutarylcarnitine (C5-DC) is elevated in glutaric acidemia type 1 (GA-1), but is not differentiated from C10-OH acylcarnitine. GA-1 is caused by a deficiency of glutaryl-CoA dehydrogenase and is characterized by bilateral striatal brain injury leading to dystonia, often a result of acute neurologic crises triggered by illness. Individuals with GA-1 typically show elevations of glutaric acid and 3OH-GA, even in those considered to be "low excretors.â€• Glutaric acidemia (GA-2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is caused by defects in either the electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase. This disease can be severe and is often fatal in the first weeks of life, with typical symptoms of hypoglycemia, muscle weakness, metabolic acidosis, dysmorphic features, cardiac defects or arrhythmias, renal cysts, and fatty infiltration of the liver. GA-2 can have a milder presentation, also known as ethylmalonic-adipic aciduria, with Reye-like illnesses in childhood and muscle weakness in childhood and adulthood. In addition to elevations in glutaric acid, individuals with GA-2 can also show increased EMA, MSA, 2OH-GA, and 3OH-GA. The American College of Medical Genetics (ACMG) newborn screening work group published diagnostic algorithms for the follow-up of infants who had a positive newborn screening result. For more information, see http://www.acmg.net.

Useful For: Evaluation of patients with an abnormal newborn screen showing elevations of glutarylcarnitine (C5-DC) Evaluation of patients with abnormal newborn screens showing elevations of C4- acylcarnitine to aid in the differential diagnosis of short chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies Diagnosis of glutaric acidemia type 1 Aids in diagnosis of glutaric acidemia type 2

Interpretation: Elevations of ethylmalonic acid (EMA) and methylsuccinic acid (MSA) are consistent with a diagnosis of short chain acyl Co-A dehydrogenase (SCAD) deficiency. Elevation of EMA is consistent with a diagnosis of ethylmalonic encephalopathy. Normal levels of EMA in the context of elevated C4 is consistent with a diagnosis of isobutyryl-CoA dehydrogenase (IBDH) deficiency. Elevation of glutaric acid (GA) and 3-hydroxy glutaric acid (3OH-GA) are consistent with a diagnosis of glutaric Current as of August 23, 2017 7:11 am CDT


Page 1137

acidemia type 1 (GA-1). Elevation of GA, 2-hydroxy glutaric acid (2OH-GA), 3OH-GA, EMA, and MSA are consistent with a diagnosis of glutaric acidemia (GA-2).

Reference Values: 2-OH Glutaric acid < or =4.5 nmol/mL 3-OH Glutaric acid < or =0.7 nmol/mL Glutaric acid < or =0.8 nmol/mL Methylsuccinic acid < or =0.3 nmol/mL Ethylmalonic acid < or =1.5 nmol/mL

Clinical References: 1. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. 2008:10(2):151-156 2. Kolker S, Christensen E, Leonar JV, et al: Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis 2011:34:677-694 3. Frerman FE, Goodman SI: Chapter 103: Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase: Glutaric Acidemia Type II. In Scriverâ€™s Online Metabolic and Molecular Bases of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al: Available at http://www.ommbid.com/

HGEMS 62231

Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Serum Clinical Information: Acylcarnitine analysis is included in newborn screening blood testing and is utilized for detection of several inborn errors of metabolism, including fatty acid oxidation disorders (FAOD) and organic acidemias (OA). A limitation of this analytic method is its inability to differentiate between several isomers. Additional testing of 2-hydroxy glutaric acid (2OH-GA), 3-hydroxy glutaric acid (3OH-GA), glutaric acid (GA), methylsuccinic acid (MSA), and ethylmalonic acid (EMA) by LC-MS/MS allows better differentiation among C4 acylcarnitine and glutarylcarnitine/C10-OH isomers. C4 acylcarnitine represents both butyrylcarnitine and isobutyrylcarnitine and is elevated in short chain acyl Co-A dehydrogenase (SCAD) deficiency, isobutyryl-CoA dehydrogenase (IBDH) deficiency and ethylmalonic encephalopathy (EE). SCAD deficiency is a condition affecting fatty acid metabolism, with reported symptoms of hypoglycemia, lethargy, developmental delays, and failure to thrive; there is controversy on whether a biochemical diagnosis necessarily confers clinical symptoms. IBDH deficiency is characterized by cardiomyopathy, hypotonia, and developmental delays, although many individuals with IBDH deficiency are asymptomatic. EE is a rare progressive encephalopathy associated with hypotonia, seizures, and abnormal movements. Individuals with SCAD deficiency demonstrate elevated plasma EMA and MSA levels and individuals with EE show only elevations in EMA, while individuals with IBDH deficiency do not typically have elevations in either EMA or MSA. Glutarylcarnitine (C5-DC) is elevated in glutaric acidemia type 1 (GA-1), but is not differentiated from C10-OH acylcarnitine. GA-1, also known as glutaric aciduria type 1, is caused by a deficiency of glutaryl-CoA dehydrogenase. GA-1 is characterized by bilateral striatal brain injury leading to dystonia, often a result of acute neurologic crises triggered by illness. Individuals with GA-1 typically show elevations of glutaric acid and 3OH-GA, even in those considered to be "low excretors." Glutaric acidemia (GA-2), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is caused by defects in either the electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase. This disease can be severe and is often fatal in the first weeks of life, with typical symptoms of hypoglycemia, muscle weakness, metabolic acidosis, dysmorphic features, cardiac defects or arrhythmias, renal cysts, and fatty infiltration of the liver. GA-2 can have a milder presentation, also known as ethylmalonic-adipic aciduria, with Reye-like illnesses in childhood, and muscle weakness in childhood and adulthood. In addition to elevations in glutaric acid, individuals with GA-2 can also show increased EMA, MSA, 2OH-GA, and 3OH-GA. The American College of Medical Genetics (ACMG) newborn screening work group published diagnostic algorithms for the follow-up of infants who had a positive newborn screening result. For more information, see http://www.acmg.net.

Useful For: Evaluation of patients with an abnormal newborn screen showing elevations of glutarylcarnitine (C5-DC) Evaluation of patients with abnormal newborn screens showing elevations of C4- acylcarnitine to aid in the differential diagnosis of short chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies Diagnosis of glutaric acidemia type 1 Aids in diagnosis of glutaric acidemia type 2 Current as of August 23, 2017 7:11 am CDT


Page 1138

Interpretation: Elevations of ethylmalonic acid (EMA) and methylsuccinic acid (MSA) are consistent with a diagnosis of short chain acyl Co-A dehydrogenase (SCAD) deficiency. Elevation of EMA is consistent with a diagnosis of ethylmalonic encephalopathy. Normal levels of EMA in the context of elevated C4 is consistent with a diagnosis of isobutyryl-CoA dehydrogenase (IBDH) deficiency. Elevation of glutaric acid (GA) and 3-hydroxy glutaric acid (3OH-GA) are consistent with a diagnosis of glutaric acidemia type 1 (GA-1). Elevation of GA, 2-hydroxy glutaric acid (2OH-GA), 3OH-GA, EMA, and MSA are consistent with a diagnosis of glutaric acidemia (GA-2).

Reference Values: 2-OH Glutaric acid < or =4.5 nmol/mL 3-OH Glutaric acid < or =0.7 nmol/mL Glutaric acid < or =0.8 nmol/mL Methylsuccinic acid < or =0.3 nmol/mL Ethylmalonic acid < or =1.5 nmol/mL

Clinical References: 1. Rinaldo P, Cowan TM, Matern D: Acylcarnitine profile analysis. 2008:10(2):151-156 2. Kolker S, Christensen E, Leonar JV, et al: Diagnosis and management of glutaric aciduria type I-revised recommendations. J Inherit Metab Dis 2011:34:677-694 3. Frerman FE, Goodman SI: Chapter 103: Defects of Electron Transfer Flavoprotein and Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase: Glutaric Acidemia Type II. In Scriverâ€™s Online Metabolic and Molecular Bases of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al: Available at http://www.ommbid.com/

FVIST

Hydroxyzine (Vistaril, Atarax), Serum

90121

Reference Values: Reference Range: 10 - 100 ng/mL

HYOX

Hyperoxaluria Panel, Urine

86213

Clinical Information: Increased urinary oxalate frequently leads to renal stone formation and renal insufficiency. Identifying the cause of hyperoxaluria has important implications in therapy, management and prognosis. Hyperoxalurias are classified as primary and secondary. Primary hyperoxaluria is an inherited disorder of oxalate metabolism while secondary hyperoxaluria is an acquired condition resulting from either increased intake of dietary oxalate or altered intestinal oxalate absorption. Primary hyperoxalurias are classified into types 1, 2, and 3. Type 1 (PH1), an autosomal recessive deficiency of peroxisomal alanine: glyoxylate aminotransferase due to mutations in the AGXT gene, is characterized by increased urinary oxalic, glyoxylic, and glycolic acids. PH1 is the most common with manifestations that include deposition of calcium oxalate in the kidneys (nephrolithiasis, nephrocalcinosis), and end-stage renal disease. Calcium oxalate deposits can be further deposited in other tissues such as the heart and eyes, and lead to a variety of additional symptoms. Age of onset is variable with a small percentage of patients presenting in the first year of life with failure to thrive, nephrocalcinosis, and metabolic acidosis. Approximately half of affected individuals show manifestations of PH1 in late childhood or early adolescence, and the remainder present in adulthood with recurrent renal stones. Some individuals with PH1 respond to supplementary pyridoxine therapy. Hyperoxaluria type 2 (PH 2) is due to a defect in GRHPR gene resulting in a deficiency of the enzyme hydroxypyruvate reductase. PH2 is autosomal recessive and identified by an increase in urinary oxalic and glyceric acids. Like PH1, PH2 is characterized by deposition of calcium oxalate in the kidneys (nephrolithiasis, nephrocalcinosis), and end-stage renal disease. Most individuals have symptoms of PH2 during childhood, and it is thought that PH2 is less common than PH1. Hyperoxaluria type 3 (PH3), due to recessive mutations in HOGA1 (formerly DHDPSL), occurs in a small percentage of individuals with primary hyperoxaluria. HOGA1 encodes a mitochondrial 4-hydroxy-2-oxoglutarate aldolase that catalyzes the 4th step in the hydroxyproline pathway. PH3 is characterized biochemically by increased urinary excretion of oxalate and 4-hydroxy-2-oxoglutarate (HOG). As with PH types 1 and 2, PH type 3 is characterized by calcium-oxalate deposition in the kidneys and/or kidney stone formation. Most individuals with PH3 have



Page 1139

early onset disease with recurrent kidney stones and urinary tract infections as common symptoms. End-stage renal disease is not a characteristic of PH3. Of note, individuals with heterozygous mutations in HOGA1 can have variable and intermittent elevations of urine oxalate. Secondary hyperoxalurias are due to hyperabsorption of oxalate (enteric hyperoxaluria); total parenteral nutrition in premature infants; ingestion of oxalate, ascorbic acid, or ethylene glycol; or pyridoxine deficiency, and may respond to appropriate therapy. A diagnostic workup in an individual with hyperoxaluria demonstrates increased concentration of oxalate in urinary metabolite screening. If glycolate, glycerate, or HOG is present, a primary hyperoxaluria is indicated. Additional analyses can include molecular testing for PH1 (AGXTG / Alanine:Glyoxylate Aminotransferase (AGXT) Mutation Analysis (G170R), Blood or AGXTZ / AGXT Gene, Full Gene Analysis), PH2 (GRHPZ / GRHPR Gene, Full Gene Analysis), or PH3 (HOGA1 testing not available at Mayo at this time).

Useful For: Distinguishing between primary and secondary hyperoxaluria Distinguishing between primary hyperoxaluria types 1, 2, and 3

Interpretation: Increased concentrations of oxalate and glycolate indicate type 1 hyperoxaluria. Increased concentrations of oxalate and glycerate indicate type 2 hyperoxaluria. Increased concentrations of oxalate and 4-hydroxy-2-oxoglutarate indicate type 3 hyperoxaluria. Increased concentrations of oxalate with normal concentrations of glycolate, glycerate, and 4-hydroxy-2-oxoglutarate indicate secondary hyperoxaluria.

Reference Values: Age Groups (mg/g creatinine) 0-1 month 2-6 months 7-12 months 13 months-6 years 7-10 years >10 years Glycolate

0-60

0-75

0-75

0-75

0-75

0-50

Glycerate

0-75

0-125

0-125

0-55

0-55

0-25

Oxalate

0-400

0-400

0-300

0-150

0-100

0-75

0-10

0-5

0-5

0-5

0-5

4-Hydroxy-2-Oxoglutarate (HOG) 0-15

Clinical References: 1. Bhasin B, Urekli HM, Atta MG: Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol 2015;4(2):235-244 DOI:10.5527/wjn.v4.i2.235 2. Danpure CJ: Primary Hyperoxaluria. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York. McGraw-Hill, 2014. Accessed August 26 2015. Available at: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62641527 3. Byrd DJ, Latta K: Hyperoxaluria. In Physicianâ€™s Guide to the Laboratory Diagnosis of Metabolic Disease. Edited by N Blau, ED Chapman. Hall Medical, 1996, pp 377-390 4. Fraser AD: Importance of glycolic acid analysis in ethylene glycol poisoning. Clin Chem 1998;44(8):1769 5. Beck BB, Baasner A, Buescher A, et al: Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. Eur J Hum Genet 2013;21:162-172

FAVI

Hypersensitivity Pneumonitis Avian Panel

91509

Clinical Information: A hypersensitivity pneumonitis (HP) due to the inhalation and sensitization to avian antigens. Immunodiffusion is used to evaluate the presence of precipitating antibodies in the sera of patients with HP due to the sensitization to various species of birds.

Reference Values: This panel includes the following antigens: Pigeon Sera Pigeon DE Cockatiel Parakeet Parrot Current as of August 23, 2017 7:11 am CDT


Page 1140

This result must be correlated with patient's clinical response and should not solely be considered in the diagnosis.

FHPP2

Hypersensitivity Pneumonitis FEIA Panel II

57595

Interpretation: mcg/mL of IgG Lower Limit of Quantitation 2.0 Upper Limit of Quantitation 200 Reference Values: Alternaria tenuis/alternata IgG or =1.5 nmol/h/mL) are not consistent with iduronate-2-sulfatase deficiency.

Reference Values: > or =1.5 nmol/h/mL

Clinical References: 1. Multiple Sulfatase Deficiency. In The Online Metabolic and Molecular Bases of Inherited Disease. #272200. Edited by W Wang. Updated 07/21/2011. Available at: www.omim.org/entry/272200 2. Neufeld EF, Muenzer J: The mucopolysaccharidoses. Chapter 136 In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 1/25/2017. Available at: www.ommbid.com 3. Scarpa M: Mucopolysaccharidosis Type II. In GeneReviews. Edited by RA Pagon, MP Adam, hh Ardinger, et al. University of Washington, Seattle; 2007 Nov 6. Accessed 1/24/17. Available at www.ncbi.nlm.nih.gov/books/NBK1274/

I2SW

Iduronate-2-sulfatase, Whole Blood

61902

Clinical Information: The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate, also known as glycosaminoglycans(GAGs). Accumulation of GAGs (previously called mucopolysaccharides) in the lysosomes interferes with normal functioning of cells, tissues, and organs. Mucopolysaccharidosis II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disorder caused by the deficiency of iduronate sulfatase (IDS) enzyme and gives rise to the physical manifestations of the disease. Clinical features and severity of symptoms are widely variable ranging from severe infantile onset disease to an attenuated form, which generally has a later onset with a milder clinical presentation. Symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. As an X-linked disorder, Hunter disease occurs primarily in males with an estimated incidence of 1 in 120,000 male births, although symptomatic carrier females have been reported. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. A diagnostic workup in an individual with MPS II typically demonstrates elevated levels of urinary glycosaminoglycans and increased amounts of both dermatan and heparan sulfate. Reduced or absent activity of IDS can confirm a diagnosis of MPS II; however, enzymatic testing is not reliable to detect carriers. Molecular genetic testing of the IDS gene allows for detection of the disease-causing mutation in affected patients and subsequent carrier detection in female relatives. Currently, no clear genotype-phenotype correlations have been established.

Useful For: Diagnosis of mucopolysaccharidosis II (MPS II, Hunter syndrome) in whole blood specimens

Interpretation: Specimens with results below 1.5 nmol/h/mL in properly submitted specimens are consistent with iduronate-2-sulfatase deficiency (mucopolysaccharidosis II: MPS II). If clinically indicated, consider further confirmation by molecular genetic analysis of the IDS gene. Please note that this enzyme's activity can also be reduced in multiple sulfatase deficiency.(1) If clinically indicated, consider biochemical genetic testing of other sulfatases or molecular genetic testing of the SUMF1 gene to exclude MSD. Normal results (> or =1.5 nmol/hour/mL) are not consistent with iduronate-2-sulfatase deficiency.

Reference Values: > or =1.5 nmol/h/mL

Clinical References: 1. Multiple Sulfatase Deficiency. In The Online Metabolic and Molecular Bases of Inherited Disease. #272200. Edited by W Wang. Updated 07/21/2011. Available at: www.omim.org/entry/272200 2. Neufeld EF, Muenzer J: The mucopolysaccharidoses. Chapter 136 In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. Current as of August 23, 2017 7:11 am CDT


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New York, McGraw-Hill Book Company. Accessed 1/25/2017. Available at: www.ommbid.com 3. Scarpa M: Mucopolysaccharidosis Type II. In GeneReviews. Edited by RA Pagon, MP Adam, hh Ardinger, et al. University of Washington, Seattle; 2007 Nov 6. Accessed 1/24/17. Available at www.ncbi.nlm.nih.gov/books/NBK1274/

IGAS

IgA Subclasses, Serum

87938

Clinical Information: IgA, the predominant immunoglobulin secreted at mucosal surfaces, consists of 2 subclasses, IgA1 and IgA2. IgA1 is the major (approximately 80%) subclass in serum. IgA2 is the major subclass in secretions such as milk. Although IgA deficiency is a common defect (1 in 700), it is usually asymptomatic. IgA deficiency with or without IgG subclass deficiency, however, can lead to recurrent pulmonary and gastrointestinal infections. Some infections (eg, recurrent sinopulmonary infections with Haemophilus influenzae) may be related to a deficiency of IgA2 in the presence of normal total IgA concentrations. Paradoxically, bacterial infections may also cause IgA deficiency. For example, IgA1 (but not IgA2) can be cleaved and inactivated by certain bacteria, thus depleting the majority of the IgA. In the presence of a concurrent IgA2 deficiency, infection by these organisms results in an apparent IgA deficiency. IgA deficiency is 1 cause of anaphylactic transfusion reactions. In these situations, IgA-deficient patients produce anti-IgA antibodies that react with IgA present in the transfusion product. While transfusion reactions typically occur in patients who have no detectable levels of IgA, they can occur in patients with measurable IgA. In these situations, the complete deficiency of 1 of the IgA subclasses may be the cause of the transfusion reactions.

Useful For: Investigation of immune deficiency due to IgA2 deficiency Evaluating patients with anaphylactic transfusion reactions

Interpretation: Low concentrations of IgA2 with normal IgA1 levels suggest an IgA2 deficiency. Elevated concentrations of IgA2 with normal or low amounts of IgA1 suggest a clonal plasma cell proliferative disorder secreting a monoclonal IgA2. Increased total IgA levels also may be seen in benign disorders (eg, infection, inflammation, allergy), hyper IgD syndrome with periodic fever and monoclonal gammopathies (eg, myeloma, monoclonal gammopathies of undetermined significance [MGUS]).

Reference Values: IgA 0-175 mcg/dL and the transferrin saturation is >55%, analysis of serum ferritin concentration (FERR / Ferritin, Serum) is indicated. A ferritin concentration >400 ng/mL is suggestive of hemochromatosis, but also can indicate other forms of hepatocyte injury such as alcoholic or viral hepatitis, or other inflammatory disorders involving the liver. HFE analysis (HFE / Hemochromatosis HFE Gene Analysis, Blood) may be used to confirm the clinical diagnosis of hemochromatosis, to diagnose hemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals who have a family history of hemochromatosis. The alleles evaluated by HFE gene analysis are evident in approximately 80% of patients with hemochromatosis; a negative report for HFE gene does not rule-out hemochromatosis. In a patient with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. Diagnosis of hemochromatosis may also be based on biochemical analysis and histologic examination of a liver biopsy. In this assay, FET / Iron Liver Tissue, results are reported as the hepatic iron index (HII) and dry weight of iron. The HII is considered the "gold standard" for diagnosis of hemochromatosis. This test is appropriate when: -Serum iron is >160 mcg/dL -Transferrin saturation is >55% -Ferritin is >400 ng/mL (males) or >200 ng/mL (females) -HFE gene test is negative for HFE variants See Hereditary Hemochromatosis Algorithm in Special Instructions.

Useful For: Diagnosis of hemochromatosis Interpretation: A hepatic iron concentration >10,000 mcg/g dry weight is diagnostic for hemochromatosis. Hepatic iron concentrations >3,000 mcg/g are seen when there is iron overload without cellular injury and cirrhosis. Hepatic iron concentrations greater than the reference range are associated with hemosiderosis, thalassemia, and sideroblastic anemia. Some patients with hepatitis or cirrhosis without significant fibrosis will have hepatic iron concentrations at the top end of normal or just slightly above the normal range. Iron accumulates in the liver normally with aging. The hepatic iron index (HII) normalizes hepatic iron concentration for age. The HII is calculated from the hepatic iron concentration by converting the concentration from mcg/g to mcmol/g dry weight and dividing by years of age. The normal range for HII is 1.9. Patients with heterozygous hemochromatosis often have HII ranging from 1.0 to 1.9. Patients with hepatitis and alcoholic cirrhosis usually have HII 0.5 mcg/mL (by HPLC); systemic infections generally require drug concentrations >1.0 mcg/mL.

Reference Values: ITRACONAZOLE (TROUGH) >0.5 mcg/mL (localized infection) >1 mcg/mL (systemic infection) HYDROXYITRACONAZOLE No therapeutic range established; activity and serum concentration are similar to parent drug.

Clinical References: 1. Andes D, Pascual A, Marchetti O: Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24-34 2. Hope WW, Billaud EM, Lestner J, Denning DW: Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis 2008;21:580-586

60910

J-Chain, Immunostain Without Interpretation Clinical Information: J-chain is a small, glycopeptide of 15 kD that is structurally unrelated to heavy or light chains. It serves to structurally link the immunoglobulin components of polymeric immunoglobulins IgA and IgM, and appears to play a role in secretion of antibodies at mucosal sites. B cells in the germinal center express J-chain at an early stage of differentiation, with the expression persisting in the plasma cells destined to produce IgA or IgM.

Useful For: Classification of lymphomas Current as of August 23, 2017 7:11 am CDT


Page 1210


Clinical References: 1. Roberts C, Jack F, Angus B, et al: Immunohistochemical detection of CD30 remains negative in nodular lymphocyte-predominant Hodgkin's disease using enhanced antigen retrieval. Histopathology. 2002 Feb;40(2):166-170 2. Isaacson P: Immunochemical demonstration of J chain: a marker of B-cell malignancy. J Clin Pathol 1979 Aug;32(8):802-807 3. Rudigar T, Ott G, Ott MM, et al: Differential diagnosis between classic Hodgkin's lymphoma, T-cell-rich B-cell lymphoma, and paragranuloma by paraffin immunohistochemistry. Am J Surg Pathol 1998 Oct;22(10):1184-1191 4. Mestecky J, Preud homme JL, Crago SS, et al: Presence of J chain in human lymphoid cells. Clin Exp Immunol 1980 Feb;39(2):371-385

JACK

Jack Fruit, IgE

82371




Page 1211


JMACK

Jack Mackerel, IgE

82819



JAK2F

JAK2 (9p24.1) Rearrangement for Hematologic Disorders, FISH

64980

Clinical Information: The JAK2 gene is a protein tyrosine kinase involved in cytokine signaling. Chromosomal translocations involving JAK2 can lead to the formation of chimeric oncoproteins in hematologic malignancies. Rearrangements involving 9p24.1 are typically aggressive and rare abnormalities seen in various hematologic diseases. JAK2 inhibitors are one of the only therapy options besides a stem cell transplant for JAK2 rearrangements.

Useful For: Providing diagnostic information and helping to determine whether a targeted JAK2 Current as of August 23, 2017 7:11 am CDT


Page 1212

inhibitor could be useful for therapy

Interpretation: A positive result is detected when the percent of cells with an abnormality exceeds the normal cutoff for the probe set. A positive result suggests rearrangement of the JAK2 locus. A negative result suggests no rearrangement of the JAK2 gene region at 9p24.1.


Clinical References: 1. Chase A, Bryant C, Score J, et al: Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements. Haematol 2013;98(3):404-408 2. Van Roosbroeck K, Cox L, Tousseyn T, et al: JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma. Blood 2011;117(15):4056-4064 3. Roberts K, Li Y, Payne-Turner D, et al: Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia. N Engl J Med 2014;371:1005-101

JAKXB

JAK2 Exon 12 and Other Non-V617F Mutation Detection, Blood

89189

Clinical Information: DNA sequence mutations in the Janus kinase 2 gene (JAK2) are found in the hematopoietic cells of several myeloproliferative neoplasms (MPNs), most frequently polycythemia vera (close to 100%), essential thrombocythemia (approximately 50%), and primary myelofibrosis (approximately 50%). Mutations in JAK2 have been reported at much lower frequency in other MPNs, chronic myelomonocytic leukemia and mixed MPN/myelodysplastic syndromes, but essentially never in chronic myelogenous leukemia (CML), reactive cytoses, or normal patients. Mutations are believed to cause constitutive activation of the JAK2 protein, which is an intracellular tyrosine kinase important for signal transduction in many hematopoietic cells. Since it is often difficult to distinguish reactive conditions from the non-CML MPNs, identification of a JAK2 mutation has diagnostic value. Potential prognostic significance of JAK2 mutation detection in chronic myeloid disorders has yet to be clearly established. The vast majority of JAK2 mutations occur as base pair 1849 in the gene, resulting in a JAK2 V617F protein change. In all cases being evaluated for JAK2 mutation status, the initial test that should be ordered is JAK2B / JAK2 V617F Mutation Detection, Blood, a sensitive assay for detection of the mutation. However, if no JAK2 V617F mutation is found, further evaluation of JAK2 may be clinically indicated. Over 50 different mutations have now been reported within exons 12 through 15 of JAK2 and essentially all of the non-V617F mutations have been identified in polycythemia vera. These mutations include point mutations and small insertions or deletions. Several of the exon 12 mutations have been shown to have biologic effects similar to those caused by the V617F mutation such that it is currently assumed other nonpolymorphic mutations have similar clinical effects. However, research in this area is ongoing. This assay for non-V617F/alternative JAK2 mutations is designed to obtain the sequence for JAK2 exons 12 through the first 90% of exon 15, which spans the region containing all mutations reported to date.

Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm, particularly when a diagnosis of polycythemia is being entertained; for use with blood specimens

Interpretation: The results will be reported as 1 of 2 states: 1. Negative for JAK2 mutation 2. Positive for JAK2 mutation If the result is positive, a description of the mutation at the nucleotide level and the altered protein sequence is reported. Positive mutation status is highly suggestive of a myeloproliferative neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative or other neoplasm.


Clinical References: 1. Ma W, Kantarjian H, Zhang X, et al: Mutation profile of JAK2 transcripts in patients with chronic myeloid neoplasias. J Mol Diagn 2009;11:49-53 2. Kilpivaara O, Levine RL: JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 2008;22:1813-1817 3. Kravolics R: Genetic complexity of myeloproliferative neoplasms. Leukemia 2008;22:1841-1848 Current as of August 23, 2017 7:11 am CDT


Page 1213

JAKXM 60025

JAK2 Exon 12 and Other Non-V617F Mutation Detection, Bone Marrow Clinical Information: DNA sequence mutations in the Janus kinase 2 gene (JAK2) are found in the hematopoietic cells of several myeloproliferative neoplasms (MPNs), most frequently polycythemia vera (close to 100%), essential thrombocythemia (approximately 50%), and primary myelofibrosis (approximately 50%). Mutations in JAK2 have been reported at much lower frequency in other MPNs, chronic myelomonocytic leukemia and mixed MPN/myelodysplastic syndromes, but essentially never in chronic myelogenous leukemia (CML), reactive cytoses, or normal patients. Mutations are believed to cause constitutive activation of the JAK2 protein, which is an intracellular tyrosine kinase important for signal transduction in many hematopoietic cells. Since it is often difficult to distinguish reactive conditions from the non-CML MPNs, identification of a JAK2 mutation has diagnostic value. Potential prognostic significance of JAK2 mutation detection in chronic myeloid disorders has yet to be clearly established. The vast majority of JAK2 mutations occur as base pair 1849 in the gene, resulting in a JAK2 V617F protein change. In all cases being evaluated for JAK2 mutation status, the initial test that should be ordered is JAK2M / JAK2 V617F Mutation Detection, Bone Marrow, a sensitive assay for detection of the mutation. However, if no JAK2 V617F mutation is found, further evaluation of JAK2 may be clinically indicated. Over 50 different mutations have now been reported within exons 12 through 15 of JAK2 and essentially all of the non-V617F mutations have been identified in polycythemia vera. These mutations include point mutations and small insertions or deletions. Several of the exon 12 mutations have been shown to have biologic effects similar to those caused by the V617F mutation such that it is currently assumed other nonpolymorphic mutations have similar clinical effects. However, research in this area is ongoing. This assay for non-V617F/alternative JAK2 mutations is designed to obtain the sequence for JAK2 exons 12 through the first 90% of exon 15, which spans the region containing all mutations reported to date.

Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm, particularly when a diagnosis of polycythemia is being entertained; for use with bone marrow specimens

Interpretation: The results will be reported as 1 of 2 states: 1. Negative for JAK2 mutation 2. Positive for JAK2 mutation If the result is positive, a description of the mutation at the nucleotide level and the altered protein sequence is reported. Positive mutation status is highly suggestive of a myeloproliferative neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative or other neoplasm.


Clinical References: 1. Ma W, Kantarjian H, Zhang X, et al: Mutation profile of JAK2 transcripts in patients with chronic myeloid neoplasias. J Mol Diagn 2009;11:49-53 2. Kilpivaara O, Levine RL: JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 2008;22:1813-1817 3. Kravolics R: Genetic complexity of myeloproliferative neoplasms. Leukemia 2008;22:1841-1848

JAK2B

JAK2 V617F Mutation Detection, Blood

88715

Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg, STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as c.G1849T; p. Val617Phe (V617F). This mutation is identified overall in approximately two-thirds of all MPN,(1-3) but the prevalence varies by MPN subtype. The JAK2 V617F is present in 95% to 98% of polycythemia vera, 50% to 60% of primary myelofibrosis, and 50% to 60% of essential thrombocythemia. It has also been described infrequently in other myeloid neoplasms, including chronic myelomonocytic



Page 1214

leukemia and myelodysplastic syndrome.(4) This mutation is not seen in chronic myelogenous leukemia (CML) or in reactive conditions with elevated blood counts. Detection of the JAK2 V617F is useful to help establish the diagnosis of MPN. However, a negative JAK2 V617F result does not indicate absence of a MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30% of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET).(5-9) Mutations in JAK2, CALR, and MPL are essentially mutually exclusive.

Useful For: Aiding in the distinction between a reactive blood cytosis and a chronic myeloproliferative disorder in blood specimens

Interpretation: The results will be reported as 1 of the 2 states: -Negative for JAK2 V617F mutation -Positive for JAK2 V617F mutation Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical and other laboratory features for definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative neoplasm or other neoplasm. Results below the laboratory cutoff for positivity are of unclear clinical significance at this time.


Clinical References: 1. Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005 March 16;365(9464):1054-1061 2. James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005 April 28;434(7037):1144-1148 3. Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790 4. Steensma DP, Dewald GW, Lasho TL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106:1207-1209

JAK2M

JAK2 V617F Mutation Detection, Bone Marrow

31155

Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg, STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as c.G1849T; p. Val617Phe (V617F). This mutation is identified overall in approximately two-thirds of all MPN,(1-3) but the prevalence varies by MPN subtype. The JAK2 V617F is present in 95% to 98% of polycythemia vera, 50% to 60% of primary myelofibrosis (PMF), and 50% to 60% of essential thrombocythemia (ET). It has also been described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia and myelodysplastic syndrome.(4) This mutation is not seen in chronic myelogenous leukemia (CML) or in reactive conditions with elevated blood counts. Detection of the JAK2 V617F is useful to help establish the diagnosis of MPN. However, a negative JAK2 V617F result does not indicate absence of a MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30% of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2, CALR, and MPL are essentially mutually exclusive.

Useful For: Aiding in the distinction between a reactive blood cytosis and a chronic myeloproliferative disorder in bone marrow specimens

Interpretation: The results will be reported as 1 of the 2 states: -Negative for JAK2 V617F mutation -Positive for JAK2 V617F mutation Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical and other laboratory features for definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative neoplasm or other neoplasm. Results below the laboratory cutoff for positivity are of unclear clinical significance at this time.



Page 1215

Clinical References: 1. Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005 March 16;365(9464):1054-1061 2. James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005 April 28;434(7037):1144-1148 3. Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790 4. Steensma DP, Dewald GW, Lasho TL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106(4):1207-1209

JAK2V

JAK2 V617F Mutation Detection, Varies

31156

Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg, STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as c.G1849T; p. Val617Phe (V617F). This mutation is identified overall in approximately two-thirds of all MPN,(1-3) but the prevalence varies by MPN subtype. The JAK2 V617F is present in 95% to 98% of polycythemia vera, 50% to 60% of primary myelofibrosis (PMF), and 50% to 60% of essential thrombocythemia (ET). It has also been described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia and myelodysplastic syndrome.(4) This mutation is not seen in chronic myelogenous leukemia (CML) or in reactive conditions with elevated blood counts. Detection of the JAK2 V617F is useful to help establish the diagnosis of MPN. However, a negative JAK2 V617F result does not indicate absence of a MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30% of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2, CALR, and MPL are essentially mutually exclusive.

Useful For: Aiding in the distinction between a reactive blood cytosis and a chronic myeloproliferative disorder in extracted DNA specimens

Interpretation: The results will be reported as 1 of the 2 states: -Negative for JAK2 V617F mutation -Positive for JAK2 V617F mutation Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative neoplasm or other neoplasm. Results below the laboratory cutoff for positivity are of unclear clinical significance at this time.


Clinical References: 1. Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005 March 16;365(9464):1054-1061 2. James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005 April 28;434(7037):1144-1148 3. Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790 4. Steensma DP, Dewald GW, Lasho TL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106:1207-1209

FJPE

Jalapeno/Chipotle (Capsicum annuum) IgE

57921


Reference Values: 25 ng/mL is a strong indicator that the patient has used ketamine.


Clinical References: 1. Ujhelyi MR, Robert S, Cummings DM, et al: Influence of digoxin immune Fab therapy and renal dysfunction on the disposition of total and free digoxin. Ann Intern Med 1993;119:273-277 2. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 10th edition. New York. McGraw-Hill Book Company, 2001 3. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. Seventh edition. Foster City, CA. Biomedical Publications, 2004 pp 1254 4. Mozayani A: Ketamine-Effects on human performance and behavior. Forensic Sci Rev 2002;14:123-131

FKMS

Ketamine and Metabolite Screen, Serum/Plasma

57857

Reference Values: Reporting limit determined each analysis Units: ng/mL Ketamine:



Page 1228

Synonyms:

Ketalar

Reported levels during anesthesia: Norketamine: Synonyms:

500 â€“ 6500 ng/mL

Ketamine Metabolite

The intravenous administration of 2 mg/kg of Ketamine followed by continuous infusion of 41 mcg/kg/minute produced an average steady-state plasma concentration of 2200 ng Ketamine/mL and an average peak Norketamine level of 1050 ng/mL which occurred near the end of the 3 hour infusion.

FKETO

Ketoconazole, Serum/Plasma

90317

Reference Values: Reporting limit determined each analysis Peak plasma levels of 5.4 +/- 1.7 mcg/mL occurred at approximately 1 hour following a single 200 mg dose and peak plasma levels of 22 +/- 3 mcg/mL occurred at approximately 2 hours following a single 800 mg dose of ketoconazole.

60921

Ki-67 (MIB-1), Immunostain Without Interpretation Clinical Information: Ki-67 (antibody clone MIB-1), is a nuclear protein playing a pivotal role in maintaining cell proliferation. Ki-67 is present in all non-G0 phases of the cell cycle. Beginning in the mid-G1, the level increases through S and G2 to reach a peak in M phase. In the end of M phase, it is rapidly catabolized. Ki-67 has been employed as a marker of proliferation and hence prognosis in neoplasms of many types, such as malignant lymphomas, prostatic and breast adenocarcinomas, astrocytic neoplasms, and soft tissue neoplasms.

Useful For: A marker of proliferation in neoplasms Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Yerushalmi R, Woods R, Ravdin PM et al: Ki67 in Breast Cancer: Prognostic and Predictive Potential. Lancet 2010;11:174-183 2. Leonardo E, Volante M, Barbareschi M, et al: Cell Membrane Reactivity of MIB-1 Antibody to Ki67 in Human Tumors: Fact or Artifact? Appl Immunohistochem Mol Morphol 2007;15(2):220-223 3. Potemski P, Pluciennik E, Bednarek AK, et al: Ki-67 Expression in Operable Breast Cancer: A Comparative Study of Immunostaining and a Real-Time RT-PCR Assay. Pathology-Research and Practice 2006;202:491-495 4. Li R, Heydon K, Hammond ME, et al: Ki-67 Staining Index Predicts Distant Metastasis and Survival in Locally Advanced Prostate Cancer Treated with Radiotherapy: An Analysis of Patients in Radiation Therapy Oncology Group Protocol 86-10. Clinical Cancer Research 2004;10:4118-4124 5. Trihia H, Murray S, Price K, et al: Ki-67 Expression in Breast Carcinoma-Its Association with Grading Systems, Clinical Parameters, and Other Prognostic Factors-A Surrogate Marker? Cancer 2003;97(5):1321-1331

89027

Ki-67(MIB-1), Breast, Quantitative Immunohistochemistry, Automated Clinical Information: Ki-67(MIB-1 clone) is a monoclonal antibody that reacts with cells undergoing DNA synthesis by binding to the Ki-67 antigen, a marker known to be expressed only in



Page 1229

proliferating cells. By measuring the amount of tumor cells expressing Ki-67, an estimate of DNA synthesis can be determined. Studies suggest that Ki-67(MIB-1) analysis of paraffin-embedded tissue specimens may provide useful prognostic information in various tumor types.

Useful For: Determining proliferation of tumor cells in paraffin-embedded tissue blocks from patients diagnosed with breast carcinoma

Interpretation: Results will be reported as a percentage of tumor cells staining positive for Ki-67(MIB-1). Quantitative Ki-67(MIB-1) results should be interpreted within the clinical context for which the test was ordered. The scoring method using the Aperio digital pathology system was developed and validated in the Molecular Anatomic Pathology Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic (see Method Description).

Reference Values: Varies by tumor type; values reported from 0% to 100%

Clinical References: 1. Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 2005 Oct 1;23(28):7212-7220 2. de Azambuja E, Cardoso F, de Castro G Jr, et al: Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients. Br J Cancer 2007 May 21;96(10):1504-1513

62968

Ki67 + Melan A, Immunostain Without Interpretation Clinical Information: Ki-67 (clone MIB-1) is a nuclear protein (detected by the chromogen DAB) playing a pivotal role in maintaining cell proliferation. Ki-67 is present in late G1-, S-, M-, and G2-phases of the cell cycle. Cells in the G0 (quiescent) phase are negative for this protein. Melan-A or melanoma antigen recognized by T cells (MART-1) (detected by the chromogen Fast Red) is expressed in the cytoplasm of melanocytes. It is a sensitive and specific marker for the diagnosis of melanoma. Melan A is also found in other tumors of melanocytic origin such as clear cell sarcoma, melanotic neurofibroma, melanotic schwannoma, as well as in perivascular epithelioid cell tumor. Melan A (clone A103) cross-reacts with steroid hormone-producing cells and tumors. Consequently, adrenocortical adenomas/carcinomas and sex cord-stromal tumors of the ovary and testis may exhibit staining.

Useful For: Ki67 is a marker of proliferation in neoplasms Melan A aids in the identification of melanoma


Clinical References: 1. Puri PK, Valdes CL, Burchette JL, et al: Accurate identification of proliferative index in melanocytic neoplasms with Melan-A/Ki-67 double stain. J Cutan Pathol 2010;37(9):1010â€“1012 2. Nielsen PS, Riber-Hansen R, Steiniche T: Immunohistochemical double stains against Ki67/MART1 and HMB45/MITF: promising diagnostic tools in melanocytic lesions. Am J Dermatopathol 2011;33(4):361-370 3. Nielsen PS, Riber-Hansen R, Jensen TO, et al: Proliferation indices of phosphohistone H3 and Ki67: strong prognostic markers in a consecutive cohort with stage I/II melanoma. Mod Pathol 2013;26:404-413

KIDBN

Kidney Bean (Red), IgE

82619

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen that may be associated with allergic disease. The allergens chosen for testing



Page 1230

often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease, the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children or =100 Strongly positive Reference values apply to all ages.


CASA

Kidney Stone Analysis

8596

Clinical Information: The composition of urinary stones may vary from a simple crystal to a complex mixture containing several different species of crystals. The composition of the nidus (center) may be entirely different from that of the peripheral layers. Eighty percent of patients with kidney stones have a history of recurrent stone formation. Knowledge of stone composition is necessary to guide therapy of patients with recurrent stone formation. Treatment of urinary calculi is complex.(1) In an overly simplified format, the following patterns are often treated as follows: -Hyperuricuria and predominately uric acid stones: alkalinize urine to increase uric acid solubility. -Hypercalciuria and predominately hydroxyapatite stones: acidify urine to increase calcium solubility. However, treatment also depends on urine pH and urine phosphate, sulfate, oxalate, and citrate concentrations. -Hyperoxaluria and calcium oxalate stones: increase daily fluid intake and consider reduction of daily calcium. However, daily requirements for calcium to maintain good bone formation complicate the treatment. -Magnesium ammonium phosphate stones (struvite): Investigate and treat urinary tract infection.

Useful For: Managing patients with recurrent renal calculi Interpretation: The interpretation of stone analysis results is complex, and beyond the scope of this text. We refer you to chapter 25 of Smith LH: Diseases of the Kidney. Vol 1. Fourth edition. Edited by RW Schrier, CW Gottscholk. Boston, MA, Little, Brown and Company, 1987. Calcium oxalate stones: -Production of calcium oxalate stones consisting of oxalate dihydrate indicate that the stone is newly Current as of August 23, 2017 7:11 am CDT


Page 1231

formed and current urine constituents can be used to assess the importance of supersaturation. -Production of calcium oxalate stones consisting of oxalate monohydrate indicate an old (>2 months since formed) stone and current urine composition may not be meaningful. Magnesium ammonium phosphate stones (struvite): -Production of magnesium ammonium phosphate stones (struvite) indicates that the cause of stone formation was infection. -Treatment of the infection is the only way to inhibit further stone formation. Ephedrine/guaifenesin stones: -Certain herbal and over-the-counter preparations (eg, Mah Jung) contain high levels of ephedrine and guaifenesin. Excessive consumption of these products can lead to the formation of ephedrine/guaifenesin stones.

Reference Values: Quantitative report

Clinical References: 1. Lieske JC, Segura JW: Evaluation and medical management of kidney stones. In Essential Urology: A Guide to Clinical Practice. Edited by JM Potts. Totowa, NJ, Humana Press, 2004, pp 117-152 2. Lieske JC: Pathophysiology and evaluation of obstructive uropathy. In Smith's Textbook of Endourology. Second edition. Edited by AD Smith, B Gopal Badlani, D Bagley, et al. Hamilton, Ontario, Canada, BC Decker Inc., 2007, pp 101-106

KKRP

Kingella kingae, Molecular Detection, PCR

65201

Clinical Information: Kingella kingae is a fastidious short Gram-negative bacillus that may colonize the oropharynx of young children. Colonization may occasionally lead to invasive disease via hematogenous dissemination, primarily in children younger than 4 years of age. This most commonly results in bone and joint infection; K kingae is the most frequent cause of osteomyelitis and septic arthritis in children aged 6 to 36 months. K kingae may also cause endocarditis, involving both native and prosthetic valves, in patients of any age and is considered part of the HACEK (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) group of organisms, known for causing culture-negative endocarditis. K kingae produces a repeat-in-toxin (RTX) toxin. Diagnosis of K kingae infection may be challenging due to the fastidious nature of the organism in culture. Evaluation of cardiac, bone, joint tissue, or fluid by PCR is a useful tool for the diagnosis of some cases of K kingae infection.

Useful For: Aids in diagnosing Kingella kingae infection Interpretation: A positive test is strongly suggestive of Kingella kingae infection. A negative test indicates the absence of detectable K kingae DNA, but does not negate the presence of the organism or recent disease and may occur due to sequence variability underlying primers and probes, or the presence of K kingae in quantities below the limit of detection of the assay.


Clinical References: 1. Murphy TF: In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Edited by GL Mandell, JE Bennett, R Dolin. Seventh edition. Philadelphia, Churchill Livingstone/Elsevier, 2010, pp 2774-2776 2. Zbinden R: Aggregatibacter, Capnocytophaga, Eikenella, Kingella, Pasteurella, and Other Fastidious or Rarely Encountered Gram-Negative Rods. In Manual of Clinical Microbiology. Edited by JH Jorgensen, KC Carroll, G Funke, MA Pfaller. 11th edition. Washington DC. ASM Press 2015. pp 652-666 3. Yagupsky P: Kingella kingae: carriage, transmission, and disease. Clin Microbiol Rev. 2015 Jan;28(1):54-79

KKBRP

Kingella kingae, Molecular Detection, PCR, Blood

65202

Clinical Information: Kingella kingae is a fastidious short Gram-negative bacillus that may colonize the oropharynx of young children. Colonization may occasionally lead to invasive disease via hematogenous dissemination, primarily in children younger than 4 years of age. This most commonly results in bone and joint infection; K kingae is the most frequent cause of osteomyelitis and septic arthritis in children aged 6 to 36 months. K kingae may also cause endocarditis, involving both native and



Page 1232

prosthetic valves, in patients of any age and is considered part of the HACEK (Haemophilus species, Aggregatibacter species, Cardiobacterium hominis, Eikenella corrodens, and Kingella species) group of organisms, known for causing culture-negative endocarditis. K kingae produces a repeat-in-toxin (RTX) toxin. Diagnosis of K kingae infection may be challenging due to the fastidious nature of the organism in culture. Evaluation of blood by PCR is a useful tool for the diagnosis of some cases of K kingae infection.

Useful For: Aids in diagnosing Kingella kingae infection Interpretation: A positive test is strongly suggestive of Kingella kingae disease. A negative result does not negate the presence of the organism or active disease, as false-negative results may occur due to inhibition of PCR, sequence variability underlying the primers and probes, or the presence of K kingae in quantities less than the limit of detection of the assay.


Clinical References: 1. Murphy TF: In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Edited by GL Mandell, JE Bennett, R Dolin. Seventh edition. Philadelphia, Churchill Livingstone/Elsevier, 2010, pp 2774-2776 2. Zbinden R: Aggregatibacter, Capnocytophaga, Eikenella, Kingella, Pasteurella, and Other Fastidious or Rarely Encountered Gram-Negative Rods. In Manual of Clinical Microbiology. Edited by JH Jorgensen, KC Carroll, G Funke, MA Pfaller. 11th edition. Washington DC. ASM Press 2015, pp 652-666 3. Yagupsky P: Kingella kingae: carriage, transmission, and disease. Clin Microbiol Rev. 2015 Jan;28(1):54-79

KITB

KIT Asp816Val Mutation Analysis, Blood

61744

Clinical Information: Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPDs). These neoplasms are characterized by excessive proliferation of 1 or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B cells are frequently part of the neoplastic clone. Function-altering point mutations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT mutation is an adenine to thymine base substitution (A->T) at nucleotide position 2468, which results in an aspartic acid to valine change in the protein (Asp816Val). Much less frequently, other mutations at this same location are found and occasional cases with mutations at other locations have also been reported. Mutations at the 816 codon are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation. Detection of a mutation at the 816 codon is included as one of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization (WHO) classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPDs. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the mutation; some having positivity only in mast cells and others having positivity in additional myeloid and even lymphoid lineages. The mutation has not been reported in normal tissues.

Useful For: Diagnosing systemic mastocytosis in blood specimens Interpretation: The test will be interpreted as positive or negative for KIT Asp816Val. Reference Values: An interpretive report will be provided indicating the mutation status as positive or negative.

Clinical References: 1. Garcia-Montero A, Jara-Acevedo M, Teodosio C, et al: KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006;108:2366-2372 2. Valent P, Akin C, Sperr WR, et al: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695-717 3. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Haematopoietic and Lymphoid Tissues. 2001, pp 291-302 Current as of August 23, 2017 7:11 am CDT


Page 1233

KITAS

KIT Asp816Val Mutation Analysis, Qualitative PCR

88802

Clinical Information: Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPDs). These neoplasms are characterized by excessive proliferation of one or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B-cells are frequently part of the neoplastic clone. Function-altering point mutations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT mutation is an adenine-to thymine base substitution (A->T) at nucleotide position 2468, which results in an aspartic acid-to-valine change in the protein (Asp816Val). Much less frequently, other mutations at this same location are found and occasional cases with mutations at other locations have also been reported. Mutations at the 816 codon are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation. Detection of a mutation at the 816 codon is included as one of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization (WHO) classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPDs. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the mutation; some having positivity only in mast cells and others having positivity in additional myeloid and even lymphoid lineages. The mutation has not been reported in normal tissues.

Useful For: Diagnosing systemic mastocytosis in extracted DNA specimens Interpretation: The test will be interpreted as positive or negative for KIT Asp816Val. Reference Values: An interpretive report will be provided indicating the mutation status as positive or negative.

Clinical References: 1. Garcia-Montero A, Jara-Acevedo M, Teodosio C, et al: KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006;108-2366-2372 2. Valent P, Akin C, Sperr WR, et al: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695-717 3. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Haematopoietic and Lymphoid Tissues. 2001, pp 291-302

KITBM 61745

KIT Asp816Val Mutation Analysis, Qualitative PCR, Bone Marrow Clinical Information: Systemic mastocytosis is a hematopoietic neoplasm that can be included in the general category of chronic myeloproliferative disorders (CMPDs). These neoplasms are characterized by excessive proliferation of 1 or more myeloid lineages, with cells filling the bone marrow and populating other hematopoietic sites. In systemic mastocytosis, mast cell proliferation is the defining feature, although other myeloid lineages and B cells are frequently part of the neoplastic clone. Function-altering point mutations in KIT, a gene coding for a membrane receptor tyrosine kinase, have been found in myeloid lineage cells in the majority of systemic mastocytosis cases. The most common KIT mutation is an adenine to thymine base substitution (A->T) at nucleotide position 2468, which results in an aspartic acid to valine change in the protein (Asp816Val). Much less frequently, other mutations at this same location are found and occasional cases with mutations at other locations have also been reported. Mutations at the 816 codon are believed to alter the protein such that it is in a constitutively activated state. The main downstream effect of KIT activation is cell proliferation. Detection of a mutation at the 816 codon is included as 1 of the minor diagnostic criteria for systemic mastocytosis in the World Health Organization (WHO) classification system for hematopoietic neoplasms and is also of therapeutic relevance, as it confers resistance to imatinib, a drug commonly used to treat CMPDs. It is now clear that individual mast cell neoplasms are variable with respect to the number of cell lineages containing the mutation; some having positivity only in mast cells and others having positivity in additional myeloid and



Page 1234

even lymphoid lineages. The mutation has not been reported in normal tissues.

Useful For: Diagnosing systemic mastocytosis in bone marrow specimens Interpretation: The test will be interpreted as positive or negative for KIT Asp816Val. Reference Values: An interpretive report will be provided indicating the mutation status as positive or negative.

Clinical References: 1. Garcia-Montero A, Jara-Acevedo M, Teodosio C, et al: KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood 2006;108:2366-2372 2. Valent P, Akin C, Sperr WR, et al: Diagnosis and treatment of systemic mastocytosis: state of the art. Br J Haematol 2003;122:695-717 3. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours. Pathology and Genetics. Tumours of the Haematopoietic and Lymphoid Tissues. 2001, pp 291-302

KIT11

KIT Exon 11, Mutation Analysis

35336

Clinical Information: Several tumors can harbor KIT mutations, including gastrointestinal stromal tumors (GIST), mast cell disease, melanoma, seminoma, acute myeloid leukemia, myeloproliferative neoplasms, and lymphomas. The frequency and type of mutations vary among these tumors and portent distinct clinical implications. The ordering physician is responsible for the diagnosis and management of disease and decisions based on the data provided.

Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or melanomas Identification of a mutation in exon 11 of the KIT gene

Interpretation: Results are reported as positive, negative, or failed. A negative result does not rule out the presence of a mutation.


Clinical References: 1. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 2. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 3. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 4. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-4349 6. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

KIT13


35337


Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or melanomas Identification of a mutation in exon 13 of the KIT gene Current as of August 23, 2017 7:11 am CDT


Page 1235



Clinical References: 1. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 2. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 3. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 4. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 6. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

KIT17


35338


Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or melanomas Identification of a mutation in exon 17 of the KIT



Clinical References: 1. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 2. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 3. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 4. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase Mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 6. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695 7. Schildhaus HU, Cavlar T, Binot E, et al: Inflammatory fibroid polyps harbour mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. J Pathol 2008;216(2):176-182

KIT8


35334

Clinical Information: Several tumors can harbor KIT mutations, including gastrointestinal stromal tumors (GIST), mast cell disease, melanoma, seminoma, acute myeloid leukemia, myeloproliferative neoplasms, and lymphomas. The frequency and type of mutations vary among these tumors and portent distinct clinical implications. The ordering physician is responsible for the diagnosis and management of



Page 1236

disease and decisions based on the data provided.

Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or other related tumors Identification of a mutation in exon 8 of the KIT gene



Clinical References: 1. Robson ME, Glogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 2. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 3. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 4. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 6. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

KIT9


35335

Clinical Information: Several tumors can harbor KIT mutations, including gastrointestinal stromal tumors, mast cell disease, melanoma, seminoma, acute myeloid leukemia, myeloproliferative neoplasms, and lymphomas. The frequency and type of mutations vary among these tumors and portent distinct clinical implications. The ordering physician is responsible for the diagnosis and management of disease and decisions based on the data provided.

Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or other related tumors Identification of a mutation in exon 9 of the KIT gene



Clinical References: 1. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 2. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 3. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 4. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 5. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 6. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

KITE

KIT Mutation Exons 8-11 and 17, Hematologic Neoplasms,



Page 1237

Sequencing Clinical Information: Acquired mutations in the KIT gene are identified in a subset of acute myeloid leukemias (AML) characterized by inv16 or t(16;16) CBFB-MYH11 or t(8;21) RUNX1-RUNX1T1 genetic abnormalities (approximately 10%-20% of cases) and in this setting, the additional presence of KIT gene mutation has been described as an adverse prognostic factor in some studies. KIT mutations in AML tend to involve exons 8 through 11 and 17, although the p.Asp816Val (D816V) variant that is highly prevalent in systemic mastocytosis is less common in AML. Mastocytosis is a hematologic disorder characterized by abnormal mast cell expansion in the bone marrow and extramedullary organ sites (eg, skin, gastrointestinal tract). Disease can be localized to skin (ie, cutaneous mastocytosis) or present systemically, with variable features of disease aggressiveness and symptomatology. Mutations in the KIT gene are identified in a large majority of patients with both cutaneous mastocytosis (CM) and systemic mastocytosis (SM). The D816V abnormality is identified in most patients with SM and this finding represents an important minor diagnostic criterion in the 2008 WHO classification. The D816V is less commonly seen in CM, although single nucleotide variants are present in other KIT exons. Rare cases of familial mastocytosis are also described with KIT mutations involving exons 8 and 9. Although KIT gene mutation represents an important diagnostic marker for SM, the number of bone marrow mast cells is often limited in aspirate samples. Therefore, if SM is clinically and pathologically suspected, KIT testing should first proceed with a sensitive and specific screen for the D816V (KITB / KIT Asp816Val Mutation Analysis, Blood; KITBM / KIT Asp816Val Mutation Analysis, Qualitative PCR, Bone Marrow; or KITAS / KIT Asp816Val Mutation Analysis, Qualitative PCR) prior to consideration of KIT gene sequencing, based on the greatly enhanced sensitivity of the PCR test for this particular variant. In AML, KIT sequencing is preferred, given the wider spectrum of mutations in other KIT exons.

Useful For: The prognostic assessment of acute myeloid leukemias with core binding factor translocations (inv16 or t[16;16] CBFB-MYH11 or t[8;21] RUNX1-RUNX1T1) and to help establish the diagnosis in some cases of mastocytosis

Interpretation: Mutations detected or not detected. An interpretive report will be issued. Reference Values: An interpretive report will be provided

Clinical References: 1. Orfao A, Garcia-Montero AC, Sanchez L, et al: Recent advances in the understanding of mastocytosis: the role of KIT mutations. Br J Haematol 2007;138:12-30 2. Arock M, Sotlar K, Broesby-Olsen S, et al: KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia 2015;6:1223-1232 3. Paschka P, Du J, Schlenk RF, et al: Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG). Blood 2013;121:170-177 4. Pardanani A: Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. Am J Hematol 2012;87:402-411 5. Paschka P, Marcucci G, Rupprt AS, et al: Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 2006;24:3905-3911

60922

KIT, Immunostain Without Interpretation Clinical Information: KIT (CD117) membrane protein is a type III tyrosine kinase growth factor receptor for stem cell factor (SCF), also known as mast cell growth factor. It is expressed in mast cells, melanocytes and interstitial cells of Cajal. KIT is expressed in various epithelia (breast, sweat glands and salivary glands, renal tubular cells, thyroid follicular cells), testicular and ovarian interstitial cells, neurons of the central nervous system, immature myeloid cells, and trophoblastic cells. KIT staining is useful in the diagnosis of gastrointestinal stromal tumors (GISTs), germ cell tumors, mast cell disorders and acute myeloid leukemias.

Useful For: An aid in the identification of gastrointestinal stromal tumors (GISTs) Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If Current as of August 23, 2017 7:11 am CDT


Page 1238

a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. This test provides qualitative results only. This test is intended for use diagnostically and not a prognostic marker.

Clinical References: 1. Lau SK, Weiss LM, Chu PG: D2-40 Immunohistochemistry in the Differential Diagnosis of Seminoma and Embryonal Carcinoma: A Comparative Immunohistochemical Study with KIT (CD117) and CD30. Modern Pathology 2007;20:320-325 2. Miettinen M, Sobin LH, Sarloma-Rikala M: Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT). Modern Pathology 2000;13(10):1134-1142 3. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M: CD117: A Sensitive Marker for Gastrointestinal Stromal Tumors That is More Specific than CD34. Modern Pathology 1998;11(8):728-734

KIWI

Kiwi Fruit, IgE

82761




Page 1239

XYMF

Known 45,X, Mosaicism Reflex Analysis, FISH

35307

Clinical Information: This test is appropriate for use in individuals with a karyotype of 45, X. Ullrich-Turner syndrome (UTS), also called Turner syndrome, is a genetic disorder associated with the apparent loss of a sex chromosome. Routine cytogenetic methods have identified 3 types of chromosomal abnormalities in UTS patients: loss of an entire X chromosome (45,X), structural X chromosome abnormalities, and mosaicism with an X or Y abnormality. In mosaicism, 2 or more populations of cells with different karyotypes are present (eg, 45,X/47,XXX). The incidence of UTS is approximately 1 in 3,000 newborn girls. Many of these patients demonstrate the 45,X karyotype. About 30% to 50% are mosaic, with either a 45,X/46,XX karyotype or a structurally abnormal X chromosome. Fewer than 15% of patients with UTS appear to have mosaicism with a 46,XY cell population or a Y chromosome rearrangement. Identifying the mosaic status of patients with UTS is of clinical importance because phenotypic expression and clinical management are dependent upon the karyotype result. Patients with a Y chromosome have a 15% to 25% increased risk of gonadoblastoma. Failure to identify an XY signal pattern does not rule out the possibility of or =1.0% cells display with 2 X chromosome signals. An XY clone is confirmed when > or =0.6% cells display a 1 X and 1 Y signal pattern. Females with a 45,X/46,XX karyotype have no increased risk of gonadoblastoma and generally have a more moderate expression of Turner syndrome features than females with a nonmosaic 45,X karyotype. The presence of a Y chromosome confers increased risk of gonadoblastoma.


Clinical References: 1. Canto P, Kofman-Alfaro S, Jiminez AL, et al: Gonadoblastoma in Turner syndrome patients with nonmosaic 45,X karyotype and Y chromosome sequences. Cancer Genet Cytogenet 2004;150:70-72 2. Wiktor A, Van Dyke, DL: FISH analysis helps identify low-level mosaicism in Ullrich-Turner syndrome patients. Genet Med 2004;6:132-135 3. Sybert VP, McCauley E: Turner syndrome. N Engl J Med 2004;351:1227-1238

KVAR1

Known Variant Analysis-1 Variant

65065

Clinical Information: This test is available for analysis of the presence of 1 sequence variant (nucleotide substitution or small insertion or deletion of nucleotides) previously identified in a family member. Targeted testing is used for diagnostic or predictive testing in cases in which variants have been previously identified in an affected family member. This testing is also used for segregation analysis to determine whether a particular variant or variants are segregating with the phenotype in an affected family. This test is used for a specific subset of genes only. Genes Available for Testing ABCC9 DTNA MYBPC3 SCN5A ACTA2 ENG MYH11 SGCD ACTC1 FBN1 MYH6 SHOC2 ACTN2 FBN2 MYH7 SKI ACVRL1 GLA MYL2 SLC2A10 AKAP9 GPD1L MYL3 SMAD3 ANK2 HRAS MYLK SNTA1 ANKRD1 JUP MYLK2 SOS1 APOB KCNE1 MYOZ2 TACI (TNFRSF13B) BRAF KCNE2 MYPN TAZ CACNA1C KCNE3 NEXN TCAP CACNA2D1 KCNH2 NRAS TGFB2 CACNB2 KCNJ5 PKLR TGFBR1 CAV3 KCNJ8 PKP2 TGFBR2 CBL KCNQ1 PLN TMEM43 CBS KRAS PRKAG2 TNNC1 COL3A1 LAMA4 PTPN11 TNNI3 CRYAB LAMP2 RAF1 TNNT2 CSRP3 LDB3 RBM20 TPM1 DES LDLR RYR2 TTN DSC2 LMNA SCN1B TTR DSG2 MAP2K1 SCN3B VCL DSP MAP2K2 SCN4B Refer to the following resources for information regarding the listed gene targets. GeneReviews-NCBI Bookshelf, available at http://www.ncbi.nlm.nih.gov/books/NBK1116/ or OMIM, available at http://www.omim.org/ If testing is needed for a gene not on this list, see FMTT / Familial Mutation, Targeted Testing, which includes targeted/site-specific testing for additional genes. Testing may be delayed if required documentation (ie, patient information sheet) is not received.

Useful For: Diagnostic or predictive testing for specific conditions when a DNA sequence variant of interest has been previously identified in a family member, and follow-up testing for this specific variant Current as of August 23, 2017 7:11 am CDT


Page 1240

in other family members is desired Carrier screening for individuals at risk for having a DNA sequence variant that was previously identified in a family member Segregation analysis for a single familial DNA sequence variant

Interpretation: Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424

KVAR2

Known Variant Analysis-2 Variants

65068

Clinical Information: This test is available for analysis of the presence of 2 sequence variants (nucleotide substitution or small insertion or deletion of nucleotides) previously identified in a family member. Targeted testing is used for diagnostic or predictive testing in cases in which variants have been previously identified in an affected family member. This testing is also used for segregation analysis to determine whether a particular variant or variants are segregating with the phenotype in an affected family. This test is used for a specific subset of genes only. Genes Available for Testing ABCC9 DTNA MYBPC3 SCN5A ACTA2 ENG MYH11 SGCD ACTC1 FBN1 MYH6 SHOC2 ACTN2 FBN2 MYH7 SKI ACVRL1 GLA MYL2 SLC2A10 AKAP9 GPD1L MYL3 SMAD3 ANK2 HRAS MYLK SNTA1 ANKRD1 JUP MYLK2 SOS1 APOB KCNE1 MYOZ2 TACI (TNFRSF13B) BRAF KCNE2 MYPN TAZ CACNA1C KCNE3 NEXN TCAP CACNA2D1 KCNH2 NRAS TGFB2 CACNB2 KCNJ5 PKLR TGFBR1 CAV3 KCNJ8 PKP2 TGFBR2 CBL KCNQ1 PLN TMEM43 CBS KRAS PRKAG2 TNNC1 COL3A1 LAMA4 PTPN11 TNNI3 CRYAB LAMP2 RAF1 TNNT2 CSRP3 LDB3 RBM20 TPM1 DES LDLR RYR2 TTN DSC2 LMNA SCN1B TTR DSG2 MAP2K1 SCN3B VCL DSP MAP2K2 SCN4B Refer to the following resources for information regarding the listed gene targets. GeneReviews-NCBI Bookshelf, available at www.ncbi.nlm.nih.gov/books/NBK1116/ or OMIM, available at www.omim.org/. If testing is needed for a gene not on this list, see FMTT / Familial Mutation, Targeted Testing, which includes targeted/site-specific testing for additional genes. Testing may be delayed if required documentation (ie, patient information sheet) is not received.

Useful For: Diagnostic or predictive testing for specific conditions when 2 DNA sequence variants of interest have been previously identified in a family member, and follow-up testing for these specific variants in other family members is desired Carrier screening for individuals at risk for having 2 DNA sequence variants that were previously identified in a family member Segregation analysis for 2 familial DNA sequence variants



Clinical References: 1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424



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KVAR3

Known Variant Analysis-3+ Variants

65072

Clinical Information: This test is for analysis of the presence of 3 to 5 sequence variants (nucleotide substitution or small insertion or deletion of nucleotides) previously identified in a family member. Targeted testing is used for diagnostic or predictive testing in cases in which variants have been previously identified in an affected family member. This testing is also used for segregation analysis to determine whether a particular variant or variants are segregating with the phenotype in an affected family. This test is used for a specific subset of genes only. Genes Available for Testing ABCC9 DTNA MYBPC3 SCN5A ACTA2 ENG MYH11 SGCD ACTC1 FBN1 MYH6 SHOC2 ACTN2 FBN2 MYH7 SKI ACVRL1 GLA MYL2 SLC2A10 AKAP9 GPD1L MYL3 SMAD3 ANK2 HRAS MYLK SNTA1 ANKRD1 JUP MYLK2 SOS1 APOB KCNE1 MYOZ2 TACI (TNFRSF13B) BRAF KCNE2 MYPN TAZ CACNA1C KCNE3 NEXN TCAP CACNA2D1 KCNH2 NRAS TGFB2 CACNB2 KCNJ5 PKLR TGFBR1 CAV3 KCNJ8 PKP2 TGFBR2 CBL KCNQ1 PLN TMEM43 CBS KRAS PRKAG2 TNNC1 COL3A1 LAMA4 PTPN11 TNNI3 CRYAB LAMP2 RAF1 TNNT2 CSRP3 LDB3 RBM20 TPM1 DES LDLR RYR2 TTN DSC2 LMNA SCN1B TTR DSG2 MAP2K1 SCN3B VCL DSP MAP2K2 SCN4B Refer to the following resources for information regarding the listed gene targets. GeneReviews-NCBI Bookshelf, available at www.ncbi.nlm.nih.gov/books/NBK1116/ or OMIM, available at www.omim.org/. If testing is needed for a gene not on this list, see FMTT / Familial Mutation, Targeted Testing, which includes targeted/site-specific testing for additional genes.

Useful For: Diagnostic or predictive testing for specific conditions when 3 to 5 DNA sequence variants of interest have been previously identified in a family member, and follow-up testing for these specific variants in other family members is desired Carrier screening for individuals at risk for having 3 to 5 DNA sequence variants that were previously identified in a family member Segregation analysis for 3 to 5 familial DNA sequence variants



Clinical References: 1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-424

KPNRP 62227

KPC (blaKPC) and NDM (blaNDM) in Gram-Negative Bacilli, Molecular Detection, PCR Clinical Information: Nonsusceptibility to carbapenems in gram-negative bacilli by means of the enzyme KPC (Klebsiella pneumoniae carbapenemase) or NDM (New Dehli metallo-beta-lactamase) is becoming more common. The genes blaKPC and blaNDM encode KPC and NDM enzyme production, respectively. In addition to KPC and NDM production, there are other mechanisms of resistance to carbapenems in gram-negative bacilli, including production of other carbapenemases, or plasmid-encoded AmpC, or extended beta-lactamase production combined with decreased membrane permeability. Detection of carbapenemases by the modified Hodge test may be subjective and is not rapid. Testing for the minimum inhibitory concentration (MIC) determines the level but not the mechanism of resistance. PCR is a sensitive, specific, and rapid means of detecting of a specific portion of the genes encoding KPC and NDM production.

Useful For: Assessing pure isolates of gram-negative bacilli for mechanism of carbapenem resistance Interpretation: This PCR detects and differentiates both blaKPC and blaNDM. A positive KPC (Klebsiella pneumoniae carbapenemase) PCR indicates that the isolate carries blaKPC. A positive NDM (New Dehli metallo-beta-lactamase) PCR indicates the isolate carries blaNDM. A negative result indicates the absence of detectable blaKPC or blaNDM DNA; however, false-negative results may occur Current as of August 23, 2017 7:11 am CDT


Page 1242

due to inhibition of PCR, sequence variability underlying primers and, or loss of a plasmid carrying blaKPC and blaNDM.


Clinical References: 1. Cunningham SA, Noorie T, Meunier D, et al: Rapid and simultaneous detection of genes encoding Klebsiella pneumoniae carbapenemase (blaKPC) and New Delhi metallo-beta-lactamase (blaNDM) in Gram-Negative Bacilli. J Clin Microbiol 2013;51:66-69 2. Multiplex Real-Time PCR Detection of Klebsiella pneumoniae Carbapenemase (KPC) and New Delhi Metallo-beta-lactamase (NDM-1) genes. Centers for Disease Control and Prevention 2011 (unpublished) 3. CLSI Document M100-S23, Vol.33 No.1, 2013. CLSI, Wayne, PA 4. New Carbapenem-Resistant Enterobacteriaceae Warrant Additional Action by Healthcare Providers. Centers for Disease Control and Prevention Health Alert Network, February 14, 2013

KNSRP

KPC (blaKPC) and NDM (blaNDM) Surveillance, PCR

62195

Clinical Information: The Centers for Disease Control and Prevention recommends active surveillance to detect unrecognized colonized patients who may be a potential source for carbapenem-resistant (drug-resistant) Enterobacteriaceae (CRE) transmission. Such surveillance testing may be focused in certain high-risk settings or patient groups (eg, ICUs, long-term acute care, patients transferred from areas or facilities with high CRE prevalence) or by infection control to investigate an outbreak. Nonsusceptibility to carbapenems in gram-negative bacilli by means of the enzyme KPC (Klebsiella pneumoniae carbapenemase) or NDM (New Dehli metallo-beta-lactamase) is becoming more common. The genes blaKPC and blaNDM encode KPC and NDM enzyme production, respectively. PCR is a sensitive, specific, and rapid means identifying patients colonized by CRE harboring blaKPC or blaNDM.

Useful For: Identifying carriers of carbapenem-resistant Enterobactericeae harboring KPC (Klebsiella pneumoniae carbapenemase) or NDM (New Dehli metallo-beta-lactamase) genes

Interpretation: This PCR detects and differentiates blaKPC and blaNDM in surveillance specimens (perirectal/rectal swabs or stool). A positive KPC (Klebsiella pneumoniae carbapenemase) and/or NDM (New Dehli metallo-beta-lactamase) PCR indicates that the patient is colonized by a Gram-negative bacillus (or Gram-negative bacilli) harboring a carbapenemase gene, blaKPC and/or blaNDM, respectively. A negative result indicates the absence of detectable DNA; however, false-negative results may occur due to inhibition of PCR, sequence variability underlying primers and probes, or the presence of the blaKPC or blaNDM genes in quantities less than the limit of detection of the assay.


Clinical References: 1. Lolans K, Calvert K, Won S, et al: Direct ertapenem disk screening method for identification of KPC-producing Klebsiella pneumoniae and Escherichia coli in surveillance swab specimens J Clin Microbiol 2010;48:836-841 2. Cunningham SA, Noorie T, Meunier D, et al: Rapid and simultaneous detection of genes encoding Klebsiella pneumoniae carbapenemase (blaKPC) and New Delhi metallo-beta-lactamase (blaNDM) in Gram-negative bacilli. J Clin Microbiol 2013;51:66-69 3. New carbapenem-resistant Enterobacteriaceae warrant additional action by healthcare providers. Centers for Disease Control and Prevention Health Alert Network, February 14, 2013 4. Vasoo S, Cunningham SA, Kohner PC, et al: Comparison of a direct and broth-enriched PCR, HardyCHROM ESBL and the CDC method for detection of Klebsiella pneumoniae carbapenemase carriage in surveillance rectal swabs. Abstracts of the Ninth International Symposium on Antimicrobial Agents and Resistance, Kuala Lumpur, Malaysia, March 13-15, 2013

KPND1

KPC and NDM PCR (Bill Only)

35207

Reference Values:



Page 1243

This test is for Billing Purposes Only. This is not an orderable test.

KD2T

Krabbe Disease Second-Tier Newborn Screen, Blood Spot

65332

Clinical Information: Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase leading to an accumulation of galactosylceramide and severe demyelination throughout the brain. Krabbe disease is primarily caused by mutations in the GALC gene, and it has an estimated frequency of 1 in 100,000 births. The clinical course of Krabbe disease can be variable, even within the same family. Eighty-five percent to 90% of patients present before the first year of life with central nervous system impairment including increasing irritability, developmental delay, and sensitivity to stimuli. Rapid neurodegeneration including white matter disease is followed by death usually by age 2. Ten percent to 15% of individuals have late onset forms of the disease that are characterized by ataxia, vision loss, weakness, and psychomotor regression presenting anytime from age 6 months to the seventh decade of life. Newborn screening for Krabbe disease has recently been implemented in some states. The early (presymptomatic) identification and subsequent testing of infants at risk for Krabbe disease may be helpful in reducing the morbidity and mortality associated with this disease. While treatment is mostly supportive, hematopoietic stem cell transplantation has shown some success if performed prior to onset of neurologic damage. Newborn screening can typically identify patients with Krabbe disease, even before onset of symptoms and also unaffected patients with GALC pseudodeficiency alleles. For these reasons, second-tier testing that includes both psychosine and 30-kb deletion analyses has been developed. Second-tier testing reduces the number of false-positive results and also limits the identification of affected individuals to patients needing immediate follow-up. Psychosine (PSY), a neurotoxin at elevated concentrations, is 1 of 4 substrates degraded by galactocerebrosidase. It has been shown to be elevated in patients with active disease and, therefore, may be a useful biomarker for the presence of disease or disease progression. The common 30-kb deletion spanning intron 10 through the end of the gene accounts for a significant proportion of disease alleles that contribute to infantile Krabbe disease. While enzyme activity alone is not predictive of age of onset, there are known genotype-phenotype correlations. Individuals who are homozygous for the deletion or compound heterozygous for the deletion and a second GALC mutation (with the exception of late-onset mutations) are predicted to have infantile Krabbe disease. Although rare, a few infants with an early onset Krabbe disease phenotype due to deficiency of saposin A (SAP-A) have been found. Saposin-A is a sphingolipid activator protein that assists galactocerebrosidase in its action on galactosylceramide.

Useful For: Second-tier testing of newborns with an abnormal screening result for Krabbe disease Follow-up testing after an abnormal newborn screening result for Krabbe disease

Interpretation: An interpretive report is provided. An elevation of psychosine is indicative of symptomatic Krabbe disease. The presence of a homozygous 30-kb deletion is indicative of early onset Krabbe disease.

Reference Values: An interpretive report is provided.

Clinical References: 1. Turgeon CT, Orsini JJ, Sanders KA, et al: Measurement of psychosine in dried blood spots-a possible improvement to newborn screening programs for Krabbe disease. J Inherit Metab Dis 2015 Sep;38(5):923-929 2. Orsini J, Morrissey M, Slavin L, et al: Implementation of newborn screening for Krabbe disease: Population study and cutoff determination. Clin Biochem 2009;42:877-884 3. Wenger DA: Krabbe Disease. In GeneReviews [Internet]. University of Washington, Seattle. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Accessed 3/2/2017. Available from: www.ncbi.nlm.nih.gov/books/NBK1238/ 4. Wenger DA, Escolar ML, Luzi P, Rafi MA: Krabbe disease (Globoid Cell Leukodystrophy). In The Online Metabolic and Molecular Bases of Inherited Disease. New York, McGraw-Hill; 2014. Edited by D Valle, AL Beaudet, B Vogelstein, et al. Accessed March 02, 2017. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62644214

KRABZ 35433

Krabbe Disease, Full Gene Analysis and Large (30 kb) Deletion,



Page 1244

PCR Clinical Information: Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase (GALC, galactosylceramide beta-galactosidase). GALC is encoded by the GALC gene located on 14q31. Krabbe disease occurs in approximately 1 in 100,000 live births with a carrier frequency of about 1 in 150 in the general population. Deficiency of GALC activity leads to an accumulation of galactosylceramide in globoid cells (multinucleated macrophages) causing severe demyelination throughout the brain. The toxic metabolite galactosylsphingosine (psychosine), an apoptotic compound, accumulates in oligodendrocytes and Schwann cells and contributes to disease pathogenicity. Severely affected individuals typically present between 3 to 6 months of age with increasing irritability and sensitivity to stimuli. Rapid neurodegeneration follows with death usually occurring by age 13 months. There are later onset forms of the disease that are characterized by ataxia, vision loss, weakness, and psychomotor regression. The clinical course of Krabbe disease can be variable even within the same family. Treatment is mostly supportive, although hematopoietic stem cell transplantation has shown some success if treatment begins before neurologic damage has occurred. The recommended first-tier test for Krabbe disease is LDSBS / Lysosomal Disorders Screen, Blood Spot, CBGC / Galactosylceramide Beta-Galactosidase, Leukocytes, or CBGT / Galactosylceramide Beta-Galactosidase, Fibroblasts. Individuals with GALC activity below the reference range for these assays are more likely to have mutations in the GALC gene that are identifiable by molecular genetic testing. The above tests are not reliable for detection of carriers of Krabbe disease. Molecular genetic testing (this test) is the recommended test for individuals with a family history of Krabbe disease in which the mutations in the family are unknown. Molecular tests form the basis of confirmatory or carrier testing. This assay includes DNA sequencing of all 17 exons within the GALC gene as well as evaluation for the common 30-kb deletion spanning intron 10 through the end of the gene. This deletion accounts for a significant proportion of disease alleles that contribute to infantile Krabbe disease. While enzyme activity is not predictive of age of onset, there are known genotype-phenotype correlations. Individuals who are homozygous for the deletion or compound heterozygous for the deletion and a second GALC mutation (with the exception of late-onset mutations) are predicted to have infantile Krabbe disease. The c.857G->A (p.Gly286Asp) mutation, on the other hand, is only associated with a late-onset phenotype.

Useful For: Second-tier test for confirming a diagnosis of Krabbe disease Carrier testing for individuals with a family history of Krabbe disease in the absence of known mutations in the family



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300 2. Wenger DA: Krabbe Disease (Most recent review March 2011). Available at http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe 3. Luzi P, Rafi MA, Wenger DA: Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics 1995;26:407-409 4. Luzi P, Rafi MA, Wenger DA: Characterization of the large deletion in the GALC gene found in patients with Krabbe disease. Hum Mol Genet 1995;4(12):2335-2338 5. Spiegel R, Bach G, Sury V, et al: A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: report of saposin A deficiency in humans. Molec Genet Metab 2005,84:160-166

KRASC

KRAS Mutation Analysis, 7 Mutation Panel, Colorectal

35469

Clinical Information: Colorectal cancer is currently among the most common malignancies diagnosed each year. Strategies that focus on early detection and prevention effectively decrease the risk of mortality associated with the disease. In addition, an increase in survival rate for individuals with advanced stage colorectal cancer has been observed as a result of advancements in standard chemotherapeutic agents and the development of specialized targeted therapies. Monoclonal antibodies



Page 1245

against epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, represent a new area of targeted therapy for such patients. However, studies have shown that not all individuals with colorectal cancer respond to EGFR-targeted molecules. Because the combination of targeted therapy and standard chemotherapy leads to an increase in toxicity and cost, strategies that help to identify the individuals most likely to benefit from such targeted therapies are desirable. EGFR is a growth factor receptor that is activated by the binding of specific ligands (epiregulin and amphiregulin), resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately regulating a number of cellular processes including cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression. Targeted therapies directed to EGFR, which inhibit activation of the RAS/MAPK pathway, have demonstrated some success (increased progression-free and overall survival) in patients with colorectal cancer. One of the most common somatic alterations in colon cancer is the presence of activating mutations in the proto-oncogene KRAS. KRAS is recruited by ligand-bound (active) EGFR to initiate the signaling cascade induced by the RAS/MAPK pathway. Because mutant KRAS constitutively activates the RAS/MAPK pathway downstream of EGFR, agents such as cetuximab and panitumumab, which prevent ligand-binding to EGFR, do not appear to have any meaningful inhibitor activity on cell proliferation in the presence of mutant KRAS. Current data suggest that the efficacy of EGFR-targeted therapies in colon cancer is confined to patients with tumors lacking KRAS mutations. As a result, the mutation status of KRAS can be a useful marker by which patients are selected for EGFR-targeted therapy. At this time, this test is approved specifically for colorectal tumors and metastatic lesions from a colorectal primary. Please refer to KRASO / KRAS Mutation Analysis, 7 Mutation Panel, Other (Non-Colorectal) for KRAS testing in noncolorectal tumors.

Useful For: Prognostic markers for cancer patients treated with epidermal growth factor receptor-targeted therapies

Interpretation: An interpretative report will be provided. Reference Values: An interpretative report will be provided.

Clinical References: 1. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of Epiregulin and Amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with Cetuximab. J Clin Oncol 2007;25:3230-3237 2. Lievre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to Cetuximab therapy in colorectal cancer. Cancer Res 2006;66(8):3992-3995 3. Spano JP, Milano G, Vignot S, Khayat D: Potential predictive markers of response to EGFR-targeted therapies in colorectal cancer. Crit Rev Oncol Hematol 2008;66:21-30

KRASO 35468

KRAS Mutation Analysis, 7 Mutation Panel, Other (Non-Colorectal) Clinical Information: Lung cancer is the leading cause of cancer-related deaths in the world. Non-small cell lung cancer (NSCLC) represents 70% to 85% of all lung cancer diagnoses. Randomized trials have suggested that targeted agents alone or combined with chemotherapy may be beneficial. Because the addition of targeted therapy may lead to an increase in toxicity and cost, strategies that help to identify the individuals most likely to benefit from targeted therapies are desirable. Monoclonal antibodies against epidermal growth factor receptor (EGFR) represent a new area of targeted therapy for such patients. However, studies have shown that not all individuals with NSCLC respond to these EGFR-targeted molecules. EGFR is a growth factor receptor that is activated by the binding of specific ligands (epiregulin and amphiregulin), resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression. Targeted therapies directed to EGFR, which inhibit activation of the RAS/MAPK pathway, have demonstrated some success in treating a subset of patients with NSCLC. In NSCLC, one of the most frequently reported alterations in the EGFR-signaling pathway is the presence of a mutation in the proto-oncogene KRAS. KRAS is recruited by ligand-bound (active) EGFR to initiate the signaling cascade induced by the RAS/MAPK pathway. Because mutant KRAS constitutively activates the RAS/MAPK pathway downstream of EGFR, agents that prevent ligand-binding to EGFR do not appear to have any meaningful inhibitor activity on cell proliferation in



Page 1246

the presence of mutant KRAS. Current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors lacking KRAS mutations. As a result, the mutation status of KRAS can be a useful marker by which patients are selected for EGFR-targeted therapy. At this time, this test is for unknown and/or unidentified primary tumors, primary tumors other than colorectal, and metastatic lesions from a primary other than colorectal. Please refer to KRASC / KRAS Mutation Analysis, 7 Mutation Panel, Colorectal for KRAS testing in colorectal tumors.

Useful For: Prognostic marker for cancer patients with noncolorectal tumors treated with epidermal growth factor receptor-targeted therapies


Clinical References: 1. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23(25):5900-5909 2. Ladanyi M, Pao W: Lung adenocarcinoma: guiding EGFR-targeted therapy and beyond. Mod Pathol 2008;21 Suppl 2:S16-S22 3. Lam DC: Clinical testing for Molecular targets for personalized treatment in lung cancer. Respirology 2013 Feb;18(2):233-237 doi: 10.1111/j.1440-1843.2012.02261.x

LACO

Lacosamide, Serum

62905

Clinical Information: Lacosamide is approved for adjunctive therapy to treat partial-onset seizures in epileptic patients 17 years of age and older. In clinical trials, the most common side effects were dizziness, headache, nausea, and double vision. Lacosamide is completely absorbed after oral administration with negligible first-pass metabolism. Peak plasma concentrations occur 1 to 4 hours after oral dosing, and the elimination half-life is approximately 13 hours. Steady-state plasma concentrations are achieved after 3 days of twice daily repeated administration. About 40% of the administered dose is eliminated by the renal system unchanged and 30% is metabolized by hepatic isoenzymes (CYP2C9, CYP2C19, and CYP3A4) to the O-desmethyl inactive metabolite. The relationship between lacosamide plasma concentrations and its efficacy or adverse effects is not well established. However, central nervous system toxicity has been associated with higher drug concentrations in plasma.

Useful For: Monitoring serum concentrations of lacosamide to ensure compliance and appropriate dosing in specific clinical conditions (ie, severe renal impairment, mild-to-moderate hepatic impairment, and end-stage renal disease)

Interpretation: The serum concentration should be interpreted in the context of the patient's clinical response and may provide useful information in patients showing poor response or adverse effects, particularly when lacosamide is coadministered with other anticonvulsant drugs. Toxic ranges have not been established.

Reference Values: Patients receiving therapeutic doses usually have lacosamide concentrations of 1.0-10.0 mcg/mL.

Clinical References: 1. VIMPAT Medication Guide. Harris FRC Corporation. UCB, Inc, Smyrna, GA 30080. Available at www.vimpat.com. Retrieved 09/2013 2. Patsalos PN, Berry DJ: Pharmacotherapy of the third-generation AEDs: lacosamide, retigabine and eslicarbazepine acetate. Expert Opin Pharmacother 2012;13(5):699-715 3. Chung SS: New treatment option for partial-onset seizures: efficacy and safety of lacosamide. Ther Adv Neurol Disord 2010;3:77-83 4. Sattler A, Schaefer M, May TW, et al: Fluctuation of lacosamide serum concentrations during the day and occurrence of adverse drug reactions-first clinical experience. Epilepsy Res 2011;95(3):207-212 5. Greenaway C, Ratnaraj N, Sander JW, Patsalos PN: Saliva and serum lacosamide concentrations in patients with epilepsy. Epilepsia 2011;52:258-263 6. McMullin M, Dalrymple R: Analysis for lacosamide in human serum by LC/MS/MS and a summary of 8,000 patient values. Ther Drug Monit 2011;33(4):520-521



Page 1247

LD_I

Lactate Dehydrogenase (LD) Isoenzymes, Serum

8679

Clinical Information: Total Lactate Dehydrogenase (LD): LD activity is present in all cells of the body with highest concentrations in heart, liver, muscle, kidney, lung, and erythrocytes. As with other proteins used as tissue-function markers, the appearance of LD in the serum occurs only after prolonged hypoxia and is elevated in a number of clinical conditions including cardiorespiratory diseases, malignancy, hemolysis, and disorders of the liver, kidneys, lung, and muscle. Isoenzymes: LD is a tetrameric cytoplasmic enzyme, composed of H and M subunits. The usual designation of the isoenzyme is LD-I (H4), LD-II (H3M), LD-III (H2M2), LD-IV (HM3), and LD-V (M4). Tissue specificity is derived from the fact that tissue-specific synthesis of subunits occurs in well-defined ratios. Most notably, heart muscle cells preferentially synthesize H subunits, while liver cells synthesize M subunits nearly exclusively. Skeletal muscle also synthesizes largely M subunits so that LD-V is both a liver and skeletal muscle form of LD. The LD-I and LD-V forms are most often used to indicate heart or liver pathology, respectively. LD-I appears elevated in the serum about 24 to 48 hours after a myocardial infarction (MI), but is generally not as useful as troponin or creatine kinase-MB (CK-MB) for detection of MI, unless the MI occurred at least 24 hours prior to testing. Normally, LD-II is greater than LD-I; however, when a MI has occurred, there is a "flip" in the usual ratio of LD-I/LD-II from less than 1 to greater than 1 (or at least >0.9). Use of the ratio for evaluation of patients with possible cardiovascular injury has largely been replaced by TPNT / Troponin T, Serum. The LD-V form is pronounced in patients with either primary liver disease or liver hypoxia secondary to decreased perfusion, such as occurs following an MI. However, LD-V is usually not as reliable as the transaminases (eg, aspartate aminotransferase, alanine aminotransferase) for evaluating liver function. LD-V also may be elevated in muscular damage and diseases of the skin. Although it does not appear to cause or be associated with any symptoms or particular diseases, the presence of macro-LD (LD combined with an immunoglobulin) can cause an idiosyncratic elevation of total LD.

Useful For: Investigating a variety of diseases involving the heart, liver, muscle, kidney, lung, and blood Differentiating heart-synthesized lactate dehydrogenase (LD) from liver and other sources Aids in the diagnosis of myocardial infarction when used in combination with total creatine kinase (CK) and CK-MB Investigating unexplained causes of LD elevations Detection of macro-LD

Interpretation: Marked elevations in lactate dehydrogenase (LD) activity can be observed in megaloblastic anemia, untreated pernicious anemia, Hodgkin disease, abdominal and lung cancers, severe shock, and hypoxia. Moderate-to-slight increases in LD levels are seen in myocardial infarction (MI), pulmonary infarction, pulmonary embolism, leukemia, hemolytic anemia, infectious mononucleosis, progressive muscular dystrophy (especially in the early and middle stages of the disease), liver disease, and renal disease. In liver disease, elevations of LD are not as great as the increases in aspartate amino transferase and alanine aminotransferase. Increased levels of the enzyme are found in about one-third of patients with renal disease, especially those with tubular necrosis or pyelonephritis. However, these elevations do not correlate well with proteinuria or other parameters of renal disease. On occasion, a raised LD level may be the only evidence to suggest the presence of a hidden pulmonary embolus. Isoenzymes: LD-II is found in myocardium. Following a severe MI, the diagnostic ratio of LD-I divided by LD-II will change from less than 0.9 to greater than 0.9. This is referred to as an LD "flip". LD-I elevation not due to myocardial damage may indicate hemolytic disease or other forms of in vivo hemolysis. Elevation of LD-V (least mobile isoenzyme) usually denotes liver damage. It is rarely helpful in defining skeletal muscle disease. Macro-LD can occur, which results in an elevation of LD for no clinical reason. Macro-LD greatly affects the migration of LD isoenzymes since the addition of an immunoglobulin molecule greatly retards the migration of the usual LD isoenzymes. If macro-LD is present, the electrophoretogram will show atypically migrating isoenzymes with LD activity localized near the origin.

Reference Values: LACTATE DEHYDROGENASE (LD) 1-30 days: 135-750 U/L 31 days-11 months: 180-435 U/L 1-3 years: 160-370 U/L 4-6 years: 145-345 U/L 7-9 years: 143-290 U/L Current as of August 23, 2017 7:11 am CDT


Page 1248

10-12 years: 120-293 U/L 13-15 years: 110-283 U/L 16-17 years: 105-233 U/L > or =18 years: 122-222 U/L LD ISOENZYMES I (fast band): 17.5-28.3% II: 30.4-36.4% III: 19.2-24.8% IV: 9.6-15.6% V (slow band): 5.5-12.7%

Clinical References: Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 2006

LDBF

Lactate Dehydrogenase (LD), Body Fluid

8022


LD

Lactate Dehydrogenase (LD), Serum

8344

Clinical Information: Lactate dehydrogenase (LD) activity is present in all cells of the body with highest concentrations in heart, liver, muscle, kidney, lung, and erythrocytes. Serum LD is elevated in a number of clinical conditions.

Useful For: Investigation of a variety of diseases involving the heart, liver, muscle, kidney, lung, and blood Monitoring changes in tumor burden after chemotherapy, although, lactate dehydrogenase elevations in patients with cancer are too erratic to be of use in the diagnosis of cancer

Interpretation: Marked elevations in lactate dehydrogenase (LD) activity can be observed in megaloblastic anemia, untreated pernicious anemia, Hodgkin disease, abdominal and lung cancers, severe shock, and hypoxia. Moderate to slight increases in LD levels are seen in myocardial infarction (MI), pulmonary infarction, pulmonary embolism, leukemia, hemolytic anemia, infectious mononucleosis, progressive muscular dystrophy (especially in the early and middle stages of the disease), liver disease, and renal disease. In liver disease, elevations of LD are not as great as the increases in aspartate amino transferase (AST) and alanine aminotransferase (ALT). Increased levels of the enzyme are found in about one-third of patients with renal disease, especially those with tubular necrosis or pyelonephritis. However, these elevations do not correlate well with proteinuria or other parameters of renal disease. On occasion a raised LD level may be the only evidence to suggest the presence of a hidden pulmonary embolus.

Reference Values: 1-30 days: 135-750 U/L 31 days-11 months: 180-435 U/L 1-3 years: 160-370 U/L 4-6 years: 145-345 U/L 7-9 years: 143-290 U/L 10-12 years: 120-293 U/L 13-15 years: 110-283 U/L 16-17 years: 105-233 U/L > or =18 years: 122-222 U/L

Clinical References: Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. Philadelphia, WB Saunders Company, 2006, pp 601-603



Page 1249

LACTD

Lactate Dehydrogenase Stain (Bill Only)

82051


LABF

Lactate, Body Fluid

8030

Clinical Information: Lactate found in cerebrospinal fluid (CSF) is predominantly produced by central nervous system (CNS) glycolysis and is independent of serum lactate. Increased CSF lactate concentrations are related to increased cerebral glycolysis or hypoxia associated with bacterial meningitis, cerebral infarction, cerebral arteriosclerosis, intracranial hemorrhage, hydrocephalus, traumatic brain injury, cerebral edema, epilepsy, and inborn errors of metabolism. Lactate measurement in CSF has been proposed as a test to differentiate bacterial from viral meningitis.

Useful For: Aid in differentiating between bacterial and viral meningitis Aid in identifying increased glycolysis or hypoxia associated with bacterial meningitis, cerebral infarction, cerebral arteriosclerosis, intracranial hemorrhage, hydrocephalus, traumatic brain injury, cerebral edema, epilepsy, and inborn errors of metabolism

Interpretation: Published studies suggest normal cerebrospinal fluid (CSF) lactate concentration is 1.1 to 2.3 mmol/L and meta-analysis of 33 studies concluded concentrations >3.9 mmol/L are suggestive of bacterial meningitis, with lower concentrations suggestive of viral meningitis.


Clinical References: Tietz Textbook of Clinical Chemistry and Molecular Diagnosis. Fifth edition. Edited by CA Burtis, ER Ashwood, DE Bruns, et al. Elsevier, St. Louis, 2012

LAA

Lactate, Plasma

8665

Clinical Information: Lactate is the end product of anaerobic carbohydrate metabolism. Major sites of production are skeletal muscle, brain, and erythrocytes. Lactate is metabolized by the liver. The concentration of lactate depends on the rate of production and the rate of liver clearance. The liver can adequately clear lactate until the concentration reaches approximately 2 mmol/L. When this level is exceeded, lactate begins to accumulate rapidly. For example, while resting lactate levels are usually 20 mmol/L within a few seconds. Lactic acidosis signals the deterioration of the cellular oxidative process and is associated with hyperpnea, weakness, fatigue, stupor, and finally coma. These conditions may be irreversible, even after treatment is administered. Lactate acidosis may be associated with hypoxic conditions (eg, shock, hypovolemia, heart failure, pulmonary insufficiency), metabolic disorders (eg, diabetic ketoacidosis, malignancies), and toxin exposures (eg, ethanol, methanol, salicylates).

Useful For: Diagnosing and monitoring patients with lactic acidosis Interpretation: While no definitive concentration of lactate has been established for the diagnosis of lactic acidosis, lactate concentrations exceeding 5 mmol/L and pH 2 years: 0.6-2.3 mmol/L

Clinical References: 1. Mizock BA: The hepatosplanchnic area and hyperlactatemia: A tale of two Current as of August 23, 2017 7:11 am CDT


Page 1250

lactates. Crit Care Med 2001;29(2):447-449 2. Duke T: Dysoxia and lactate. Arch Dis Child 1999;81(4):343-350

FLACF

Lactoferrin, Fecal by ELISA

57827

Interpretation: A positive result is indicative of the presence of lactoferrin, a marker for fecal leukocytes. A negative result does not exclude the presence of intestinal inflammation.


64464

Lactotransferrin, Immunostain Without Interpretation Clinical Information: Lactotransferrin (also referred to as lactoferrin) is a secreted iron-binding glycoprotein found in milk, tears, and leukocytes. It has been shown to be expressed in various tissues including tonsil, intestinal epithelium, kidney, and various regions of the brain where it is thought to play a role in iron metabolism and defense against bacteria. Lactotransferrin also plays a role in amyloidosis, specifically of the cornea, but has been observed in other tissue types.

Useful For: Identifing the presence of lactotransferrin in amyloid deposits An adjunct to amyloid subtyping analysis by mass spectrometry

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ando Y, Nakamura M, Kai H, et al: A novel localized amyloidosis associated with lactoferrin in the cornea. Lab Invest 2002;82(6):757-765 2. Furuya S, Masurmori N, Furuya R, et al: Characterization of localized seminal vesicle amyloidosis causing hemospermia: An analysis using immunohistochemistry and magnetic resonance imaging. J Urol 2005;173:1273-1277 3. Kebbel A, Rocken C: Immunohistochemical classification of amyloid in surgical pathology revisited. Am J Surg Pathol 2006;30(6):673-683 4. Tuccari G, Barresi G: Lactoferrin in human tumours: immunohistochemical investigations during more than 25 years. Biometals 2011;24:775-784

FLBAE

Ladybeetle Multicolored Asian (Harmonia axyridis) IgE

57572

Interpretation: Class IgE (kU/L Comment 0 99.99 Very Strong Positive

Reference Values: or =20.0 mcg/dL Adults (> or =16 years): > or =70.0 mcg/dL ZINC PROTOPORPHYRIN or =200

* Desirable: < 200 Borderline high: 200 - 239 High: > or = 240

Triglycerides (mg/dL)

** Acceptable: high: 75-99 High: > or =100

* Normal: high: 150-199 High: 200-499 Very high: > or =500

LDL Cholesterol (mg/dL)


*** Desirable: Desirable: 100-129 Borderline high: 130-159 High: 160-189 Very high: > or =190

LDL Triglycerides (mg/dL)

< or = 50

< or = 50

Apolipoprotein B (mg/dL)


Desirable: Desirable: 90-99 Borderline high: 100-119 High: 120-139 Very high: > or =140

HDL Cholesterol (mg/dL)

** Low: low: 40-45 Acceptable: > 45

*** Males: > or =40 Females: > or =50

Chylomicron Cholesterol

Undetectable

Undetectable

Chylomicron Triglycerides

Undetectable

Undetectable

Undetectable

Undetectable Reference values have not been established for patients that are of age. *National Cholesterol Education Program (NCEP) **Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents ***National Lipid Association


>18 years

VLDL Cholesterol (mg/dL) VLDLTriglycerides (mg/dL) Beta VLDL Cholesterol (mg/dL) Beta VLDL Triglycerides (mg/dL)

Lp(a) cholesterol LpX

Clinical References: 1. Schriver CR, Beaudet AL, Sly WS, Valle D: Lipoprotein and lipid disorders. In The Metabolic Basis of Inherited Disease. Sixth edition. Edited by JB Stanbury, JB Wyngaarden, DS Frederickson. New York, McGraw-Hill Book Company, 1989, pp 1129-1302 2. Grinstead GF, Ellefson RD: Heterogeneity of lipoprotein Lp(a) and apolipoprotein(a). Clin Chem 1988;34:1036-1040 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol 2014 Sep-Oct;8(5):473-488 4. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011 Dec;128 Suppl 5:S213-S256 5. Contois JH, McConnell JP, Sethi AA, et al: Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clinical Chemistry 2009:55:3:407-419 Current as of August 23, 2017 7:11 am CDT


Page 1286

PLACA

Lipoprotein-Associated Phospholipase A2 Activity, Serum

65013

Clinical Information: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory protein produced in the vascular intima and is highly upregulated in atherosclerotic plaques, especially within the necrotic core and macrophages surrounding vulnerable plaques. It circulates bound to low density lipoproteins and, to a lesser extent, high density lipoproteins. Patients with higher plaque burden have higher circulating Lp-PLA2. In multivariate analysis with traditional risk factors and C-reactive protein, Lp-PLA2 activity is an independent predictor of coronary heart disease and stroke in the general population. Recently, elevated Lp-PLA2 activity was found to associate with faster stenosis progression in patients with mild aortic stenosis.

Useful For: Identifying persons at increased risk for coronary heart disease events Interpretation: Individuals with increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity are at higher risk of coronary heart disease events and stroke. In one population-based study using the REGARDS cohort, individuals with levels > or =225 nmol/min/mL were at increased risk of coronary heart disease events.

Reference Values: > or =18 years: Males: < or =284 nmol/min/mL Females: < or =228 nmol/min/mL Reference values have not been established for patients who are 1.6 mmol/L There is no relationship between peak concentration and degree of intoxication.

Clinical References: 1. Judd LL: The therapeutic use of psychotropic medications: lithium and other mood-normalizing medications. In Harrison's Principles of Internal Medicine. 12th edition. Edited by JD Wilson, E Braunwald, KJ Isselbacher, et al. New York, McGraw-Hill Book Company, 1991, pp 2141-2143 2. Gelenberg AJ, Kane JM, Kekller MB, et al: Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989;321:1489-1493 3. Lithium Product Monograph, Physicians' Desk Reference (PDR). 61st edition. Montvale, NJ: Thomson PDR, 2007

62481

Liver Fatty Acid Binding Protein (L-FABP), Immunostain Without Interpretation Clinical Information: Liver fatty acid binding protein (L-FABP) is a cytoplasmic protein that binds free fatty acids and their coenzyme A derivative, bilirubin, and other hydrophobic ligands. It may have roles in lipid transport, uptake, and metabolism. L-FABP can be used with a panel of immunohistochemical markers (beta-catenin, glutamine synthetase, C-reactive protein, and amyloid A) to distinguish hepatic adenoma from focal nodular hyperplasia and non-neoplastic liver. L-FABP is downregulated in type 1 adenomas, but is expressed in normal liver and other adenoma types.

Useful For: Classification of hepatic adenomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. van Aalten SM, Verheij J, Terkivatan T, et al: Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol 2011;55(1):120-125 2. Bioulac-Sage P, Cubel G, Balabaud C, et al: Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis 2011;31(1):91-103 3. Bioulac-Sage P, Rebouissou S, Thomas C, et al: Hepatocellular adenoma subype classification using molecular markers and immunohistochemistry. Hepatology 2007;46(3):740-748

FLFFT

Liver Fibrosis, Fibro Test-ActiTest Panel

75039

Reference Values: Test

Reference Range

Fibrosis Score

No reference range available

Fibrosis Stage


Fibrosis Interpretation

FibroTest Score

Metavir Score

0.00-0.21

F0 no fibrosis

0.22-0.27

F0-F1

0.28-0.31

F1 minimal fibrosis

0.32-0.48

F1-F2

0.49-0.58

F2 moderate fibrosis

0.59-0.72

F3 advanced fibrosis

0.73-0.74

F3-F4



Page 1288

0.75-1.00

F4 severe fibrosis

Necroinflammat Act Score


Necroinflammat Act Grade


Necroinflammat Interp

ActiTest Score

Metavir Score

0.00-0.17

A0 no activity

0.18-0.29

A0-A1

0.30-0.36

A1 minimal activity

0.37-0.52

A1-A2

0.53-0.60

A2 significant activity

0.61-0.62

A2-A3

0.63-1.00

A3 severe activity Alpha-2-Macroglobins Not established > or =18 Years: 106-279 mg/dL Haptoglobin Not established > or =18 Years: 43-212 mg/dL Apolioprotein A-1 Males: Not established > or =18 Years: 94-176 mg/dL Females: Not established > or =18 Years: 101-198 mg/dL Total Bilirubin 2-9 Years: 0.2-0.8 mg/dL 10-19 Years: 0.2-1.1 mg/dL > or =20 Years: 0.2-1.2 mg/dL GGT Males: 2-12 Years: 3-22 U/L 13-15 Years: 8-32 U/L 16-19 Years: 9-31 U/L 20-29 Years: 3-70 U/L 30-39 Years: 3-90 U/L 40-54 Years: 3-95 U/L 55-59 Years: 3-85 U/L > or =60 Years: 3-70 U/L Females: 2-12 Years: 3-22 U/L 13-15 Years: 7-18 U/L 16-19 Years: 6-26 U/L 20-29 Years: 3-40 U/L 30-39 Years: 3-50 U/L 40-49 Years: 3-55 U/L 50-59 Years: 3-70 U/L > or =60 Years: 3-65 U/L Alanine Aminotransferase (ALT) Males: 2-3 Years: 5-30 U/L 4-12 Years: 8-30 U/L 13-15 Years: 7-32 U/L 16-19 Years: 8-46 U/L > or =20 Years: 9-46 U/L Females: 2-3 Years: 5-30 U/L 4-12 Years: 8-24 U/L 13-15 Years: 5-32 U/L 16-19 Years: 5-32 U/L > or =20 Years: 6-29 U/L The reliability of results is dependent on compliance with the pre-analytical and analytical conditions recommended by BioPredictive. The Tests have to be deferred for: acute hemolysis, acute hepatitis, acute inflammation, extra hepatic cholestasis. The advice of a specialist should be sought for interpretation in chronic hemolysis and Gilbert's syndrome. The Test interpretation is not validated in liver transplant patients. Isolated extreme values of one of the components should lead to caution in interpreting the results. In case of discordance between a biopsy result and a Test, it is recommended to seek the advice of a specialist. The cause of these discordances could be due to a flaw of the Test or to a flaw in the biopsy: i.e. a liver biopsy has a 33% variability rate for one fibrosis stage. FibroTest is interpretable for chronic hepatitis B and C, alcoholic and non-alcoholic steatosis. ActiTest is interpretable for chronic hepatitis B and C.



Page 1289

LKM

Liver/Kidney Microsome Type 1 Antibodies, Serum

80387

Clinical Information: Autoimmune liver disease (eg, autoimmune hepatitis and primary biliary cirrhosis) is characterized by the presence of autoantibodies including smooth muscle antibodies (SMA), antimitochondrial antibodies (AMA), and anti-liver/kidney microsomal antibodies type 1 (anti-LKM-1).(1) Subtypes of autoimmune hepatitis (AIH) are based on autoantibody reactivity patterns. Anti-LKM-1 antibodies serve as a serologic marker for AIH type 2 and typically occur in the absence of SMA and antinuclear antibodies. These antibodies react with a short linear sequence of the recombinant antigen cytochrome monooxygenase P450 2D6.(2) Patients with AIH type 2 more often tend to be young, female, and have severe disease that responds well to immunosuppressive therapy.

Useful For: Evaluation of patients with liver disease of unknown etiology Evaluation of patients with suspected autoimmune hepatitis

Interpretation: Seropositivity for anti-LKM-1 antibodies is consistent with a diagnosis of AIH type 2. Reference Values: < or =20.0 Units (negative) 20.1-24.9 Units (equivocal) > or =25.0 Units (positive) Reference values apply to all ages.

Clinical References: 1. Clinical Immunology Principles and Practice. Third edition. Edited by RR Rich, TA Fliesher, WT Shearer, et al: Philadelphia, PA, Mosby Elsevier, 2008 2. Czaja AJ, Homburger HA: Autoantibodies in liver disease. Gastroenterology. January 2001;120(1):239-249

LOB

Lobster, IgE

82744



FLBE

Locust Black (Robinia pseudoacacia) IgE

57946


Reference Values: 50% demonstrate a signal pattern consistent with an ALK rearrangement and considered negative if 10% and 15% of cells exhibit a signal pattern consistent with an ALK rearrangement and negative if 3-6 months) *See Pediatric Hemostasis References in Coagulation Studies in Special Instructions. DILUTE RUSSELL'S VIPER VENOM TIME or =75.0% Maximum proliferation of anti-CD3 as % CD45: > or =19.4% Maximum proliferation of anti-CD3 as % CD3: > or =20.3% Maximum proliferation of anti-CD3 + anti-CD28 as % CD45: > or =37.5% Maximum proliferation of anti-CD3 + anti-CD28 as % CD3: > or =44.6% Maximum proliferation of anti-CD3 + IL-2 as % CD45: > or =41.7% Maximum proliferation of anti-CD3 + IL-2 as % CD3: > or =46.2%

Clinical References: 1. Dupont B, Good RA: Lymphocyte transformation in vitro in patients with immunodeficiency diseases: use in diagnosis, histocompatability testing and monitoring treatment. Birth Defects Orig Artic Ser 1975;11:477-485 2. Stone KD, Feldman HA, Huisman C, et al: Analysis of in vitro lymphocyte proliferation as a screening tool for cellular immunodeficiency. Clin Immunol 2009;131:41-49 3. Frauwirth KA, Thompson CB: Activation and inhibition of lymphocytes by costimulation. J Clin Invest 2002;109:295-299 4. Smith KA, Gillis S, Baker PE, et al: T-cell growth factor-mediated T cell proliferation. Ann NY Acad Sci 1979;332:423 5. Cantrell DA, Smith KA: The interleukin-2 T cell system: a new cell growth model. Science 1984;224:1212 6. Ledbetter JA, Gentry LE, June CH, et al: Stimulation of T cells through the CD3/T cell receptor complex: role of cytoplasmic calcium, protein kinase C translocation, and phosphorylation of pp60c-src in the activation pathway. Mol Cell Biol 1987;7(2):650-656 7. Davis LS, Lipsky PE: T cell activation induced by anti-CD3 antibodies requires prolonged stimulation of protein kinase C. Cell Immunol 1989;118:208-221 8. Yu Y, Arora A, Min W, et al: EdU-Click iT flow cytometry assay as an alternative to 3H-thymidine for measuring proliferation of human and mice lymphocytes. J Allergy Clin Immunol 2009;123(2):S87 9. Salic A, Mitchison TJ: A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci USA 2008;105:2415-2420 10. Hicks MJ, Jones JK, Thies AC, et al: Age-related changes in mitogen-induced lymphocyte function from birth to old age. Am J Clin Pathol 1983;80:159-163 11. Fletcher MA, Urban RG, Asthana D, et al: Lymphocyte proliferation. In Manual of Clinical Laboratory Immunology. Fifth edition. Edited by NR Rose, EC de Macario, JD Folds, et al: Washington DC. ASM Press, 1997, pp 313-319

LPAGF

Lymphocyte Proliferation to Antigens, Blood

60592

Clinical Information: Determining impaired T-cell function by culturing human peripheral blood mononuclear cells (PBMC) in vitro with recall antigens, including Candida albicans (CA) and tetanus toxoid (TT), has been part of the diagnostic immunology repertoire for many years.(1,2) The widely used method for assessing lymphocyte proliferation to antigens has hitherto been the measurement of 3H-thymidine incorporated into the DNA of proliferating cells. The disadvantages with the 3H-thymidine method of lymphocyte proliferation are: 1. The technique is cumbersome due to the use of radioactivity 2. It does not allow discrimination of responding cell populations in response to stimulation 3. It does not provide any information on contribution of activation-induced cell death to the interpretation of the final result Further, decreased lymphocyte proliferation could be due to several factors, including overall diminution of T-cell proliferation or decrease in proliferation of only a subset of T cells, or an apparent decrease in total lymphocyte proliferation due to T-cell lymphopenia and under representation of T cells in the PBMC pool. None of these can be discriminated by the thymidine uptake assay, but can be assessed by flow cytometry, which uses antibodies to identify specific responder cell populations. Cell viability can also be measured within the same assay without requiring additional cell manipulation or sample. Antigens, like CA and TT, have been widely used to measure antigen-specific recall (anamnestic) T-cell



Page 1311

responses when assessing cellular immunity. In fact, it may be more revealing about cellular immune compromise than assessing the response of lymphocytes to mitogens because the latter can induce T-cell proliferative responses even if those T cells are incapable of responding adequately to antigenic (physiologic) stimuli. Therefore, abnormal T-cell responses to antigens are considered a diagnostically more sensitive, but less specific, test of aberrant T-cell function.(2) Antigens used in recall assays measure the ability of T cells bearing specific T-cell receptors (TCR) to respond to such antigens when processed and presented by antigen-presenting cells. The antigens used for assessment of the cellular immune response are selected to represent antigens, seen by a majority of the population, either through natural exposure (CA) or as a result of vaccination (TT). This assay uses a method that directly measures the S-phase proliferation of lymphocytes through the use of click chemistry. Cell viability, apoptosis, and death can also be measured by flow cytometry using 7-AAD and Annexin V. The Click-iT-EdU assay has already been shown to be an acceptable alternative to the 3H-thymidine assay for measuring lymphocyte/T-cell proliferation.(3) The degree of impairment of antigen-specific T-cell responses can vary depending on the nature of the cellular immune compromise. For example, some, but not all, patients with partial DiGeorge syndrome, a primary cellular immunodeficiency, have been reported to have either decreased or absent T-cell responses to CA and TT.(4) Similarly, relative immune compromise, especially to TT, has been reported in children with vitamin A deficiency, but the measurements have been largely of the humoral immune response. Since this requires participation of the cellular immune compartment, it can be postulated that there could be a potential impairment of antigen-specific T-cell responses as well.(5)

Useful For: Assessing T-cell function in patients on immunosuppressive therapy, including solid-organ transplant patients Evaluating patients suspected of having impairment in cellular immunity Evaluation of T-cell function in patients with primary immunodeficiencies, either cellular (DiGeorge syndrome, T-negative severe combined immunodeficiency: SCID, etc) or combined T- and B-cell immunodeficiencies (T- and B-negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency, among others) where T-cell function may be impaired Evaluation of T-cell function in patients with secondary immunodeficiency, either disease related or iatrogenic Evaluation of recovery of T-cell function and competence following bone marrow transplantation or hematopoietic stem cell transplantation

Interpretation: Abnormal test results to antigen stimulation are indicative of impaired T-cell function, if T-cell counts are normal or only modestly decreased. If there is profound T-cell lymphopenia, it must be kept in mind that there could be a "dilution" effect with underrepresentation of T cells within the peripheral blood mononuclear cell (PBMC) population that could result in lower T-cell proliferative responses. However, this is not a significant concern in the flow cytometry assay, since acquisition of additional cellular events during analysis can compensate for artificial reduction in proliferation due to lower T-cell counts. In the case of antigen-specific T-cell responses to tetanus toxoid (TT), there can be absent responses due to natural waning of cellular immunity, if the interval between vaccinations has exceeded the recommended period, especially in adults. In such circumstances, it would be appropriate to measure TT-specific T-cell responses 4 to 6 weeks after a booster vaccination. There is no absolute correlation between T-cell proliferation in vitro and a clinically significant immunodeficiency, whether primary or secondary, since T-cell proliferation in response to activation is necessary, but not sufficient, for an effective immune response. Therefore, the proliferative response to antigens can be regarded as a more sensitive, but less specific, test for the diagnosis of infection susceptibility. It should also be kept in mind that there is no single laboratory test that can identify or define impaired cellular immunity, with the exception of an opportunistic infection. Controls in this laboratory and most clinical laboratories are healthy adults. Since this test is used for screening and evaluating cellular immune dysfunction in infants and children, it is reasonable to question the comparability of proliferative responses between healthy infants, children, and adults. It is reasonable to expect robust T-cell-specific responses to TT in children without cellular immune compromise, as a result of repeated childhood vaccinations. The response to Candida albicans can be more variable depending on the extent of exposure and age of exposure. A comment will be provided in the report documenting the comparison of pediatric results with an adult reference range and correlation with clinical context for appropriate interpretation. It should be noted that without obtaining formal pediatric reference values, it remains a possibility that the response in infants and children can be underestimated. However, the practical challenges of generating a pediatric range for this assay necessitate comparison of pediatric data with adult reference values or controls.



Page 1312

Viability of lymphocytes at day 0: > or =75.0% Maximum proliferation of Candida albicans as % CD45: > or =5.7% Maximum proliferation of Candida albicans as % CD3: > or =3.0% Maximum proliferation of tetanus toxoid as % CD45: > or =5.2% Maximum proliferation of tetanus toxoid as % CD3: > or =3.3%

Clinical References: 1. Dupont B, Good RA: Lymphocyte transformation in vitro in patients with immunodeficiency diseases: use in diagnosis, histocompatibility testing and monitoring treatment. Birth Defects Orig Artic Ser 1975;11:477-485 2. Stone KD, Feldman HA, Huisman C, et al: Analysis of in vitro lymphocyte proliferation as a screening tool for cellular immunodeficiency. Clin Immunol 2009;131:41-49 3. Yu Y, Arora A, Min W, et al: EdU-Click iT flow cytometry assay as an alternative to 3H-thymidine for measuring proliferation of human and mice lymphocytes. J Allergy Clin Immunol 2009;123(2):S87 4. Davis CM, Kancheria VS, Reddy A, et al: Development of specific T cell responses to Candida and tetanus antigens in partial DiGeorge syndrome. J Allergy Clin Immunol 2008,122:1194-1199 5. Semba RD, Muhilal, Scott AL, et al: Depressed immune response to tetanus in children with vitamin A deficiency. J Nutr 1992;122:101-107 6. Fletcher MA, Urban RG, Asthana D, et al: Lymphocyte proliferation. In Manual of Clinical Laboratory Immunology. Fifth edition. Edited by NR Rose, EC de Macario, JD Folds, et al. Washington, DC. ASM Press, 1997, pp 313-319 7. Lis H, Sharon N: Lectins: carbohydrate-specific proteins that mediate cellular recognition. Chem Rev 1998;98:637-674 8. Salic A, Mitchison TJ: A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci USA 2008;105:2415-2420

LPMGF

Lymphocyte Proliferation to Mitogens, Blood

60591

Clinical Information: The method of determining impaired T-cell function by culturing human peripheral blood mononuclear cells (PBMC) in vitro with mitogenic plant lectins (mitogens) such as phytohemagglutinin (PHA) and pokeweed mitogen (PWM) has been part of the diagnostic immunology repertoire for many years.(1,2) The widely used method for assessing lymphocyte proliferation has hitherto been the measurement of 3H-thymidine incorporated into the DNA of proliferating cells. The disadvantages with the 3H-thymidine method of lymphocyte proliferation are: 1. The technique is cumbersome due to the use of radioactivity 2. It does not allow discrimination of responding cell populations in response to stimulation 3. It does not provide any information on contribution of activation-induced cell death to the interpretation of the final result Further, decreased lymphocyte proliferation could be due to several factors, including overall diminution of T-cell proliferation or decrease in proliferation of only a subset of T cells, or an apparent decrease in total lymphocyte proliferation due to T-cell lymphopenia and under-representation of T cells in the PBMC pool. None of these can be discriminated by the thymidine uptake assay, but can be assessed by flow cytometry, which uses antibodies to identify specific responder cell populations. Cell viability can also be measured within the same assay without requiring additional cell manipulation or specimen. Mitogens are very potent stimulators of T-cell activation and proliferation independent of their antigenic specificity.(3) It has been suggested that mitogens can induce T-cell proliferative responses even if they are incapable of responding adequately to antigenic (physiologic) stimuli. Therefore, abnormal T-cell responses to mitogens are considered a diagnostically less sensitive but more specific test of aberrant T-cell function. Lectin mitogens have been shown to bind the T-cell receptor, which is glycosylated through its carbohydrate moiety, thereby activating quiescent T cells. Mitogenic stimulation has been shown to increase intracellular calcium (CA++) in T cells, which is absolutely essential for T-cell proliferation. While PHA is a strong T-cell mitogen, PWM is a weak T-cell mitogen, but it also induces B-cell activation and proliferation as well. For this assay, we use a method that directly measures the S-phase proliferation of lymphocytes through the use of Click chemistry. In the Invitrogen Click-iT-EdU assay, the Click chemistry has been adapted to measure cell proliferation through direct detection of nucleotide incorporation. In the assay, an alkyne-modified nucleoside is supplied in cell-growth media for a defined time period and is incorporated within cells. The cells are subsequently fixed, permeabilized, and reacted with a dye-labeled azide, catalyzed by copper. A covalent bond is formed between the dye and the incorporated nucleotide, and the fluorescent signal is then measured by flow cytometry.(4) Specific proliferating cell populations can be visualized by the addition of cell-specific antibodies. Cell viability, apoptosis, and death can also be measured by flow cytometry using 7-AAD and Annexin V. The Click-iT-EdU assay has already been shown to be an acceptable alternative to the 3H-thymidine assay for



Page 1313

measuring lymphocyte/T-cell proliferation.(5) The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 am and noon, with no change between noon and afternoon. Natural killer (NK)-cell counts, on the other hand, are constant throughout the day. Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration. In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells. It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening, and during summer compared to winter. These data, therefore, indicate that timing and consistency in timing, of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Assessing T-cell function in patients on immunosuppressive therapy, including solid-organ transplant patients Evaluating patients suspected of having impairment in cellular immunity Evaluation of T-cell function in patients with primary immunodeficiencies, either cellular (DiGeorge syndrome, T-negative severe combined immunodeficiency: SCID, etc) or combined T- and B-cell immunodeficiencies (T- and B-negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency, among others) where T-cell function may be impaired Evaluation of T-cell function in patients with secondary immunodeficiency, either disease related or iatrogenic Evaluation of recovery of T-cell function and competence following bone marrow transplantation or hematopoietic stem cell transplantation

Interpretation: Abnormal test results to mitogen stimulation are indicative of impaired T-cell function if T-cell counts are normal or only modestly decreased. If there is profound T-cell lymphopenia, it must be kept in mind that there could be a "dilution" effect with under-representation of T cells within the peripheral blood mononuclear cell (PBMC) population that could result in lower T-cell proliferative responses. However, this is not a significant concern in the flow cytometry assay, since acquisition of additional cellular events during analysis can compensate for artificial reduction in proliferation due to lower T-cell counts. There is no absolute correlation between T-cell proliferation in vitro and a clinically significant immunodeficiency, whether primary or secondary, since T-cell proliferation in response to activation is necessary, but not sufficient, for an effective immune response. Therefore, the proliferative response to mitogens can be regarded as a more specific but less sensitive test for the diagnosis of infection susceptibility. It should also be kept in mind that there is no single laboratory test that can identify or define impaired cellular immunity, with the exception of an opportunistic infection. Controls in this laboratory and most clinical laboratories are healthy adults. Since this test is used for screening and evaluating cellular immune dysfunction in infants and children, it is reasonable to question the comparability of proliferative responses between healthy infants, children, and adults. One study has reported that the highest mitogen responses are seen in newborn infants with subsequent decline to 6 months of age, and a continuing decline through adolescence to half the neonatal response.(6) In our evaluation of 43 pediatric specimens (of all ages) with adult normal controls, only 21% and 14% were below the tenth percentile of the adult reference range for pokeweed (PWM) and phytohemagglutinin (PHA), respectively. A comment will be provided in the report documenting the comparison of pediatric results with an adult reference range and correlation with clinical context for appropriate interpretation. It should be noted that without obtaining formal pediatric reference values it remains a possibility that the response in infants and children can be underestimated. However, the practical challenges of generating a pediatric range for this assay necessitate comparison of pediatric data with adult reference values or controls. Lymphocyte proliferation responses to mitogens and antigens are significantly affected by time elapsed since blood collection. Results have been shown to be variable for specimens assessed more than 24- and less than 48-hours postblood collection; therefore, lymphocyte proliferation results must be interpreted with due caution and results should be correlated with clinical context.

Reference Values: Viability of lymphocytes at day 0: > or =75.0% Maximum proliferation of phytohemagglutinin as % CD45: > or =49.9% Maximum proliferation of phytohemagglutinin as % CD3: > or =58.5% Maximum proliferation of pokeweed mitogen as % CD45: > or =4.5% Maximum proliferation of pokeweed mitogen as % CD3: > or =3.5% Maximum proliferation of pokeweed mitogen as % CD19: > or =3.9% Current as of August 23, 2017 7:11 am CDT


Page 1314

Clinical References: 1. Dupont B, Good RA: Lymphocyte transformation in vitro in patients with immunodeficiency diseases: use in diagnosis, histocompatibility testing and monitoring treatment. Birth Defects Orig Artic Ser 1975;11:477-485 2. Stone KD, Feldman HA, Huisman C, et al: Analysis of in vitro lymphocyte proliferation as a screening tool for cellular immunodeficiency. Clin Immunol 2009;131:41-49 3. Lis H, Sharon N: Lectins: carbohydrate-specific proteins that mediate cellular recognition. Chem Rev 1998;98:637-674 4. Salic A, Mitchison TJ: A chemical method for fast and sensitive detection of DNA synthesis in vivo. Proc Natl Acad Sci USA 2008;105:2415-2420 5. Yu Y, Arora A, Min W, et al: EdU-Click iT flow cytometry assay as an alternative to 3H-thymidine for measuring proliferation of human and mice lymphocytes. J Allergy Clin Immunol 2009;123(2):S87 6. Hicks MJ, Jones JK, Thies AC, et al: Age-related changes in mitogen-induced lymphocyte function from birth to old age. Am J Clin Pathol 1983;80:159-163 7. Fletcher MA, Urban RG, Asthana D, et al: Lymphocyte proliferation. In Manual of Clinical Laboratory Immunology. Fifth edition. Edited by NR Rose, EC de Macario, JD Folds, et al. Washington, DC. ASM Press, 1997, pp 313-319

64720

Lymphoid Enhancer-Binding Factor 1(LEF1), Immunostain Without Interpretation Clinical Information: Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor that participates in the activation of genes within the Wnt signaling pathway. LEF1 is expressed by inactive T cells and a subset of B cells.

Useful For: Differentiating cancers of B-cell origin Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ghamlouch H, Darwiche W, Hodroge A, et al: Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells. Oncotarget 2015 Jul 30;6(21):18484-18503 2. Menter T, Dirnhofer S, Tzankov A: LEF1: a highly specific marker for the diagnosis of chronic lymphocytic B cell leukaemia/small lymphocytic B cell lymphoma. J Clin Pathol 2015 Jun;68(6):473-478 3. Gutierrez A Jr, Tschumper RC, Wu X, et al: LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis. Blood 2010 Oct 21;116(16):2975-2983

LYNCH

Lynch Syndrome Panel

64333

Clinical Information: While the risk for colorectal cancer in the general population is 6%, rarely colon cancer is attributable to hereditary factors associated with a single abnormal gene that predisposes individuals to increased risks for cancer in a family. Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3' end of the EPCAM gene, which lead to inactivation of the MSH2 promotor, have also been associated with Lynch syndrome. Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome-related genes. The lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are less than 15%. Of the 4 mismatch repair genes, mutations within the PMS2 gene confer the lowest risk for any of the tumors within the Lynch syndrome spectrum. The National Comprehensive Cancer Network and the American Cancer Society provide recommendations



Page 1315

regarding the medical management of individuals with Lynch syndrome.

Useful For: Establishing a diagnosis of Lynch syndrome Identification of familial MLH1, MSH2, MSH6, PMS2, or EPCAM mutations to allow for predictive testing in family members



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Lindor NM, McMaster ML, Lindor CJ, et al: Concise Handbook of Familial Cancer Susceptibility Syndromes. Second edition. J Natl Cancer Inst Monogr 2008;(38):1-93 3. Lynch Syndrome-GeneReviews-NCBI Bookshelf. Accessed 6/1/2015. Available at http://www.ncbi.nlm.nih.gov/books/NBK1211/ 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Genetic/Familial High-Risk Assessment: Colorectal Version 2.2014. Accessed 6/1/2015. Available at www.nccn.org 5. Vasen HFA, Moslein G, Alonso A, et al: Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007;44:353-362 6. Baglietto L, Lindor NM, Dowty JG, et al: Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 2010 Feb3;102(3):193-201 7. Senter L, Clendenning M, Sotamaa K, et al: The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008;135:419-428 8. Vaughn CP, Hart J, Samowitz WS, Swensen JJ: Avoidance of pseudogene interference in the detection of 3' deletions in PMS2. Hum Mutat 2011;32:1063-1071 9. Clendenning M, Hampel H, LaJeunesse J, et al: Long-range PCR facilitates the identification of PMS2-specific mutations. Hum Mutat 2006;27(5):490-495

LSDX 62731

Lysergic Acid Diethylamide (LSD) Confirmation, Chain of Custody, Urine Clinical Information: Lysergic acid diethylamide (LSD) is an extremely potent psychedelic ergot alkaloid derived from the fungus, Claviceps purpurea.(1) The drug LSD binds to serotonin receptors in the central nervous system and acts as a serotonin agonist. The clearance half-life of LSD averages 3 to 4 hours. It takes 5 to 7 half-lives to clear 98% of a drug dose. Therefore, the presence of LSD greater than the lower limit of quantification (LOQ; cutoff concentration) indicates exposure to LSD within 1 day.(2) LSD is metabolized to 2-oxo-3-hydroxy-LSD, which is present at concentrations 16 to 43 times higher than LSD, and is likely to be present in urine for up to 4 days after last exposure.(3,4) Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Confirming use of lysergic acid diethylamide Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: Lysergic acid diethylamide (LSD) exposure is confirmed if LSD is present >0.5 ng/mL or if 2-oxo-3-hydroxy-LSD is present >5.0 ng/mL.

Reference Values: Negative Cutoff concentrations: IMMUNOASSAY SCREEN Current as of August 23, 2017 7:11 am CDT


Page 1316

or =1.75 nmol/mL/hr

Niemann-Pick A/B Sphingomyelinase

> or =2.5 nmol/mL/hr

Pompe

Acid Alpha-Glucosidase


Krabbe

Galactocerebrosidase


Fabry

Alpha-Galactosidase


MPS I

Alpha-L-Iduronidase


NA

C20 Lysophosphatidylcholine < or =1.00 mcg/mL



Page 1324

NA

C22 Lysophosphatidylcholine < or =0.25 mcg/mL

ALD/PBD/ALDH C24 Lysophosphatidylcholine < or =0.30 mcg/mL ALD/PBD/ALDH C26 Lysophosphatidylcholine < or =0.30 mcg/mL

Clinical References: 1. DeJesus VR, Zhou H, Vogt RF, Hannon WH: Changes in solvent composition in tandem mass spectrometry multiplex assay for lysosomal storage disorders do not affect assay results. Clin Chem 2009;55(3):596-598 2. Li Y, Scott CR, Chamoles NA, et al: Direct multiplex assay of lysosomal enzymes in dried blood spots for newborn screening. Clin Chem 2004;50(10):1785-1796 3. Hubbard WC, Moser AB, Liu AC, et al: Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab 2009;97(3):212-220 4. Scriver's The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Part 15 Peroxisomes. Accessed April 17, 2017. Available at: http://ommbid.mhmedical.com/book.aspx?bookid=971 5 Scriver's The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Part 16 Lysosomal Disorders. Accessed April 17, 2017. Available at: http://ommbid.mhmedical.com/book.aspx?bookid=971

LSDP 64908

Lysosomal Storage Disease Panel by Next-Generation Sequencing Clinical Information: Lysosomal storage diseases (LSDs) encompass a group of over 40 inherited biochemical diseases in which genetic mutations cause defective lysosomal functioning. Lysosomes perform catabolic functions for cells, which is accomplished through activity of various proteins such as lysosomal enzymes, transport proteins, and other proteins. Functional deficits in these proteins cause an accumulation of substrates in cells leading to progressive organ dysfunction. This leads to variable clinical features that can affect the cardiovascular, neurological, ocular, and skeletal systems, among others. Clinical features are dependent on the amount and location of the substrate accumulation, but may include the following: characteristic facial features (coarse features), hepatomegaly, deafness, vision loss, abnormal skeletal findings, hydrops fetalis, ataxia, hypotonia, developmental delay/regression, and intellectual disability. Age of onset is variable, with symptoms presenting from the prenatal period to adulthood, but generally LSDs are progressive and cause significant morbidity and mortality with a decreased lifespan. Enzyme replacement therapy and oral substrate inhibitors are therapeutic options for some LSDs. LSDs are inherited in an autosomal recessive manner with the exception of Hunter, Fabry, and Danon diseases, which are X-linked. There are some founder mutations associated with particular LSDs in the Ashkenazi Jewish and Finnish populations, leading to an increased carrier frequency for some. Overall, the prevalence of LSDs is estimated at 1/7000 to 1/8000. Neuronal ceroid lipofuscinoses (NCLs) are a subset of lysosomal storage diseases that involve defective cellular processing of lipids. NCLs are clinically characterized by epilepsy, intellectual and motor decline, and blindness. Electron microscopy typically shows a characteristic accumulation of granular osmophilic deposits (GROD), curvilinear profiles (CVB), or fingerprint profiles (FP). Enzymatic testing may show deficiency in palmitoyl-protein thioesterase 1 (PPT1), tripeptidyl-peptidase 1 (TPP1), or cathepsin D (CTSD). Currently there are at least 14 genetically distinct forms. Age of onset and clinical features can be variable, from congenital to adult onset. NCL is typically inherited in an autosomal recessive manner, although one adult onset form (ANCL; DNAJC5 gene) has been shown to be autosomal dominant. First-tier biochemical testing is available for the 2 most common types of enzyme deficiency resulting in NCL: TPPTL / Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Leukocytes; and TPPTF / Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Fibroblasts. This panel includes sequencing of 43 genes related to various LSDs, as well as 15 genes specific to neuronal ceroid lipofuscinosis, for a total of 58 genes. See gene table below for genes and conditions that are included on the panel. Recommended first-tier biochemical testing is also provided. Note: Testing for the 15 neuronal ceroid lipofuscinosis genes is also available separately (NCLP / Neuronal Ceroid Lipofuscinosis [NCL, Batten Disease] Panel by Next-Generation Sequencing). Gene Disease Name OMIM ID Inheritance ACP2 Lysosomal acid phosphatase deficiency (ACPHD) 200950 AR AGA Aspartylglucosaminuria (AGU) 208400 AR *Finnish Founder mutation ARSA Metachromatic leukodystrophy 250100 AR ARSB Mucopolysaccharidosis Type VI maroteaux-lamy 253200 AR ARSH



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Multiple sulfatase deficiency 300586 AR ASAH1 Farber lipogranulomatosis 228000 AR CHIT1 Chitotriosidase deficiency (with Gaucher 1) 600031, 614122 AR CTNS Cystinosis 219800 AR CTSA Galactosialidosis 256540 AR FUCA1 Fucosidosis 230000 AR GAA Pompe disease-glycogen storage disease type II 232300 AR GALC Krabbe disease 245200 AR GALNS Mucopolysaccharidosis Type IVA Morquio A 612222 AR GBA Gaucher Disease 230800, 230900, 231000 AR GFAP Alexander disease 203450 AR GLA Fabry disease 301500 X linked GLB1 Mucopolysaccharidosis type IVB-MorquioB 253010 AR GM2A GM2-gangliosidosis, AB variant 272750 AR GNPTAB Mucolipidosis II, and III 252500, 252600 AR GNPTG Mucolipidosis III gamma 232605 AR GNS Mucopolysaccharidosis type IIID Sanfilippo D 252940 AR GUSB Mucopolysaccharidosis type VII Sly 253220 AR HEXA Tay-Sachs disease 272800 AR HEXB Sandhoff disease 268800 AR HGSNAT Mucopolysaccharidosis type IIIC (Sanfilippo) 252930 AR HYAL1 Mucopolysaccharidosis type IX: Hyaluroindase deficiency 601492 AR IDS Mucopolysaccharidosis type II Hunter disease 309900 X linked IDUA Mucopolysaccharidosis type I (Hurler/Scheie) 607014 AR LAMP2 Glycogen Storage Disease Type IIB-Danon Disease 300257 AR LIPA Lysosomal acid lipase deficiency/Wolman disease 278000 AR MAN2B1 Alpha-mannosidase deficiency 248500 AR MANBA Beta-mannosidosis 248510 AR MCOLN1 Mucolipidosis type IV 252650 AR NAGA Schindler disease 609241 AR NAGLU Mucopolysaccharidosis Type IIIB 252920 AR NEU1 Sialidosis 256550 AR NPC1 Niemann-Pick type C1 and C2 257220 AR NPC2 Niemann-Pick type C1 and C3 607625 AR PSAP Prosaposin Deficiency (Variants of other disorders as well) 611721, 610539, 611722, 249900 AR SGSH Mucopolysaccharidosis Type IIIA Sanfilippo 252900 AR SLC17A5 Sialic acid storage disease 269920 AR SMPD1 Niemann-Pick type A/B 257200, 607616 AR SUMF1 Multiple Sulfatase Deficiency 272200 AR AR=autosomal recessive AD=autosomal dominant

Useful For: Follow up for abnormal biochemical results and confirmation of suspected lysosomal storage disease (LSD) Identifying mutations within genes known to be associated with lysosomal storage disease, allowing for predictive testing of at-risk family members

Interpretation: All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Wang RY, Bodamer OA, Watson MS, et al: ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases: Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. Genet Med 2011;13(5):457-484 3. Parenti G, Andria G, Ballabio A: Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med 2015;66:471-486 4. Filocamo, M. Morrone A: Lysosomal storage disorders: Molecular basis and laboratory testing. Human Genomics 2011;5:156-169 5. Coutinho MF, Alves S: From rare to common and back again: 60 years of lysosomal dysfunction. Mol Genet Metab 2015

LSD6

Lysosomal Storage Disorders Newborn Screen, Blood Spot

64906

Clinical Information: Lysosomes are intracellular organelles that contain hydrolytic enzymes that degrade a variety of macromolecules. Lysosomal storage disorders are a diverse group of inherited diseases characterized by the intracellular accumulation of macromolecules due to defects in their transport mechanisms across the lysosomal membrane or due to defective lysosomal enzyme function. The accumulation of these macromolecules leads to cell damage and, eventually, organ dysfunction. More than 40 lysosomal storage disorders have been described with a wide phenotypic spectrum. Gaucher disease, which is inherited as an autosomal recessive lysosomal storage disorder, is caused by a deficiency of acid beta-glucosidase (glucocerebrosidase: GBA), resulting in increased storage of glucocerebroside (D-glucosylceramide). The deposition of glucocerebroside in macrophages of the reticuloendothelial



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system (Gaucher cells) causes organ dysfunction and organomegaly. Gaucher cells, found in the spleen, bone marrow, lung, lymph nodes, and liver, are characteristic of the disease. There are 3 clinical types of Gaucher disease: -Type 1: adult/chronic -Type 2: acute neuropathic/infantile -Type 3: subacute neuropathic/juvenile Type 1, the most frequent form of the disease, is characterized by organomegaly, thrombocytopenia, and bone pain, and is frequent among the Ashkenazi Jewish population. Hepatosplenomegaly is usually present in all 3 types. Involvement of the central nervous system (CNS) is limited to the infantile type (type 2). Treatment is available in the form of enzyme replacement therapy, substrate reduction therapy, and chaperone therapy for types 1 and 3. Currently, only supportive therapy is available for type 2. Niemann-Pick disease types A and B are caused by a deficiency of sphingomyelinase, which results in extensive storage of sphingomyelin and cholesterol in the liver, spleen, lungs, and, to a lesser degree, brain. Niemann-Pick type A disease is more severe than type B and characterized by early onset with feeding problems, dystrophy, persistent jaundice, development of hepatosplenomegaly, neurological deterioration, deafness, and blindness, leading to death by age 3. Niemann-Pick type B disease is limited to visceral symptoms with survival into adulthood. Some patients have been described with intermediary phenotypes. Characteristic of the disease are large lipid-laden foam cells. Approximately 50% of cases have cherry-red spots in the macula. Niemann-Pick types A and B are caused by mutations in the SMPD1 gene. Pompe disease, also known as glycogen storage disease type II, is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA; acid maltase) due to mutations in the GAA gene. The estimated incidence is 1 in 40,000 live births. In Pompe disease, glycogen that is taken up by lysosomes during physiologic cell turnover accumulates, causing lysosomal swelling, cell damage, and, eventually, organ dysfunction. This leads to progressive muscle weakness, cardiomyopathy, and, eventually, death. The clinical phenotype appears to be dependent on residual enzyme activity. Complete loss of enzyme activity causes onset in infancy leading to death, typically within the first year of life. Juvenile and adult-onset forms, as the names suggest, are characterized by later onset and longer survival. Because Pompe disease is considered a rare condition that progresses rapidly in infancy, the disease, in particular the juvenile and adult-onset forms, is often considered late, if at all, during the evaluation of patients presenting with muscle hypotonia, weakness, or cardiomyopathy. Treatment by enzyme replacement therapy became available recently, making early diagnosis of Pompe disease desirable, as early initiation of treatment may improve prognosis. Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by mutations in the GALC gene resulting in a deficiency of galactocerebrosidase (GALC, galactosylceramide beta-galactosidase). Galactosylceramide (as with sulfated galactosylceramide) is a lipid component of myelin. The absence of GALC results in globular, distended, multinucleated bodies in the basal ganglia, pontine nuclei, and cerebral white matter. There is severe demyelination throughout the brain with progressive cerebral degenerative disease affecting primarily the white matter. Patients with this early infantile onset variant of Krabbe disease (200 mcg/mL may be seen in acute nonlymphocytic leukemia (M2, M4, M5) or chronic granulocytic leukemias.

Reference Values: > or =12 months: 2.7-9.4 mcg/mL Reference values have not been established for patients who are G transition at nucleotide 985 (985A->G). Among MCAD-deficient patients, approximately 52% are homozygous for the 985A->G mutation. The majority of the remaining patients are compound heterozygous for the 985A->G mutation



Page 1363

and a different mutation.

Useful For: Confirmation of diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (as a follow-up to biochemical analyses) Screening of at-risk carriers of MCAD deficiency when an affected relative has not had molecular testing Diagnosis of MCAD deficiency in autopsy specimens



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Grosse SD, Khoury MJ, Greene CL, et al: The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: An update. Genet Med 2006 April:8(4):205-212 2. Ziadeh R, Hoffman EP, Finegold DM, et al: Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequency. Pediatr Res 1995 May;37(5):675-678 3. Roe CR, Coates PM: Mitochondrial fatty acid oxidation. In The Metabolic and Molecular Bases of Inherited Disease. Vol 1. Seventh edition. Edited by CR Scriver, AL Beaudet, WS Sly, D Valle. New York, McGraw-Hill Book Company, 1995, pp 1501-1533

MEDF

Medulloblastoma, FISH, Tissue

58122

Clinical Information: Medulloblastoma is the most common malignant brain tumor in children. Current treatment decisions are based on clinical variables. Biomarkers have been identified that allow classification of medulloblastoma into subtypes that are associated with a specific clinical behavior. FISH analyses for the MYCN, MYB, and MYC loci may be useful in medulloblastoma patients to help provide prognostic information and guide treatment.

Useful For: Identifying MYCN amplification, MYC amplification, and monosomy of chromosome 6 (detected using MYB probe), to aid in the classification of medulloblastoma patients into specific clinical categories

Interpretation: MYCN: -The MYCN locus is reported as amplified when the MYCN:D2Z1 ratio is 2.0 or greater and demonstrates 8 or more copies of the MYCN locus. -A tumor with a MYCN:D2Z1 ratio 0.60.(6) An EDDP:methadone ratio 50 mg/m[2]) to identify the time at which active intervention by leucovorin rescue should be initiated. Criteria for serum concentrations indicative of a potential for toxicity after single-bolus, high-dose therapy are as follows: -Methotrexate >10 mcmol/L 24 hours after dose -Methotrexate >1 mcmol/L 48 hours after dose -Methotrexate >0.1 mcmol/L 72 hours after dose

Reference Values: Nontoxic drug concentration after 72 hours: 2.0 mcg/mL (trough value) and is characterized by symptoms of nausea, hypotension, sinus bradycardia, paresthesia, seizures, intermittent left bundle branch block, and temporary asystole.

Useful For: Assessing achievement of optimal therapeutic concentrations Assessing potential toxicity Interpretation: Optimal response to mexiletine occurs when the serum concentration is within the range of 0.8 to 2.0 mcg/mL (trough value).

Reference Values: Therapeutic concentration: 0.8-2.0 mcg/mL (trough value) Toxic concentration: >2.0 mcg/mL (trough value)

Clinical References: 1. Burtis CA, Ashwood ER, Bruns DE, et al: Tietz Textbook of Clinical Chemistry and Molecular Diagnosis (Fifth edition), Elsevier, St. Louis, USA, 2012 2. Joseph SP, Holt DW: Electrophysiological properties of mexiletine assessed with respect to plasma concentrations. Eur J Current as of August 23, 2017 7:11 am CDT


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Cardiol 1980;11:115-121

MGMT

MGMT Promoter Methylation, Tumor

36733

Clinical Information: Glioblastoma (WHO Grade IV astrocytoma) is the most frequent malignant primary central nervous system tumor in adults. It has a very poor prognosis, with median survival of less than a year. Current standard of care consists of surgical resection followed by radiotherapy in addition to alkylating chemotherapy with temozolomide. MGMT (O[6]-methylguanine-DNA methyltransferase) is a DNA repair enzyme. This enzyme rescues tumor cells from alkylating agent-induced damage, and this leads to resistance to chemotherapy with alkylating agents. Epigenetic silencing of the MGMT gene by promoter methylation results in decreased MGMT protein expression, reduced DNA repair activity, and potential increased sensitivity to therapy. MGMT promoter methylation status has been most widely evaluated by methylation-specific PCR method, which is both sensitive and specific. In newly diagnosed glioblastomas, the presence of MGMT promoter methylation has been shown to be an independent favorable prognostic factor and a strong predictor of responsiveness to alkylating chemotherapy (ie, temozolomide). This is particularly relevant for elderly patients (older than 60-65 years), who usually have decreased tolerance for combined aggressive chemoradiation. For this group of patients, recent clinical trials have provided strong evidence supporting an alternative therapeutic strategy consisting of monotherapy with the alkylating agent temozolomide for patients whose tumors show MGMT promoter methylation and radiotherapy alone for patients whose tumors lack MGMT promoter methylation. Thus, in addition to the significant prognostic and predictive value, MGMT methylation status has emerged as a valuable biomarker to guide therapy decision making for newly diagnosed glioblastoma in elderly patients, preventing unnecessary treatment toxicities and costs. MGMT promoter methylation has been reported to high rates in oligodendrogliomas and astrocytomas of lower grade, in which they variably correlate with 1p19q codeletion and IDH mutations. Prognostic and predictive significance of MGMT promoter methylation status in these tumors has been shown in some studies, but not in others.

Useful For: Prognostication of newly diagnosed glioblastomas Identifying newly diagnosed glioblastomas that may respond to alkylating chemotherapy (ie, temozolomide) Guidance for therapy decision making for newly diagnosed glioblastomas in elderly patients (older than 60-65 years)


Clinical References: 1. Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997-1003 2. Weller M, Stupp R, Reifenberger G, et al: MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 2010;6:39-51 3. Wick W, Platten M, Meisner C, et al: Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 2012;13:707-715 4. Malmstrom A, Gronberg BH, Marosi C, et al: Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 2012;13:916-926 5. Wick W, Weller M, van den Bent M, et al: MGMT testing-the challenges for biomarker-based glioma treatment. Nat Rev Neurol 2014;10:372-385

FMI2

MI-2

57186

Clinical Information: Interpretation: MI-2 is a Myositis specific Autoantibody and is seen in 5-10% of adult Dermatomyositis and in 5% of Juvenile Dermatomyositis cases.




Page 1394

RMA

Microalbumin, Random, Urine

81260

Clinical Information: Diabetic nephropathy is a complication of diabetes and is characterized by proteinuria (normal urinary albumin excretion is 300 mg/day). Before overt proteinuria develops, albumin excretion increases in those diabetic patients who are destined to develop diabetic nephropathy. Therapeutic maneuvers (eg, aggressive blood pressure maintenance, particularly with angiotensin-converting enzyme inhibitors; aggressive blood sugar control; and possibly decreased protein intake) can significantly delay, or possibly prevent, development of nephropathy. Thus, there is a need to identify small, but abnormal, increases in the excretion of urinary albumin (in the range of 30-300 mg/day, ie, microalbuminuria). The National Kidney Foundation guidelines for the management of patients with diabetes and microalbuminuria recommend that all type 1 diabetic patients older than 12 years and all type 2 diabetic patients younger than 70 years have their urine tested for microalbuminuria yearly when they are under stable glucose control.(1) The preferred specimen is a 24-hour collection, but a random collection is acceptable. Studies have shown that correcting albumin for creatinine excretion rates has similar discriminatory value with respect to diabetic renal involvement. The albumin:creatinine ratio from a random urine specimen is also considered a valid screening tool.(2) Several studies have addressed whether the specimen needs to be a fasting urine, an exercised urine, or an overnight urine specimen. These studies have shown that the first-morning urine specimen is less sensitive, but more specific. Studies also have shown that microalbuminuria is a marker of generalized vascular disease and is associated with stroke and heart disease.

Useful For: Assessing the potential for early onset of nephropathy in diabetic patients Interpretation: In random urine specimens, normal urinary albumin excretion is below 17 mg/g creatinine for males and below 25 mg/g creatinine for females.(3) Microalbuminuria is defined as an albumin:creatinine ratio of 17 to 299 for males and 25 to 299 for females. A ratio of albumin:creatinine of 300 or higher is indicative of overt proteinuria. Due to biologic variability, positive results should be confirmed by a second, first-morning random or 24-hour timed urine specimen. If there is discrepancy, a third specimen is recommended. When 2 out of 3 results are in the microalbuminuria range, this is evidence for incipient nephropathy and warrants increased efforts at glucose control, blood pressure control, and institution of therapy with an ACE inhibitor (if the patient can tolerate it).

Reference Values: Males: 90% of patients with primary biliary cirrhosis (PBC), but this method also detects AMAs of differing specificities in other diseases. The mitochondrial antigens recognized by AMAs in patients' sera have been classified numerically as M1 through M9, with the M2 antigen complex recognized by AMAs in sera from patients with PBC. M2 antigen is comprised of enzyme proteins of the 2-oxoacid dehydrogenase complex that are located on inner mitochondrial membranes. Included in this group of autoantigens are the pyruvate dehydrogenase complex, and 2-oxoglutarate dehydrogenase complex.

Useful For: Establishing the diagnosis of primary biliary cirrhosis Interpretation: Positive results for antimitochondrial antibody (AMA) of M2 specificity are highly specific for primary biliary cirrhosis (PBC), and false-negative results are rare. A positive result for AMA of M2 specificity in a patient with clinical features of PBC is virtually diagnostic for this disease.

Reference Values: Negative: or =1.0 Units Reference values apply to all ages.

Clinical References: 1. Rich RR, et al: Inflammatory hepatobiliary cirrhosis. In Clinical Immunology Principles and Practice. Third edition. Philadelphia, Elsevier, 2008 2. Muratori L, Granito A, Muratori P, et al: Antimitochondrial antibodies and other antibodies in primary biliary cirrhosis: diagnostic and prognostic value. Clin Liver Dis 2008;12:261-276 3. Kaplan MM, Gershwin ME: Primary biliary cirrhosis. N Engl J Med 2005;353(12):1261-1273 4. Van Norstrand MD, Malinchoc M, Lindor KD, et al: Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship to levels of autoantibodies to disease progression. Hepatology 1997;25(1):6-11

MITOP 62510

Mitochondrial Full Genome Analysis by Next-Generation Sequencing (NGS) Clinical Information: The mitochondrion occupies a unique position in eukaryotic biology. First, it is the site of energy metabolism, without which aerobic metabolism and life as we know it would not be possible. Second, it is the sole subcellular organelle that is composed of proteins derived from 2 genomes, mitochondrial and nuclear. A group of hereditary disorders due to mutations in either the mitochondrial genome or nuclear mitochondrial genes have been well characterized. The diagnosis of mitochondrial disease can be particularly challenging as the presentation can occur at any age, involving virtually any organ system, and with widely varying severities. This test utilizes massively parallel sequencing, also termed next-generation sequencing (NGS) to determine the exact sequence of the entire 16,569 base-pair mitochondrial genome. The utility of this test is to assist in the diagnosis of the subset of mitochondrial diseases that result from mutations in the mitochondrial genome (mtDNA). This includes certain types of myopathies and neuro-opthalomologic diseases, such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy (MM), neurogenic muscle weakness, ataxia, retinitis pigmentosa (NARP), Leigh syndrome, Leber hereditary optic neuropathy (LHON), and chronic progressive external ophthalmoplegia (CPEO). In addition to the detection of single base changes with these disorders, large deletions, such as those associated with Kearns-Sayre or Pearson syndromes, are also detected. Mutations in mitochondrial proteins that are encoded by genes in the nucleus, such as the enzymes of fatty acid oxidation, are not detected using this test. In contrast to mutations in nuclear genes, which are present in either 0, 1, or 2 copies, mitochondrial mutations can be present in any fraction of the total organelles, a phenomenon known as heteroplasmy. Typically, the severity of disease presentation is a function of the degree of heteroplasmy. Individuals with a higher fraction of mutant mitochondria present with more severe disease than those with lower percentages of mutant alleles. The sensitivity for the detection of mutant alleles in a background of wild-type (or normal) mitochondrial sequences by NGS is approximately 10%.

Useful For: Diagnosis of the subset of mitochondrial diseases that results from mutations in the mitochondrial genome A second-tier test for patients in whom previous targeted gene mutation analyses for specific mitochondrial disease-related genes were negative Identifying mutations within genes of the mitochondrial genome that are known to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members

Interpretation: All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. The degree of heteroplasmy of each single nucleotide or INDEL variant, defined as the ratio (percentage) of variant sequence reads to the total number of reads, will also be reported. Large deletions will be reported as either homoplasmic or heteroplasmic, but the degree of heteroplasmy will not be estimated, due to possible preferential amplification of the smaller deletion product by long-range PCR.


Clinical References: 1. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Chapter 99: Clinical Current as of August 23, 2017 7:11 am CDT


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presentation of respiratory chain deficiency. In The Metabolic and Molecular Bases of Inherited Disease. Available at: Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Medical. Retrieved 2013 2. Wallace DC, Lott MT, Brown MD, Kerstann K: Chapter 105: Mitochondria and neuro-ophthalmologic diseases. In The Metabolic and Molecular Bases of Inherited Disease. Available at: Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Medical. Retrieved 2013 3. Wong LJ: Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 2010 Jun;16(2):154-162

MITON 64979

Mitochondrial Nuclear Gene Panel by Next-Generation Sequencing (NGS) Clinical Information: The mitochondrion occupies a unique position in eukaryotic biology. It is the site of energy metabolism, and it is the sole subcellular organelle that is composed of proteins derived from 2 genomes, mitochondrial and nuclear. A group of hereditary disorders due to mutations in either the mitochondrial genome or nuclear mitochondrial genes has been well characterized. The diagnosis of mitochondrial disease can be particularly challenging as the presentation can occur at any age, involve virtually any organ system, and be associated with widely varying severities. Due to the considerable overlap in the clinical phenotypes of various mitochondrial disorders, it is often difficult to distinguish these specific inherited disorders without genetic testing. This test utilizes massively parallel sequencing, also termed next-generation sequencing (NGS), to analyze 176 nuclear-encoded genes implicated in mitochondrial disease. The utility of this test is to assist in the diagnosis of the subset of mitochondrial diseases that result from mutations in the nuclear encoded genes. This includes disorders of mitochondrial protein synthesis, disorders of coenzyme Q10 biosynthesis, disorders of the respiratory chain complexes and disorders of mtDNA maintenance (ie, mitochondrial DNA depletion disorders). See Targeted Genes Interrogated by Mitochondrial Nuclear Gene Panel in Special Instructions for details regarding the targeted genes identified by this test.

Useful For: Diagnosis of the subset of mitochondrial disease that results from mutations in the nuclear-encoded genes A second-tier test for patients in whom previous targeted gene mutation analyses for specific mitochondrial disease-related genes were negative Identifying mutations within genes of the nuclear genome that are known to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members



Clinical References: 1. Richards CS, Nazneen A, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424 2. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Chapter 99: Clinical presentation of respiratory chain deficiency. In The Metabolic and Molecular Bases of Inherited Disease. Available at: Scriver's The Online Metabolic and Molecular Basis of Inherited Disease (OMBBID). Edited by D Valle, AL Beaudet, B Vogelstein, et al. McGraw-Hill Medical. Retrieved 2013 3. Wong LJ: Molecular genetics of mitochondrial disorders. Dev Disabil Res Rev 2010 Jun;16(2):154-162

FETCE 91844

Mitochondrial Respiratory Chain Enzyme Analysis - Skin Fibroblasts Reference Values: A final report will be attached in Mayo Access.



Page 1419

FMITO

Mitotane (Lysodren)

91130

Reference Values: Units:

ug/mL

Therapeutic and toxic ranges have not been established. Usual therapeutic doses produce Mitotane serum concentrations of less than 100 ug/mL.

MLH1I

MLH-1, Immunostain (Bill Only)

35493


MLH1Z

MLH1 Gene, Full Gene Analysis

35499

Clinical Information: Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene have also been associated with Lynch syndrome, as this leads to inactivation of the MSH2 promoter. Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer-associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome-related genes. The lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are or =1.0 AI) Unvaccinated: Negative (< or =0.7 AI)

Clinical References: 1. Perry RT, Halsey NA: The clinical significance of measles-a review. J Infect Diseases 2004;189(Supp 1):S4-S16 2. Morbidity and Mortality Weekly Report: Increased transmission and outbreaks of measles-European Region, 2011. 2011;60(47):1605-1610 3. Hviid A, Rubin S, Muhlemann K: Mumps. Lancet 2008 Mar;371(9616):932-944 4. Hodinka RL, Moshal KL: Childhood Infections. In Essentials of Diagnostic Virology. Edited by GA Storch. Churchill Livingstone, New York, 2000, pp 168-178 5. American Academy of Pediatrics. Rubella. In Red Book. 2012 Report of the Committee on Infectious Diseases. Edited by LK Pickering. Elk Grove Village, IL 6. Best JM: Rubella. Semin Fetal Neonatal Med 2007;12(3):182 7. Duszak RS: Congenital rubella syndrome-major review. Optometry 2009;80(1):36 8. Morbidity and Mortality Weekly Report: Notifiable diseases and mortality tables. 2012;61(34):466-479 9. Yankowitz J, Grose C: Congenital Infections. In Essentials of Diagnostic Virology. Edited by GA Storch. Churchill Livingstone, New York, 2000, pp 187-201

60933

MOC-31, Immunostain Without Interpretation Clinical Information: MOC31 reacts with an antigen present on most normal and malignant epithelia. Antibodies to the MOC31 antigen stains tumors of epithelial origin, adenocarcinomas, papillary serous carcinoma, breast, lung, prostate, and cholangiocarcinoma, among others. MOC31 may be used as part of a panel of stains to rule out mesothelioma and support the diagnosis of carcinoma.

Useful For: Marker of epithelial cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Current as of August 23, 2017 7:11 am CDT


Page 1428

Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Gonzalez-Lois C, Ballestin C, Sotelo MT, et al: Combined Use of Novel Epithelial (MOC-31) and Mesothelial (HBME-1) Immunohistochemical Markers for Optimal First Line Diagnostic Distinction Between Mesothelioma and Metastatic Carcinoma in Pleura. Histopathology 2001;18:528-534 2. Pai RK, West RB: MOC31 Exhibits Superior Reactivity Compared with Ber-EP4 in Invasive Lobular and Ductal Carcinoma of the Breast. Appl Immunohistochem Mol Morphol 2009;17(3):202-206 3. Porcell AI, DeYoung BR, Proca DM, Frankel WL: Immunohistochemical Analysis of Hepatocellular and Adenocarcinoma in the Liver: MOC31 Compare Favorably with Other Putative Markers. Modern Pathology 2000;13(7):773-778

MOLD1

Mold Panel

81878





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 1429

MOWB

Molybdenum, Blood

64272

Clinical Information: Molybdenum is an essential trace element and a component of metalloflavoproteins. High concentrations are found in leafy vegetables and legumes. The recommended daily dietary allowance for molybdenum is 45 mcg for adults.(1) As an industrial metal, molybdenum is used in the manufacturing of steel alloys, lubricants, or pigments. Occupational exposure is generally from inhalation of dusts or fumes. The current threshold limit is 0.5 mg/m(2) for soluble compounds and 3 mg/m(2) (respirable fraction) for the metal and its insoluble compounds.(1) Oral absorption varies from 28% to 77%. Whole blood concentrations averaged 0.43 mcg/L (range 0.6-4.0 mcg/L) in unexposed individuals.(3) However, exposed adults averaged 2.7 mcg/L (range 1.2-4.8 mcg/L).(4) Once absorbed, molybdenum is primarily eliminated in the urine over 5 or more days.(5) Molybdenum deficiency can cause irritability, altered levels of consciousness, and a variety of biochemical abnormalities.(6) Toxicity can range from auditory and visual hallucinations, diarrhea, insomnia, painful extremities, and seizures.(7)

Useful For: Determining molybdenum toxicity Interpretation: Normal blood concentrations are 0.6-4.0 ng/mL in unexposed individuals and 1.2-4.8 ng/mL in exposed individuals.(4)

Reference Values: 10 ng/mL in a patient with molybdenum-based implant suggest significant prosthesis wear. Increased serum trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure. Serum molybdenum or =100 Strongly positive Reference values apply to all ages.


MOTH

Moth, IgE

82738





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4




Page 1438

5


6



FMOT

Motilin, Plasma or Serum

90157

Clinical Information: Motilin is a 22 amino acid peptide produced primarily by the enterochromaffin cells (EC2 or M cells) in the intestine, duodenum and the jejunum. It is absent from the stomach and colon. Motilin accelerates gastric emptying and colonic motor activity. Motilin also stimulates the feeding response. It has no structural similarities with other gastrointestinal peptides. Motilin secretion can be stimulated by acid and a fat-rich meal. Motilin can increase the secretion of pepsin and causes increased intra-gastric pressure. Motilin also stimulates lower esophageal sphincter contraction. Motilin levels are suppressed by Calcitonin. Motilin has a short half-life of approximately five minutes.

Reference Values: Up to 446 pg/mL This test was developed and its performance characteristics determined by Inter Science Institute. It has not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.

FMONP

Motor Neuropathy Panel

75067

Reference Values: 0 â€“ 30 days:

1 â€“ 7 mg/dL

9 â€“ 11 months:

16 â€“ 83 mg/dL

1 month:

1 â€“ 53 mg/dL 1 year:

14 â€“ 105 mg/dL

2 months:

3 â€“ 47 mg/dL 2 years:

14 â€“ 122 mg/dL

3 months:


22 â€“ 157 mg/dL

4 months:


25 â€“ 152 mg/dL

5 months:

8 â€“ 83 mg/dL 5 - 7 years:

33 â€“ 300 mg/dL

6 months:

8 â€“ 67 mg/dL 8 â€“ 9 years:

45 â€“ 234 mg/dL

7 â€“ 8 months: 11 â€“ 89 mg/dL 10 years and older: 68 â€“ 408 mg/dL Immunoglobulin G 0 â€“ 30 days:

611 â€“ 1542 mg/dL 9 â€“ 11 months:

282 â€“ 1026 mg/dL

1 month:

241 â€“ 870 mg/dL 1 year:

331 â€“ 1164 mg/dL

2 months:

198 â€“ 577 mg/dL 2 years:

407 â€“ 1009 mg/dL

3 months:

169 â€“ 558 mg/dL 3 years:

423 â€“ 1090 mg/dL

4 months:

188 â€“ 536 mg/dL 4 years:

444 â€“ 1187 mg/dL

5 months:

165 â€“ 781 mg/dL 5 â€“ 7 years:

608 â€“ 1229 mg/dL

6 months:

206 â€“ 676 mg/dL 8 â€“ 9 years:

584 â€“ 1509 mg/dL

7 â€“ 8 months: 208 â€“ 868 mg/dL 10 years and older: 768 â€“ 1632 mg/dL Immunoglobulin M Current as of August 23, 2017 7:11 am CDT


Page 1439

0 â€“ 30 days:

0 â€“ 24 mg/dL


39 â€“ 142 mg/dL

1 month:

19 â€“ 83 mg/dL

1 year:

41 â€“ 164 mg/dL

2 months:

16 â€“ 100 mg/dL

2 years:

46 â€“ 160 mg/dL

3 months:

23 â€“ 85 mg/dL

3 years:

45 â€“ 190 mg/dL

4 months:

26 â€“ 96 mg/dL

4 years:

41 â€“ 186 mg/dL

5 months:

31 â€“ 103 mg/dL

5 â€“ 7 years:

46 â€“ 197 mg/dL

6 months:

33 â€“ 97 mg/dL

8 â€“ 9 years:

49 â€“ 230 mg/dL


32 â€“ 120 mg/dL

10 years and older:

35 â€“ 263 mg/dL Myelin Associated Glycoprotein (MAG) Antibody, IgM Less than 1000 TU An elevated IgM antibody concentration greater than 999 TU against myelin-associated glycoprotein (MAG) suggests active demyelination in peripheral neuropathy. A normal concentration (less than 999 TU) generally rules out an anti-MAG antibody-associated peripheral neuropathy. TU= Titer Units Sulfate-3 Glucuronyl Paragloboside (SGPG) Antibody, IgM Less than 1.00 IV The majority of sulfate-3-glucuronyl paragloboside (SGPG) IgM-positive sera will show reactivity against MAG. Patients who are SGPG IgM positive and MAG IgM negative may have multi-focal motor neuropathy with conduction block.

CED

Mountain Cedar, IgE

82668




Reference Values: Class IgE kU/L Interpretation Current as of August 23, 2017 7:11 am CDT


Page 1440

0

Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MOUS

Mouse Epithelium, IgE

82707





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 1441


MOSP

Mouse Serum Protein, IgE

82792





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MOUP

Mouse Urine Protein, IgE

82795

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and



Page 1442

clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MPLB

MPL Exon 10 Mutation Detection, Blood

89776

Clinical Information: DNA sequence mutations in exon 10 of the myeloproliferative leukemia virus oncogene (MPL) have been detected in approximately 5% of patients with primary myelofibrosis (PMF) and essential thrombocythemia (ET), which are hematopoietic neoplasms classified within the broad category of myeloproliferative neoplasms. MPL codes for a transmembrane tyrosine kinase and the most common MPL mutations are single base pair substitutions at codon 515. These mutations have been shown to promote constitutive, cytokine-independent activation of the JAK/STAT signaling pathway and contribute to the oncogenic phenotype. At least 8 different MPL exon 10 mutations have been identified in PMF and ET to date, and mutations outside of exon 10 have not yet been reported. The vast majority of MPL mutations have been found in specimens testing negative for the most common mutation identified in myeloproliferative neoplasms, JAK2 V716F, although a small number of cases with both types of mutations have been reported. MPL mutations have not been identified in patients with polycythemia vera, chronic myelogenous leukemia, or other myeloid neoplasms. Identification of MPL mutations can aid in the diagnosis of a myeloproliferative neoplasm and is highly suggestive of either PMF or ET.

Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm in blood specimens

Interpretation: The results will be reported as 1 of 2 states: -Negative for MPL exon 10 mutation -Positive for MPL exon 10 mutation If the result is positive, a description of the mutation at the nucleotide level and the altered protein sequence is reported. Positive mutation status is highly suggestive of a Current as of August 23, 2017 7:11 am CDT


Page 1443

myeloproliferative neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative or other neoplasm.


Clinical References: 1. Pikman Y, Lee BH, Mercher T, et al: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. FLoS Med 2006;3:e270 2. Pardanani A, Levine R, Lasho T, et al: MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;15:3472 3. Kilpivaara O, Levine RL: JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. Leukemia 2008;22:1813-1817

MPLM

MPL Exon 10 Mutation Detection, Bone Marrow

60024


Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm in bone marrow specimens

Interpretation: The results will be reported as 1 of 2 states: -Negative for MPL exon 10 mutation -Positive for MPL exon 10 mutation If the result is positive, a description of the mutation at the nucleotide level and the altered protein sequence is reported. Positive mutation status is highly suggestive of a myeloproliferative neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative or other neoplasm.



MPLR

MPL Exon 10 Mutation Detection, Reflex

36682

Clinical Information: The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Signaling via JAK2 activation causes phosphorylation of downstream signal transducers and activators of transcription (STAT) proteins (eg, STAT5) ultimately leading to cell growth and differentiation. BCR-ABL1-negative myeloproliferative neoplasms (MPN) frequently harbor an acquired single nucleotide mutation in JAK2 characterized as c.G1849T; p. Val617Phe (V617F). The JAK2 V617F is present in 95% to 98% of polycythemia vera



Page 1444

(PV), and 50% to 60% of primary myelofibrosis (PMF) and essential thrombocythemia (ET). It has also been described infrequently in other myeloid neoplasms, including chronic myelomonocytic leukemia and myelodysplastic syndrome. Detection of the JAK2 V617F is useful to help establish the diagnosis of MPN. However, a negative JAK2 V617F result does not indicate the absence of MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutation (20%-30% of PMF and ET) and MPL exon 10 mutation (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2, CALR, and MPL are essentially mutually exclusive. A CALR mutation is associated with decreased risk of thrombosis in both ET and PMF, and confers a favorable clinical outcome in PMF patients. A triple negative (JAK2 V617F, CALR, and MPL-negative) genotype is considered a high-risk molecular signature in PMF.

Useful For: Aiding in the distinction between a reactive cytosis and a chronic myeloproliferative disorder Evaluates for mutations in MPL in an algorithmic process for the MPNR / Myeloproliverative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL.

Interpretation: An interpretation will be provided under the MPNR / Myeloproliferative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL.

Reference Values: Only orderable as a reflex. For more information see MPNR / Myeloproliferative Neoplasm (MPN), JAK2 V617F with reflex to CALR and MPL. An interpretive report will be provided.

MPLVA

MPL Exon 10 Mutation Detection, Varies

61746


Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm Interpretation: The results will be reported as 1 of 2 states: -Negative for MPL exon 10 mutation -Positive for MPL exon 10 mutation If the result is positive, a description of the mutation at the nucleotide level and the altered protein sequence is reported. Positive mutation status is highly suggestive of a myeloproliferative neoplasm, but must be correlated with clinical and other laboratory features for a definitive diagnosis. Negative mutation status does not exclude the presence of a myeloproliferative or other neoplasm.





Page 1445

MPNML

MPL Exon 10 Sequencing, Reflex

44179

Clinical Information: JAK2 V617F mutation is present in 95% to 98% of polycythemia vera (PV), and 50% to 60% of primary myelofibrosis (PMF) and essential thrombocythemia (ET). Detection of the JAK2 V617F is useful to help establish the diagnosis of a myeloproliferative neoplasm (MPN). However, a negative JAK2 V617F result does not indicate the absence of MPN. Other important molecular markers in BCR-ABL1-negative MPN include CALR exon 9 mutations (20%-30% of PMF and ET) and MPL exon 10 mutations (5%-10% of PMF and 3%-5% of ET). Mutations in JAK2, CALR, and MPL are essentially mutually exclusive. A CALR mutation is associated with decreased risk of thrombosis in both ET and PMF, and confers a favorable clinical outcome in PMF patients. A triple negative (JAK2 V617F, CALR, and MPL-negative) genotype is considered a high-risk molecular signature in PMF.

Useful For: Aiding in the distinction between a reactive cytosis and a myeloproliferative neoplasm when JAK2V617F testing result is negative. Evaluates for mutations in MPL in an algorithmic process for the MPNCM / MPN (CALR, MPL) Reflex.

Interpretation: The results will be reported as 1 of the 3 following states: -Positive for CALR mutation -Positive for MPL mutation -Negative for CALR and MPL mutations Positive mutation status is highly suggestive of a myeloid neoplasm and clinicopathologic correlation is necessary in all cases. Negative mutation status does not exclude the presence of a myeloproliferative neoplasm or other neoplasms.

Reference Values: Only orderable as a reflex. For more information see MPNCM / Myeloproliferative Neoplasm (MPN), CALR with Reflex to MPL. An interpretive report will be provided.

Clinical References: 1. Klampfl T, Gisslinger H, Harutyunyan AS, et al: Somatic mutation of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-2390 2. Nangalia J, Massie CE, Baxter EJ, et al: Somatic CALR mutation in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-2405 3. Rotunno G, Mannarelli C, Guglielmelli P, et al: Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2014;123:1552-1555 4. Tefferi A, Lasho TL, Finke CM, et al: CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia advance online publication 21 January 2014 5. Pikman Y, Lee BH, Mercher T, et al: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. FLoS Med 2006;3:e270 6. Pardanani A, Levine R, Lasho T, et al: MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006;15:3472

MSH2I

MSH-2, Immunostain (Bill Only)

35508


MSH6I

MSH-6, Immunostain (Bill Only)

35511


MSH2Z

MSH2 Gene, Full Gene Analysis

35510

Clinical Information: Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or



Page 1446

HNPCC) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene have also been associated with Lynch syndrome, as this leads to inactivation of the MSH2 promoter. Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer-associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome-related genes. The lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are G and del6.4kb

35482

Clinical Information: Mucolipidosis IV is a lysosomal storage disease characterized by mental retardation, hypotonia, corneal clouding, and retinal degeneration. Mutations in the MCOLN1 gene are responsible for the clinical manifestations of mucolipidosis IV. The carrier rate in the Ashkenazi Jewish population is 1 in 127. Two mutations in the MCOLN1 gene account for the majority of mutations in the Ashkenazi Jewish population: IVS3(-2)A->G and del6.4kb. The detection rate for these 2 mutations is approximately 95%.

Useful For: Carrier testing for mucolipidosis IV in individuals of Ashkenazi Jewish ancestry Prenatal diagnosis of mucolipidosis IV for at-risk pregnancies Confirmation of suspected clinical diagnosis of mucolipidosis IV in individuals of Ashkenazi Jewish ancestry


Clinical References: 1. Gross SJ, Pletcher BA, Monaghan KG: Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008 Jan;10(1):54-56 2. Bach G: Mucolipidosis type IV. Mol Genet Metab 2001;73(3):197-203

MQLNR

Mucopolysaccharides (MPS) Qualitative, Urine

38000

Clinical Information: The qualitative urine mucopolysaccharides (MPS) screen provides analysis of the specific sulfates via liquid chromatography-tandem mass spectrometry that are associated with at least 13 different diseases.

Useful For: Screening for mucopolysaccharidosis (MPS) Interpretation: The pattern of sulfates obtained by liquid chromatography-tandem mass spectrometry is usually characteristic of the enzyme deficiency. When abnormal results are detected with characteristic patterns, a detailed interpretation is given, including an overview of the results and their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and in vitro confirmatory studies (enzyme assay and molecular test).



Page 1451

Only orderable as part of a profile. See LYSDU / Lysosomal Storage Disorders Screen, Urine. For information regarding qualitative mucopolysaccharides, see MPSSC / Mucopolysaccharides (MPS) Screen, Urine.

MPSSC

Mucopolysaccharides (MPS) Screen, Urine

84464

Clinical Information: The mucopolysaccharidoses (MPSs) are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAGs). Undegraded or partially degraded GAGs (also called mucopolysaccharides) are stored in lysosomes and excreted in the urine. Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders. There are 11 known enzyme deficiencies that result in MPS. In addition, abnormal GAG storage is observed in multiple sulfatase deficiency and in I-cell disease. Finally, an abnormal excretion of GAGs in urine is observed occasionally in other disorders including active bone diseases, connective tissue disease, hypothyroidism, urinary dysfunction, and oligosaccharidoses. MPS are autosomal recessive disorders with the exception of MPS II, which follows an X-linked inheritance pattern. Affected individuals typically experience a period of normal growth and development followed by progressive disease involvement encompassing multiple systems. The severity and features vary and may include facial coarsening, organomegaly, skeletal changes, cardiac abnormalities, and developmental delays. Moreover, disease presentation varies from as early as late infancy to adulthood. A diagnostic workup for individuals with suspected MPS should begin with MPSSC / Mucopolysaccharides (MPS) Screen, Urine, which includes both the quantitative analysis of total GAGs and qualitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the specific sulfates. Interpretation is based upon pattern recognition of the specific sulfates detected by MS/MS and the qualitative analysis of their relative amounts of excretion. However, an abnormal MPS analysis is not sufficient to conclusively establish a specific diagnosis. It is strongly recommended to seek confirmation by an independent method, typically in vitro enzyme assay (available in either blood or cultured fibroblasts from a skin biopsy) and/or molecular analysis. After a specific diagnosis has been established, MPSQN / Mucopolysaccharides (MPS), Quantitative, Urine, which does not include the analysis of the specific sulfates, can be appropriate for monitoring the effectiveness of treatment, such as a bone marrow transplant or enzyme replacement therapy. However, some clinicians will opt to perform the MPS screen, which allows for monitoring of not only the total amount of GAGs, but also the excretion of specific sulfates, as these may change in patients with an MPS disorder undergoing treatment. Table: Enzyme Defects and Excretion Products of Mucopolysaccaridoses Disorder Alias Enzyme Deficiency (Mayo Medical Laboratories' Test, if applicable) Sulfates Excreted MPS I Hurler/Scheie alpha-L-iduronidase (IDST, IDSWB, IDSBS) DS/HS MPS II Hunter Iduronate 2-sulfatase (I2SW, I2SBS) DS/HS MPS III A Sanfilippo A Heparan N-sulfatase HS MPS III B Sanfilippo B N-acetyl-alpha-D-glucosaminidase (ANAS) HS MPS III C Sanfilippo C Acetyl-CoA:alpha-glucosaminide N-acetyltransferase HS MPS III D Sanfilippo D N-acetylglucosamine-6-sulfatase HS MPS IV A Morquio A Galactosamine-6-sulfatase (G6ST) KS/C6S MPS IV B Morquio B beta-galactosidase (BGAT, BGA, BGAW, BGABS) KS MPS VI Maroteaux-Lamy Arylsulfatase B (ARSB) DS MPS IX Hyaluronidase deficiency Hyaluronidase None KEY: C6S, chondroitin 6-sulfate; DS, dermatan sulfate; HS, heparan sulfate; KS, keratan sulfate MPS I (Hurler/Scheie syndrome) is caused by a reduced or absent activity of the alpha-L-iduronidase enzyme. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. This enzyme deficiency results in a wide range of clinical phenotypes that are further categorized into 3 phenotypes: MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), which cannot be distinguished via biochemical methods. Clinically, they are also referred to as MPS I and attenuated MPS I. MPS IH is the most severe and has an early onset consisting of skeletal deformities, coarse facial features, hepatosplenomegaly, macrocephaly, cardiomyopathy, hearing loss, macroglossia, and respiratory tract infections. Developmental delay is noticed as early as 12 months with death occurring usually before 10 years of age. MPS IH/S has an intermediate clinical presentation characterized by progressive skeletal symptoms called dysostosis multiplex. Individuals typically have little or no intellectual dysfunction. Corneal clouding, joint stiffness, deafness, and valvular heart disease can develop by early to mid-teens. Survival into adulthood is common. Cause of death usually results from cardiac complications or upper



Page 1452

airway obstruction. Comparatively, MPS IS presents with the mildest phenotype. The onset occurs after 5 years of age. It is characterized by normal intelligence and stature; however, affected individuals do experience joint involvement, visual impairment, and obstructive airway disease. MPS II (Hunter syndrome) is caused by a reduced or absent activity of the enzyme iduronate 2-sulfatase. The clinical features and severity of symptoms of MPS II are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. The clinical presentation of MPS II is similar to that of MPS I with the notable difference of the lack of corneal clouding in MPS II. The inheritance pattern is X-linked and as such MPS II is observed almost exclusively in males with an estimated incidence of 1 in 170,000 male births. Symptomatic carrier females have been reported, but are very rare. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. MPS III (Sanfilippo syndrome) is caused by a reduced or absent activity of 1 of 4 enzymes (see Table above), resulting in a defect of heparan sulfate degradation. Patients with MPS III uniformly excrete heparan sulfate resulting in similar clinical phenotypes, and are further classified as type A, B, C, or D based upon the specific enzyme deficiency. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPS. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s. The occurrence of MPS III varies by subtype with types A and B being the most common and types C and D being very rare. The collective incidence is approximately 1 in 58,000 live births. MPS IVA (Morquio A syndrome) is caused by a reduced or absent N-acetylgalactosamine-6-sulfate sulfatase. Clinical features and severity of symptoms of MPS IVA are widely variable, but may include skeletal dysplasia, short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal. Estimates of the incidence of MPS IVA syndrome range from 1 in 200,000 to 1 in 300,000 live births. Treatment with enzyme replacement therapy is available. MPS IVB (Morquio B syndrome) is caused by a reduced or absent beta-galactosidase activity, which gives rise to the physical manifestations of the disease. Clinical features and severity of symptoms of MPS IVB are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, but no neurological involvement. The incidence of MPS IVB is estimated to be about 1 in 250,000 live births. Treatment options are limited to symptomatic management. MPS VI (Maroteaux-Lamy syndrome) is caused by a deficiency of the enzyme arylsulfatase B. Clinical features and severity of symptoms are widely variable, but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, claw-hand deformities, carpal tunnel syndrome, hepatosplenomegaly, corneal clouding, and cardiac defects. Intelligence is usually normal. Estimates of the incidence of MPS VI range from 1 in 200,000 to 1 in 300,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. MPS VII (Sly syndrome) is caused by a deficiency of the enzyme beta-glucuronidase. The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function. Likewise, the age of onset is variable ranging from prenatal to adulthood. MPS VII is extremely rare, affecting approximately 1 in 1,500,000 individuals. MPS IX is a very rare disorder caused by a deficiency of the enzyme hyaluronidase. Patients present with short stature, flat nasal bridge, and joint findings. Urine GAGs are normal in MPS IX. Multiple sulfatase deficiency (MSD) is an autosomal recessive disorder caused by mutations in the sulfatase-modifying factor-1 gene (SUMF1). Sulfatases undergo a common process that allows for normal expression of enzyme activity. Mutations in SUMF1 impair that process, thereby resulting in decreased activity of all known sulfatase enzymes. Individuals with MSD have a complex clinical presentation encompassing features of each of the distinct enzyme deficiencies, including iduronate 2-sulfatase (MPS II), N-acetylgalactosamine-6-sulfate sulfatase (MPS IVA), arylsulfatase B (MPS VI), and arylsulfatase A (metachromatic leukodystrophy), steroid sulfatase (X-linked ichthyosis) and arylsulfatase F (chondrodysplasia punctata). MSD is extremely rare, affecting approximately 1 in 1,400,000 individuals.

Useful For: Preferred screening test for mucopolysaccharidoses Current as of August 23, 2017 7:11 am CDT


Page 1453

Interpretation: An abnormally elevated excretion of glycosaminoglycans is characteristic of mucopolysaccharidoses. The pattern of sulfates obtained by liquid chromatography-tandem mass spectrometry (LC-MS/MS) is usually characteristic of the enzyme deficiency. When abnormal results are detected with characteristic patterns, a detailed interpretation is given, including an overview of the results and their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing, and in vitro confirmatory studies (enzyme assay and molecular test).

Reference Values: MPS, QUANTITATIVE 0-4 months: < or =53.0 mg/mmol creatinine 5-18 months: < or =31.0 mg/mmol creatinine 19 months-2 years: < or =24.0 mg/mmol creatinine 3-5 years: < or =16.0 mg/mmol creatinine 6-10 years: < or =12.0 mg/mmol creatinine 11-14 years: < or =10.0 mg/mmol creatinine >14 years: < or =6.5 mg/mmol creatinine MPS, QUALITATIVE An interpretive report will be provided.

Clinical References: Neufeld EF, Muenzer J: Chapter 136: The mucopolysaccharidoses. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, NY: McGraw-Hill; 2014. Accessed February 12, 2016. Available at http://ommbid.mhmedical.com/content.aspx?sectionid=62642135&bookid=971&Resultclick=2&q=The+ Mucopolysaccharidoses

MPSQN

Mucopolysaccharides (MPS), Quantitative, Urine

81473

Clinical Information: The mucopolysaccharidoses (MPS) are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans; GAGs). Undegraded or partially degraded GAGs (also called mucopolysaccharides) are stored in lysosomes and excreted in the urine. Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders. There are 11 known enzyme deficiencies that result in MPS. In addition, abnormal GAG storage is observed in multiple sulfatase deficiency and in I-cell disease. Finally, an abnormal excretion of GAGs in urine is observed occasionally in other disorders including active bone diseases, connective tissue disease, hypothyroidism, urinary dysfunction, and oligosaccharidoses. MPS are autosomal recessive disorders with the exception of MPS II, which follows an X-linked inheritance pattern. Affected individuals typically experience a period of normal growth and development followed by progressive disease involvement encompassing multiple systems. The severity and features vary, and may include facial coarsening, organomegaly, skeletal changes, cardiac abnormalities, and developmental delays. Moreover, disease presentation varies from as early as late infancy to adulthood. Additional information regarding individual disorders can be found under test MPSSC / Mucopolysaccharides (MPS) Screen, Urine. A diagnostic workup for individuals with suspected MPS should begin with MPSSC / Mucopolysaccharides (MPS) Screen, Urine, which includes both the quantitative analysis of total GAGs and qualitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the specific sulfates. Interpretation is based upon pattern recognition of the specific sulfates detected by MS/MS and the qualitative analysis of their relative amounts of excretion. However, an abnormal MPS analysis is not sufficient to conclusively establish a specific diagnosis. It is strongly recommended to seek confirmation by an independent method, typically in vitro enzyme assay (available in either blood or cultured fibroblasts from a skin biopsy) or molecular analysis. After a specific diagnosis has been established, MPSQN / Mucopolysaccharides (MPS), Quantitative, Urine, which does not include the analysis of the specific sulfates, can be appropriate for monitoring the effectiveness of treatment, such as a bone marrow transplant or enzyme replacement therapy. However, some clinicians will opt to perform the MPS screen, which allows for monitoring of not only the total amount of GAGs, but also the excretion of specific sulfates, as these may change in patients with an MPS disorder



Page 1454

undergoing treatment. Table: Enzyme Defects and Excretion Products of Mucopolysaccaridoses Disorder Alias Enzyme Deficiency (Mayo Medical Laboratories' Test, if applicable) Sulfate(s) Excreted MPS I Hurler/Scheie alpha-L-iduronidase (IDST, IDSWB, IDSBS) DS/HS MPS II Hunter Iduronate 2-sulfatase (I2SW, I2SBS) DS/HS MPS III A Sanfilippo A Heparan N-sulfatase HS MPS III B Sanfilippo B N-acetyl-alpha-D-glucosaminidase (ANAS) HS MPS III C Sanfilippo C Acetyl-CoA:alpha-glucosaminide N-acetyltransferase HS MPS III D Sanfilippo D N-acetylglucosamine-6-sulfatase HS MPS IV A Morquio A Galactosamine-6-sulfatase (G6ST) KS/C6S MPS IV B Morquio B beta-galactosidase (BGAT, BGA, BGAW, BGABS) KS MPS VI Maroteaux-Lamy Arylsulfatase B (ARSB) DS MPS IX Hyaluronidase deficiency Hyaluronidase None C6S, chondroitin 6-sulfate; DS, dermatan sulfate; HS, heparan sulfate; KS, keratan sulfate MPS I (Hurler/Scheie syndrome) is caused by a reduced or absent activity of the alpha-L-iduronidase enzyme. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. This enzyme deficiency results in a wide range of clinical phenotypes that are further categorized into 3 phenotypes: MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), which cannot be distinguished via biochemical methods. Clinically, they are also referred to as MPS I and attenuated MPS I. MPS IH is the most severe and has an early onset consisting of skeletal deformities, coarse facial features, hepatosplenomegaly, macrocephaly, cardiomyopathy, hearing loss, macroglossia, and respiratory tract infections. Developmental delay is noticed as early as 12 months with death occurring usually before 10 years of age. MPS IH/S has an intermediate clinical presentation characterized by progressive skeletal symptoms called dysostosis multiplex. Individuals typically have little or no intellectual dysfunction. Corneal clouding, joint stiffness, deafness, and valvular heart disease can develop by early to midteens. Survival into adulthood is common. Cause of death usually results from cardiac complications or upper airway obstruction. Comparatively, MPS IS presents with the mildest phenotype. The onset occurs after 5 years of age. It is characterized by normal intelligence and stature; however, affected individuals do experience joint involvement, visual impairment, and obstructive airway disease. MPS II (Hunter syndrome) is caused by a reduced or absent activity of the enzyme iduronate 2-sulfatase. The clinical features and severity of symptoms of MPS II are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. The clinical presentation of MPS II is similar to that of MPS I with the notable difference of the lack of corneal clouding in MPS II. The inheritance pattern is X-linked and as such MPS II is observed almost exclusively in males with an estimated incidence of 1 in 170,000 male births. Symptomatic carrier females have been reported, but are very rare. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. MPS III (Sanfilippo syndrome) is caused by a reduced or absent activity of 1 of 4 enzymes (see Table above), resulting in a defect of heparan sulfate degradation. Patients with MPS III uniformly excrete heparan sulfate resulting in similar clinical phenotypes, and are further classified as type A, B, C, or D based upon the specific enzyme deficiency. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPSs. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s. The occurrence of MPS III varies by subtype with types A and B being the most common and types C and D being very rare. The collective incidence is approximately 1 in 58,000 live births. MPS IVA (Morquio A syndrome) is caused by a reduced or absent N-acetylgalactosamine-6-sulfate sulfatase. Clinical features and severity of symptoms of MPS IVA are widely variable, but may include skeletal dysplasia, short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal. Estimates of the incidence of MPS IVA syndrome range from 1 in 200,000 to 1 in 300,000 live births. Treatment with enzyme replacement therapy is available. MPS IVB (Morquio B syndrome) is caused by a reduced or absent beta-galactosidase activity, which gives rise to the physical manifestations of the disease. Clinical features and severity of symptoms of MPS IVB are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, but no neurological involvement. The incidence of MPS IVB is estimated to be about 1 in 250,000 live births. Treatment options are limited to symptomatic management. MPS VI (Maroteaux-Lamy syndrome) is caused by a deficiency of the enzyme arylsulfatase B. Clinical features Current as of August 23, 2017 7:11 am CDT


Page 1455

and severity of symptoms are widely variable, but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, claw-hand deformities, carpal tunnel syndrome, hepatosplenomegaly, corneal clouding, and cardiac defects. Intelligence is usually normal. Estimates of the incidence of MPS VI range from 1 in 200,000 to 1 in 300,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. MPS VII (Sly syndrome) is caused by a deficiency of the enzyme beta-glucuronidase. The phenotype varies significantly from mild to severe presentations and may include macrocephaly, short stature, dysostosis multiplex, hepatomegaly, coarse facies, and impairment of cognitive function. Likewise, the age of onset is variable ranging from prenatal to adulthood. MPS VII is extremely rare, affecting approximately 1 in 1,500,000 individuals. MPS IX is a very rare disorder caused by a deficiency of the enzyme hyaluronidase. Patients present with short stature, flat nasal bridge, and joint findings. Urine GAGs are normal in MPS IX. Multiple sulfatase deficiency (MSD) is an autosomal recessive disorder caused by mutations in the sulfatase-modifying factor-1 gene (SUMF1). Sulfatases undergo a common process that allows for normal expression of enzyme activity. Mutations in SUMF1 impair that process, thereby resulting in decreased activity of all known sulfatase enzymes. Individuals with MSD have a complex clinical presentation encompassing features of each of the distinct enzyme deficiencies, including iduronate 2-sulfatase (MPS II), N-acetylgalactosamine-6-sulfate sulfatase (MPS IVA), arylsulfatase B (MPS VI), and arylsulfatase A (metachromatic leukodystrophy), steroid sulfatase (X-linked ichthyosis) and arylsulfatase The preferred test to screen for mucopolysaccharides (MPS) is MPSSC / Mucopolysaccharides (MPS) Screen, Urine, which includes both the quantitative analysis of total glycosaminoglycans and qualitative liquid chromatography-tandem mass spectrometry analysis of the specific sulfates. F (chondrodysplasia punctata). MSD is extremely rare, affecting approximately 1 in 1,400,000 individuals.

Useful For: Monitoring patients with mucopolysaccharidosis who have had bone marrow transplants or are receiving enzyme therapy

Interpretation: An abnormally elevated excretion of glycosaminoglycan (GAG) is characteristic of mucopolysaccharidoses. GAG levels may normalize or remain elevated in patients who have undergone bone marrow transplants or are receiving enzyme replacement therapy.

Reference Values: 0-4 months: < or =53.0 mg/mmol creatinine 5-18 months: < or =31.0 mg/mmol creatinine 19 months-2 years: < or =24.0 mg/mmol creatinine 3-5 years: < or =16.0 mg/mmol creatinine 6-10 years: < or =12.0 mg/mmol creatinine 11-14 years: < or =10.0 mg/mmol creatinine >14 years: < or =6.5 mg/mmol creatinine

Clinical References: Neufeld EF, Muenzer J: Chapter 136: The mucopolysaccharidoses. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, NY: McGraw-Hill; 2014. Accessed February 12, 2016. Available at: http://ommbid.mhmedical.com/content.aspx?sectionid=62642135&bookid=971&Resultclick=2&q=The+ Mucopolysaccharidoses

MQNNR

Mucopolysaccharides (MPS), Quantitative, Urine

37999

Clinical Information: The quantitative urine mucopolysaccharides (MPS) screen provides value for total glycosaminoglycan (GAG)s. This test can be used to monitor patients with mucopolysaccharidosis who have had bone marrow transplants or are receiving enzyme therapy.

Useful For: Monitoring patients with mucopolysaccharidosis who have had bone marrow transplants or are receiving enzyme therapy

Interpretation: An abnormally elevated excretion of glycosaminoglycan (GAG) is characteristic of mucopolysaccharidoses. GAG levels may normalize or remain elevated in patients who have undergone bone marrow transplants or are receiving enzyme replacement therapy.



Page 1456

Only orderable as part of a profile. See LYSDU / Lysosomal Storage Disorders Screen, Urine. For information regarding quantitative mucopolysaccharides, see MPSQN / Mucopolysaccharides (MPS), Quantitative, Urine.

SFPAN

Mucopolysaccharidosis III, Multi-Gene Panel

62576

Clinical Information: Mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome, is an autosomal recessive condition that consists of 4 different types (A, B, C, and D). Each type of MPS-III results from the absence of 1 of 4 lysosomal enzymes, which leads to the accumulation of heparan sulfate in various tissues. Sanfilippo syndrome A is caused by mutations in SGSH and is characterized by reduced or absent activity of the sulfamidase enzyme. Sanfilippo syndrome B is caused by mutations in NAGLU and is characterized by reduced or absent activity of the N-acetyl-alpha-D-glucosaminidase. Sanfilippo syndrome C is caused by mutations in HGSNAT and is characterized by reduced or absent activity of the acetyl-CoA:alpha-glucosaminide N-acetyltransferase enzyme. Sanfilippo syndrome D is caused by mutations in GNS and is characterized by reduced or absent activity of the N-acetylglucosamine-6-sulfatase enzyme. Sanfilippo syndrome presents with a spectrum of central nervous system degeneration and physical disease. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years, accompanied by a rapid deterioration of social and adaptive skills.

Useful For: Identifying mutations within the SGSH, NAGLU, HGSNAT, and GNS genes Confirmation of a diagnosis of mucopolysaccharidosis type III, also known as Sanfilippo syndrome

Interpretation: All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17(5):405-24 2. Ruijter GJ, Valstar MJ, van de Kamp JM, et al: Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol Genet Metab 2008;93(2):104-111 3. Valstar MJ, Ruijter GJ, van Diggelen OP, et al: Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31(2):240-252 4. Yogalingam G, Hopwood JJ: Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001;18(4):264-281

MP3AZ

Mucopolysaccharidosis IIIA, Full Gene Analysis

35502

Clinical Information: Mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome, is an autosomal recessive condition that consists of 4 different types (A, B, C, and D). Each type of MPS-III results from the absence of 1 of 4 lysosomal enzymes, which leads to the lysosomal accumulation of heparan sulfatase. Mucopolysaccharidosis type IIIA (MPS-IIIA), or Sanfilippo syndrome A, is caused by mutations in the SGSH gene and is characterized by reduced or absent activity of the sulfamidase enzyme. This test screens for mutations in all 8 exons of the SGSH gene. Sanfilippo syndrome is characterized by severe central nervous system degeneration with only mild physical disease. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s.

Useful For: Identifying mutations within the SGSH gene Confirmation of a diagnosis of Current as of August 23, 2017 7:11 am CDT


Page 1457

mucopolysaccharidosis type IIIA Carrier testing, when there is a family history of mucopolysaccharidosis type IIIA, but disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 2. Valstar MJ, Neijs S, Bruggenwirth HT, et al: Mucopolysaccharidosis type IIIA: clinical spectrum and genotype-phenotype correlations. Ann Neurol 2010;68(6):876-887 3. Yogalingam G, Hopwood JJ: Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001;18(4):264-281

MP3BZ

Mucopolysaccharidosis IIIB, Full Gene Analysis

35504

Clinical Information: Mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome, is an autosomal recessive condition that consists of 4 different types (A, B, C, and D). Each type of MPS-III results from the absence of 1 of 4 lysosomal enzymes, which leads to the lysosomal accumulation of heparan sulfatase. Mucopolysaccharidosis type IIIB (MPS-IIIB), or Sanfilippo syndrome B, is caused by mutations in the NAGLU gene and is characterized by reduced or absent activity of the N-acetyl-alpha-D-glucosaminidase. This test screens for mutations in all 6 exons of the NAGLU gene. Sanfilippo syndrome is characterized by severe central nervous system degeneration with only mild physical disease. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s.

Useful For: Identifying mutations within the NAGLU gene Confirmation of a diagnosis of mucopolysaccharidosis type IIIB Carrier testing, when there is a family history of mucopolysaccharidosis type IIIB, but disease-causing mutations have not been previously identified

Interpretation: All detected alterations will be evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Valstar MJ, Ruijter GJ, van Diggelen OP, et al: Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31(2):240-252 3. Yogalingam G, Hopwood JJ: Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat 2001;18(4):264-281

MP3CZ

Mucopolysaccharidosis IIIC, Full Gene Analysis

35678

Clinical Information: Mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome, is an autosomal recessive condition that consists of 4 different types (A, B, C, and D). Each type of MPS-III results from the absence of 1 of 4 lysosomal enzymes, which leads to the lysosomal accumulation of heparan sulfate. Mucopolysaccharidosis type IIIC (MPS-IIIC), or Sanfilippo syndrome C, is caused by mutations in the HGSNAT gene and is characterized by reduced or absent activity of the heparin acetyl-CoA:alpha-glucosaminide N-acetyltransferase enzyme. This test screens for mutations in



Page 1458

all 18 exons of the HGSNAT gene. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration with only mild physical disease. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s.

Useful For: Identifying mutations within the HGSNAT gene Confirmation of a diagnosis of mucopolysaccharidosis type IIIC Carrier testing, when there is a family history of mucopolysaccharidosis type IIIC, but disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 2. Ruijter GJ, Valstar MJ, van de Kamp JM, et al: Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol Genet Metab 2008;93(2):104-111 3. Valstar MJ, Ruijter GJ, van Diggelen OP, et al: Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31(2):240-252

MP3DZ

Mucopolysaccharidosis IIID, Full Gene Analysis

35728

Clinical Information: Mucopolysaccharidosis type III (MPS-III), also known as Sanfilippo syndrome, is an autosomal recessive condition that consists of 4 different types (A, B, C, and D). Each type of MPS-III results from the absence of 1 of 4 lysosomal enzymes, which leads to the lysosomal accumulation of heparan sulfate. Mucopolysaccharidosis type IIID (MPS-IIID), or Sanfilippo syndrome D, is caused by mutations in the GNS gene and is characterized by reduced or absent activity of the N-acetylglucosamine-6-sulfatase enzyme. This test screens for mutations in all 14 exons of the GNS gene. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration with only mild physical disease. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years, accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s.

Useful For: Identifying mutations within the GNS gene Confirmation of a diagnosis of mucopolysaccharidosis type IIID Carrier testing when there is a family history of mucopolysaccharidosis type IIID, but disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 2. Jansen AC, Cao H, Kaplan P, et al: Sanfilippo syndrome type D: natural history and identification of 3 novel mutations in the GNS Gene. Arch Neurol 2007;64(11):1629-1634 3. Valstar MJ, Ruijter GJ, van Diggelen OP, et al: Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 2008;31(2):240-252



Page 1459

MPS6Z

Mucopolysaccharidosis VI, Full Gene Analysis

35507

Clinical Information: Mucopolysaccharidosis type VI (MPS-VI), also known as Maroteaux-Lamy syndrome, is an autosomal recessive condition that is caused by mutations in the ARSB gene and is characterized by reduced or absent activity of the arylsulfatase B enzyme. This test screens for mutations in all 8 exons of the ARSB gene. The clinical features and severity of symptoms of Maroteaux-Lamy are widely variable. Typically it is characterized by short stature, dysostosis multiplex, facial dysmorphism, stiff joints, hepatosplenomegaly, corneal clouding, cardiac defects, and usually normal intelligence. With a rapidly progressing form of MPS-VI, onset occurs before 2 to 3 years of age with death typically occurring in the second to third decade. With a slowly progressing form of MPS-VI, a diagnosis usually occurs after 5 years of age but may not occur until the second or third decade. The recommended first-tier test for MPS-VI is biochemical testing that measures arylsulfatase B enzyme activity in fibroblasts (ARSB / Arylsulfatase B, Fibroblasts). Individuals with decreased or absent enzyme activity are more likely to have 2 identifiable mutations in the ARSB gene by molecular genetic testing. However, enzymatic testing is not reliable to detect carriers.

Useful For: Identifying mutations within the ARSB gene Confirmation of a diagnosis of mucopolysaccharidosis type VI Carrier testing, when there is a family history of mucopolysaccharidosis type VI, but disease-causing mutations have not been previously identified



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300 2. Litjens T, Hopwood JJ: Mucopolysaccharidosis type VI: Structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase. Hum Mutat 2001;18(4):282-295 3. Valayannopoulos V, Nicely H, Harmatz P, et al: Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010;5:5

MPSBS

Mucopolysaccharidosis, Blood Spot

65095

Clinical Information: The mucopolysaccharidoses (MPS) are a group of disorders caused by a deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAGs, also called mucopolysaccharides). Undegraded or partially degraded GAGs are stored in lysosomes and excreted in the urine. Accumulation of GAGs in lysosomes interferes with normal functioning of cells, tissues, and organs resulting in the clinical features observed in MPS disorders. Depending on the extent of the enzyme deficiency and type of accumulating storage material, MPS patients may present with a variety of clinical findings that can include coarse facial features, cardiac abnormalities, organomegaly, intellectual disabilities, short stature and skeletal abnormalities. MPS I is an autosomal recessive disorder caused by reduced or absent activity of the enzyme alpha-L-iduronidase due to mutations in the IDUA gene. This enzyme deficiency results in a wide range of clinical phenotypes that are further categorized as MPS IH (Hurler syndrome), MPS IS (Scheie syndrome), and MPS IH/S (Hurler-Scheie syndrome), and which cannot be distinguished via biochemical methods. Clinically, they are also referred to as MPS I and attenuated MPS I. MPS IH is the most severe and has an early onset consisting of skeletal deformities, coarse facial features, hepatosplenomegaly, macrocephaly, cardiomyopathy, hearing loss, macroglossia, and respiratory tract infections. Developmental delay is noticed as early as 12 months, and without treatment, death usually occurs before 10 years of age. MPS IH/S has an intermediate clinical presentation characterized by progressive skeletal symptoms called dysostosis multiplex. Individuals typically have little or no intellectual dysfunction. Corneal clouding, joint stiffness, deafness, and valvular heart disease can develop by early to mid-teens. Survival into adulthood is common. Comparatively, MPS IS presents with the mildest phenotype. The onset occurs after 5 years of age. It is characterized by normal intelligence and stature; however, affected individuals do experience joint involvement, visual



Page 1460

impairment, and obstructive airway disease. The incidence of MPS I is approximately 1 in 100,000 live births. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy. MPS II, Hunter syndrome is an X-linked lysosomal storage disorder caused by a reduced or absent activity of the enzyme iduronate 2-sulfatase. The clinical features and severity of symptoms of MPS II are widely variable ranging from severe disease to an attenuated form, which generally presents later in life with a milder clinical presentation. In general, symptoms may include coarse facial features, short stature, enlarged liver and spleen, hoarse voice, stiff joints, cardiac disease, and profound neurologic involvement leading to developmental delays and regression. The clinical presentation of MPS II is similar to that of MPS I with the notable difference of the lack of corneal clouding in MPS II. Due to the x-linked inheritance pattern, MPS II is observed almost exclusively in males with an estimated incidence of 1 in 170,000 male births. Symptomatic carrier females have been reported, but are very rare. Treatment options include hematopoietic stem cell transplantation and enzyme replacement therapy MPS-III, Sanfilippo syndrome is caused by a reduced or absent activity of 1 of 4 enzymes involved in heparan sulfate degradation. Patients with MPS III uniformly excrete heparan sulfate resulting in similar clinical phenotypes, and are further classified as type A, B, C, or D based upon the specific enzyme deficiency. Sanfilippo syndrome is characterized by severe central nervous system (CNS) degeneration, but only mild physical disease. Such disproportionate involvement of the CNS is unique among the MPSs. Onset of clinical features, most commonly behavioral problems and delayed development, usually occurs between 2 and 6 years in a child who previously appeared normal. Severe neurologic degeneration occurs in most patients by 6 to 10 years of age accompanied by a rapid deterioration of social and adaptive skills. Death generally occurs by the 20s. The occurrence of MPS III varies by subtype with types A and B being the most common and types C and D being very rare. The collective incidence is approximately 1 in 58,000 live births. MPS VI; Maroteaux-Lamy syndrome is an autosomal recessive lysosomal storage disorder caused by the deficiency of the enzyme arylsulfatase B. Clinical features and severity of symptoms are widely variable, but typically include short stature, dysostosis multiplex, facial dysmorphism, stiff joints, claw-hand deformities, carpal tunnel syndrome, hepatosplenomegaly, corneal clouding, and cardiac defects. Intelligence is usually normal. Rapidly progressing forms have an early onset of symptoms, significantly elevated GAGs especially dermatan sulfate, and can lead to death before the second or third decade. A more slowly progressing form has a later onset, milder skeletal manifestations, smaller elevations of GAGs, and typically a longer lifespan. Estimates of the incidence of MPS VI range from 1 in 250,000 to 1 in 300,000. Treatment options include hematopoietic stem cell transplantation and/or enzyme replacement therapy. Elevations of dermatan and/or heparan sulfate are seen MPS types I, II, III, and VI.

Useful For: Quantification of heparan sulfate and dermatan sulfate in dried blood spots can support the biochemical diagnosis of one of the mucopolysaccharidoses types I, II, III, or VI

Interpretation: Elevations of dermatan sulfate and/or heparan sulfate may be indicative of one of the mucopolysaccharidoses types I, II, III, or VI.

Reference Values: DERMATAN SULFATE (DS) Newborn-< or =2 weeks: < or =200 nmol/L >2 weeks: < or =130 nmol/L HEPARAN SULFATE (HS) Newborn-< or =2 weeks: < or =96 nmol/L >2 weeks: < or =95 nmol/L

Clinical References: 1. de Ruijter J, de Ru MH, Wagemans T, et al: Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III. Mol Genet Metab 2012;107:705-710 2. de Ru MH, van der Tol L, van Vlies N, et al: Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans. J Inherit Metab Dis 2013;36:247-255 3. Osago H, Shibata T, Hara N, et al: Quantitative analysis of glycosaminoglycans, chondroitin/dermatan sulfate, hyaluronic acid, heparan sulfate, and keratan sulfate by liquid chromatography-electrospray ionization-tandem mass spectrometry. Anal Biochem 2014;467:62-74 Current as of August 23, 2017 7:11 am CDT


Page 1461

MUC

Mucor, IgE

82675





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MUG

Mugwort, IgE

82683




Page 1462





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MULB

Mulberry, IgE

82864






Page 1463


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



MSP2

Multiple Sclerosis (MS) Profile

83305

Clinical Information: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease characterized by visual, motor, and sensory disturbances. The diagnosis of MS is dependent on clinical, radiological, and laboratory findings. The detection of increased intrathecal immunoglobulin (Ig) synthesis is the basis for current diagnostic laboratory tests for MS. These tests include the cerebrospinal fluid (CSF) IgG index and CSF oligoclonal band detection.

Useful For: Diagnosing multiple sclerosis, especially helpful in patients with equivocal clinical or radiological findings

Interpretation: Oligoclonal banding (OCB): > or =4 cerebrospinal fluid (CSF)-specific bands are consistent with multiple sclerosis (MS). CSF IgG index: >0.85 is consistent with MS. Abnormal CSF IgG indexes and OCB patterns have been reported in 70% to 80% of MS patients. If both tests are performed, at least 1 of the tests has been reported to be positive in >90% of multiple sclerosis patients. A newer methodology for OCB detection, isoelectric focusing, is utilized in this test and has been reported to be more sensitive (90%-95%). The presence of OCB or elevated CSF IgG index is unrelated to disease activity.

Reference Values: OLIGOCLONAL BANDS or =18 years: 767-1,590 mg/dL Current as of August 23, 2017 7:11 am CDT


Page 1464

Serum albumin: 3,200-4,800 mg/dL CSF IgG/albumin: 0.0-0.21 Serum IgG/albumin: 0.00-0.40 CSF IgG synthesis rate: 0-12 mg/24 hours

Clinical References: 1. Andersson M, Alvarez-Cermeno J, Bernardi G, et al: Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994 Aug;57(8):897-902 2. Tourtellotte WW, Walsh MJ, Baumhefner RW, et al: The current status of multiple sclerosis intra-blood-brain-barrier IgG synthesis. Ann NY Acad Sci 1984;436:52-67

SUMFZ

Multiple Sulfatase Deficiency, Full Gene Analysis

35559

Clinical Information: Multiple sulfatase deficiency (MSD) is a rare autosomal recessive lysosomal storage disorder (LSD) caused by mutations in the sulfatase-modifying factor 1 (SUMF1) gene. SUMF1 encodes for a formylglycine-generating enzyme (FGE) that performs a critical posttranslational modification of the catalytic residue necessary for activation of all human sulfatases. MSD is often confused for a single sulfatase deficiency because it is characterized by deficiency of all known sulfatases, which results in tissue accumulation of sulfatides, sulfated glycoaminoglycans, sphingolipids, and steroid sulfates. Indeed, the clinical phenotype encompasses symptoms of every single sulfatase deficiency, including metachromatic leukodystrophy (MLD), the mucopolysaccharidoses, X-linked ichthyosis, and chondrodysplasia punctata type I. Age of onset and clinical severity are variable and correspond with the level of residual FGE enzyme activity. A severe neonatal form of MSD closely overlaps the clinical presentation of the mucopolysaccharidoses but it is often fatal within 1 year. Late-infantile MSD (onset 0-2 years) accounts for most cases and is characterized by a clinical presentation similar to MLD. Patients show progressive cognitive and motor impairment as well as skeletal changes. More rarely, MSD presents in late childhood (juvenile-onset) with more mild symptoms and slower progression. Patients with late-infantile or juvenile-onset MSD may have less severe sulfatase deficiency. Patients with a clinical suspicion of MLD, a mucopolysaccharidosis, X-linked ichthyosis, or chondrodysplasia should be investigated for possible FGE deficiency. Urine sulfatide analysis is the recommended first tier biochemical test (CTSA / Ceramide Trihexoside/Sulfatide Accumulation in Urine Sediment, Urine). If positive, iduronate sulfatase and arylsulfatase A and B enzyme levels should be assayed and are typically decreased in patients with MSD. While enzyme replacement therapy has been used to treat a subset of single LSD, its effectiveness is not well established for patients with MSD. Therefore, confirmation or exclusion of a diagnosis of MSD has important implications for patient management as well as prognosis.

Useful For: Confirmation of multiple sulfatase deficiency for patients with clinical features Identification of SUMF1 mutation to allow for genetic testing in family members

Interpretation: All detected alterations will be evaluated according to the American College of Medical Genetics and Genomics (AMCG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Dierks T, Schlotawa L, Frese MA, et al: Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease-Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim Biophys Acta 2009 Apr;1793(4):710-725 3. Schlotawa L, Ennemann EC, Radhakrishnan K, et al: SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. Eur J Hum Genet 2011 Mar;19(3):253-261

60934

MUM-1/IRF4, Immunostain Without Interpretation



Page 1465

Clinical Information: Multiple myeloma oncogene-1 (MUM-1) is expressed in the nucleus of a subset of B cells in the light zone of the germinal center (representing late stages of B-cell differentiation), plasma cells, activated T cells, and a variety of hematolymphoid neoplasms derived from these cells. Among nonhematolymphoid neoplasms, MUM-1 expression has been reported in melanomas.

Useful For: An aid in the identification of hematolymphoid neoplasms and melanomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Choi WWL, Weisenburger DD, Greiner TC, et al: A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy. Clinical Cancer Research 2009;15:5494-5502 2. Gualco G, Weiss LW, Bacchi CE: MUM1/IRF4. A Review. Appl Immunohistochem Mol Morphol 2010;18(4):301-310 3. Hans CP, Weisenburger DD, Greiner TC, et al: Confirmation of the Molecular Classification of Diffuse Large B-Cell Lymphoma by Immunohistochemistry Using a Tissue Microarray. Blood 2004;103:275-282 4. Natkunam Y, Warnke RA, Montgomery K, et al: Analysis of MUM1/IRF4 Protein Expression Using Tissue Microarrays and Immunohistochemistry. Modern Pathology 2001;14(7):686-694

CMUMP 81435

Mumps Virus Antibodies, IgG and IgM (Separate Determinations), Spinal Fluid Clinical Information: There is only 1 serotype of mumps virus that infects humans. Mumps has been recognized since antiquity by virtue of the parotitis that is often a striking clinical feature of the disease. Generally, a trivial childhood illness, the varied presentation of mumps reflects the widespread invasion of visceral organs and central nervous system that commonly follows infection with mumps virus.

Useful For: Aiding in the diagnosis of central nervous system infection by mumps virus Interpretation: Normals: IgG: 5%) on a liver biopsy, a steatosis score >0.5 had a sensitivity of 71% and a specificity of 72% for identification of significant steatosis (2). NASH marker: In a population of 257 NAFLD patients, where 62% had at least some NASH by liver biopsy, a prediction of NASH had a sensitivity of 88% for identifying NASH and a specificity of 50% (3). Fibrosis Scoring: 0.74 = Stage F4 â€“ Cirrhosis Steatosis Grading 0.69 = S3 â€“ Marked or Severe Steatosis NASH Scoring 0.25 = N0 - Not NASH 0.50 = N1 - Borderline or probable NASH 0.75 = N 2 - NASH

Reference Values: Fibrosis Score

0.00-0.21

Steatosis Score

0.00-0.30



Page 1509

NASH Score

0.25

Alpha2-Macroglobulins, Qn

110-276 mg/dL

Haptoglobin

34-200 mg/dL

Apolioprotein A-1

Females:

116-209 mg/dL

Males:

101-178 mg/dL

Bilirubin, Total

Adults:

0.0-1.2 mg/dL

GGT

Females:

0-60 IU/L

Males:

0-65 IU/L

Females:

0-40 IU/L

Males:

0-55 IU/L

ALT (SGPT) P5P

AST (SGOT) P5P

0-40 IU/L

Cholesterol, Total

100-199 mg/dL

Glucose, Serum

65-99 mg/dL

Triglycerides

0-149 mg/dL

Limitations: NASH FibroSure is recommended for patients with suspected nonalcoholic fatty liver disease. It is not recommended for patient with other liver diseases. It is also not recommended in patients with Gilbert disease, acute hemolysis, acute viral hepatitis, drug induced hepatitis, genetic liver disease, autoimmune hepatitis and/or, extra-hepatic cholestasis. Any of these clinical situations may lead to inaccurate quantitative predictions of fibrosis.

Clinical References: 1. Ratziu V. et al. Diagnostic Value of Biochemical Markers (FibroTest) for the prediction of Liver Fibrosis in patients with Non-Alcoholic Fatty Liver Disease. BMC Gastroenterology 2006; 6:6. 2. Poynard, T. et al. The Diagnostic Value of Biomarkers (Steato Test) for the Prediction of Liver Steatosis. Comparative Hepatol. 2005; 4:10 3. Poynard, T, Ratziu, Charlotte F, et al. Diagnostic value of biochemical markers (NASH TEST) for the prediction of non alcohol steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology 2006; 6:34 doi:10.1186/1471-230X-6-34.

NKSP

Natural Killer (NK)/Natural Killer T (NKT) Cell Subset Panel

60615

Clinical Information: Natural killer (NK) cells are derived from pluripotent hematopoietic stem cell precursors, but develop independently of the thymus. They comprise a key lymphocyte subset (approximately 10%-15% of peripheral blood mononuclear cells) and are a constituent of the innate immune system, since these cells do not rearrange their germline DNA to obtain specificity. NK cells serve an important role in host defense against viral infections, as well as tumor surveillance. They are also a component of the adaptive immune response through cytokine production. NK cell functions are governed by a balance between activating receptors and inhibitory receptors. NK cells are identified by expression of different cell-surface receptors and they are not a homogeneous population.(1) In general, the most common combination of surface markers used to identify the majority of NK cells is the absence of CD3 (CD3-), along with expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity IgG Fc receptor-FcgammaRIII). However, not all NK cells express the CD56 and CD16 markers uniformly and, therefore, can be divided into subsets based on expression of these 2 molecules.(2) The



Page 1510

CD16+ CD56+/- (dim or negative) that are CD3- are referred to as cytotoxic NK cells, while the CD56+ (bright) CD16- NK cells are called regulatory or cytokine secreting NK cells.(3) These are not only phenotypically and functionally distinct subsets but also developmentally separate. The majority of human NK cells (approximately 90%) have dim expression of CD56 and moderate to high levels of CD16, as well as perforin and granzymes (2 proteins mediating cytolytic activity), and are therefore high in cytotoxic capability. The remaining minority (approximately 10%) of NK cells are the CD56(bright) cytokine-producing NK cells. Therefore, cytotoxicity and cytokine production are the major functions of NK cells. Cytotoxicity can be subdivided into (1) natural cytotoxicity directed largely toward virally infected cells or tumor cells, in the absence of prior stimulation or immunization, and (2) antibody-dependent cellular cytotoxicity (ADCC) directed against antibody-coated target cells.(4) Circulating NK cells are enriched for the CD56(dim) phenotype, while within the lymph nodes, NK cells are largely CD56(bright). This differential localization is related to the pattern of homing receptors expressed on NK cells: CD56(dim) NK cells express homing markers for inflamed peripheral sites, while CD56(bright) NK cells express receptors for secondary lymphoid organs. The majority of circulating human NK cells, which have cytotoxic function and phenotype (CD56[dim]), are CD27-, while the CD56(bright) cells are CD27+. Therefore, the absence of CD27 expression identifies cytotoxic effector cells within the mature NK cell subsets.(5) Other markers are: --NKp46 (CD335) is a marker expressed on the majority of human NK cells and is an activating receptor involved in non-major histocompatibility complex (MHC)-restricted natural NK cytotoxicity. It is expressed in all resting and activated NK cells, including the minor CD56(bright) cytokine-producing population. NKp46 is considered to be involved in tumor cell eradication in vivo. --NKG2D is an activating receptor expressed on all NK cells, as well as on natural killer T (NKT) cells. NKG2D has been described as being relevant in tumor surveillance and organ transplantation.(6) --CD69 is a marker for NK-cell activation and triggers NK-mediated cytolytic activity and sustains NK-cell activation.(7) --CD95 (Fas or APO-1) is a marker expressed on a variety of immune cells, including lymphocytes and NK cells. CD95 is involved in mediating programmed cell death or apoptosis and has been shown to associate with NK cell regulatory function in multiple sclerosis.(8) --CD107a and CD107b (lysosomal-associated membrane proteins 1 and 2: LAMP-1 and LAMP-2) expression are markers of NK cell functional activity and correlate with both cytokine production and NK-cell-mediated lysis of target cells.(9) --Perforin, granzyme A, and granzyme B are components of the cytolytic granules in NK cells and associated with NK cell cytotoxic function, while interferon gamma (IFN-gamma) is produced by NK cells on activation.(10) --NK cells also secrete other cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-3, and granulocyte monocyte-colony stimulating factor (GM-CSF). NKT cells represent a specialized T-cell population that is distinct from conventional T cells. They express an invariant T-cell receptor (TCR) that recognizes self and bacterial glycosphingolipid antigens presented by the MHC class I-like molecule, CD1d.(11) The development of NKT cells is also unique from regular T cells, as NKT cell precursors are positively selected by CD4+CD8+ cortical thymocytes and the signaling pathways differ from the conventional T cells. Activated NKT cells rapidly produce large amounts of Th1 and Th2 cytokines that transactivate other immune components and, therefore, NKT cells are involved in both innate and adaptive immune responses.(11) NK cell deficiencies can be present as part of a larger immunological syndrome or as an isolated deficiency. Some of the primary (monogenic) immunodeficiencies that affect NK cell function or numbers include autoimmune lymphoproliferative syndrome (ALPS) related to CASP8 (caspase 8 mutations); familial hemophagocytic lymphohistiocytosis (FHL) types 2, 3, and 4 due to mutations in the PFP1 (encoding perforin), UNC13D (encoding the Munc13-4 protein), and STX-11 (encoding syntaxin -11), respectively; Hermansky-Pudlak syndrome (AP3B1); Papillon-Lefevre syndrome (CTSC, cathepsin C); nuclear factor kappa-beta essential modulator deficiency (NEMO) due to mutations in the IKBKG gene; severe combined immunodeficiencies due to mutations in the IL-2RG, JAK3, ADA, PNP, ADK2 genes; bare lymphocyte syndrome (TAP2 gene); X-linked inhibitor of apoptosis deficiency (XIAP gene); X-linked lymphoproliferative disease (XLP): XLP-1 (due to mutations in the SAP gene); Griscelli syndrome (RAB27A gene); Chediak-Higashi syndrome (LYST gene); and Wiskott-Aldrich syndrome (WAS gene).(12) Patients with X-linked inhibitor of apoptosis protein (XIAP) deficiency have been variably reported as having either normal numbers of NKT cells (13) or low numbers of NKT cells.(14) The apparent discrepancy in the numbers of NKT cells is likely related to the difference in size of the sample control groups and disease stage of patients between the 2 reports. At the present time, the role of XIAP in development of NKT cells has not been clearly delineated. The isolated NK cell deficiencies include the absolute NK cell deficiency (ANKD), the classic NK cell deficiency (CNKD), and the functional NK cell deficiency (FNKD). NK cell function is absent in ANKD and CNKD and deficient in FNKD, while NK cells are present in the latter, but absent in the former 2 conditions. NKT cells are Current as of August 23, 2017 7:11 am CDT


Page 1511

absent only in ANKD and present in both CNKD and FNKD.(12) NK cell dysfunction has also been reported in systemic juvenile rheumatoid arthritis and macrophage activation syndrome.(15) There is also more data emerging on the pathogenic role of NK cells in atopic and autoimmune diseases.(4) HIV-1 patients show a gradual loss of NK cells that correlates with disease progression. There is a selective loss of CD56(dim) NK cells, while the numbers of CD56(bright) NK cells remain the same. There appears to be a defect in differentiation from immature CD56- NK cells to mature CD56(dim) NK cells (16), with an expansion of the former (CD56-CD16+) NK cells in HIV viremic patients.(17) Differential mobilization of NK-cell subsets has also been reported related to acute exercise, with CD56(bright) NK cells being less responsive than CD56(dim) NK cells and the ratio of CD56(bright):CD56(dim) favors the former at least up to 1-hour postexercise.(18) NK cells also play an important role in regulating viral infections, and their deficiency predisposes to susceptibility with herpes virus infections. NKG2D expression has been reported to decrease during human CMV infection.(19) NK cells that express inhibitory receptors to self-MHC class I molecules are called "licensed," which means they are functionally more responsive to stimulation, while "unlicensed" NK cells lack receptors for self-MHC class I and are hyporesponsive. Contrary to the hypothesis that "licensed" NK cells are key for viral immunity, the depletion of "unlicensed" NK cells impairs control of viremia, suggesting that these cells are critical for protection against viral infection. NK-cell lymphocytosis is seen in NK-neoplasias, extranodal NK/T-cell lymphoma, aggressive NK-cell leukemia, and blastic NK-cell lymphoma. Chronic NK-cell lymphocytosis (CNKL) is an indolent disorder characterized by proliferation of CD3-CD56+CD16- NK cells. Epstein-Barr virus (EBV) can infect nonneoplastic NK cells(20), and there is an expansion of CD16+CD56(dim) NK cells. Chronic active EBV infection involving NK cells can present with severe inflammatory and necrotic skin reactions typically associated with EBV+ NK-cell lymphoproliferative disease.(21) This assay provides both absolute and relative quantitation of various NK-cell subsets relative to total NK cells (NK cell subsets) or total lymphocytes (NKT cells) and can be used for assessment in the following clinical contexts: HIV, primary immune deficiencies with NK cell defects, NK-cell lymphocytosis, solid-organ transplantation, immune reconstitution following bone marrow or hematopoietic cell transplantation, evaluation of NK cells in neoplasias, only for quantitation (not for diagnosis or classification of NK cell malignancies).

Useful For: Quantitation of natural killer (NK)/natural killer T (NKT) cell subsets as well as quantitation of specific cell-surface and intracellular proteins required for NK cell function

Interpretation: Interpretive comments will be provided, where applicable, along with reference range values for adult samples. Since a separate pediatric reference range could not be established at this time, interpretation of pediatric samples will be made using the adult reference range as an approximate guideline. For the surface marker and intracellular protein expression on natural killer (NK) subsets, relevant values that are abnormal will be provided in a table format within the interpretation along with textual interpretive comments. If results for surface and/or intracellular subsets are quantitatively normal, then only interpretive comments will be provided without actual numeric data. Clients may request numerical data for specific subsets that are not included within the report through the Laboratory Director.

Reference Values: The appropriate age-related reference values will be provided on the report. Pediatric reference values are not available and therefore, interpretation will be based on adult ranges with appropriate cautionary statements in the interpretation.

Clinical References: 1. Fan YY, Yang BY, Wu CY: Phenotypically and functionally distinct subsets of natural killer cells in human PBMCs. Cell Biol International 2008;32:188-197 2. Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer subsets. Trends in Immunol 2001;22(11):633-640 3. Poli A, Michel T, Theresine M, et al: CD56(bright) NK cells: an important NK cell subset. Immunology 2009;126:458-465 4. von Bubnoff D, Andres E, Hentges F, et al: Natural killer cells in atopic and autoimmune diseases of the skin. J Allergy Clin Immunol 2010;125:60-68 5. Vossen M, Matmati M, Hertoghs KML, et al: CD27 defines phenotypically and functionally distinct human NK cell subsets. J Immunol 2008;180:3739-3745 6. Suarez-Alvarez B, Lopez-Vazquez A, Baltar JM, et al: Potential role of NKG2D and its ligands in organ transplantation: a new target for immunointervention. Am J Transplant 2009;9:251-257 7. Borrego F, Robertson MJ, Ritz J, et al: CD69 is a stimulatory receptor for NK cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology 1999;97:159-165 8. Takahashi K, Aranami T, Endoh M, et al: The regulatory role of NK cells in multiple sclerosis. Brain 2004;127:1917-1927 9. Alter G, Malenfant JM, Altfeld M: CD107a as a functional Current as of August 23, 2017 7:11 am CDT


Page 1512

marker for the identification of NK cell activity. J Imm Methods 2004;294:15-22 10. Mathew PA, Chuang SS, Vaidya SV, et al: The LLT1 receptor induces IFN-gamma production by human natural killer cells. Mol Immunol 2004;20:1157-1163 11. Godfrey DI, Stankovic S, Baxter AG: Raising the NKT cell family. Nat Immunol 2010;11(3):197-206 12. Orange JS: Human NK cell deficiencies. Curr Opin Allergy Immunol 2006;6:399-409 13. Marsh RA, Villaneuva J, Kim MO, et al: Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol 2009;132:116-123 14. Rigaud S, Fondaneche M-C, Lambert N, et al: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006;444:110-114 15. Villanueva J, Lee S, Giannini EH, et al: Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther 2005;7:R30-R37 16. Tarazona R, Casado JG, Delarosa O, et al: Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 2002;22(3):176-183 17. Mavilio D, Lombardo G, Benjamin J, et al: Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA 2005;102(8):2886-2891 18. Timmons BW, Cieslak T: Human NK subsets and acute exercise: a brief review. Exercise Immunology Review 2008;14:8-23 19. Muntasell A, Magri G, Pende D, et al: Inhibition of NKG2D in NK cells by cytokines secreted in response to human cytomegalovirus (CMV) infection. Blood 2010;115(25):5170-5179 20. Trempat P, Tabiasco J, Andre P, et al: Evidence for early infection on non-neoplastic natural killer (NK) cells by Epstein-Barr virus (EBV). J Virol 2002;76(21):11139-11142 21. Pacheco SE, Gottschalk SM, Gresik MV, et al: Chronic active Epstein-Barr virus (EBV) infection of NK cells presenting as severe skin reaction to mosquito bites. J Allergy Clin Immunol 2005;116:470-472

QNKS 60616

Natural Killer (NK)/Natural Killer T (NKT) Cell Subsets, Quantitative Clinical Information: Natural killer (NK) cells are derived from pluripotent hematopoietic stem cell precursors, but develop independently of the thymus. They comprise a key lymphocyte subset (approximately 10%-15% of peripheral blood mononuclear cells) and are a constituent of the innate immune system, since these cells do not rearrange their germline DNA to obtain specificity. NK cells serve an important role in host defense against viral infections, as well as tumor surveillance. They are also a component of the adaptive immune response through cytokine production. NK cell functions are governed by a balance between activating receptors and inhibitory receptors. NK cells are identified by expression of different cell-surface receptors and they are not a homogeneous population.(1) In general, the most common combination of surface markers used to identify the majority of NK cells is the absence of CD3 (CD3-), along with expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity IgG Fc receptor-Fc gamma RIII). However, not all NK cells express the CD56 and CD16 markers uniformly and, therefore, can be divided into subsets based on expression of these 2 molecules.(2) The CD16+ CD56+/- (dim or negative) that are CD3- are referred to as cytotoxic NK cells, while the CD56+ (bright) CD16- NK cells are called regulatory or cytokine secreting NK cells.(3) These are not only phenotypically and functionally distinct subsets but also developmentally separate. The majority of human NK cells (approximately 90%) have dim expression of CD56 and moderate to high levels of CD16, as well as perforin and granzymes (2 proteins mediating cytolytic activity), and are therefore high in cytotoxic capability. The remaining minority (approximately 10%) of NK cells are the CD56(bright) cytokine-producing NK cells. Therefore, cytotoxicity and cytokine production are the major functions of NK cells. Cytotoxicity can be subdivided into (1) natural cytotoxicity directed largely toward virally infected cells or tumor cells, in the absence of prior stimulation or immunization, and (2) antibody-dependent cellular cytotoxicity (ADCC) directed against antibody-coated target cells.(4) Circulating NK cells are enriched for the CD56(dim) phenotype, while within the lymph nodes, NK cells are largely CD56(bright). This differential localization is related to the pattern of homing receptors expressed on NK cells: CD56(dim) NK cells express homing markers for inflamed peripheral sites, while CD56(bright) NK cells express receptors for secondary lymphoid organs. The majority of circulating human NK cells, which have cytotoxic function and phenotype (CD56[dim]), are CD27-, while the CD56(bright) cells are CD27+. Therefore, the absence of CD27 expression identifies cytotoxic effector cells within the mature NK cell subsets.(5) Natural killer T (NKT) cells represent a specialized T-cell population that is distinct from conventional T cells. They express an invariant T-cell receptor (TCR) that



Page 1513

recognizes self and bacterial glycosphingolipid antigens presented by the MHC class I-like molecule, CD1d.(11) The development of NKT cells is also unique from regular T cells, as NKT cell precursors are positively selected by CD4+CD8+ cortical thymocytes and the signaling pathways differ from the conventional T cells. Activated NKT cells rapidly produce large amounts of Th1 and Th2 cytokines that transactivate other immune components and, therefore, NKT cells are involved in both innate and adaptive immune responses.(11) NK cell deficiencies can be present as part of a larger immunological syndrome or as an isolated deficiency. Some of the primary (monogenic) immunodeficiencies that affect NK cell function or numbers include autoimmune lymphoproliferative syndrome (ALPS) related to CASP8 (caspase 8 mutations); familial hemophagocytic lymphohistiocytosis (FHL) types 2, 3, and 4 due to mutations in the PFP1 (encoding perforin), UNC13D (encoding the Munc13-4 protein) and STX-11 (encoding syntaxin -11), respectively; Hermansky-Pudlak syndrome (AP3B1); Papillon-Lefevre syndrome (CTSC, cathepsin C); nuclear factor kappa-beta essential modulator deficiency (NEMO) due to mutations in the IKBKG gene; severe combined immunodeficiencies due to mutations in the IL-2RG, JAK3, ADA, PNP, ADK2 genes; bare lymphocyte syndrome (TAP2 gene); X-linked inhibitor of apoptosis deficiency (XIAP gene); X-linked lymphoproliferative disease (XLP): XLP-1 (due to mutations in the SAP gene); Griscelli syndrome (RAB27A gene); Chediak-Higashi syndrome (LYST gene); and Wiskott-Aldrich syndrome (WAS gene).(12) Patients with X-linked inhibitor of apoptosis protein (XIAP) deficiency have been variably reported as having either normal numbers of NKT cells (13) or low numbers of NKT cells.(14) The apparent discrepancy in the numbers of NKT cells is likely related to the difference in size of the sample control groups and disease stage of patients between the 2 reports. At the present time, the role of XIAP in development of NKT cells has not been clearly delineated. The isolated NK cell deficiencies include the absolute NK cell deficiency (ANKD), the classic NK cell deficiency (CNKD), and the functional NK cell deficiency (FNKD). NK cell function is absent in ANKD and CNKD and deficient in FNKD, while NK cells are present in the latter but absent in the former 2 conditions. NKT cells are absent only in ANKD and present in both CNKD and FNKD.(12) NK cell dysfunction has also been reported in systemic juvenile rheumatoid arthritis and macrophage activation syndrome.(15) There is also more data emerging on the pathogenic role of NK cells in atopic and autoimmune diseases.(4) HIV-1 patients show a gradual loss of NK cells that correlates with disease progression. There is a selective loss of CD56(dim) NK cells, while the numbers of CD56(bright) NK cells remain the same. There appears to be a defect in differentiation from immature CD56- NK cells to mature CD56(dim) NK cells (16), with an expansion of the former (CD56-CD16+) NK cells in HIV viremic patients.(17) Differential mobilization of NK-cell subsets has also been reported related to acute exercise, with CD56(bright) NK cells being less responsive than CD56(dim) NK cells and the ratio of CD56(bright):CD56(dim) favors the former at least up to 1-hour post-exercise.(18) NK cells also play an important role in regulating viral infections, and their deficiency predisposes to susceptibility with herpes virus infections. NKG2D expression has been reported to decrease during human CMV infection.(19) NK cells that express inhibitory receptors to self-MHC class I molecules are called "licensed, " which means they are functionally more responsive to stimulation, while "unlicensed" NK cells lack receptors for self-MHC class I and are hyporesponsive. Contrary to the hypothesis that "licensed" NK cells are key for viral immunity, the depletion of "unlicensed" NK cells impairs control of viremia, suggesting that these cells are critical for protection against viral infection. NK-cell lymphocytosis is seen in NK-neoplasias, extranodal NK/T-cell lymphoma, aggressive NK-cell leukemia, and blastic NK-cell lymphoma. Chronic NK-cell lymphocytosis (CNKL) is an indolent disorder characterized by proliferation of CD3-CD56+CD16- NK cells. Epstein-Barr virus (EBV) can infect nonneoplastic NK cells(20), and there is an expansion of CD16+CD56(dim) NK cells. Chronic active EBV infection involving NK cells can present with severe inflammatory and necrotic skin reactions typically associated with EBV+ NK-cell lymphoproliferative disease.(21)

Useful For: Quantitation of ONLY the major natural killer (NK)-cell subsets relative to total NK cells (NK cell subsets) or total lymphocytes (NK T cells) Assessment in the following clinical contexts: HIV, primary immune deficiencies with NK cell defects, NK-cell lymphocytosis, solid-organ transplantation, immune reconstitution following bone marrow or hematopoietic cell transplantation, evaluation of NK cells in neoplasias

Interpretation: Interpretive comments will be provided, where applicable, along with reference range values for adult samples. Since a separate pediatric reference range could not be established at this time, interpretation of pediatric samples will be made using the adult reference range as an approximate guideline.



Page 1514

The appropriate age-related reference values will be provided on the report. Pediatric reference values are not available and therefore, interpretation will be based on adult ranges with appropriate cautionary statements in the interpretation.

Clinical References: 1. Fan YY, Yang BY, Wu CY: Phenotypically and functionally distinct subsets of natural killer cells in human PBMCs. Cell Biol International 2008;32:188-197 2. Cooper MA, Fehniger TA, Caligiuri MA: The biology of human natural killer subsets. Trends in Immunol 2001;22(11):633-640 3. Poli A, Michel T, Theresine M, et al: CD56(bright) NK cells: an important NK cell subset. Immunology 2009;126:458-465 4. von Bubnoff D, Andres E, Hentges F, et al: Natural killer cells in atopic and autoimmune diseases of the skin. J Allergy Clin Immunol 2010;125:60-68 5. Vossen M, Matmati M, Hertoghs KML, et al: CD27 defines phenotypically and functionally distinct human NK cell subsets. J Immunol 2008;180:3739-3745 6. Suarez-Alvarez B, Lopez-Vazquez A, Baltar JM, et al: Potential role of NKG2D and its ligands in organ transplantation: a new target for immunointervention. Am J Transplant 2009;9:251-257 7. Borrego F, Robertson MJ, Ritz J, et al: CD69 is a stimulatory receptor for NK cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology 1999;97:159-165 8. Takahashi K, Aranami T, Endoh M, et al: The regulatory role of NK cells in multiple sclerosis. Brain 2004;127:1917-1927 9. Alter G, Malenfant JM, Altfeld M: CD107a as a functional marker for the identification of NK cell activity. J Imm Methods 2004;294:15-22 10. Mathew PA, Chuang SS, Vaidya SV, et al: The LLT1 receptor induces IFN-gamma production by human natural killer cells. Mol Immunol 2004;20:1157-1163 11. Godfrey DI, Stankovic S, Baxter AG: Raising the NKT cell family. Nat Immunol 2010;11(3):197-206 12. Orange JS: Human NK cell deficiencies. Curr Opin Allergy Immunol 2006;6:399-409 13. Marsh RA, Villaneuva J, Kim MO, et al: Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol 2009;132:116-123 14. Rigaud S, Fondaneche M-C, Lambert N, et al: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 2006;444:110-114 15. Villanueva J, Lee S, Giannini EH, et al: Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res Ther 2005;7:R30-R37 16. Tarazona R, Casado JG, Delarosa O, et al: Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol 2002;22(3):176-183 17. Mavilio D, Lombardo G, Benjamin J, et al: Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA 2005;102(8):2886-2891 18. Timmons BW, Cieslak T: Human NK subsets and acute exercise: a brief review. Exercise Immunology Review 2008;14:8-23 19. Muntasell A, Magri G, Pende D, et al: Inhibition of NKG2D in NK cells by cytokines secreted in response to human cytomegalovirus (CMV) infection. Blood 2010;115(25):5170-5179 20. Trempat P, Tabiasco J, Andre P, et al: Evidence for early infection on non-neoplastic natural killer (NK) cells by Epstein-Barr virus (EBV). J Virol 2002;76(21):11139-11142 21. Pacheco SE, Gottschalk SM, Gresik MV, et al: Chronic active Epstein-Barr virus (EBV) infection of NK cells presenting as severe skin reaction to mosquito bites. J Allergy Clin Immunol 2005;116:470-472

FNECT

Nectarine (Prunus spp) IgE

57941


Reference Values: 0.10 nmol/min/mg Prot

Clinical References: 1. Thomas GH: Chapter 140: Disorders of glycoprotein degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 04/03/2017. Available at www.ommbid.com 2. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth. New York, McGraw-Hill Medical Division, 2009, pp 725-726, 745-746 3. d'Azzo A, Andria G, Bonten E, Annunziata I: Chapter 152: Galactosialidosis. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by D Valle. AL Beaudet, B Vogelstein. New York, McGraw-Hill Book Company. Accessed 04/03/2017. Available at www.ommbid.com

NONTP

Neuro-Oncology Panel, Tumor

64905

Clinical Information: Molecular analysis of biomarkers is increasingly being used in oncology practice to support and guide diagnosis, prognosis, and therapeutic management. Within the context of central nervous system (CNS) tumors, molecular profiling allows for robust delineation of diagnostic groups characterized by distinct molecular profiles with superior prognostic significance than histologic classification alone. Targeted cancer therapies are defined as antibody or small molecule drugs that block the growth and spread of cancer by interfering with specific cell molecules involved in tumor growth and progression. Multiple targeted therapies have been approved by the US FDA for treatment of specific cancers. Integrated molecular profiling allows for effective identification of mutations associated with response or resistance to specific targeted therapies, which can guide therapeutic management while minimizing treatment costs and therapy-associated risks. The Neuro-Oncology Panel interrogates targeted regions across 50 genes to assess for the presence of somatic mutations. The results of this test can be useful for diagnosis, prognostication, and therapeutic management for patients with CNS tumors. See Targeted Gene Regions Interrogated by Neuro-Oncology Panel in Special Instructions for details regarding the targeted gene regions identified by this test.

Useful For: Identifying mutations that may support a diagnosis for patients with tumors of the central nervous system Identifying mutations that may help determine prognosis for patients with tumors of the central nervous system Identifying central nervous system tumors that may respond to targeted therapies by assessing multiple gene targets simultaneously Identifying specific mutations within genes known to be associated with response or resistance to specific cancer therapies


Clinical References: 1. Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med 2015 Jun Current as of August 23, 2017 7:11 am CDT


Page 1521

25;372(26):2499-2508. doi: 10.1056/NEJMoa1407279 2. Brat DJ, Verhaak RG, Aldape KD, et al: Cancer Genome Atlas Research Network. Comprehensive Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 2015 Jun 25;372(26):2481-2498. DOI: 10.1056/NEJMoa1402121 3. Ceccarelli M, Barthel FP, Malta TM, et al: Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell 2016 Jan 28;164(3):550-563. doi: 10.1016/j.cell.2015.12.028 4. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK: WHO classification of tumours of the central nervous system. Fourth edition. International Agency for Research, Lyon, France. 2007 5. Nabors LB, Portnow J, Ammirati M, et al: Central Nervous System Cancers Version 1.2015. J Natl Compr Canc Netw 2015 Oct;13(10);1191-202

MYCNF

Neuroblastoma, 2p24 (MYCN) Amplification, FISH

35290

Clinical Information: Neuroblastoma is a solid tumor that occurs in early childhood and is usually found in the adrenal glands, but rarely is found in other areas of the body. Approximately 25% of all neuroblastomas have amplification of the MYCN oncogene, located on chromosome 2 at p24.1. Amplification of the MYCN oncogene correlates with an unfavorable prognosis and aggressive disease. This test is not diagnostic for neuroblastoma. Other tumors including medulloblastoma, retinoblastoma, astrocytoma, and small cell lung cancer may have amplification of MYCN.

Useful For: As a prognostic factor for patients with neuroblastoma As an aid to treatment decisions in some patients with neuroblastoma

Interpretation: MYCN gene amplification is detected when the percent of cells with an abnormality exceeds the normal cutoff for the MYCN probe. A positive result is consistent with MYCN gene amplification. A negative result suggests no MYCN gene amplification. However, this result does not exclude the diagnosis of neuroblastoma.


Clinical References: 1. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Edited by CDM Fletcher, K Unni, F Mertens: IARC:Lyon 2002, pp 150-152 2. Ambros PF, Ambros IM, SIOP Europe Blastoma Pathology, Biology, and Bone Marrow Group: Pathology and biology guidelines for resectable and unresectable neuroblastic tumors and bone marrow examination guidelines. Med Pediatr Oncol 2001 Dec;37(6):492-504 3. Spitz R, Hero B, Skowron M, et al: MYCN-status in neuroblastoma: characteristics of tumours showing amplification, gain, and non-amplification. Eur J Cancer 2004 Dec;40(18):2753-2759 4. Valent A, Le Roux G, Barrois M, et al: MYCN gene overrepresentation detected in primary neuroblastoma tumour cells without amplification. J Pathol 2002 Dec;198(4):495-501 5. Schwab M: Amplified MYCN in human neuroblastoma: paradigm for the translation of molecular genetics to clinical oncology. Ann NY Acad Sci 2002 Jun;963:63-73 6. Schwab M: MYCN in neuronal tumours. Cancer Lett 2004 Feb 20;204(2):179-187

MNBF 35288

Neuroblastoma, 2p24 (MYCN) Amplification, FISH, Blood or Bone Marrow Clinical Information: Neuroblastoma is a small blue cell tumor that occurs typically in early childhood and is usually found in the adrenal glands, but rarely is found in other areas of the body. Approximately 25% of all neuroblastomas have amplification of the MYCN oncogene, located on chromosome 2 at p24. Amplification of the MYCN oncogene correlates with an unfavorable prognosis and aggressive disease. Since metastasis to the bone marrow is common, detection of MYCN amplification in tumor cells present in the bone marrow is important. Prior to ordering this bone marrow test, if possible, testing on the primary tumor sample should be performed. If the primary tumor tests negative for MYCN amplification, bone marrow testing is not indicated. If the primary tumor demonstrates MYCN amplification, identification of MYCN amplification in the bone marrow will confirm the presence of metastatic disease. In some cases, the diagnostic biopsy specimen from the primary tumor is small and insufficient specimen may be available for ancillary tests such as FISH. In



Page 1522

addition, if the primary sample is a bone biopsy, it cannot be used for FISH analysis. In such cases, if metastatic disease involving the bone marrow is identified, FISH testing on the bone marrow can be performed to evaluate for MYCN status in the tumor.

Useful For: Aids in identifying metastatic disease in patients with a neuroblastoma that has been previously determined to be positive for the MYCN oncogene

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff for any given probe. The presence of a positive clone supports a diagnosis of metastatic disease. The absence of an abnormal clone does not rule out the presence of metastatic disease.


Clinical References: 1. Van Noesel MM, Versteeg R: Pediatric neuroblastomas: genetic and epigenetic 'danse macabre'. Gene 2004;325:1-15 2. Ambros PF, Ambros IM, Brodeur GM, et al: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 2009;5:1471-1482

60940

Neurofilament (2F11)(NF 2F11), Immunostain Without Interpretation Clinical Information: Neurofilament (NF) constitutes the main structural elements of neuronal axons and dendrites. NF subunits are present in neurons, neuronal processes, peripheral nerves, and sympathetic ganglion cells. In brain tissue, immunoperoxidase staining for NF labels the cytoplasm in the body of neurons and also labels neuronal processes. Within tumors, only neoplastic cells of neural origin or those exhibiting neuronal differentiation have been observed to express NF. Positive immunostaining has been observed in neuromas, gangliogliomas, neuroblastomas, and medulloblastomas. Other tumors that can stain for NF include pheochromocytoma, chemodectomas, and carcinoid tumors.

Useful For: An aid in the identification of neoplastic cells of neural origin or those exhibiting neuronal differentiation


Clinical References: 1. Diepholder HM, Schwechheimer K, Mohadjer M, et al: A Clinicopathologic and Immunomorphologic Study of 13 Cases of Ganglioglioma. Cancer 1991;68(10):2192-2201 2. Franquemont DW, Mills SE, Lack EE: Immunohistochemical Detection of Neuroblastomatous Foci in Composite Adrenal Pheochromocytoma-Neuroblastoma. Am J Clin Pathol 1994;102(2):163-170 3. Matsunou H, Shimoda T, Kakimoto S, et al: Histopathologic and Immunohistochemical Study of Malignant Tumors of Peripheral Nerve Sheath (Malignant Schwannoma). Cancer 1985;56:2269-2279

64559

Neurofilament (SMI31), Immunostain Without Interpretation Clinical Information: Neurofilament antibody clone SMI 31 reacts with a phosphorylated epitope on neurofilament H and, to a lesser degree, neurofilament M. Both of these proteins contain multiple tandemly repeated serine phosphorylation sites. Clone SMI 31 reacts with thick and thin axons and specific dendrites such as basket cell dendrites. SMI 31 may also stain neuronal cell bodies in pathological conditions.

Useful For: Differentiating neurons (neurofilament positive) from glia (neurofilament negative) Interpretation: This test includes only technical performance of the stain (no pathologist interpretation Current as of August 23, 2017 7:11 am CDT


Page 1523

is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Rudrabhatla P, Jaffe H, Pant HC: Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimerâ€™s NFTs. FASEB J 2011;25(11):3896-3905 2. Raina AK, Takeda A, Nunomura A, et al: Genetic evidence for oxidative stress in Alzheimerâ€™s disease. NeuroReport 1999;10:1355-1357 3. Yang CC, Alvarez RB, Engel WK, et al: Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies. Brain 1998;121:1089-1097 4. Giasson BI, Mushynski WE: Aberrant Stress-induced Phosphorylation of Perikaryal Neurofilaments. J Biol Chem 1996;271(48):30404-30409

PNEFS

Neuroimmunology Antibody Follow-up, Serum

84300

Clinical Information: Paraneoplastic autoimmune neurological disorders reflect a patient's humoral and cellular immune responses to cancer. The cancer may be new or recurrent, is usually limited in metastatic volume, and is often occult by standard imaging procedures. Autoantibodies specific for onconeural proteins found in the plasma membrane, cytoplasm, and nucleus of neurons or muscle are generated in this immune response and serve as serological markers of paraneoplastic autoimmunity. The most commonly recognized cancers in this context are small-cell lung carcinoma (SCLC), thymoma, ovarian (or related mullerian) carcinoma, breast carcinoma, and Hodgkin's lymphoma. Pertinent childhood neoplasms recognized thus far include neuroblastoma, thymoma, Hodgkin's lymphoma, and chondroblastoma. An individual patient's autoantibody profile can predict a specific neoplasm with 90% certainty, but not the neurological syndrome. Four classes of autoantibodies are recognized: -Neuronal nuclear (antineuronal nuclear antibody-type 1 [ANNA-1], ANNA-2, ANNA-3) -Neuronal and muscle cytoplasmic (Purkinje cell cytoplasmic antibody, type 1 [PCA-1], PCA-2, PCA-Tr, CRMP-5, amphiphysin, and striational) -Glial nuclear (anti-glial nuclear antibody) -Plasma membrane cation channel Antibodies (neuronal P/Q-type and N-type calcium channel and muscle acetylcholine receptor autoantibodies). These autoantibodies are potential effectors of neurological dysfunction. Seropositive patients usually present with subacute neurological symptoms and signs. The patient may present with encephalopathy, cerebellar ataxia, myelopathy, radiculopathy, plexopathy, sensory, sensorimotor, or autonomic neuropathy, with or without coexisting evidence of a neuromuscular transmission disorder: Lambert-Eaton syndrome (LES), myasthenia gravis, or neuromuscular hyperexcitability. Initial signs may be subtle, but a subacute multifocal and progressive syndrome usually evolves. Sensorimotor neuropathy and cerebellar ataxia are common presentations, but the clinical picture in some patients is dominated by striking gastrointestinal dysmotility, limbic encephalopathy, basal ganglionitis, or cranial neuropathy (especially loss of vision, hearing, smell, or taste). Cancer risk factors include past or family history of cancer, history of smoking or social/environmental exposure to carcinogens. Early diagnosis and treatment of the neoplasm favor less neurological morbidity and offer the best hope for survival.

Useful For: Monitoring patients who have previously tested positive for 1 or more antibodies in the Mayo Neuroimmunology Laboratory within the past 5 years. Requests for the follow-up assay in serum specimens must have previously been positive in a serum evaluation.

Interpretation: Antibodies directed at onconeural proteins shared by neurons, muscle, and certain cancers are valuable serological markers of a patient's immune response to cancer. They are not found in healthy subjects and are usually accompanied by subacute neurological symptoms and signs. Several autoantibodies have a syndromic association, but no known autoantibody predicts a specific neurological syndrome. Conversely, a positive autoantibody profile has 80% to 90% predictive value for a specific cancer. It is not uncommon for more than 1 paraneoplastic autoantibody to be detected, each predictive of the same cancer.

Reference Values: NEURONAL NUCLEAR ANTIBODIES Antineuronal Nuclear Antibody-Type 1 (ANNA-1) Current as of August 23, 2017 7:11 am CDT


Page 1524

2.0 ng/mL represent possible environmental or job-related exposure. Toxic concentrations are > or =10 ng/mL. Normal values are based on a Mayo Clinic study using healthy volunteers. Toxic values have been deduced from observation and unpublished internal study. Clinical concern about nickel toxicity should be limited to patients with potential for exposure to toxic nickel compounds such as nickel carbonyl. Hypernickelemia, in the absence of exposure to that specific form of nickel, may be an incidental finding or could be due to specimen contamination.

Reference Values: 10 ng/mL or nornicotine >30 ng/mL in urine indicates current tobacco use, irrespective of whether the subject is on nicotine replacement therapy. The presence of nornicotine without anabasine is



Page 1545

consistent with use of nicotine replacement products. Heavy tobacco users who abstain from tobacco for 2 weeks exhibit urine nicotine values 2000 Lipids LDL-C

0 â€“ 19 years

0 - 109 mg/dL

>19 years

0 - 99 mg/dL

Optimal: Above Optimal: 100 - 129 Borderline:

130 - 159

High:

160 - 189

Very High:

>189 Comment: LDL-C is inaccurate if patient is non-fasting.

HDL-C

>39 mg/dL

Triglycerides 0 â€“ 9 yrs:

0 - 74 mg/dL

10 â€“ 19 yrs: 0 - 89 mg/dL >19 years

0 - 149 mg/dL Total Cholesterol

0 â€“ 19 yrs: 100 - 169 mg/dL

>19 years

100 - 199 mg/dL LDL and HDL Particles

HDL-P (Total)

>or= 30.5 umol/L

Small LDL-P

nmol/L

LDL Size

>20.5 nm PARTICLE CONCENTRATION AND SIZE LDL AND HDL PARTICLES Percentile in Reference Population

HDL-P (total) High 75th 50th 25th Low >34.9 34.9 30.5 26.7 Small LDL-P Low 25th 50th 75th High 117 527 839 >839 LDL Size



Page 1552

23.0

20.6

20.5

19.0

Comment: Small LDL-P and LDL Size are associated with CVD risk, but not after LDL-P is taken into account. These assays were developed and their performance characteristics determined by LipoScience. These assays not been cleared by the US Food and Drug Administration. The clinical utility of these laboratory values have not been fully established. Insulin Resistance and Diabetes Risk

Large VLDL-P

nmol/L

Small LDL-P

nmol/L

Large HDL-P

>or = 4.8 umol/L

VLDL Size

nm

LDL Size

>or= 20.8 nm

HDL Size

>or= 9.2 nm Insulin Resistance Score LP-IR Score < or = 45 Comment: LP-IR Score is inaccurate if patient is non-fasting. INSULIN RESISTANCE/DIABETES RISK MARKERS Insulin Resistant --> Percentile in Reference Population

Large VLDL-P Low 25th 50th 75th High 0.9 2.7 6.9 >6.9 Small LDL-P

Low 25th 50th 75th High 117 527 839 >839

Large HDL-P

High 75th 50th 25th Low >7.3 7.3 4.8 3.1

VLDL Size

Small 25th 50th 75th Large 42.4 46.6 52.5 >52.5

LDL Size

Large 75th 50th 25th Small >21.2 21.2 20.8 20.4

HDL Size

Large 75th 50th 25th Small >9.6 9.6 9.2 8.9 Insulin Resistance Score

LP-IR SCORE


Low

25th

50th

75th

High

27

45

63

>63 The LP-IR score is a laboratory developed index that has been associated with insulin resistance and diabetes risk and should be used as one component of a physician's clinical assessment. Neither the LP-IR score nor the subclasses listed above have been cleared by the US Food and Drug Administration.


Page 1553

SSF1

Nocardia Stain

87294

Reference Values: The laboratory will provide an interpretive report. Reported as positive or negative.

NSIP

Non-Seasonal Inhalant Allergen Profile

31769





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



NSRGP 63161

Noonan Syndrome and Related Disorders Multi-Gene Panel, Blood Clinical Information: Noonan syndrome (NS) is an autosomal dominant disorder of variable



Page 1554

expressivity characterized by short stature, congenital heart defects, characteristic facial dysmorphology, unusual chest shape, developmental delay of varying degree, cryptorchidism, and coagulation defects, among other features. Heart defects include pulmonary valve stenosis (20%-50%), hypertrophic cardiomyopathy (20%-30%), atrial septal defects (6%-10%), ventricular septal defects (approximately 5%), and patent ductus arteriosus (approximately 3%). Facial features, which tend to change with age, may include hypertelorism, downward-slanting eyes, epicanthal folds, and low-set and posteriorly rotated ears. Mild mental retardation is seen in up to one-third of adults. The incidence of NS is estimated to be between 1 in 1,000 and 1 in 2,500, although subtle expression in adulthood may cause this number to be an underestimate. NS is genetically heterogeneous, with 4 genes currently associated with the majority of cases: PTPN11, RAF1, SOS1, and KRAS. Heterozygous mutations in NRAS, HRAS, BRAF, SHOC2, MAP2K1, MAP2K2, and CBL have also been associated with a smaller percentage of NS and related phenotypes. All of these genes are involved in a common signal transduction pathway known as the Ras-mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is important for cell growth, differentiation, senescence, and death. Molecular genetic testing of all of the known genes identifies a mutation in approximately 75% of affected individuals. NS can be sporadic and due to new mutations; however, an affected parent can be recognized in 30% to 75% of families. Some studies have shown that there is a genotype-phenotype correlation associated with NS. An analysis of a large cohort of individuals with NS has suggested that PTPN11 mutations are more likely to be found when pulmonary stenosis is present, while hypertrophic cardiomyopathy is commonly associated with RAF1 mutations, but rarely associated with PTPN11. A number of related disorders exist that have phenotypic overlap with NS and are caused by mutations in the same group of genes. PTPN11 and RAF1 mutations have been associated with LEOPARD (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and deafness) syndrome, an autosomal dominant disorder sharing several clinical features with NS. Mutations in BRAF, MAP2K1, MAP2K2, and KRAS have been identified in individuals with cardiofaciocutaneous (CFC) syndrome, a condition involving congenital heart defects, cutaneous abnormalities, Noonan-like facial features, and severe psychomotor developmental delay. Costello syndrome, which is characterized by coarse facies, short stature, distinctive hand posture and appearance, severe feeding difficulty, failure to thrive, cardiac anomalies, and developmental disability has been primarily associated with mutations in HRAS. Variation in SHOC2 has been associated with a distinctive phenotype involving features of NS and loose anagen hair. Genes included in the Noonan Syndrome and Related Disorders Multi-Gene Panel Gene Protein Inheritance Disease Association BRAF V-RAF murine sarcoma viral oncogene homolog b1 AD Noonan/CFC/Costello syndrome CBL CAS-BR-M murine ecotropic retroviral transforming sequence homolog AD Noonan syndrome-like disorder HRAS V-HA-RAS Harvey rat sarcoma viral oncogene homolog AD Costello syndrome KRAS V-KI-RAS Kirsten rat sarcoma viral oncogene homolog AD Noonan/CFC/Costello syndrome MAP2K1 Mitogen-activated protein kinase kinase 1 AD Noonan/CFC MAP2K2 Mitogen-activated protein kinase kinase 2 AD Noonan/CFC NRAS Neuroblastoma ras viral oncogene homolog AD Noonan syndrome PTPN11 Protein-tyrosine phosphatase, nonreceptor-type, 11 AD Noonan/CFC/LEOPARD syndrome RAF1 V-raf-1 murine leukemia viral oncogene homolog 1 AD Noonan/LEOPARD syndrome SHOC2 Suppressor of clear, c. Elegans, homolog of AD Noonan-syndrome like with loose anagen hair SOS1 Son of sevenless, drosophila, homolog 1 AD Noonan-syndrome like with loose anagen hair Abbreviations: Autosomal dominant (AD)

Useful For: Providing a comprehensive genetic evaluation for patients with a personal or family history suggestive of Noonan syndrome (NS) or related disorders Establishing a diagnosis of a NS or related disorders, in some cases, allowing for appropriate management and surveillance for disease features based on the gene involved Identifying mutations within genes known to be associated with increased risk for disease features allowing for predictive testing of at-risk family members

Interpretation: Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.



Page 1555

An interpretive report will be provided.

Clinical References: 1. Online Mendelian Inheritance in Man. Available at www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM 2. Tartaglia M, Gelb BD, Zenker M: Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab 2011;25(1):161-179 3. Rauen KA: Cardiofaciocutaneous Syndrome. In GeneReviews (Internet). Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. Seattle, WA. 1993-2014. 2007 Jan 18 (Updated 2012 Sep 6). Available at http://www.ncbi.nlm.nih.gov/books/NBK1186/ 4. Allanson JE, Roberts AE: Noonan Syndrome. In GeneReviews (Internet). Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington. Seattle. Seattle WA. 1993-2014. 2001 Nov 15 (Updated 2011 Aug 4). Available at http://www.ncbi.nlm.nih.gov/books/NBK1124/ 5. Gripp KW, Lin AE: Costello SyndromeIn. In GeneReviews (Internet). Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. Seattle WA. 1993-2014. 2006 Aug 29 (Updated 2012 Jan 12). Available at http://www.ncbi.nlm.nih.gov/books/NBK1507/ 6. Gelb BD, Tartaglia M: LEOPARD Syndrome. In GeneReviews (Internet). Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle. Seattle WA. 1993-2014. Available at http://www.ncbi.nlm.nih.gov/books/NBK1383/

LNORO

Norovirus PCR, Molecular Detection, Feces

65170

Clinical Information: Noroviruses, previously known as Norwalk-like viruses, are highly contagious RNA viruses that cause acute gastroenteritis (diarrhea, vomiting). Although 6 genogroups of norovirus have been identified, only 3 genogroups (genogroup: G1, G2, and G4) cause disease in humans. Furthermore, the majority of outbreaks have been associated with G1 and G2, with G2 being most common.(1) Noroviruses are transmitted through close, personal contact with an infected individual or via the fecal-oral route, in which the virus becomes ingested in contaminated food or water. These viruses are extremely contagious, with fewer than 20 virions being able to cause disease.(1) Once infected, the incubation period is typically short, between 24 and 72 hours. The onset of symptoms is abrupt, with vomiting and watery nonbloody diarrhea being common. Patients may also experience a low-grade fever, as well as headache and mild body aches.(1) The diagnosis of norovirus infection can often be made on clinical grounds, and symptoms generally resolve in 24 to 48 hours. However, in certain patients, especially those who are immunocompromised or hospitalized, laboratory testing may be indicated for infection control purposes and to limit the use of antibiotics. Testing of diarrheal stool by real-time PCR allows for a rapid and sensitive means of detecting and differentiating norovirus G1 and G2 in clinical stool samples.

Useful For: Diagnosis of gastrointestinal disease (diarrhea or vomiting) caused by norovirus genogroups 1 and 2

Interpretation: A positive result indicates that nucleic acid (RNA) from norovirus genogroups 1 and/or 2 was present in the clinical specimen. A negative result suggests that nucleic acid (RNA) from norovirus genogroups 1 or 2 was absent in the clinical specimen.


Clinical References: 1. Norovirus: Clinical Overview. Center for Disease Control and Prevention, 2013. Accessed 12/29/16. Available at www.cdc.gov/norovirus/hcp/clinical-overview.html 2. Echenique IA, Stosor V, Gallon L, et al: Prolonged norovirus infection after pancreas transplantation: a case report and review of chronic norovirus. Transpl Infect Dis 2016 18(1):98-104

FNLV

Norovirus, EIA (Stool)

91366

Reference Values: Norovirus Antigen:

Not Detected

A negative result does not exclude norovirus infection. Current as of August 23, 2017 7:11 am CDT


Page 1556

NEREG

Northeast Regional Allergen Profile

31767





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



NOTRP

Nortriptyline, Serum

37119

Clinical Information: Nortriptyline is a tricyclic antidepressant used for treatment of endogenous depression. It also is a metabolite of the antidepressant amitriptyline. Nortriptyline is used when its stimulatory side effect is considered to be of clinical advantage; amitriptyline is used when the side effect of mild sedation is desirable. Nortriptyline is unique among the antidepressants in that its blood level exhibits the classical therapeutic window effect; blood concentrations above or below the therapeutic window correlate with poor clinical response. Thus, therapeutic monitoring to ensure that the blood level is within the therapeutic window is critical to accomplish successful treatment with this drug. Like amitriptyline, nortriptyline can cause major cardiac toxicity when the concentration is above 500 ng/mL, characterized by QRS widening, which leads to ventricular tachycardia and asystole. In some patients, toxicity may manifest at lower concentrations.



Page 1557

Useful For: Monitoring serum concentration during therapy Evaluating potential toxicity The test may also be useful to evaluate patient compliance

Interpretation: Most individuals display optimal response to nortriptyline with serum levels of 70 to 170 ng/mL. Risk of toxicity is increased with nortriptyline levels above 500 ng/mL. Some individuals may respond well outside of this range, or may display toxicity within the therapeutic range; thus, interpretation should include clinical evaluation. Therapeutic ranges are based on specimens drawn at trough (ie, immediately before the next dose).

Reference Values: Therapeutic concentration: 70-170 ng/mL Note: Therapeutic ranges are for specimens drawn at trough (ie, immediately before next scheduled dose). Levels may be elevated in non-trough specimens.

Clinical References: 1. Wille SM, Cooreman SG, Neels HM, Lambert WE: Relevant issues in the monitoring and the toxicology of antidepressants. Crit Rev Clin Lab Sci 2008;45(1):25-89 2. Thanacoody HK, Thomas SH: Antidepressant poisoning. Clin Med 2003;3(2):114-118 3. Hiemke C, Baumann P, Bergemann N, et al: AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011. Pharmacopsychiatry 2011;44(6):195-235 4. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. 2012. Fifth edition. Elsevier

FCCEV

Notch3 DNA Sequencing Test

57461

Reference Values: A final report will be attached in MayoAccess.

PBNP

NT-Pro B-Type Natriuretic Peptide (BNP), Serum

84291

Clinical Information: B-type natriuretic peptide (brain natriuretic peptide: BNP) is a small, ringed peptide secreted by the heart to regulate blood pressure and fluid balance.(1) This peptide is stored in and secreted predominantly from membrane granules in the heart ventricles in a pro form (proBNP). Once released from the heart in response to ventricle volume expansion or pressure overload, the N-terminal (NT) piece of 76 amino acids (NT-proBNP) is rapidly cleaved by the enzymes corin and furin to release the active 32-amino acid peptide (BNP).(2) Both BNP and NT-proBNP are markers of atrial and ventricular distension due to increased intracardiac pressure. The New York Heart Association (NYHA) developed a 4-stage functional classification system for congestive heart failure (CHF) based on the severity of the symptoms. Studies have demonstrated that the measured concentrations of circulating BNP and NT-proBNP increase with the severity of CHF based on the NYHA classification.

Useful For: Aids in the diagnosis of congestive heart failure Interpretation: Under 50 years of age: N-terminal pro brain natriuretic peptide (NT-proBNP) values below 300 pg/mL have a 99% negative predictive value for excluding acute congestive heart failure (CHF). A cutoff of 1,200 pg/mL for patients with an estimated glomerular filtration rate (eGFR) below 60 yields a diagnostic sensitivity and specificity of 89% and 72% for acute CHF. NT-proBNP values greater than 450 pg/mL are consistent with CHF in adults under 50 years of age. 50-75 years of age: NT-proBNP values below 300 pg/mL have a 99% negative predictive value for excluding acute CHF. A cutoff of 1,200 pg/mL, for patients with an eGFR below 60 yields a diagnostic sensitivity and specificity of 89% and 72% for acute CHF. A diagnostic NT-proBNP cutoff of 900 pg/mL has been suggested in adults 50 to 75 years of age in the absence of renal failure. Over 75 years of age: NT-proBNP values below 300 pg/mL have a 99% negative predictive value for excluding acute CHF. A cutoff of 1,200 pg/mL for patients with an eGFR below 60 yields a diagnostic sensitivity and specificity of 89% and 72% for acute CHF. A diagnostic NT-proBNP cutoff of 1,800 pg/mL has been suggested in adults over 75 years of age in the absence of renal failure. NT-Pro BNP levels are loosely correlated with New York Heart Association (NYHA) functional class (see Table). Interpretive Levels for CHF Functional Class 5th to 95th Percentile Median I 31-1,110 pg/mL 377 pg/mL II 55-4,975 pg/mL 1,223 pg/mL III 77-26,916 pg/mL 3,130 pg/mL IV * * *In a Mayo Clinic study of 75 patients with CHF, only 4 were characterized Current as of August 23, 2017 7:11 am CDT


Page 1558

as Class IV. Accordingly, range and median are not provided.

Reference Values: Males < or =45 years: 10-51 pg/mL 46 years: 10-53 pg/mL 47 years: 10-55 pg/mL 48 years: 10-56 pg/mL 49 years: 10-58 pg/mL 50 years: 10-59 pg/mL 51 years: 10-61 pg/mL 52 years: 10-62 pg/mL 53 years: 10-64 pg/mL 54 years: 10-67 pg/mL 55 years: 10-68 pg/mL 56 years: 10-70 pg/mL 57 years: 10-71 pg/mL 58 years: 10-73 pg/mL 59 years: 10-76 pg/mL 60 years: 10-77 pg/mL 61 years: 10-79 pg/mL 62 years: 10-82 pg/mL 63 years: 10-83 pg/mL 64 years: 10-85 pg/mL 65 years: 10-88 pg/mL 66 years: 10-89 pg/mL 67 years: 10-92 pg/mL 68 years: 10-95 pg/mL 69 years: 10-97 pg/mL 70 years: 10-100 pg/mL 71 years: 10-103 pg/mL 72 years: 10-104 pg/mL 73 years: 10-107 pg/mL 74 years: 10-110 pg/mL 75 years: 10-113 pg/mL 76 years: 10-116 pg/mL 77 years: 10-119 pg/mL 78 years: 10-122 pg/mL 79 years: 10-125 pg/mL 80 years: 10-128 pg/mL 81 years: 10-131 pg/mL 82 years: 10-135 pg/mL > or =83 years: 10-138 pg/mL Females < or =46 years: 10-140 pg/mL 47 years: 10-141 pg/mL 48 years: 10-144 pg/mL 49 years: 10-146 pg/mL 50 years: 10-149 pg/mL 51 years: 10-150 pg/mL 52 years: 10-152 pg/mL 53 years: 10-155 pg/mL 54 years: 10-157 pg/mL 55 years: 10-160 pg/mL 56 years: 10-162 pg/mL 57 years: 10-166 pg/mL 58 years: 10-168 pg/mL Current as of August 23, 2017 7:11 am CDT


Page 1559

59 years: 10-171 pg/mL 60 years: 10-173 pg/mL 61 years: 10-177 pg/mL 62 years: 10-179 pg/mL 63 years: 10-183 pg/mL 64 years: 10-185 pg/mL 65 years: 10-189 pg/mL 66 years: 10-193 pg/mL 67 years: 10-196 pg/mL 68 years: 10-199 pg/mL 69 years: 10-202 pg/mL 70 years: 10-206 pg/mL 71 years: 10-210 pg/mL 72 years: 10-214 pg/mL 73 years: 10-218 pg/mL 74 years: 10-222 pg/mL 75 years: 10-227 pg/mL 76 years: 10-230 pg/mL 77 years: 10-235 pg/mL 78 years: 10-239 pg/mL 79 years: 10-244 pg/mL 80 years: 10-248 pg/mL 81 years: 10-253 pg/mL 82 years: 10-258 pg/mL > or =83 years: 10-263 pg/mL

Clinical References: 1. Januzzi JL, van Kimmenade R, Lainchbury J: NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1,256 patients; The International Collaborative of NT-proBNP Study. Eur Heart J 2006;27:330-337 2. van Kimmenade R, Pinto YM, Bayes-Genis A: Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure. Am J Cardiol 2006;98:386-390 3. DeFilippi C, van Kimmenade R, Pinto YM: Amino-terminal pro-B-type natriuretic peptide testing in renal disease. Am J Cardiol 2008;101[suppl]:82A- 88A

NTXPR

NTX-Telopeptide, Urine

61656

Clinical Information: Human bone is continuously remodeled through a process of osteoclast-mediated bone formation and resorption. This process can be monitored by measuring serum and urine markers of bone formation and resorption. Approximately 90% of the organic matrix of bone is type I collagen, a helical protein that is cross-linked at the N- and C-terminal ends of the molecule. The amino acid sequences and orientation of the cross-linked alpha 2 N-telopeptide of type 1 collagen make it a specific marker of human bone resorption. N-terminal telopeptide (NTx) molecules are mobilized from bone by osteoclasts and subsequently excreted in the urine. Elevated levels of NTx indicate increased bone resorption. Bone turnover markers are physiologically elevated during childhood, growth, and during fracture healing. The elevations in bone resorption markers and bone formation markers are typically balanced in these circumstances and of no diagnostic value. By contrast, abnormalities in the process of bone remodeling can result in changes in skeletal mass and shape. Many diseases, in particular hyperthyroidism, all forms of hyperparathyroidism, most forms of osteomalacia and rickets (even if not associated with hyperparathyroidism), hypercalcemia of malignancy, Paget disease, multiple myeloma, and bony metastases, as well as various congenital diseases of bone formation and remodeling can result in accelerated and unbalanced bone turnover. Unbalanced bone turnover, usually without increase in bone turnover, is also found in age-related and postmenopausal osteopenia and osteoporosis. Disease-associated bone turnover abnormalities should normalize in response to effective therapeutic interventions, which can be monitored by measurement of serum and urine bone resorption and formation markers.

Useful For: As an adjunct in the diagnosis of medical conditions associated with increased bone turnover Monitoring effectiveness of antiresorptive therapy in patients treated for osteopenia, Current as of August 23, 2017 7:11 am CDT


Page 1560

osteoporosis, Paget disease, or other metabolic bone disorders

Interpretation: Elevated levels of N-terminal telopeptide (NTx) indicate increased bone resorption. Most patients with osteopenia or osteoporosis have low, but unbalanced, bone turnover, with bone resorption dominating over bone formation. While this may result in mild elevations in bone turnover markers in these patients, finding significantly elevated urine NTx levels is atypical. Therefore, if levels are substantially elevated above the young adult reference range (>1.5- to 2-fold), the likelihood of coexisting osteomalacia, or of an alternative diagnosis as described in the Clinical Information section, should be considered. When alternative causes for elevated NTx have been excluded in an osteopenia/osteoporosis patient, the patient must be considered at increased risk for accelerated progression of osteopenia/osteoporosis. A 30% or greater reduction in this resorption marker 3 to 6 months after initiation of therapy indicates a probably adequate therapeutic response. The Negotiated Rulemaking Committee of HCFA also recommends: "Because of significant specimen to specimen collagen crosslink physiologic variability (15%-20%), current recommendations for appropriate utilization include: 1 or 2 baseline assays from specified urine collections on separate days; followed by a repeat assay about 3 months after starting antiresorptive therapy; followed by a repeat assay in 12 months; thereafter not more than annually, if medically necessary."

Reference Values: All units are reported in nmol Bone Collagen Equivalents/mmol creatinine. Adult (> or =18 years of age) Males: 21-83 nmol BCE/mmol creatinine Females: Premenopausal: 17-94 nmol BCE/mmol creatinine Postmenopausal: 26-124 nmol BCE/mmol creatinine Pediatric Males: Tanner Stage I: 55-508 nmol BCE/mmol creatinine Tanner Stage II: 21-423 nmol BCE/mmol creatinine Tanner Stage III: 27-462 nmol BCE/mmol creatinine Tanner Stage IV: or =50 ng/g or 6-monoacetlymorphine at > or =10 ng/g indicates the newborn was exposed to opiates/opioids during gestation.



Page 1579

Positives are reported with a quantitative LC-MS/MS result. Cutoff concentrations Codeine by LC-MS/MS: 50 ng/mL Hydrocodone by LC-MS/MS: 50 ng/mL Hydromorphone by LC-MS/MS: 50 ng/mL Morphine by LC-MS/MS: 50 ng/mL Oxycodone by LC-MS/MS: 50 ng/mL Oxymorphone by LC-MS/MS: 50 ng/mL

Clinical References: 1. Gutstein HB, Akil H: Opioid analgesics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by LL Brunton, JS Lazo, KL Parker. 11th edition. McGraw-Hill Companies Inc, 2006. Available at URL: www.accessmedicine.com/content.aspx?aID=940653 2. Disposition of Toxic Drugs and Chemical in Man. Edited by RC Baselt. Foster City, CA. Biomedical Publications, 2008, pp 355-360; 730-735; 745-747; 750-752; 1057-1064; 1166-1168; 1470-1171 3. Ostrea EM Jr, Lynn SM, Wayne RN, Stryker JC: Tissue distribution of morphine in the newborns of addicted monkeys and humans. Clinical implications. Dev Pharmacol Ther 1980;1:163-170 4. Szeto HH: Kinetics of drug transfer to the fetus. Clin Obstet Gynecol 1993;36:246-254 5. Kwon TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of Clinical Biochemistry. Clin Chem 1997;43:235-242 6. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an alternative to urine testing. J Pediatr 1989;115:474-477 7. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005;60:45-56

OPATM

Opiate Confirmation, Meconium

84326

Clinical Information: Opiates are naturally occurring alkaloids that are derived from the opium poppy and demonstrate analgesic effects. Opioids are derived from natural and semisynthetic alkaloids of opium or synthetic compounds(1): -Codeine is a naturally occurring opioid agonist often incorporated into formulations along with acetaminophen or aspirin to increase its analgesic effect.(2) Codeine is metabolized to morphine and subsequently undergoes glucuronidation and sulfation. -Morphine is an opioid receptor agonist that is used for major pain analgesia.(2) It has been shown to distribute widely into many fetal tissues,(4) and has been detected in meconium. -Hydrocodone is a semisynthetic analgesic derived from codeine. Hydrocodone is 6 times more potent than codeine and is prescribed for treatment of moderate-to-moderately severe pain.(2) Hydrocodone undergoes O-demethylation in vivo, forming hydromorphone. -Hydromorphone, a semisynthetic derivative of morphine, is an opioid analgesic. It is 7 to 10 times more potent than morphine, its addiction liability is similar to morphine.(2) -Oxycodone, a semisynthetic narcotic derived from thebaine. It is metabolized by O-demethylation, forming oxymorphone.(2) -Oxymorphone is a semisynthetic opioid derivative of thebaine and is indicated for moderate-to-severe pain.(2) -Heroin, a semisynthetic derivative of morphine, is rapidly deacetylated in vivo to the active metabolite 6-monoacetlymorphine (6-MAM), which is further hydrolyzed to morphine.(2) Opiates have been shown to readily cross the placenta and distribute widely into many fetal tissues. Opiate use by the mother during pregnancy increases the risk of prematurity and small size for gestational age. Furthermore, heroin-exposed infants exhibit an early onset of withdrawal symptoms compared to methadone-exposed infants. These infants demonstrate a variety of symptoms including irritability, hypertonia, wakefulness, diarrhea, yawning, sneezing, increased hiccups, jitteriness, excessive sucking, and seizures. Long-term intrauterine drug exposure may lead to abnormal neurocognitive and behavioral development as well as an increased risk of sudden infant death syndrome. The disposition of opiates and opioids in meconium, the first fecal material passed by the neonate, is not well understood. The proposed mechanism is that the fetus excretes drug into bile and amniotic fluid. Drug accumulates in meconium either by direct deposition from bile or through swallowing of amniotic fluid. The first evidence of meconium in the fetal intestine appears at approximately the 10th to 12th week of gestation, and slowly moves into the colon by the 16th week of gestation. Therefore, the presence of drugs in meconium has been proposed to be indicative of in utero drug exposure during the final 4 to 5 months of pregnancy, a longer historical measure than is possible by urinalysis.

Useful For: Detection of maternal prenatal opiate/opioid use up to 5 months before birth Current as of August 23, 2017 7:11 am CDT


Page 1580

Interpretation: The presence of any of the following opiates (codeine, morphine, hydrocodone, hydromorphone, oxycodone, oxymorphone) at > or =50 ng/g or 6-monoacetlymorphine at > or =10 ng/g indicates the newborn was exposed to opiates/opioids during gestation.

Reference Values: Negative Positives are reported with a quantitative LC-MS/MS result. Cutoff concentrations Codeine by LC-MS/MS: 50 ng/g Hydrocodone by LC-MS/MS: 50 ng/g Hydromorphone by LC-MS/MS: 50 ng/g Morphine by LC-MS/MS: 50 ng/g Oxycodone by LC-MS/MS: 50 ng/g Oxymorphone by LC-MS/MS: 50 ng/g

Clinical References: 1. Gutstein HB, Akil H: Opioid analgesics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by LL Brunton, JS Lazo, KL Parker. 11th edition. McGraw-Hill Companies Inc, 2006. Available at URL: www.accessmedicine.com/content.aspx?aID=940653 2. Disposition of Toxic Drugs and Chemical in Man. Edited by RC Baselt. Foster City, CA. Biomedical Publications, 2008, pp 355-360; 730-735; 745-747; 750-752; 1057-1064; 1166-1168; 1470-1171 3. Ostrea EM Jr, Lynn SM, Wayne RN, Stryker JC: Tissue distribution of morphine in the newborns of addicted monkeys and humans. Clinical implications. Dev Pharmacol Ther 1980;1:163-170 4. Szeto HH: Kinetics of drug transfer to the fetus. Clin Obstet Gynecol 1993;36:246-254 5. Kwon TC, Ryan RM: Detection of intrauterine illicit drug exposure by newborn drug testing. National Academy of Clinical Biochemistry. Clin Chem 1997;43:235-242 6. Ostrea EM Jr, Brady MJ, Parks PM, et al: Drug screening of meconium in infants of drug-dependent mothers: an alternative to urine testing. J Pediatr 1989;115:474-477 7. Ahanya SN, Lakshmanan J, Morgan BL, Ross MG: Meconium passage in utero: mechanisms, consequences, and management. Obstet Gynecol Surv 2005;60:45-56

OPATX

Opiates Confirmation, Chain of Custody, Urine

62735

Clinical Information: Codeine is converted by hepatic metabolism to morphine and norcodeine with a half-life of 2 to 4 hours. If codeine is ingested, the ratio of codeine to morphine generally exceeds 1.0 in urine during the first 24 hours. The ratio may fall below 1.0 after 24 hours; and after 30 hours, only morphine may be detected. Morphine is a naturally occurring narcotic analgesic obtained from the poppy plant, Papaver somniferum. Morphine is converted by hepatic metabolism to normorphine with a half-life of 2 to 4 hours. The presence of morphine in urine can indicate exposure to morphine, heroin, or codeine within 2 to 3 days. Ingestion of bakery products containing poppy seeds can also cause morphine to be excreted in urine. If excessively large amounts are consumed, this can result in urine morphine concentrations up to 2,000 ng/mL for a period of 6 to 12 hours after ingestion. Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation, and 6-keto reduction to the 6-beta hydroxymetabolites. Hydromorphone and norhydrocodone are both metabolites of hydrocodone. Dihydrocodeine is also a minor metabolite. Trace amounts of hydrocodone can also be found in the presence of approximately 100-fold higher concentrations of oxycodone or hydromorphone since it can be a pharmaceutical impurity in these medications. The presence of hydrocodone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is metabolized primarily in the liver and is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites. The presence of hydromorphone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is also a metabolite of hydrocodone; therefore, the presence of hydromorphone could also indicate exposure to hydrocodone. Dihydrocodeine is a semisynthetic narcotic analgesic prepared by the hydrogenation of codeine. It is also a minor metabolite of hydrocodone. It is metabolized to dihydromorphine and has a half-life of 3.4 to 4.5 hours. Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides and is excreted primarily via the kidney. The presence of oxycodone >100 ng/mL indicates exposure to oxycodone within 2 to 3 days prior to specimen collection. Oxymorphone is metabolized in the liver to noroxymorphone and



Page 1581

excreted via the kidney primarily as the glucuronide conjugates. Oxymorphone is also a metabolite of oxycodone and, therefore, the presence of oxymorphone could also indicate exposure to oxycodone. Naloxone is a synthetic narcotic antagonist and used for partial or complete reversal of opioid depression induced by natural or synthetic opioids. It has also been incorporated into oral tablets of opioids to discourage abuse. The duration of action is dependent on the dose and route of administration. The half-life in adults is approximately 30 to 81 minutes. The detection interval for the opiates is generally 2 to 3 days after last ingestion. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection and quantification of codeine, hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, noroxycodone, noroxymorphone, norhydrocodone, dihydrocodeine, and naloxone in urine Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.


Reference Values: Negative Cutoff concentrations IMMUNOASSAY SCREEN 300 ng/mL Codeine by LC-MS/MS: 25 ng/mL Dihydrocodeine-by LC-MS/MS: 25 ng/mL Hydrocodone by LC-MS/MS: 25 ng/mLNorhydrocodone-by LC-MS/MS: 25 ng/mL Hydromorphone by LC-MS/MS: 25 ng/mL Oxycodone by LC-MS/MS: 25 ng/mL Noroxycodone-by LC-MS/MS: 25 ng/mL Oxymorphone by LC-MS/MS: 25 ng/mL Noroxymorphone-by LC-MS/MS: 25 ng/mL Naloxone-by LC-MS/MS: 25 ng/mL Morphine by LC-MS/MS: 25 ng/mL

Clinical References: 1. Gutstein HB, Akil H: Chapter 21: Opioid Analgesics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. Eleventh edition. Edited by LL Brunton, JS Lazo, KL Parker. New York, McGraw-Hill Companies Inc, 2006. Available at: http://www.accessmedicine.com/content.aspx?aID=940653 2. Baselt RC: Dispositition of Toxic Drugs and Chemical in Man. Ninth edition. Edited by RC Baselt. Foster City, CA: Biomedical Publications, 2011 3. Hackett LP, Dusci LJ, Ilett KF, Chiswell GM: Optimizing the hydrolysis of codeine and morphine glucuronides in urine. Ther Drug Monit 2002;24(5):652-657

OPATU

Opiates Confirmation, Urine

8473

Clinical Information: Codeine is converted by hepatic metabolism to morphine and norcodeine with a half-life of 2 to 4 hours. If codeine is ingested, the ratio of codeine to morphine generally exceeds 1.0 in urine during the first 24 hours. The ratio may fall below 1.0 after 24 hours, and after 30 hours, only morphine may be detected. Morphine is a naturally occurring narcotic analgesic obtained from the poppy plant, Papaver somniferum. Morphine is converted by hepatic metabolism to normorphine with a half-life of 2 to 4 hours. The presence of morphine in urine can indicate exposure to morphine, heroin, or codeine within 2 to 3 days. Ingestion of bakery products containing poppy seeds can also cause morphine to be excreted in urine. If excessively large amounts are consumed, this can result in urine morphine concentrations up to 2,000 ng/mL for a period of 6 to 12 hours after ingestion. Hydrocodone exhibits a



Page 1582

complex pattern of metabolism including O-demethylation, N-demethylation, and 6-keto reduction to the 6-beta hydroxymetabolites. Hydromorphone and norhydrocodone are both metabolites of hydrocodone. Dihydrocodeine is also a minor metabolite. Trace amounts of hydrocodone can also be found in the presence of approximately 100-fold higher concentrations of oxycodone or hydromorphone since it can be a pharmaceutical impurity in these medications. The presence of hydrocodone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is metabolized primarily in the liver and is excreted primarily as the glucuronidated conjugate, with small amounts of parent drug and minor amounts of 6-hydroxy reduction metabolites. The presence of hydromorphone >100 ng/mL indicates exposure within 2 to 3 days prior to specimen collection. Hydromorphone is also a metabolite of hydrocodone; therefore, the presence of hydromorphone could also indicate exposure to hydrocodone. Dihydrocodeine is a semisynthetic narcotic analgesic prepared by the hydrogenation of codeine. It is also a minor metabolite of hydrocodone. It is metabolized to dihydromorphine and has a half-life of 3.4 to 4.5 hours. Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides, and is excreted primarily via the kidney. The presence of oxycodone >100 ng/mL indicates exposure to oxycodone within 2 to 3 days prior to specimen collection. Oxymorphone is metabolized in the liver to noroxymorphone and excreted via the kidney primarily as the glucuronide conjugates. Oxymorphone is also a metabolite of oxycodone and, therefore, the presence of oxymorphone could also indicate exposure to oxycodone. Naloxone is a synthetic narcotic antagonist and used for partial or complete reversal of opioid depression induced by natural or synthetic opioids. It has also been incorporated into oral tablets of opioids to discourage abuse. The duration of action is dependent on the dose and route of administration. The half-life in adults is approximately 30 to 81 minutes. The detection interval for opiates is generally 2 to 3 days after last ingestion.

Useful For: Detection and quantification of codeine, hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, noroxycodone, noroxymorphone, norhydrocodone, dihydrocodeine, and naloxone in urine


Reference Values: Negative Cutoff concentrations Codeine by LC-MS/MS: 25 ng/mL Dihydrocodeine-by LC-MS/MS: 25 ng/mL Hydrocodone by LC-MS/MS: 25 ng/mL Norhydrocodone-by LC-MS/MS: 25 ng/mL Hydromorphone by LC-MS/MS: 25 ng/mL Oxycodone by LC-MS/MS: 25 ng/mL Noroxycodone-by LC-MS/MS: 25 ng/mL Oxymorphone by LC-MS/MS: 25 ng/mL Noroxymorphone-by LC-MS/MS: 25 ng/mL Naloxone-by LC-MS/MS: 25 ng/mL Morphine by LC-MS/MS: 25 ng/mL

Clinical References: 1. Gutstein HB, Akil H: Chapter 21: Opioid Analgesics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th edition. Edited by LL Brunton, JS Lazo, KL Parker. New York, McGraw-Hill Companies Inc, 2006. Available at: http://www.accessmedicine.com/content.aspx?aID=940653 2. Baselt RC: Dispositition of Toxic Drugs and Chemical in Man. Ninth edition. Edited by RC Baselt. Foster City, CA. Biomedical Publication, 2011 3. Hackett LP, Dusci LJ, Ilett KF, Chiswell GM: Optimizing the hydrolysis of codeine and morphine glucuronides in urine. Ther Drug Monit 2002;24(5):652-657

FOPIA

Opiates, Serum or Plasma, Quantitative

75030

Interpretation: Identification of specific drug(s) taken by specimen donor is problematic due to common metabolites, some of which are prescription drugs themselves. The absence of expected drug(s) and/or drug metabolite(s) may indicate non-compliance, inappropriate timing of specimen collection



Page 1583

relative to drug administration, poor drug absorption, or limitations of testing. The concentration value must be greater than or equal to the cutoff to be reported as positive. A very small amount of an unexpected drug analyte in the presence of a large amount of an expected drug analyte may reflect pharmaceutical impurity. Interpretive questions should be directed to the laboratory.

Reference Values: Drugs covered: codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone. All drugs covered and the non-glucuronidated (free) form. Positive cutoff: 2 ng/mL For medical purposes only; not valid for forensic use.

OPRM1 89612

Opioid Receptor, Mu 1 (OPRM1) Genotype for Naltrexone Efficacy Clinical Information: The mu-opioid receptor (OPRM1) is the primary binding site of action for many opioid drugs and for binding of beta-endorphins. One of the effects of opiate and alcohol use is to increase release of beta-endorphins, which subsequently increases release of dopamine and stimulates cravings. Naltrexone is an opioid antagonist used to treat abuse of opiates, alcohol, and other substances. Naltrexone binds to OPRM1, preventing beta-endorphin binding and subsequently reducing the craving for substances of abuse.(1) The A355G polymorphism (rs1799971) in exon 1 of the OPRM1 gene (OPRM1) results in an amino acid change, Asn102Asp. Historically, this mutation has been referred to in the literature as 118A->G (Asn40Asp).(2) The G allele leads to loss of the putative N-glycosylation site in the extracellular receptor region, causing a decrease in OPRM1 mRNA and protein levels, but a 3-fold increase in beta-endorphin binding at the receptor.(3) Studies have shown individuals who carry at least 1 G allele have significantly better outcomes with naltrexone therapy including lower rate of relapse (P=0.044), a longer time to return to heavy drinking, and G locus was predictive of response to naltrexone treatment.(1) Frequency of the 355G allele varies with ethnicity but ranges between 10% and 40% (European 20%, Asian 40%, African American 10%, and Hispanic 25%).

Useful For: Identifying individuals with a higher probability of successful treatment for alcoholism with naltrexone


Clinical References: 1. Somogyi A, Barratt D, Coller J: Pharmacogenetics of opioids. Clin Pharmacol Ther 2007;81:429-444 2. Oroszi G, Anton R, Oâ€™Malley S, et al: OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol Clin Exp Res 2009;33:383-393 3. Anton R, Oroszi G, Oâ€™Malley, et al: An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence. Arch Gen Psychiatry 2008;65:135-144 4. Oslin D, Berrettini W, Kranzler H, et al: A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003;28:1546-1552

OPRMO 60352

Opioid Receptor, Mu 1 (OPRM1) Genotype for Naltrexone Efficacy, Saliva Clinical Information: The mu-opioid receptor (OPRM1) is the primary binding site of action for



Page 1584

many opioid drugs and for binding of beta-endorphins. One of the effects of opiate and alcohol use is to increase release of beta-endorphins, which subsequently increases release of dopamine and stimulates cravings. Naltrexone is an opioid antagonist used to treat abuse of opiates, alcohol, and other substances. Naltrexone binds to OPRM1, preventing beta-endorphin binding and subsequently reducing the craving for substances of abuse.(1) The A355G polymorphism (rs1799971) in exon 1 of the OPRM1 gene (OPRM1) results in an amino acid change, Asn102Asp. Historically, this mutation has been referred to in the literature as 118A->G (Asn40Asp).(2) The G allele leads to loss of the putative N-glycosylation site in the extracellular receptor region, causing a decrease in OPRM1 mRNA and protein levels, but a 3-fold increase in beta-endorphin binding at the receptor.(3) Studies have shown individuals who carry at least 1 G allele have significantly better outcomes with naltrexone therapy including lower rate of relapse (P=0.044), a longer time to return to heavy drinking, and G locus was predictive of response to naltrexone treatment.(1) Frequency of the 355G allele varies with ethnicity but ranges between 10% and 40% (European 20%, Asian 40%, African American 10%, and Hispanic 25%).

Useful For: Identifying individuals with a higher probability of successful treatment for alcoholism with naltrexone


Clinical References: 1. Somogyi A, Barratt D, Coller J: Pharmacogenetics of Opioids. Clin Pharmacol Ther 2007;81:429-444 2. Oroszi G, Anton R, O'Malley S, et al: OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol Clin Exp Res 2009;33:383-393 3. Anton R, Oroszi G, O'Malley, et al: An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence. Arch Gen Psychiatry 2008;65:135-144 4. Oslin D, Berrettini W, Kranzler H, et al: A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 2003;28:1546-1552

FORNG

Orange IgG

57632



FORGG

Oregano IgG

57661



OAU

Organic Acids Screen, Urine

80619

Clinical Information: Organic acids occur as physiologic intermediates in a variety of metabolic pathways. Organic acidurias are a group of disorders in which one or more of these pathways are blocked, resulting in a deficiency of normal products and an abnormal accumulation of intermediate metabolites (organic acids) in the body. These excess metabolites are excreted in the urine. The incidence of individual inborn errors of organic acid metabolism varies from 1 in 10,000 to >1 in 1,000,000 live births. Collectively, their incidence approximates 1 in 3,000 live births. This estimate, however, does not include other inborn errors of metabolism (ie, amino acid disorders, urea cycle disorders, congenital lactic acidemias) for which diagnosis and monitoring may also require organic acid analysis. All possible disease entities included, the incidence of conditions where informative organic acid profiles could be detected in urine is likely to approach 1 in 1,000 live births. Organic acidurias typically present with either an acute life-threatening illness in early infancy or unexplained developmental delay with intercurrent episodes of metabolic decompensations in later childhood. A situation of severe and persistent metabolic acidosis of unexplained origin, elevated anion gap, and severe neurologic manifestations, such as seizures, should be considered strong diagnostic indicators of one of these diseases. The presence of ketonuria, occasionally massive, provides an important clue toward the recognition of disorders, especially in the neonatal period. Hyperammonemia, hypoglycemia, and lactic acidemia are frequent findings, especially during acute episodes of metabolic decompensations.

Useful For: Diagnosis of inborn errors of metabolism Interpretation: When no significant abnormalities are detected, the organic acid analysis is reported Current as of August 23, 2017 7:11 am CDT


Page 1588

and interpreted in qualitative terms only. When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, and recommendations for additional biochemical testing, and in vitro confirmatory studies (enzyme assay, molecular analysis).


Clinical References: 1. Lehotay DC, Clarke JT: Organic acidurias and related abnormalities. Crit Rev Clin Lab Sci 1995;32:377-429 2. Seashore MR: The Organic Acidemias: An Overview. Reviewed April 8, 2015. Available at www.researchgate.net/publication/221964037_The_Organic_Acidemias_An_Overview

IDENT

Organism Referred for Identification, Aerobic Bacteria

9221

Clinical Information: Organisms are referred to confirm identification or when the identity is unknown. This may provide helpful information regarding the significance of the organism, its role in the disease process, and its possible origin. Techniques employed may include conventional biochemical analysis, commercial identification strips or panels, MALDI-TOF mass spectrometry or sequencing nucleic acid of the 16S ribosomal RNA (rRNA) gene.

Useful For: Identification of pure isolates of aerobic bacteria Interpretation: Genus and species are reported on aerobic bacterial isolates, whenever possible. Bacillus species will be reported out as "Large spore-forming aerobic gram-positive Bacillus, not Bacillus cereus or Bacillus anthracis," unless species identification is specifically requested on the request form.

Reference Values: Identification of organism

Clinical References: 1. Manual of Clinical Microbiology. 11th edition. Edited by JH Jorgensen, MA Pfaller, KC Carrol, et al. Washington, DC, ASM Press, 2015 2. Koneman's Color Atlas and Textbook of Diagnostic Microbiology. Seventh edition. Edited by GW Procop, DL Church, GS Hall, et al. Philadelphia, Lippincott Williams and Wilkins. 2017

ANIDE

Organism Referred for Identification, Anaerobic Bacteria

8114

Clinical Information: Anaerobic bacteria are the greatest component of the human body's normal bacterial flora colonizing the skin, oral cavity, and genitourinary and lower gastrointestinal tracts. Their presence is important in promoting vitamin and other nutrient absorption and in preventing infection with pathogenic bacteria. Anaerobes generally are of low pathogenicity, but may possess virulence factors such as endotoxin or polysaccharide capsules or produce extracellular toxins. Disease occurs when a large inoculum develops in an area lacking oxygen or with a poor blood supply. Typical anaerobic infections include peritonitis, abdominal or pelvic abscesses, endometritis, pelvic inflammatory disease, aspiration pneumonia, empyema, lung abscesses, sinusitis, brain abscesses, gas gangrene, and other soft tissue infections. Many Bacteroides produce beta-lactamase and are resistant to penicillins and cephalosporins. Imipenem, metronidazole, and clindamycin are effective agents, although resistance to clindamycin is increasing.

Useful For: Identification of anaerobic bacteria involved in human infections Interpretation: Isolation of anaerobes in significant numbers from well-collected specimens from blood, other normally sterile body fluids, or closed collections of purulent fluid indicates infection with the identified organism.

Reference Values: Identification of organism

Clinical References: 1. Jousimies-Somer HR, Summanen P, Citron DM, et al: Wadsworth Current as of August 23, 2017 7:11 am CDT


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Anaerobic Bacteriology Manual. Sixth edition. Belmont, CA, Star Publishing Co. 2002 2. Anaerobic Bacteria. Chapters 50-54. In Manual of Clinical Microbiology. 11th edition. Edited by JH Jorgensen, MA Pfaller. Washington, DC, ASM Press, 2015 3. Hall GS: Section 4. Anaerobic bacteriology. In Clinical Microbiology Procedures Handbook. Vol 1. Third edition. Edited by LS Garcia. Washington, DC, ASM Press, 2010

OROT

Orotic Acid, Urine

8905

Clinical Information: The urinary excretion of orotic acid, an intermediate in pyrimidine biosynthesis, is increased in many urea cycle disorders and in a number of other disorders involving the metabolism of arginine. The determination of orotic acid can be useful to distinguish between various causes of elevated ammonia (hyperammonemia). Hyperammonemia is characteristic of all urea cycle disorders, but orotic acid is elevated in only some, including ornithine transcarbamylase deficiency, citrullinemia, and argininosuccinic aciduria. Orotic acid is also elevated in the transport defects of dibasic amino acids (lysinuric protein intolerance and hyperornithinemia, hyperammonemia, and homocitrullinuria [HHH] syndrome), and greatly elevated in patients with hereditary orotic aciduria (uridine monophosphate synthase [UMPS] deficiency). Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder that affects both males and females due to random X-inactivation. It is thought to be the most common urea cycle disorder with an estimated incidence of 1:56,000. In OTC deficiency, carbamoyl phosphate accumulates and is alternatively metabolized to orotic acid. Allopurinol inhibits orotidine monophosphate decarboxylase and, when given to OTC carriers (who may have normal orotic acid excretion), can cause increased excretion of orotic acid. A carefully monitored allopurinol challenge followed by several determinations of a patient's orotic acid excretion can be useful to identify OTC carriers, as approximately 20% of OTC mutations are not detectable by current molecular genetic testing methods.

Useful For: Evaluation of the differential diagnosis of hyperammonemia and hereditary orotic aciduria When orotic acid is measured after a protein load or administration of allopurinol, excretion of orotic acid is a very sensitive indicator of ornithine transcarbamylase (OTC) activity. An allopurinol challenge may be helpful in determining whether a female patient may be a carrier of an OTC mutation if molecular genetic testing was not informative.

Interpretation: The value for the orotic acid concentration is reported. The interpretation of the result must be correlated with clinical and other laboratory findings.

Reference Values: or =11 years: 0.4-1.2 mmol/mol creatinine

Clinical References: 1. Singh RH, Rhead WJ, Smith W, et al: Nutritional management of urea cycle disorders. Crit Care Clin 2005 Oct;21(4 Suppl):S27-35 2. Lee B, Singh RH, Rhead WJ, et al: Considerations in the difficult-to-manage urea cycle disorder patient. Crit Care Clin 2005 Oct;21(4 Suppl):S19-25 Review 3. Brusilow SW, Horwich AL: Urea Cycle Enzymes. OMMBID. Accessed 10 Nov 2015. Available from URL: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62674945 4. Webster DR: Hereditary Orotic Aciduria and Other Disorders of Pyrimidine Metabolism. OMMBID. Accessed 10 Nov 2015. Available from URL: http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62636333 5. Ah MN, Lanpher BC, Gropman A, et al: Urea Cycle Disorders Overview. GeneReviews. Accessed 29 Apr 2015. Available from URL: http://www.ncbi.nlm.nih.gov/books/NBK1217/

FORRT

Orris Root (Iris florentina) IgE

57968


Reference Values: 100 ng/mL indicates exposure to oxycodone within 2 to 3 days prior to specimen collection. Oxymorphone is metabolized in the liver to noroxymorphone and excreted via the kidney primarily as the glucuronide conjugates. Oxymorphone is also a metabolite of oxycodone and, therefore, the presence of oxymorphone could also indicate exposure to oxycodone. The detection interval for opiates is generally 2 to 3 days after last ingestion.

Useful For: Detection and quantification of oxycodone, oxymorphone, noroxycodone, and Current as of August 23, 2017 7:11 am CDT


Page 1604

noroxymorphone in urine


Reference Values: Negative Cutoff concentrations: Oxycodone-by LC-MS/MS: 25 ng/mL Noroxycodone-by LC-MS/MS: 25 ng/mL Oxymorphone-by LC-MS/MS: 25 ng/mL Noroxymorphone-by LC-MS/MS: 25 ng/mL


P50B

Oxygen Dissociation, P50, Erythrocytes

81432

Clinical Information: Abnormal oxygen affinity is demonstrated in the presence of some hemoglobin variants: -High oxygen affinity causes erythrocytosis -Low oxygen affinity causes cyanosis and/or low oxygen saturation. Increased oxygen affinity of hemoglobin, reflected in a low p50, left-shifted oxygen dissociation curve, and loss of normal sigmoidal configuration, are characteristic of many hemoglobin variants that are responsible for polycythemia. Measurement of oxygen affinity is an important method for diagnosis of these disorders.

Useful For: Identifying hemoglobin variants associated with polycythemia or cyanotic and hypoxic disorders

Interpretation: Normal: p50 =24 to 30 mm Hg (with sigmoidal oxygen dissociation curve) Reference Values: > or =12 months: 24-30 mm Hg Reference values have not been established for patients who are or =100 Strongly positive Reference values apply to all ages.


PDSOX

Pain Clinic Drug Screen, Chain of Custody, Urine

62738

Clinical Information: This panel was designed to screen for and confirm by gas chromatography-mass spectrometry (GC-MS) or gas chromatography-flame ionization detection (GC-FID) the following drugs: -Barbiturates -Benzodiazepines -Cocaine -Ethanol -Methadone -Phencyclidine -Tetrahydrocannabinol Confirmation by liquid chromatograph-tandem mass spectrometry (LC-MS/MS) is completed for all opiates and amphetamines. This panel uses the screening technique that involves immunoassay testing for drugs by class. All positive screening results are confirmed by GC-MS, GC-FID, or LC-MS/MS, and quantitated, before a positive result is reported. The panel includes PDSUX / Drug Screen, Prescription/OTC, Chain of Custody, Urine, which looks for a broad spectrum of prescription and over-the-counter drugs. It is designed to detect drugs that have toxic effects, as well as known antidotes or active therapies that a clinician can initiate to treat the toxic effect. The test is intended to help physicians manage an apparent overdose or intoxicated patient, to determine if a specific set of symptoms might be due to the presence of drugs, or to evaluate a patient who might be abusing these drugs intermittently. The test is not designed to screen for intermittent use of illicit drugs. Chain-of-custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detecting drug abuse involving amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, methadone, opiates, phencyclidine, and tetrahydrocannabinol Detection and identification of prescription or over-the-counter drugs frequently found in drug overdose or used with a suicidal intent This test is intended to be used in a setting where the identification of the drug is required. Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: A positive result indicates that the patient has used the drugs detected in the recent past. See individual tests (eg, AMPHX / Amphetamines Confirmation, Chain of Custody, Urine) for more information. For information about drug testing, including estimated detection times, see Drugs of Abuse Testing at http://www.mayomedicallaboratories.com/test-info/drug-book/index.html

Reference Values: Negative Screening cutoff concentrations Amphetamines: 500 ng/mL Barbiturates: 200 ng/mL Benzodiazepines: 100 ng/mL Cocaine (benzoylecgonine-cocaine metabolite): 150 ng/mL Ethanol: 10 mg/dL Methadone metabolite: 300 ng/mL Current as of August 23, 2017 7:11 am CDT


Page 1614

Opiates: 300 ng/mL Phencyclidine: 25 ng/mL Tetrahydrocannabinol carboxylic acid: 50 ng/mL This report is intended for use in clinical monitoring or management of patients. It is not intended for use in employment-related testing.

Clinical References: 1. Physician's Desk Reference. 61st edition. Montvale, NJ. Thomson PDR, 2007 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. Tenth edition. New York, NY. McGraw-Hill Professional, 2001 3. Langman LJ, Bechtel L, Holstege CP: Chapter 35. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188 4. Principles of Forensic Toxicology. Second edition. Washington DC. AACC Press, 2003, p 385

PCDSO

Pain Clinic Drug Screen, Urine

36071

Clinical Information: This panel was designed to screen for and confirm by gas chromatography-mass spectrometry (GC-MS) or gas chromatography-flame ionization detection (GC-FID) the following drugs: -Barbiturates -Benzodiazepines -Cocaine -Ethanol -Methadone -Phencyclidine -Tetrahydrocannabinol Confirmation by liquid chromatograph-tandem mass spectrometry (LC-MS/MS) is completed for all opiates and amphetamines. This panel uses the screening technique which involves immunoassay testing for drugs by class. All positive screening results are confirmed by GC-MS, GC-FID, or LC-MS/MS, and quantitated, before a positive result is reported. The panel includes PDSU / Drug Screen, Prescription/OTC, Urine, which looks for a broad spectrum of prescription and over-the-counter drugs. It is designed to detect drugs that have toxic effects, as well as known antidotes or active therapies that a clinician can initiate to treat the toxic effect. The test is intended to help physicians manage an apparent overdose or intoxicated patient, to determine if a specific set of symptoms might be due to the presence of drugs, or to evaluate a patient who might be abusing these drugs intermittently. The test is not designed to screen for intermittent use of illicit drugs.

Useful For: Detecting drug abuse involving amphetamines, barbiturates, benzodiazepines, cocaine, ethanol, methadone, opiates, phencyclidine, and tetrahydrocannabinol Detection and identification of prescription or over-the-counter drugs frequently found in drug overdose or used with a suicidal intent This test is intended to be used in a setting where the identification of the drug is required.

Interpretation: A positive result indicates that the patient has used the drugs detected in the recent past. See individual tests (eg, AMPHU / Amphetamines Confirmation, Urine) for more information. For information about drug testing, including estimated detection times, see Drugs of Abuse Testing at http://www.mayomedicallaboratories.com/test-info/drug-book/index.html

Reference Values: Negative Screening cutoff concentrations: Amphetamines: 500 ng/mL Barbiturates: 200 ng/mL Benzodiazepines: 100 ng/mL Cocaine (benzoylecgonine-cocaine metabolite): 150 ng/mL Ethanol: 10 mg/dL Methadone metabolite: 300 ng/mL Opiates: 300 ng/mL Phencyclidine: 25 ng/mL Tetrahydrocannabinol carboxylic acid: 50 ng/mL This report is intended for use in clinical monitoring or management of patients. It is not intended for use in employment-related testing.

Clinical References: 1. Physicians' Desk Reference. 61st edition. Montvale, NJ. Thomson, 2007 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th edition. New York, NY. McGraw-Hill Professional, 2001 3. Langman LJ, Bechtel L, Holstege CP: Chapter 35. In Tietz Textbook Current as of August 23, 2017 7:11 am CDT


Page 1615

of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company. 2011, pp 1109-1188 4. Principles of Forensic Toxicology. Second edition. Washington, DC. AACC Press, 2003, p 385

PNRCH

Pain Clinic Immunoassay Panel, Urine

65061

Reference Values: Only orderable as part of a profile. For more information see PNCSU / Pain Clinic Survey, Urine.

PN10X

Pain Clinic Survey 10, Chain of Custody

62911

Reference Values: Only orderable as part of a profile. For more information see PANOX / Pain Clinic Survey 10, Chain of Custody, Urine.

PANOX

Pain Clinic Survey 10, Chain of Custody, Urine

62737

Clinical Information: This assay was designed to test for and confirm by gas chromatography-mass spectrometry (GC-MS) the following: -Barbiturates -Benzodiazepines -Cocaine -Methadone -Phencyclidine -Tetrahydrocannabinol Confirmation by liquid chromatograph-tandem mass spectrometry (LC-MS/MS) is completed for all opiates and amphetamines. This test uses the simple screening technique which involves immunologic testing for drugs by class. Oxycodone is not detected well with the opiate screening assay; therefore, OPATX / Opiate Confirmation, Chain of Custody, Urine is included to detect this drug. All positive screening results are confirmed by GC-MS or LC-MS/MS, and quantitated, before a positive result is reported. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny. Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Useful For: Detecting drug use involving amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates, phencyclidine, and tetrahydrocannabinol This chain-of-custody test is intended to be used in a setting where the test results can be used to make a definitive diagnosis.

Interpretation: A positive result derived by this testing indicates that the patient has used 1 of the drugs detected by this technique in the recent past. See individual tests (eg, AMPHX / Amphetamines Confirmation, Chain of Custody, Urine) for more information. For information about drug testing, including estimated detection times, see Drugs of Abuse Testing at http://www.mayomedicallaboratories.com/test-info/drug-book/index.html

Reference Values: Negative Screening cutoff concentrations Amphetamines: 500 ng/mL Barbiturates: 200 ng/mL Benzodiazepines: 100 ng/mL Cocaine (benzoylecgonine-cocaine metabolite): 150 ng/mL Methadone metabolite: 300 ng/mL Opiates: 300 ng/mL Phencyclidine: 25 ng/mL Tetrahydrocannabinol carboxylic acid: 50 ng/mL This report is intended for use in clinical monitoring or management of patients. It is not intended for use in employment-related testing. Current as of August 23, 2017 7:11 am CDT


Page 1616

Clinical References: 1. Physicianâ€™s Desk Reference (PDR). 60th edition. Montvale, NJ, Medical Economics Company, 2006 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th edition. Edited by LL Bruntman. New York, McGraw-Hill Book Company, 2006 3. Langman LJ, Bechtel L, Holstege CP: Chapter 35. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, 2011, pp 1109-1188

PNCSU

Pain Clinic Survey, Urine

65062

Clinical Information: This test uses the simple screening technique that involves immunologic testing for drugs by class. All positive immunoassay screening results are confirmed by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS), and quantitated, before a positive result is reported. This assay was designed to test for and confirm by the following: -Barbiturates -Benzodiazepines -Cocaine -Phencyclidine -Tetrahydrocannabinol Confirmation by LC-MS/MS is completed for all amphetamines. The targeted opioid screen portion is performed by liquid chromatography-tandem mass spectrometry, high-resolution accurate mass (LC-MS/MS HRAM) and is completed for all opioids. Opioids are a large class of medications commonly used to relieve acute and chronic pain or help manage opioid abuse and dependence. Medications that fall into this class include: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, oxymorphone, tapentadol, tramadol, and others. Opioids work by binding to the opioid receptors that are found in the brain, spinal cord, gastrointestinal tract, and other organs. Common side effects include drowsiness, confusion, nausea, constipation, and in severe cases respiratory depression depending on the dose. These medications can also produce physical and psychological dependence and have a high risk for abuse and diversion, which is one of the main reasons many professional practice guidelines recommend compliance testing in patientsâ€™ prescribed these medications. Opioids are readily absorbed from the gastrointestinal tract, nasal mucosa, lungs, and after subcutaneous or intermuscular injection. Opioids are primarily excreted from the kidney in both free and conjugated forms. This assay doesnâ€™t hydrolyze the urine sample and looks for both parent drugs and metabolites (including glucuronide forms). The detection window for most opioids in urine is approximately 1 to 3 days with longer detection times for some compounds (ie, methadone).

Useful For: Detecting drug use involving amphetamines, barbiturates, benzodiazepines, cocaine, opioids, phencyclidine, and tetrahydrocannabinol This test is intended to be used in a setting where the test results can be used to make a definitive diagnosis.

Interpretation: A positive result derived by this testing indicates that the patient has used 1 of the drugs detected by these techniques in the recent past. See individual tests (eg, AMPHU / Amphetamines Confirmation, Urine) for more information. For information about drug testing, including estimated detection times, see Drugs of Abuse Testing at http://www.mayomedicallaboratories.com/test-info/drug-book/index.html

Reference Values: ADULT: Normal Cutoff concentrations Oxidants: 200 mg/L Nitrites: 500 mg/L PNRCH: Negative Screening cutoff concentrations: Amphetamines: 500 ng/mL Barbiturates: 200 ng/mL Benzodiazepines: 100 ng/mL Cocaine (benzoylecgonine-cocaine metabolite): 150 ng/mL Phencyclidine: 25 ng/mL Tetrahydrocannabinol carboxylic acid: 50 ng/mL This report is intended for use in clinical monitoring or management of patients. It is not intended for use Current as of August 23, 2017 7:11 am CDT


Page 1617

in employment-related testing. TOPSU: Not Detected Cutoff concentrations: Codeine: 25 ng/mL Codeine-6-beta-glucuronide: 100 ng/mL Morphine: 25 ng/mL Morphine-6-beta-glucuronide: 100 ng/mL 6-monoacetylmorphine: 25 ng/mL Hydrocodone: 25 ng/mL Norhydrocodone: 25 ng/mL Dihydrocodeine: 25 ng/mL Hydromorphone: 25 ng/mL Hydromorphone-3-beta-glucuronide: 100 ng/mL Oxycodone: 25 ng/mL Noroxycodone: 25 ng/mL Oxymorphone: 25 ng/mL Oxymorphone-3-beta-glucuronide: 100 ng/mL Noroxymorphone: 25 ng/mL Fentanyl: 2 ng/mL Norfentanyl: 2 ng/mL Meperidine: 25 ng/mL Normeperidine: 25 ng/mL Naloxone: 25 ng/mL Naloxone-3-beta-glucuronide: 100 ng/mL Methadone: 25 ng/mL EDDP: 25 ng/mL Propoxyphene: 25 ng/mL Norpropoxyphene: 25 ng/mL Tramadol: 25 ng/mL O-desmethyltramadol: 25 ng/mL Tapentadol: 25 ng/mL N-desmethyltapentadol: 50 ng/mL Tapentadol-beta-glucuronide: 100 ng/mL Buprenorphine: 5 ng/mL Norbuprenorphine: 5 ng/mL Norbuprenorphine glucuronide: 20 ng/mL

Clinical References: 1. Physicians' Desk Reference: 60th edition. Montvale, NJ, Medical Economics Company, 2006 2. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 11th edition. Edited by LL Bruntman. New York, NY. McGraw-Hill Book Company, 2006 3. Langman LJ, Bechtel L, Holstege CP: Chapter 35. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company. 2011, pp 1109-1188 4. Gutstein HB, Akil H: Opioid Analgesics. In The Pharmacological Basis of Therapeutics. 11th edition. Edited by LL Brunton, JS Lazo, KL Parker. Goodman & Gilman's: McGraw-Hill Companies, Inc, 2006 5. Chronic Pain in America: Roadblocks to Relief, survey conducted for the American Pain Society, The American Academy of the Pain Medicine and Janssen Pharmaceutica, 1999 6. Magnani B, Kwong T: Urine drug testing for pain management. Clinical Lab Med 2012;32(32):379-390

FPANS

Pancreastatin

57129

Reference Values: 0-88 pg/mL



Page 1618

FPANC

Pancreatic Elastase Stool

91415

Clinical Information: This assay allows the diagnosis or exclusion of pancreatic exocrine insufficiency, which can be caused by chronic pancreatitis, cystic fibrosis, pancreatic tumor, cholelithiasis or diabetes mellitus.

Reference Values: >200 ug Elastase/g stool = Normal 100 to 200 ug Elastase/g stool = Moderate to slight exocrine pancreatic insufficiency 90% of the total circulating PTH and are primarily cleared by the kidneys. In patients with renal failure, PTH-C fragments can accumulate to high levels. PTH 1-84 is also elevated in these patients, with mild elevations being considered a beneficial compensatory response to end organ PTH resistance, which is observed in renal failure. The serum calcium level regulates PTH secretion via negative feedback through the parathyroid calcium sensing receptor (CASR). Decreased calcium levels stimulate PTH release. Secreted PTH interacts with its specific type II G-protein receptor, causing rapid increases in renal tubular reabsorption of calcium and decreased phosphorus reabsorption. It also participates in long-term calciostatic functions by enhancing mobilization of calcium from bone and increasing renal synthesis of 1,25-dihydroxy vitamin D, which, in turn, increases intestinal calcium absorption. In rare inherited syndromes of parathyroid hormone resistance or unresponsiveness and in renal failure, PTH release may not increase serum calcium levels. Hyperparathyroidism causes hypercalcemia, hypophosphatemia, hypercalcuria, and hyperphosphaturia. Long-term consequences are dehydration, renal stones, hypertension, gastrointestinal disturbances, osteoporosis and sometimes neuropsychiatric and neuromuscular problems. Hyperparathyroidism is most commonly primary and caused by parathyroid adenomas. It can also be secondary in response to hypocalcemia or hyperphosphatemia. This is most commonly observed in renal failure. Long-standing secondary hyperparathyroidism can result in tertiary hyperparathyroidism, which represents the secondary development of autonomous parathyroid hypersecretion. Rare cases of mild, benign hyperparathyroidism can be caused by inactivating CASR mutations. Hypoparathyroidism is most commonly secondary to thyroid surgery, but can also occur on an autoimmune basis, or due to activating CASR mutations. The symptoms of hypoparathyroidism are primarily those of hypocalcemia, with weakness, tetany, and possible optic nerve atrophy.

Useful For: Diagnosis and differential diagnosis of hypercalcemia Diagnosis of primary, secondary, and tertiary hyperparathyroidism Diagnosis of hypoparathyroidism Monitoring end-stage renal failure patients for possible renal osteodystrophy

Interpretation: About 90% of the patients with primary hyperparathyroidism have elevated parathyroid hormone (PTH) levels. The remaining patients have normal (inappropriate for the elevated calcium level) PTH levels. About 40% of the patients with primary hyperparathyroidism have serum phosphorus levels or =16 years: 0.8-1.3 mg/dL Females 0-11 months: not established 1-3 years: 0.1-0.4 mg/dL 4-5 years: 0.2-0.5 mg/dL 6-8 years: 0.3-0.6 mg/dL 9-15 years: 0.4-0.7 mg/dL > or =16 years: 0.6-1.1 mg/dL *The serum concentration of calcium varies significantly during the immediate neonatal period. In general, the serum calcium concentration decreases over the first days of life, followed by a gradual increase to adult concentrations by the second or third week of life. **The plasma concentrations of inorganic phosphate in the neonatal period can be greater than those of the adult.

Clinical References: 1. Boudou P, Ibrahim F, Cormier C, et al: Third- or second-generation parathyroid hormone assays: a remaining debate in the diagnosis of primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90(12):6370-6372 2. Silverberg SJ, Bilezikian JP: The diagnosis and management of asymptomatic primary hyperparathyroidism. Nat Clin Pract Endocrinol Metab 2006;2(9):494-503 3. Brossard JH, Cloutier M, Roy L, et al: Accumulation of a non-(1-84) molecular form of parathyroid hormone (PTH) detected by intact PTH assay in renal failure: importance in the interpretation of PTH values. J Clin Endocrinol Metab 1996;81:3923-3929 4. Garfield N, Karaplis AC: Genetics and animal models of hypoparathyroidism. Trends Endocrinol Metab 2001;12:288-294 5. Sakhaee K: Is there an optimal parathyroid hormone level in end-stage renal failure: the lower the better? Curr Opin Nephrol Hypertens 2001;10:421-427 6. Vetter T, Lohse MJ: Magnesium and the parathyroid. Curr Opin Nephrol Hypertens 2002;11:403-410 7. Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al: Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353-5361

PTHFN 61526

Parathyroid Hormone, Fine-Needle Aspiration Biopsy (FNAB)-Needle Wash Clinical Information: Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands, which are located along the posterior aspect of the thyroid gland. PTH analysis in rinse material obtained from fine-needle aspiration biopsies (FNAB) has gained popularity to discriminate thyroid tissues from enlarged parathyroid glands and also to facilitate parathyroid localization prior to surgery. Various groups have reported on the utility of this technique with specificity of 91% to100% and sensitivity of 91% to 100%. Measuring PTH in the rinse material proved very useful in cases of nondiagnostic cytology. Comparing the results of the PTH rinse material with serum PTH is highly recommended. An elevated PTH in the serum could falsely elevate PTH in the washings if the rinse is contaminated with blood. In these cases, only PTH values significantly higher than the serum should be considered as true positives. Cytologic examination and measurement of PTH can be performed on the same specimen. To measure PTH, the fine-needle aspirate (FNA) needle is rinsed with a small volume of normal saline solution immediately after a specimen for cytological examination has been expelled from the needle for a smear or CytoTrap preparation. Specimen collection is critical for the performance of the assay and the needle should be rinsed with a minimal volume. Each FNA needle from a single biopsied area is washed with 0.1 to 0.5 mL of normal saline. The washes from a single area are pooled (final volume 1-1.5 mL). PTH levels are measured in the saline wash.

Useful For: An adjunct to cytology examination of fine-needle aspiration specimens to confirm or exclude presence of parathyroid tissue in the biopsied area Current as of August 23, 2017 7:11 am CDT


Page 1631

Interpretation: Parathyroid hormone (PTH) values less than 100 pg/mL suggest the biopsied site does not contain PTH-secreting tissue. PTH values greater than or equal to 100 pg/mL are suggestive of the presence PTH-secreting tissue at the site biopsied or along the needle track. This result is dependent on accurate sampling and a total needle wash volume of greater than or equal to 1.5 mL. This test should be interpreted in the context of the clinical presentation, imaging and cytology findings. If the results are discordant with the clinical presentation, a sampling error at the time of the biopsy should be considered.


Clinical References: 1. Erbil Y, Salmaslioglu A, Kabul E, et al: Use of preoperative parathyroid fine-needle asipiration and parathyroid hormone assay in primary hyperparathyroidism with concomitant thyroid nodules. Am J Surg 2007;193:665-671 2. Owens CL, Rekhtman N, Sokoll L, Ali SZ: Parathyroid hormone assay in fine-needle aspirate is useful in differentiating inadvertently sampled parathyroid tissue from thyroid lesions. Diagn Cytopathol 2008 Apr;36(4):227-331 3. Giusti M, Dolcino M, Vera L, et al: Institutional experience of PTH evaluation on fine-needle washing after aspiration biopsy to locate hyperfunctioning parathyroid tissue. J Zhejiang Univ Sci B 2009 May;10(5):323-330 4. Kiblut N, Cussac J, Soudan B, et al: Fine needle aspiration and intraparathyroid intact parathyroid hormone measurement for reoperative parathyroid surgery. World J Surg 2004 Nov;28(11):1143-1147

PTHRP

Parathyroid Hormone-Related Peptide (PTHrP), Plasma

81774

Clinical Information: Hypercalcemia of malignancy is a common cause of hypercalcemia in hospitalized patients. Hypercalcemia of malignancy is typically not due to excess parathyroid hormone (PTH). In these disorders, PTH is usually suppressed due to elevated serum calcium concentrations. A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include: -Impaired renal function due to a tumor or its treatment -Osteolytic activity within bony metastases -Release of calcemic cytokines by non-osteolytic bony metastases -Eectopic 1-alpha hydroxylase activity in tumor tissues -Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases) -Other, as yet unknown factors Frequently, a single cause cannot be pinpointed. Amongst the defined causes of the condition, PTHrP secretion is believed to be the most common culprit. PTHrP is a single monomeric peptide that exists in several isoforms, ranging from approximately 60 amino acids to 173 amino acids in size, which are created by differential splicing and post-translational processing by prohormone convertases. PTHrP is produced in low concentrations by virtually all tissues. The physiological role of PTHrP remains incompletely understood. Its functions can be broadly divided into 4 categories, not all of which are present in all PTHrP isoforms or in all tissues: -Transepithelial calcium transport, particularly in the kidney and mammary gland -Smooth muscle relaxation in the uterus, bladder, gastrointestinal tract, and arterial wall -Regulation of cellular proliferation -Cellular differentiation and apoptosis of multiple tissues -As an indispensable component of successful pregnancy and fetal development (embryonic gene deletion is lethal in mammals) PTHrP's diverse functions are mediated through a range of different receptors, which are activated by different portions of PTHrP. Among the many receptors that respond to PTHrP is the PTH receptor, courtesy of the fact that 8 of the 13 N-terminal amino acids of PTH and of 3 common PTHrP isoforms are identical. Since most of PTHrP's actions in normal physiology are autocrine or paracrine, with circulating levels being very low, this receptor cross-talk only becomes relevant when there is extreme and sustained over-production of PTHrP. This is seen occasionally in pregnancy, lactation and, rarely, in a variety of non-malignant diseases. However, most commonly it is observed when tumors secrete PTHrP ectopically. In rough correlation with physiological production levels of PTHrP in the corresponding healthy tissues, ectopic PTHrP production is most commonly seen in carcinomas of breast, lung (squamous), head and neck (squamous), kidney, bladder, cervix, uterus, and ovary. Neuroendocrine tumors may also occasionally produce PTHrP. Most other carcinomas, sarcomas, and hemato-lymphatic malignancies only sporadically produce PTHrP, with the notable exceptions of T-cell lymphomas and myeloma. Patients with HHM may have increased PTHrP values before treatment. PTHrP level decreases and PTH level increases, accompanied by decreased serum calcium values, with successful treatment.



Page 1632

Useful For: Diagnostic work-up of patients with suspected hypercalcemia of malignancy Diagnostic work-up of patients with hypercalcemia of unknown origin

Interpretation: Depending on the patient population, up to 80% of patients with malignant tumors and hypercalcemia will be suffering from humoral hypercalcemia of malignancy (HHM). Of these, 50% to 70% might have an elevated parathyroid hormone-related peptide (PTHrP) level. These patients will also usually show typical biochemical changes of excess parathyroid hormone (PTH)-receptor activation, namely, besides the hypercalcemia, the might have hypophosphatemia, hypercalcuria, hyperphosphaturia and elevated serum alkaline phosphatase. Their PTH levels will typically be less than 30 pg/mL or undetectable. In patients with biochemical findings that suggest but do not prove primary hyperparathyroidism (eg, hypercalcemia, but normal or near normal serum phosphate and a PTH level that is within the population reference range, but above 30 pg/mL), HMM should be considered as a diagnostic possibility, particularly if the patient is elderly, has a history of malignancy or risk factors for malignancy. An elevated PTHrP level in such a patient is highly suggestive of HHM as the cause for the hypercalcemia.

Reference Values: or =25.0 Units Reference values apply to all ages.

Clinical References: 1. Toh BH, Van Driel IR, Gleeson PA: Pernicious anemia. N Eng J Med 1997;337(20):1441-1448 2. Lahner E, Annibale B: Pernicious anemia: new insights from a gastroenterological point of view. World J Gastroenterol 2009;15(41):5121-5128 3. Lahner E, Normal GL, Severi C, et al: Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency. Am J Gastroenterol 2009;104(8):2071-2079 4. Product Insert: QUANTA Lite GPA, INOVA Diagnostics, Inc., San Diego, CA

PJUD

Parietaria judaica, IgE

82877



POFF

Parietaria officinalis, IgE

82549





Page 1635

PARO

Paroxetine, Serum

83731

Clinical Information: Paroxetine (Paxil and Paxil CR) is approved for treatment of depression. Paroxetine is completely absorbed. Metabolites of paroxetine are inactive. Paroxetine metabolism is carried out by cytochrome P450 (CYP) 2D6. Paroxetine can saturate CYP2D6 resulting in a nonlinear relationship between dose and serum concentration. Paroxetine clearance is significantly affected by reduced hepatic function, but only slightly by reduced renal function. A typical adult paroxetine dose is 30 mg per day. Paroxetine is 100% bioavailable, 95% protein bound, and the apparent volume of distribution is 17 L/Kg. Time to peak serum concentration is 5 hours for the regular product and 8 hours for the controlled release product. The elimination half-life is 20 hours. Half-life is prolonged in the elderly and with cirrhosis.

Useful For: Monitoring paroxetine therapy Identifying noncompliance, although regular blood level monitoring is not indicated in most patients Identifying states of altered drug metabolism when used in conjunction with CYP2D6 genotyping

Interpretation: Steady-state serum concentrations associated with optimal response to paroxetine are in the range of 30 to 120 ng/mL. The most common toxicities associated with excessive serum concentration are asthenia, anticholinergic effects, anxiety, blurred vision, and changes in sexual function. Toxic range: > or =400 ng/mL.

Reference Values: 30-120 ng/mL

Clinical References: 1. Hiemke C, Baumann P, Bergemann N, et al: AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011;44:195-235 2. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. Elsevier, Mosby, Saunders, 2011

FPRTF

Parrot Australian (Budgerigar) Feathers IgE

57967




70012

Pathology Consultation Clinical Information: Mayo Clinic Rochester is staffed by pathologists whose expertise and special interests cover the entirety of pathology-from surgical pathology with all of its respective subspecialty areas, to Hematopathology, Renal Pathology, and Dermatopathology. We provide consultation services on difficult diagnostic problems. Consultation cases may be sent by a referring pathologist and directed to one of the pathologists who is an expert in the given area or directed more broadly to the subspecialty group. Cases are frequently shared and sometimes transferred between the pathologists, as deemed appropriate for the type of case or diagnostic problem encountered. Emphasis is placed on prompt and accurate results. Stained slides and paraffin blocks received are reviewed in conjunction with the clinical



Page 1640

history provided, laboratory findings, radiographic findings (if applicable), and sending pathologist's report or letter. If additional special stains or studies are needed, the results are included in the final interpretive report. In some cases, electron microscopy and other special procedures are utilized as required. A variety of ancillary studies are available (eg, cytochemistry, immunohistochemistry, immunofluorescence, electron microscopy, mass spectrometry, cytogenetics, and molecular genetics) to aid in establishing a diagnosis. These ancillary studies are often expensive and labor intensive, and are most efficiently utilized and interpreted in the context of the morphologic features. It is our goal to provide the highest possible level of diagnostic consultative service, while trying to balance optimal patient care with a cost-conscious approach to solving difficult diagnostic problems.

Useful For: Obtaining a rapid, expert second opinion on specimens referred by the primary pathologist Obtaining special studies not available locally

Interpretation: Results of the consultation are reported in a formal pathology report that includes a description of ancillary test results (if applicable) and an interpretive comment. When the case is completed, results are communicated by a phone call. The formal pathology report is faxed. In our consultative practice, we strive to bring the customer the highest quality of diagnostic pathology, in all areas of expertise, aiming to utilize only those ancillary tests that support the diagnosis in a cost-effective manner, and to provide a rapid turnaround time for diagnostic results.

60950

PAX-5, Immunostain Without Interpretation Clinical Information: PAX-5, also known as B-cell-specific activator protein (BSAP), is a B-cell specific transcription factor expressed during differentiation. Plasma cells (terminally differentiated B cells) are usually negative. Used in the classification of B-cell lymphomas.


Clinical References: 1. Desouki MM, Post GR, Cherry D, Lazarchick J. PAX-5: A Valuable Immunohistochemical Marker in the Differential Diagnosis of Lymphoid Neoplasms. Clin Med Res 2010;8(2):84-88 2. Feldman AL, Dogan A. Diagnostic Uses of PAX5 Immunohistochemistry. Adv Anat Pathol 2007;14(5):323-334 3. Jensen KC, Higgins JPT, Montgomery K, et al: The Utility of PAX5 Immunohistochemistry in the Diagnosis of Undifferentiated Malignant Neoplasms. Modern Pathology 2007;20:871-877

62690

PAX8, Immunostain Without Interpretation Clinical Information: PAX8 is a member of the paired box gene (PAX) family of transcription factors involved in kidney cell and thyroid development. PAX8 has been shown to be expressed in a high percentage of renal neoplasms, including both malignant renal cell carcinomas and benign renal tumors (oncocytomas). PAX8 has also been reported to be expressed in ovarian carcinomas.

Useful For: Aids in the identification of renal cell carcinomas, as well as papillary thyroid carcinomas and tumors of Mullerian origin

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact Mayo Medical Laboratories at 800-533-1710. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a Current as of August 23, 2017 7:11 am CDT


Page 1641

qualified pathologist.

Clinical References: 1. Chang A, Brimo F, Montgomery EA, et al: Use of PAX8 and GATA3 in diagnosing sarcomatoid renal cell carcinoma and sarcomatoid urothelial carcinoma. Hum Pathol 2013;44:1563-1568 2. Hu Y, Hartmann A, Stoehr C, et al: PAX8 is expressed in the majority of renal epithelial neoplasms: an immunohistochemical study of 223 cases using a mouse monoclonal antibody. J Clin Pathol 2012;65:254-256 3. Laury AR, Perets R, Piao H, et al: A comprehensive analysis of PAX8 expression in human epithelial tumors. Am J Surg Pathol 2011;35(6):816-826 4. Ozcan A, Shen SS, Hamilton C, et al: PAX8 expression in non-neoplastic tissues, primary tumors, and metastatic tumors: a comprehensive immunohistochemical study. Mod Pathol 2011;24:751-764 5. Tacha D, Qi W, Zhou D, et al: PAX8 mouse monoclonal antibody (BC12) recognizes a restricted epitope and is highly sensitive in renal cell and ovarian cancers but does not cross-react with B cells and tumors of pancreatic origin. Appl Immunohistochem Mol Morphol 2013;21(1):59-63 6. Tacha D, Zhou D, Cheng L, et al: Expression of PAX8 in normal and neoplastic tissuesâ€“A comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol 2011;19(4):293-299

FPPCA

PCA3 (Prostate Cancer Antigen 3)

75211

Clinical Information: Prostate cancer antigen 3 (PCA3, also known as Differential Display Code 3 or DD3) is a prostate-specific gene that was present in 95% of prostate cancer samples initially studied, and significantly over-expressed in cancer versus benign tissue. PCA3 is known to be a non-coding messenger ribonucleic acid (mRNA) with no resultant protein. Clinically, PCA3 mRNA is detectable in the urine and appears to be independent of prostate volume and serum PSA. The PCA3 urinary assay is reported out as a ratio of PCA3 mRNA to PSA mRNA.

Reference Values: A score less than 25 is considered negative A score greater than or equal to 25 is considered positive

88725

PD-L1 (B7-H1, CD274), Semi-Quantitative Immunohistochemistry, Manual Clinical Information: Programmed cell death 1 ligand 1 (PD-L1), also known as B7 homolog 1 (B7-H1) or CD274, is a transmembrane protein involved in the regulation of cell-mediated immune responses through interaction with the receptor programmed death-1 (PD-1). PD-L1 has been identified as both a prognostic and theranostic marker in a variety of neoplasms. Overexpression of PD-L1 has been observed in carcinomas of the bladder, lung, thymus, colon, pancreas, ovary, breast, kidney, and in melanoma and glioblastoma.

Useful For: Identification of neoplasms expressing programmed cell death 1 ligand 1 Interpretation: This test will be answered as percent tumor cells positive or negative and immune cells positive or negative. If additional interpretation or analysis is needed, request test 70012 / Pathology Consultation along with this test.

Clinical References: 1. D'Incecco A, Andreozzi M, Ludovini V, et al: PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer 2015 Jan 6;112(1):95-102 2. Bigelow E, Bever, KM, Xu H, et al: Immunohistochemical staining of B7-H1 (PD-L1) on paraffin-embedded slides of pancreatic adenocarcinoma tissue. J Vis Exp 2013 Jan 3;(71):e4059 3. Nakanishi J, Wada Y, Matsumoto K, et al: Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 2007 Aug;56(8):1173-1182 4. Dong H, Zhu G, Tamada K, Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999 Dec 5;(12):1365-1369



Page 1642

PDGF 58102

PDGFB (22q13), Dermatofibrosarcoma Protuberans/Giant Cell Fibroblastoma, FISH, Tissue Clinical Information: Dermatofibrosarcoma protuberans (DFSP) is a superficial, low-grade sarcoma genetically characterized by the unbalanced chromosomal translocation t(17;22)(q21;q13), usually in the form of a supernumerary ring chromosome. The product of this chromosomal translocation is the chimeric gene COL1A1-PDGFB. Rearrangements of this gene have been detected in approximately 90% of DFSP and its related infantile form, giant cell fibroblastoma, but not in other tumors.

Useful For: Confirming the diagnosis of dermatofibrosarcoma protuberans (DFSP)/giant cell fibroblastoma (GCF) and excluding other spindle neoplasms that closely simulate the DFSP histology, including dermatofibroma (benign fibrous histiocytoma), neurofibroma, spindle cell lipoma, and a variety of other benign and malignant spindle cell neoplasms

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for the PDGFB FISH probe. A positive result is consistent with rearrangement/amplification of the PDGFB gene locus on 22q13 and supports the diagnosis of dermatofibrosarcoma protuberans (DFSP) or giant cell fibroblastoma (GCF). A negative result is consistent with no rearrangement/amplification of the PDGFB gene locus on 22q13. However, this result does not exclude the diagnosis of DFSP or GCF. The degree of PDGFB copy gain/amplification/rearrangement varies in individual tumors and among different cells in the same tumor. It is not currently known if patients with different levels of rearrangement/amplification have the same prognosis and response to therapy.


Clinical References: 1. Abbott JJ, Erickson-Johnson M, Wang X, et al: Gains of COL1A1-PDGFB genomic copies occur in fibrosarcomatous transformation of dermatofibrosarcoma protuberans. Mod Pathol 2006 Nov;19(11):1512-1518 2. Labropoulos SV, Fletcher JA, Oliveira AM, et al: Sustained complete remission of metastatic dermatofibrosarcoma protuberans with imatinib mesylate. Anticancer Drugs 2005 April;16(4):461-466 3. Macarenco RS, Zamolyi R, Franco MF, et al: Genomic gains of COL1A1-PDGFB occur in the evolution of giant cell fibroblastoma into dermatofibrosarcoma protuberans. Genes Chromosomes Cancer 2008 Mar;47(3):260-265

PDG12

PDGFRA Exon 12, Mutation Analysis

35339

Clinical Information: Occasional cases of gastrointestinal stromal tumors (GIST) can harbor mutations in PDGFRA, a gene structurally related to KIT. The frequency and type of mutations vary among these tumors and portent distinct clinical implications. The ordering physician is responsible for the diagnosis and management of disease and decisions based on the data provided.

Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or other related tumors Identification of a mutation in exon 12 of the PDGFRA gene



Clinical References: 1. Schildhaus HU, Cavlar T, Binot E, et al: Inflammatory fibroid polyps harbour mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. J Pathol 2008;216(2):176-182 2. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 3. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 4. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. Current as of August 23, 2017 7:11 am CDT


Page 1643

J Clin Oncol 2004;22:3813-3825 5. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 6. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib mesylate response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 7. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

PDG14


35340


Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or other tumors Identification of a mutation in exon 14 of the PDGFRA gene



Clinical References: 1. Schildhaus HU, Cavlar T, Binot E, et al: Inflammatory fibroid polyps harbour mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. J Pathol 2008;216(2):176-182 2. Robson ME, Blogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 3. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743 4. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 5. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 6. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 7. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695

PDG18


35341


Useful For: Diagnosis and management of patients with gastrointestinal stromal tumors or other related tumors Identification of a mutation in exon 18 of the PDGFRA gene



Clinical References: 1. Schildhaus HU, Cavlar T, Binot E, et al: Inflammatory fibroid polyps harbour mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene. J Pathol Current as of August 23, 2017 7:11 am CDT


Page 1644

2008;216(2):176-182 2. Corless CL, Fletcher JA, Heinrich MC: Biology of gastrointestinal stromal tumors. J Clin Oncol 2004;22:3813-3825 3. Debiec-Rychter M, Raf Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-1103 4. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Onc 2003;21:4342-4349 5. Debiec-Rychter M, Dumez H, Judson I, et al: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2004;40:689-695 6. Robson ME, Glogowski E, Sommer G, et al: Pleomorphic characteristics of a germ-line KIT mutation in a large kindred with gastrointestinal stromal tumors, hyperpigmentation, and dysphagia. Clin Cancer Res 2004;10:1250-1254 7. Li FP, Fletcher JA, Heinrich MC, et al: Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 2005;23:2735-2743

512F 35254

PDGFRB/TEL Translocation (5;12) for Chronic Myelomonocytic Leukemia (CMML), FISH Clinical Information: Platelet-derived growth factor receptor-beta (PDGFRB) produces a tyrosine kinase involved in cell proliferation. Translocation-ets-leukemia protein (encoded by the gene ETV6) is a gene transcription protein that is frequently rearranged in leukemias. A 5;12 translocation, t(5;12)(q33;p13), results in a fusion product (PDGFRB/ETV6) that is seen in approximately 1% to 2% of patients diagnosed with chronic myelomonocytic leukemia. Patients with this translocation often have associated hypereosinophilia. Imatinib mesylate is an inhibitor of tyrosine kinases, including PDGFRB. Patients with the 5;12 translocation are reportedly responsive to imatinib mesylate; upon treatment, they usually go into complete remission.

Useful For: Identifying patients with chronic myelomonocytic leukemia and other hematologic disorders who may be responsive to imatinib mesylate Identifying and tracking chromosome abnormalities and response to therapy

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal cutoff. The presence of a positive clone supports a diagnosis of malignancy. The absence of an abnormal clone does not rule out the presence of neoplastic disorder.


Clinical References: 1. Pardanani A, Reeder T, Porrata LF, et al: Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003;101:3391-3397 2. Cain JA, Grisolano JL, Laird AD, et al: Complete remission of TEL-PDGFRB-induced myeloproliferative disease in mice by receptor tyrosine kinase inhibitor SU11657. Blood 2004;104:561-564

FBEP

Pea Black-Eyed/Cow Pea (Vigna sinensis) IgE

57935




PAS38

Pediatric Allergy Screen 3 to 8 Years, Serum

83346



Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the Current as of August 23, 2017 7:11 am CDT


Page 1652

concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PAS3

Pediatric Allergy Screen

83345





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5




Page 1653

6



PAS8

Pediatric Allergy Screen >8 Years, Serum

83347





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PBPO

Penicillin G, IgE

82660

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from



Page 1654

immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PENIV

Penicillin V, IgE

82656


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm Current as of August 23, 2017 7:11 am CDT


Page 1655

sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PENL

Penicillium chrysogenum, IgE

82913




Reference Values: Class IgE kU/L Interpretation 0 1

Negative 0.35-0.69 Equivocal



Page 1656

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PENTS

Pentobarbital, Serum

8239

Clinical Information: Pentobarbital is a short-acting barbiturate with anticonvulsant and sedative-hypnotic properties. Uses include sedation induction; relief of preoperative anxiety; control of status epilepticus or seizures resulting from meningitis, tetanus, alcohol withdrawal, poisons, chorea, or eclampsia; and induction of coma in the management of cerebral ischemia and increased intracranial pressure that may follow stroke or head trauma.(1,2) Pentobarbital is administered orally, parenterally, and rectally. The duration of hypnotic effect is about 1 to 4 hours. The drug distributes throughout the body, with about 35% to 45% of a dose bound to plasma proteins in the blood. Metabolism takes place in the liver via oxidation to the inactive metabolite hydroxypentobarbital. Elimination is biphasic; half-life is about 4 hours in the first phase, and 35 to 50 hours in the second phase. Excretion occurs through the urine, mainly as glucuronide conjugates of metabolites, with only about 1% excreted as unchanged drug.(1,2) Tolerance to pentobarbital's hypnotic effects occurs after about 2 weeks of continuous dosing.

Useful For: Monitoring of pentobarbital therapy treatment Interpretation: Therapeutic range(3) Hypnotic: 1 to 5 mcg/mL Therapeutic coma: 20 to 50 mcg/mL Reducing intracranial pressure: 30 to 40 mcg/mL -This degree of sedation requires artificial respiratory support. Toxic: >10 mcg/mL -The concentration at which toxicity occurs varies; results should be interpreted in light of clinical situation.

Reference Values: Therapeutic range Hypnotic: 1-5 mcg/mL Therapeutic coma: 20-50 mcg/mL Reducing intracranial pressure: 30-40 mcg/mL This degree of sedation requires artificial respiratory support. Toxic concentration: >10 mcg/mL The concentration at which toxicity occurs varies; results should be interpreted in light of clinical situation.

Clinical References: 1. Package insert: NEMBUTAL Sodium Solution (pentobarbital sodium injection). Deerfield, IL: Ovation Pharmaceuticals Inc., October, 2007 2. Physician's Desk Reference (PDR). 61st edition. Montvale, NJ: Thomson PDR, 2007 3. Teitz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. St. Louis, MO. Elsevier Saunders, 2006 pp 2312

FPBPG

Pepper Bell/Paprika IgG

57657

Interpretation: mcg/mL of IgG Lower Limit of Quantitation 2.0 Upper Limit of Quantitation 200 Reference Values: or =30.0 mcg/mL Phenytoin, Free Therapeutic: 1.0-2.0 mcg/mL Critical value: > or =2.5 mcg/mL

Clinical References: 1. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153-169 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 2005, pp 1237-1285



Page 1672

PNYG

Phenytoin, Total and Phenobarbital Group, Serum

37050

Clinical Information: Phenytoin, Total: Phenytoin is the drug of choice to treat and prevent tonic-clonic and psychomotor seizures. If phenytoin alone will not prevent seizure activity, coadministration with phenobarbital is usually effective. Initial therapy with phenytoin is started at doses of 100 to 300 mg/day for adults or 4 mg/kg/day for children. Because absorption is variable and the drug exhibits zero-order (nonlinear) kinetics, dose must be adjusted within 5 days using blood concentration to guide therapy. Oral bioavailability ranges from 80% to 95% and is diet-dependent. Phenytoin exhibits zero-order pharmacokinetics; the rate of clearance of the drug is dependent upon the concentration of drug present. Therefore, phenytoin does not have a classical half-life like other drugs, since it varies with blood concentration. At a blood concentration of 15 mcg/mL, approximately half the drug in the patient's body will be eliminated in 20 hours. As the blood concentration drops, the rate at which phenytoin is excreted increases. Phenytoin has a volume of distribution of 0.65 L/kg, and is highly protein bound (90%), mostly to albumin. Some drug side-effects occur in the therapeutic range; these include gingival hyperplasia, hyperglycemia, and skin rash. Phenytoin pharmacokinetics are significantly affected by a number of other drugs. As noted above, phenytoin and phenobarbital are frequently coadministered. Induction of the cytochrome P450 enzyme system by phenobarbital will increase the rate at which phenytoin is metabolized and cleared. At steady-state, enzyme induction will increase the rate of clearance of phenytoin such that the dose must be increased approximately 30% to maintain therapeutic levels. Uremia has a similar effect on phenytoin protein binding. In uremia, by-products of normal metabolism accumulate and bind to albumin, displacing phenytoin which causes an increase in the free fraction. Valproic acid, an antiepileptic frequently coadministered with phenytoin, competes for the same binding sites on albumin as phenytoin. Valproic acid displaces phenytoin from albumin, reducing the bound fraction and increasing the free fraction. The overall effect of coadministration of a therapeutic dose of valproic acid is that the total concentration of phenytoin decreases due to increased clearance but the free fraction increases; the free concentration of phenytoin, which is the active form remains virtually the same. Thus, no dosage adjustment is needed when valproic acid is added to maintain the same pharmacologic effect, but the total concentration of phenytoin decreases. In contrast to the valproic acid situation, in renal failure, there is not the same opportunity for the free phenytoin fraction to be cleared. The end result is that both the total and free concentration of phenytoin increase, with the free concentration increasing faster than the total. Dosage must be reduced to avoid toxicity. The free phenytoin level is the best indicator of adequate therapy in renal failure. Toxicity is a constant possibility because of the manner in which phenytoin is metabolized. Small increases in dose can lead to very large increases in blood concentration, resulting in early signs of toxicity such as nystagmus, ataxia, and dysarthria. Severe toxicity occurs when the blood concentration is >30 mcg/mL and is typified by tremor, hyperreflexia, and lethargy. The outcome of phenytoin toxicity is not as serious as phenobarbital because phenytoin is not a central nervous system sedative. Phenobarbital: Phenobarbital is a general central nervous system (CNS) suppressant that has proven effective in the control of generalized and partial seizures. It is frequently coadministered with phenytoin for control of complex seizure disorders and with valproic acid for complex parietal seizures. Phenobarbital is administered in doses of 60 to 300 mg/day in adults or 3 to 6 mg/kg/day in children. Phenobarbital is slowly but completely absorbed, with bioavailability in the range of 100%. It is approximately 50% protein bound with a volume of distribution of 0.5 L/kg. Phenobarbital has a long half-life of 96 hours, with no known active metabolites. Sedation is common at therapeutic concentrations for the first 2 to 3 weeks of therapy, but this side effect disappears with time. Toxicity due to phenobarbital overdose is characterized by CNS sedation and reduced respiratory function. Mild symptoms characterized by ataxia, nystagmus, fatigue, or attention loss, occur at blood concentrations >40 mcg/mL. Symptoms become severe at concentrations > or =60 mcg/mL. Toxicity becomes life-threatening at concentrations >100 mcg/mL. Death usually occurs due to respiratory arrest when pulmonary support is not supplied manually. There are no known drug interactions that significantly affect the pharmacokinetics of phenobarbital; conversely, phenobarbital affects the pharmacokinetics of other drugs significantly because it induces the synthesis of enzymes associated with the hepatic cytochrome P450 metabolic pathway. Acute intermittent porphyria attacks may be induced by phenobarbital stimulation of hepatic cytochrome P450.

Useful For: Monitoring for appropriate therapeutic concentration of phenytoin and phenobarbital Assessing compliance or toxicity

Interpretation: The therapeutic ranges for adults taking phenytoin have been established at 10 to 20 mcg/mL for total phenytoin (bound plus unbound). The therapeutic range for phenobarbital is10 to 40 Current as of August 23, 2017 7:11 am CDT


Page 1673

mcg/mL. Within these ranges, most people will respond to the drugs without symptoms of toxicity. However, response and side effects will be individual. Dosage determinations and adjustments must be evaluated on a case-by-case basis. A free (unbound) phenytoin level may also need to be ordered when a person has kidney failure, liver disease, hypoalbuminemia, or is taking other medications like aspirin, naproxen, or ibuprofen, in which situation the percentage of free (active) phenytoin may be increased.

Reference Values: PHENYTOIN, TOTAL Therapeutic: 10.0-20.0 mcg/mL Critical value: > or =30.0 mcg/mL PHENOBARBITAL Therapeutic: 10.0-40.0 mcg/mL: Critical value: > or =60.0 mcg/mL

Clinical References: Phenytoin, Total: 1. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153-169 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. WB Saunders Company, Philadelphia, 2005, pp 1237-1285 Phenobarbital: Foero O, Kastrup KW, Nielsen EL, et al: Successful prophylaxis of febrile convulsions with phenobarbital. Epilepsia 1972;13:279-285

PNYA

Phenytoin, Total, Serum

37048

Clinical Information: Phenytoin is the drug of choice to treat and prevent tonic-clonic and psychomotor seizures. If phenytoin alone will not prevent seizure activity, coadministration with phenobarbital is usually effective. Initial therapy with phenytoin is started at doses of 100 to 300 mg/day for adults or 4 mg/kg/day for children. Because absorption is variable and the drug exhibits zero-order (nonlinear) kinetics, dose must be adjusted within 5 days using blood concentration to guide therapy. Oral bioavailability ranges from 80% to 95% and is diet-dependent. Phenytoin exhibits zero-order pharmacokinetics; the rate of clearance of the drug is dependent upon the concentration of drug present. Therefore, phenytoin does not have a classical half-life like other drugs, since it varies with blood concentration. At a blood concentration of 15 mcg/mL, approximately half the drug in the patient's body will be eliminated in 20 hours. As the blood concentration drops, the rate at which phenytoin is excreted increases. Phenytoin has a volume of distribution of 0.65 L/kg, and is highly protein bound (90%), mostly to albumin. Some drug side-effects occur in the therapeutic range; these include gingival hyperplasia, hyperglycemia, and skin rash. Phenytoin pharmacokinetics are significantly affected by a number of other drugs. As noted above, phenytoin and phenobarbital are frequently coadministered. Induction of the cytochrome P450 enzyme system by phenobarbital will increase the rate at which phenytoin is metabolized and cleared. At steady-state, enzyme induction will increase the rate of clearance of phenytoin such that the dose must be increased approximately 30% to maintain therapeutic levels. Uremia has a similar effect on phenytoin protein binding. In uremia, by-products of normal metabolism accumulate and bind to albumin, displacing phenytoin, which causes an increase in the free (active) fraction. Concurrent use of phenytoin and valproic acid (another frequently used antiepileptic) may result in altered valproic acid levels and/or altered phenytoin levels. Due to the complex situation involving displacement of protein-bound phenytoin and inhibition of phenytoin metabolism, as well as the potential for decreased valproic acid concentrations, patients should be monitored for both phenytoin toxicity and therapeutic efficacy. Free phenytoin levels should be measured to provide the most accurate assessment of phenytoin activity early in therapy. At steady-state, free phenytoin and free valproic acid concentrations should be normalized. The free phenytoin level is the best indicator of adequate therapy in renal failure. In renal failure, the opportunity for the free phenytoin fraction to be cleared is significantly reduced. The end result is that both the total and free concentration of phenytoin increase, with the free concentration increasing faster than the total. Dosage must be reduced to avoid toxicity. Accordingly, the free phenytoin level is the best indicator of adequate therapy in renal failure. Toxicity is a constant possibility because of the manner in which phenytoin is metabolized. Small increases in dose can lead to very large increases in blood concentration, resulting in early signs of toxicity such as nystagmus, ataxia, and dysarthria. Severe toxicity occurs when the blood concentration is above 30 mcg/mL and is typified by tremor, hyperreflexia, and lethargy. The outcome of phenytoin toxicity is not as serious as phenobarbital because



Page 1674

phenytoin is not a central nervous system sedative.

Useful For: Monitoring for appropriate therapeutic concentration Assessing compliance or toxicity Interpretation: Dose should be adjusted to achieve steady-state total phenytoin concentrations between 10.0 and 20.0 mcg/mL. In patients with renal failure, total phenytoin is likely to be less than the therapeutic range of 10.0 to 20.0 mcg/mL. Severe toxicity occurs when the total blood concentration exceeds 30.0 mcg/mL.


Clinical References: 1. Richens A: Clinical pharmacokinetics of phenytoin. Clin Pharmacokinet 1979;4:153-169 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. WB Saunders Company, Philadelphia, 2005, pp 1237-1285

PHMA

Phoma betae, IgE

82736





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 1675


FPGA

Phosphatidylglycerol Antibodies, IgG, IgM and IgA

58042

Reference Values: Phosphatidylglycerol Antibody, IgG: 0 â€“ 11 U/mL: Normal 12 â€“ 18 U/mL: Equivocal. Suggest repeat testing in 4 â€“ 6 weeks or consider antibody testing for cardiolipin IgG and IgM, beta-2 glycoprotein 1 IgG and IgM and lupus anticoagulant. 19 U/mL or greater: Positive Phosphatidylglycerol Antibody, IgM: 0 â€“ 11 U/mL: Normal 12 â€“ 18 U/mL: Equivocal. Suggest repeat testing in 4 â€“ 6 weeks or consider antibody testing for cardiolipin IgG and IgM, beta-2 glycoprotein 1 IgG and IgM and lupus anticoagulant. 19 U/mL or greater: Positive Phosphatidylglycerol Antibody, IgA: 0 â€“ 11 U/mL: Normal 12 â€“ 18 U/mL: Equivocal. Suggest repeat testing in 4 â€“ 6 weeks or consider antibody testing for cardiolipin IgG and IgM, beta-2 glycoprotein 1 IgG and IgM and lupus anticoagulant. 19 U/mL or greater: Positive

FPHAB

Phosphatidylinositol Antibodies, IgG, IgM and IgA

57371

Reference Values: Phosphatidylinositol Antibody IgG Phosphatidylinositol Antibody IgM Phosphatidylinositol Antibody IgA

(0 â€“ 18) U/mL (0 â€“ 18) U/mL (0 â€“ 18) U/mL

0 â€“ 11 u/mL: Normal 12 â€“ 18 u/mL: Equivocal. Suggest repeat testing in 4 â€“ 6 weeks or consider antibody testing for cardiolipin IgG and IgM, beta-2 glycoprotein 1 IgG and IgM and lupus anticoagulant. 19 or greater u/mL: Positive

PSPT

Phosphatidylserine/Prothrombin Antibody, IgG and IgM, Serum

64704

Clinical Information: A diagnosis of antiphospholipid syndrome (APS) is based on clinical and laboratory evaluation. The clinical manifestations associated with APS include arterial and venous thrombosis and recurrent pregnancy loss. The laboratory testing for APS focuses on assessment for autoantibodies specific for phospholipid/protein cofactor complexes. The current criteria require detection of anticardiolipin, anti-beta 2-glycoprotein I, or lupus anticoagulant (LAC) for classification of APS. Cardiolipin is an anionic phospholipid that interacts with the protein cofactor beta 2-glycoprotein I. Anticardiolipin and anti-beta 2-glycoprotein I antibodies are detected by immunoassay using the antigen of cardiolipin/beta 2-glycoprotein I or purified beta 2-glycoprotein I, respectively. LAC is an indirect assessment for the presence of antiphospholipid antibodies, which is evident in the in vitro prolongation of phospholipid-dependent coagulation. There is evidence to suggest that patients with APS may develop autoantibodies to other phospholipid/protein complexes, specifically phosphatidylserine/prothrombin (PS/PT). Similar to cardiolipin/beta 2-glycoprotein I, PS/PT is a complex composed of the anionic phospholipid phosphatidylserine and the protein cofactor prothrombin. A recent systematic review has demonstrated that anti-PS/PT antibodies are a significant risk factor for arterial and venous thrombotic events, with an odds ratio of 5.11 (4.2-6.3). In addition, a separate study indicated that anti-PS/PT



Page 1676

antibodies showed the highest correlation with LAC, compared to anticardiolipin or anti-beta 2-glycoprotein I antibodies (p=0.002). Anti-PS/PT antibodies may be a useful additional marker for evaluation of patients with suspected APS, particularly for those individuals with evidence of thrombosis or abnormal LAC testing.

Useful For: Evaluation of patients with suspected antiphospholipid syndrome Evaluation of patients with a strong suspicion of antiphospholipid syndrome for whom anticardiolipin/beta 2-glycoprotein I and anti-beta 2-glycoprotein I antibody testing was negative Evaluation of patients with evidence of a functional lupus anticoagulant Detection of both IgM and IgG antibodies against phosphatidylserine/prothrombin

Interpretation: A positive result is consistent with the presence of an antibody specific for the phosphatidylserine/prothrombin complex, and may be consistent with a diagnosis of antiphospholipid syndrome (APS) in patients with evidence of arterial or venous thrombosis or recurrent pregnancy loss. A negative result is consistent with the absence of an antibody specific for the phosphatidylserine/prothrombin complex. However, this does not exclude the diagnosis of APS, as other phospholipid/protein antibodies are also associated with this disorder.

Reference Values: Negative < or =30.0 U Borderline 30.1-40.0 U Positive > or =40.1 U

Clinical References: 1. Otomo K, Atsumi T, Amenqual O, et al: Efficacy of the antiphospholipid score for the diagnosis of antiphospholipid syndrome and its predictive value for thrombotic events. Arthritis Rheum 2012;64:504-512 2. Hoxha A, Ruffatti A, Tonello M, et al: Antiphosphatidylserine/prothrombin antibodies in primary antiphospholipid syndrome. Lupus 2012;21:787-789 3. Sciascia S, Sanna G, Murru V, et al: Validation of a commercially available kit to detect anti-phosphatidylserine/prothrombin antibodies in a cohort of systemic lupus erythematosus patients. Thromb Res 2014;133:451-454 4. Sciascia S, Sanna G, Murru V, et al: Anti-prothrombin (aPT) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome: A systematic review. Thromb Haemost 2014;111:354-364 5. Heikal NM, Jaskowski TD, Malmberg E, et al: Laboratory evaluation of anti-phospholipid syndrome: A preliminary prospective study of phosphatidylserine/prothrombin antibodies in an at-risk patient cohort. Clin Exp Immunol 2015;180:218-226

PSPTG

Phosphatidylserine/Prothrombin Antibody, IgG, Serum

62578

Clinical Information: A diagnosis of antiphospholipid syndrome (APS) is based on clinical and laboratory evaluation. The clinical manifestations associated with APS include arterial and venous thrombosis and recurrent pregnancy loss. The laboratory testing for APS focuses on assessment for autoantibodies specific for phospholipid/protein cofactor complexes. The current criteria require detection of anticardiolipin, anti-beta 2-glycoprotein I, or lupus anticoagulant (LAC) for classification of APS. Cardiolipin is an anionic phospholipid that interacts with the protein cofactor beta 2-glycoprotein I. Anticardiolipin and anti-beta 2-glycoprotein I antibodies are detected by immunoassay using the antigen of cardiolipin/beta 2-glycoprotein I or purified beta 2-glycoprotein I, respectively. LAC is an indirect assessment for the presence of antiphospholipid antibodies, which is evident in the in vitro prolongation of phospholipid-dependent coagulation. There is evidence to suggest that patients with APS may develop autoantibodies to other phospholipid/protein complexes, specifically phosphatidylserine/prothrombin (PS/PT). Similar to cardiolipin/beta 2-glycoprotein I, PS/PT is a complex composed of the anionic phospholipid phosphatidylserine and the protein cofactor prothrombin. A recent systematic review has demonstrated that anti-PS/PT antibodies are a significant risk factor for arterial and venous thrombotic events, with an odds ratio of 5.11 (4.2-6.3). In addition, a separate study indicated that anti-PS/PT antibodies showed the highest correlation with LAC, compared to anticardiolipin or anti-beta 2-glycoprotein I antibodies (p=0.002). Anti-PS/PT antibodies may be a useful additional marker for evaluation of patients with suspected APS, particularly for those individuals with evidence of thrombosis or abnormal LAC testing.



Page 1677

Useful For: Evaluation of patients with suspected antiphospholipid syndrome Evaluation of patients with a strong suspicion of antiphospholipid syndrome for whom anticardiolipin/beta 2-glycoprotein I and anti-beta 2-glycoprotein I antibody testing was negative Evaluation of patients with evidence of a functional lupus anticoagulant Detection of IgG antibodies against phosphatidylserine/prothrombin

Interpretation: A positive result is consistent with the presence of an antibody specific for the phosphatidylserine/prothrombin complex, and may be consistent with a diagnosis of antiphospholipid syndrome (APS) in patients with evidence of arterial or venous thrombosis or recurrent pregnancy loss. A negative result is consistent with the absence of an antibody specific for the phosphatidylserine/prothrombin complex. However, this does not exclude the diagnosis of APS, as other phospholipid/protein antibodies are also associated with this disorder.



PSPTM

Phosphatidylserine/Prothrombin Antibody, IgM, Serum

62579

Clinical Information: A diagnosis of antiphospholipid syndrome (APS) is based on clinical and laboratory evaluation. The clinical manifestations associated with APS include arterial and venous thrombosis and recurrent pregnancy loss. The laboratory testing for APS focuses on assessment for autoantibodies specific for phospholipid/protein cofactor complexes. The current criteria require detection of anticardiolipin, anti-beta 2-glycoprotein I, or lupus anticoagulant (LAC) for classification of APS. Cardiolipin is an anionic phospholipid that interacts with the protein cofactor beta 2-glycoprotein I. Anticardiolipin and anti-beta 2-glycoprotein I antibodies are detected by immunoassay using the antigen of cardiolipin/beta 2-glycoprotein I or purified beta 2-glycoprotein I, respectively. LAC is an indirect assessment for the presence of antiphospholipid antibodies, which is evident in the in vitro prolongation of phospholipid-dependent coagulation. There is evidence to suggest that patients with APS may develop autoantibodies to other phospholipid/protein complexes, specifically phosphatidylserine/prothrombin (PS/PT). Similar to cardiolipin/ beta 2-glycoprotein I, PS/PT is a complex composed of the anionic phospholipid phosphatidylserine and the protein cofactor prothrombin. A recent systematic review has demonstrated that anti-PS/PT antibodies are a significant risk factor for arterial and venous thrombotic events, with an odds ratio of 5.11 (4.2-6.3). In addition, a separate study indicated that anti-PS/PT antibodies showed the highest correlation with LAC, compared to anticardiolipin or anti-beta 2-glycoprotein I antibodies (p=0.002). Anti-PS/PT antibodies may be a useful additional marker for evaluation of patients with suspected APS, particularly for those individuals with evidence of thrombosis or abnormal LAC testing.

Useful For: Evaluation of patients with suspected antiphospholipid syndrome Evaluation of patients with a strong suspicion of antiphospholipid syndrome for whom anticardiolipin/beta 2-glycoprotein I and anti-beta 2-glycoprotein I antibody testing was negative Evaluation of patients with evidence of a functional lupus anticoagulant Detection of IgM antibodies against phosphatidylserine/prothrombin

Interpretation: A positive result is consistent with the presence of an antibody specific for the Current as of August 23, 2017 7:11 am CDT


Page 1678

phosphatidylserine/prothrombin complex, and may be consistent with a diagnosis of antiphospholipid syndrome (APS) in patients with evidence of arterial or venous thrombosis or recurrent pregnancy loss. A negative result is consistent with the absence of an antibody specific for the phosphatidylserine/prothrombin complex. However, this does not exclude the diagnosis of APS, as other phospholipid/protein antibodies are also associated with this disorder.



65038

Phospho TDP-43, Immunostain Without Interpretation Clinical Information: TAR DNA-binding protein 43 (TDP-43) has multiple functions in transcriptional repression, translational regulation, and pre-mRNA splicing. In normal cells, TDP-43 is found in the nucleus, whereas in affected cells TDP-43 is phosphorylated and found in intracytoplasmic inclusions and neurites. The phosphoTDP-43-specific antibody will only stain the intracytoplasmic inclusions and neurites, thus highlighting the patterns that are hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal lobular degeneration.

Useful For: Identification of pathological forms of TDP-43 in neurodegenerative diseases Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ling JP, Pletnikova O, Troncoso JC, et al: TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 2015 Aug 7;349(6248):650-655 2. Hasegawa M, Arai T, Nonaka T, et al: Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 2008 Jul;64(1):60-70 3. Lee EB, Lee VM, Trojanowski JQ: Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 2011 Nov 30;13(1):38-50 4. Smethurst P, Sidle KCL, Hardy J: Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS). Neuropathol Appl Neurobiol 2015;41(5):578-597 5. Serrano GE, Intorcia A, Carew J, et al: Feasibility Study: Comparison of Frontal Cortex Needle Core Versus Open Biopsy for Detection of Characteristic Proteinopathies of Neurodegenerative Diseases. J Neuropathol Exp Neurol 2015;74(9):934-942

PHOST

Phosphofructokinase Stain

82052

Reference Values: This test is for billing purposes only.



Page 1679

This is not an orderable test. Order MPCT / Muscle Pathology Consultation or MBCT / Muscle Biopsy Consultation, Outside Slides and/or Paraffin Blocks. The consultant will determine the need for special stains.

60951

Phosphohistone-H3 (pHH3), Immunostain Without Interpretation Clinical Information: Phosphohistone-H3 (pHH3) is one of the main histone proteins involved in the structure of chromatin in eukaryotic cells. The phosphorylation of histone H3 plays an important role in gene expression, chromatin remodeling, chromosome condensation, and cell division. pHH3 phosphorylation may initiate at different phases of cell division in different organisms, but metaphase chromosomes are always found to be heavily phosphorylated. pHH3 is useful for identification of mitotic figures in a variety of neoplastic diseases.

Useful For: Identification of mitotic figures in a variety of neoplastic diseases Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Colman H, Giannini C, Huang L, et al: Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol 2006;30:657-664 2. Tapia C, Kutzner H, Mentzel T, et al: Two mitosis-specific antibodies, MPM-2 and phospho-histone H3 (Ser28), allow rapid and precise determination of mitotic activity. Am J Surg Pathol 2006;30:83-89 3. Kim YJ, Ketter R, Steudel WI, Feiden W: Prognostic significance of the mitotic index using the mitosis marker anti-phosphohistone H3 in meningiomas. Am J Clin Pathol 2007;128:118-125

64944

Phospholipase A2 Receptor (PLA2R), Frozen, Immunofluorescence, Renal Clinical Information: Membranous nephropathy is the most common cause of nephrotic syndrome in white adults. Eighty-five percent of membranous nephropathy cases are primary or idiopathic and the other 15% are secondary. Phospholipase A2 receptor (PLA2R) is an antigen located on podocytes. The majority of cases of primary membranous nephropathy have circulating autoantibodies against PLA2R.

Useful For: Distinguishing primary membranous nephropathy from secondary membranous nephropathy

Interpretation: This test, (when not accompanied by a pathology consultation request) will be reported as either positive or negative.

Reference Values: This test will report as negative or positive for autoantibodies to PLA2R.

Clinical References: 1. Larsen CP, Messias NC, Silva FG, et al: Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies. Mod Pathol 2013;26(5):709-715 2. Larsen CP, Walker PD: Phospholipase A2 receptor (PLA2R) staining is useful in the determination of de novo versus recurrent membranous glomerulopathy. Transplantation 2013;95(10):1259-1262 3. Beck LH, Bonegio RG, Lambeau G, et al: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361(1):11-21



Page 1680

PLA2R

Phospholipase A2 Receptor Antibodies, Serum

64327

Clinical Information: Membranous nephropathy (MN) is a rare disease in which immune complexes deposit at the glomerular basement membrane, causing damage to the filtration barrier, resulting in proteinuria. Recent studies have shown that in approximately 70% of patients with primary MN (pMN), the immune complexes consist of autoantibodies against the podocyte protein M-type phospholipase A2 receptor (PLA2R).(1) There is also evidence that levels of anti-PLA2R autoantibodies correlate well with disease activity and progression.(2) The presence of anti-PLA2R antibodies could also potentially be used to differentiate pMN from other causes of nephrotic syndrome if a biopsy is not possible. Among patients with chronic kidney disease (CKD) awaiting kidney transplantation, higher levels of anti-PLA2R could predict those more likely to recur after transplantation.(2)

Useful For: Distinguishing primary from secondary membranous nephropathy Interpretation: Therapy outcome can be monitored by measuring the anti-phospholipase A2 receptor (PLA2R) antibody titer. A titer increase, decrease, or disappearance generally precedes a change in clinical status. Thus, the determination of the antibody titer has a high predictive value with respect to clinical remission, relapse, or risk assessment after kidney transplantation.

Reference Values: ELISA: Negative: or =14- or =20 RU/mL IFA: Negative

Clinical References: 1. Beck L, Bonegio R, Lambeau G, et al: M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11-21 2. Schlumberger W, Hornig N, Lange S, et al: Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1. Autoimmun Rev 2014 Feb;13(2)108-113

EURO 64328

Phospholipase A2 Receptor, Enzyme Linked Immunosorbent Assay, Serum Reference Values: For more information see PLA2R / Phospholipase A2 Receptor Antibodies, Serum.

SCOPE 64326

Phospholipase A2 Receptor, Indirect Immunofluorescence Assay, Serum Reference Values: For more information see PLA2R / Phospholipase A2 Receptor Antibodies, Serum.

ACLIP

Phospholipid (Cardiolipin) Antibodies, IgA, Serum

86179

Clinical Information: The plasma membranes of mammalian cells are formed from phospholipids. Anionic phospholipids (eg, phosphatidylserine) are found on the cytoplasmic surface and neutral phospholipids (eg, phosphatidylcholine) predominate on the external surface. Membrane phospholipids participate in several important cellular functions including exchanging metabolites across membranes, transferring molecular signals and serving as a platform for the assembly of protein-lipid complexes.(1) Cellular activation is often accompanied by the translocation of anionic phospholipids to the external membrane surface. For example, during platelet-mediated blood coagulation, phosphatidylserine is translocated from the inner platelet membrane and provides a surface for the assembly of the



Page 1681

prothrombinase enzyme complex that catalyzes the formation of thrombin. Complexes of negatively charged (anionic) phospholipids and endogenous plasma proteins provide epitopes recognized by natural autoantibodies.(2) Plasma from normal individuals contains low concentrations of natural IgG autoantibodies of moderate affinity. Pathologic levels of autoantibodies reflect loss of tolerance and increased production of antibodies. These autoantibodies are called phospholipid or cardiolipin antibodies when they are detected by immunoassays that employ anionic phospholipids as substrates. The most commonly used phospholipid substrate is cardiolipin. The term phospholipid antibody is actually a misnomer. The autoantibodies react with epitopes of protein molecules that associate noncovalently with reagent phospholipids. The best characterized phospholipid-binding protein is beta 2-glycoprotein 1 (beta-2 GP1) and most immunoassays for phospholipid antibodies employ a composite substrate consisting of cardiolipin plus beta-2 GP1. Beta-2 GP1 is a 326-amino acid polypeptide that contains 5 homologous domains of approximately 60 amino acids each. Most phospholipid antibodies bind to an epitope associated with domain 1 near the N-terminus. Autoantibodies can also be detected by the use of functional, phospholipid-dependent coagulation assays. Phospholipid antibodies detected by functional assays are often called lupus anticoagulants because they produce prolongation of phospholipid-dependent clotting in vitro and are found in some patients with systemic lupus erythematosus. Not all phospholipid antibodies possess lupus anticoagulant activity.(3) Only those phospholipid antibodies that are capable of cross-linking beta-2 GP1 molecules can interact efficiently with phospholipid surfaces in functional coagulation assays. It is hypothesized that complexes formed in vivo between bivalent, natural autoantibodies and beta-2 GP1 bind to translocated, anionic phospholipid on activated platelets at sites of endothelial injury. This binding is believed to promote further platelet activation that may lead to thrombosis. Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboses, complications of pregnancy, and certain laboratory abnormalities. The diagnosis of APS requires at least 1 clinical criteria and 1 laboratory criteria be met.(4) The clinical criteria include vascular thrombosis (arterial or venous in any organ or tissue) and pregnancy morbidity (unexplained fetal death, premature birth, severe preeclampsia, or placental insufficiency). Other clinical manifestations, including heart valve disease, livedo reticularis, thrombocytopenia, nephropathy and neurological symptoms, are often associated with APS but are not included in the diagnostic criteria. The laboratory criteria for diagnosis of APS are presence of lupus anticoagulant, presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40 MPL, or >99th percentile), and/or presence of IgG and/or IgM anti-beta-2 GP1 antibody (>99th percentile). All antibodies must be demonstrated on 2 or more occasions separated by at least 12 weeks. Anticardiolipin and anti-beta-2 GP1 antibodies of the IgA isotype are not part of the laboratory criteria for APS due to lack of specificity.(4)

Useful For: Evaluation of patients with suspected antiphospholipid syndrome by identification of phospholipid IgA antibodies

Interpretation: APL, GPL and MPL units refer to arbitrary units. The abbreviation APL denotes the result is from the IgA isotype, the abbreviation GPL denotes the result is from the IgG isotype and the abbreviation MPL denotes the result is from the IgM isotype. The letters "PL" denote specificity for phospholipid antigens. Positive and strongly-positive results for IgG and IgM phospholipid (cardiolipin) antibodies (>40 GPL and/or >40 MPL) are diagnostic criteria for antiphospholipid syndrome (APS). Lesser levels of IgG and IgM phospholipid (cardiolipin) antibodies and antibodies of the IgA isotype (APL) may occur in patients with clinical signs of APS but the results are not considered diagnostic. Phospholipid (cardiolipin) antibodies must be detected on 2 or more occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. IgA phospholipid (cardiolipin) antibody results >15 APL with negative IgG and IgM phospholipid (cardiolipin) antibody results are not diagnostic for APS. Detection of phospholipid (cardiolipin) antibodies is not affected by anticoagulant treatment.

Reference Values: or =80.0 APL (strongly positive) APL refers to IgA Phospholipid Units. One APL unit is 1 microgram of IgA antibody. Reference values apply to all ages.

Clinical References: 1. Bevers EM, Comfurius P, Dekkers DW, et al: Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1999;1439:317-330 2. Arnout J, Vermylen Current as of August 23, 2017 7:11 am CDT


Page 1682

J: Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Thromb Haemost 2003;1:931-942 3. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004;79:467-475 4. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4: 295-306 5. Fontaine MJ, Jacob GL, Nichols WL, et al: Comparative evaluation of three assays for anti-cardiolipin antibodies. J Autoimmun 2000;15(2):A56 6. Favaloro EJ, Wong RC, Silvertrini R, et al: A multilaboratory peer assessment quality assurance program-based evaluation of anticardiolipin antibody, and beta 2 glycoprotein 1 antibody testing. Semin Thromb Hemost 2005;31(1):73-84

CLPMG

Phospholipid (Cardiolipin) Antibodies, IgG and IgM, Serum

82976

Clinical Information: The plasma membranes of mammalian cells are formed from phospholipids. Anionic phospholipids (eg, phosphatidylserine) are found on the cytoplasmic surface and neutral phospholipids (eg, phosphatidylcholine) predominate on the external surface. Membrane phospholipids participate in several important cellular functions including exchanging metabolites across membranes, transferring molecular signals and serving as a platform for the assembly of protein-lipid complexes.(1) Cellular activation is often accompanied by the translocation of anionic phospholipids to the external membrane surface. For example, during platelet-mediated blood coagulation phosphatidylserine is translocated from the inner platelet membrane and provides a surface for the assembly of the prothrombinase enzyme complex that catalyzes the formation of thrombin. Complexes of negatively charged (anionic) phospholipids and endogenous plasma proteins provide epitopes recognized by natural autoantibodies.(2) Plasma from normal individuals contains low concentrations of natural IgG autoantibodies of moderate affinity. Pathologic levels of autoantibodies reflect loss of tolerance and increased production of antibodies. These autoantibodies are called phospholipid or cardiolipin antibodies when they are detected by immunoassays that employ anionic phospholipids as substrates. The most commonly used phospholipid substrate is cardiolipin. The term phospholipid antibody is actually a misnomer. The autoantibodies react with epitopes of protein molecules that associate noncovalently with reagent phospholipids. The best characterized phospholipid-binding protein is beta 2 glycoprotein 1 and most immunoassays for phospholipid antibodies employ a composite substrate consisting of cardiolipin plus beta-2 glycoprotein 1(beta-2 GP1beta-2 GP1). Beta-2 GP1 is a 326 amino acid polypeptide that contains 5 homologous domains of approximately 60 amino acids each. Most phospholipid antibodies bind to an epitope associated with domain 1 near the N-terminus. Autoantibodies can also be detected by the use of functional, phospholipid-dependent coagulation assays. Phospholipid antibodies detected by functional assays are often called lupus anticoagulants because they produce prolongation of phospholipid-dependent clotting in vitro. Not all phospholipid antibodies possess lupus anticoagulant activity.(3) Only those phospholipid antibodies that are capable of cross-linking beta-2 GP1 molecules can interact efficiently with phospholipid surfaces in functional coagulation assays. It is hypothesized that complexes formed in vivo between bivalent, natural autoantibodies and beta-2 GP1 bind to translocated, anionic phospholipid on activated platelets at sites of endothelial injury. This binding is believed to promote further platelet activation that may lead to thrombosis. Phospholipid antibodies occur in patients with a variety of clinical signs and symptoms notably thrombosis (arterial or venous) pregnancy morbidity (unexplained fetal death, premature birth, severe preeclampsia, or placental insufficiency) unexplained cutaneous circulation disturbances (livido reticularis or pyoderma gangrenosum) thrombocytopenia or hemolytic anemia and nonbacterial thrombotic endocarditis. Phospholipid antibodies and lupus anticoagulants are found with increased frequency in patients with systemic rheumatic diseases especially lupus erythematosus. The term antiphospholipid syndrome (APS) or Hughes syndrome is used to describe the triad of thrombosis, recurrent fetal loss and thrombocytopenia accompanied by phospholipid antibodies or a lupus anticoagulant. The diagnosis of APS requires 1 or more of the above mentioned clinical findings plus positive test results for phospholipid antibodies (> or =40 GPL or MPL) or positive tests for a lupus anticoagulant on more than 1 occasion separated by at least 6 weeks.(4)

Useful For: Testing for phospholipid antibodies is indicated in the following clinical situations: -Unexplained arterial or venous thrombosis -A history of pregnancy morbidity defined as 1 or more unexplained deaths of a morphologically normal fetus beyond the 10th week of gestation, 1 or more premature births before 34 weeks of gestation caused by severe preeclampsia or placental insufficiency, or 3 or more unexplained, consecutive spontaneous abortions before the 10th week of gestation with no Current as of August 23, 2017 7:11 am CDT


Page 1683

identifiable maternal hormonal or anatomic, or maternal or paternal chromosomal causes -Presence of an unexplained cutaneous circulatory disturbance, eg, livido reticularis or pyoderma gangrenosum -Presence of a systemic rheumatic disease especially lupus erythematosus -Unexplained thrombocytopenia or hemolytic anemia -Possible nonbacterial, thrombotic endocarditis

Interpretation: Positive and strongly positive results for phospholipid antibodies (> or =40 GPL and/or MPL) are a diagnostic criterion for antiphospholipid syndrome (APS). Lesser levels of phospholipid antibodies and antibodies of the IgA isotype may occur in patients with clinical signs of APS but the results are not considered diagnostic. Detection of phospholipid antibodies is not affected by anticoagulant treatment.

Reference Values: or =80.0 MPL or GPL (strongly positive) MPL refers to IgM Phospholipid Units. One MPL unit is 1 microgram of IgM antibody. GPL refers to IgG Phospholipid Units. One GPL unit is 1 microgram of IgG antibody. Reference values apply to all ages.

Clinical References: 1. Bevers EM, Comfurius P, Dekkers DW, et al: Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1999;1439:317-330 2. Arnout J, Vermylen J: Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Thromb Haemost 2003;1:931-942 3. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004;79:467-475 4. Wilson WW, Gharavi AE, Koike T, et al: International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum 1999;42(7):1309-1311 5. Fontaine MJ, Jacob GL, Nichols WL, et al: Comparative evaluation of three assays for anti-cardiolipin antibodies. J Autoimmun 2000;15(2):A56 6. Favaloro EJ, Wong RC, Silvertrini R, et al: A multilaboratory peer assessment quality assurance program-based evaluation of anticardiolipin antibody, and beta 2 glycoprotein 1 antibody testing. Semin Thromb Hemost 2005;31(1):73-84

GCLIP

Phospholipid (Cardiolipin) Antibodies, IgG, Serum

80993

Clinical Information: The plasma membranes of mammalian cells are formed from phospholipids. Anionic phospholipids (eg, phosphatidylserine) are found on the cytoplasmic surface and neutral phospholipids (eg, phosphatidylcholine) predominate on the external surface. Membrane phospholipids participate in several important cellular functions including exchanging metabolites across membranes, transferring molecular signals and serving as a platform for the assembly of protein-lipid complexes.(1) Cellular activation is often accompanied by the translocation of anionic phospholipids to the external membrane surface. For example, during platelet-mediated blood coagulation phosphatidylserine is translocated from the inner platelet membrane and provides a surface for the assembly of the prothrombinase enzyme complex that catalyzes the formation of thrombin. Complexes of negatively charged (anionic) phospholipids and endogenous plasma proteins provide epitopes recognized by natural autoantibodies.(2) Plasma from normal individuals contains low concentrations of natural IgG autoantibodies of moderate affinity. Pathologic levels of autoantibodies reflect loss of tolerance and increased production of antibodies. These autoantibodies are called phospholipid or cardiolipin antibodies when they are detected by immunoassays that employ anionic phospholipids as substrates. The most commonly used phospholipid substrate is cardiolipin. The term phospholipid antibody is actually a misnomer. The autoantibodies react with epitopes of protein molecules that associate noncovalently with reagent phospholipids. The best characterized phospholipid-binding protein is beta-2 glycoprotein 1 (beta-2 GP1) and most immunoassays for phospholipid antibodies employ a composite substrate consisting of cardiolipin plus beta-2 GP1. Beta-2 GP1 is a 326-amino acid polypeptide that contains 5 homologous domains of approximately 60 amino acids each. Most phospholipid antibodies bind to an epitope associated with domain 1 near the N-terminus. Autoantibodies can also be detected by the use of functional, phospholipid-dependent coagulation assays. Phospholipid antibodies detected by functional assays are often called lupus anticoagulants because they produce prolongation of phospholipid-dependent



Page 1684

clotting in vitro and are found in some patients with systemic lupus erythematosus. Not all phospholipid antibodies possess lupus anticoagulant activity.(3) Only those phospholipid antibodies that are capable of cross-linking beta-2 GP1 molecules can interact efficiently with phospholipid surfaces in functional coagulation assays. It is hypothesized that complexes formed in vivo between bivalent, natural autoantibodies and beta-2 GP1 bind to translocated, anionic phospholipid on activated platelets at sites of endothelial injury. This binding is believed to promote further platelet activation that may lead to thrombosis. Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboses, complications of pregnancy, and certain laboratory abnormalities. The diagnosis of APS requires at least 1 clinical criteria and 1 laboratory criteria be met.(4) The clinical criteria include vascular thrombosis (arterial or venous in any organ or tissue) and pregnancy morbidity (unexplained fetal death, premature birth, severe preeclampsia, or placental insufficiency). Other clinical manifestations, including heart valve disease, livedo reticularis, thrombocytopenia, nephropathy and neurological symptoms, are often associated with APS but are not included in the diagnostic criteria. The laboratory criteria for diagnosis of APS are the presence of lupus anticoagulant, the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40 MPL, or >99th percentile), and/or the presence of IgG and/or IgM anti-beta-2 GP1 antibody (>99th percentile). All antibodies must be demonstrated on 2 or more occasions separated by at least 12 weeks. Anticardiolipin and beta GP1 antibodies of the IgA isotype are not part of the laboratory criteria for APS due to lack of specificity.(4)

Useful For: Evaluation of patients with suspected antiphospholipid syndrome by identification of phospholipid IgG antibodies

Interpretation: APL, GPL, and MPL units refer to arbitrary units. The abbreviation APL denotes the result is from the IgA isotype, the abbreviation GPL denotes the result is from the IgG isotype and the abbreviation MPL denotes the result is from the IgM isotype. The letters "PL" denote specificity for phospholipid antigens. Positive and strongly-positive results for IgG and IgM phospholipid (cardiolipin) antibodies (>40 GPL and/or >40 MPL) are diagnostic criteria for antiphospholipid syndrome (APS). Lesser levels of IgG and IgM phospholipid (cardiolipin) antibodies and antibodies of the IgA isotype may occur in patients with clinical signs of APS but the results are not considered diagnostic. Phospholipid (cardiolipin) antibodies must be detected on 2 or more occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. An IgA phospholipids (cardiolipin) antibody result above 15 APL with negative IgG and IgM phospholipids (cardiolipin) antibody results is not diagnostic for APS. Detection of phospholipid (cardiolipin) antibodies is not affected by anticoagulant treatment.

Reference Values: or =80.0 GPL (strongly positive) GPL refers to IgG Phospholipid Units. One GPL unit is 1 microgram of IgG antibody. Reference values apply to all ages.

Clinical References: 1. Bevers EM, Comfurius P, Dekkers DW, et al: Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1999;1439:317-330 2. Arnout J, Vermylen J: Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Thromb Haemost 2003;1:931-942 3. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004;79:467-475 4. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306 5. Fontaine MJ, Jacob GL, Nichols WL, et al: Comparative evaluation of three assays for anti-cardiolipin antibodies. J Autoimmun 2000;15(2):A56 6. Favaloro EJ, Wong RC, Silvertrini R, et al: A multilaboratory peer assessment quality assurance program-based evaluation of anticardiolipin antibody, and beta 2 glycoprotein 1 antibody testing. Semin Thromb Hemost 2005;31(1):73-84

MCLIP

Phospholipid (Cardiolipin) Antibodies, IgM, Serum

81900

Clinical Information: The plasma membranes of mammalian cells are formed from phospholipids. Anionic phospholipids (eg, phosphatidylserine) are found on the cytoplasmic surface and neutral



Page 1685

phospholipids (eg, phosphatidylcholine) predominate on the external surface. Membrane phospholipids participate in several important cellular functions including exchanging metabolites across membranes, transferring molecular signals and serving as a platform for the assembly of protein-lipid complexes.(1) Cellular activation is often accompanied by the translocation of anionic phospholipids to the external membrane surface. For example, during platelet-mediated blood coagulation, phosphatidylserine is translocated from the inner platelet membrane and provides a surface for the assembly of the prothrombinase enzyme complex that catalyzes the formation of thrombin. Complexes of negatively charged (anionic) phospholipids and endogenous plasma proteins provide epitopes recognized by natural autoantibodies.(2) Plasma from normal individuals contains low concentrations of natural IgG autoantibodies of moderate affinity. Pathologic levels of autoantibodies reflect loss of tolerance and increased production of antibodies. These autoantibodies are called phospholipid or cardiolipin antibodies when they are detected by immunoassays that employ anionic phospholipids as substrates. The most commonly used phospholipid substrate is cardiolipin. The term phospholipid antibody is actually a misnomer. The autoantibodies react with epitopes of protein molecules that associate noncovalently with reagent phospholipids. The best characterized phospholipid-binding protein is beta-2 glycoprotein 1 (beta-2 GP1) and most immunoassays for phospholipid antibodies employ a composite substrate consisting of cardiolipin plus beta-2 GP1. Beta-2 GP1 is a 326-amino acid polypeptide that contains 5 homologous domains of approximately 60 amino acids each. Most phospholipid antibodies bind to an epitope associated with domain 1 near the N-terminus. Autoantibodies can also be detected by the use of functional, phospholipid-dependent coagulation assays. Phospholipid antibodies detected by functional assays are often called lupus anticoagulants because they produce prolongation of phospholipid-dependent clotting in vitro and are found in some patients with systemic lupus erythematosus. Not all phospholipid antibodies possess lupus anticoagulant activity.(3) Only those phospholipid antibodies that are capable of cross-linking beta-2 GP1 molecules can interact efficiently with phospholipid surfaces in functional coagulation assays. It is hypothesized that complexes formed in vivo between bivalent, natural autoantibodies and beta-2 GP1 bind to translocated, anionic phospholipid on activated platelets at sites of endothelial injury. This binding is believed to promote further platelet activation that may lead to thrombosis. Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thromboses, complications of pregnancy, and certain laboratory abnormalities. The diagnosis of APS requires at least 1 clinical criteria and 1 laboratory criteria be met.(4) The clinical criteria include vascular thrombosis (arterial or venous in any organ or tissue) and pregnancy morbidity (unexplained fetal death, premature birth, severe preeclampsia, or placental insufficiency). Other clinical manifestations, including heart valve disease, livedo reticularis, thrombocytopenia, nephropathy and neurological symptoms, are often associated with APS but are not included in the diagnostic criteria. The laboratory criteria for diagnosis of APS are the presence of lupus anticoagulant, the presence of IgG and/or IgM anticardiolipin antibody (>40 GPL, >40 MPL, or >99th percentile), and/or the presence of IgG and/or IgM anti-beta-2 GP 1 antibody (>99th percentile). All antibodies must be demonstrated on 2 or more occasions separated by at least 12 weeks. Anticardiolipin and anti-beta-2 GP1 antibodies of the IgA isotype are not part of the laboratory criteria for APS due to lack of specificity.(4)

Useful For: Evaluation of patients with suspected antiphospholipid syndrome by identification of phospholipid IgM antibodies

Interpretation: APL, GPL, and MPL units refer to arbitrary units. The abbreviation APL denotes the result is from the IgA isotype, the abbreviation GPL denotes the result is from the IgG isotype and the abbreviation MPL denotes the result is from the IgM isotype. The letters "PL" denote specificity for phospholipid antigens. Positive and strongly-positive results for IgG and IgM phospholipid (cardiolipin) antibodies (>40 GPL and/or >40 MPL) are diagnostic criteria for antiphospholipid syndrome (APS). Lesser levels of IgG and IgM phospholipid (cardiolipin) antibodies and antibodies of the IgA isotype may occur in patients with clinical signs of APS but the results are not considered diagnostic. Phospholipid (cardiolipin) antibodies must be detected on 2 or more occasions at least 12 weeks apart to fulfill the laboratory diagnostic criteria for APS. An IgA phospholipid (cardiolipin) antibody result above 15 APL with negative IgG and IgM phospholipids (cardiolipin) antibody results is not diagnostic for APS. Detection of phospholipid (cardiolipin) antibodies is not affected by anticoagulant treatment.

Reference Values: or =80.0 MPL (strongly positive) MPL refers to IgM Phospholipid Units. One MPL unit is 1 microgram of IgM antibody. Reference values apply to all ages.

Clinical References: 1. Bevers EM, Comfurius P, Dekkers DW, et al: Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1999;1439:317-330 2. Arnout J, Vermylen J: Current status and implications of autoimmune antiphospholipid antibodies in relation to thrombotic disease. J Thromb Haemost 2003;1:931-942 3. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test results for lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 2004;79:467-475 4. Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306 5. Fontaine MJ, Jacob GL, Nichols WL, et al: Comparative evaluation of three assays for anti-cardiolipin antibodies. J Autoimmun 2000;15(2):A56 6. Favaloro EJ, Wong RC, Silvertrini R, et al: A multilaboratory peer assessment quality assurance program-based evaluation of anticardiolipin antibody, and beta 2 glycoprotein 1 antibody testing. Semin Thromb Hemost 2005;31(1):73-84

PPL

Phospholipids, Serum

8296

Clinical Information: The phospholipids comprise about 1/3 of the total lipids in serum. These consist in a large part of a lipid, phosphatidylcholine (formerly lecithin), in which 1 of the glycerol carbons is esterified with choline phosphate. A major step in lipoprotein particle remodeling results from lecithin-cholesterol acyltransferase (LCAT) activity, which normally transesterifies free cholesterol with fatty acids derived from phosphatidylcholine. LCAT deficiency results in a lack of remodeling of primary lipoprotein particles, affecting eventual cholesterol uptake and elimination. In cases of deficiency of LCAT, the concentration of lecithin in the serum are increased several-fold. Clinical findings in LCAT deficiency include corneal opacities, anemia, and frequently, proteinuria. The disorder is inherited as an autosomal recessive trait. Early atherosclerosis develops in many individuals with this disorder. In addition, sphingomyelin normally comprises about 5% to 20% of the total phospholipids of serum. In Niemann-Pick Type A and B diseases, sphingomyelin accumulates in visceral and neural tissues and may become increased in the serum. Other disorders involving alterations of the concentration, composition, and/or lipoprotein distribution include: abeta- or hypobetalipoproteinemia, Tangier disease, or fish eye disease.

Useful For: First-order test in the diagnosis of lecithin-cholesterol acyltransferase deficiency Interpretation: Elevated in cases of lecithin-cholesterol acyltransferase deficiency deficiency due to elevations of lecithin

Reference Values: 155-275 mg/dL Reference values have not been established for patients who are 350 nmol/h/mg protein PHOSPHOMANNOSE ISOMERASE Normal >1,300 nmol/h/mg protein

Clinical References: 1. Sparks SE, Krasnewich DM: Congenital Disorders of N-linked Glycosylation Pathway Overview. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle; Updated 2014 Jan 30. Available at www.ncbi.nlm.nih.gov/books/NBK1332/ 2. Scott K, Gadomski T, Kozicz T, Morava E: Congenital disorders of glycosylation: new defects and still counting. J Inherit Metab Dis 2014 Jul;37(4):609-617

PHOS

Phosphorus (Inorganic), Serum

8408

Clinical Information: Eighty-eight percent of the phosphorus contained in the body is localized in bone in the form of hydroxyapatite. The remainder is involved in intermediary carbohydrate metabolism and in physiologically important substances such as phospholipids, nucleic acids, and adenosine triphosphate (ATP). Phosphorus occurs in blood in the form of inorganic phosphate and organically bound phosphoric acid. The small amount of extracellular organic phosphorus is found exclusively in the form of phospholipids. Serum contains approximately 2.5 to 4.5 mg/dL of inorganic phosphate (the fraction measure in routine biochemical assays). Serum phosphate concentrations are dependent on meals and variation n the secretion of hormones such as parathyroid hormone (PTH) and may vary widely. Hypophosphatemia may have 4 general causes: shift of phosphate from extracellular to intracellular, renal phosphate wasting, loss from the gastrointestinal tract, and loss from intracellular stores. Hyperphosphatemia is usually secondary to an inability of the kidneys to excrete phosphate. Other factors may relate to increased intake or a shift of phosphate from the tissues into the extracellular fluid.



Page 1688

Useful For: Phosphate levels may be used in the diagnosis and management of a variety of disorders including bone, parathyroid and renal disease.

Interpretation: Hypophosphatemia is relatively common in hospitalized patients. Serum concentrations of phosphate between 1.5 and 2.4 mg/dL may be consider moderately decreased and are not usually associated with clinical signs and symptoms. Levels less than 1.5 mg/dL may result in muscle weakness, hemolysis of red cells, coma, and bone deformity and impaired bone growth. The most acute problem associated with rapid elevations of serum phosphate levels is hypocalcemia with tetany, seizures, and hypotension. Soft tissue calcification is also an important long-term effect of high phosphorus levels. Phosphorus levels less than 1.0 mg/dL are potentially life-threatening and are considered a critical value in the Mayo Health System.

Reference Values: Males 1-4 years: 4.3-5.4 mg/dL 5-13 years: 3.7-5.4 mg/dL 14-15 years: 3.5-5.3 mg/dL 16-17 years: 3.1-4.7 mg/dL > or =18 years: 2.5-4.5 mg/dL Reference values have not been established for patients that are less than 12 months of age. Females 1-7 years: 4.3-5.4 mg/dL 8-13 years: 4.0-5.2 mg/dL 14-15 years: 3.5-4.9 mg/dL 16-17 years: 3.1-4.7 mg/dL > or =18 years: 2.5-4.5 mg/dL Reference values have not been established for patients that are less than 12 months of age.

Clinical References: 1. Tietz Textbook of Clinical Chemistry. Edited by Burtis and Ashwood. WB Saunders Co, Philadelphia, PA, 1994 2. Yu GC, Lee DBN: Clinical disorders of phosphorus metabolism. West J Med 1987;147:569-576

POU

Phosphorus, 24 Hour, Urine

8526

Clinical Information: Approximately 80% of filtered phosphorus is reabsorbed by renal proximal tubule cells. The regulation of urinary phosphorus excretion is principally dependent on regulation of proximal tubule phosphorus reabsorption. A variety of factors influence renal tubular phosphate reabsorption, and consequent urine excretion. Factors which increase urinary phosphorus excretion include high phosphorus diet, parathyroid hormone, extracellular volume expansion, low dietary potassium intake and proximal tubule defects (eg, Fanconi Syndrome, X-linked hypophosphatemic Rickets, tumor-induced osteomalacia). Factors which decrease, or are associated with decreases in, urinary phosphorus excretion include low dietary phosphorus intake, insulin, high dietary potassium intake, and decreased intestinal absorption of phosphorus (eg, phosphate-binding antacids, vitamin D deficiency, malabsorption states). A renal leak of phosphate has also been implicated as contributing to kidney stone formation in some patients.

Useful For: Evaluation of hypo- or hyper-phosphatemic states Evaluation of patients with nephrolithiasis

Interpretation: Interpretation of urinary phosphorus excretion is dependent upon the clinical situation, and should be interpreted in conjunction with the serum phosphorus concentration.



FPIGD

Pigeon Droppings, IgE

75275

Reference Values: Class Conc IU/mL Interpretation Neg

Negative

0/I

0.05 - 0.08

Equivocal

I

0.08 - 0.15

Positive

II

0.15 - 0.50

With

III

0.50 - 2.50

Increasing

IV

2.50 - 12.50 Antibody

V

12.50 - 62.50 Concentration

VI

>62.50

PIGF

Pigeon Feathers, IgE

82145

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from



Page 1692

immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



60952

PIN2 (p63/p504S), Immunostain Without Interpretation Clinical Information: Prostatic intraepithelial neoplasia (PIN) Cocktail-2 is a cocktail including 2 antibodies directed against p63 (nuclear) and P504S (cytoplasm) used in the diagnosis of high grade PIN and prostate cancer. p63 stains the nuclei of normal myoepithelial cells that surround the prostatic epithelial cells. This myoepithelial layer is lost in carcinoma. P504S is abnormally expressed in high grade PIN and prostate cancer epithelial cells, but is normally expressed in epithelial cells of the renal tubules, gall bladder and bronchi, and in hepatocytes.

Useful For: An aid in the identification of high grade prostatic intraepithelial neoplasia and prostate cancer

Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist. Current as of August 23, 2017 7:11 am CDT


Page 1693

Clinical References: 1. Hameed O, Sublett J, Humphrey PA: Immunohistochemical stains for p63 and alpha-methylacyl-CoA racemase, versus a cocktail comprising both, in the diagnosis of prostatic carcinoma: a comparison of the immunohistochemical staining of 430 foci in radical prostatectomy and needle biopsy tissues. Am J Surg Pathol 2005;29(5):579-587 2. Molinie V, Fromont G, Sibony M, et al: Diagnostic utility of a p63/alpha-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate. Mod Pathol 2004;17(10):1180-1190 3. Tacha DE, Miller RT: Use of p63/P504S monoclonal antibody cocktail in immunohistochemical staining of prostate tissue. Appl Immunohistochem Mol Morphol 2004 Mar;12(1):75-78

FPMLP

Pine Mix (Lodgepole, Ponderosa) IgE

57948




FPIAP

Pineapple IgG

57670



PINW

Pinworm Exam, Perianal

9204

Clinical Information: Enterobius vermicularis (pinworms) are nematodes (roundworms) which are found worldwide in both temperate and tropical areas. The adults reside in the upper large intestine of humans and transmission is by the fecal-oral route. Adult females migrate to the perianal area, especially during the night, and deposit large numbers of eggs. Pinworm infection is the most common helminth infection in the United States and is the most common in young school-age children of all social classes. Pinworms do not produce significant intestinal disease but can cause irritating pruritus in the perianal area. They have also been implicated in vulvovaginitis in pre-pubertal girls and possibly in urinary tract infections. Several agents are effective in treating pinworm infection (pyrantel pamoate, mebendazole), and good personal hygiene will prevent transmission of the eggs.

Useful For: Detection of the eggs of Enterobius vermicularis on the skin of the perianal folds Interpretation: Positive results are provided indicating the presence of eggs of Enterobius vermicularis.


Clinical References: Mahmoud AAF: Intestinal nematodes (roundworms). In Principles and Practice of Infectious Diseases. Fourth edition. Edited by GL Mandell, RG Douglas Jr, JE Bennett. New York, Churchill Livingstone, 1995, pp 2526-2530

PIPA

Pipecolic Acid, Serum

81326

Clinical Information: Pipecolic acid (PA) is an intermediate of lysine metabolism and is oxidized in the peroxisomes by the enzyme L-pipecolate oxidase. In peroxisome biogenesis disorders (eg, Zellweger syndrome), the activity of this enzyme is lost, resulting in an increase in pipecolic acid levels. In contrast, in peroxisomal disorders involving single enzyme deficiencies such as D-bifunctional protein deficiency, PA is not elevated; therefore PA analysis is useful for differentiating between these 2 groups of disorders. Increased pipecolic acid levels may also be seen in alpha-aminoadipic semialdehyde dehydrogenase deficiency (pyridoxine-dependent epilepsy), hyperlysinemia types 1 and 2, and defects in proline metabolism. Theoretically, a defect in L-pipecolate oxidase can exist and several cases of hyperpipecolic acidemia have been reported, but a specific enzyme deficiency has not been described in any of the patients.

Useful For: Differentiating between disorders of peroxisomal biogenesis (eg, Zellweger syndrome) and disorders with loss of a single peroxisomal function Detecting abnormal elevations of pipecolic acid in serum

Interpretation: Elevated pipecolic acid levels are seen in disorders of peroxisomal biogenesis; normal levels are seen in disorders with loss of a single peroxisomal function. Abnormal levels of pipecolic acid should be interpreted together with the results of other biochemical markers of peroxisomal disorders, such as plasma C22-C26 very long-chain fatty acids, phytanic acid, and pristanic acid (POX / Fatty Acid Profile, Peroxisomal [C22-C26], Serum); RBC plasmalogens; and bile acid intermediates.



Page 1696

or =1 year: < or =5.7 nmol/mg creatinine

Clinical References: 1. Gould SJ, Raymond GV, Valle D: Chapter 129: The peroxisome biogenesis disorders. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Education. Accessed 06/30/17. Available at www.ommbid.com 2. Wanders RJA, Barth PG, Heymans HAS: Chapter 130: Single peroxisomal enzyme deficiencies. In Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill Education. Accessed 06/30/17. Available at www.ommbid.com 3. Peduto A, Baumgartner MR, Verhoeven NM, et al: Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders. Mol Genet Metab 2004;82:224-230 4. Braverman N, Raymond G, Rizzo WB, et al: Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab 2016 Mar;117(3):313-321



Page 1697

PISTA

Pistachio, IgE

82808





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PIOR

Pityrosporum orbiculare, IgE

82851




Page 1698




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



60953

Placental Alkaline Phosphatase (PLAP), Immunostain Without Interpretation Clinical Information: Placental alkaline phosphatase (PLAP) is expressed in cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblast cells. PLAP has been shown to be positive in various tumors, particularly germ-cell tumors and adenocarcinomas. PLAP expression has been described in tumors of Mullerian derivation, pulmonary and colonic carcinomas, and renal cell carcinomas.

Useful For: An aid in the identification of germ cell tumors Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Bailey D, Marks A, Stratis M, Baumal R: Immunohistochemical staining of germ cell tumors and intratubular malignant germ cells of the testis using antibody to placental alkaline phosphatase and a monoclonal anti-seminoma antibody. Modern Pathology 1991;4(2):167-171 2. Goldsmith JD, Pawel B, Goldblum JR, et al: Detection and diagnostic utilization of placental alkaline phosphatase in muscular tissue and tumors with myogenic differentiation. Am J Surg Pathol 2002;26(12):1627-1633 3. Niehans GA, Manivel C, Copland GT, et al: Immunohistochemistry of germ cell and trophoblastic neoplasms. Cancer 1988;62:1113-1123

PLAI

Plaice, IgE



Page 1699





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PBLI

Plasma Cell Assessment, Blood

9302

Clinical Information: Plasma cell proliferative disorders are a group of hematologic neoplasms, all of which are derived from clonal plasma cells. These disorders exhibit a wide range of biologic activity ranging from monoclonal gammopathy of uncertain significance (MGUS), a usually indolent disorder with a low rate of disease progression, to multiple myeloma, a disease that most often is aggressive with poor long-term survival. Detecting plasma cell immunoglobulin (Ig) light chain restriction (ie, the presence of either predominately kappa or predominately lambda light chains) is an important element in assessing plasma cell clonality and, hence, establishing the diagnosis. Furthermore, a greater degree of peripheral blood involvement by these disorders is associated with more aggressive disease types and, therefore, is an adverse prognostic indicator. Flow cytometric immunophenotyping (FCIP) is a recognized method for detecting plasma cell Ig light chain restriction. However, shortcomings of this technique, as traditionally performed, include its relative insensitivity and its consistent underestimation of the number of clonal plasma cells present. Both of these short-comings are likely attributable to limitations of the



Page 1700

instruments and antibodies used, as well as the presence of intraclonal phenotypic heterogeneity, which created difficulties in accurately detecting and enumerating all of the clonal plasma cells. For this reason, the FCIP plasma cell clonality assessment previously performed in our laboratory was supplemented with a slide-based immunofluorescence technique. However, recent advances in flow cytometry have led to the development of more powerful instruments and antibody reagents that allow for the use of greater antibody combinations and increased resolution of the data. With these tools, the ability of FCIP to detect and enumerate plasma cell clones has been greatly enhanced, allowing us to discontinue the supplemental, labor-intensive, slide-based plasma cell evaluation in peripheral blood specimens. The following algorithms are available in Special Instructions: -Laboratory Screening Tests for Suspected Multiple Myeloma -Laboratory Approach to the Diagnosis of Amyloidosis

Useful For: Detecting peripheral blood involvement by plasma cell proliferative disorders Establishing the diagnosis of and determining prognosis for plasma cell proliferative disorders

Interpretation: In normal peripheral blood specimens, no clonal plasma cells are present (polytypic or too few to detect). Plasma cells are CD38 and CD138 positive. Normal (polyclonal, nonneoplastic) plasma cells are typically CD19-positive, whereas neoplastic (clonal) plasma cells typically are CD19-negative. CD19 expression is especially helpful in distinguishing clonal from nonclonal plasma cells when few analyzable cells are present. CD45 may be expressed by both normal and neoplastic plasma cells. In some plasma cell proliferative disorders there are both CD45-positive and CD45-negative subsets within the clonal cell population. The evaluation of these antigens aids in the identification of abnormal plasma cells, however, they will not be reported independently.

Reference Values: CD38+/CD138+ plasma cells=0.0

Clinical References: Nowakowski GS, Witzig TE, Dingli D, et al: Circulating plasma cells detected by flow cytometry as a predictor of survival in 302 patients with newly diagnosed multiple myeloma. Blood 2006;106(7):2276-2279

PCPRO

Plasma Cell DNA Content and Proliferation, Bone Marrow

61654

Clinical Information: Plasma cell proliferative disorders are a group of plasma cell derived clonal hematologic neoplasms that exhibit a wide range of biologic activity ranging from monoclonal gammopathy of uncertain significance (MGUS), a usually indolent disorder with a low rate of disease progression, to multiple myeloma (MM), a disease that is often aggressive with poor long-term survival. Detecting plasma cell clonality through demonstrating immunoglobulin (Ig) light chain restriction (ie, the presence of either predominately kappa or predominately lambda light chains), supplemented by the plasma cell immunophenotype and DNA index, is an important element in establishing the diagnosis. It is important to correctly classify patients with plasma cell proliferative disorders as the various disease entities are treated differently. A number of factors are used for this classification including the proportions of clonal bone marrow plasma cells, the DNA index of the clonal plasma cells, and their proliferative activity. The plasma cell DNA index and proliferation assessment by flow cytometry are rapid and reliable. This information can be used to distinguish patients with overt active MM from less aggressive diseases such as MGUS and smoldering MM. Furthermore, in combination with other laboratory data, the results of these studies can be used as a measure of disease aggressiveness in newly diagnosed MM and also to determine therapeutic efficacy and detect disease relapse in treated MM patients. See Laboratory Screening Tests for Suspected Multiple Myeloma in Special Instructions.

Useful For: Establishing a diagnosis of a plasma cell proliferative disorder Providing prognostic information for newly diagnosed multiple myeloma and other plasma cell proliferative disorders Assessing response to therapy and detecting disease relapse and progression in treated plasma cell proliferative disorder patients Determining plasma cell DNA content and proliferation

Interpretation: Plasma Cell Clonality: Plasma cell populations with a kappa to lambda ratio of either greater than 3.9 or less than 0.5 will be considered either kappa or lambda immunoglobulin light chain restricted (monotypic), respectively. As, in rare instances, immunoglobulin light chain restricted plasma cell populations may be polyclonal at the genetic level, the term monotypic rather than monoclonal Current as of August 23, 2017 7:11 am CDT


Page 1701

plasma cells will be used. In addition to immunoglobulin light chain expression, other data collected will be used to supplement the detection of abnormal plasma cell populations. In plasma cells, CD19 expression is associated with the presence of benign, polytypic cell populations. Therefore CD19 expression will be used as a secondary element in detecting clonal plasma cells. While loss of plasma cell CD45 expression is associated with neoplasia, CD45 is expressed by both normal and neoplastic plasma cells. Therefore, absence of plasma cell CD45 expression will be used as an aid in detecting abnormal plasma cells. In some plasma cell proliferative disorders there are both CD45-positive and CD45-negative subsets within the clonal cell population, therefore inclusion of antibodies to this antigen allows for more sensitive detection of both subtypes. In addition, as DNA content will be simultaneously assessed, the detection of plasma cell aneuploidy will also serve as a tool for identifying abnormal plasma cell populations. These additional phenotypic tools for identifying abnormal plasma cells will increase the sensitivity of the method beyond examining light chain expression; particularly in biclonal plasma cell proliferative disorders in which there are both kappa and lambda immunoglobulin light chain expressing subsets. Plasma Cell Proliferation: The proportion of plasma cells in S-phase will be determined by measuring the proportion of cells with DNA content between the G0/G1 and G2/M peaks. In some instances, plasma cell proliferation will not be able to be determined by this method, including when there are fewer than 300 abnormal plasma cell events and when there are multiple aneuploid plasma cell populations. In newly diagnosed multiple myeloma, a plasma cell labeling index (PCLI) of greater than or equal to 3.0 is associated with a more aggressive disease course.(1,2) As there was a 100% concordance between a PCLI of greater than 3.0 and an estimated S-phase of greater than 1.5%, and this value is published standard for identifying plasma cell neoplasms with a high proliferative rate, it will be noted in the report if the estimated S-phase exceeds this value.(3,4) DNA Index: Processed cells are stained with DAPI to determine the DNA index of the abnormal plasma cells. This will be determined by dividing the measured DNA content of the G0/G1 abnormal plasma cells by the DNA content of the normal G0/G1 plasma cells present. For this determination, normal plasma cells are the optimal control cell population due to similarities in nuclear and overall cell size. Plasma cells with a G0/G1 DNA content index of less than 0.95 will be considered hypodiploid (worst prognosis); those with a G0/G1 DNA content index of greater than 1.05 will be considered hyperdiploid (favorable prognosis). Plasma cells with a DNA index of 1.9 to 2.1 will be considered tetraploid (nonfavorable prognosis) if a confirmatory G2/M population with a DNA index of 4 is identified. As noted above, since normal plasma cells are neither hyper- nor hypodiploid, DNA index will be used as a supplemental tool in detecting clonal plasma cells. Percent Polyclonal Plasma Cells in Total Plasma Cells: It has been shown that higher percent polyclonal plasma cells in total plasma cells can mean longer progression-free survival, higher response rates, and lower frequency of high-risk cytogenetics abnormalities. Studies have also shown a higher incidence of polytypic plasma cells in monoclonal gammopathy of uncertain significance and smoldering myeloma in comparison to multiple myeloma.

Reference Values: Plasma Cell Clonality: Normal bone marrow No monotypic clonal plasma cells detected DNA Index: Normal polytypic plasma cells DNA index (G0/G1 cells): Diploid 0.95-1.05

Clinical References: 1. Kumar SK, Mikhael JR, Buadi FK, et al: Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc 2009 Dec;84(12):1095-1110 2. Rajkumar SV, Greipp PR: Prognostic factors in multiple myeloma. Hematol Oncol Clin North Am 1999 Dec;13(6):1295-1314 3. Garcia-Sanz R, Gonzalez-Fraile MI, Mateo G, et al: Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients. Int J Cancer 2004 Dec 10;112(5):884-889 4. Morice WG, Hanson CA, Kumar S, et al: Novel multi-parameter flow cytometry sensitively detects phenotypically distinct plasma cell subsets in plasma cell proliferative disorders. Leukemia 2007 Sep;21(9):2043-2046 5. Morice WG, Chen D, Kurtin PJ, et al: Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenstrom's macroglobulinemia. Mod Pathol 2009 Jun;22(6):807-816 6. Paiva B, Vidriales MB, Mateo G, et al: The persistence of immunophenotypically normal residual bone marrow plasma cells at diagnosis identifies a good Current as of August 23, 2017 7:11 am CDT


Page 1702

prognostic subgroup of symptomatic multiple myeloma patients. Blood 2009 Nov;114(20):4369-4372

PCPDF

Plasma Cell Proliferative Disorder (PCPD), FISH

35292

Clinical Information: Multiple myeloma is a hematologic neoplasm that generally originates in the bone marrow and develops from malignant plasma cells. There are 4 main categories of plasma cell proliferative disorders (PCPD): asymptomatic myeloma, smoldering myeloma, indolent myeloma, and multiple myeloma. Asymptomatic myeloma patients have nonspecific symptoms that may be attributed to other diseases. Generalized bone pain, anemia, numbness or limb weakness, symptoms of hypercalcemia, and recurrent infections are all symptoms that may indicate myeloma. In smoldering myeloma there is a monoclonal protein spike, but it is stable. Indolent myeloma is a slowly progressing myeloma. As myeloma progresses, the malignant plasma cells interfere with normal blood product formation in the bone marrow resulting in anemia and leukopenia. Myeloma also causes an overstimulation of osteoclasts, causing excessive breakdown of bone tissue without the normal corresponding bone formation. These bone lesions are seen in approximately 66% of myeloma patients. In advanced disease, bone loss may reach a degree where the patient suffers fractures easily. Multiple myeloma is increasingly recognized as a disease characterized by marked cytogenetic, molecular, and proliferative heterogeneity. This heterogeneity is manifested clinically by varying degrees of disease aggressiveness. Multiple myeloma patients with more aggressive disease experience suboptimal responses to some therapeutic approaches; therefore, identifying these patients is critically important for selecting appropriate treatment options.

Useful For: Aiding in the diagnosis of new cases of multiple myeloma or other plasma cell proliferative disorders Identifying prognostic markers based on the anomalies found

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe.


Clinical References: 1. Fonseca R, Blood E, Rue M, et al: Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003 Jun;101(11):4569-4575 2. Fonseca R, Blood EA, Oken MM, et al: Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients. Blood 2002 May;99(10):3735-3741 3. Shaughnessy J, Tian E, Sawyer J, et al: High incidence of chromosome 13 deletion in multiple myeloma detected by multiprobe interphase FISH. Blood 2000 Aug;96(4):1505-1511

PLASF

Plasma Cell Proliferative Disorder, FISH, Tissue

35293

Clinical Information: A plasmacytoma is a localized proliferation of plasma cells that are cytologically and immunophenotypically identical to the plasma cell clones seen in myeloma. There are 2 primary types of plasmacytomas; solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EP). SPBs are a localized bone tumor comprised of plasma cells and account for about 5% of all plasma cell neoplasms. Common sites for SPBs are the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Patients often present with pathological fracture and/or bone pain near the lesion. Treatment is typically radiation therapy; at 10 years, 35% of patients appear to be cured, 55% develop myeloma, and 10% have local recurrence. EPs are tumors of plasma cells that form in areas away from the bone and account for 3% to 5% of all plasma cell neoplasms. Approximately 80% of EPs occur in the upper respiratory tract. Less common locations include the gastrointestinal tract, bladder, testis, central nervous system, and skin. Treatment consists of radiation therapy. Regional recurrence develops in about 25% of patients, but development of myeloma is less frequent, occurring in only about 15% of patients. Genetics of both types of plasmacytomas, while not extensively studied, appears to be the same as plasma cell myeloma.

Useful For: Supporting the diagnosis of plasmacytoma when coordinated with a surgical pathology consultation

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds Current as of August 23, 2017 7:11 am CDT


Page 1703

the normal reference range for a given probe set. A positive result supports the diagnosis of a plasmacytoma. A negative result does not exclude the diagnosis of a plasmacytoma.


Clinical References: 1. Jaffe ES, Harris NL, Stein H, Vardiman, JW: World Health Organization Classification of Tumours: Pathology and Genetic, Tumours of Haematopoietic and Lymphoid Tissue. 2001, pp 148-150 2. Nolan KD, Mone MC, Nelson EW: Plasma cell neoplasms: review of disease progression and report of a new variant. Surg Oncol 2005;14:85-90 3. Dingli D, Kyle RA, Rajkumar SV, et al: Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood 2006;108(6):1979-1983

PLHBB

Plasma Hemoglobin, Plasma

9096

Clinical Information: Plasma normally contains no free hemoglobin ie, no hemoglobin that is not contained within erythrocytes. Due to normal blood draw procedures, a small amount may be present in normal people, and when detectable, the total plasma hemoglobin and the subcomponent, oxyhemoglobin, are both reported. Significant amounts of free hemoglobin occur in plasma following hemolysis for any reason. This might result from a transfusion reaction or mechanical fragmentation of red blood cells due to instrumentation, surgical procedures, or mechanical devices. Patients requiring support from extracorporeal membrane oxygenation (ECMO) or centrifugal ventricular assist devices (cVAD) are commonly monitored for trends in plasma free hemoglobin levels to assess for increasing hemolysis. Sharp spikes in plasma hemoglobin levels can indicate pump disruption. However, plasma hemoglobin can be artifactually increased due to a traumatic blood draw or prolonged exposure to post-draw red blood cells. Additionally, bilirubin interferes substantially with the ability to calculate total plasma hemoglobin levels and gives spurious and unreliable results, a difficulty frequently encountered in serially tested patients. When this occurs, the oxyhemoglobin level tends to show less interference and it is the only analyte reported in the presence of increased bilirubin (>5 mg/dL). When using trending data, total plasma hemoglobin and oxyhemoglobin levels are not interchangeable and should be compared within their subgroups only.

Useful For: Determining whether hemolysis is occurring such as from: -Transfusion reaction -Mechanical fragmentation of red blood cells -Relative comparison to baseline levels in extracorporeal membrane oxygenation (ECMO) and centrifugal ventricular assist device (cVAD) patients to assess pump disruption

Interpretation: Total hemoglobin: > or =12 months: 0.0-15.2 mg/dL Reference values have not been established for patients who are or =12 months: 0.0-12.4 mg/dL Reference values have not been established for patients who are or =12 months: 0.0-15.2 mg/dL Reference values have not been established for patients who are or =12 months: 0.0-12.4 mg/dL Reference values have not been established for patients who are 70.0% >70.0% >60.0% >70.0%

Clinical References: 1. Miller, JL: Glycoprotein analysis for the diagnostic evaluation of platelet disorders. Semin Thromb Hemost 2009;35(2):224-232 2. Kannan M, Ahmad F, Yadav BK, et al: Carrier detection in Glanzmann thrombasthenia: comparison of flow cytometry and Western blot with respect to DNA mutation. Am J Clin Pathol 2008;130(1):93-98 3. Savoia A, Pastore A, De Rocco D, et al: Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica 2011;96(3):417-423 4. Nurden AT, Freson K, Selifsohn U: Inherited platelet disorders. Haemophilia 2012;18(4):154-160 5. Dumont B, Lasne D, Rothschild C, et al: Absence of collagen-induced platelet activation caused by compound heterozygous GPVI mutations. Blood 2009;114(9):1900-1903

PTEM

Platelet Transmission Electron Microscopic Study

63682

Clinical Information: Patients with either hereditary or acquired platelet disorders usually have bleeding diathesis, which can potentially be life threatening. A reliable laboratory diagnosis of a platelet disorder can significantly impact patientsâ€™ and, potentially, their family membersâ€™ clinical management and outcome. Platelet transmission electron microscopy (PTEM) has been an essential tool for laboratory diagnosis of various hereditary platelet disorders since it was first used to visualize fibrin-platelet clot formation in 1955. PTEM employs 2 main methods to visualize platelet ultrastructure, whole mount (WM) TEM and thin section (TS) TEM. WM-TEM is considered the gold standard test for diagnosing dense granule deficiencies in Hermansky-Pudlak syndrome, alpha-delta platelet storage pool deficiency, Paris-Trousseus-Jacobsen syndrome, Wiskott-Aldrich syndrome, TAR (thrombocytopenia, absent radii) syndrome, Chediak-Higashi syndrome, and more. TS-TEM is a preferred method to visualize platelet alpha granules, other organelles and abnormal inclusions. Platelet disorders that can be detected by PTEM include (but are not limited to): Delta granules (dense bodies): -Hermansky Pudlak syndrome -Wiskott-Aldrich syndrome -Chediak Higashi syndrome -Jacobson/Paris Trousseau syndrome -York platelet syndrome -Storage pool deficiency, not otherwise specified Alpha granules: -Gray platelet syndrome -White platelet syndrome -X-linked GATA 1 mutation -Jacobson/Paris Trousseau syndrome Alpha and delta granules: -Alpha-delta storage pool deficiency

Useful For: Diagnosing platelet disorders Interpretation: Ultrastructural abnormalities identified by platelet transmission electron microscopy are evaluated by a Mayo hematopathologist. Platelet size, alpha granules, golgi complex, and abnormal inclusions will be assessed as part of the morphologic examination under transmission electron microscopy. Distinct and sometimes pathognomonic ultrastructural abnormalities are found in Hermansky Pudlak syndrome, gray platelet syndrome with virtually absent alpha granules, white platelet syndrome, Medich giant platelet disorder, X-linked GATA-1 macrothrombocytopenia, and, recently described, York platelet syndrome.

Reference Values: Mean dense granules/platelet > or =1.2

Clinical References: 1. White JG: Electron-dense chains and clusters in platelets from patients with storage pool-deficiency disorders. J Thromb Haemost 2003 Jan;1(1):74-79 2. White JG: Use of the electron microscope for diagnosis of platelet disorders. Semin Thromb Hemost 1998;24(2):163-168

PTSE

Platinum, Serum

61749

Clinical Information: Cisplatin (cis-diamminedichloroplatinum)(1) and carboplatin (cyclobutanedicarboxylatoplatinum)(2,3) are used in cancer chemotherapy. Clinical trials demonstrate



Page 1709

schedule-dependent activity of carboplatin in patients with relapsed and refractory acute leukemia. Patients responding to carboplatin therapy had peak serum platinum concentration in the range of 0.6 to 1.8 mcg/mL. Trough concentrations ranged from 0.1 to 0.4 mcg/mL. Platinum concentrations maintained >1.8 mcg/mL can induce neutropenia and renal failure if coadministered with nephrotoxic antibiotics.(1,2) Unexposed individuals should have platinum concentrations 1.8 mcg/mL can induce neutropenia, and renal failure if coadministered with nephrotoxic antibiotics. -Unexposed patients should have platinum concentrations 80%) being the promyelocytic leukemia gene (PML). The fusion gene is designated PML/RARA and may be seen in a karyotype as t(15;17)(q22;q12). Messenger RNA (PML/RARA) produced from the fusion gene can be detected using a PCR-based assay, and indicates the presence of neoplastic cells. The PCR-based assay has greater sensitivity than standard methods such as morphology review, karyotyping, or FISH. Recent studies have indicated that sensitive monitoring is important because the majority of patients who remain PCR positive, or become PCR positive again following treatment, will relapse and likely benefit from early intervention for residual/recurrent disease. This quantitative assay allows PML/RARA levels to be monitored rather than simply detecting the presence or absence of disease.

Useful For: Diagnosis of acute promyelocytic leukemia (APL) Detection of residual or recurrent APL Monitoring the level of promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA) in APL patients

Interpretation: The assay is reported in the form of a normalized ratio of promyelocytic leukemia/retinoic acid receptor alpha (PML-RARA) fusion transcript to the control gene GusB expressed as a percentage, which is an estimate of the level of PML/RARA RNA present in the specimen, expressed in relation to the level of RNA from an internal control gene (beta glucuronidase, designated GUSB). The normalized ratio has no units but is directly related to the level of PML/RARA detected (ie, larger numbers indicate higher levels of PML/RARA and smaller numbers indicate lower levels). A relative expression value minimizes variability in the RNA levels measured in separate specimens tested at different times. Although a quantitative PCR assay is performed, the precision of the assay is such that results must be considered semiquantitative, and it is recommended that only log changes be considered significant. Critical results, such as a change in the status of positivity, should be repeated on a separate specimen to verify the result.

Reference Values: An interpretive report will be provided. If positive, a value representing a ratio of PML-RARA fusion transcript to the control gene GusB expressed as a percentage will be reported.

Clinical References: Grimwade D, Lo Coco F: Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 2002 October;16(10):1959-1973

PMP22

PMP22, Peripheral Neuropathy, FISH

64738

Clinical Information: This test is appropriate for individuals with clinical features suggestive of



Page 1711

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). CMT1A is a dominantly inherited disease caused by a duplication of the proximal short arm of chromosome 17, including the PMP22 gene. Clinical characteristics of CMT1A include progressive distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity starting early in life. Deletions of this region are associated with hereditary neuropathy with liability to pressure palsies (HNPP), a dominantly inherited disease resulting in peripheral neuronal demyelination. HNPP is characterized clinically by recurrent focal motor and sensory neuropathy in a single nerve that can manifest as numbness, muscular weakness, and atrophy. FISH studies are highly specific and do not exclude other chromosome abnormalities.

Useful For: Diagnosis of Charcot-Marie-Tooth type 1A or hereditary neuropathy with liability to pressure palsies

Interpretation: An interpretive report is provided. The presence of duplication of PMP22 confirms the diagnosis of Charcot-Marie-Tooth type 1A. The presence of heterozygous deletion of PMP22 confirms the diagnosis of hereditary neuropathy with liability to pressure palsies.


Clinical References: 1. van Paassen BW, van der Kooi AJ, van Spaendonck-Zwarts KY, et al: PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Orphanet J Rare Dis 2014 Mar 19;9:38 2. Li J, Parker B, Martyn C, et al: The PMP22 Gene and Its Related Diseases. Mol Neurobiol 2013 April;47(2):673-698 3. Patel PI, Lupski JR: Charcot-Marie-Tooth disease: A new paradigm for the mechanism of inherited disease. Trends Genet 1994 Apr;10(4):128-133

PMS2I

PMS-2, Immunostain (Bill Only)

35525


PMS2Z

PMS2 Gene, Full Gene Analysis

35528

Clinical Information: Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC) is an autosomal dominant hereditary cancer syndrome associated with germline mutations in the mismatch repair genes, MLH1, MSH2, MSH6, and PMS2. Deletions within the 3-prime end of the EPCAM gene have also been associated with Lynch syndrome, as this leads to inactivation of the MSH2 promoter. Lynch syndrome is predominantly characterized by significantly increased risks for colorectal and endometrial cancer. The lifetime risk for colorectal cancer is highly variable and dependent on the gene involved. The risk for colorectal cancer associated MLH1 and MSH2 mutations (approximately 50%-80%) is generally higher than the risks associated with mutations in the other Lynch syndrome-related genes, and the lifetime risk for endometrial cancer (approximately 25%-60%) is also highly variable. Other malignancies within the tumor spectrum include gastric cancer, ovarian cancer, hepatobiliary and urinary tract carcinomas, and small bowel cancer. The lifetime risks for these cancers are 1.3 ug/mL >1.3 ug/mL >1.3 ug/mL >1.3 ug/mL >1.3 ug/mL >1.3 ug/mL >1.3 ug/mL


Page 1714

Pneumo Ab Type 19 (19F) Pneumo Ab Type 23 (23F) Pneumo Ab Type 26 (6B) Pneumo Ab Type 51 (7F) Pneumo Ab Type 56 (18C)

>1.3 ug/mL >1.3 uh/mL >1.3 ug/mL >1.3 ug/mL >1.3 ug/mL

PNRP

Pneumocystis jiroveci, Molecular Detection, PCR

81698

Clinical Information: Pneumocystis pneumonia is an important cause of opportunistic infection in immunocompromised patients, particularly those with HIV. The causative agent, Pneumocystis jiroveci, cannot be cultured in vitro and, therefore, laboratory detection has historically relied upon microscopic identification directly from patient specimens using fluorescent stains or antibodies. Unfortunately, stains often lack sensitivity and require expertise on the part of the reader in order to differentiate Pneumocystis jiroveci from staining artifacts and other fungi. This real-time PCR assay provides sensitive (21% more sensitive than direct detection using fluorescent calcofluor white stain), specific, and objective detection of Pneumocystis from bronchoalveolar lavage fluid and other specimens.

Useful For: Preferred test for detection of Pneumocystis Interpretation: A positive result indicates the presence of Pneumocystis DNA. A negative result indicates the absence of detectable Pneumocystis DNA.


Clinical References: 1. Cushion MT: Pneumocystis. In Manual of Clinical Microbiology. Eighth edition. Edited by PR Murray, EJ Baron, JH Jorgensen, et al: Washington, DC, ASM Press, 2003, pp 1712-1725 2. Maskell NA, Waine DJ, Lindley A, et al: Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study. Thorax 2003;58(7):594-597 3. Miller RF, Ambrose HE, Wakefield AE: Pneumocystis carinii f. sp. hominis DNA in immunocompetent health care workers in contact with patients with P. carinii pneumonia. J Clin Microbiol 2001;39(11):3877-3882 4. Takahashi T, Goto M, Endo T, et al: Pneumocystis carinii carriage in immunocompromised patients with and without human immunodeficiency virus infection. J Med Microbiol 2002;51(7):611-614 5. Vargas SL, Hughes WT, Santolaya ME, et al: Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clin Infect Dis 2001;32(6):855-861 6. Wakefield AE, Lindley AR, Ambrose HE, et al: Limited asymptomatic carriage of Pneumocystis jiroveci in human immunodeficiency virus-infected patients. J Infect Dis 2003;187(6):901-908

FPJD

Pneumocystis jirovecii DFA

58046


SPN

Pneumocystis Smear

8047

Clinical Information: Pneumocystis jiroveci is one of the major microbial pathogens associated with opportunistic pulmonary infections in patients receiving immunosuppressive therapy or with immune deficiencies. Presently, the most common means to diagnose Pneumocystis jiroveci infection is by microscopic detection of the organisms in specimens such as bronchoalveolar lavage, open lung biopsy tissue, induced sputum and transtracheal aspirate.

Useful For: Diagnosis of Pneumocystis jiroveci pneumonia Interpretation: Negative: no cysts observed Positive: cysts present Reference Values: Negative Current as of August 23, 2017 7:11 am CDT


Page 1715

Clinical References: 1. Olsson M, Elvin K, Linder E, et al: Pneumocystis carinii is still a dangerous opportunist. The infection is continuously a threat to immunocompromised patients. Lakartidningen 1999 Jan27;96(4):328-331 2. Shelhamer JH, Gill VJ, Quinn TC, et al: The laboratory evaluation of opportunistic pulmonary infections. Ann Intern Med 1996 Mar 15;124(6):585-599 3. Kim YK, Parulekar S, Yu PK, et al: Evaluation of calcofluor white stain for detection of Pneumocystis carinii. Diagn Microbiol Infect Dis 1990;13:307-310 4. Baselski VS, Robison MK, Pifer LW, Woods DR: Rapid detection of Pneumocystis carinii in bronchoalveolar lavage samples by using Cellufluor staining. J Clin Microbiol 1990;28:393-394

PLINK

PNH, PI-Linked Antigen, Blood

62139

Clinical Information: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder characterized by nocturnal hemoglobinuria, chronic hemolytic anemia, thrombosis, pancytopenia, and, in some patients, acute or chronic myeloid malignancies. PNH appears to be a hematopoietic stem cell disorder that affects erythroid, granulocytic, and megakaryocytic cell lines. The abnormal cells in PNH have been shown to lack glycosylphosphatidylinositol (GPI)-linked proteins in erythroid, granulocytic, megakaryocytic, and, in some instances, lymphoid cells. Mutations in the phosphatidylinositol glycan A gene, PIGA, have been identified consistently in patients with PNH, thus confirming the biological defect in this disorder. A flow cytometric-based assay can detect the presence or absence of these GPI-linked proteins in granulocytes, monocytes, erythrocytes, and lymphocytes, thus avoiding the problems associated with red cell-based diagnostic methods (Ham test) in which recent hemolytic episodes or recent transfusions can give false-negative results. A partial list of known GPI-linked proteins include CD14, CD16, CD24, CD55, CD56, CD58, CD59, C8-binding protein, alkaline phosphatase, acetylcholine esterase, and a variety of high frequency human blood antigens. In addition, fluorescent aerolysin (FLAER) binds directly to the GPI anchor and can be used to evaluate the expression of the GPI linkage. Our studies, as well as others in the literature, have shown that flow cytometry-based assays will detect all Ham-positive PNH cases, as well as some Ham-negative PNH cases. This assay replaces the sugar water test and the Ham test for the evaluation of patients with possible PNH. Patients with PNH should be transfused with ABO-specific RBCs, which do not need to be washed. If, for some reason, they need to receive non-ABO type-specific (type O) cells, these RBC units should be washed. Since recipient antibodies to granulocyte antigens can trigger hemolytic episodes in PNH, if they have such antibodies these patients should receive leukoreduced RBCs and platelets.

Useful For: Screening for and confirming the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) Monitoring patients with PNH

Interpretation: Individuals with paroxysmal nocturnal hemoglobinuria (PNH) have absent or decreased expression of all the glycosylphosphatidylinositol (GPI)-linked antigens and fluorescent aerolysin (FLAER) on peripheral blood cells derived from the PNH clone. Recent data showed that small PNH clones can be detected in a relatively high percentage of cases of aplastic anemia and myelodysplastic syndrome. While the significance of this finding is still uncertain, it appears that these patients may benefit from immunosuppressive therapy. This test incorporates a sophisticated technique of separating different cell populations using gating on antigen-positive cells, as well as the sensitivity to enable detection of small PNH clones. In addition, this test detects a partial loss of CD59 on RBCs (type II RBC). Patients with large proportion of type II RBC are unlikely to show high levels of hemolysis, unlike patients with complete loss of GPI-linked proteins (predominantly type III cells). While PNH is a disorder of hematopoietic stem cells and all lineages are affected, the percentage of affected cells can differ between lineages, most commonly due to RBC hemolysis and/or transfusion. Individuals without PNH have normal expression of FLAER (neutrophils and monocytes) and normal expression of all GPI-linked antigens-CD14 (monocytes), CD16 (neutrophils and NK cells), CD24 (neutrophils), and CD59 (RBCs).

Reference Values: An interpretive report will be provided. RED BLOOD CELLS: PNH RBC-Partial Antigen loss: 0.00-0.99% Current as of August 23, 2017 7:11 am CDT


Page 1716

PNH RBC-Complete Antigen loss: 0.00-0.01% PNH Granulocytes: 0.00-0.01% PNH Monocytes: 0.00-0.05%

Clinical References: 1. Miyata T, Yamada N, Iida Y, et al: Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 1994;330:249-255 2. Brodsky RA. Advances in the diagnosis and therapy of paroxysmal nocturnal hemoglobinuria. Blood Rev 2008 Mar;22(2):65-74 3. Richards SJ, Barnett D: The role of flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria in the clinical laboratory. Clin Lab Med 2007 Sep;27(3):577-590 4. Parker C, Omine M, Richards S, et al: Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005 Dec 1;106(12):3699-3709 5. Richards SJ, Hill A, Hillman P: Recent advances in the diagnosis, monitoring and management of patients with paroxysmal nocturnal hemoglobinuria. Cytometry B Clin Cytom 2007 Sep;72(5):291-298 6. Shichishima T, Terasawa T, Hashimoto C, et al: Discordant and heterogeneous expression of GPI-anchored membrane proteins on leukemic cells in a patient with paroxysmal nocturnal hemoglobinuria. Blood 1993;81:1855-1862 7. Brodsky RA, Mukhina GL, Li S, et al: Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000;114:459-466 8. Rosse WF: Phosphatidylinositol-linked proteins and paroxysmal nocturnal hemoglobinuria. Blood 1990;75:1595-1601 9. Borowitz MJ, Craig FE, DiGiuseppe JA, et al: Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010 78(4):211-230 10. van der Schoot CE, Huizinga TW, van't Veer-Korthof ET, et al: Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay. Blood 1990;76:1853-1859

60954

Podoplanin (D2-D40), Immunostain Without Interpretation Clinical Information: Podoplanin (D2-40) is a mucin-type transmembrane glycoprotein that is expressed in reactive follicular dendritic cells (FDCs), and its expression has been recently reported in FDC sarcomas. Podoplanin is expressed in a variety of other tissues, including lymphatic endothelium, bile duct cells, mesothelial cells, ependyma, myoepithelial cells, and granulosa cells. The D2-40 antibody to podoplanin has been used in the diagnosis of mesothelioma and seminoma.

Useful For: An aid in the identification of reactive follicular dendritic cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Xie Q, Chen L, Fu K, et al: Podoplanin (D2-40): a new immunohistochemical marker for reactive follicular dendritic cells and follicular dendritic cell sarcomas. Int J Clin Exp Pathol 2008 Jan;1(3):276-284 2. Ordonex NG: D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma. Hum Pathol 2005 Apr;36(4):372-380

FPOLO

Poliovirus (Types 1, 3) Antibodies, Neutralization

75165

Reference Values: Polio 1 Titer: 90% of hypertensive patients with aldosteronism have hypokalemia. Abnormally high extracellular potassium levels produce symptoms of mental confusion; weakness, numbness and tingling of the extremities; weakness of the respiratory muscles; flaccid paralysis of the extremities; slowed heart rate; and eventually peripheral vascular collapse and cardiac arrest. Hyperkalemia may be seen in end-stage renal failure, hemolysis, trauma, Addison's disease, metabolic acidosis, acute starvation, dehydration, and with rapid potassium infusion.

Useful For: Evaluation of electrolyte balance, cardiac arrhythmia, muscular weakness, hepatic encephalopathy, and renal failure Potassium should be monitored during treatment of many conditions but especially in diabetic ketoacidosis and any intravenous therapy for fluid replacement.

Interpretation: Potassium levels 6.0 mmol/L are potentially life-threatening. Levels >10.0 mmol/L are, in most cases, fatal.

Reference Values: > or =12 months: 3.6-5.2 mmol/L Reference values have not been established for patients that are less than 12 months of age.

Clinical References: Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. WB Saunders Company, Philadelphia, 2006;27:984-987; 2006;46:1754-1757

FPTWG

Potato White IgG

57539

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: 50%) to chronic disease. In the United States, HCV infection is quite common, with an estimated 3.5 to 4 million chronic HCV carriers. Cirrhosis and hepatocellular carcinoma are sequelae of chronic HCV. See HBV Infection-Diagnostic Approach and Management Algorithm and Testing Algorithm for the Diagnosis of Hepatitis C in Special Instructions.

Useful For: Determining if an individual has been infected following exposure to an unknown type of hepatitis Obtaining baseline serologic markers of an individual exposed to a source with an unknown type of hepatitis Determining immunity to hepatitis A and B viral infections

Interpretation: Hepatitis A: Antibody against hepatitis A antigen (anti-HAV) is almost always detectable by the onset of symptoms (usually 15-45 days after exposure). The initial antibody consists almost entirely of the IgM subclass of antibody. Anti-HAV IgM usually falls to undetectable levels 3 to 6 months after infection. Anti-HAV, IgG levels rise quickly once the virus is cleared and persist for many years. Hepatitis B: Hepatitis B surface antigen (HBsAg) is the first serologic marker appearing in the serum 6 to 16 weeks following hepatitis B virus (HBV) infection. In acute cases, HBsAg usually disappears 1 to 2 months after the onset of symptoms. Hepatitis B surface antibody (anti-HBs) appears with the resolution of HBV infection after the disappearance of HBsAg. Anti-HBs also appears as the immune response following a course of inoculation with the hepatitis B vaccine. Hepatitis B core antibody (anti-HBc) appears shortly after the onset of symptoms of HBV infection and may be the only serologic marker remaining years after exposure to hepatitis B. Hepatitis C: Hepatitis C virus antibody (anti-HCV) is usually not detectable during the early months following infection, but is almost always detectable by the late convalescent stage of infection. Anti-HCV is not neutralizing and does not provide immunity.

Reference Values: HEPATITIS B SURFACE ANTIGEN Negative (reported as reactive, positive or negative) HEPATITIS B SURFACE ANTIBODY, QUALITATIVE/QUANTITATIVE Hepatitis B Surface Antibody Unvaccinated: negative Vaccinated: positive Hepatitis B Surface Antibody, Quantitative Unvaccinated: or =12.0 mIU/mL HEPATITIS B CORE ANTIBODY Negative (reported as positive or negative) HEPATITIS A ANTIBODY, TOTAL Negative (reported as positive or negative) HEPATITIS C VIRUS ANTIBODY Negative (reported as reactive or negative) HEPATITIS C VIRUS, RT-PCR Negative for HCV-RNA If positive, reported as positive for HCV-RNA HEPATITIS BS ANTIGEN CONFIRMATION Negative (reported as positive or negative) Current as of August 23, 2017 7:11 am CDT


Page 1748

Clinical References: 1. Roque-Afonso AM, Desbois D, Dussaix E: Hepatitis A virus: serology and molecular diagnostics. Future Virology 2010;5(2):233-242 2. De Paula VS: Laboratory diagnosis of hepatitis A. Future Virology 2012;7(5):461-472 3. Bonino F. Piratvisuth T, Brunetto MR, et al: Diagnostic markers of chronic hepatitis B infection and disease. Antiviral Therapy 2010;15(Suppl. 3):35-44 4. Wasley A, Fiore A, Bell BP: Hepatitis A in the era of vaccination. Epidemiol Rev 2006;28:101-111 5. American Association for the Study of Liver Diseases/Infectious Diseases Society of America/International Antiviral Society-USA. Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed on January 27, 2015. Avaliable at www.hcvguidelines.org

PRMB

Primidone and Phenobarbital, Serum

37053

Clinical Information: Primidone is used for control of grand mal seizures that are refractory to other antiepileptics and seizures of psychomotor or focal origin. Primidone is initially dosed in progressively increasing amounts starting with 100 mg at bedtime to 250 mg 3 times a day after 10 days of therapy in adults. Primidone exhibits a volume of distribution of 0.6 L/kg and a half-life of 8 hours. When monitoring primidone and phenobarbital levels simultaneously, the specimen should be drawn just before the next dose is administered. Primidone is not highly protein bound, approximately 10%. Phenobarbital is a metabolite of primidone. Like phenobarbital, there are no known major drug-drug interactions that affect the pharmacology of primidone. Toxicity associated with primidone is primarily due to the accumulation of phenobarbital. Diagnosis and treatment are as described for PBAR / Phenobarbital, Serum.

Useful For: Assessing compliance Monitoring for appropriate therapeutic levels of primidone and phenobarbital Assessing toxicity

Interpretation: At steady-state, which is achieved approximately 2 weeks after therapy is initiated, blood levels of primidone that correlate with optimal response to the drug range from 9.0 to 12.5 mcg/mL for adults and 7.0 to 10.0 mcg/mL for children or =60.0 mcg/mL

Clinical References: Rall TW, Schleifer LS: Drugs effective in the therapy of the epilepsies: primidone. In Goodman and Gilman's The Pharmacological Basis of Therapeutics. Eighth edition. Edited by AG Gilman, TW Rall, AS Nies, P Taylor. New York, Pergamon Press, 1990, pp 446-447

PTRE

Privet Tree, IgE

82784




Page 1749





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



PROCG

Procainamide and N-acetylprocainamide, Serum

37055

Clinical Information: Procainamide (PA) is indicated in the treatment of premature ventricular contractions, ventricular tachycardia, atrial fibrillation, and paroxysmal atrial tachycardia. PA is contraindicated in patients with complete atrioventricular block. PA is metabolized to an active metabolite, N-acetylprocainamide (NAPA), with metabolism controlled by genetically determined enzymes. In patients with normal renal function, fast metabolizers will have a PA:NAPA ratio 2 after 3 hours) are more likely to develop a positive test for antinuclear antibodies and present with systemic lupus erythematosus-like symptoms. Patients who have prolonged exposure to procainamide >12 mcg/mL or NAPA concentration > or =40.0 mcg/mL are very likely to exhibit symptoms of toxicity that are characterized by hypotension, ventricular fibrillation, widened QRS complex, junctional tachycardia, oliguria, confusion, nausea, and vomiting. Renal disease, hepatic disease, cardiac failure, and states of low cardiac output reduce the metabolism and clearance of PA and NAPA. Coadministration of histamine H2 receptor antagonists, such as cimetidine and ranitidine reduce renal clearance of PA and NAPA resulting in higher plasma concentrations of each.

Useful For: Monitoring therapy with procainamide Assessing compliance Evaluating toxicity Interpretation: Administration of a dose of 50 mg/kg will usually yield the optimal trough concentration in the range of 4.0 to 10.0 mcg/mL for procainamide and 12.0 to 18.0 mcg/mL for N-acetylprocainamide.

Reference Values: Procainamide Therapeutic: 4.0-10.0 mcg/mL Current as of August 23, 2017 7:11 am CDT


Page 1750

Critical value: >12.0 mcg/mL N-acetylprocainamide Therapeutic: 12.0-18.0 mcg/mL Critical value: > or =40.0 mcg/mL

Clinical References: Myerburg RJ, Kessler KM, Kiem I, et al: Relationship between plasma levels of procainamide, suppression of premature ventricular complexes and prevention of recurrent ventricular tachycardia. Circulation 1981;64;280-290

PCT

Procalcitonin, Serum

83169

Clinical Information: Procalcitonin (ProCT) is a 116 amino acid precursor of calcitonin (CT). ProCT is processed to an N-terminal 57 amino acid peptide (CT [32 amino acids] and a 21 amino acid C-terminal peptide, catacalcin [CCP-1]). Expression of this group of peptides is normally limited to thyroid C cells and, to a small extent, other neuroendocrine cells. CT is the only hormonally active of these peptides. CT is secreted by C cells in response to hypercalcemia and inhibits bone resorption by osteoclasts, minimizing oscillations in serum calcium and calcium loss. During severe systemic inflammation, in particular related to bacterial infection, the tissue specific control of CT-related peptides expression breaks down and ProCT and CCP-1 (referred collectively to as ProCT) are secreted in large quantities by many tissues. CT levels do not change. Noninfectious inflammatory stimuli need to be extremely severe to result in ProCT elevations, making it a more specific marker for severe infections than most other inflammatory markers (cytokines, interleukins, and acute-phase reactants). ProCT elevations are also more sustained than those of most other markers and occur in neutropenic patients. This reduces the risk of false-negative results. ProCT becomes detectable within 2 to 4 hours after a triggering event and peaks by 12 to 24 hours. ProCT secretion parallels closely the severity of the inflammatory insult, with higher levels associated with more severe disease and declining levels with resolution of illness. In the absence of an ongoing stimulus, ProCT is eliminated with a half-life of 24 to 35 hours, making it suitable for serial monitoring. Finally, the dependence of sustained ProCT elevations on ongoing inflammatory stimuli allows identification of secondary septic events in conditions that can result in noninfectious ProCT elevations, such as cardiac surgery, severe trauma, severe burns, and multiorgan failure. ProCT levels should fall at a predictable pace in the absence of secondary infection.

Useful For: Diagnosis of bacteremia and septicemia in adults and children (including neonates) Diagnosis of renal involvement in urinary tract infection in children Diagnosis of bacterial infection in neutropenic patients Diagnosis, risk stratification, and monitoring of septic shock Diagnosis of systemic secondary infection post-surgery, and in severe trauma, burns, and multiorgan failure Differential diagnosis of bacterial versus viral meningitis Differential diagnosis of community-acquired bacterial versus viral pneumonia Monitoring of therapeutic response to antibacterial therapy

Interpretation: General considerations: -In children older than 72 hours and in adults, levels 2.0 ng/mL are highly suggestive of systemic bacterial infection/sepsis or severe localized bacterial infection, such as severe pneumonia, meningitis, or peritonitis. They can also occur after severe noninfectious inflammatory stimuli such as major burns, severe trauma, acute multiorgan failure, or major abdominal or cardiothoracic surgery. In cases of noninfectious elevations, ProCT levels should begin to fall after 24 to 48 hours. -Autoimmune diseases, chronic inflammatory processes, viral infections, and mild localized bacterial infections rarely lead to elevations of ProCT of >0.5 ng/mL. Specific diagnostic applications, based on the current consensus in the literature: -Diagnosis of bacteremia in neonates: After birth ProCT values increase from birth to reach peak values at about 24 hours of life and the decrease gradually by 48 hours of life. Therefore, during the first 72 hours of life different reference ranges will apply to newborn infants at different hours of age. ProCT levels on newborns suffering from early sepsis are significantly higher than those of noninfected newborns when reference ranges by hours of age are used.(1,2) Adult levels should apply at > or =72 hours after birth. -Diagnosis of renal involvement in pediatric urinary tract infections: In children with urinary tract infections, a ProCT level of >0.5 ng/mL has a 70% to 90% sensitivity and an 80% to 90% Current as of August 23, 2017 7:11 am CDT


Page 1751

specificity for renal involvement. -ProCT responses in neutropenic patients are similar to patients with normal neutrophil counts and function, and the cutoffs discussed under general considerations above should be used. In the appropriate clinical setting, ProCT levels above 2.0 ng/mL on the first day of admission to the intensive care unit (ICU) represent a high risk for progression to severe sepsis and/or septic shock. ProCT levels below 0.5 ng/mL on the first day of ICU admission represent a low risk for progression to severe sepsis and/or septic shock. Reported sensitivity and specificity for the diagnosis of sepsis range from 60% to 100%, depending on underlying and coexisting diseases and the patient populations studied. The higher the ProCT level the worse the prognosis. A ProCT level of 10 times this level. With successful antibiotic therapy, ProCT levels should fall with a half-life to 24 to 35 hours.

Reference Values: Adults and children > or =72 hours: < or =0.15 ng/mL Children < 72 hours: or =21% (least significant change) from baseline PINP levels indicates an adequate therapeutic response. This assay is specific for the intact trimeric form of PINP. The direction of the change in PINP levels (decrease or increase) will depend on the type of osteoporosis treatment. In patients taking bisphosphonates, PINP levels have been shown to decrease up to 70% from baseline after 6 months of therapy. Treatment with hormone replacement therapy also shows a decrease in Current as of August 23, 2017 7:11 am CDT


Page 1752

PINP levels, but to a lesser degree than bisphosphonates therapy. In patients treated with teriparatide (recombinant human parathyroid hormone 1-34), PINP levels increase from baseline reflecting the stimulatory effect of teriparatide on osteoblasts and bone formation. PINP levels have been shown to significantly increase as early as 1 month after teriparatide treatment, peaking at 6 months following treatment. Increases of >10 mcg/L have been reported in 77% to 79% of teriparatide-treated patients after 3 months of therapy and are considered a successful response.

Reference Values: Reference values have not been established for patients who are or =80

< or =7.2 Females: not applicable

Clinical References: 1. Oesterling JE, Jacobsen SJ, Chute CG, et al: Serum prostate-specific antigen in a community-based population of healthy men. JAMA 1993 Aug 18;270:860-864 2. Smith RA, Cokkinides V, von Eschenbach A, et al: American Cancer Society guidelines for the early detection of Current as of August 23, 2017 7:11 am CDT


Page 1767

cancer. CA Cancer J Clin 2002;52:8-22 3. Barry MJ, Albertsen PC, Bagshaw MA, et al: Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostatectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer 2001 June 15;91(12):2302-2314 4. Blute ML, Bergstralh EJ, Scherer BG, et al: Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J Urol 2001 January;165(1):119-125

SPSA

Prostate-Specific Antigen (PSA) Screen, Serum

82023

Clinical Information: Prostate-specific antigen (PSA) is a glycoprotein that is produced by the prostate gland, the lining of the urethra, and the bulbourethral gland. Normally, very little PSA is secreted in the blood. Increases in glandular size and tissue damage caused by benign prostatic hypertrophy, prostatitis, or prostate cancer may increase circulating PSA levels. In patients with previously diagnosed prostate cancer, PSA testing is advocated as an early indicator of tumor recurrence and as an indicator of response to therapy. The role of PSA in early detection of prostate cancer is controversial. The American Cancer Society recommends annual examination with digital rectal examination and serum PSA beginning at age 50, and also for those men with a life expectancy of at least 10 years after detection of prostate cancer. For men in high-risk groups, such as African Americans or men with a first-degree relative diagnosed at a younger age, testing should begin at a younger age. It is generally recommended that information be provided to patients about the benefits and limitations of testing and treatment so they can make informed decisions.

Useful For: Monitoring patients with a history of prostate cancer as an early indicator of recurrence and response to treatment Prostate cancer screening

Interpretation: Prostate-specific antigen (PSA) values are reported with the 95th percentile limits by decade of age. These reference limits include men with benign prostatic hyperplasia. They exclude all cases with proven cancer. PSA values exceeding the age-specific limits are suspicious for prostate disease, but further testing, such as prostate biopsy, is needed to diagnose prostate pathology. The minimal reporting value is 0.1 ng/mL. Values above 0.2 ng/mL are considered evidence of biochemical recurrence of cancer in men after prostatectomy.

Reference Values: Age (Years) PSA Upper Limit (ng/mL) < or =2.0 40-49

< or =2.5

50-59

< or =3.5

60-69

< or =4.5

70-79

< or =6.5

> or =80


Clinical References: 1. Oesterling JE, Jacobsen SJ, Chute CG, et al: Serum prostate-specific antigen in a community-based population of healthy men. JAMA 1993 Aug 18;270:860-864 2. Smith RA, Cokkinides V, von Eschenbach A, et al: American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52:8-22 3. Barry MJ, Albertsen PC, Bagshaw MA, et al: Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostatectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer 2001 June 15;91(12):2302-2314 4. Blute ML, Bergstralh EJ, Scherer BG, et al: Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J Urol 2001 January;165(1):119-125



Page 1768

PSAU

Prostate-Specific Antigen (PSA) Ultrasensitive, Serum

64061

Clinical Information: Prostate-specific antigen (PSA) is the most widely used method to detect prostate cancer recurrence after radical prostatectomy (RP). Approximately 20% to 35% of patients develop a rising PSA following RP for clinically localized prostate cancer. Biochemical recurrence (BCR) is defined as an increase in PSA after curative therapy without clinical or radiological evidence of disease. The median time to biochemical recurrence (BCR) could vary between 2 to 3 years. A standard PSA cutpoint to indicate BCR has yet to be established. For example, the American Urological Association and the American Society for Radiation Oncology defined BCR after surgery as initial and confirmatory PSA concentrations of 0.2 ng/mL or greater. However, a BCR definition of 0.4 ng/mL PSA has also been proposed. Assays that measure PSA to concentrations below 0.1 ng/mL are denoted ultrasensitive PSA (USPSA). The use of USPSA cutpoints below currently recommended PSA thresholds may be helpful in identifying cases of early biochemical recurrence and for selecting patients with adverse clinicopathologic risk factors for secondary therapy. However, some authors believe that USPSA assays offers minimal advantages and could lead to increased anxiety in patients who have clinically meaningless rises of PSA and might lead to overtreatment.

Useful For: Monitoring disease after radical prostatectomy This test should not be used for initial prostate cancer screening.

Interpretation: An undetectable ( or =0.01 ng/mL) after radical prostatectomy does not necessarily translate into disease progression or recurrence. Interpretation of a detectable PSA needs to be made in conjunction with other clinicopathologic risk factors. The cutpoint for interpretation of ultrasensitive PSA assays remains controversial and has ranged from 0.01 to 0.05 ng/mL. For example, in a study that included 754 men after RP, a cutpoint of 0.01 ng/mL was an independent predictor of BCR. BCR-free survival at 5 years was 92.4% for patients with a PSA post-RP of less than 0.01 ng/mL and 56.8% for patients with a PSA post-RP of 0.01 ng/mL or higher.(1) In the same study a cutoff of 0.03 ng/ml also predicted BCR independent of clinicopathological factors and BCR-free survival at 5 yrs was 90.8% for patients with a PSA post-RP of less than 0.03 ng/mL and 26.9% for patients with a PSA post-RP of greater or equal to 0.03 ng/mL.(1)

Reference Values: Age (Years) PSA Upper Limit (ng/mL) < or =2.0 40-49

< or =2.5

50-59

< or =3.5

60-69

< or =4.5

70-79

< or =6.5

> or =80


Clinical References: 1. Sokoll LJ, Zhang Z, Chan DW, et al: Do Ultrasensitive Prostate Specific Antigen Measurements Have a Role in Predicting Long-Term Biochemical Recurrence-Free Survival in Men after Radical Prostatectomy? J Urol 2016 Feb;195(2):330-336 2. Thompson IM, Valicenti RK, Albertsen P, et al: Adjuvant and salvage radiotherapy after prostatectomy:AUA/ASTRO Guideline. J Urol 2013 Aug;190(2):441-449 3. Mir MC, Li J, Klink JC, et al: Optimal definition of biochemical recurrence after radical prostatectomy depends on pathologic risk factors: Identifying candidates for early salvage therapy. Eur Urol 2014 Aug;66(2):204-210

PSAFT

Prostate-Specific Antigen (PSA), Total and Free, Serum

81944

Clinical Information: Prostate-specific antigen (PSA) is a glycoprotein that is produced by the



Page 1769

prostate gland, the lining of the urethra, and the bulbourethral gland. Normally, very little PSA is secreted in the blood. Increases in glandular size and tissue damage caused by benign prostatic hypertrophy, prostatitis, or prostate cancer may increase circulating PSA levels. PSA exists in serum in multiple forms: complexed to alpha-1-anti-chymotrypsin (PSA-ACT complex), unbound (free PSA), and enveloped by alpha-2-macroglobulin (not detected by immunoassays). Higher total PSA levels and lower percentages of free PSA are associated with higher risks of prostate cancer. Most prostate cancers are slow growing, so the utility of prostate cancer screening is marginal in most men with a life expectancy of less than 10 years.

Useful For: The percentage of measured prostate-specific antigen (PSA) existing in the free form (free:total PSA ratio) is useful in assessing the risk of prostate cancer in patients with borderline or moderately increased total PSA (4.0-10.0 ng/mL) and has been used to help select men who should have follow-up prostate biopsy

Interpretation: When total prostate-specific antigen (PSA) concentration is below 2.0 ng/mL, the probability of prostate cancer in asymptomatic men is low, further testing and free PSA may provide little additional information. When total PSA concentration is above 10.0 ng/mL, the probability of cancer is high and prostate biopsy is generally recommended. The total PSA range of 4.0 to 10.0 ng/mL has been described as a diagnostic "gray zone," in which the free:total PSA ratio helps to determine the relative risk of prostate cancer (see table below). Therefore, some urologists recommend using the free:total ratio to help select which men should undergo biopsy. However, even a negative result of prostate biopsy does not rule-out prostate cancer. Up to 20% of men with negative biopsy results have subsequently been found to have cancer. Based on free:total PSA ratio: the percent probability of finding prostate cancer on a needle biopsy by age in years: Free:total PSA ratio 50-59 years 60-69 years > or =70 years < or =0.10 49.2% 57.5% 64.5% 0.11-0.18 26.9% 33.9% 40.8% 0.19-0.25 18.3% 23.9% 29.7% >0.25 9.1% 12.2% 15.8%

Reference Values: Age (Years)

PSA Upper Limit (ng/mL) < or =2.0

40-49

< or =2.5

50-59

< or =3.5

60-69

< or =4.5

70-79

< or =6.5

> or =80

< or =7.2 Females: not applicable FREE PSA Males: When total PSA is in the range of 4.0-10.0 ng/mL, a free:total PSA ratio < or =0.10 indicates 49% to 65% risk of prostate cancer depending on age; a free:total PSA ratio >0.25 indicates a 9% to 16% risk of prostate cancer, depending on age. Females: not applicable

Clinical References: 1. Oesterling JE, Jacobsen SJ, Chute CG, et al: Serum prostate-specific antigen in a community-based population of healthy men. JAMA 1993 Aug 18;270:860-864 2. Catalona WJ, Smith DS, Wolfert RL, et al: Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995:274(15);214-1220 3. Jacobsen SJ, Bergstralh EJ, Guess HA, et al: Predictive properties of serum prostate-specific antigen testing in a community-based setting. Arch Intern Med 1996;156:2462-2468 4. Oesterling JE, Jacobsen SJ, Klee GG, et al: Free, complexed and total serum prostate specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios. J Urol 1995;154:1090-1095 5. Dworschack RT, Thiel RP, Picolli SP: Clinical evaluation of the free/total PSA ratio generated with the Elecsys total and free PSA assays on the Elecsys 1010 and 2010 systems. Clin Chem 2001 Jun;47(6 Suppl S):A149 (Abstract)

60959

Prostatic Acid Phosphatase (PACP), Immunostain Without



Page 1770

Interpretation Clinical Information: Prostatic acid phosphatase (PACP) is a cytoplasmic enzyme produced in normal prostatic epithelium and prostatic adenocarcinoma. PACP is a useful adjunct to the immunostain for prostate specific antigen; if 1 of these 2 markers is immunoreactive, a tumor of prostatic origin is likely. Bladder epithelium and certain neuroendocrine tumors such as rectal carcinoid may be weakly immunoreactive.

Useful For: Enzyme produced in normal prostatic epithelium and prostatic adenocarcinoma Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Hameed O, Humphrey PA: Immunohistochemistry in Diagnostic Surgical Pathology of the Prostate. Seminars in Diagnostic Pathology 2005;22(1):88-104 2. Hammerich KH, Ayala GE, Wheeler TM: Application of Immunohistochemistry to the Genitourinary System (Prostate, Urinary Bladder, Testis, and Kidney). Arch Pathol Lab Med 2008;132:432-440 3. Varma M, Berney DM, Rhodes A: Technical Variations in Prostatic Immunohistochemistry: Need for Standardisation and Stringent Quality Assurance in PSA and PSAP Immunostaining. J Clin Pathol 2004;57:687-690

PACP

Prostatic Acid Phosphatase (PAP), Serum

8019

Clinical Information: Prostatic acid phosphatase (PAP), a glycoprotein synthesized by the prostate gland, is a member of a diverse group of isoenzymes, the acid phosphatases, which are capable of hydrolyzing phosphate esters in acidic medium. They are classified on the basis of their electrophoretic mobilities. PAP was a major tumor marker for prostate cancer for more than 50 years.(1) However, PAP is no longer used to screen for or stage prostate cancer. In most instances, serum prostate specific antigen (PSA) is used instead. PAP usefulness is now limited to niche applications. Pre-treatment PAP measurement may add unique, clinically useful prognostic information for predicting recurrence in men who are undergoing radical prostatectomy for clinically localized prostate cancer. PAP also may be useful for following the progression of disease response to therapy in men treated by androgen ablation. However, for both of these applications, PSA provides more information and also should be utilized.

Useful For: Predicting recurrence after radical prostatectomy for clinically localized prostate cancer and following response to androgen ablation therapy, when used in conjunction with prostate-specific antigen

Interpretation: Prostatic acid phosphatase (PAP) levels above the reference range may indicate prostate cancer, but can be due to many other factors, see Cautions. A rise in PAP levels in patients with known prostate cancer can indicate tumor progression or recurrence. However, there is considerable intra-subject biological variability, limiting the usefulness of this test.

Reference Values: < or =2.1 ng/mL

Clinical References: 1. Moul JW, Connelly RR, Perahia B, McLeod DG: The contemporary value of pretreatment prostatic acid phosphatase to predict pathological stage and recurrence in radical prostatectomy cases. J Urol 1998;159:935-940 2. Beaver TR, Schultz AL, Fink LM, et al: Discordance between concentration of prostate-specific antigen and acid phosphatase in serum of patients with adenocarcinoma of the prostate. Clin Chem 1988;34:1524

CFX

Protein C Activity, Plasma

9339

Clinical Information: Physiology: Protein C is a vitamin K-dependent anticoagulant proenzyme. It is



Page 1771

synthesized in the liver and circulates in the plasma. The biological half-life of plasma protein C is approximately 6 to 10 hours, similar to the relatively short half-life of coagulation factor VII. Protein C is activated by thrombin, in the presence of an endothelial cell cofactor (thrombomodulin), to form the active enzyme activated protein C (APC). APC functions as an anticoagulant by proteolytically inactivating the activated forms of coagulation factors V and VIII (factors Va and VIIIa). APC also enhances fibrinolysis by inactivating plasminogen activator inhibitor (PAI-1). Expression of the anticoagulant activity of APC is enhanced by a cofactor, protein S, another vitamin K-dependent plasma protein. Pathophysiology: Congenital homozygous protein C deficiency results in a severe thrombotic diathesis, evident in the neonatal period and resembling purpura fulminans. Congenital heterozygous protein C deficiency may predispose to thrombotic events, primarily venous thromboembolism; arterial thrombosis (stroke, myocardial infarction, etc.) may occur. Some individuals with hereditary heterozygous protein C deficiency may have no personal or family history of thrombosis and may or may not be at increased risk. Congenital heterozygous protein C may predispose to development of coumarin-associated skin necrosis. Skin necrosis has occurred during the initiation of oral anticoagulant therapy. Two types of hereditary heterozygous protein C deficiency are recognized: -Type I (concordantly decreased protein C function and antigen) -Type II (decreased protein C function with normal antigen level) Acquired deficiencies of protein C may occur in association with: -Vitamin K deficiency -Oral anticoagulation with coumarin compounds -Liver disease -Intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC) The clinical hemostatic significance of acquired protein C deficiency is uncertain. Assay of protein C functional activity is recommended for the initial laboratory evaluation of patients suspected of having congenital protein C deficiency (personal or family history of thrombotic diathesis), rather than assay of protein C antigen (PCAG / Protein C Antigen, Plasma).

Useful For: As an initial test for evaluating patients suspected of having congenital protein C deficiency, including those with personal or family histories of thrombotic events Because coagulation testing and its interpretation is complex, Mayo Medical Laboratories suggests ordering THRMP / Thrombophilia Profile. Detecting and confirming congenital Type I and Type II protein C deficiencies, detecting and confirming congenital homozygous protein C deficiency, and identifying decreased functional protein C of acquired origin (eg, due to oral anticoagulant effect, vitamin K deficiency, liver disease, intravascular coagulation and fibrinolysis/disseminated intravascular coagulation.)

Interpretation: Values or =50%) probably is present by age 3 to 6 months. Current as of August 23, 2017 7:11 am CDT


Page 1774

Clinical References: 1. Borgel D, Gandrille S, Aiach M: Protein S deficiency. Thromb Haemost 1997 July;78(1):351-356 2. Faioni EM: Protein S activity. In Laboratory Techniques in Thrombosis-A Manual. Second edition. Kluwer Academic Publishers, Boston, MA, 1999, pp 153-161 3. De Stefano V, Finazzi G, Mannucci PM: Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996 May 1;87(9):3531-3544 4. Zoller B, Garcia de Frutos P, Dahlback B: Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995 June 15;85(12):3524-3531 5. Grandrille S, Borgel D, Ireland H, et al: Protein S deficiency: a database of mutations. Thromb Haemost 1997 June;77(6):1201-1214 6. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG: A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med 2002 November;126(11):1349-1366

PSTF

Protein S Antigen, Plasma

83049

Clinical Information: Protein S is a vitamin K-dependent glycoprotein present in platelets and synthesized within the liver and endothelial cells. Protein S works as part of the natural anticoagulant system by acting as a cofactor to activated protein C (APC) in the proteolytic inactivation of procoagulant factors Va and VIIIa. In addition, protein S has direct APC-independent anticoagulant activity by inhibiting formation of the prothrombin and tenase complexes, possibly due to its high affinity for anionic phospholipid membranes. In human plasma, protein S forms a complex with the compliment regulatory protein, C4b-binding protein (C4bBP). Of the total plasma protein S, approximately 60% circulates bound to C4bBP while the remaining 40% circulates as "free" protein S. Only free protein S has anticoagulant function. C4bBP is composed of 6 or 7 alpha-chains and 1 or no beta-chain (C4bBP-beta). Different C4bBP isoforms are present in plasma, but only C4bBP-beta binds protein S. Congenital protein S deficiency is an autosomal dominant disorder that is present in 2% to 6% of patients with venous thrombosis. Patients with protein S deficiency have an approximately 10-fold increased risk of venous thrombosis. In addition they may also experience recurrent miscarriage, complications of pregnancy (preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth) and possibly arterial thrombosis. Three types of protein S deficiency have been described according to the levels of total protein S antigen, free protein S antigen, and protein S activity in plasma. Types I and III protein S deficiency are much more common than type II (dysfunctional) protein S deficiency. Type III protein S deficiency appears to be partly due to mutations within the protein S binding region for C4bBP-beta. Homozygous protein S deficiency is rare, but can present as neonatal purpura fulminans, reflecting severe disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) caused by the absence of plasma protein S. Acquired deficiency of protein S has causes that are generally of unknown haemostatic significance (ie, uncertain thrombosis risk), and is much more common than hereditary protein S deficiency. Acquired protein S deficiency can present through vitamin K deficiency, oral anticoagulant therapy, liver disease, DIC/ICF, thrombotic thrombocytopenia purpura, pregnancy or estrogen therapy, nephritic syndrome, and sickle cell anemia. As an acute-phase reactant, plasma C4bBP levels increase with acute illness and may cause acquired free protein S deficiency. Measurement of plasma free protein S antigen is performed as the initial testing for protein S deficiency. When the free protein S antigen level is below the age- and sex-adjusted normal range, reflexive testing will be performed for total plasma protein S antigen.

Useful For: Investigation of patients with a history of thrombosis Interpretation: Protein S values vary widely in the normal population and are age- and sex-dependent. Types of Heterozygous Protein S Deficiency Type Protein S Antigen Free Protein S Antigen Total Protein S Activity I Low Low Low II Normal Normal Low III Low Normal Low Protein S and C4bBP are coordinately regulated, and an increased total protein S antigen and low free protein S antigen most commonly reflect acute or chronic inflammation or illness with an associated increase in plasma C4bBP. For patients in whom hereditary protein S deficiency is strongly suspected and the free plasma protein S antigen level is normal, consideration should be given to testing of free protein S activity, S_FX / Protein S Activity, Plasma, for detecting type II protein S deficiency (which is rare). An increased total protein S antigen is of uncertain clinical significance because free protein S antigen levels are usually normal, in such situations. However, the total protein S antigen level may be helpful in distinguishing acquired Current as of August 23, 2017 7:11 am CDT


Page 1775

versus congenital protein S deficiency. High normal or increased total protein S antigen and reduced free protein S antigen suggests acquired protein S deficiency, as may be seen in pregnancy or inflammation. In contrast, low normal or decreased total protein S antigen and reduced free protein S antigen suggests vitamin K deficiency or a warfarin effect, but also could reflect congenital protein S deficiency (type I or III). Vitamin K deficiency, oral anticoagulant therapy, presence of liver disease, or disseminated intravascular coagulation/intravascular coagulation and fibrinolysis (DIC/ICF) are common acquired causes of protein S deficiency, which is of uncertain significance when such conditions are present. Concomitant assay of coagulation factor II activity may be helpful in differentiating congenital protein S deficiency from oral anticoagulation effects, but supportive data are currently suboptimal. Differentiation of congenital and acquired protein S deficiency requires clinical correlation and may require repeated laboratory study of the patient and selected family members in some instances. DNA-based testing may be helpful, but is generally not yet available.

Reference Values: TOTAL Males: 80-160% Females or =50 years: 80-160% FREE Males: 65-160% Females or =50 years: 65-160% Normal, full-term newborn infants or healthy premature infants may have decreased levels of total protein S (15-50%); but because of low levels of C4bBP, free protein S may be normal or near the normal adult level (> or =50%). Total protein S reaches adult levels by 90 to 180 days postnatal.*

Clinical References: 1. Borgel D, Gandrille S, Aiach M: Protein S deficiency. Thromb Haemost 1997 July;78(1):351-356 2. De Stefano V, Finazzi G, Mannucci PM: Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996 May 1;87(9):3531-3544 3. Zoller B, Garcia de Frutos P, Dahlback B: Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995 June 15;85(12):3524-3531 4. Grandrille S, Borgel D, Ireland H, et al: Protein S deficiency: a database of mutations. Thromb Haemost 1997 June;77(6):1201-1214 5. Wolf M, Boyer-Neumann C, Peynaud-Debayle E, et al: Clinical applications of a direct assay of free protein S antigen using monoclonal antibodies. A study of 59 cases. Blood Coagul Fibrinolysis 1994 April;5(2):187-192 6. Laroche P, Plassart V, Amiral J: Rapid quantitative latex immunoassays for diagnosis of thrombotic disorders. Thromb Haemost 1989:62:379 7. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, Bovill EG: A review of the technical, diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med 2002;126:1349-1366 8. Sales M, Begona A, Rosen S: IL Test Free Protein S: A diagnostic tool for protein S deficiency. IL Laboratories; Hemostaisis Monograph 9. Serra J, Sales M, Chitolie A, et al: Multicentre evaluation of IL Test Free PS: a fully automated assay to quantify free protein S. Thromb Haemost 2002;88:975-983

12PTU

Protein, Total, 12 Hour, Urine

89043

Clinical Information: Protein in urine normally consists of plasma proteins that have been filtered by glomeruli and not reabsorbed by the proximal tubule, and proteins secreted by renal tubules or other accessory glands. Increased amounts of protein in the urine may be due to: -Glomerular proteinuria: defects in permselectivity of the glomerular filtration barrier to plasma proteins (eg, glomerulonephritis or nephrotic syndrome) -Tubular proteinuria: incomplete tubular reabsorption of proteins (eg, interstitial nephritis) -Overflow proteinuria: increased plasma concentration of proteins that exceeds capacity for proximal tubular reabsorption (eg, multiple myeloma, myoglobinuria) -Urinary tract inflammation or tumor -Preeclampsia -Orthostatic proteinuria In pregnant women, a urinary protein excretion of more than 300 mg/24 hours is frequently cited as consistent with preeclampsia, and 12-hour total protein excretion



Page 1776

highly correlates with 24-hour values in this patient population.(1,2) Orthostatic proteinuria is characterized by increased protein excretion in the upright position, but normal levels when supine. This condition can be detected by comparing urine protein levels in a collection split between day and night (see OPTU / Orthostatic Protein, Timed Collection, Urine). Orthostatic proteinuria is common in childhood and adolescence, but rare after age 30.

Useful For: Evaluation of renal disease Screening for monoclonal gammopathy Screening for postural (orthostatic) proteinuria In select clinical situations, collection of a 12-hour specimen may allow more rapid detection of proteinuria states (eg, screening pregnant patients for preeclampsia)

Interpretation: Total urine protein determined to be greater than 500 mg/24 hours should be evaluated by immunofixation to assess if there is a monoclonal immunoglobulin light chain and, if present, identify it as either kappa or lambda type. Urinary protein levels may rise to 300 mg/24 hours in healthy individuals after vigorous exercise. Low-grade proteinuria may be seen in inflammatory or neoplastic processes involving the urinary tract.




Page 1792


PUPYU

Purines and Pyrimidines Panel, Urine

41977

Clinical Information: Purines (adenine, guanine, xanthine, hypoxanthine) and pyrimidines (uracil, thymine, cytosine, orotic acid) are involved in all biological processes, providing the basis for storage, transcription, and translation of genetic information as RNA and DNA. Purines are required by all cells for growth and survival and also play a role in signal transduction and translation. Purines and pyrimidines originate primarily from endogenous synthesis, with dietary sources playing only a minor role. The end product of purine metabolism is uric acid (2,6,8-trioxypurine), which must be excreted continuously to avoid toxic accumulation. Numerous inborn errors of purine and pyrimidine metabolism have been documented. Clinical features are dependent upon the specific disorder, but represent a broad spectrum of manifestations that may include immunodeficiency, developmental delay, nephropathy, and neurologic involvement. The most commonly described disorder involves a deficiency of hypoxanthine phosphoribosyl transferase (HPRT) which causes 3 overlapping clinical syndromes depending on the amount of residual enzyme activity. The majority of patients with HPRT deficiency have classic Lesch-Nyhan syndrome, a severe disorder, described in 1964 as the first disorder of purine metabolism. It is an X-linked disorder characterized by severe neurologic impairment, severe to moderate cognitive impairment, the development of a compulsive self-destructive behavior, and uric acid nephropathy. Treatment is mainly supportive and includes the use of special devices to prevent self-injury. Disorders of purine and pyrimidine metabolism can involve all organ systems at any age. The diagnosis of the specific disorders of purine and pyrimidine metabolism is based upon the clinical presentation of the patient, determination of specific concentration patterns of purine and pyrimidine metabolites, and confirmatory enzyme assays and/or molecular genetic testing.

Useful For: Evaluating patients with symptoms suspicious for disorders of purine and pyrimidine metabolism Monitoring patients with disorders of purine and pyrimidine metabolism Laboratory evaluation of primary and secondary hyperuricemias

Interpretation: Abnormal concentrations of measurable compounds will be reported along with an interpretation. The interpretation of an abnormal metabolite pattern includes an overview of the results and of their significance, a correlation to available clinical information, possible differential diagnosis, recommendations for additional biochemical testing and confirmatory studies (enzyme assay, molecular analysis), name, and phone number of contacts who may provide these studies at the Mayo Clinic or elsewhere, and a phone number of the laboratory directors in case the referring physician has additional questions.

Reference Values: 0-3 Years

4-6 Years

7-12 Years

13-18 Years

>18 Years

mmol/mol creatinine

mmol/mol creatinine

mmol/mol creatinine

mmol/mol creatinine

mmol/mol creatinine

Uracil

< or =50

< or =30

< or =25

< or =20

< or =20

Thymine

< or =3

< or =3

< or =3

< or =3

< or =3

Adenine

< or =3

< or =3

< or =3

< or =3

< or =3

Hypoxanthine

< or =65

< or =30

< or =30

< or =30

< or =30

Xanthine

< or =54

< or =21

< or =35

< or =15

< or =20

Orotic

< or =4

< or =4

< or =3

< or =3

< or =5

Dihydroorotic Acid

< or =3

< or =3

< or =3

< or =3

< or =3

Uric Acid

350-2500

200-2000

200-1400

150-700

70-700

Deoxythymidine

< or =3

< or =3

< or =3

< or =3

< or =3



Page 1793

Deoxyuridine

< or =3

< or =3

< or =3

< or =3

< or =3

Thymidine

< or =3

< or =3

< or =3

< or =3

< or =3

Uridine

< or =10

< or =3

< or =3

< or =3

< or =3

Deoxyadenosine

< or =3

< or =3

< or =3

< or =3

< or =3

Deoxyinosine

< or =3

< or =3

< or =3

< or =3

< or =3

Deoxyguanosine

< or =3

< or =3

< or =3

< or =3

< or =3

Adenosine

< or =3

< or =3

< or =3

< or =3

< or =3

Inosine

< or =6

< or =3

< or =3

< or =3

< or =3

Guanosine

< or =4

< or =3

< or =3

< or =3

< or =3

5-Aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)

< or =3

< or =3

< or =3

< or =3

< or =3

Succinyladenosine

< or =16

< or =3

< or =3

< or =3

< or =3

Dihydrouracil

< or =15

< or =6

< or =6

< or =6

< or =6

Dihydrothymine

< or =11

< or =3

< or =3

< or =3

< or =3

N-carbamoyl-B-alanine

< or =30

< or =10

< or =10

< or =10

< or =10

< or =3

< or =3

< or =3

< or =3

N-carbamoyl-B-aminoisobutyric Acid < or =20

Clinical References: 1. Jurecka A: Inborn errors of purine and pyrimidine metabolism. J Inherit Metab Dis 2009;32:247-263 2. Jinnah HA, Friedmann T: Lesch-Nyhan Disease and Its Variants. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein, KW Kinzler, SE Antonarakis, A Ballabio, K Gibson, G Mitchell. New York, NY. McGraw-Hill 2014. Accessed April 20, 2017. Available from http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62635320

FPYRE

Pyrethrum IgE

57540


Reference Values: 25.00 nmol/min/g protein (Normal) 5.00-25.00 nmol/min/g protein (Indeterminate) or =12 months: 6.7-14.3 U/g Hb Reference values have not been established for patients who are 20. A low L:P ratio (disproportionately elevated pyruvic acid) may indicate an inherited disorder of pyruvate metabolism. Defects of the pyruvate dehydrogenase complex result in L:P ratios 20. A low L:P ratio (disproportionately elevated pyruvic acid) may indicate an inherited disorder of pyruvate metabolism. Defects of the pyruvate dehydrogenase complex result in L:P ratios or =1:64. IgM class antibody titers appear very early in the disease, reaching maximum phase II titers by week 3 and declining to very low levels by week 14. Phase I titers follow the same pattern, although at much lower levels, and may not be initially detected until Current as of August 23, 2017 7:11 am CDT


Page 1800

convalescence.

Reference Values: Q FEVER PHASE I ANTIBODY, IgG or =100 Strongly positive Reference values apply to all ages.


RSER

Rabbit Serum Proteins, IgE

82544




Page 1808


Useful For: Establishing the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms Identifying allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



RUPR

Rabbit Urine Proteins, IgE

82148


Useful For: Establishing the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms Identifying allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of allergic reactions to insect venom allergens, drugs, or chemical allergens




Page 1809


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FRFIT

Rabies Antibody Endpoint

90330

Interpretation: Quantitative results. For those who want to know their exact titer between the reportable range. RFFIT stands for Rapid Fluorescent Foci Inhibition Test. It is a serum neutralization (inhibition) test, which means it measures the ability of rabies specific antibodies to neutralize rabies virus and prevent the virus from infecting cells. The antibodies are called rabies virus neutralizing antibodies (RVNA).

Reference Values: Reportable range is 0.1 to 15.0 IU/mL Less than 0.1 IU/mL: Below detection limit In humans a results of 0.5 IU/mL or higher is considered an acceptable response to rabies vaccination according to the World Health Organization (WHO) guidelines; see WHO and Advisory Committee on Immunization Practices documents for additional guidance.

FRAD

Radish (Raphanus sativus) IgE

57933




MAL

Rapid Malaria/Babesia Smear

9240

Clinical Information: Malaria is a major tropical disease infecting approximately 500 million people and causing 1.5 to 2.7 million deaths annually. Ninety percent of the deaths occur in sub-Saharan Africa and most of these occur in children 1.5. See Renin-Aldosterone Studies in Special Instructions.

Reference Values: 0-2 years: 4.6 ng/mL/hour (mean)* Range: 1.4-7.8 ng/mL/hour 3-5 years: 2.5 ng/mL/hour (mean)* Range: 1.5-3.5 ng/mL/hour 6-8 years: 1.4 ng/mL/hour (mean)* Range: 0.8-2.0 ng/mL/hour 9-11 years: 1.9 ng/mL/hour (mean)* Range: 0.9-2.9 ng/mL/hour 12-17 years: 1.8 ng/mL/hour (mean)* Range: 1.2-2.4 ng/mL/hour Mean data not standardized as to time of day or diet. Infants were supine, children sitting. Na-depleted, upright (peripheral vein specimen) 18-39 years: 10.8 ng/mL/hour (mean) 2.9-24.0 ng/mL/hour (range) > or =40 years: 5.9 ng/mL/hour (mean) 2.9-10.8 ng/mL/hour (range) Na-replete, upright (peripheral vein specimen) 18-39 years: 1.9 ng/mL/hour (mean) < or =0.6-4.3 ng/mL/hour (range) > or =40 years: 1.0 ng/mL/hour (mean) < or =0.6-3.0 ng/mL/hour (range) *Stalker HP, Holland NH, Kotchen JM, Kotchen TA: Plasma renin activity in healthy children. J Pediatr 1976;89:256-258

Clinical References: 1. Young WF Jr: Primary aldosteronism: A common and curable form of hypertension. Cardiol Rev 1999;7:207-214 2. Young WF Jr: Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:801-827 Current as of August 23, 2017 7:11 am CDT


Page 1827

RPTL

Reptilase Time, Plasma

9078

Clinical Information: Prolonged clotting times may be associated with a wide variety of coagulation abnormalities including: -Deficiency or functional abnormality (congenital or acquired) of any of the coagulation proteins -Deficiency or functional abnormality of platelets -Specific factor inhibitors -Acute disseminated intravascular coagulation -Exogenous anticoagulants (eg, heparin, warfarin) The prothrombin time (PT) and activated partial thromboplastin time (APTT) are first-order tests for coagulation abnormalities and are prolonged in many bleeding disorders. A battery of coagulation tests is often required to determine the cause of prolonged clotting times. The thrombin time (TT) test is used to identify the cause of prolonged APTT or dilute Russell's viper venom time (DRVVT). Reptilase time (RT) test is used to evaluate a prolonged TT. Reptilase is a thrombin-like enzyme isolated from the venom of Bothrops atrox. Thrombin splits small fibrinopeptides A and B from fibrinogen molecules, producing fibrin monomer, which polymerizes to form a clot. Reptilase, however, splits off fibrinopeptide A but not B, which results in fibrin polymerization. In contrast to thrombin and the TT test which are inhibited by heparin, the RT is normal in the presence of heparin. Similar to the TT test, the RT is prolonged in the presence of hypofibrinogenemia and dysfibrinogenemia.

Useful For: Evaluation of a prolonged thrombin time (TT): It is mainly used to confirm or exclude the presence of heparin in the specimen or specimen type Evaluating hypofibrinogenemia or dysfibrinogenemia in conjunction with the TT and fibrinogen assay

Interpretation: As seen in the following table, reptilase time can help distinguish among the various causes of a prolonged thrombin time (TT). Thrombin Time Reptilase Time Causes Remarks Prolonged Prolonged Hypo- or afibrinogenemia Ascertain by determination of fibrinogen Prolonged Prolonged Dysfibrinogenemia Ascertain by specific assay Prolonged Normal Heparin or inhibitor of thrombin Differentiate by human TT and/or heparin assays Prolonged Prolonged Fibrin(ogen) split products (FSP) Ascertain by FSP or D-dimer assay


Clinical References: 1. Greaves M, Preston FE: Approach to the bleeding patient. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al: Philadelphia, JB Lippincott Company, 2001, pp 783-837 2. Funk C, Gmur J, Herold R, Straub PW: Reptilase-R: A new reagent in blood coagulation. Br J Haematol 1971 July;21(1):43-52 3. Latallo ZS, Teisseyre E: Evaluation of reptilase R and thrombin clotting time in the presence of fibrinogen degradation products and heparin. Scand J Haematol Suppl 1971;13:261-266

RPR1 62046

Respiratory Profile, Region 1, North Atlantic (CT, MA, ME, NJ, NH, NY, PA, RI, VT) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE



Page 1828

measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the North Atlantic region including Connecticut, Maryland, Maine, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, and Vermont

Interpretation: Elevated concentrations of total IgE may be found in a variety of clinical diseases, including allergic disease, certain primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Detection of allergen-specific IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6

> or =100 Strongly positive Reference values apply to all ages. Total IgE:

Results Reported in kU/L Age

Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537

18 years and older < or =214

Clinical References: 1. Homburger HA: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. New York, WB Saunders Company, 2007, pp 961-971 2. Bernstein IL, Li JT, Bernstein DI, et al: Allergy diagnostic testing: An updated practice parameter. Ann Allergy Asthma Immunol 2008 Mar;100(3 Suppl 3):S1-148



Page 1829

RPR10 62056

Respiratory Profile, Region 10, Southwestern Grasslands (OK, TX) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Southwestern Grasslands region including Oklahoma and Texas



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34



Page 1830

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR11 62057

Respiratory Profile, Region 11, Rocky Mountain (AZ [Mt]; CO; ID [Mt]; NM, UT [Mt]; WY) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Rocky Mountain region including Arizona, Colorado, Idaho, New Mexico, Utah and Wyoming




Page 1831


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR12 62058

Respiratory Profile, Region 12, Arid Southwest (Southern AZ Desert, Southern CA Desert) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In



Page 1832

this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Arid Southwest region including the southern Arizona desert and the southern California desert



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537





Page 1833

RPR13

Respiratory Profile, Region 13, Southern Coastal California

62059

Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Southern Coastal California region



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199



Page 1834

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR14

Respiratory Profile, Region 14, Central California

62060


Useful For: Assessing sensitization to various inhalant allergens commonly found in Central California Interpretation: Elevated concentrations of total IgE may be found in a variety of clinical diseases, including allergic disease, certain primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Detection of allergen-specific IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive



Page 1835

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR15 62061

Respiratory Profile, Region 15, Intermountain West (Southern ID, NV) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust



Page 1836

mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Intermountain West region including southern Idaho and Nevada



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR16 62062

Respiratory Profile, Region 16, Inland Northwest (OR, Central and Eastern WA) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well



Page 1837

characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Inland Northwest region including Oregon and central and east Washington



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629



Page 1838

16 and 17 years

< or =537



RPR17 62063

Respiratory Profile, Region 17, Pacific Northwest (Northwestern CA, Western OR, WA) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Pacific Northwest including the region of Northwestern California, Western Oregon and Washington



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4




Page 1839

5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR18

Respiratory Profile, Region 18, Alaska

62064


Useful For: Assessing sensitization to various inhalant allergens commonly found in Alaska Current as of August 23, 2017 7:11 am CDT


Page 1840



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR19

Respiratory Profile, Region 19, Puerto Rico

62065

Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads



Page 1841

to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in Puerto Rico Interpretation: Elevated concentrations of total IgE may be found in a variety of clinical diseases, including allergic disease, certain primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Detection of allergen-specific IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be responsible for eliciting signs and symptoms.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537


Clinical References: 1. Homburger HA: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. New York, WB Saunders Company, 2007, pp 961-971 2. Bernstein Current as of August 23, 2017 7:11 am CDT


Page 1842

IL, Li JT, Bernstein DI, et al: Allergy diagnostic testing: An updated practice parameter. Ann Allergy Asthma Immunol 2008 Mar;100(3 Suppl 3):S1-148

RPR2

Respiratory Profile, Region 2, Mid-Atlantic (DC, DE, MD, NC, VA)

62047


Useful For: Assessing sensitization to various inhalant allergens commonly found in the Mid-Atlantic region including the District of Columbia, Delaware, Maryland, North Carolina and Virginia



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13



Page 1843

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR3

Respiratory Profile, Region 3, South Atlantic (GA, N.FA, SC)

62048


Useful For: Assessing sensitization to various inhalant allergens commonly found in the South Atlantic region including Georgia, Northern Florida and South Carolina




Page 1844


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR4 62049

Respiratory Profile, Region 4, Sub-tropic Florida (Florida S. of Orlando) Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In



Page 1845

this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in sub-tropic Florida, which is south of Orlando



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537





Page 1846

RPR5

Respiratory Profile, Region 5, Ohio Valley (IN, KY, OH, TN, WV)

62050


Useful For: Assessing sensitization to various inhalant allergens commonly found in the Ohio Valley region including Indiana, Kentucky, Ohio, Tennessee and West Virginia



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199



Page 1847

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR6

Respiratory Profile, Region 6, South Central (AL, AR, LA, MS)

62051


Useful For: Assessing sensitization to various inhalant allergens commonly found in the South Central region including Alabama, Arkansas, Louisiana and Mississippi


Reference Values: Class IgE kU/L Interpretation 0 1

Negative 0.35-0.69 Equivocal



Page 1848

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537



RPR7

Respiratory Profile, Region 7, Northern Midwest (MI, MN, WI)

62052

Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of



Page 1849

allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Northern Midwest region including Michigan, Minnesota, and Wisconsin.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537


Clinical References: 1. Homburger HA: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. New York, WB Saunders Company, 2007, pp 961-971 2. Bernstein IL, Li JT, Bernstein DI, et al: Allergy diagnostic testing: An updated practice parameter. Annals Allergy Asthma and Immunol 2008;100:S1-S148

RPR8

Respiratory Profile, Region 8, Central Midwest (IA, IL, MO)

62053

Clinical Information: Immunoglobulin E (IgE) is one of the 5 classes of immunoglobulins, and is defined by the presence of the epsilon heavy chain. It is the most recently described immunoglobulin, having first been identified in 1966. IgE exists as a monomer, and is present in circulation at very low concentrations, approximately 300-fold lower than that of IgG. The physiologic role of IgE is not well



Page 1850

characterized, although it is thought to be involved in defense against parasites, specifically helminthes. The function of IgE is also distinct from other immunoglobulins in that it induces activation of mast cells and basophils through the cell-surface receptor Fc epsilon RI. Fc epsilon RI is a high-affinity receptor specific for IgE present at a high density on tissue-resident mast cells and basophils. Because of this high-affinity interaction, almost all IgE produced by B cells is bound to mast cells or basophils, which explains the low concentration present in circulation. Cross-linking of the Fc epsilon RI -bound IgE leads to cellular activation, resulting in immediate release of preformed granular components (histamine and tryptase) and subsequent production of lipid mediators (prostaglandins and leukotrienes) and cytokines (interleukin-4 and interleukin-5). Elevated concentrations of IgE may occur in the context of allergic disease. However, increases in the amount of circulating IgE can also be found in various other diseases, including primary immunodeficiencies, infections, inflammatory diseases, and malignancies. Total IgE measurements have limited utility for diagnostic evaluation of patients with suspected allergic disease. In this scenario, testing for the presence of allergen-specific IgEs may provide more information. Clinical manifestations of allergic disease result from activation of mast cells and basophils, which occurs when Fc epsilon RI -bound IgE antibodies interact with allergen. In vitro serum testing for specific IgE antibodies may provide an indication of the immune response to an allergen that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. Sensitization to inhalant allergens (dust mite, mold, and pollen inhalants) primarily occurs in older children, adolescents, and adults, and usually manifests as respiratory disease (rhinitis and asthma).

Useful For: Assessing sensitization to various inhalant allergens commonly found in the Central Midwest region including Iowa, Illinois and Missouri



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629



Page 1851

16 and 17 years

< or =537


Clinical References: 1. Homburger HA: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. New York, WB Saunders Company, 2007, pp 961-971 2. Bernstein IL, Li JT, Bernstein DI, et al: Allergy diagnostic testing: An updated practice parameter. Annals Allergy Asthma and Immunol 2008; 100:S1-S148

RPR9

Respiratory Profile, Region 9, Great Plains (KS, ND, NE, SD)

62054


Useful For: Assessing sensitization to various inhalant allergens commonly found in the Great Plains region including Kansas, North Dakota, Nebraska and South Dakota



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5




Page 1852

6



Reference interval

0-5 months

< or =13

6-11 months

< or =34

1 and 2 years

< or =97

3 years

< or =199

4-6 years

< or =307

7 and 8 years

< or =403

9-12 years

< or =696

13-15 years

< or =629

16 and 17 years

< or =537


Clinical References: 1. Homburger HA: Allergic diseases. In Clinical Diagnosis and Management by Laboratory Methods. 21st edition. New York, WB Saunders Company, 2007, pp 961-971 2. Bernstein IL, Li JT, Bernstein DI, et al: Allergy diagnostic testing: An updated practice parameter. Annals Allergy Asthma and Immunol 2008; 100:S1-S148

SRSV 8301

Respiratory Syncytial Virus (RSV) Antibodies, IgG and IgM (Separate Determinations), Serum Clinical Information: Respiratory syncytial virus (RSV) is an important cause of human respiratory infection. It strikes most frequently and severely in the very young and is a common cause of bronchiolitis, pneumonia, or croup in young infants. Infections in older children and adults tend to be milder and to involve the upper respiratory tract. RSV infections are seasonal, from late fall to spring, and often occur in epidemic form.

Useful For: Aiding in the diagnosis of a recent respiratory syncytial virus infection Interpretation: Normals: -IgG: or =35.0 U Reference values apply to all ages.

Clinical References: 1. The Autoimmune Diseases: Inflammatory Bowel Diseases. Edited by NR Rose, IR Mackay. New York, NY, Elsevier Academic Press, 2008 2. Sandborn WJ, Loftus EV Jr, Homburger HA, et al: Evaluation of serological disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 2001 Aug;7(3):192-201

GASCA

Saccharomyces cerevisiae Antibody, IgG, Serum

83023

Clinical Information: Inflammatory bowel disease (IBD) refers to 2 diseases, ulcerative colitis (UC) and Crohn's disease (CD), which produce inflammation of the large or small intestines.(1) The diagnoses of both diseases are based on clinical features, radiographic findings, colonoscopy, mucosal biopsy histology, and, in some cases, operative findings and resected bowel pathology and histology. Patients with IBD have also been shown to have antibodies in serum that help distinguish between CD and UC.(2) Patients with UC often have measurable neutrophil-specific antibodies (NSA) that react with as yet uncharacterized target antigens in human neutrophils; whereas patients with CD often have measurable antibodies of the IgA and/or IgG isotypes that react with cell wall mannan of Saccharomyces cerevisiae strain Su 1.

Useful For: Helping clinicians distinguish between ulcerative colitis and Crohn's disease in patients suspected of having inflammatory bowel disease

Interpretation: In IBDP / Inflammatory Bowel Disease Serology Panel, Serum, anti-Saccharomyces cerevisiae antibodies (ASCA) and neutrophil-specific antibodies (NSA) are measured. The finding of NSA with normal levels of IgA and IgG ASCA is consistent with the diagnosis of ulcerative colitis (UC); the finding of negative NSA with elevated IgA and IgG ASCA is consistent with Crohn's disease (CD). NSA are detectable in approximately 50% of patients with UC. Elevated levels of either IgA or IgG ASCA occur in approximately 55% of patients with CD. Elevated levels of both IgA and IgG ASCA occur in approximately 40% of patients with CD. Employed together, the tests for NSA and ASCA have the following positive predictive values (PPV) for UC and CD, respectively:(2) -NSA-positive with normal levels of IgA and IgG ASCA, PPV of 91% -NSA-negative with elevated levels of IgA and IgG ASCA, PPV of 90%

Reference Values: Negative: < or =20.0 U Current as of August 23, 2017 7:11 am CDT


Page 1872

Equivocal: 20.1-24.9 U Weakly positive: 25.0-34.9 U Positive: > or =35.0 U Reference values apply to all ages.

Clinical References: 1. The Autoimmune Diseases: Inflammatory Bowel Diseases. Edited by NR Rose, IR Mackay. New York, NY, Elsevier Academic Press, 2008 2. Sandborn WJ, Loftus EV Jr, Homburger HA, et al: Evaluation of serological disease markers in a population-based cohort of patients with ulcerative colitis and Crohn's disease. Inflamm Bowel Dis 2001 Aug;7(3):192-201

FSFLE

Safflower (Carthamus tinctorius) IgE

57541




SEAS

Seasonal Inhalants Allergen Profile

31766

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of



Page 1887

sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



SECOS

Secobarbital, Serum

8243

Clinical Information: Secobarbital is a short-acting barbiturate with hypnotic properties used as a preanesthetic agent and in the short-term treatment of insomnia.(1,2) Secobarbital is administered orally. The duration of its hypnotic effect is about 3 to 4 hours. The drug distributes throughout the body, with a volume of distribution (Vd) of 1.6 to 1.9 L/kg, and about 46% to 70% of a dose is bound to plasma proteins. Metabolism takes place in the liver primarily via hepatic microsomal enzymes. Secobarbital's half-life is about 15 to 40 hours (mean: 28 hours).(2,3)

Useful For: Monitoring secobarbital therapy Interpretation: Therapeutic concentration: 1.0 to 2.0 mcg/mL Toxic concentration: >5.0 mcg/mL Reference Values: Therapeutic concentration: 1.0-2.0 mcg/mL Toxic concentration: >5.0 mcg/mL Concentration at which toxicity occurs varies and should be interpreted in light of clinical situation.

Clinical References: 1. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 10th edition. New York, McGraw-Hill Book Company, 2001 2. Teitz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis, MO, Elsevier Saunders, 2006, p 1091 3. Disposition of Toxic Drugs and Chemicals in Man. Seventh edition. Edited by RC Baselt. Foster City, CA, Biomedical Publications, 2004, p 1254 Current as of August 23, 2017 7:11 am CDT


Page 1888

FSEC

Secretin

90173

Clinical Information: Secretin is a 27 amino acid basic peptide produced by S cells and released by acid delivered into the duodenum. Secretin is released into the blood when duodenal pH drops below 4. Secretin shares structural similarity with Glucagon, Gastric Inhibitory Polypeptide, Vasoactive Intestinal Polypeptide, PHIM, and Growth Hormone- Releasing Hormone. Secretin is a potent stimulus for bicarbonate secretion. Secretin also stimulates secretion of bile, release of Insulin, and release of Gastric Pepsin in the stomach. Secretin inhibits Glucagon release, intestinal motility, and prevents the uptake of water and sodium ions by the intestine. In normal patients, Secretin has little effect on Gastrin levels, but stimulates Gastrin greatly in Zollinger-Ellison patients. Secretin is also elevated in Zollinger-Ellison patients and in patients with duodenal ulcer. Secretin levels are low in patients with pernicious anemia and achlorhydria. Secretin secretion can be suppressed by Somatostatin, Cimetidine, and Methionine-Enkephalin.

Reference Values: 12 - 75 pg/mL (mean=25) This test was developed and its performance characteristics determined by Inter Science Institute. It has not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.

FSHPU

Sedative Hypnotic Panel, Urine-Forensic

58038

Reference Values: The following threshold concentrations are used for this analysis. Drug Screening Threshold Confirmation Threshold Ethyl Alcohol 0.020 gm/dL 0.020 gm/dL Barbiturates 300 ng/mL 100 ng/mL Benzodiazepines 100 ng/mL 75 ng/mL Flunitrazepam 100 ng/mL 300 ng/mL Ketamine: Negative Screening threshold: 100 ng/mL Gamma-Hydroxybutyric Acid (GHB): Negative Screening threshold: 5.0 ug/mL

SES

Selenium, Serum

9765

Clinical Information: Selenium is an essential element. It is a cofactor required to maintain activity of glutathione peroxidase (GSH-Px), an enzyme that catalyzes the degradation of organic hydroperoxides. The absence of selenium correlates with loss of GSH-Px activity and is associated with damage to cell membranes due to accumulation of free radicals. The normal daily dietary intake of selenium is 0.01 to 0.04 parts per million (ppm), which is similar to the typical content of soil (0.05 ppm) and sea water (0.09 ppm). Selenium is found in many over-the-counter vitamin preparations because its antioxidant activity is thought to be anticarcinogenic. There is no supporting evidence that selenium suppresses cancer. In humans, cardiac muscle is the most susceptible to selenium deficiency. With cell membrane damage, normal cells are replaced by fibroblasts. This condition is known as cardiomyopathy and is characterized by an enlarged heart whose muscle is largely replaced by fibrous tissue. In the United States, selenium deficiency is related to use of total parenteral nutrition. This is therapy administered to patients with no functional bowel, such as after surgical removal of the small and large intestine because of cancer, or because of acute inflammatory bowel disease such as Crohn's disease. Selenium supplementation to raise serum concentration >70 ng/mL is the usual treatment. Serum monitoring done on a semiannual basis checks the adequacy of supplementation. Selenium toxicity has been observed in animals when daily



Page 1889

intake exceeds 4 ppm. Teratogenic effects are frequently noted in the offspring of animals living in regions where soil content is high in selenium such as south-central South Dakota and northern-coastal regions of California. Selenium toxicity in humans is not known to be a significant problem except in acute overdose cases. Selenium is not classified as a human teratogen.

Useful For: Monitoring selenium replacement therapy Interpretation: Selenium accumulates in biological tissue. The normal concentration in adult human blood serum is 70 to 150 ng/mL (0.15 parts per million) with a population mean value of 98 ng/mL. Optimal selenium concentration is age dependent (see Reference Values); children require less circulating selenium than do adults. In the state of selenium deficiency associated with loss of glutathione peroxidase activity, the serum concentration is usually 1 year: 70-150 ng/mL

Clinical References: 1. Muntau AC, Streiter M, Kappler M, et al: Age-related reference values for serum selenium concentrations in infants and children. Clin Chem 2002 March;48(3):555-560 2. Gonzalez S, Huerta JM, Fernandez S, et al: Food intake and serum selenium concentration in elderly people. Ann Nutr Metab 2006;50(2):126-131 3. Skelton JA, Havens PL, Werlin SL: Nutrient deficiencies in tube fed children. Clin Pediatr 2006;45:37-41 4. Gosney MA, Haldiman MF, Allsup SS: Effect of micronutrient supplementation on mood in nursing home residents. Gerontology 2008;54:292-299 5. Burri J, Haldiman M, Dudler V: Selenium status of the Swiss population: assessment and change over a decade. J Trace Elem Med Biol 2008;22(2):112-119

FER

Semen Analysis

81641

Clinical Information: Semen is composed of spermatozoa suspended in seminal fluid (plasma). The function of the seminal fluid is to provide nutrition and volume for conveying the spermatozoa to the endocervical mucus. Male infertility can be affected by a number of causes. Chief among these is a decrease in the number of viable sperm. Other causes include sperm with abnormal morphology and abnormalities of the seminal fluid.

Useful For: Determining male fertility status Interpretation: Semen specimens can vary widely in the same man from specimen to specimen. Semen parameters falling outside of the normal ranges do not preclude fertility for that individual. Multiple samples may need to be analyzed prior to establishing patient's fertility status.

Reference Values: Appearance: normal Volume: > or =1.5 mL pH: > or =7.2 Motile/mL: > or =6.0 x 10(6) Sperm/mL: > or =15.0 x 10(6) Motility: > or =40% Grade: > or =2.5 Note: Multiple laboratory studies have indicated that semen parameters for motility and grade on average retain 80% of original parameters when our shipping method is used for transport. Using these averages, samples with 32% to 39% motility and grade of 2 may be in the normal range if testing was performed shortly after collection. Therefore, these borderline patients may need to collect another sample at a local fertility center to verify fertility status. Motile/ejaculate: > or =9.0 x 10(6) Viscosity: > or =3.0 Agglutination: > or =3.0 Supravital: > or =58% live Current as of August 23, 2017 7:11 am CDT


Page 1890

Fructose: positive Note: Fructose testing cannot be performed on semen analysis specimens shipped through Mayo Medical Laboratories. If patient is azoospermic, refer to FROS / Fructose, Semen or Seminal Plasma. Submit separate specimen to rule out ejaculatory duct blockage. Positive result indicates no blockage.

Clinical References: The World Health Organization Laboratory Manual for the examination of human semen and sperm-cervical mucus interaction. Fifth edition. Cambridge University Press, 2010

SEMB

Semen Analysis with Strict Morphology

60556

Clinical Information: Infertility affects 1 out of 6 couples of child-bearing age. Approximately 40% of infertility has a female-factor cause and 40% a male-factor cause. The remaining 20% of infertility is due to a combination of male- and female-factor disorders or is unexplained. Semen is composed of spermatozoa suspended in seminal fluid (plasma). The function of the seminal fluid is to provide nutrition and volume for conveying the spermatozoa to the endocervical mucus. Male infertility can be affected by a number of causes. Chief among these is a decrease in the number of viable sperm. Other causes include sperm with abnormal morphology and abnormalities of the seminal fluid. One of the more successful treatments for male and female infertility is in vitro fertilization (IVF). Male partners are tested with the strict criteria sperm morphology test prior to IVF to assist in the diagnosis of male-factor defects. Abnormalities in sperm morphology are related to: defects in sperm transport, sperm capacitation, the acrosome reaction, binding and penetration of the zona pellucida, and fusion with the oocyte vitelline membrane. All of these steps are essential to normal fertility. Strict criteria sperm morphology testing also greatly assists with selecting the most cost-effective in vitro sperm processing and insemination treatment for the couple's IVF cycle. Sperm with severe head abnormalities are unlikely to bind to the zona pellucida. These patients may require intracytoplasmic sperm injection in association with their IVF cycle to ensure optimal levels of fertilization are achieved. This, in turn, provides the patient with the best chance of pregnancy. Multiple semen analyses are usually conducted over the course of the spermatogenic cycle (approximately 70 days).

Useful For: Determining male fertility status Selecting the most cost-effective therapy for treating male-factor infertility Quantifying the number of germinal and WBCs per mL of semen

Interpretation: Semen specimens can vary widely in the same man from specimen to specimen. Semen parameters falling outside of the normal ranges do not preclude fertility for that individual. Multiple samples may need to be analyzed prior to establishing patientâ€™s fertility status. Sperm are categorized according to strict criteria based on measurements of head and tail sizes and shapes. Sperm with abnormalities in head/tail size/shape may not be capable of completing critical steps in sperm transport and fertilization.

Reference Values: SEMEN ANALYSIS Appearance: normal Volume: > or =1.5 mL pH: > or =7.2 Motile/mL: > or =6.0 x 10(6) Sperm/mL: > or =15.0 x 10(6) Motility: > or =40% Grade: > or =2.5 Note: Multiple laboratory studies have indicated that semen parameters for motility and grade on average retain 80% of original parameters when our shipping method is used for transport. Using these averages, samples with 32% to 39% motility and grade of 2 may be in the normal range if testing was performed shortly after collection. Therefore, these borderline patients may need to collect another sample at a local fertility center to verify fertility status Motile/ejaculate: > or =9.0 x 10(6) Viscosity: > or =3.0 Agglutination: > or =3.0 Supravital: > or =58% live Fructose: positive Current as of August 23, 2017 7:11 am CDT


Page 1891

Note: Fructose testing cannot be performed on semen analysis specimens shipped through Mayo Medical Laboratories. If patient is azoospermic, refer to FROS / Fructose, Semen or Seminal Plasma. Submit separate specimen to rule-out ejaculatory duct blockage. Positive result indicates no blockage. STRICT MORPHOLOGY Normal forms: > or =4.5% normal oval sperm heads Germ cells: or =4 x 10(6)/mL (elevated germinal cells in semen are of unknown clinical significance) WBC: or =1 x 10(6)/mL (elevated white blood cells in semen are of questionable clinical significance)

Clinical References: 1. Kruger Morphology Conference, Boston, MA, October 9, 1993 2. The World Health Organization Laboratory Manual for the examination of human semen and sperm-cervical mucus interaction. Fifth edition. Cambridge University Press, 2010

SMFL

Seminal Fluid, IgE

82858





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 1892


MIC

Sensitivity, MIC (Bill Only)

801659


FSMN

SensoriMotor Neuropathy Evaluation-Complete

91449


SEPTZ

SEPT9 Gene, Mutation Screen

35548

Clinical Information: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder characterized by periods of severe pain involving the brachial plexus followed by muscle atrophy and weakness. These recurrent episodes can also be accompanied by decreased sensation and paresthesias. Individuals with this disease are generally symptom-free between pain attacks, though many experience lingering effects with repeated attacks. The pain episodes are frequently triggered by physical, emotional, or immunological stress. Less commonly, affected individuals can exhibit nonneurological features including short stature, skin folds, hypotelorism, and cleft palate. Mutations in the SEPT9 gene cause the clinical manifestations of HNA. There are 3 common mutations that have been reported in affected individuals: c.-134G->C, p.R88W, and p.S93F. Additionally, a common exonic duplication attributed to the founder effect has been identified in North American HNA families. Other private duplications of varying sizes have also been identified in affected individuals. SEPT9 is currently the only known gene associated with HNA, although approximately 15% of HNA families do not show linkage to this gene.

Useful For: Confirmation of a diagnosis of hereditary neuralgic amyotrophy Interpretation: All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Hannibal MC, Ruzzo EK, Miller LR, et al: SEPT9 gene sequencing analysis reveals recurrent mutations in hereditary neuralgic amyotrophy. Neurology 2009 May 19;72(20):1755-1759 3. Landsverk ML, Ruzzo EK, Mefford HC, et al: Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy. Hum Mol Genet 2009 Apr 1;18(7):1200-1208 4. Collie AM, Landsverk ML, Ruzzo E, et al: Non-recurrent SEPT9 duplications cause hereditary neuralgic amyotrophy. J Med Genet 2010 Sep;47(9):601-607

SEQU

Sequential Maternal Screening, Part 1, Serum

60698

Clinical Information: Maternal serum screening has historically been used in obstetric care to identify pregnancies that may have an increased risk for certain birth defects, such as Down syndrome and trisomy 18. Screening in the second trimester has been available in some version (ie, alpha fetoprotein [AFP] test, triple screen, quad screen) for decades. Screening in the first trimester became an established alternative over the last decade. More recently, sequential screening, which has an improved detection rate as compared to either first- or second-trimester screening, has become a standard option. Sequential



Page 1893

screening has a higher detection rate because information about a pregnancy is collected in both trimesters, which provides a greater opportunity for detecting problems. Sequential Maternal Screening, Part 1, Serum involves an ultrasound and a blood draw. The ultrasound measurement is of the back of the fetal neck, where fluid tends to accumulate in babies who have chromosome conditions, heart conditions, and other health problems. This measurement, referred to as the nuchal translucency (NT), is difficult to perform accurately. Therefore, NT data is accepted only from NT-certified sonographers. Along with the NT measurement, a maternal serum specimen is drawn and 1 pregnancy-related marker is measured (pregnancy-associated plasma protein A: PAPP-A). The results of the ultrasound measurement and blood work are then entered, along with the maternal age and demographic information, into a mathematical model that calculates Down syndrome and trisomy 18 risk estimates. If the result from the first-trimester Sequential Maternal Screening, Part 1, Serum indicates a risk for Down syndrome that is higher than the screen cutoff, the screen is completed and a report is issued. In that event, the patient is typically offered counseling and diagnostic testing (ie, either chorionic villus sampling or amniocentesis). When the screen is completed after Sequential Maternal Screen Part 1, a neural tube defect (NTD) risk is not provided. For a stand-alone NTD-risk assessment, order MAFP / Alpha-Fetoprotein (AFP), Single Marker Screen, Maternal, Serum. If the risk from the first trimester is below the established cutoff, an additional serum specimen is drawn in the second trimester for Sequential Maternal Screen, Part 2, which includes tests for AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A. Once that specimen is processed, information from both trimesters is combined and a report is issued. If results are positive, the patient is typically offered counseling and diagnostic testing (ie, amniocentesis). Nuchal Translucency (NT): The NT measurement, an ultrasound marker, is obtained by measuring the fluid-filled space within the nuchal region (back of the neck) of the fetus. While fetal NT measurements obtained by ultrasonography increase in normal pregnancies with advancing gestational age, fetuses with Down syndrome have larger NT measurements than gestational age-matched normal fetuses. Increased fetal NT measurements can, therefore, serve as an indicator of an increased risk for Down syndrome. Pregnancy-Associated Plasma Protein A (PAPP-A): PAPP-A is a 187-kDA protein comprised of 4 subunits: 2 PAPP-A subunits and 2 pro-major basic protein (proMBP) subunits. PAPP-A is a metalloproteinase that cleaves insulin-like growth factor-binding protein-4 (IGFBP-4), dramatically reducing IGFBP-4 affinity for IGF1 and IGF2, thereby regulating the availability of these growth factors at the tissue level. PAPP-A is highly expressed in first-trimester trophoblasts, participating in regulation of fetal growth. Levels in maternal serum increase throughout pregnancy. Low PAPP-A levels before the fourteenth week of gestation are associated with an increased risk for Down syndrome and trisomy 18.

Useful For: Prenatal screening for Down syndrome and trisomy 18 Prenatal screening for neural tube defects (this is only applicable to Part 2 [second trimester] of the test)

Interpretation: Maternal screens provide an estimation of risk, not a diagnosis. A negative result indicates that the estimated risk falls below the screen cutoff. A positive result indicates that the estimated risk exceeds the screen cutoff. Down Syndrome: Sequential Maternal Screening, Part 1, Serum results are negative when the calculated risk is below 1/50 (2%). If Part 1 is negative, submit an additional specimen in the second trimester (order SEQF / Sequential Maternal Screening, Part 2, Serum). Sequential Maternal Screening, Part 2, Serum results are negative when the calculated risk is below 1/270 (0.37%). Negative results mean that the risk is less than the established cutoff; they do not guarantee the absence of Down syndrome. Results are positive when the risk is greater than the established cutoff (ie, > or =1/50 in Sequential Maternal Screening, Part 1, Serum and > or =1/270 in Sequential Maternal Screening, Part 2, Serum). Positive results are not diagnostic. When both Sequential Maternal Screening Part 1 and Part 2 are performed with a screen cutoff of 1/270, the combination of maternal age, nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A has an overall detection rate of approximately 90% with a false-positive rate of approximately 3% to 4%. In practice, both the detection rate and false-positive rate vary with maternal age. Trisomy 18: In Part 1, trisomy 18 results are only reported if the Down syndrome risk is positive. In Part 2, the screen cutoff for trisomy 18 is 1 in 100 (1%). Risks that are > or =1% are screen-positive; positive results are not diagnostic. Risks 2.5. Down Syndrome: Sequential Maternal Screening, Part 2, Serum results are Current as of August 23, 2017 7:11 am CDT


Page 1896

negative when the calculated risk is below 1/270 (0.37%). Negative results mean that the risk is less than the established cutoff; they do not guarantee the absence of Down syndrome. Results are positive when the risk is greater than the established cutoff (> or =1/270 in Sequential Maternal Screening, Part 2, Serum). Positive results are not diagnostic. When both Sequential Maternal Screening Part 1 and Part 2 are performed with a screen cutoff of 1/270, the combination of maternal age, nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), AFP, unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and inhibin A has an overall detection rate of approximately 90% with a false-positive rate of approximately 3% to 4%. In practice, both the detection rate and false-positive rate vary with maternal age. Trisomy 18: In Part 2, the screen cutoff for trisomy 18 is 1 in 100 (1%). Risks that are > or =1% are screen-positive; positive results are not diagnostic. Risks 95% of cases) without any symptoms suggestive of carcinoid syndrome by measurement of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), or chromogranin A. In patients with more advanced tumors, circulating 5-HT is elevated in nearly all patients with midgut tumors, but only in approximately 50% of those with foregut carcinoids, and in no more than 20% of individuals with hindgut tumors. Foregut and hindgut tumors often have low or absent 5-hydroxytryptophan (5-HTP) decarboxylase activity and, therefore, may produce little if any 5-HT. Urinary 5-HIAA is elevated in almost all carcinoid-syndrome patients with midgut tumors, in about 30% of individuals with foregut carcinoids, but almost never in hindgut tumors. Serum chromogranin A measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly all cases, even though 5-HT and 5-HIAA are often normal. Chromogranin A is also elevated in 80% to 90% of patients with foregut and midgut tumors. Therefore, to achieve maximum sensitivity in the initial diagnosis of suspected carcinoid tumors, 5-HT in serum/blood, 5-HIAA in urine, and serum chromogranin A should all be measured. In most cases, if none of these 3 analytes is elevated, carcinoids can be excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests, such as urinary 5-HT measurement will be required. An example would be a nonchromogranin-secreting foregut tumor that only produces 5-HTP, rather than 5-HT. In this case, circulating chromogranin, 5-HT levels, and urinary 5-HIAA levels would not be elevated. However, the kidneys can convert 5-HTP to 5-HT, leading to high urinary 5-HT levels. Disease Current as of August 23, 2017 7:11 am CDT


Page 1903

progression can be monitored in patients with serotonin-producing carcinoid tumors by measurement of 5-HT in blood. However, at levels above approximately 5,000 ng/mL, the serotonin storage capacity of platelets becomes limiting, and there is no longer a linear relationship between tumor burden and blood 5-HT levels. Urinary 5-HIAA and serum chromogranin A continue to increase in proportion to the tumor burden to much higher 5-HT production levels, and are therefore better suited for follow-up in patients with extensive disease.

Reference Values: < or =330 ng/mL

Clinical References: 1. Kema IP, Schellings AM, Meibotg G, et al: Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992;38:1730-1736 2. Kema IP, de Vries EG, Muskiet FA: Clinical chemistry of serotonin and metabolites. J Chromatogr B Biomed Appl 2000;747:33-48 3. Meijer W, Kema I, Volmer M, et al: Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin Chem 2000;46:1588-1596 4. Ganim RB, Norton JA: Recent advances in carcinoid pathogenesis, diagnosis and management. Surg Oncol 2000;9:173-179

SER

Serotonin, Serum

84395

Clinical Information: Serotonin (5-hydroxytryptamine; 5-HT) is synthesized from the essential amino acid tryptophan via the intermediate 5-hydroxytryptophan (5-HTP). 5-HT production sites are the central nervous system (CNS), where it acts as a neurotransmitter, and neuroectodermal cells, chiefly gastrointestinal (GI) enterochromaffin cells (EC-cells). The CNS and peripheral 5-HT pools are isolated from each other. EC-cell production accounts for 80% of the body's 5-HT content. Many different stimuli can release 5-HT from EC-cells. Once secreted, in concert with other gut hormones, 5-HT increases GI blood flow, motility, and fluid secretion. On first pass through the liver 30% to 80% of 5-HT is metabolized, predominately to 5-hydroxyindoleacetic acid (5-HIAA), which is excreted by the kidneys. Ninety-percent of the remainder is metabolized in the lungs, also to 5-HIAA. Of the remaining 10%, almost all is taken up by platelets, where it remains until it is released during clotting, promoting further platelet aggregation. The main diseases that may be associated with measurable increases in 5-HT are neuroectodermal tumors, in particular tumors arising from EC-cells, which are termed carcinoids. They are subdivided into foregut carcinoids, arising from respiratory tract, stomach, pancreas, or duodenum (approximately 15% of cases); midgut arcinoids, occurring within jejunum, ileum, or appendix (approximately 70% of cases); and hindgut carcinoids, which are found in the colon or rectum (approximately 15% of cases). Carcinoids display a spectrum of aggressiveness with no clear distinguishing line between benign and malignant. The majority of carcinoid tumors do not cause significant clinical disease. Those tumors that behave more aggressively tend to cause nonspecific GI disturbances, such as intermittent pain and bloating, for many years before more overt symptoms develop. In advanced tumors, morbidity and mortality relate as much, or more, to the biogenic amines, chiefly 5-HT, and peptide hormones secreted, as to local and distant spread. The symptoms of this so-called carcinoid syndrome consist of flushing, diarrhea, right-sided valvular heart lesions, and bronchoconstriction. All of these symptoms are at least partly caused by 5-HT. The carcinoid syndrome is usually caused by midgut tumors, as foregut and hindgut neoplasms produce far less 5-HT. Since midgut tumors drain into the portal circulation, which passes into the liver, symptoms do not usually occur until liver or other distant metastases have developed, bypassing the extensive hepatic first-pass 5-HT degradation. Serotonin production by disseminated carcinoid tumors can sometimes be so substantial that body tryptophan stores become depleted and clinical tryptophan deficiency, resembling pellagra (triad of diarrhea, dementia, and dermatitis), develops. Diagnosis of carcinoid tumors with symptoms suggestive of carcinoid syndrome rests on measurements of circulating and urinary 5-HT, urinary 5-HIAA (HIAA / 5-Hydroxyindoleacetic Acid [5-HIAA], 24 Hour, Urine), and serum chromogranin A (CGAK / Chromogranin A, Serum), a peptide that is cosecreted alongside specific hormones by neuroectodermal cells.

Useful For: In conjunction with, or as an alternative to first-order test in the differential diagnosis of isolated symptoms suggestive of carcinoid syndrome, in particular flushing (5-HIAA or serum chromogranin A measurements are first-line tests) Second-order test in the follow-up of patients with Current as of August 23, 2017 7:11 am CDT


Page 1904

known or treated carcinoid tumors in serum specimens

Interpretation: Metastasizing midgut carcinoid tumors usually produce blood or serum 5-hydroxytryptamine (5-HT) concentrations greater than 1,000 ng/mL. However, elevations above 400 ng/mL are suggestive of carcinoid tumors as the cause of carcinoid syndrome-like symptoms. Lesser increases may be nonspecific or drug-related (see Cautions). Only a minority of patients with carcinoid tumors will have elevated 5-HT levels. It is usually impossible to diagnose small carcinoid tumors (>95% of cases) without any symptoms suggestive of carcinoid syndrome by measurement of 5-HT, 5 hydroxyindoleacetic acid (5-HIAA), or chromogranin A. In patients with more advanced tumors, circulating 5-HT is elevated in nearly all patients with midgut tumors, but only in approximately 50% of those with foregut carcinoids, and in no more than 20% of individuals with hindgut tumors. Foregut and hindgut tumors often have low or absent 5-hydroxytryptophan (5-HTP) decarboxylase activity and, therefore, may produce little if any 5-HT. Urinary 5-HIAA is elevated in almost all carcinoid-syndrome patients with midgut tumors, in about 30% of individuals with foregut carcinoids, but almost never in hindgut tumors. Serum chromogranin A measurements are particularly suited for diagnosing hindgut tumors, being elevated in nearly all cases, even though 5-HT and 5-HIAA are often normal. Chromogranin A is also elevated in 80% to 90% of patients with foregut and midgut tumors. Therefore, to achieve maximum sensitivity in the initial diagnosis of suspected carcinoid tumors, 5-HT in serum/blood, 5-HIAA in urine, and serum chromogranin A should all be measured. In most cases, if none of these 3 analytes is elevated, carcinoids can be excluded as a cause of symptoms suggestive of carcinoid syndrome. For some cases, additional tests, such as urinary 5-HT measurement will be required. An example would be a nonchromogranin-secreting foregut tumor that only produces 5-HTP, rather than 5-HT. In this case, circulating chromogranin, 5-HT levels, and urinary 5-HIAA levels would not be elevated. However, the kidneys can convert 5-HTP to 5-HT, leading to high urinary 5-HT levels. Disease progression can be monitored in patients with serotonin-producing carcinoid tumors by measurement of 5-HT in blood. However, at levels above approximately 5,000 ng/mL, the serotonin storage capacity of platelets becomes limiting, and there is no longer a linear relationship between tumor burden and blood 5-HT levels. Urinary 5-HIAA and serum chromogranin A continue to increase in proportion to the tumor burden to much higher 5-HT production levels, and are therefore better suited for follow-up in patients with extensive disease.

Reference Values: < or =230 ng/mL

Clinical References: 1. Kema IP, Schellings AM, Meibotg G, et al: Influence of a serotonin and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992;38:1730-1736 2. Kema IP, de Vries EG, Muskiet FA: Clinical chemistry of serotonin and metabolites. J Chromatogr B Biomed Sci Appl 2000;747:33-48 3. Meijer W, Kema I, Volmer M, et al: Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin Chem 2000;46:1588-1596 4. Ganim RB, Norton JA: Recent advances in carcinoid pathogenesis, diagnosis and management. Surg Oncol 2000;9:173-179

FSERT

Sertraline (Zoloft) and Desmethylsertraline

91345

Reference Values: Sertraline: Reference Range: 30 â€“ 200 ng/mL Desmethylsertraline: ng/mL No reference range provided The stated reference range is the range of observed steady-state concentrations in individuals receiving therapeutic dosage regimens of sertraline. This is not a defined therapeutic range.

FSESG

Sesame Seed IgG



Page 1905

Interpretation: mcg/mL of IgG Lower Limit of Quantitation 2.0 Upper Limit of Quantitation 200 Reference Values: < 2 mcg/mL The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG tests has not been established. These tests can be used in special clinical situations to select foods for evaluation by diet elimination and challenge in patients who have food-related complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as evidence of food allergy and only indicates immunologic sensitization by the food allergen in question. This test should only be ordered by physicians who recognize the limitations of the test.

SESA

Sesame Seed, IgE

82728





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





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SCTF

Sex Chromosome Determination, FISH, Tissue

35843

Clinical Information: Genotypically normal females possess 2 X chromosomes (XX); genotypically normal males possess 1 X chromosome and 1 Y chromosome (XY). Determining the sex chromosome complement in a tissue specimen can be used to: -Identify opposite sex-donor cells post-transplant -Help resolve cases of suspected sample mix-up

Useful For: Identifying the sex chromosome complement in paraffin-embedded tissues Interpretation: An interpretive report is provided. Reference Values: An interpretive report will be provided.

Clinical References: 1. Nakhleh RE, Zarbo RJ: Surgical pathology specimen identification and accessioning: A College of American Pathologists Q-Probes study of 1,004,115 cases from 417 institutions. Arch Pathol Lab Med 1996;120:227-233 2. Riopel MA, Yu IT, Hruban RH, et al: Whose tumor is this: FISHing for the answer. Mod Pathol 1995;8:456-457 3. Valenstein PN, Raab SS, Walsh MK: Identification errors involving clinical laboratories: a College of American Pathologists Q-Probes study of patient and specimen identification errors at 120 institutions. Arch Pathol Lab Med 2006;130:1106-1113

SHBG

Sex Hormone-Binding Globulin (SHBG), Serum

9285

Clinical Information: Sex hormone-binding globulin (SHBG), a homodimeric 90,000 to 100,000 molecular weight glycoprotein, is synthesized in the liver. Metabolic clearance of SHBG is biphasic, with a fast initial distribution from vascular compartment into extracellular space (half-life of a few hours), followed by a slower degradation phase (half-life of several days). SHBG binds sex steroids with high affinity (KD approximately 10[-10]M), dihydrotestosterone (DHT) ->testosterone (T) ->estrone/estradiol (E). Although each monomeric subunit contains 1 steroid binding site, the dimer tends to bind only a single sex-steroid molecule. The main function of SHBG is sex-steroid transport within the blood stream and to extravascular target tissues. SHBG also plays a key role in regulating bioavailable sex-steroid concentrations through competition of sex steroids for available binding sites and fluctuations in SHBG concentrations. Because of the higher affinity of SHBG for DHT and T, compared to E, SHBG also has profound effects on the balance between bioavailable androgens and estrogens. Increased SHBG levels may be associated with symptoms and signs of hypogonadism in men, while decreased levels can result in androgenization in women. SHBG levels in prepubertal children are higher than in adults. With the increase in fat mass during early puberty they begin to fall, a process that accelerates as androgen levels rise. Men have lower levels compared with women and nutritional status is inversely correlated with SHBG levels throughout life, possibly mediated by insulin resistance. Insulin resistance, even without obesity, results in lower SHBG levels. This is associated with increased intra-abdominal fat deposition and an unfavorable cardiovascular risk profile. In postmenopausal women, it may also predict the future development of type 2 diabetes mellitus. Androgens and norethisterone-related synthetic progesterones also decrease SHBG in women. Endogenous or exogenous thyroid hormones or estrogens increase SHBG levels. In men, there is also an age-related gradual rise, possibly secondary to the mild age-related fall in testosterone production. This process can result in bioavailable testosterone levels that are much lower than would be expected based on total testosterone measurements alone.

Useful For: Diagnosis and follow-up of women with symptoms or signs of androgen excess (eg, polycystic ovarian syndrome and idiopathic hirsutism) An adjunct in monitoring sex-steroid and anti-androgen therapy An adjunct in the diagnosis of disorders of puberty An adjunct in the diagnosis and follow-up of anorexia nervosa An adjunct in the diagnosis of thyrotoxicosis (tissue marker of thyroid hormone excess) A possible adjunct in diagnosis and follow-up of insulin resistance and cardiovascular and type 2 diabetes risk assessment, particularly in women In laboratories without access to bioavailable testosterone or equilibrium dialysis-based "true" free testosterone assays, sex hormone-binding globulin measurement is crucial in cases when assessment of the free testosterone fraction (aka free androgen index or calculated free testosterone) is required. At Mayo Medical Laboratories, both bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) and free testosterone (TGRP / Testosterone, Total and Free, Serum) measurements are available. Free testosterone (TGRP) is measured Current as of August 23, 2017 7:11 am CDT


Page 1907

by equilibrium dialysis, obviating the need for sex hormone-binding globulin measurements to calculate free androgen fractions.

Interpretation: Many conditions of mild-to-moderate androgen excess in women, particularly polycystic ovarian syndrome, are associated with low sex hormone-binding globulin (SHBG) levels. Most of these women are also insulin resistant and many are obese. A defect in SHBG production could lead to bioavailable androgen excess, in turn causing insulin resistance that depresses SHBG levels further. There are rare cases of SHBG mutations that clearly follow this pattern. SHBG levels are typically very low in these individuals. However, in most patients, SHBG levels are mildly depressed or even within the lower part of the normal range. In these patients, the primary problem may be androgen overproduction, insulin resistance, or both. A definitive cause cannot be usually established. Any therapy that either increases SHBG levels (eg, estrogens or weight loss), reduces bioactivity of androgens (eg, androgen receptor antagonists, alpha-reductase inhibitors), or reduces insulin resistance (eg, weight loss, metformin, peroxisome proliferator-activated receptor [PPAR] gamma agonists), can be effective. Improvement is usually associated with a rise in SHBG levels, but bioavailable or free testosterone levels should also be monitored. The primary method of monitoring sex-steroid or antiandrogen therapy is direct measurement of the relevant sex-steroids and gonadotropins. However, for many synthetic androgens and estrogens (eg, ethinyl-estradiol) clinical assays are not available. In those instances, rises in SHBG levels indicate successful anti-androgen or estrogen therapy, while falls indicate successful androgen treatment. Adult SHBG levels in boys with signs of precocious puberty support that the condition is testosterone driven, rather than representing premature adrenarche. Patients with anorexia nervosa have high SHBG levels. With successful treatment, levels start to fall as nutritional status improves. Normalization of SHBG precedes, and may be predictive of, future normalization of reproductive function. Thyrotoxicosis increases SHBG levels. In situations when assessment of true functional thyroid status may be difficult (eg, patients receiving amiodarone treatment, individuals with thyroid hormone transport-protein abnormalities, patients with suspected thyroid hormone resistance or suspected inappropriate thyroid-stimulating hormone [TSH] secretion such as a TSH-secreting pituitary adenoma), an elevated SHBG level suggests tissue thyrotoxicosis, while a normal level indicates euthyroidism or near-euthyroidism. In patients with gradual worsening of thyrotoxicosis (eg, toxic nodular goiter), serial SHBG measurement, in addition to clinical assessment, thyroid hormone, and TSH measurement, may assist in the timing of treatment decisions. Similarly, SHBG measurement may be of value in fine-tuning suppressive TSH therapy for patients with nodular thyroid disease or treated thyroid cancer. Results are not definitive in the short-term in patients receiving drugs that displace total thyroxine (T4) from albumin. SHBG is also produced by placental tissue and therefore values will be elevated during pregnancy. Reference ranges for pregnant females have not been established in our institution. In patients with known insulin resistance, "metabolic syndrome," or high risk of type 2 diabetes (eg, women with a history of gestational diabetes), low SHBG levels may predict progressive insulin resistance, cardiovascular complications, and progression to type 2 diabetes. An increase in SHBG levels may indicate successful therapeutic intervention. A genetic variant of SHBG (Asp327->Asn) introduces an additional glycosylation site in 10% to 20% of the population, resulting in significantly slower degradation. These individuals tend to have higher SHBG levels for any given level of other factors influencing SHBG.

Reference Values: Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

31-167

Stage II

11.5

49-179

Stage III

13.6

5.8-182

Stage IV

15.1

14-98



Page 1908

Stage V

18.0

10-57 *Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for boys at a median age of 11.5 (+/-2) years. For boys, there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18. Females

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

43-197

Stage II

10.5

7.7-119

Stage III

11.6

31-191

Stage IV

12.3

31-166

Stage V

14.5

18-144 *Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for girls at a median age of 10.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African American girls. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18. ADULTS Males: 10-57 nmol/L Females (non-pregnant): 18-144 nmol/L

Clinical References: 1. Pugeat M, Crave JC, Tourniare J, Forest MG: Clinical utility of sex hormone-binding globulin measurement. Horm Res 1996;45:148-155 2. Tehernof A, Despres JP: Sex steroid hormone, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000;32:526-536 3. Kahn SM, Hryb DJ, Nakhle AM, Romas NA: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 2002;175:113-120 4. Hammond GL: Access of reproductive steroids to target issues. Obstet Gynecol Clin North Am 2002;29:411-423 5. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), cortisol and ferritin in neonates, children, and young adults. Clin Chem Lab Med 2002;40(11):1151-1160

SRYF

Sex-Determining Region Y, Yp11.3 Deletion, FISH

35301

Clinical Information: This test is appropriate for individuals with a 46,XX karyotype and phenotypically normal male external genitalia, a 46,XY karyotype and phenotypically normal female external genitalia, clinical features suggestive of 46,XX testicular disorder of sex development with normal male external genitalia, and clinical features suggestive of 46,XY complete gonadal dysgenesis. The SRY (sex-determining region on the Y chromosome) gene is required for normal embryonic wolffian (male) genital development, although numerous other genes are involved in completing the process of normal male development. Some gene mutations block the action of SRY in development. Thus, a 46,XY individual with an SRY deletion or mutation will develop as a female, and a 46,XX individual with translocation of SRY to 1 X chromosome will develop as a male. Structural abnormalities of the Y chromosome result in a spectrum of abnormalities from primary infertility (male or female) to various forms of ambiguous genitalia. SRY-negative 46,XX males often have ambiguous genitalia, whereas those who are positive for SRY usually have a normal male phenotype with azoospermia. SRY-negative 46,XY females may have another mutation, such as 1 involving the SOX9 gene. We recommend conventional chromosome studies (CHRCB / Chromosome Analysis, Congenital Disorders, Blood) to detect Y chromosome abnormalities and to rule out other chromosome abnormalities or translocations, and FISH studies to detect cryptic translocations involving the SRY region that are not demonstrated by



Page 1909

conventional chromosome studies.

Useful For: Detecting the deletion or addition of the SRY gene in conjunction with conventional chromosome studies (CHRCB / Chromosome Analysis, Congenital Disorders, Blood)

Interpretation: Any male individual with an SRY signal on a structurally normal Y chromosome is considered negative for a deletion in the region tested by this probe. Any patient with a FISH signal pattern indicating loss of the critical region will be reported as having a deletion of the regions tested by this probe. Any patient with a FISH signal on an X chromosome will be reported as having a cryptic X;Y translocation involving the critical region.


Clinical References: 1. Ostrer H: 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis. 2008 May 21 (Updated 2009 Sep 15). In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1547/Accessed 05/27/2013 2. Vilain EJ: 46,XX Testicular Disorder of Sex Development. 2003 Oct 30 (Updated 2009 May 26). In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1416/ Accessed 05/27/2013

SZDIA

Sezary Diagnostic Flow Cytometry, Blood

64750

Clinical Information: Sezary syndrome is a leukemic form of cutaneous T-cell lymphoma (CTCL). By definition, it is associated with systemic skin involvement (erythroderma) and the presence of at least 1000/microL of circulating cells with irregular nuclear features (Sezary cells). Morphologic assessment of the number of Sezary cells has been proven to have low reproducibility. Therefore, WHO/European Organization for Research and Treatment of Cancer (EORTC) classification of skin tumors adopted alternative methods to assess circulating T-cells in order to establish the diagnosis of Sezary syndrome. These include CD4:CD8 ratio of more than 10:1, and selective loss of CD7 and/or CD26 on 40% and 30% of the CD4-positive cell population, respectively. It is important to recognize that the later criteria (fulfilled by peripheral blood flow cytometry immunophenotyping) are relative, and not in direct correlation with absolute counts of Sezary cells defined by morphology.

Useful For: Identifying phenotypically aberrant T-cell population in peripheral blood as part of the diagnostic workup for Sezary syndrome Roughly assessing the circulating tumor burden in mycosis fungoides, if the phenotype of the neoplastic cells is distinctive enough

Interpretation: Sezary cells typically show loss of CD7 and/or CD26. As loss of these markers is not completely sensitive or specific for Sezary cells, and there are circulating normal CD4-positive T-cells, which usually cannot be excluded from the analysis, the WHO/European Organization for Research and Treatment of Cancer (EORTC) classification of skin tumors proposed cutoffs of 30% for CD26 loss and 40% for CD7 loss on CD4-positive T-cells as diagnostic criteria for Sezary syndrome. In addition, a CD4:CD8 ratio of greater than or equal to 10:1 in a gated T-cell population is also considered abnormal and part of the diagnostic algorithm for Sezary syndrome. In mycosis fungoides staging studies the cutoffs are even less clearly defined. The clinical outcome was worse in patients with more than 5% of circulating lymphocytes showing Sezary-like morphology. However, flow cytometry immunophenotyping is deemed useful for relative quantification of these cells only if they can be separated by aberrant expression of other surface markers. In majority of cases, this cannot be accomplished to the proposed cutoff point (5% of circulating lymphocytes). The test will be resulted as "No phenotypically aberrant T-cell population detected" if there is no specific phenotype that allows separation of potentially abnormal CD4-positive T-cells, loss of CD26 (and/or CD7) is present in less than 30% (40%), and CD4:CD8 ratio is less than 10:1. If any of the above aberrancies are present, the test will be resulted as "Phenotypically distinct T-cell population is detected" with a description of phenotype, percentage of total CD4-positive population, and percentage of total analyzed events. In addition, the phenotype will be compared to that of any distinct T-cell population previously seen in the same patient by our laboratory.



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An interpretive report will be provided. This test will be processed as a laboratory consultation. An interpretation of the immunophenotypic findings and, if available, morphologic features will be provided by a board-certified hematopathologist for every case.

Clinical References: 1. Honra P, Deaver DM, Qin D, et al: Quantitative flow cytometric identification of aberrant T cell clusters in erythrodermic cutaneous T cell lymphoma: Implications for staging and prognosis. J Clin Pathol 2014;67:431-436 2. Vaughan J, Harrington AM, Hari PN, et al: Immunophenotypic stability of Sezary cells by flow cytometry: usefulness of flow cytometry in assessing response to and guiding alemtuzumab therapy. Am J Clin Pathol 2012 Mar;137(3):403-411 3. Kelemen K, Guitart J, Kuzel TM, et al: The usefulness of CD26 in flow cytometric analysis of peripheral blood in Sezary syndrome. Am J Clin Pathol 2008 Jan;129(1):146-156 4. Wilcox RA: Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016;91:152-165; doi: 10.1002/ajh.24233 5. Olsen E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007 Sep 15;110(6):1713-1722 6. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-3785

SZMON

Sezary Monitoring Flow Cytometry, Blood

64749

Clinical Information: Sezary syndrome is a leukemic form of cutaneous T-cell lymphoma (CTCL). By definition, it is associated with systemic skin involvement (erythroderma) and the presence of at least 1000/microL of circulating cells with irregular nuclear features (Sezary cells). Morphologic assessment of the number of Sezary cells has been proven to have low reproducibility. Therefore, WHO/European Organization for Research and Treatment of Cancer (EORTC) classification of skin tumors adopted alternative methods to assess circulating T-cells in order to establish the diagnosis of Sezary syndrome. These include CD4:CD8 ratio of more than 10:1, and selective loss of CD7 and/or CD26 on 40% and 30% of the CD4-positiveT-cell population, respectively. It is important to recognize that the later criteria (fulfilled by peripheral blood flow cytometry immunophenotyping) are relative, and not in direct correlation with absolute counts of Sezary cells defined by morphology.

Useful For: Monitoring response to therapy in patients with previously diagnosed Sezary syndrome or mycosis fungoides

Interpretation: Sezary cells typically show loss of CD7 and/or CD26. As loss of these markers is not completely sensitive or specific for Sezary cells, the WHO/European Organization for Research and Treatment of Cancer (EORTC) classification of skin tumors proposed cutoffs of 30% for CD26 loss and 40% for CD7 loss on CD4-positive T-cells, as diagnostic criteria for Sezary syndrome. In addition, CD4:CD8 ratio of greater than or equal to 10:1 in a gated T-cell population is also considered abnormal, and part of diagnostic algorithm for Sezary syndrome. In mycosis fungoides staging studies the cutoffs are even less clearly defined. The clinical outcome was worse in patients with more than 5% of circulating lymphocytes showing Sezary-like morphology. However, flow cytometry immunophenotyping is deemed useful for relative quantification of these cells only if they can be separated by aberrant expression of other surface markers. In majority of cases, this cannot be accomplished to the proposed cut-off point (5% of circulating lymphocytes). The test will be resulted as "No phenotypically aberrant T-cell population detected" if there is no specific phenotype that allows separation of potentially abnormal CD4-positive T-cells, loss of CD26 (and/or CD7) is present in less than 30% (40%), and CD4:CD8 ratio is less than 10:1. If any of the above aberrancies are present, the test will be resulted as "Phenotypically distinct T-cell population is detected" with a description of phenotype, percentage of total CD4-positive population and percentage of total analyzed events. In addition, the phenotype will be compared to that of any distinct T-cell population previously seen in the same patient by our laboratory.

Reference Values: An interpretive report will be provided. This test will be processed as a laboratory consultation. An interpretation of the immunophenotypic findings and, if available, morphologic features will be provided by a board-certified hematopathologist for every case. Current as of August 23, 2017 7:11 am CDT


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Clinical References: 1. Honra P, Deaver DM, Qin D, et al: Quantitative flow cytometric identification of aberrant T cell clusters in erythrodermic cutaneous T cell lymphoma. Implications for staging and prognosis. J Clin Pathol 2014;67:431-436 2. Vaughan J, Harrington AM, Hari PN, et al: Immunophenotypic stability of Sezary cells by flow cytometry: usefulness of flow cytometry in assessing response to and guiding alemtuzumab therapy. Am J Clin Patho. 2012 Mar;137(3):403-411 3. Kelemen K, Guitart J, Kuzel TM, et al: The usefulness of CD26 in flow cytometric analysis of peripheral blood in Sezary syndrome. Am J Clin Pathol 2008 Jan;129(1):146-156 4. Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016;91:152-165; doi: 10.1002/ajh.24233 5. Olsen E, Vonderheid E, Pimpinelli N, et al: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007 Sep 15;110(6):1713-1722 6. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-3785

SHWL

Sheep Wool, IgE

82747





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




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STFRP

Shiga Toxin, Molecular Detection, PCR, Feces

35148

Clinical Information: Shiga toxins (also known as Shiga-like toxins, Vero toxins, or Vero-like toxins) are encoded by some strains of Escherichia coli, most notably O157:H7. Shiga toxin can also be produced by other serogroups of enterohemorrhagic E coli (EHEC), as well as Shigella dysenteriae type 1. Generally, Shiga toxin-producing organisms cause bloody diarrhea, although this is not universal. Unlike some bacterial gastrointestinal infections, antimicrobial therapy is contraindicated, as antimicrobials may exacerbate disease. Treatment is primarily supportive (eg, hydration). A complication of infection by an organism producing Shiga toxin is hemolytic uremic syndrome (HUS). The percentage of people that develop HUS varies among outbreaks of E coli O157:H7, but generally ranges from 3% to 20%. HUS is characterized by a triad of findings: hemolytic anemia, thrombocytopenia, and kidney failure. Most people recover completely, however, some require permanent dialysis, and some die as a result of complications. Several diagnostic methods available for the detection of EHEC lack sensitivity, are labor intensive, or have a long turnaround time. There are more than 160 serogroups of EHEC; the first serogroup to be associated with HUS was O157:H7. This is also the serogroup that is most commonly implicated in outbreaks. EHEC O157:H7 is detectable as nonfermenting colonies when cultured on sorbitol MacConkey (SMAC) agar, but the majority of non-O157:H7 Shiga toxin-producing E coli strains ferment sorbitol and, therefore, are undetectable by this method. The Vero cell line is susceptible to the Shiga toxin, but the assay can take up to 48 hours and is nonspecific. Commercial enzyme-linked immunosorbent assay (ELISA) antigen detection kits have a sensitivity of 90% when compared to culture, but an overnight enrichment step is necessary for adequate sensitivity. PCR detection of stx, the gene encoding Shiga toxin, directly from stool specimens is a sensitive and specific technique, providing same-day results. PCR assay identifies non-O157:H7 Shiga toxin-producing bacteria, extending the utility beyond strains identifiable on SMAC agar.

Useful For: Sensitive, specific, and rapid detection of the presence of Shiga toxin-producing organisms such as Escherichia coli O157:H7 and Shigella dysenteriae type 1 in stool

Interpretation: A positive PCR result indicates the likely presence of Shiga toxin-producing Escherichia coli in the specimen. Although Shigella dysenteriae serotype 1 may produce a positive result, it is extremely rare in the United States. A negative result indicates the absence of detectable Shiga toxin DNA in the specimen, but does not rule out the presence of Shiga toxin-producing E coli, as false-negative results may occur due to inhibition of PCR, sequence variability underlying the primers and probes, or the presence of the Shiga toxin gene in quantities less than the limit of detection of the assay. Shiga toxins are encoded on mobile genetic elements and can theoretically be lost by their bacterial host.


Clinical References: 1. Gould LH, Bopp C: Recommendations for diagnosis of Shiga toxin-producing Escherichia coli infection by clinical laboratories. MMWR Morb Mortal Wkly Rep 2009 Oct;16:v58 2. Grys TE, Sloan LM, Rosenblatt JE, Patel R: Rapid and sensitive detection of Shiga toxin-producing Escherichia coli from nonenriched stool specimens by real-time PCR in comparison to enzyme immunoassay and culture. J Clin Microbiol 2009;47:2008-2012 3. Grys TE, Patel R: Update on Shiga toxin-producing Escherichia coli. Mayo Clinic, Mayo Medical Laboratories Communique 4. Nyre LM, Kiemele DL, Zomok CD, et al: Clinical experience with rapid PCR for detection of Shiga toxin in stool. Abstract of the Annual Meeting of the American Society for Microbiology, 2010 General Meeting, San Diego, CA, May 23-27, 2010

SRW

Short Ragweed, IgE

82667

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the



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immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



SCADZ 35544

Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency, Full Gene Analysis Clinical Information: Short-chain acyl-CoA dehydrogenase (SCAD) catalyzes the first step in the mitochondrial beta-oxidation of fatty acids with a chain length of 6 to 4 carbons. SCAD deficiency is a rare autosomal recessive condition. The clinical phenotype of SCAD shows considerable variability and is incompletely defined. Of those reported cases, hypoglycemia, developmental delay, and muscle hypotonia are the most common indicated features. The diagnosis of SCAD deficiency is challenging and should be based on the clinical presentation, 2 or more findings of ethylmalonic aciduria, and determination of fatty acid flux in fibroblasts indicating deficient SCAD activity. Molecular genetic analysis of the gene associated with SCAD (ACADS) may confirm the biochemical phenotype of SCAD deficiency. The first step in evaluation for SCAD deficiency is identification of 2 or more findings of ethylmalonic aciduria, as determined by either OAU / Organic Acids Screen, Urine or ACYLG / Acylglycines, Quantitative, Urine. Ethylmalonic aciduria is a common, although not specific, laboratory finding in patients with SCAD deficiency. Determination of fatty acid flux in fibroblasts (FAO / Fatty Acid Oxidation Probe Assay, Fibroblast Culture) is warranted for an individual with 2 or more findings of ethylmalonic aciduria. DNA sequencing of the ACADS gene is typically utilized only when SCAD deficiency is identified through biochemical analysis. The ACADS gene, associated with SCAD deficiency, is located on chromosome 12q22 and consists of 10 exons. Molecular genetic studies revealed that some patients carry ACADS gene



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mutations that cause complete absence of SCAD activity, while others carry ACADS gene variants (511C->T;625G->A) that may confer disease susceptibility only in association with other factors. The allele frequencies in the general population of the 511C->T and 625G->A gene variants are 3% and 22%, respectively. The presence of 2 of these gene variants is not considered an independent diagnostic marker for SCAD deficiency. Although further investigation is needed, it is most likely that these variants are not clinically significant. Identification of 2 ACADS gene mutations that cause complete absence of SCAD activity alone is not sufficient to explain or determine possible clinical phenotype or prognosis. The clinical significance of carrying 2 mutations is often uncertain. Therefore, the results of ACADS gene sequencing for SCAD deficiency should be interpreted in light of the clinical presentation and biochemical findings in each case.

Useful For: Preferred molecular analysis to confirm a diagnosis of short-chain acyl-CoA dehydrogenase deficiency (as a follow-up to the biochemical analyses only)



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300 2. Nagan N, Kruckeberg KE, Tauscher AL, et al: The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C4-acylcarnitine concentration in newborn blood spots. Mol Genet Metab 2003 April;78:239-246 3. Corydon MJ, Vockley J, Rinaldo P, et al: Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Pediatr Res 2001 January;49(1):18-23 4. van Maldegem BT, Duran M, Wanders RJ, et al: Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. JAMA 2006 August;296(8):943-952

FSHOX

SHOX-DNA-DxTM

57127

Reference Values: Testing is complete. Report has been attached in MayoAccess.

FSHRG

Shrimp IgG

57542

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: or =100 Strongly positive Reference values apply to all ages.


62885

Signal Transducer and Activator of Transcription 6 (STAT6), Immunostain Without Interpretation Clinical Information: Signal transducer and activator of transcription 6 (STAT6) is a signal transducer/transcription activator expressed in the cytoplasm of various normal tissues including bladder epithelium, bronchial epithelium, and epidermis. NAB2-STAT6 fusions have recently been described in the majority of solitary fibrous tumors (SFT), and lead to aberrant strong nuclear STAT6 staining.

Useful For: An aid in distinguishing solitary fibrous tumor from morphologic mimics Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Doyle LA, Vivero M, Fletcher CD, et al: Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics. Mod Pathol 2014 Mar;27(3):390-395 2. Schweizer L, Koelsche C, Sahm F, et al: Meningeal hemangiopericytoma and solitary fibrous tumors Current as of August 23, 2017 7:11 am CDT


Page 1916

carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol 2013;125:651-658 3. Robinson DR, Wu YM, Kalyana-Sundaram S, et al: Identification of recurrent NAB2-STAT6 fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013;45(2):180-185 4. Chmielecki J, Crago AM, Rosenberg M, et al: Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet 2013;45(2):131-132

FSIL

Silicon, Serum/Plasma

80771

Reference Values: Reporting limit determined each analysis. Generally: Less than 0.05 mg/dL Silicon concentrations are influenced by diet, especially vegetable intake.

SILK

Silk, IgE

82771





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




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BIR

Silver Birch, IgE

82674





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



AGS

Silver, Serum

8607

Clinical Information: The bacteriostatic properties of silver have long been recognized. In the 19th century, silver nitrate was used to treat gonorrheal ophthalmia in the newborn. Current medical uses of silver-containing compounds include sulfadiazine ointment for burn patients and some nasal decongestants. Silver-coated sutures and catheters have shown some effectiveness against a broad range of bacteria. Colloidal silver is contained in various over-the-counter preparations sold in health food stores. Environmental silver exposure can be the result of manufacture of silver nitrates as germicides, antiseptics, caustics, and analytical reagents; and for use in photography, mirrors, plating, inks, dyes, and porcelain. Additionally, sources of exposure include manufacture of silver salts as catalysts in



Page 1918

oxidation-reduction and polymerization reactions; in chemical synthesis, in glass manufacture, in silver plating, as laboratory reagents, and in medicinal compounds. Silver is not an essential constituent of the human body. Silver metabolism in humans has been inadequately studied and little reliable data is available. Some individuals seem to absorb silver selectively. Silver deposits in many organs, including the subepithelium of skin and mucous membranes producing a syndrome called argyria (greying of the skin). Argyria is associated with growth retardation, hemopoiesis, cardiac enlargement, degeneration of the liver, and destruction of renal tubules.

Useful For: Determination of silver exposure Interpretation: A finding of silver >1,000 ng/mL is indicative of acute silver exposure. Argyria occurs when silver levels are >2,000 ng/mL. No link between moderately elevated silver serum levels and symptoms has been reported in peer-reviewed medical literature.

Reference Values: 10 ng/mL. When sirolimus is given without calcineurin inhibitors, higher trough levels are needed; usually 12 to 20 ng/mL, but occasionally up to 20 to 30 ng/mL.

Useful For: Monitoring whole blood sirolimus concentration during therapy, particularly in individuals Current as of August 23, 2017 7:11 am CDT


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coadministered CYP3A4 substrates, inhibitors, or inducers Adjusting dose to optimize immunosuppression while minimizing toxicity Evaluating patient compliance

Interpretation: Most individuals display optimal response to sirolimus with trough whole blood levels 4 to 20 ng/mL. Preferred therapeutic ranges may vary by transplant type, protocol, and comedications. Therapeutic ranges are based on specimens drawn at trough (ie, immediately before a scheduled dose). Blood drawn at other times will yield higher results. The assay is specific for sirolimus; it does not cross-react with cyclosporine, cyclosporine metabolites, tacrolimus, tacrolimus metabolites, or sirolimus metabolites. Results by liquid chromatography with detection by liquid chromatography-tandem mass spectrometry are approximately 30% less than by immunoassay.

Reference Values: 4-20 ng/mL (Trough) Target steady-state trough concentrations vary depending on the type of transplant, concomitant immunosuppression, clinical/institutional protocols, and time post-transplant. Results should be interpreted in conjunction with this clinical information and any physical signs/symptoms of rejection/toxicity.

Clinical References: 1. Kahan BD: Ten years of mTOR inhibitor therapy. Transplant Proc 2003;35(3A):3S-240S 2. Yakupoglu YK, Kahan BD: Sirolimus: a current perspective. Exp Clin Transplant 2003;1:8-18 3. Groth CG, Backman L, Morales JM, et al: Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999 April;67(7):1036-1042

SLIRV

Slide Review in Molecular Genetics (Bill Only)

35549


SM

Sm Antibodies, IgG, Serum

81358

Clinical Information: Sm is a small nuclear ribonucleoprotein composed of several protein autoantigens designated B, B1, D, E, F, and G, which range in size from 11 kD to 26 kD. Sm antibodies are specific for lupus erythematosus (LE) and occur in approximately 30% of LE patients. The levels of Sm antibodies remain relatively constant over time in patients with LE and are usually found in patients that also have RNP antibodies. (1,2) Sm is 1 of 4 autoantigens commonly referred to as extractable nuclear antigens (ENAs). The other ENAs are RNP, SS-A/Ro, and SS-B/La. Each ENA is composed of 1 or more proteins associated with small nuclear RNA species (snRNP) ranging in size from 80 to approximately 350 nucleotides. Antibodies to ENAs are common in patients with connective tissue diseases (systemic rheumatic diseases) including LE, mixed connective tissue disease, Sjogren syndrome, scleroderma (systemic sclerosis), and polymyositis/dermatomyositis. See Connective Tissue Disease Cascade (CTDC) in Special Instructions.

Useful For: Evaluating patients with signs and symptoms of a connective tissue disease in whom the test for antinuclear antibodies is positive

Interpretation: A positive result for anti-Sm antibodies is consistent with a diagnosis of lupus erythematosus.

Reference Values: or =1.0 U (positive) Reference values apply to all ages.

Clinical References: 1. Homburger H, Larsen S: Detection of specific antibodies. In Clinical Current as of August 23, 2017 7:11 am CDT


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Immunology: Principles and Practice. First edition. Edited by R Rich, T Fleisher, B Schwartz, et al. St. Louis, Mosby-Year Book, 1996, pp 2096-2109 2. Kotzin B, West S: Systemic lupus erythematosus. In Clinical Immunology Principles and Practice. Second edition. Edited by R Rich, T Fleisher, W Shearer, et al. St. Louis, Mosby-Year Book, 2001, pp 60.1-60.24

SMADZ

SMAD4 Gene, Full Gene Analysis

35551

Clinical Information: Juvenile polyposis syndrome (JPS) is a rare hereditary cancer predisposition syndrome caused by mutations in the SMAD4 or BMPR1A genes. JPS is characterized by the presence of multiple histologically defined juvenile polyps in the upper and/or lower gastrointestinal (GI) tract and an increased risk for GI cancers. Age of onset for cancer development is typically in the second or third decade of life, although some patients present with a more severe infantile-onset form of the disease. JPS is inherited in an autosomal dominant fashion, although a significant proportion of probands have no family history. Approximately 50% of patients with JPS have an identifiable mutation in the SMAD4 or BMPR1A genes. Of note, some patients with mutations in the SMAD4 gene exhibit a combined juvenile polyposis/hereditary hemorrhagic telangiectasia phenotype (JP/HHT). Clinical features of HHT include development of arteriovenous malformations (AVMs) of the skin, mucosa, and viscera; spontaneous, recurrent epistaxis (nosebleeds); as well as additional complications such as transient ischemic attacks, embolic stroke, heart failure, cerebral abscess, massive hemoptysis, massive hemothorax, seizure, and cerebral hemorrhage.

Useful For: Confirmation of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia for patients with clinical features This test should be ordered only for individuals with symptoms suggestive of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia. Asymptomatic patients with a family history of juvenile polyposis syndrome or juvenile polyposis/hereditary hemorrhagic telangiectasia should not be tested until a mutation has been identified in an affected family member.

Interpretation: All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity, and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008:10(4):294-300 2. Brosens LAA, Langeveld D, van Hattern WA, et al: Juvenile Polyposis syndrome. World J Gastroenterol 2011;17(44):4839-4844 3. Calva-Cerqueira D, Chinnathambi S, Bechman B, et al: The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet 2009;75:79-85 4. Brosens LAA, van Hattern A, Hylind LM, et al: Risk of colorectal cancer in juvenile polyposis. Gut 2007;56:965-967 5. Gallione C, Aylsworth A, Beis J, et al: Overlapping spectra of SMAD4 mutations in Juvenile Polyposis (JP) and JP-HHT syndrome. Am J of Med Genet Part A 2010;152:333-339 6. Larsen Haidle J, Howe JR. Juvenile Polyposis Syndrome. 2003 May 13 [Updated 2014 May 22]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1469

SLLF

Small Lymphocytic Lymphoma, FISH, Tissue

35858

Clinical Information: Small lymphocytic lymphoma (SLL) is the nonleukemic form of chronic lymphocytic leukemia (CLL), the most common adult leukemia in North America. The most common cytogenetic abnormalities detected in CLL are deletions of 6q, 11q, 13q, and 17p, trisomy 12, and the occasional occurrence of IGH translocations at 14q32. Cytogenetics has proven to be a reliable predictor of outcome for patients with CLL. It is unknown if SLL has the same prognostic significance when these genetic abnormalities are observed. This FISH test detects an abnormal clone in approximately 65% of



Page 1921

patients with SLL. Patients with t(11;14)(q13;q32) associated with CCND1/IGH fusion, have mantle cell lymphoma which can be distinguished from SLL and other B-cell lymphomas with this assay. Patients with t(14;18)(q32;q21) or t(14;19)(q32;q13.3) may have an atypical form of SLL or another low-grade B-cell lymphoma.

Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen in patients with small lymphocytic lymphoma (SLL) and other low-grade B-cell lymphomas Distinguishing patients with 11;14 translocations who have mantle cell lymphoma from patients who have SLL

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe. A positive result is not diagnostic for small lymphocytic lymphoma, but may provide relevant prognostic information. The absence of an abnormal clone does not rule out the presence of a neoplastic disorder.


Clinical References: 1. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Fourth edition. Edited by SH Swerdlow, E Campo, NL Harris. IARC Press, Lyon, France, 2008 2. Dohner H, Stilgenbauer S, Benner A, et al: Genomic aberrations and survival in chronic lymphocytic leukemmia. N Engl J Med 2000;343(26):1910-1916 3. Nowakowski G, Dewald G, Hoyer J, et al: Interphase fluorescence in situ hybridization with an IGH probe is important in the evaluation of patients with a clinical diagnosis of chronic lymphocytic leukemia. Br J Haematol 2005;130(1):36-42 4. Shanafelt TD: Predicting clinical outcome in CLL: how and why. Hematology Am Soc Hematol Educ Program 2009;421-429 5. Van Dyke DL, Werner L, Rassenti LZ, et al: The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience. Br J Haematol 2016;173:105-113

SLO

Smith-Lemli-Opitz Screen, Plasma

81595

Clinical Information: Cholesterol plays an essential role in many cellular and developmental processes. In addition to its role as a membrane lipid, it is the precursor to numerous molecules that play important roles in cell growth and differentiation, protein glycosylation, and signaling pathways. The biosynthesis of cholesterol and its subsequent conversion to other essential compounds is complex, involving a number of intermediates and enzymes. Disorders that result from a deficiency of these enzymes lead to an accumulation of specific intermediates and inhibit the formation of important biomolecules. Clinical findings common to cholesterol biosynthesis disorders include congenital skeletal malformations, dysmorphic facial features, psychomotor retardation, and failure to thrive. Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder caused by mutations in the DHCR7 gene leading to a deficiency of the 7-dehydrocholesterol reductase enzyme. It is characterized biochemically by markedly increased plasma concentrations of 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) levels. Clinically, features can include microcephaly, growth retardation, developmental delay, dysmorphic facial features, cleft palate, limb abnormalities (especially 2-3 syndactyly of the toes and postaxial polydactyly), and heart and kidney malformations. However, the clinical spectrum ranges from mild to severe with some mildly affected individuals presenting with only 2 to 3 toe syndactyly and mild cognitive impairment. The reported incidence is between 1 in 10,000 and 1 in 60,000, but it may be more prevalent due to underdiagnosis of mildly affected individuals. Other disorders of cholesterol biosynthesis, including desmosterolosis (desmosterol reductase deficiency) and sitosterolemia, may present with similar manifestations. These disorders can be detected biochemically by performing a quantitative profile of plasma sterols (STER / Sterols, Plasma).

Useful For: Diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency) Interpretation: Elevated plasma concentrations of 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) are highly suggestive of a biochemical diagnosis of Smith-Lemli-Opitz (SLO). Mild elevations of these cholesterol precursors can be detected in patients with Current as of August 23, 2017 7:11 am CDT


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hypercholesterolemia and patients treated with haloperidol. However, the 7-DHC to cholesterol ratio is only elevated in SLO patients.

Reference Values: Negative (reported as positive or negative) Quantitative results are provided when positive.

Clinical References: 1. Haas D, Kelley RI, Hoffmann GF: Defects of cholesterol biosynthesis. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou. New York, McGraw-Hill Medical, 2009, pp 313-321 2. Nowaczyk MJM: Smith-Lemli-Opitz Syndrome. In GeneReviews Edited by RA Pagon, MP Adam, HH Ardinger. University of Washington, Seattle;1993-2015. 1998 Nov 13 (Updated 2013 Jun 20). Available at: http://www.ncbi.nlm.nih.gov/books/NBK1143/ 3. Hall P, Michels V, Gavrilov D, et al: Aripiprazole and trazodone cause elevations of 7-dehydrocholesterol in the absence of Smith-Lemli-Opitz Syndrome. Mol Genet Metab 2013 Sep-Oct;110(1-2):176-178

DD17F 35300

Smith-Magenis/Potocki-Lupski Syndromes, 17p11.2 Deletion/Duplication, FISH Clinical Information: This test is appropriate for individuals with clinical features suggestive of Smith-Magenis syndrome and Potocki-Lupski syndrome. Smith-Magenis syndrome is associated with a deletion of the proximal short arm of chromosome 17, including the critical RAI1 gene region. Although the phenotype is variable, the syndrome can be suspected in patients with failure to thrive, brachycephaly (short head), prominent forehead, microcephaly (small head), flat and broad midface, broad nasal bridge, strabismus, myopia, malformed ears, high and cleft palate, prognathism (protruding mandible), short and broad hands and feet, scoliosis (laterally curved spine), and cryptorchidism (undescended testes). Unusual features of the syndrome include specific self-destructive behavior, including insertion of foreign objects into bodily orifices, pulling out fingernails and toenails, and sleep abnormalities (especially disturbed rapid eye movement sleep). Mental retardation is variable but usually severe with seizures and hyperactivity. Patients with duplications of this region (Potocki-Lupski syndrome) tend to have a milder but overlapping phenotype. FISH studies are highly specific and do not exclude other chromosome abnormalities.

Useful For: Establishing a diagnosis of Smith-Magenis syndrome Establishing a diagnosis of Potocki-Lupski syndrome Detecting cryptic rearrangements involving 17p11.2, that are not demonstrated by conventional chromosome studies

Interpretation: Any individual with a normal signal pattern (2 signals for RAI1) in each metaphase is considered negative for a deletion or duplication in the region tested by this probe. Any patient with a FISH signal pattern indicating loss of the RAI1 critical region will be reported as having a deletion of the regions tested by this probe. This is consistent with a diagnosis of 17p11.2 deletion (Smith-Magenis) syndrome. Any patient with a FISH signal pattern indicating additional critical region signals will be reported as having a duplication of the regions tested by this probe. This is consistent with a diagnosis of 17p11.2 duplication (Potocki-Lupski) syndrome.


Clinical References: 1. Potocki L, Chen KS, Park SS, et al: Molecular mechanism for duplication 17p11.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat Genet 2000;24:84-87 2. Elsea SH, Girirajan S: Smith-Magenis Syndrome. Eur J Hum Genet 2008;16:412-421 3. Smith ACM, Boyd KE, Elsea SH, et al. Smith-Magenis Syndrome. 2001 Oct 22 [Updated 2012 Jun 28]. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews (Internet). Seattle (WA): University of Washington, Seattle; 1993-2014. Available at http://www.ncbi.nlm.nih.gov/books/NBK1310/Accessed 05/27/2013



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SMA

Smooth Muscle Antibodies, Serum

6284

Clinical Information: Sera from patients with autoimmune chronic active hepatitis contain antibodies to smooth muscle antigens that are detectable by indirect immunofluorescence on substrates that contain smooth muscle. The antibodies are predominantly of the IgG isotype. Other diseases in this differential diagnosis group include primary biliary cirrhosis, chronic viral hepatitis, and alcoholic chronic hepatitis.

Useful For: Evaluating patients with chronic liver disease in whom the diagnosis of chronic active autoimmune hepatitis is suspected

Interpretation: Antibody titers in the range of 80 to 320 occur commonly in patients with active chronic hepatitis; lower titers (usually 25.0 U

Antibodies to soluble liver antigen (SLA) appear to be directed against the UGA-suppressor tRNA associated protein. These antibodies are highly specific for autoimmune hepatitis (AIH) and may rarely, be the only autoantibodies detected in serum from such patients. Antibodies to SLA are most closely associated with AIH type 1; the presence of these antibodies in patients with cryptogenic hepatitis suggests that these patients may have AIH type 1. Anti-SLA antibodies may be detected in some patients with the primary biliary cirrhosis-AIH overlap syndrome, but not in healthy controls.

STFR

Soluble Transferrin Receptor (sTfR), Serum

84283

Clinical Information: Iron uptake into cells is mediated through internalizing iron-transferrin complexes. The iron-transferrin complex binds to transferrin receptors present on the external face of the plasma membrane, and is internalized through endosomes with ultimate release of iron into the cytoplasm. Plasma membrane-bound transferrin receptor is released by proteolytic cleavage of the extracellular domain, resulting in the formation of a truncated soluble transferrin receptor (sTfR) that circulates freely in the blood. The concentration of sTfR is an indicator of iron status. Iron deficiency causes overexpression of transferrin receptor and sTfR levels, while iron repletion results in decreased sTfR levels. While ferritin measurement is the accepted method for assessment of iron deficiency, ferritin is an acute-phase reactant and elevates in response to processes that do not correlate with iron status, including inflammation, chronic disease, malignancy, and infection. sTfR is not an acute-phase reactant and the



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interpretation of iron status using sTfR measurement is not affected by these confounding pathologies.

Useful For: Evaluation of suspected iron deficiency in patients who may have inflammation, infection, or chronic disease and other conditions in which ferritin concentration does not correlate with iron status, including: -Cystic fibrosis patients who frequently have inflammation or infections(1-2) -Evaluating insulin-dependent diabetics who may have iron-deficiency resulting from gastric autoimmunity and atrophic gastritis(3)

Interpretation: Soluble transferrin receptor (sTfR) concentrations are inversely related to iron status; sTfR elevates in response to iron deficiency and decreases in response to iron repletion.

Reference Values: 1.8-4.6 mg/L It is reported that African Americans may have slightly higher values.

Clinical References: 1. Cook JD, Skikne BS, Baynes RD: Serum transferrin receptor. Ann Rev Med 1993;44:63-74 2. Keevil B, Rowlands D, Burton I, Webb AK: Assessment of iron status in cystic fibrosis patients. Ann Clin Biochem 2000;37:662-665 3. De Block CEM, Van Capenhout CM, De Leeuw IH, et al: Soluble transferrin receptor level: a new marker of iron deficiency anemia, a common manifestation of gastric autoimmunity in type 1 diabetes. Diabetes Care 2000;23: 1384-1388 4. Mast AE, Blinder MA, Gronowski AM, et al: Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem 1998;44:45-51 5. Rees DC, Williams TN, Maitland K, et al: Alpha thalassaemia is associated with increased soluble transferrin receptor levels. Br J Haematol 1998;103:365-369 6. Duits AJ, Roker RA, van Endt T, et al: Erythropoiesis and Serum sVCAM-1 levels in adults with sickle cell disease. Ann Hematol 2003;82:171-174

SLC1B 61736

Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) Genotype, Statin, Blood Clinical Information: SLCO1B1 encodes the organic anion-transporting polypeptide 1B1 (OATP1B1) influx transporter located on the basolateral membrane of hepatocytes. OATP1B1 facilitates the hepatic uptake of statins as well as other endogenous compounds (eg, bilirubin). Changes in the activity of this transporter (eg, through genetic variations or drug-drug interactions) can increase the severity of statin-associated myopathy (ie, statin intolerance).(1) The most common adverse drug reaction associated with statins is skeletal muscle toxicity, which can include myalgia (with and without elevated creatine kinase levels), muscle weakness, muscle cramps, myositis, and rhabdomyolysis.(2) Rhabdomyolysis, while rare, is of clinical concern because of the risk for death as a result of cardiac arrhythmia, renal failure, and disseminated intravascular coagulation. While the underlying causes of statin-associated myopathy are not known, several hypotheses have been formulated, including those related to the biochemical pathway of cholesterol synthesis inhibition and statin metabolism. The SLCO1B1*5 (c.521T>C, p.V174A; rs4149056) allele interferes with localization of the transporter to the plasma membrane, and can lead to increased systemic statin concentrations.(3) All statins are substrates of OATP1B1, but the association with SLCO1B1*5 and statin intolerance varies depending on statin and dose, and is most pronounced with higher doses of simvastatin therapy. A case-control study of simvastatin-induced myopathy observed an odds ratio (OR) for myopathy of 4.5 per copy of the *5 allele in patients receiving high-dose (80 mg/day) simvastatin therapy (the OR was 16.9 in *5 homozygotes compared to individuals who did not carry *5).(4) Also demonstrated was a dose relationship in a replication cohort of patients taking 40 mg/day simvastatin with a relative risk of 2.6 per copy of the *5 allele. While SLCO1B1 genotype has been shown to affect systemic exposure of other statins (eg, atorvastatin, pravastatin, rosuvastatin) in addition to simvastatin,(3) there is less evidence demonstrating a clinical association between SLCO1B1 genotype and myopathy with statins other than simvastatin.(1) Frequency of the SLCO1B1*5 allele varies across different racial and ethnic groups. The *5 allele occurs in the homozygous or heterozygous state in approximately 20% to 28% of Caucasians and Asians, and 8% of Africans.

Useful For: Aiding risk prediction for statin-associated myopathy in patients beginning statin therapy, especially simvastatin therapy, in whole blood specimens Determining a potential genetic effect related to statin intolerance in patients with statin-associated myopathy, especially related to simvastatin Current as of August 23, 2017 7:11 am CDT


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Interpretation: Heterozygosity and homozygosity for the SLCO1B1*5 allele is associated with decreased organic anion-transporting polypeptide 1B1 (OATP1B1) activity and an increased risk for simvastatin-associated myopathy. Absence of the SLCO1B1*5 allele decreases, but does not rule out the risk of simvastatin-associated myopathy. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Ramsey LB, Johnson SG, Caudle KE, et al: The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther 2014 Oct;96(4):423-428 2. Wilke RA, Lin DW, Roden DM, et al: Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 2007;6(11):904-916 3. Niemi M: Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 2012;87:130-133 4. Link E, Parish S, Armitage J, et al: SLCO1B1 variants and statin-induced myopathy-a genomewide study. N Engl J Med 2008 Aug 21;359(8):789-799

SLC1O 61737

Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) Genotype, Statin, Saliva Clinical Information: SLCO1B1 encodes the organic anion-transporting polypeptide 1B1 (OATP1B1) influx transporter located on the basolateral membrane of hepatocytes. OATP1B1 facilitates the hepatic uptake of statins as well as other endogenous compounds (eg bilirubin). Changes in the activity of this transporter (eg, through genetic variations or drug-drug interactions) can increase the severity of statin-associated myopathy (ie, statin intolerance).(1) The most common adverse drug reaction associated with statins is skeletal muscle toxicity, which can include myalgia (with and without elevated creatine kinase levels), muscle weakness, muscle cramps, myositis, and rhabdomyolysis.(2) Rhabdomyolysis, while rare, is of clinical concern because of the risk for death as a result of cardiac arrhythmia, renal failure, and disseminated intravascular coagulation. While the underlying causes of statin-associated myopathy are not known, several hypotheses have been formulated, including those related to the biochemical pathway of cholesterol synthesis inhibition and statin metabolism. The SLCO1B1*5 (c.521T>C, p.V174A; rs4149056) allele interferes with localization of the transporter to the plasma membrane, and can lead to increased systemic statin concentrations.(3) All statins are substrates of OATP1B1, but the association with SLCO1B1*5 and statin intolerance varies depending on statin and dose, and is most pronounced with higher doses of simvastatin therapy. A case-control study of simvastatin-induced myopathy observed an odds ratio (OR) for myopathy of 4.5 per copy of the *5 allele in patients receiving high-dose (80 mg/day) simvastatin therapy (the OR was 16.9 in *5 homozygotes compared to individuals who did not carry *5).(4) Also demonstrated was a dose relationship in a replication cohort of patients taking 40 mg/day simvastatin with a relative risk of 2.6 per copy of the *5 allele. While the SLCO1B1 genotype has been shown to affect systemic exposure of other statins (eg, atorvastatin, pravastatin, rosuvastatin), in addition to simvastatin,(3) there is less evidence demonstrating a clinical association between SLCO1B1 genotype and myopathy with statins other than simvastatin.(1) Frequency of the SLCO1B1*5 allele varies across different racial and ethnic groups. The *5 allele occurs in the homozygous or heterozygous state in approximately 20% to 28% of Caucasians and Asians, and 8% of Africans.

Useful For: Aiding risk prediction of statin-associated myopathy for patients beginning statin therapy, especially simvastatin therapy, in saliva specimens Determining a potential genetic effect related to statin intolerance in patients with statin-associated myopathy, especially related to simvastatin Genotyping patients who prefer not to have venipuncture done

Interpretation: Heterozygosity and homozygosity for the SLCO1B1*5 allele is associated with decreased organic anion-transporting polypeptide 1B1 (OATP1B1) activity and an increased risk for simvastatin-associated myopathy. Absence of the SLCO1B1*5 allele decreases, but does not rule out the risk of simvastatin-associated myopathy. For additional information regarding pharmacogenomic genes Current as of August 23, 2017 7:11 am CDT


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and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Ramsey LB, Johnson SG, Caudle KE, et al: The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy:2014 update. Clin Pharmacol Ther 2014 Oct;96(4):423-428 2. Wilke RA, Lin DW, Roden DM, et al: Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 2007;6(11):904-916 3. Niemi M: Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 2012;87:130-133 4. Link E, Parish S, Armitage J, et al: SLCO1B1 variants and statin-induced myopathy-a genomewide study. N Engl J Med 2008 Aug 21;359(8):789-799

FSOMA

Somatostatin

90172

Clinical Information: Somatostatin is a cyclic peptide originally isolated from sheep hypothalami and shown to inhibit the release of Growth Hormone. Somatostatin is present primarily in three main forms: a 14 amino acid peptide, a 28 amino acid peptide (Big Somatostatin), and a 12,000 molecular weight Pro-Somatostatin. This assay measures only the 14 amino acid form of Somatostatin. All three forms of Somatostatin have similar biological properties and overall potencies. Somatostatin is a physiological regulator of islet cell and gastrointestinal functions, and is a suppressor of many pituitary hormones including Growth Hormone, Prolactin, and Thyrotropin (TSH). Somatostatin levels are often elevated in diabetics, but the levels return to normal upon correction of the hormonal and metabolic deficiencies present. In many cases of APUDomas including VIPoma, Insulinoma, Glucagonoma, and Gastrinoma, elevated levels of Somatostatin are found.

Reference Values: Up to 25 pg/ml This test was developed and its performance characteristics determined by Inter Science Institute. It has not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary.

60963

Somatostatin (SOMATO), Immunostain Without Interpretation Clinical Information: Somatostatin is a cyclic polypeptide hormone originally isolated from the hypothalamus and characterized by its ability to inhibit the release of growth hormone from the pituitary. In the digestive system, somatostatin production occurs in the intrinsic nerves of the intestinal wall, endocrine cells of the digestive mucosa and in the D-cells of pancreatic islets. Antibodies to somatostatin can be used to characterize pancreatic islet cell tumors or other neuroendocrine tumors.

Useful For: An aid in the characterization of pancreatic islet cell tumors or other neuroendocrine tumors


Clinical References: 1. Govindaraian Me, Mohan V, Deepa R, et al: Histopathology and Immunohistochemistry of Pancreatic Islets in Fibrocalculous Pancreatic Diabetes. Diabetes Research and Clinical Practice 2001;51(1):29-38 2. Kasacka I, Lebkowski W, Janiuk I, et al: Immunohistochemical Current as of August 23, 2017 7:11 am CDT


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Identification and Localisation of Gastrin and Somatostatin in Endocrine Cells of Human Pyloric Gastric Mucosa. Folia Morphol 2012;71(1):39-44 3. Sporrong B, Falkmer S, Robboy SJ, et al: Neurohormonal Peptides in Ovarian Carcinoids: An Immunohistochemical Study of 81 Primary Carcinoids and of Intraovarian Metastases from Six Mid-Gut Carcinoids. Cancer 1982;49:68-74

FSOTA

Sotalol (Betapace)

91123

Reference Values: Reference Range: 500 - 4000 ng/mL Serum Sotalol concentrations producing beta-blockade: 500 - 4000 ng/mL Toxic range has not been established.

63424

SOX10 Immunostain Without Interpretation Clinical Information: SOX10 is a nuclear transcription factor that plays an important role in schwannian and melanocytic cell differentiation, and has been shown to be a useful marker in the diagnosis of melanocytic and schwannian tumors. SOX10 is expressed in benign melanocytic naevi and melanomas, including desmoplastic melanoma and spindle cell melanoma. It is also expressed by tumors with schwannian differentiation, including malignant peripheral nerve sheath tumors, Schwannomas, and neurofibromas. SOX10 is expressed in normal tissues, including Schwann cells, melanocytes, and myoepithelial cells of salivary, bronchial, and mammary glands.

Useful For: Identification of malignant melanomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ramos-Herberth FI, Karamchandani J, Kim J, Dadras SS: SOX10 immunostaining distinguishes desmoplastic melanoma from excision scar. J Cutan Pathol 2010;37:944-9522 2. Blochin E, Nonaka D: Diagnostic value of Sox10 immunohistochemical staining for the detection of metastatic melanoma in sentinel lymph nodes. Histopathology 2009;55:626-628 3. Flammiger A, Besch R, Cook AL, et al: SOX9 and SOX10 but not BRN2 are required for nestin expression in human melanoma cells. J Invest Dermatol 2009;129:945-953 4. Nonaka D, Chiriboga L, Rubin BP: Sox10: a pan-schwannian and melanocytic marker. Am J Surg Pathol 2008;32(9):1291-1298

63425

SOX11 Immunostain Without Interpretation Clinical Information: SOX11 is a transcription factor involved in embryonic neurogenesis and tissue remodeling. Nuclear SOX11 is expressed in most B- and T-lymphoblastic leukemia/lymphomas and a proportion of Burkitt lymphomas, but only weakly expressed in some hairy cell leukemias. Mantle cell lymphomas (MCL) show SOX11 expression and it has been suggested to correlate with overall survival.

Useful For: Identification of mantle cell lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 855-516-8404. Interpretation of this test should be performed in the Current as of August 23, 2017 7:11 am CDT


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context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Chen YH, Gao J, Fan G, Peterson LC: Nuclear expression of sox11 is highly associated with mantle cell lymphoma but is independent of t(11;14)(q13;q32) in non-mantle cell B-cell neoplasms. Mod Pathol 2010;23:105-112 2. Dictor M, Ek S, Sundberg M, et al: Strong lymphoid nuclear expression of SOX11 transcription factor defines lymphoblastic neoplasms, mantle cell lymphoma and Burkittâ€™s lymphoma. Haematologica 2009;94(11):1563-1568 3. Ek S, Dictor M, Jerkeman M, et al: Nuclear expression of the non-B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma. Blood 2008;111(2):800-805 4. Fernandez V, Salamero O, Espinet B, et al: Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010;70(4):1408-1418 5. Mozos A, Royo C, Hartmann E, et al: SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 2009;94(11):1555-1562 6. Soldini D, Valera A, Sole C, et al: Assessment of SOX11 expression in routine lymphoma tissue sections: characterization of new monoclonal antibodies for diagnosis of mantle cell lymphoma. Am J Surg Pathol 2014;38(1):86-93

FSOYG

Soybean IgG

57551

Interpretation: mcg/mL of IgG Lower Limit of Quantitation* 2.0 Upper Limit of Quantitation** 200 Reference Values: < 2 mcg/mL The reference range listed on the report is the lower limit of quantitation for the assay. The clinical utility of food-specific IgG tests has not been established. These tests can be used in special clinical situations to select foods for evaluation by diet elimination and challenge in patients who have food-related complaints. It should be recognized that the presence of food-specific IgG alone cannot be taken as evidence of food allergy and only indicates immunologic sensitization by the food allergen in question. This test should only be ordered by physicians who recognize the limitations of the test.

FSYG4

Soybean IgG4

57574

Interpretation: mcg/mL of IgG4 Lower Limit of Quantitation 0.15 Upper Limit of Quantitation 30.0 Reference Values: or =100 Strongly positive Reference values apply to all ages.


SPAG

Special Red Cell Antigen Typing

8980

Clinical Information: The presence or absence of a cellular antigen is an inherited trait. As a general rule, individuals will not make antibody directed against an antigen present on their own red blood cells.

Useful For: Added proof of alloantibody specificity Determining possible antibody specificities in complex cases This test is not done for the purpose of establishing paternity

Interpretation: Each antigen typed will be listed by name, followed by "pos" indicating that the antigen is present, or by "neg" indicating that the antigen is absent.

Clinical References: Standards for Blood Banks and transfusion Services. 21st edition. AABB, 2002

SGBF

Specific Gravity, Body Fluid

8275

Clinical Information: Specific gravity (SG), the ration of the mass of a solution compared to the mass of an equal volume of water, is an estimate of the concentration of substances dissolved in the solution. Assessing whether a body fluid specimen is exudative or transudative in nature is the initial step in determining the etiology of the fluid. Transudative fluids result from hemodynamic aberrations or oncotic changes and are associated with ultrafiltration of serum across membranes. Transudates most commonly occur in association with clinically apparent conditions such as heart failure and cirrhosis. Exudative fluids tend to develop as a consequence of inflammation or malignant disorders such as tuberculosis, pneumonia or cancer, in which capillary permeability is increased, allowing large-molecular-weight compounds to be released into the accumulating fluid. If the fluid is transudate, further diagnostic procedures are often not necessary, however the presence of an exudative fluid often



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triggers additional testing that may be invasive in nature. Determination of body fluid SG can aid in the distinction between transudative and an exudative fluid. SG in exudates is greater than in transudates. This same information can be obtained from the total protein using 3 g/dL as the cutoff.

Useful For: Used to determine concentration of body fluid, to help determine type of body fluid Interpretation: Exudate fluid SG is >1.015 and transudate fluid SG is or =1:8 indicate presumptive evidence of sporotrichosis. Titers of 1:4 to 1:8 are commonly seen in normal persons. Some cutaneous infections are associated with negative serologic results. Current as of August 23, 2017 7:11 am CDT


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Clinical References: 1. Rex JH, Okhuysen PC: Sporothrix schenckii. In Principles and Practice of Infectious Diseases. Edited by GL Mandell, RG Douglas, JE Bennet. Philadelphia, Churchill Livingstone, 2000, pp 2695-2699 2. Barros MB, de Almeida Paes R, Schubach AO: Sporothrix schenckii and Sporotrichosis. Clin Micro Rev 2011;24(4):633-654

SSPC

Sporothrix Antibody, Spinal Fluid

81532

Clinical Information: Sporotrichosis is an endemic fungal infection caused by the dimorphic fungus Sporothrix schenckii. Most cases of sporotrichosis have been reported from the subtropical and tropical regions of the Americas, but a global distribution is likely. The organism is often isolated from soil, plants, or plant products (wood), and occupational or recreational exposure to these materials is often implicated in infected individuals. Infections due to Sporothrix schenckii can be differentiated into several distinct syndromes: -The cutaneous form of the disease is most common, often arising from sites of minor skin trauma. The primary erythematous, papulonodular lesion may range from several millimeters to 4 cm in size. Secondary lesions develop proximally along lymphatic channels. These generally painless lesions usually do not involve lymph nodes, although lymphadenopathy may develop. -Extracutaneous sporotrichosis can be manifested as osteoarticular involvement of a single joint. Major joints of the extremities (ankle, knee, elbow, hand) are most often involved. The affected joint is swollen and painful, with an attendant effusion. Systemic symptoms are minimal. -Pulmonary sporotrichosis with cavitary lesions also has been described. -A multifocal extracutaneous syndrome has been described, consisting of multijoint involvement, or widely scattered cutaneous lesions. Constitutional symptoms (fever, weight loss) are often noted, and spread to bone and central nervous system may occur. Underlying immune system suppression is often a contributing factor. Untreated infection is ultimately fatal.(1)

Useful For: Aiding in the diagnosis of extracutaneous sporotrichosis Interpretation: Any titer should be considered clinically significant, however, clinical correlation must be present. Extracutaneous infections, including disseminated and articular infections, produce positive tests.


Clinical References: 1. Rex JH, Okhuysen PC: Sporothrix schenckii. In Principles and Practice of Infectious Diseases. Edited by GL Mandell, RG Douglas, JE Bennet. Philadelphia, Churchill Livingstone, 2000, pp 2695-2699 2. Blumer SO, Kaufman L, Kaplan W, et al: Comparative evaluation for 5 serological methods for the diagnosis of sporotrichosis. Appl Microbiol 1973 July;26(1):4-8

SFGP

Spotted Fever Group Antibody, IgG and IgM, Serum

83679

Clinical Information: Species of Rickettsia are small (0.3-0.5 mcm x 1-2 mcm) obligately intracellular bacteria (Proteobacteria). They have a gram-negative cell wall structure. Rickettsia are found in arthropod hosts for at least part of their life cycle. Rickettsial infections in the United States are caused by 2 major groups within the genus Rickettsia: spotted fever group and typhus fever group. The spotted fever group includes Rickettsia rickettsii (Rocky Mountain spotted fever), Rickettsia akari, Rickettsia conorii (Boutonneuse fever), Rickettsia australis (Queensland tick typhus), and Rickettsia sibirica (North Asian tick typhus). The typhus fever group includes Rickettsia typhi (murine typhus; endemic typhus), and Rickettsia prowazekii (epidemic typhus). Rickettsia rickettsiae is the most common rickettsial species encountered in the United States and is transmitted through a tick vector (Dermacentor species or, less commonly, Rhipicephalus sanguineus). Following a 2- to 14-day incubation period, patients most commonly present with fever, chills, and myalgia. A maculopapular rash typically appears 2 to 5 days after fever onset, though approximately 10% of patients will not develop a rash. Antibodies to the spotted fever group agents are detectable within 7 to 10 days after illness onset. Demonstration of either 1) seroconversion or 2) a 4-fold change in IgG specific antibody titers in acute and convalescent serum



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samples is consistent with acute or ongoing disease.

Useful For: An aid in the diagnosis of spotted fever group rickettsial infections Interpretation: This test detects reactivity to the group-specific rickettsia. For example, antibody reactivity to the Rickettsia rickettsii will also react with other organisms within the spotted fever group. IgG > or =1:256: -Serum end point titers of > or =1:256 are considered presumptive evidence of recent or current infection by organisms of appropriate rickettsial antigen group. or =1:64: -Single serum end point titers > or =1:64 and or =1:64: -Titers of > or =1:64 are considered presumptive evidence of recent or current infection by organisms of appropriate rickettsial antigen group. or =10.7

8 (8)

> or =2.9

9N (9)

> or =9.2

12F (12) > or =0.6 14 (14)

> or =7.0

17F (17) > or =7.8 19F (19) > or =15.0 20 (20)

> or =1.3

22F (22) > or =7.2 23F (23) > or =8.0 6B (26)

> or =4.7

10A (34) > or =2.9 11A (43) > or =2.4 7F (51)

> or =3.2

15B (54) > or =3.3 18C (56) > or =3.3 19A (57) > or =17.1 9V (68) > or =2.6 33F (70) > or =1.7

Clinical References: 1. Weisberg SS: Pneumococcus. Dis Mon 2007 October;53(10):495-502 2. Braido F, Bellotti M, De Maria A, et al: The role of pneumococcal vaccine. Pulm Pharm Ther 2008 August;21(4):608-615 3. Nuorti JP, Whitney CG: Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR 2010 September;59(34)1102-1106 4. Moffitt KL, Malley R: Next generation pneumococcal vaccines. Curr Opin Immunol 2011 June;23(3):407-413 5. Paradiso PR: Advances in pneumococcal disease prevention: 13-valent pneumococcal conjugate vaccine for infants and children. Clin Infect Dis 2011 May;52(10):1241-1247 6. Nuorti JP, Whitney CG: Prevention of pneumococcal disease among infants and children-Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine. MMWR Recomm Rep 2010 December;59(RR-11):1-18 7. Jacob GL, Homburger HA: Simultaneous Quantitative Measurement of IgG Antibodies to Streptococcus Pneumoniae Serotypes Current as of August 23, 2017 7:11 am CDT


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by Microsphere Photometry. J Allergy Clin Immunol,2004;113(2) Suppl (Abstract 1049, pS288) 8. Plikaytis BD, Holder PF, Pais LB, et al: Determination of parallelism and nonparallelism in bioassay dilution curves. J Clin Microbiology 1994 October;32:2441-2447 9. Plikaytis BD, Goldblatt D, Frasch CE, et al: An analytical model applied to a multicenter pneumococcal enzyme-linked immunosorbent assay study. J Clin Microbiol 2000 June;38(6):2043-2050 10. Park MA, Snyder MR, Smith C, et al: New guidelines for interpretation of IgG pneumococcal antibody data: results from a cohort study of healthy adults. Clin Immunol 2010 May;135(2):38

FSTSC

Streptozyme Screen with Reflex to Titer

91984


STR

Striational (Striated Muscle) Antibodies, Serum

8746

Clinical Information: Autoantibodies directed against the contractile elements of striated muscle are found in 30% of adult patients with myasthenia gravis and in 80% of those with thymoma. These antibodies may also be detected in patients with: Lambert-Eaton myasthenic syndrome, small-cell lung carcinoma, breast carcinoma, patients treated with D-penicillamine, bone marrow transplant recipients having graft-versus-host disease, and autoimmune liver disorders. While this test is used as a serological aid in the diagnosis of thymoma, especially in patients with onset of myasthenia gravis (MG) younger than 45 years, it is more predictive of thymoma when accompanied by a muscle acetylcholine receptor (AChR) modulating antibody value of 90% or greater AChR loss and is most predictive of thymoma when accompanied by collapsin response-mediator protein-5-IgG (CRMP-5-IgG). Serial measurements are useful after treatment of thymoma. Measurements of muscle AChR binding, muscle AChR modulating antibody, and CRMP-5-IgG (if initially positive) are also recommended.

Useful For: As a serological aid in the diagnosis of thymoma, especially in patients with onset of myasthenia gravis (MG) younger than 45 years As a screening test for MG in older patients, especially when tests for muscle acetylcholine receptor (AChR) antibodies are negative Serial measurements are useful in monitoring the efficacy of immunosuppressant treatment in patients with MG Serial measurements are useful after treatment of thymoma Serial measurements in recipients of D-penicillamine or bone marrow allografts may be useful in monitoring autoimmune complications and graft-versus-host disease, respectively

Interpretation: Striational antibodies occur in approximately: -14% of patients with thymoma without clinical evidence of myasthenia gravis (MG) -30% of patients with acquired (autoimmune) MG -74% of patients with thymoma in association with MG -25% of rheumatoid arthritis (RA) patients treated with D-penicillamine, 4% in untreated RA patients -5% of patients with Lambert-Eaton myasthenic syndrome (LES) and/or small-cell lung carcinoma (SCLC) (MGL1 / Myasthenia Gravis [MG]/Lambert-Eaton Syndrome [LES] Evaluation and PAVAL / Paraneoplastic Autoantibody Evaluation, Serum) -In some bone marrow recipients with graft-versus-host disease The incidence in healthy subjects is under 1%. A rising titer after removal of thymoma may be indicative of tumor recurrence.

Reference Values: or =4.5% Germinal cells/mL or =4 x 10(6) (elevated germinal cells in semen are of unknown clinical significance) WBC/mL or =1 x 10(6) (elevated white blood cells in semen are of questionable clinical significance)

Clinical References: 1. Kruger Morphology Conference, Boston, MA, October 9, 1993 2. The World Health Organization Laboratory Manual for the examination of human semen and sperm-cervical mucus interaction. Fifth edition. Cambridge University Press, 2010

STRNG

Strongyloides Antibody, IgG, Serum

63866

Clinical Information: Strongyloidiasis is caused by Strongyloides stercoralis, a nematode endemic to tropical and subtropical regions worldwide. Strongyloides stercoralis is also prominent in the southeastern United States, including in rural areas of Kentucky, Tennessee, Virginia, and North Carolina. A small series of epidemiological studies in the United States identified that between 0 to 6.1% of individuals sampled had antibodies to Strongyloides stercoralis. Strongyloides stercoralis has a complex lifecycle that begins with maturation to the infective filariform larva in warm, moist soil. The larvae subsequently penetrate exposed skin and migrate hematogenously to the lungs, from where they ascend the bronchial tree and are swallowed. Once in the small intestine, filariform larva mature into the adult worms that burrow into the mucosa. Gravid female worms produce eggs that develop into noninfectious rhabditiform larvae in the gastrointestinal tract and are eventually released in the stool. The time from dermal penetration to appearance of Strongyloides in stool samples is approximately 3 to 4 weeks. The most common manifestations of infection are mild and may include epigastric pain, mild diarrhea, nausea, and vomiting. At the site of filariform penetration, skin may be inflamed and itchy- this is referred to as "ground itch." Migration of the larva through the lungs and up the trachea can produce a dry cough, wheezing, and mild hemoptysis. Eosinophilia, though common among patients with strongyloidiasis, is not a universal finding and the absence of eosinophilia cannot be used to rule-out infection. In some patients, particularly those with a depressed immune system, the rhabditiform larvae may mature into the infectious filariform larvae in the gastrointestinal tract and lead to autoinfection. The filariform larvae subsequently penetrate the gastrointestinal mucosa, migrate to the lungs and can complete their lifecycle. Low level autoinfection can maintain the nematode in the host for years to decades. Among patients who become severely immunocompromised, however, autoinfection may lead to hyperinfection and fatal disseminated disease. Hyperinfection has also been associated with underlying human T-cell lymphotropic virus type 1 (HTLV-1) infection. Uncontrolled, the larvae can disseminate to the lungs, heart, liver, and central nervous system. Septicemia and meningitis are common in cases of Strongyloides hyperinfection due to seeding of the bloodstream and central nervous system with bacteria originating from the gastrointestinal tract.

Useful For: Screen for the presence of IgG-class antibodies to Strongyloides Interpretation: Positive: IgG antibodies to Strongyloides were detected, suggesting current or past infection. False-positive results may occur with other helminth infections (eg, Trichinella, Taenia solium). Clinical correlation is required. Negative: No detectable levels of IgG antibodies to Strongyloides. Repeat testing in 10 to 14 days if clinically indicated.


Clinical References: 1. Ramanathan R, Burbelo PD, Groot S, et al: A luciferase immunoprecipitation systems assay enhances the sensitivity and specificity of diagnosis of Strongyloides stercoralis infection. J Infect Dis 2008;198(3):444-451 2. Starr MC, Montgomery SP: Soil-transmitted Helminthiasis in the United States: a systematic review-1940-2010. Am J Trop Med Hyg 2011;85(4):680-684 3. Krolewiecki AJ, Ramanathan R, Fink V, et al: Improved diagnosis of Strongyloides stercoralis using recombinant antigen-based serologies in a community-wide study in northern Argentina. Clin Vaccine Immunol 2010;17(10):1624-1630 4. Centers for Disease Control and Current as of August 23, 2017 7:11 am CDT


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Prevention. Global Health. Division of Parasitic Diseases and Malaria. Stongyloides. Epidemiology and Risk Factors. Accessed March 2014. Available at: http://www.cdc.gov/parasites/strongyloides/epi.html

STCH

Strychnine, Serum/Plasma

9928

Reference Values: Reporting limit determined each analysis Potentially lethal concentrations are in excess of 500 ng/mL

FSTYR

Styrene, Occupational Exposure, Blood

91094

Reference Values: Normal (Unexposed population): None detected Exposed: Biological Exposure Index (BEI): 0.55 mg/L (end of shift) 0.02 mg/L (prior to next shift) Toxic: Not established

TELOF

Subtelomeric Region Anomalies, FISH

35297

Clinical Information: This test is appropriate for individuals with clinical features including intellectual disability, developmental delay, mental retardation, autism, dysmorphic features, behavior disorders, learning disability, cognitive impairment of unknown etiology or individuals with a family member previously diagnosed with a subtelomere abnormality. Telomere caps of (TTAGGG)n repeats constitute 3 Kb to 20 Kb at the ends of each human chromosome. Centromeric to the telomere caps are 100 Kb to 300 Kb of telomere-associated repeats (TAR). Unique DNA sequences investigated for this test are centromeric to the TAR ending. The telomere-specific DNA probes are derived from the area near the junction of the TARs and unique sequences. Because of high gene concentrations in telomeric regions, there is an intense interest in subtle abnormalities involving the telomeres. For example, subtle abnormalities have been reported involving the telomeres in 7.4% of a large population of children with moderate-to-severe mental retardation. Abnormalities involving the telomere regions also are suspected in individuals with nonspecific dysmorphic features or couples with multiple miscarriages who are karyotypically normal. A standard chromosome analysis must be performed first to rule out microscopically observable karyotypic abnormalities. Microdeletions that are outside of the probe location are undetectable and this test cannot detect DNA molecular alterations such as point mutations.

Useful For: Diagnosis of subtelomeric chromosome abnormalities and rearrangements Interpretation: A deletion results in the loss of a p-arm or q-arm specific probe, and a cryptic translocation causes an exchange between the involved chromosome arms. Duplications, derivative chromosomes, and insertions of subtelomeric regions also can be detected. Family studies may be necessary following abnormal results from this FISH study, as parents may carry balanced translocations or deletions that are found in their children.


Clinical References: 1. Knight SJ, Regan R, Nicod A, et al: Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 1999;354:1676-1681 2. Jalal SM, Harwood AR, Current as of August 23, 2017 7:11 am CDT


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Sekhon GS, et al: Utility of subtelomeric fluorescent DNA probes for detection of chromosome anomalies in 425 patients. Genet Med 2003;5:28-34

SDS

Succinic Dehydrogenase Stain (Bill Only)

80866


SUAC

Succinylacetone, Blood Spot

83635

Clinical Information: Tyrosinemia type 1 (Tyr 1) is an autosomal recessive condition caused by fumarylacetoacetate hydrolase (FAH) deficiency. Tyr 1 can cause severe liver disease, hypophosphatemic rickets, renal tubular dysfunction, and neurologic crises. If left untreated, most patients die of liver failure in the first years of life. Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione is available and is particularly effective when initiated in newborns. The incidence of Tyr 1 is approximately 1 in 100,000 live births. While tyrosine can be determined by routine newborn screening, it is not a specific marker for Tyr I and often may be associated with common and benign transient tyrosinemia of the newborn. Succinylacetone (SUAC) is a specific marker for Tyr I, but is not detectable by routine newborn screening. This assay determines SUAC in newborn blood spots by tandem mass spectrometry. Additional follow-up testing may include confirmatory molecular analysis of the FAH gene.

Useful For: Second-tier newborn screening for tyrosinemia type 1 (Tyr 1) in blood spots with nonspecific elevations of tyrosine Diagnosis of Tyr 1 Follow-up of patients with Tyr 1

Interpretation: Normal: or =100 Strongly positive Reference values apply to all ages.


SFZ

Sulfamethoxazole, Serum

8238

Clinical Information: Sulfamethoxazole is a sulfonamide antibiotic that is administered in conjunction with another antibacterial, trimethoprim. These agents are used to treat a variety of infections including methicillin-resistant Staphylococcus aureus, and for prophylaxis in immunosuppressed patients such as HIV-positive individuals. Therapeutic drug monitoring is not commonly performed unless there are concerns about adequate absorption, clearance, or compliance. Monitoring of sulfamethoxazole is indicated only when prolonged (>3 months) therapy is required. Sulfamethoxazole is absorbed readily after oral administration, with peak serum concentration occurring 2 to 3 hours after an oral dose. Its average elimination half-life is 6 to 10 hours. Toxicity includes crystalluria with resultant calculi and renal disease. Toxicity is due to a high concentration of acetylated, relatively insoluble forms of the drug. Excess fluid should be taken with sulfamethoxazole to avoid formation of urine sulfonamide crystals.

Useful For: Monitoring therapy to ensure drug absorption, clearance, or compliance Interpretation: Serum drug concentrations should be interpreted with respect to the minimum inhibitory concentration (MIC) of targeted organisms. Most patients will display peak steady-state serum concentrations >50 mcg/mL when drawn at least 1 hour after an oral dose. Targets concentrations may be higher, depending on the intent of therapy. For Pneumocystis carinii pneumonia (PCP pneumonia), peak concentrations: 100-150 mcg/mL Toxicity: >200 mcg/mL Toxicity (formation of urinary crystals) associated with sulfamethoxazole occurs with prolonged exposure to serum concentrations >125 mcg/mL.



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>50 mcg/mL

Clinical References: 1. Hughes WT, Feldman S, Chaudhary SC, Ossi MJ, et al: Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr 1978;92(2):285-291 2. Dao BD, Barreto JN, Wolf RC, Dierkhising RA, et al: Serum peak sulfamethoxazole concentrations demonstrate difficulty in achieving a target range: a retrospective cohort study. Curr Ther Res Clin Exp 2014;76:104-109 3. Young T, Oliphant C, Araoyinbo I, Volmink J: Co-trimoxazole prophylaxis in HIV: the evidence. S Afr Med J 2008;98(4):258-259 4. Avdic, Cosgrove: Management and control strategies for community-associated methicillin-resistant Staphylococcus aureus. Expert Opin Pharmacother 2008;9(9):1463-1479 5. Kamme C, Melander A, Nilsson N: Serum and saliva concentrations of sulfamethoxazole and trimethoprim in adults in children: relation between saliva concentrations and in vitro activity against nasopharyngeal pathogens. Scand J Infect Dis 1983;15:107-113 6. Goodman, Gilman's: The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill Publishing, 2006, p 1112

SULFU

Sulfate, 24 Hour, Urine

81815

Clinical Information: Urinary sulfate is a reflection of dietary protein intake, particularly meat, fish, and poultry, which are rich in sulfur-containing amino acids methionine and cysteine. Urinary sulfate can be used to assess dietary protein intake for nutritional purposes. A protein-rich diet has been associated with an increased risk for stone formation, possibly due, in part, to an increase in urinary calcium excretion caused by acid production from metabolism of sulfur-containing amino acids.(1,2) Indeed, urinary sulfate excretion is higher in patients who have kidney stones than in individuals who do not form stones. Thus, urinary sulfate excretion may provide an index for protein-induced calciuria.(1) Sulfate is a major anion in the urine that has significant affinity for cations and modulates the availability of cations for reacting with other anions in the urine. It thus is an important factor of urinary supersaturation(3) for various crystals or stones such as calcium oxalate, hydroxyapatite, and brushite. For example, a high sulfate concentration may modulate the availability of calcium for reacting with oxalate and thus affect the propensity for calcium oxalate stone or crystal formation. Urinary sulfate also has a major impact on buffering or providing hydrogen ions and as such modulates the supersaturation of uric acid.

Useful For: Assessing the nutrition intake of animal protein The calculation of urinary supersaturation of various crystals or stones

Interpretation: Urinary sulfate is a reflection of dietary protein intake, particularly of meat, and thus can be used as an index of nutritional protein intake. It also is used in the calculation of urinary supersaturation of various crystals or stones.

Reference Values: 7-47 mmol/24 hours

Clinical References: 1. Tschope W, Ritz E: Sulfur-containing amino acids are a major determinant of urinary calcium. Miner Electrolyte Metab 1985;11:137-139 2. Puche RC, Vacarro D, Sanchez A, et al: Increased fractional excretion of sulphate in stone formers. Br J Urol 1993;71:523-526 3. Parks JH, Coward M, Coe FL: Correspondence between stone composition and urine supersaturation in nephrolithiasis. Kidney Int 1997;51:894-900 4. Houterman S, van Faassen A, Ocke MC, et al: Is urinary sulfate a biomarker for the intake of animal protein and meat? Cancer Lett 1997;114:295-296

FSUAB

Sulfatide Autoantibody Test

75230

Clinical Information: Background information: Peripheral neuropathies (PNs) are a group of neurological disorders affecting one or more of the peripheral nerves (1,2). Causes of PN include nerve compression, genetic mutations, inflammation, metabolic abnormalities, vitamin deficiencies, exposure to toxins or drugs, or the presence of autoimmune antibodies (1). Symptoms of PN vary based on location and mechanism of nerve damage but can include sensory impairment, distal weakness, loss of sensation, muscle weakness, and pain (1,2). PNs are typically classified based on the types of nerves affected, predominantly motor, predominantly sensory, or a combination of both (2). IgG and more commonly IgM



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Antibodies to sulfatide have been associated with sensory and sensory-motor neuropathies sometimes accompanied by pain (3,4,5). Additionally, IgG anti-sulfatide antibodies have been associated with distal sensory polyneuropathy (DSP) in individuals with HIV (6).


Clinical References: 1. Andreoli et al. (2007) Cecil Essentials of Medicine. 7th ed. Sauders Elsevier. (ISBN-13: 978-1-4160-2933-5) 2. Latov, N. (2007) Peripheral Neuropathy: When the Numbness, Weakness and Pain Won't Stop. AAN press. (ISBN-13: 978-1-932603-59-0) 3. Pestronk, A, et al. (1991) Neurology 41: 357-62, (PMID: 1706491) 4. Lopate, G, et al. (1997) J Neurol Neurosurg Psychiatry 62: 581-5. (PMID: 9219742) 5. van den Berg, LH, et al. (1993) J Neurol Neurosurg Psychiatry 56: 1164-8. (PMID: 8229027) 6. Lopate, G, et al. (2005) Neurology 64: 1632-4. (PMID: 15883332)

FSLFU

Sulfonylurea Screen, Urine

57710

Reference Values: Reference Range:

Not Established

Acetohexamide, UR Chlorpropamide, UR Tolazamide, UR Tolbutamide, UR Glimepiride, UR Glipizide, UR Glyburide, UR Nateglinide, UR Repaglinide, UR

ug/mL ug/mL ug/mL ug/mL ng/mL ng/mL ng/mL ng/mL ng/mL

FSUNG

Sunflower Seed IgG

57681



SUNF

Sunflower, IgE

82615






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Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



SAT24

Supersaturation Profile, 24 Hour, Urine

36971

Clinical Information: Urine is often supersaturated, which favors precipitation of several crystalline phases such as calcium oxalate, calcium phosphate, and uric acid. However, crystals do not always form in supersaturated urine because supersaturation is balanced by crystallization inhibitors that are also present in urine. Urinary inhibitors include ions (eg, citrate) and macromolecules but remain poorly understood. Urine supersaturation is calculated by measuring the concentration of all the ions that can interact (potassium, calcium, phosphorus, oxalate, uric acid, citrate, magnesium, sodium, chloride, sulfate, and pH). Once the concentrations of all the relevant urinary ions are known, a computer program can calculate the theoretical supersaturation with respect to the important crystalline phases (eg, calcium oxalate).(1) Since the supersaturation of urine has been shown to correlate with stone type,(2) therapy is often targeted towards decreasing those urinary supersaturations that are identified. Treatment strategies include alterations in diet and fluid intake as well as drug therapy, all designed to decrease the urine supersaturation.

Useful For: Diagnosis and management of patients with renal lithiasis: -In patients who have a radiopaque stone, for whom stone analysis is not available, the supersaturation data can be used to predict the likely composition of the stone. This may help in designing a treatment program -Individual components of the supersaturation profile can identify specific risk factors for stones -During follow-up, changes in the urine supersaturation can be used to monitor the effectiveness of therapy by confirming that the crystallization potential has indeed decreased -Urine ammonium can be used to evaluate renal excretion of acid and urine pH -The protein catabolic rate, calculated from the urine urea nitrogen, can be used to estimate a patient's protein intake

Interpretation: Delta G (DG), the Gibbs free energy of transfer from a supersaturated to a saturated solution is negative for undersaturated solutions and positive for supersaturated solutions. In most cases the supersaturation levels are slightly positive even in normal individuals but are balanced by an inhibitor activity. While the DG of urine is often positive, even in the urine of nonstone formers, on average, the DG is even more positive in those individuals who do form kidney stones. The "normal" values were simply derived by comparing urinary DG values for the important stone-forming crystalline phases between a population of stone formers and a population of non-stone formers. Those DG values that are outside the expected range in a population of non-stone formers are marked "abnormal." If the urine citrate is low, secondary causes should be excluded including hypokalemia, renal tubular acidosis, gastrointestinal bicarbonate losses (eg, diarrhea or malabsorption), or an exogenous acid load (eg, excessive consumption of meat protein). A normal or increased citrate value suggests that potassium citrate may be a less effective choice for treatment of a patient with calcium oxalate or calcium phosphate stones. An increased urinary oxalate value may prompt a search for genetic abnormalities of oxalate production (ie, primary hyperoxaluria). Secondary hyperoxaluria can result from diverse gastrointestinal disorders that result in malabsorption. Milder hyperoxaluria could result from excess dietary oxalate Current as of August 23, 2017 7:11 am CDT


Page 1967

consumption, or reduced calcium (dairy) intake, perhaps even in the absence of gastrointestinal disease. High urine ammonium and low urinary pH suggests ongoing gastrointestinal losses. Such patients are at risk of uric acid and calcium oxalate stones. Low urine ammonium and high urine pH suggests renal tubular acidosis. Such patients are at risk of calcium phosphate stones. Patients with calcium oxalate and calcium phosphate stones are often treated with citrate to raise the urine citrate (a natural inhibitor of calcium oxalate and calcium phosphate crystal growth). However, since citrate is metabolized to bicarbonate (a base) this drug can also increase the urine pH. If the urine pH gets too high with citrate treatment, one may unintentionally increase the risk of calcium phosphate stones. Monitoring the urine ammonium is one way to titrate the citrate dose and avoid this problem. A good starting citrate dose is about one-half of the urine ammonium excretion (in mEq of each). One can monitor the effect of this dose on urine ammonium, citrate, and pH values, and adjust the citrate dose based upon the response. A fall in urine ammonium should indicate whether the current citrate is enough to partially (but not completely) counteract the daily acid load of that given patient. The protein catabolic rate is calculated from urine urea. Under routine conditions, the required protein intake is often estimated as 0.8 g/ kg body weight. The results can be used to determine the likely effect of a therapeutic intervention on stone-forming risk. For example, taking oral potassium citrate will raise the urinary citrate excretion, which should reduce calcium phosphate supersaturation (by reducing free ionic calcium), but citrate administration also increases urinary pH (because it represents an alkali load) and a higher urine pH promotes calcium phosphate crystallization. The net result of this or any therapeutic manipulation could be assessed by collecting a 24-hour urine and comparing the supersaturation calculation for calcium phosphate before and after therapy. Important stone-specific factors: -Calcium oxalate stones: urine volume, calcium, oxalate, citrate, and uric acid excretion are all risk factors that are possible targets for therapeutic intervention. -Calcium phosphate stones (apatite or brushite): urinary volume, calcium, pH, and citrate significantly influence the supersaturation for calcium phosphate. Of note, a urine pH of less than6 may help reduce the tendency for these stones to form. -Uric acid stones: urine pH, volume, and uric acid excretion levels influence the supersaturation. Urine pH is especially critical, in that uric acid is unlikely to crystallize if the pH is greater than 6. -Sodium urate stones: alkaline pH and high uric acid excretion promote stone formation. A low urine volume is a universal risk factor for all types of kidney stones.

Reference Values: SUPERSATURATION REFERENCE MEANS (Delta G: DG) Calcium oxalate: 1.77 DG Brushite: 0.21 DG Hydroxyapatite: 3.96 DG Uric acid: 1.04 DG Sodium urate: 1.76 DG INDIVIDUAL URINE ANALYTES OSMOLALITY 0-11 months: 50-750 mOsm/kg > or =12 months: 150-1,150 mOsm/kg pH 4.5-8.0 ALL REFERENCE RANGES BELOW ARE BASED ON 24-HOUR COLLECTIONS. SODIUM 41-227 mmol/24 hours Reference values have not been established for patients 90% of T-cell prolymphocytic leukemias, resulting in overexpression of the TCL-1 protein. TCL-1 is also found in plasmacytoid monocytes in reactive tissues, and the putative malignant counterpart, blastic plasmacytoid dendritic cell neoplasm. In normal tonsil, expression is limited to the B-cell compartment.

Useful For: Identification of T-cell leukemia/lymphoma protein overexpression in neoplasms Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Said JW, Hoyer KK, French SW, et al: TCL1 oncogene expression in B cell subsets from lymphoid hyperplasia and distinct classes of B cell lymphoma. Lab Invest 2001 Apr;81(4):555-564 2. Herling M, Teitell MA, Shen RR, et al: TCL1 expression in plasmacytoid dendritic cells (DC2s) and the related CD4+ CD56+ blastic tumors of skin. Blood 2003 Jun 15;101(12):5007-5009

60966

T Cell Receptor Beta (TCR Beta F1), Immunostain Without Interpretation Clinical Information: T-cell receptor beta (TCR Beta F1) antibody is directed against the beta chain



Page 1988

of the alpha/beta T-cell receptor, thus staining the majority of T lymphocytes. Staining is localized at cell membranes with weak cytoplasmic staining in some cells. Positive staining in malignant lymphomas can confirm T-cell lineage and further subtype as alpha/beta T cells.


Clinical References: 1. Chan WC, Borowitz MJ, Hammami A, et al: T-Cell Receptor Antibodies in the Immunohistochemical Studies of Normal and Malignant Lymphoid Cells. Cancer 1988;62(10):2118-2124 2. Chuang S, Young-Hyeh K: Cutaneous Nonmycotic T- and Natural Killer/T-Cell Lymphomas: Diagnostic Challenges and Dilemmas. J Am Acad Dermatol 2014;70:724-735 3. Krajewski AS, Myskow MW, Salter DM, et al: Diagnosis of T-Cell Lymphoma Using Beta F1, Anti-T-Cell Receptor Beta Chain Antibody. Histopathology 1989:15(3):239-247 4. Rudiger T, Weisenburger DD, Anderson JR, et al: Peripheral T-Cell Lymphoma (Excluding Anaplastic Large-Cell Lymphoma): Results from the Non-Hodgkinâ€™s Lymphoma Classification Project. Annals of Oncology 2002;13:140-149

60984

T Cell Receptor Delta (TCRD), Immunostain Without Interpretation Clinical Information: T-cell receptor delta expression is seen in a small proportion of total T cells. Recognition of T-cell lymphomas that are derived from the delta T-cell subset is important as they often have a more aggressive clinical behavior.

Useful For: Classification of lymphomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Roullet M, Gheith SMF, Mauger J, et al: Percentage of gamma-delta T cells in panniculitis by paraffin immunohistochemical analysis. Am J Clin Pathol 2009;131:820-826 2. Willemze R, Jansen PM, Cerroni L, et al: Subcutaneous panniculitis-like T-Cell lymphoma: Definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 38 Cases. Blood 2008;111:838-845 3. Vega F, Medeiros LJ, Gaulard P: Hepatosplenic and other gamma-delta T-Cell lymphomas. Am J Clin Pathol 2007;127:869-880

TBNY

T, B and NK Lymphocyte Quantitation, New York

82589

Clinical Information: Lymphocytes in peripheral blood (circulation) are heterogeneous and can be broadly classified into T cells, B cells, and natural killer (NK) cells. There are various subsets of each of these individual populations with specific cell-surface markers and function. This assay provides absolute (cells/mcL) and relative (%) quantitation for the main categories of T cells, B cells, and NK cells, in addition to a total lymphocyte count (CD45+). Each of these lymphocyte subpopulations have distinct effector and regulatory functions and are maintained in homeostasis under normal physiological conditions. Each of these lymphocyte subsets can be identified by a combination of 1 or more cell surface markers. The CD3 antigen is a pan-T cell marker, and T cells can be further divided into 2 broad categories, based on the expression of CD4 or CD8 coreceptors. B cells can be identified by expression of



Page 1989

CD19, while NK cells are typically identified by the coexpression of CD16 and CD56. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 a.m. and noon with no change between noon and afternoon. NK-cell counts, on the other hand, are constant throughout the day.(1) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(2-4) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(2) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared to the evening(5) and during summer compared to winter.(6) These data therefore indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets. Abnormalities in the number and percent of T (CD3+, CD4+, CD8+), B (CD19), and NK (CD16+CD56) lymphocytes have been described in a number of different disease conditions. In patients who are infected with HIV, the CD4 count is measured for AIDS diagnosis and for initiation of antiviral therapy. The progressive loss of CD4 T-lymphocytes inpatients infected with HIV is associated with increased infections and complications. The Public Health Service has recommended that all HIV-positive patients be tested every 3 to 6 months for the level of CD4 T-lymphocytes. Lymphocyte subset quantitation is also very useful in the evaluation of patients with primary immunodeficiencies of all ages, including follow-up for newborn screening for severe combined immunodeficiency and immune monitoring following immunosuppressive therapy for transplantation, autoimmunity or any other relevant clinical condition where immunomodulatory treatment is used. It is also helpful as a preliminary screening assay for gross quantitative anomalies in any lymphocyte subset, whether related to malignancies or infection. The 2008 guidelines for diagnosis and treatment of chronic lymphocytic leukemia (CLL) from the International Workshop on Chronic Lymphocytic Leukemia(7) recommend changing the diagnostic criteria for CLL from an absolute lymphocyte count greater than 5 x 10(9)/L to a circulating B-cell count greater than 5 x 10(9)/L(8,9) previously defined in the 1996 National Cancer Institute guidelines for CLL. This flow cytometric assay enables accurate quantitation of circulating B cells using a single platform technology with absolute quantitation through the use of flow cytometry beads.

Useful For: Only orderable by New York clients Serial monitoring of CD4 T-cell count in HIV-positive patients Follow-up and diagnostic evaluation of primary immunodeficiencies, including severe combined immunodeficiency Immune monitoring following immunosuppressive therapy for transplantation, autoimmunity, and other immunological conditions where such treatment is utilized Assessment of immune reconstitution posthematopoietic cell transplantation Early screening of gross quantitative anomalies in lymphocyte subsets in infection or malignancies Absolute quantitation of circulating B cells for diagnosis of chronic lymphocytic leukemia patients as indicated in the 2008 International Workshop on Chronic Lymphocytic Leukemia guidelines

Interpretation: HIV treatment guidelines from the US Department of Health and Human Services and the International Antiviral Society-USA Panel recommend antiviral treatment in all patients with HIV infection, regardless of CD4 T-cell count.(10,11) Additionally, antibiotic prophylaxis for Pneumocystis jiroveci infection and other opportunistic infections is recommended for patients with CD4 count less than 200 cells/mcL.


Clinical References: 1. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract # B11052 2. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009;113:5134-5143 3. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 4. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 5. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 6. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion Current as of August 23, 2017 7:11 am CDT


Page 1990

1994;34:512-516 7. Hallek M, Cheson BD, Catovsky D, et al: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on CLL updating the National Cancer Institute Working Group 1996 guidelines. Blood 2008;111:5446-5456 8. Hanson CA, Kurtin PJ, Dogan A: The proposed diagnostic criteria change for chronic lymphocytic leukemia: unintended consequences? Blood 2009;113:6495-6496 9. Hillmen P, Cheson BD, Catovsky D, et al: Letter to Editor. Blood 2009;113:6497-6498 10. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at http://aidsinfo.nih.gov/guidelines 11. Thompson MA, Aberg JA, Hoy JF, et al: Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA Panel. JAMA 2012;308:387-402

60969

T-Box Expressed in T Cells (TBET), Immunostain Without Interpretation Clinical Information: The T-box transcription factor, TBET, is a master regulator of Th1 lymphoid development. It is expressed in other hematopoietic cells including stem cells, B cells and natural killer cells. In normal tonsil, TBET staining is seen in scattered small interfollicular T lymphocytes, with virtually no staining in the germinal centers. It is preferentially positive in T-cell lymphomas with Th1 differentiation, B-cell lymphomas of memory B-cell origin, and both classical and nodular lymphocyte predominant Hodgkin lymphoma.


Clinical References: 1. Atayar C, Poppema S, Blokzijl T, et al: Expression of the T-cell transcription factors, GATA-3 and T-bet, in the neoplastic cells of Hodgkin lymphomas. Am J Pathol 2005 Jan;166(1):127-134 2. Dorfman DM, Hawang ES, Shahsafaei A, Glimcher LH: T-bet, a T-cell associated transcription factor, is expressed in a subset of B-cell lymphoproliferative disorders. Am J Clin Pathol 2004 Aug;122(2):292-297 3. Dorfman DM, van den Elzen P, Weng AP, et al: Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas. Am J Clin Pathol 2003 Dec;120(6):866-873

TALLF

T-Cell Acute Lymphoblastic Leukemia (T-ALL), FISH

35296

Clinical Information: In the United States, the incidence of acute lymphoblastic leukemia (ALL) is roughly 6,000 new cases per year (as of 2009), or approximately 1 in 50,000. ALL accounts for approximately 70% of all childhood leukemia cases (ages 0 to 19 years), making it the most common type of childhood cancer. Approximately 85% of pediatric cases of ALL are B-cell lineage (B-ALL) and 15% are T-cell lineage (T-ALL). T-ALL is more common in adolescents than younger children and accounts for 25% of adult ALL. When occurring as a primary lymphoblastic lymphoma (LBL), approximately 90% are T-cell lineage versus only 10% B-cell lineage. T-LBL often present as a mediastinal mass in younger patients with or without concurrent bone marrow involvement. Specific genetic abnormalities are identified in the majority of cases of T-ALL, although many of the classic abnormalities are "cryptic" by conventional chromosome studies and must be identified by FISH studies. Each of the genetic subgroups are important to detect and can be critical prognostic markers. One predictive marker, amplification of the ABL1 gene region, has been identified in 5% of T-ALL, and these patients may be responsive to targeted tyrosine kinase inhibitors. A combination of cytogenetic and FISH testing is currently recommended in all pediatric and adult patients to characterize the T-ALL clone for the prognostic genetic subgroups. A summary of the characteristic chromosome abnormalities identified in T-ALL are listed in the following table. Common Chromosome Abnormalities in T-cell Acute Lymphoblastic Leukemia Cytogenetic



Page 1991

change Genes involved del(1p33) TAL1/STIL t(5;14)(q35;q32) TLX3(HOX11L2)/BCL11B t(10;11)(p13;q14) MLLT10(AF10)/PICALM Episomal amplification ABL1 del(9p) CDKN2A(p16) t(11q23;var) MLL(KMT2A) t(4;11)(q21;q23) AFF1(AF4)/MLL(KMT2A) t(6;11)(q27;q23) MLLT4(AF6)/MLL(KMT2A) t(9;11)(p22;q23) MLLT3(AF9)/MLL(KMT2A) t(10;11)(p13;q23) MLLT10(AF10)/MLL(KMT2A) t(11;19)(q23;p13.1) MLL(KMT2A)/ELL t(11;19)(q23;p13.3) MLL(KMT2A)/MLLT1(ENL) t(7q34;var) TRB t(6;7)(q23;q34) MYB/TRB t(7;10)(q34;q24) TRB/TLX1(HOX11) t(7;11)(q34;p15) TRB/LMO1 t(7;11)(q34;p13) TRB/LMO2 t(14q11.2;var) TRAD t(8;14)(q24.1;q11.2) MYC/TRAD t(10;14)(q24;q11.2) TLX1(HOX11)/TRAD t(11;14)(p15;q11.2) LMO1/TRAD t(11;14)(p13;q11.2) LMO2/TRAD del(17p) TP53 Complex karyotype (> or =4 abnormalities)

Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen in patients with T-cell acute lymphoblastic leukemia (T-ALL) Identifying and tracking known chromosome abnormalities in patients with T-ALL and tracking response to therapy An adjunct to conventional chromosome studies in patients with T-ALL

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe. The absence of an abnormal clone does not rule out the presence of neoplastic disorder.


Clinical References: 1. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Edited by ES Jaffe, NL Harris, H Stein, JW Vardiman. Lyon, IARC Press, 2001 2. Gesk S, Martin-Subero JI, Harder L, et al: Molecular cytogenetic detection of chromosomal breakpoints in T-cell receptor gene loci. Leukemia 2003;17:738-745 3. Chin M, Mugishima H, Takamura M, et al: Hemophagocytic syndrome and hepatosplenic (gamma)(delta) T-cell lymphoma with isochromosome 7q and 8 trisomy. J Pediatr Hematol Oncol 2004;26(6):375-378 4. Graux C, Cools J, Michaux L, et al: Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496-1510 5. Cayuela JM, Madani A, Sanhes L, et al: Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia. Blood 1996;87:2180-2186 6. Hayette S, Tigaud I, Maguer-Satta V, et al: Recurrent involvement of the MLL gene in adult T-lineage acute lymphoblastic leukemia. Blood 2002;99:4647-4649 7. Graux C, Cools J, Melotte C, et al: Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 2004;36:1084-1089

TLPF

T-Cell Lymphoma, FISH, Blood or Bone Marrow

35298

Clinical Information: T-cell neoplasms are relatively uncommon, accounting for approximately 12% of all non-Hodgkin lymphomas. There are several subtypes of T-cell neoplasms: T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), T-cell large granular lymphocytic leukemia (T-LGL), anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma, and various other cutaneous, nodal, and extranodal lymphoma subtypes. The 2 most prevalent lymphoma subtypes are unspecified peripheral T-cell lymphoma (3.7%) and ALCL (2.4%). T-cell neoplasms are among the most aggressive of all hematologic and lymphoid neoplasms with the exception of ALCL, which is usually responsive to chemotherapy. There are a few common chromosome abnormalities associated with specific subtypes, which this FISH test can detect: -inv(14)(q11q32) and t(14;14)(q11;q32), which involve the T-cell leukemia/lymphoma 1 gene (TCL1A) and have been associated with T-PLL -Isochromosome 7q and trisomy 8, which have been associated with hepatosplenic T-cell lymphoma These probes have diagnostic relevance and can also be used to track response to therapy. This assay detects chromosome abnormalities observed in the blood and bone marrow of patients with T-cell lymphoma (for patients with T-cell acute leukemia, order TALLF / T-Cell Acute Lymphoblastic Leukemia [T-ALL], FISH).

Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen in patients with various T-cell lymphomas Tracking known chromosome abnormalities and response to Current as of August 23, 2017 7:11 am CDT


Page 1992

therapy in patients with T-cell lymphoma

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe. Detection of an abnormal clone supports a diagnosis of a T-cell lymphoma. The specific abnormality detected may help subtype the neoplasm. The absence of an abnormal clone does not rule out the presence of neoplastic disorder.


Clinical References: 1. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Edited by ES Jaffe, NL Harris, H Stein, JW Vardiman. Lyon, IARC Press, 2001 2. Gesk S, Martin-Subero JI, Harder L, et al: Molecular cytogenetic detection of chromosomal breakpoints in T-cell receptor gene loci. Leukemia 2003;17:738-745 3. Chin M, Mugishima H, Takamura M, et al: Hemophagocytic syndrome and hepatosplenic (gamma)(delta) T-cell lymphoma with isochromosome 7q and 8 trisomy. J Pediatr Hematol Oncol 2004;26(6):375-378

TLYMF

T-Cell Lymphoma, FISH, Tissue

35299

Clinical Information: T-cell malignancies account for approximately 12% of all non-Hodgkin lymphomas. There are several subtypes of T-cell neoplasms: T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), T-cell large granular lymphocytic leukemia (T-LGL), anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma, and various other cutaneous, nodal, and extrandodal lymphoma subtypes. The 2 most prevalent lymphoma subtypes are unspecified peripheral T-cell lymphoma (3.7%) and ALCL (2.4%). A few common chromosome abnormalities are associated with specific T-cell lymphoma subtypes, including: -inv(14)(q11q32) and t(14;14)(q11;q32) involving the T-cell leukemia/lymphoma 1 gene (TCL1A) at 14q32 -Translocations involving the ALK gene at 2p23 in ALCL -Isochromosome 7q and trisomy 8 in hepatosplenic T-cell lymphoma

Useful For: Detecting a neoplastic clone associated with the common chromosome abnormalities seen in patients with various T-cell lymphomas Tracking known chromosome abnormalities and response to therapy in patients with T-cell lymphomas

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for any given probe. Detection of an abnormal clone is supportive of a diagnosis of a T-cell lymphoma. The specific abnormality detected may help subtype the neoplasm. The absence of an abnormal clone does not rule out the presence of a neoplastic disorder.


Clinical References: 1. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Edited by ES Jaffe, NL Harris, H Stein, JW Vardiman. Lyon, IARC Press, 2001 2. Gesk S, Martin-Subero JI, Harder L, et al: Molecular cytogenetic detection of chromosomal breakpoints in T-cell receptor gene loci. Leukemia 2003;17:738-745 3. Chin M, Mugishima H, Takamura M, et al: Hemophagocytic syndrome and hepatosplenic (gamma)(delta) T-cell lymphoma with isochromosome 7q and 8 trisomy. J Pediatr Hematol Oncol 2004;26(6):375-378 4. Graux C, Cools J, Michaux L, et al: Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496-1510 5. Cayuela JM, Madani A, Sanhes L, et al: Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic in T-cell lymphoblastic leukemia. Blood 1996;87:3180-3186

TREC

T-Cell Receptor Excision Circles (TREC) Analysis, Blood

87959

Clinical Information: T cell reconstitution is a critical feature of the recovery of the adaptive immune response and has 2 main components: thymic output of new T cells and peripheral homeostatic expansion of preexisting T cells. It has been shown that though thymic function declines with age, a



Page 1993

reasonable output is still maintained into late adult life.(1) In many clinical situations, thymic output is crucial to the maintenance and competence of the T cell effector immune response. Thymic function can be determined by T-cell receptor excision circle (TREC) analysis. TRECs are extrachromosomal DNA byproducts of T-cell receptor (TCR) rearrangement, which are nonreplicative. TRECs are expressed only in T cells of thymic origin and each cell is thought to contain a single copy of TREC. Hence, TREC analysis provides a very specific assessment of T-cell recovery (eg, after hematopoietic cell transplantation) or numerical T-cell competence. There are several TRECs generated during the process of TCR rearrangement and the TCR delta deletion TREC (deltaREC psi-J-alpha signal joint TREC) has been shown to be the most accurate TREC for measuring thymic output.(2) This assay measures this specific TREC using quantitative, real-time PCR. Clinical use of TRECs in HIV and Antiretroviral Therapy: HIV infection leads to a decrease in thymic function. Adult patients treated with highly active antiretroviral therapy (HAART) show a rapid and sustained increase in thymic output.(1) Clinical use of TRECs in Hematopoietic Cell Transplantation (HCT) and Primary Immunodeficiencies (PID): Following HCT, there is a period of prolonged immunodeficiency that varies depending on the nature and type of stem cell graft used and the conditioning regimen, among other factors. This secondary immunodeficiency also includes defects in thymopoiesis.(3-5) It has been shown that numerical T cell recovery is usually achieved by day 100 posttransplant, though there is an inversion of the CD4:CD8 ratio that can persist for up to a year.(4) Also, recovery of T-cell function and diversity can take up to 12 months, although this can be more rapid in pediatric patients. However, recovery of T-cell function is only possible when there is numerical reconstitution of T cells. T cells, along with the other components of adaptive immunity, are key players in the successful response to vaccination post-HCT.(6) Recently, it has been shown in patients who received HCT for severe combined immunodeficiency (SCID) that T cell recovery early after stem cell transplant is crucial to long-term T cell reconstitution.(7) Patients who demonstrated impaired reconstitution were shown to have poor early grafting, as opposed to immune failure caused by accelerated loss of thymic output or long-term graft failure. In this study, the numbers of TRECs early after HCT were most predictive for long-term reconstitution. This data suggests that frequent monitoring of T-cell immunity and TREC numbers after HCT can help identify patients who will fail to reconstitute properly, which would allow additional therapies to be instituted in a timely manner.(7) It would be reasonable to extrapolate such a conclusion to other diseases that are also treated by HCT. TREC Copies and Thymic Output in Adults: Since the adult thymus involutes after puberty and is progressively replaced by fat with age, thymus-dependent T cell recovery has been assumed to be severely limited in adults. However, with TREC analysis it has been shown that the change in thymic function in adults is a quantitative phenomenon rather than a qualitative one and thymic output is not totally eliminated.(1,8,9) Thus, after HCT or HAART, the remaining thymic tissue can be mobilized in adults to replenish depleted immune systems with a potentially broader repertoire of naive T cells. Douek et al have shown that there is a significant contribution by the thymus to immune reconstitution after myeloablative chemotherapy and HCT in adults.(8) In fact, this data shows that there is both a marked increase in the TREC numbers and a significant negative correlation of TREC copies with age posttransplant. In addition to the specific clinical situations elucidated above, TREC analysis can be helpful in identifying patients with primary immunodeficiencies and assessing their numerical T-cell immune competence. It can also be used as a measure of immune competence in patients receiving immunotherapy or cancer vaccines, where maintenance of, T-cell outputis integral to the immune response against cancer. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 am and noon, with no change between noon and afternoon. Natural killer (NK) cell counts, on the other hand, are constant throughout the day.(10) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(11-13) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(11) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening,(14) and during summer compared to winter.(15) These data, therefore, indicate that timing and consistency in timing of blood collection are critical when serially monitoring patients for lymphocyte subsets.

Useful For: Measuring T-cell output or reconstitution (thymopoiesis) following hematopoietic cell transplantation or highly active antiretroviral therapy Evaluating thymic function in patients with cellular or combined primary immunodeficiencies, or receiving immunotherapy or cancer vaccines Assessing T-cell recovery following thymus transplants for DiGeorge syndrome Current as of August 23, 2017 7:11 am CDT


Page 1994

Interpretation: T-cell receptor excision circles (TRECs) generally show an inverse correlation with age, though there can be substantial variations in TREC copies relative to T-cell count within a given age group. Following hematopoietic cell transplantation (HCT), highly active antiretroviral therapy (HAART), thymic transplants, etc, TREC typically increases from absent or very low levels (below age-matched reference range) to baseline levels or exceeds baseline levels, showing evidence of thymic rebound, which is consistent with recovery of thymic output and T-cell reconstitution. When a patient is being monitored for thymic recovery posttransplant treatment, this assay recommends that a pretransplant (prior to myeloablative or nonmyeloablative conditioning) or a pretreatment baseline specimen be provided so that appropriate comparisons can be made between the pre- and posttransplant treatment specimens. Since there is substantial variability between individuals in TREC copies, the best comparison is made to the patient's own baseline specimen rather than the reference range (which provides a guideline for TREC copies for age-matched healthy controls). A consultative report will be generated for each patient.


Clinical References: 1. Douek DC, McFarland RD, Keiser PH, et al: Changes in thymic function with age and during the treatment of HIV infection. Nature 1998;396:690-694 2. Hazenberg MD, Verschuren MC, Hamann D, et al: T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med 2001;79:631-640 3. Parkman R, Weinberg K: Immunological reconstitution following hematopoietic stem cell transplantation. In Hematopoietic Cell Transplantation. Second edition. Edited by ED Thomas, KG Blume, SJ Forman. Blackwell Scientific, Oxford, UK, 1999, pp 704-711 4. Weinberg K, Blazar BR, Wagner JE, et al: Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001;97:1458-1466 5. Weinberg K, Annett G, Kashyap A, et al: The effect of thymic function on immunocompetence following bone marrow transplantation. Biol Blood Marrow Transplant 1995;1:18-23 6. Auletta JJ, Lazarus HM: Immune restoration following hematopoietic stem cell transplantation: an evolving target. Bone Marrow Transplant 2005;35:835-857 7. Borghans JA, Bredius RG, Hazenberg MD, et al: Early determinants of long-term T cell reconstitution after hematopoietic stem cell transplantation for severe combined immunodeficiency. Blood 2006;108:763-769 8. Douek DC, Vescio RA, Betts MR, et al: Assessment of thymic output in adults after hematopoietic stem cell transplantation and prediction of T cell reconstitution. Lancet 2000;355:1875-1881 9. Jamieson BD, Douek DC, Killian S, et al: Generation of functional thymocytes in the human adult. Immunity 1999;10:569-575 10. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 11. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009 May 21;113(21):5134-5143 12. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 13. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 14. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 15. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516

TCGR

T-Cell Receptor Gene Rearrangement, PCR, Blood

83122

Clinical Information: The T-cell receptor (TCR) genes (alpha, beta, delta, and gamma) are comprised of numerous, discontinuous coding segments that somatically rearrange to produce heterodimeric cell surface T-cell receptors, either alpha/beta (90%-95% of T cells) or gamma/delta (5%-10% of T cells). With rare exceptions (eg, some neoplastic B-lymphoid proliferations), other cell types retain the "germline" configuration of the TCR genes without rearrangement. The marked diversity of somatic TCR-gene rearrangements is important for normal immune functions, but also serves as a valuable marker to distinguish abnormal T-cell proliferations from reactive processes. A monoclonal expansion of a T-cell population will result in the predominance of a single TCR-gene rearrangement



Page 1995

pattern. In contrast, reactive T-cell expansions are polyclonal (or multiclonal), with no single clonotypic population predominating in the population of T cells. These distributive differences in both TCR sequence and genomic rearrangement fragment sizes can be detected by molecular techniques (ie, PCR) and used to determine if a population of T cells shows monoclonal or polyclonal features.

Useful For: Determining whether a T-cell population is polyclonal or monoclonal Interpretation: An interpretive report will be provided. Results will be characterized as positive, negative, or indeterminate for a clonal T-cell population. In the appropriate clinicopathologic setting, a monoclonal result is associated with a neoplastic proliferation of T cells (see Cautions).

Reference Values: An interpretive report will be provided. Positive, negative, or indeterminate for a clonal T-cell population

Clinical References: 1. Liu H, Bench AJ, Bacon CM, et al: A practical strategy for the routine use of BIOMED-2 PCR assays for detection of B- and T-cell clonality in diagnostic haematopathology. Br J Haematol 2007;138(1):31-43 2. Van Krieken JH, Langerak AW, Macintyre EA, et al: Improved reliability of lymphoma diagnostics via PCR-based clonality testing: report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007;21(2):201-206 3. Bruggemann M, White H, Gaulard P, et al: Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia 2007;21(2):215-221

TCGBM

T-Cell Receptor Gene Rearrangement, PCR, Bone Marrow

31139

Clinical Information: The T-cell receptor (TCR) genes (alpha, beta, delta, and gamma) are comprised of numerous, discontinuous coding segments that somatically rearranged to produce heterodimeric cell surface T-cell receptors, either alpha/beta (90%-95% of T cells) or gamma/delta (5%-10% of T cells). With rare exceptions (eg, some neoplastic B-lymphoid proliferations), other cell types retain the "germline" configuration of the TCR genes without rearrangement. The marked diversity of somatic TCR-gene rearrangements is important for normal immune functions, but also serves as a valuable marker to distinguish abnormal T-cell proliferations from reactive processes. A monoclonal expansion of a T-cell population will result in the predominance of a single TCR-gene rearrangement pattern. In contrast, reactive T-cell expansions are polyclonal (or multiclonal), with no single clonotypic population predominating in the population of T cells. These distributive differences in both TCR sequence and genomic rearrangement fragment sizes can be detected by molecular techniques (ie, PCR) and used to determine if a population of T cells shows monoclonal or polyclonal features.



Clinical References: 1. Liu H, Bench AJ, Bacon CM, et al: A practical strategy for the routine use of BIOMED-2 PCR assays for detection of B- and T-cell clonality in diagnostic haematopathology. Br J Haematol 2007;138(1):31-43 2. Van Krieken JH, Langerak AW, Macintyre EA, et al: Improved reliability of lymphoma diagnostics via PCR-based clonality testing: report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007;21(2):201-206 3. Bruggermann M, White H, Gaulard P, et al: Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia 2007;21(2):215-221

TCGRV

T-Cell Receptor Gene Rearrangement, PCR, Varies



Page 1996

Clinical Information: The T-cell receptor (TCR) genes (alpha, beta, delta, and gamma) are comprised of numerous, discontinuous coding segments that somatically rearranged to produce heterodimeric cell surface T-cell receptors, either alpha/beta (90%-95% of T cells) or gamma/delta (5%-10% of T cells). With rare exceptions (eg, some neoplastic B-lymphoid proliferations), other cell types retain the "germline" configuration of the TCR genes without rearrangement. The marked diversity of somatic TCR-gene rearrangements is important for normal immune functions, but also serves as a valuable marker to distinguish abnormal T-cell proliferations from reactive processes. A monoclonal expansion of a T-cell population will result in the predominance of a single TCR-gene rearrangement pattern. In contrast, reactive T-cell expansions are polyclonal (or multiclonal), with no single clonotypic population predominating in the population of T cells. These distributive differences in both TCR sequence and genomic rearrangement fragment sizes can be detected by molecular techniques (ie, PCR) and used to determine if a population of T cells shows monoclonal or polyclonal features.



Clinical References: 1. Liu H, Bench AJ, Bacon CM, et al: A practical strategy for the routine use of BIOMED-2 PCR assays for detection of B- and T-cell clonality in diagnostic haematopathology. Br J Haematol 2007;138(1):31-43 2. Van Krieken JH, Langerak AW, Macintyre EA, et al: Improved reliability of lymphoma diagnostics via PCR-based clonality testing: report of the BIOMED-2 Concerted Action BHM4-CT98-3936. Leukemia 2007;21(2):201-206 3. Bruggemann M, White H, Gaulard P, et al: Powerful strategy for polymerase chain reaction-based clonality assessment in T-cell malignancies Report of the BIOMED-2 Concerted Action BHM4 CT98-3936. Leukemia 2007;21(2):215-221

TCP

T-Cell Subsets, Naive, Memory and Activated

89319

Clinical Information: T cells, after completing development and initial differentiation in the thymus, enter the periphery as naive (n) T cells. Naive T cells undergo further differentiation into effector and memory T cells in the peripheral lymphoid organs after recognizing specific antigenic peptides in the context of major histocompatibility (MHC) molecules, through the antigen-specific T-cell receptor. In addition to the cognate signal of the peptide-MHC complex interaction (the term cognate refers to 2 biological molecules that normally interact), T cells require additional costimulatory signals to complete T-cell activation. Naive T cells circulate continuously through the lymph nodes and, on recognition of specific antigen, undergo activation. Due to their antigen-inexperienced state, naive T cells require activation by more potent antigen-presenting cells, such as dendritic cells. Naive T cells can survive in circulation for prolonged periods of time and are very important in contributing to T-cell repertoire diversity. They proliferate in response to interleukin-2, as a consequence of their response to antigen through recognition of peptide-MHC costimulation. These expanded antigen-specific T cells undergo further differentiation into effector cells. The differentiation of naive CD8 T cells into cytotoxic effectors capable of killing target T cells loaded with endogenous peptides on MHC class I molecules may require additional costimulatory signals from CD4 T cells. Naive CD4 T cells also differentiate into different effector subsets such as Th1, Th2, and Th17, which produce specific cytokines.(1) T cells can be subdivided into naive and memory subsets based on the expression of cell-surface markers, such as CD45RA and CD45RO, among others. It was initially thought that the presence of cell-surface CD45RA indicated the naive subset, while the presence of CD45RO indicated memory subsets. But, it has now been shown that multiple, rather than single, markers are required to distinguish these subsets.(2) Lanzavecchia and Sallusto proposed a model where naive T cells expressing CD45RA and CCR7 lose CD45RA expression on recognition of antigen.(3) The surface markers for identifying naive T-cell subsets include CD45RA, CD62L (L-selectin), and CD27.(4,5) Memory T cells are antigen-experienced cells that are present in greater numbers than antigen-specific precursors, and can respond more efficiently and rapidly to specific antigen. Memory T cells can maintain their populations independent of antigen by



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homeostatic proliferation in response to cytokines. While there are subcategories of memory T cells based on effector function and cell surface and cytolytic molecule expression, the 2 main categories of memory T cells are central memory T cells (Tcm) and effector memory T cells (Tem).(1,6) Tcm express the CD45RO molecule along with CD62L (L-selectin) and CCR7, and are present mainly in lymphoid tissue.(6,7) They are able to respond to antigen through rapid proliferation and expansion and differentiation into Tem. By themselves, Tcm are not directly effective in effector cytolytic function. Unlike Tcm, Tem express only CD45RO (not CD62L and CCR7).(6) As the name suggests, Tem have remarkable effector function, though they do not proliferate well. Tem are present throughout the circulation in peripheral tissues providing immune surveillance. Memory T cells are particularly important for maintenance of immune competence since they are associated with a rapid and effective response to pathogens. Therefore, depletion of this compartment has more immediate significance than the depletion of naive T cells. Activation of human T cells is critical for the optimal and appropriate performance of T-cell functions within the adaptive immune response. Activated naive T cells undergo proliferation, as well as subsequent differentiation into effector T cells, and are capable of producing cytokines that can modulate the immune response in a variety of ways.(8) There are several markers associated with T-cell activation, but those most commonly used include CD25 (IL-25R)(8) and MHC class II.(9) Additionally, the expression of the costimulatory molecule CD28 augments the T-cell activation response.(10) The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 am and noon, with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant throughout the day.(11) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(12-14) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(11) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening(15), and during summer compared to winter.(16) These data, therefore, indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Determining the presence of naive, memory, and activated T cells in various clinical contexts including autoimmune diseases, immunodeficiency states, T-cell recovery posthematopoietic stem cell transplant, DiGeorge syndrome, and as a measure for T-cell immune competence Naive T-cells results can be used as a surrogate marker for thymic-derived T-cell reconstitution, when used in conjunction with assessment of T-cell receptor excision circles (TREC / T-Cell Receptor Excision Circles [TREC] Analysis for Immune Reconstitution) Assessing a patient's relative risk for infections Evaluation of patients with cellular or combined primary immunodeficiencies Evaluation of T-cell reconstitution after hematopoietic stem cell transplant, chemotherapy, biological therapy, immunosuppression or immunomodulator therapy Evaluation of patients with autoimmune diseases Evaluation of HIV-positive patients for naive and memory subsets Evaluation of T-cell immune competence (presence of memory and activated T cells) in patients with recurrent infections

Interpretation: Absence or reduction of naive T cells with or without T-cell lymphopenia indicates absent or impaired T-cell reconstitution or thymic output. Reduction in activated T cells can also indicate a reduced T-cell immune competent state. Increases in naive T cells with corresponding decreases in the memory T-cell compartment indicates a failure of further differentiation and effector function or selective loss of memory T cells and an increased risk for infection.


Clinical References: 1. Bettelli E, Oukka M, Kuchroo VK: Th17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007;8:345-350 2. De Rosa SC, Herzenberg LA, Herzenberg LA, et al: 11-color, 13-parameter flow cytometry: identification of human naive T-cells by phenotype, function, and T-cell receptor diversity. Nat Med 2001;7:245-248 3. Sallusto F, Lenig D, Forster R, et al: Two subsets of memory T-lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708-712 4. Picker LJ, Treer JR, Ferguson-Darnell B, et al: Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T-cells during the virgin to memory cell transition. J Immunol 1993;150:1105-1121 5. Morimoto C, Schlossman SF: Human naive and memory T-cells revisited: new markers (CD31 and CD27) that help define CD4+ T-cell Current as of August 23, 2017 7:11 am CDT


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subsets. Clin Exp Rheumatol 1993;11:241-247 6. LaRosa DF, Orange JS: Lymphocytes. J Allergy Clin Immunol 2008;121:S364-369 7. Foster AE, Marangolo M, Sartor MM, et al: Human CD62L-memory T-cells are less responsive to alloantigen stimulation than CD62L+ naive T-cells: potential for adoptive immunotherapy and allodepletion. Blood 2004;104:2403-2409 8. Brenchley JM, Douek DC, Ambrozal DR, et al: Expansion of activated human naive T-cells preceded effector function. Clin Exp Immunol 2002;130:431-440 9. Holling TM, van der Stoep N, Quinten E, et al: Activated human T-cells accomplish MHC class II expression through T-cell specific occupation of class II transactivator promoter III. J Immunol 2002;168:763-770 10. Thompson CB, Lindsten T, Ledbetter JA, et al: CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci USA 1989;86:1333-1337 11. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 12. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 2009;113(21):5134-5143 13. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 14. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 15. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 16. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516

TREGS

T-Cell Subsets, Regulatory (Tregs)

89318

Clinical Information: Regulatory T cells (Tregs) are a population of CD4+ T cells with a unique role in the immune response. Tregs are crucial in suppressing aberrant pathological immune responses in autoimmune diseases, transplantation, and graft-vs-host disease after allogeneic hematopoietic stem cell transplantation.(1) Tregs are activated through the specific T-cell receptor, but their effector function is nonspecific and they regulate the local inflammatory response through cell-to-cell contact and cytokine secretion.(2) Tregs secrete interleukin (IL)-9 (IL-9), IL-10, and transforming growth factor-beta 1 (TGF-beta 1), which aid in the mediation of immunosuppressive activity. Chief characteristics of the Treg population are surface expression of the CD25 protein (IL-2Ra) and the intracellular presence of the transcription factor Foxp3. The IL-7 receptor (CD127) is downregulated on Foxp3+CD4+CD25+ T cells and provides an excellent alternative cell-surface marker to Foxp3 for detecting natural Tregs (CD4+CD25+CD127lo).(2) Natural Tregs account for 5% to 10% of the total CD4 T-cell population and are derived from thymic precursors.(3) Since CD25 is also expressed on activated T cells, the concomitant use of CD127 permits the differentiation of Tregs from activated T cells.(4) Natural Tregs express the memory marker CD45RO and have limited ability to proliferate. However, within the CD4+CD25+Treg population, there is a subset of Tregs that express the CD45 isoform generally associated with naive T cells (CD45RA), and this subset has been called natural naive (Nn) Tregs. Nn Tregs are most prominent in young adults and decrease with age along with the rest of the naive CD4 T-cell population.(5) Like other naive T cells, Nn Tregs have high proliferative capacity, as well as the suppressor activity of other Treg subsets. Present evidence suggests that Nn Tregs also have a thymic ancestry and are the precursors of the natural Tregs (that are of the memory, antigen-experienced phenotype) and appear to be composed of T cells with self-reactive T-cell receptors.(5) Other subsets of Tregs include the Th3 cells, which secrete high levels of TGF-beta 1 and can be induced by oral administration of antigen, and regulatory T class 1 (Tr1) cells, which secrete interferon-gamma and IL-10.(5) These Treg subsets are most likely induced in the periphery and are responsible for peripheral tolerance to self antigens. The suppressive activity of Th3 and Tr1 cells are related to the cytokines they produce, TGF-beta 1 and IL-10, respectively. The absence of Tregs as a result of mutations in the FOXP3 gene cause a primary immunodeficiency called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance).(6) Patients with IPEX have a complex manifestation of symptoms including severe watery diarrhea due to significant villous atrophy and lymphocytic infiltration of bowel mucosa, early-onset autoimmune endocrinopathies involving the pancreas or thyroid, and a dermatitic (eczematous) rash. In addition, there are other autoimmune manifestations including autoimmune cytopenias and autoimmune hepatitis. Renal disease is quite common in these patients. Finally, these patients also have a significant predisposition to infections including sepsis, pneumonia, meningitis, and osteomyelitis.(6) Decreased



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Foxp3+CD4+CD25+Tregs have been reported in 1 patient with a STAT5b mutation.(7) There is an expansion of Nn Tregs in patients with monoclonal gammopathy of undetermined significance and multiple myeloma, likely as a response to the process of malignant transformation.(8) Expansion of Tregs has also been reported in other neoplasias including B-cell chronic lymphocytic leukemia, Hodgkin disease, and solid tumors. The absolute counts of lymphocyte subsets are known to be influenced by a variety of biological factors, including hormones, the environment, and temperature. The studies on diurnal (circadian) variation in lymphocyte counts have demonstrated progressive increase in CD4 T-cell count throughout the day, while CD8 T cells and CD19+ B cells increase between 8:30 am and noon, with no change between noon and afternoon. Natural killer cell counts, on the other hand, are constant throughout the day.(9) Circadian variations in circulating T-cell counts have been shown to be negatively correlated with plasma cortisol concentration.(10-12) In fact, cortisol and catecholamine concentrations control distribution and, therefore, numbers of naive versus effector CD4 and CD8 T cells.(10) It is generally accepted that lower CD4 T-cell counts are seen in the morning compared with the evening,(13) and during summer compared to winter.(14) These data, therefore, indicate that timing and consistency in timing of blood collection is critical when serially monitoring patients for lymphocyte subsets.

Useful For: Evaluating patients with clinical features of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance) and other primary immunodeficiencies, autoimmune diseases, allergy and asthma, and graft-vs-host disease post-hematopoietic stem cell transplantation

Interpretation: The lack of regulatory T (Treg) cells is associated with mutations in the FOXP3 gene. Low Tregs are also seen in the context of STAT5b mutations. Reduced Nn Tregs and natural Tregs are likely to predispose to autoimmunity, while reductions in Th3/Tr1 cells may impair oral and peripheral tolerance, also facilitating the development of autoimmunity. The presence of expanded naive Tregs may indicate a process of malignant transformation, if other clinical features of malignant disease are present. Increased Tregs in donor stem cell allografts have been associated with a reduced incidence of graft-versus-host disease (ie, mediating a protective effect) after allogeneic stem cell transplantation.


Clinical References: 1. Sakaguchi S, Sakaguchi N, Shimizu J, et al: Immunologic tolerance maintained by CD25+CD4+ regulatory T-cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001;182:18-32 2. Liu W, Putnam A, Xu-yu Z, et al: CD127 expression inversely correlates with FOXP3 and suppressive function of human CD4+ Treg cells. J Exp Med 2006;203(7):1701-1711 3. Seddiki N, Santner-Nanan B, Tangye SG, et al: Persistence of naive CD45RA+ regulatory T-cells in adult life. Blood 2006;107:2830-2838 4. Seddiki N, Santner-Nanan B, Martinson J, et al: Expression of IL-2 and IL-7 receptors discriminates between human regulatory and activated T-cells. J Exp Med 2006;203(7):1693-1700 5. Valmori D, Merlo A, Souleimanian NE, et al: A peripheral circulating compartment of natural naive CD4+Tregs. J Clin Invest 2005;115(7):1953-1962 6. Torgerson TR, Ochs HD: IPEX: FOXP3 mutations and lack of regulatory T-cells. J Allergy Clin Immunol 2007;120:744-750 7. Cohen AC, Nadeau KC, Tu W, et al: Decreased accumulation and regulatory function of CD4+CD25 (high) T-cells in human STAT5b deficiency. J Immunol 2006;177:2770-2774 8. Beyer M, Kochanek M, Giese T, et al: In vivo peripheral expansion of naive CD4+CD25(high) FOXP3+ regulatory T-cells in patients with multiple myeloma. Blood 2006;107:3940-3949 9. Carmichael KF, Abayomi A: Analysis of diurnal variation of lymphocyte subsets in healthy subjects and its implication in HIV monitoring and treatment. 15th Intl Conference on AIDS, Bangkok, Thailand, 2004, Abstract B11052 10. Dimitrov S, Benedict C, Heutling D, et al: Cortisol and epinephrine control opposing circadian rhythms in T-cell subsets. Blood 2009;113(21):5134-5143 11. Dimitrov S, Lange T, Nohroudi K, Born J: Number and function of circulating antigen presenting cells regulated by sleep. Sleep 2007;30:401-411 12. Kronfol Z, Nair M, Zhang Q, et al: Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosom Med 1997;59:42-50 13. Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from HIV 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 1990;3:144-151 14. Paglieroni TG, Holland PV: Circannual variation in lymphocyte subsets, revisited. Transfusion 1994;34:512-516



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FRT3

T3 (Triiodothyronine), Free, Serum

9404

Clinical Information: Normally triiodothyronine (T3) circulates tightly bound to thyroxine-binding globulin and albumin. Only 0.3% of the total T3 is unbound (free); the free fraction is the active form. In hyperthyroidism, both thyroxine (tetraiodothyronine; thyroxine: T4) and T3 levels (total and free) are usually elevated, but in a small subset of hyperthyroid patients (T3 toxicosis) only T3 is elevated. Generally, free T3 (FT3) measurement is not necessary since total T3 will suffice. However, FT3 levels may be required to evaluate clinically euthyroid patients who have an altered distribution of binding proteins (eg, pregnancy, dysalbuminemia). Some investigators recommend the FT3 assay for monitoring thyroid replacement therapy, although its clinical role is not precisely defined.

Useful For: Free triiodothyronine (T3) is a second- or third-level test of thyroid function; it provides further confirmation of hyperthyroidism, supplementing the tetraiodothyronine (T4), sensitive thyrotropin (sTSH), and total T3 assays Evaluating clinically euthyroid patients who have an altered distribution of binding proteins Monitoring thyroid hormone replacement therapy

Interpretation: Elevated free triiodothyronine (FT3) values are associated with thyrotoxicosis or excess thyroid hormone replacement.

Reference Values: > or =1 year: 2.8-4.4 pg/mL

Clinical References: 1. Demers LM, Spencer Cl: The thyroid: pathophysiology and thyroid function testing. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Fourth edition. Edited by CA Burtis, ER Ashwood, DE Bruns. St. Louis, Elsevier Saunders Company. 2006, pp 2053-2087 2. FT3 Validation 2005 and AIA Retrospective Validation V-139, 2009. Unpublished data

RT3

T3 (Triiodothyronine), Reverse, Serum

9405

Clinical Information: Reverse triiodothyronine (rT3) differs from triiodothyronine (T3) in the positions of the iodine atoms attached to the aromatic rings. The majority of rT3 found in the circulation is formed by peripheral deiodination (removal of an iodine atom) of T4 (thyroxine). rT3 is believed to be metabolically inactive. The rT3 level tends to follow the T4 level: low in hypothyroidism and high in hyperthyroidism. Additionally, increased levels of rT3 have been observed in starvation, anorexia nervosa, severe trauma and hemorrhagic shock, hepatic dysfunction, postoperative states, severe infection, and in burn patients (ie, "sick euthyroid" syndrome). This appears to be the result of a switchover in deiodination functions with the conversion of T4 to rT3 being favored over the production of T3.

Useful For: An aid in the diagnosis of the "sick euthyroid" syndrome Interpretation: In hospitalized or sick patients with low triiodothyronine (T3) values, elevated reverse triiodothyronine (rT3) values are consistent with "sick euthyroid" syndrome. Also, the finding on an elevated rT3 level in a critically ill patient helps exclude a diagnosis of hypothyroidism. The rT3 is high in patients on medications such as propylthiouracil, ipodate, propranolol, amiodarone, dexamethasone, and the anesthetic agent halothane. Dilantin decreases rT3 due to the displacement from thyroxine-binding globulin, which causes increased rT3 clearance. To convert from ng/dL to nmol/L, multiply the ng/dL result by 0.01536.

Reference Values: 10-24 ng/dL

Clinical References: Moore WT, Eastman RC: Diagnostic Endocrinology. St. Louis, Mosby, 1990, pp.182-183

T3

T3 (Triiodothyronine), Total, Serum

8613

Clinical Information: Thyroid hormones regulate a number of developmental, metabolic, and neural



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activities throughout the body. The thyroid gland synthesizes 2 hormones. The 2 main hormones secreted by the thyroid gland are thyroxine, which contains 4 atoms of iodine (T4), and triiodothyronine (T3). T3 production in the thyroid gland constitutes approximately 20% of the total T3; the rest is generated by the conversion (deiodination) of T4 to T3 is also produced by conversion (deiodination) of T4 in peripheral tissues. Circulating levels of T4 are much greater than T3 levels, but T3 is biologically the most metabolically active hormone (3-4 times more potent than T4) although its effect is briefer due to its shorter half-life compared to T4. Thyroid hormones circulate primarily bound to carrier proteins (eg, thyroid-binding globulin: TBG, prealbumin, and albumin); whereas only a small fraction circulates unbound (free). Only the free forms are metabolically active. While both T3 and T4 are bound to TBG, T3 is bound less firmly than T4. Total T3 consists of both the bound and unbound fractions. In hyperthyroidism, both T4 and T3 levels are usually elevated, but in a small subset of hyperthyroid patients only T3 is elevated (T3 toxicosis). In hypothyroidism T4 and T3 levels are decreased. T3 levels are frequently low in sick or hospitalized euthyroid patients. See Thyroid Function Ordering Algorithm in Special Instructions.

Useful For: Second-order testing for hyperthyroidism in patients with low thyroid-stimulating hormone values and normal thyroxine levels Diagnosis of triiodothyronine toxicosis

Interpretation: Triiodothyronine (T3) values >200 ng/dL in adults or > age related cutoffs in children are consistent with hyperthyroidism or increased thyroid hormone-binding proteins. Abnormal levels (high or low) of thyroid hormone-binding proteins (primarily albumin and thyroid-binding globulin) may cause abnormal T3 concentrations in euthyroid patients.

Reference Values: Adult (> or =20 years): 80-200 ng/dL Pediatric: 0-5 days: 73-288 ng/dL 6 days-2 months: 80-275 ng/dL 3-11 months: 86-265 ng/dL 1-5 years: 92-248 ng/dL 6-10 years: 93-231 ng/dL 11-19 years: 91-218 ng/dL

Clinical References: 1. Hay ID, Klee GG: Linking medical needs and performance goals: clinical and laboratory perspectives on thyroid disease. Clin Chem 1993;39:1519-1524 2. Klee GG: Clinical usage recommendations and analytic performance goals for total and free triiodothyronine measurements. Clin Chem 1996;42:155-159

FRT4D

T4 (Thyroxine), Free by Dialysis, Serum

8859

Clinical Information: Thyroxine (T4) and triiodothyronine (T3) are the 2 biologically active thyroid hormones. T4 makes up more than 80% of circulating thyroid hormones. Following secretion by the thyroid gland, approximately 70% of circulating T4 and T3 are bound to thyroid-binding globulin (TBG), while 10% to 20% each are bound to transthyretin (TTR) and albumin, respectively. Less than 0.1% circulates as free T4 (FT4) or free T3 (FT3). FT4 and FT3 enter and leave cells freely by diffusion. Only the free hormones are biologically active, but bound and free fractions are in equilibrium. Equilibrium with TTR and albumin is rapid. By contrast, TBG binds thyroid hormones very tightly and equilibrium dissociation is slow. Biologically, TBG-bound thyroid hormone serves as a hormone reservoir and T4 serves as a prohormone for T3. Within cells, T4 is either converted to T3, which is about 5 times as potent as T4, or reverse T3, which is biologically inactive. Ultimately, T3, and to a much lesser degree T4, bind to the nuclear thyroid hormone receptor, altering gene expression patterns in a tissue-specific fashion. Under normal physiologic conditions, FT4 and FT3 exert direct and indirect negative feedback on pituitary thyrotropin (thyroid-stimulating hormone: TSH) levels, the major hormone regulating thyroid gland activity. This results in tight regulation of thyroid hormone production and constant levels of FT4 and FT3 independent of the binding protein concentration. Measurement of FT4 and FT3, in conjunction with TSH measurement, therefore represents the best method to determine thyroid function status. It also allows determination of whether hyperthyroidism (increased FT4) or hypothyroidism (low FT4) are primary (the majority of cases, TSH altered in the opposite direction as FT4) or secondary/tertiary



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(hypothalamic/pituitary origin, TSH altered in the same direction as FT4). By contrast, total T4 and T3 levels can vary widely as a response to changes in binding protein levels, without any change in free thyroid hormone levels and, hence, actual thyroid function status. FT4 is usually measured by automated analog immunoassays. In most instances, this will result in accurate results. However, abnormal types or quantities of binding proteins found in some patients and most often related to other illnesses or drug treatments, may interfere in the accurate measurement of FT4 by analog immunoassays. These problems can be overcome by measuring FT4 by equilibrium dialysis, free from interfering proteins.

Useful For: Determining thyroid status of sick, hospitalized patients Used where abnormal binding proteins are known to exist Possibly useful in pediatric patients

Interpretation: All free hormone assays should be combined with thyroid-stimulating hormone measurements. Free thyroxine (FT4) 2.0 ng/dL indicates possible hyperthyroidism. Neonates can have significantly higher FT4 levels. The hypothalamic-pituitary-thyroid axis can take several days or, sometimes, weeks to mature.

Reference Values: 0.8-2.0 ng/dL Reference values apply to all ages.

Clinical References: 1. De Brabandere VI, Hou P, Stockl D, et al: Isotope dilution-liquid chromatography/electrospray ionization-tandem mass spectrometry for the determination of serum thyroxine as a potential reference method. Rapid Commun Mass Spectrom 1998;12:1099-1103 2. Jain R, Uy HL: Increase in serum free thyroxine levels related to intravenous heparin treatment. Ann Intern Med 1996 Jan 1;124:74-75 3. Stockigt JR: Free thyroid hormone measurement. A critical appraisal. Clin Endocrinol Metab 2001 Jun;30:265-289

FRT4

T4 (Thyroxine), Free, Serum

8725

Clinical Information: Free thyroxine (FT4) comprises a small fraction of total thyroxine. The FT4 is available to the tissues and is, therefore, the metabolically active fraction. Elevations in FT4 cause hyperthyroidism, while decreases cause hypothyroidism.

Useful For: Evaluation of suspected thyroid function disorders using free thyroxine measured together with thyroid-stimulating hormone

Interpretation: Elevated values suggest hyperthyroidism or exogenous thyroxine. Decreased values suggest hypothyroidism. Free thyroxine (FT4) works well to correct total T4 values for thyroxine-binding globulin alterations, but may give misleading values when abnormal binding proteins are present or the patient has other major illnesses (euthyroid sick syndrome).

Reference Values: Adult (> or =20 years): 0.9-1.7 ng/dL Pediatric: 0-5 days: 0.9-2.5 ng/dL 6 days-2 months: 0.9-2.2 ng/dL 3-11 months: 0.9-2.0 ng/dL 1-5 years: 1.0-1.8 ng/dL 6-10 years: 1.0-1.7 ng/dL 11-19 years: 1.0-1.6 ng/dL

Clinical References: Melmed S, Polonsky KS, Larsen PR, et al: Williams Textbook of Endocrinology. 12th edition. Elsevier Saunders Company, 2011, pp 348-414

T4FT4

T4 (Thyroxine), Total and Free

36108

Clinical Information: THYROXINE (T4), TOTAL: T4 is synthesized in the thyroid gland. T4 is metabolized to T3 peripherally by deiodination. T4 is considered a reservoir or prohormone for T3, the



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biologically most active thyroid hormone. About 0.05% of circulating T4 is in the free or unbound portion. The remainder is bound to thyroxine-binding globulin (TBG), prealbumin, and albumin. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the pituitary to release thyroid-stimulating hormone (TSH). TSH stimulates the thyroid to secrete T4. T4 is partially converted peripherally to triidothyronine (T3). High amounts of T4 and T3 (mostly from peripheral conversion of T4) cause hyperthyroidism. T4 and T3 cause positive feedback to the pituitary and hypothalamus with resultant suppression or stimulation of the thyroid gland as follows: decrease of TSH if T3 or T4 is high (hyperthyroidism), and increase of TSH if T3 or T4 is low (hypothyroidism). Measurement of total T4 gives a reliable reflection of clinical thyroid status in the absence of protein binding abnormalities. However, changes in binding proteins can occur which affect the level of total T4 but leave the level of unbound hormone unchanged. THYROXINE (T4), FREE: Free thyroxine comprises a small fraction of total thyroxine. The free T4 (FT4) is available to the tissues and is, therefore, the metabolically active fraction. Elevations in FT4 cause hyperthyroidism, while decreases cause hypothyroidism.

Useful For: Thyroxine (T4) and free T4 are measured together with thyroid-stimulating hormone when thyroid function disorders are suspected.

Reference Values: T4 (THYROXINE), TOTAL ONLY Adult (> or =20 years): 4.5-11.7 mcg/dL Pediatric: 0-5 days: 5.0-18.5 mcg/dL 6 days-2 months: 5.4-17.0 mcg/dL 3 -11 months: 5.7-16.0 mcg/dL 1 -5 years: 6.0-14.7 mcg/dL 6 -10 years: 6.0-13.8 mcg/dL 11 -19 years: 5.9-13.2 mcg/dL T4 (THYROXINE), FREE Adult (> or =20 years of age): 0.9-1.7 ng/dL 0-5 days: 0.9-2.5 ng/dL 6 days-2 months: 0.9-2.2 ng/dL 3-11 months: 0.9-2.0 ng/dL 1-5 years: 1.0-1.8 ng/dL 6-10 years: 1.0-1.7 ng/dL 11-19 years: 1.0-1.6 ng/dL

Clinical References: Melmed S, Polonsky KS, Larsen PR, et al: Williams textbook of Endocrinology. 12th edition. Elsevier Saunders Company, 2011, pp 348-414

T4

T4 (Thyroxine), Total Only, Serum

8724

Clinical Information: Thyroxine (T4) is synthesized in the thyroid gland. T4 is metabolized to triiodothyronine (T3) peripherally by deiodination. T4 is considered a reservoir or prohormone for T3, the biologically most active thyroid hormone. About 0.05% of circulating T4 is in the free or unbound portion. The remainder is bound to thyroxine-binding globulin (TBG), prealbumin, and albumin. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the pituitary to release thyroid-stimulating hormone (TSH). TSH stimulates the thyroid to secrete T4. T4 is partially converted peripherally to T3. High amounts of T4 and T3 (mostly from peripheral conversion of T4) cause hyperthyroidism. T4 and T3 cause positive feedback to the pituitary and hypothalamus with resultant suppression or stimulation of the thyroid gland as follows: decrease of TSH if T3 or T4 is high (hyperthyroidism), and increase of TSH if T3 or T4 is low (hypothyroidism). Measurement of total T4 gives a reliable reflection of clinical thyroid status in the absence of protein-binding abnormalities and nonthyroidal illness. However, changes in binding proteins can occur that affect the level of total T4, but leave the level of unbound hormone unchanged. See Thyroid Function Ordering Algorithm in Special Instructions.

Useful For: Monitoring treatment with synthetic hormones (synthetic triiodothyronine will cause a low Current as of August 23, 2017 7:11 am CDT


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total thyroxine: T4) Monitoring treatment of hyperthyroidism with thiouracil and other antithyroid drugs

Interpretation: Values of more than 11.7 mcg/dL in adults or more than the age-related cutoffs in children are seen in hyperthyroidism and patients with acute thyroiditis. Values below 4.5 mcg/dL in adults or below the age-related cutoffs in children are seen in hypothyroidism, myxedema, cretinism, chronic thyroiditis, and occasionally, subacute thyroiditis. Increased total thyroxine (T4) is seen in pregnancy and patients who are on estrogen medication. These patients have increased total T4 levels (increased thyroxine-binding globulin: TBG levels). Decreased total T4 is seen in patients on treatment with anabolic steroids, or nephrosis (decreased TBG levels). A thyrotropin-releasing hormone stimulation test may be required for certain cases of hyperthyroidism. Clinical findings are necessary to determine if thyroid-stimulating hormone, TBG, or free T4 testing is needed.

Reference Values: Adult (> or =20 years): 4.5-11.7 mcg/dL Pediatric: 0-5 days: 5.0-18.5 mcg/dL 6 days-2 months: 5.4-17.0 mcg/dL 3-11 months: 5.7-16.0 mcg/dL 1-5 years: 6.0-14.7 mcg/dL 6-10 years: 6.0-13.8 mcg/dL 11-19 years: 5.9-13.2 mcg/dL

Clinical References: Wilson JD, Foster DW, Kronenburg MD, et al: In Williams Textbook of Endocrinology. Ninth edition. WB Saunders Company, 1998

TAKRO

Tacrolimus, Blood

35145

Clinical Information: Tacrolimus is a macrolide antibiotic derived from the fungus Streptomyces tsukubaensis. Like cyclosporine, tacrolimus inhibits calcineurin to suppress T cells. Tacrolimus is metabolized by CYP3A4, thus its concentrations are affected by drugs that inhibit (calcium channel blockers, antifungal agents, some antibiotics, grapefruit juice) or induce (anticonvulsants, rifampin) this enzyme. Tacrolimus has a narrow therapeutic range, and adverse effects are common, particularly at high dose and concentrations, making therapeutic drug monitoring essential. Since 90% of tacrolimus is in the cellular components of blood, especially erythrocytes, whole blood is the preferred specimen for analysis of trough concentrations. Target steady-state concentrations vary depending on clinical protocol, the presence or risk of rejection, time from transplant, type of allograft, concomitant immunosuppression, and side effects (mainly nephrotoxicity). Optimal trough blood concentrations are generally between 5.0 and 15.0 ng/mL. Higher levels are often sought immediately after transplant, but as organ function stabilizes at about 4 weeks from transplant, doses are generally reduced in stable patients for most solid organ transplants. Trough concentrations should be maintained below 20 ng/mL.

Useful For: Monitoring whole blood tacrolimus concentration during therapy, particularly in individuals coadministered CYP3A4 substrates, inhibitors, or inducers Adjusting dose to optimize immunosuppression while minimizing toxicity Evaluating patient compliance

Interpretation: Most individuals display optimal response to tacrolimus with trough whole blood levels of 5.0 to 15.0 ng/mL. Preferred therapeutic ranges may vary by transplant type, protocol, and comedications. Therapeutic ranges are based on samples drawn at trough (ie, immediately before a scheduled dose). Blood drawn at other times will yield higher results. The assay is specific for tacrolimus; it does not cross-react with cyclosporine, cyclosporine metabolites, sirolimus, sirolimus metabolites, or tacrolimus metabolites. Results by liquid chromatography with detection by tandem mass spectrometry are approximately 30% less than by immunoassay.

Reference Values: 5.0-15.0 ng/mL (Trough) Target steady-state trough concentrations vary depending on the type of transplant, concomitant immunosuppression, clinical/institutional protocols, and time post-transplant. Results should be Current as of August 23, 2017 7:11 am CDT


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interpreted in conjunction with this clinical information and any physical signs/symptoms of rejection/toxicity.

Clinical References: 1. Kahan BD, Keown P, Levy GA, et al: Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002 March;24(3):330-350 2. Scott LJ, McKeage K, Keam SJ, et al: Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003;63(12):1247-1297

TACPK

Tacrolimus, Peak, Blood

88157

Clinical Information: Tacrolimus (Prograf) is a macrolide antibiotic derived from the fungus Streptomyces tsukubaenesis. Like cyclosporine, tacrolimus inhibits calcineurin to suppress T cells. Tacrolimus is metabolized by CYP3A4; thus, its concentration is affected by drugs that inhibit (calcium channel blockers, antifungal agents, some antibiotics, grapefruit juice) or induce (anticonvulsants, rifampin) this enzyme. Tacrolimus has a narrow therapeutic range and adverse effects are common, particularly at high dose and concentrations, making therapeutic drug monitoring essential. Since 90% of tacrolimus is in the cellular components of blood, especially erythrocytes, whole blood is the preferred specimen for analysis of trough concentrations. Target steady-state concentrations vary depending on clinical protocol, the presence or risk of rejection, time from transplant, type of allograft, concomitant immunosuppression, and side effects (mainly nephrotoxicity). Optimal trough blood concentrations are generally between 5.0 and 15.0 ng/mL. Higher levels are often sought immediately after transplant, but as organ function stabilizes at about 4 weeks from transplant, doses are generally reduced in solid organ transplant patients who are stable. Trough concentrations should be maintained below 20 ng/mL. Optimal postdose sampling strategies and blood concentrations have not been well established for tacrolimus. A study of 54 liver transplant patients suggested that most individuals have tacrolimus blood concentrations ranging between 5.0 and 30.0 ng/mL in samples drawn 1 to 4 hours after dosing, although some patients showed slightly higher blood concentrations at 1-hour postdose.

Useful For: Assessment of postdosing (peak) blood tacrolimus concentrations Interpretation: This test measures postdose levels of tacrolimus. Established reference ranges reflect trough measurement, and are not applicable to samples drawn after dosing. No reference ranges or standard sampling protocols have been established for postdosing tacrolimus levels, but a limited study of liver transplant recipients suggests most patients will show postdose tacrolimus levels ranging from 5.0 to 30.0 ng/mL when drawn 1 to 4 hours after dosing. The narrow therapeutic window and high individual pharmacokinetic variability of tacrolimus make regulation of dose by blood concentrations essential. Since 90% of the drug is in the cellular components of blood, especially erythrocytes, whole blood, rather than plasma, concentrations are measured and correlate better with efficacy and toxicity. This assay is specific for tacrolimus; it does not cross-react with cyclosporine, cyclosporine metabolites, sirolimus, sirolimus metabolites, or tacrolimus metabolites. Results by liquid chromatography with detection by tandem mass spectrometry (LC-MS/MS) are approximately 30% less than by immunoassay.

Reference Values: 5.0-30.0 ng/mL Target steady-state trough concentrations vary depending on the type of transplant, concomitant immunosuppression, clinical/institutional protocols, and time posttransplant. Results should be interpreted in conjunction with this clinical information and any physical signs or symptoms of rejection or toxicity.

Clinical References: 1. Kahan BD, Keown P, Levy GA, et al: Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002 March;24(3):330-350 2. Scott LJ, McKeage K, Keam SJ, et al: Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003;63(12):1247-1297

TAPEN

Tapentadol and Metabolite, Random Urine

62594

Clinical Information: Tapentadol, a centrally acting opioid analgesic, is used in the treatment of



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moderate to severe acute and chronic pain and for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults (extended release formulation only). Tapentadol acts as an opiate agonist through its binding to mu-opioid receptors and through the inhibition of norepinephrine reuptake. About 97% of the parent drug is metabolized. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. Tapentadol and its metabolites (N-desmethyltapentadol and hydroxyl-tapentadol) are excreted almost exclusively via the kidneys and approximately 70% of the drug is excreted in urine in the conjugated form. The metabolites of tapentadol have no analgesic activity. The half-life of tapentadol is approximately 4 hours. Opioid analgesics have high abuse potential and the regular use of tapentadol may result in physical dependence and tolerance. Tapentadol is a schedule II controlled substance with abuse liability similar to other opioid agonists.

Useful For: Monitoring of compliance utilizing tapentadol Detection and confirmation of the illicit use of tapentadol

Interpretation: The presence of tapentadol or N-desmethyltapentadol levels of 25 ng/mL or higher is a strong indicator that the patient has used tapentadol.

Reference Values: Cutoff: 25 ng/mL Note: Tapentadol concentrations will be reported quantitatively and N-desmethyltapentadol will be reported qualitatively (Present or Negative).

Clinical References: 1. Wade WE, Spruill WJ: Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther 2009;31(12):2804-2818 2. Tzschentke TM, Christoph T, Kogel B et al: (-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCL): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 2007;323:265-276

FIOCA

Tapioca IgE

57944


Reference Values: 200 ng/dL. Monitoring of testosterone replacement therapy: The efficacy of testosterone replacement in females is under study. If it is used, then levels should be kept within the normal female range at all times. Bioavailable (TTBS / Testosterone, Total and Bioavailable, Serum) or free testosterone (TGRP / Testosterone, Total and Free, Serum) levels should also be monitored to avoid overtreatment. Monitoring of antiandrogen therapy: Antiandrogen therapy is most commonly employed in the management of mild-to-moderate idiopathic female hyperandrogenism, as seen in polycystic ovarian syndrome. Total testosterone levels are a relatively crude guideline for therapy and can be misleading. Therefore, bioavailable (TTBS / Testosterone, Total and Bioavailable, Serum) or free testosterone (TGRP / Testosterone, Total and Free, Serum) also should be monitored to ensure treatment adequacy. However, there are no universally agreed biochemical end points and the primary treatment end point is the clinical response. See Steroid Pathways in Special Instructions.

Reference Values: Males 0-5 months: 75-400 ng/dL 6 months-9 years: or =100 Strongly positive Reference values apply to all ages.


FFTEN

Tetrahydrobiopterin and Neopterin Profile (BH4, N)

57102

Reference Values: Tetrahydrobiopterin/Neopterin Profile Age (years) 0 â€“ 0.2 0.2 â€“ 0.5 0.5 â€“ 2.0 2.0 â€“ 5.0 5.0 â€“ 10 10 â€“ 15 Adults

BH4 (nmol/L) 40 â€“ 105 23 â€“ 98 18 â€“ 58 18 â€“ 50 9 â€“ 40 9 â€“ 32 10 â€“ 30

Neop (nmol/L) 7â€“ 65 7 â€“ 65 7 â€“ 65 7 â€“ 65 7 â€“ 40 8 â€“ 33 8 â€“ 28

Note: If test results are inconsistent with the clinical presentation, please call our laboratory to discuss the case and/or submit a second sample for confirmatory testing. An important consideration for false positive or false negative results is the improper labeling of the patient sample.

THEVP

Thalassemia and Hemoglobinopathy Evaluation

84158

Clinical Information: The thalassemias are a group of autosomal recessive disorders of hemoglobin (Hb) synthesis. Normal adult Hb consists of 2 alpha globin chains (encoded by 2 pairs of alpha globin



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genes, each pair located on 1 of the chromosomes 16), and 2 beta globin chains (encoded by 2 beta globin genes, each located on 1 of the chromosomes 11). Thalassemia syndromes result from an underproduction of 1 or 2 types of globin chains and are characterized by the type (alpha, beta, delta) and magnitude of underproduction (number of defective genes) and the severity of clinical symptoms (minor, major). The severity of the clinical and hematologic effects is directly related to the number of genes deleted or affected. The most common form of thalassemia is heterozygous alpha thalassemia 2, with 1 affected alpha globin gene. In heterozygous alpha thalassemia 2, there is no clinical effect and the blood count, including the mean cell volume, is normal. Heterozygous alpha thalassemia 1 and homozygous alpha thalassemia 2 (both with 2 affected genes) have the typical thalassemic picture (eg, hypochromic microcytic anemia, pallor, fatigue, shortness of breath, jaundice, and splenomegaly). Hemoglobin H (Hb H) disease, having a deletion of 3 alpha chains, is a moderate-to-severe hemolytic disease. The severity of Hb H disease is related to the amount of Hb H in the red cells. The morphology of the red cells is often very bizarre due to denatured Hb found within the red cells. The deletion of all 4 alpha chains is incompatible with life. Affected fetuses are hydropic and die in utero or shortly after premature birth. The blood smears show large hypochromic red cells, nucleated red cells, target cells, and red cell fragments. Hb Barts, Hb H, and Hb Portland are present in significant quantities. It is the most common cause of hydrops fetalis in Southeast Asia and southern China. This consultative study tests for the detection of alpha-thalassemias, beta-thalassemias, delta-beta-thalassemia, and for Hb variants that are commonly accompanied by thalassemias: Hb H, Hb Lepore, Hb Barts, unstable Hb, hemolytic anemias, Hb E, hereditary persistence of high fetal Hb (several varieties), and combinations of Hb S with alpha- or beta-thalassemia, Hb E/beta-O-thalassemia, and many other complex thalassemic disorders. Some of the alpha-thalassemias (eg, Hb H disease) can be reliably identified by Hb electrophoresis alone; some require DNA probe studies. Since iron deficiency can mimic thalassemias, ferritin levels are measured to evaluate this possibility.

Useful For: Diagnosis of thalassemia Interpretation: A hematopathologist expert in these disorders evaluates the case, appropriate tests are performed, and an interpretive report is issued.

Reference Values: Definitive results and an interpretive report will be provided.

Clinical References: Hoyer JD, Hoffman DR: The thalassemia and hemoglobinopathy syndromes. In Clinical Laboratory Medicine. Second edition. Edited by KD McMlatchey. Philadelphia, Lippencott Williams and Wilkins, 2002, pp 866-892

TLU

Thallium, 24 Hour, Urine

8603

Clinical Information: Thallium is found in some depilatories and rodenticides. Accidental ingestion may lead to vomiting, diarrhea, and leg pains followed by a severe and sometimes fatal sensorimotor polyneuropathy and renal failure. Alopecia (hair loss) may occur 3 weeks after poisoning. The fatal dose is approximately 1 g.

Useful For: Detecting toxic thallium exposure Interpretation: Normal daily output is 10 mcg/day. The long-term consequences of such an exposure are poor.

Reference Values: 0-1 mcg/specimen Reference values apply to all ages.

Clinical References: 1. Bank WJ, Pleasure DE, Suzuki K, et al: Thallium poisoning. Arch Neurol 1972;26:456-464 2. Pelclova D, Urban P, Ridson P, et al: Two-year follow-up of two patients after severe thallium intoxication. Hum Exp Toxicol. 2009 May;28(5):263-272 3. Zhao G, Ding M, Zhang B, et al: Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008;60(6):292-297



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TLB

Thallium, Blood

8149

Clinical Information: Thallium is a by-product of lead smelting. The clinical interest in thallium derives primarily from its use as a rodenticide since this is the most frequent route of human exposure. Thallium is rapidly absorbed via ingestion, inhalation, skin contact, and through the mucous membranes of the mouth, gastrointestinal tract, and lungs. It is considered to be as toxic as lead and mercury, with similar sites of action. The mechanism of action of thallium is: -Competition with potassium at cell receptors to affect ion pumps -Inhibition of DNA synthesis -Binds to sulfhydryl groups on proteins in neural axons -Concentrates in renal tubular cells and reacts with protein to cause necrosis Patients exposed to high doses of thallium (>1 g) present with alopecia (hair loss), peripheral neuropathy and seizures, and renal failure.

Useful For: Detecting toxic thallium exposure Interpretation: Normal blood concentrations are 10 ng/mL, and blood concentrations as high as 50 ng/mL. The long-term sequelae from such an exposure is poor.

Reference Values: 0-1 ng/mL Reference values apply to all ages.

Clinical References: 1. Pelcloval D, Urbanl, P, Ridsonl P, et al: Two-year follow-up of two patients after severe thallium intoxication. Hum Exper Toxicol 2009;28:263-272 2. Zhao G, Ding M, Zhang B, et al: Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008;60:292-297

TLRU

Thallium, Random, Urine

60324

Clinical Information: Thallium is found in some depilatories and rodenticides. Accidental ingestion may lead to vomiting, diarrhea, and leg pains followed by a severe and sometimes fatal sensorimotor polyneuropathy and renal failure. Alopecia (hair loss) may occur 3 weeks after poisoning. The fatal dose is approximately 1 g.

Useful For: Detecting toxic thallium exposure Interpretation: Normal daily output is 10 mcg/day. The long-term consequences of such an exposure are poor.

Reference Values: 0-1 mcg/L Reference values apply to all ages.

Clinical References: 1. Bank WJ, Pleasure DE, Suzuki K, et al: Thallium poisoning. Arch Neurol 1972;26:456-464 2. Pelclova D, Urban P, Ridson P, et al: Two-year follow-up of two patients after severe thallium intoxication. Hum Exp Toxicol. 2009 May;28(5):263-272 3. Zhao G, Ding M, Zhang B, et al: Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008;60(6):292-297

TLCRU

Thallium/Creatinine Ratio, Random, Urine

60325

Clinical Information: Thallium is found in some depilatories and rodenticides. Accidental ingestion may lead to vomiting, diarrhea, and leg pains followed by a severe and sometimes fatal sensorimotor polyneuropathy. Alopecia (hair loss) may occur 3 weeks after poisoning. The fatal dose is approximately 1 gram.

Useful For: Detecting toxic thallium exposure Interpretation: Patients exposed to high doses of thallium (>1 g) present with alopecia, peripheral neuropathy and seizures, and renal failure. Normal daily output is 10 mcg/day. The long-term consequences of such an exposure are poor. Current as of August 23, 2017 7:11 am CDT


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Reference Values: 0-1 mcg/g Creatinine Reference values apply to all ages.

Clinical References: 1. Bank WJ, Pleasure DE, Suzuki K, et al: Thallium poisoning. Arch Neurol 1972;26:456-464 2. Pelclova D, Urban P, Ridson P, et al: Two-year follow-up of two patients after severe thallium intoxication. Hum Exp Toxicol 2009 May;28(5):263-272 3. Zhao G, Ding M, Zhang B, et al: Clinical manifestations and management of acute thallium poisoning. Eur Neurol 2008;60(6):292-297

FFTCC

THC Confirmation, MS, SP

75149

Interpretation: Assay threshold: 1.0 ng/mL Reference Values: Negative Units: ng/mL Test Performed by:

Medtox Laboratories, Inc. 402 W. County Road D St. Paul, MN 55112

THEOA

Theophylline, Serum

37062

Clinical Information: Theophylline and its congener, aminophylline, are used to relax smooth muscles of the bronchial airways and pulmonary blood vessels to relieve and prevent symptoms of asthma and bronchospasm. Theophylline is administered orally at a dose of 400 mg/day or 6 mg/kg, whichever is lower, or intravenously as aminophylline at 0.6 mg/kg/hour. Oral dosage may be increased at 200-mg increments to a maximum of 900 mg/day, or 13 mg/kg if the steady-state blood concentration is within the therapeutic range of 8.0 to 20.0 mcg/mL. Theophylline has a half-life of 4 hours in children and adult smokers, and 7 hours in nonsmoking adults, thus steady-state is reached in approximately 1 day. The volume of distribution is 0.5 L/kg, and the drug is approximately 50% protein bound. Theophylline exhibits zero-order clearance kinetics like phenytoin, small increases in dose yield disproportionately large increases in blood concentration. Coadministration of cimetidine and erythromycin will significantly inhibit theophylline clearance, requiring dosage reduction. Other drugs such as allopurinol, ciprofloxacin, oral contraceptives, and propranolol inhibit theophylline clearance to a lesser degree. Smoking induces the synthesis of cytochrome P448, the antipyrine-dependent cytochrome, which significantly increases the rate of metabolism of theophylline. Drugs such as phenobarbital, phenytoin, carbamazepine, and rifampin slightly increase the rate at which the drug is cleared. Theophylline exhibits rather severe toxicity that is proportional to blood level.

Useful For: Assessing and adjusting dosage for optimal therapeutic level Assessing toxicity Interpretation: Response to theophylline is directly proportional to serum level. Patients usually receive the best response when the serum level is above 8.0 mcg/mL, with minimal toxicity experienced as long as the level is less than or equal to 20.0 mcg/mL.

Reference Values: Therapeutic: Bronchodilation: 8.0-20.0 mcg/mL Neonatal apnea (< or =4 weeks old): 6.0-13.0 mcg/mL Critical value: >20.0 mcg/mL

Clinical References: 1. Pesce AJ, Rashkin M, Kotagal U: Standards of laboratory practice: theophylline and caffeine monitoring. Clin Chem 1998 May;44(5):1124-1128 2. McCudden CR, Broussard LA: Caffeine, lithium and theophylline. In Therapeutic Drug Monitoring Data: A Concise Guide. Third edition. Edited by CA Hammett-Stabler, A Dasgupta, AACC Press, 2007 3. Vassallo R, Current as of August 23, 2017 7:11 am CDT


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Lipsky JJ: Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. Mayo Clin Proc 1998;73:346-354

TAE

Therapeutic Antibody by Flow Cytometry

82977

Clinical Information: Monoclonal antibodies are critical tools for detecting cellular antigens in various hematologic diseases and are used to provide critical diagnostic information. Monoclonal antibodies are also used as therapeutic agents in a variety of hematologic diseases. For example: -Anti-CD20 (Rituxan): B-cell malignant lymphomas and multiple myeloma -Anti-CD52 (Campath-1H): B-cell chronic lymphocytic leukemia and T-cell disorders -Anti-CD49d: estimates prognosis for B-cell chronic lymphocytic leukemia patients This list will undoubtedly expand over time to include other antibodies. It may be necessary to document expression of these markers by the malignant cells prior to initiating the respective monoclonal antibody therapy. Expression of these markers may also be required for follow-up to monitor the impact of treatment on residual normal counterparts (eg, CD20-positive lymphocytes in patients treated with anti-CD20). The distribution of these cellular antigens is well established in normal, reactive, and in various malignant disorders. The laboratory has several years of experience with therapeutic antibody monitoring of Mayo Clinic patients as part of the routine B-cell, T-cell, or acute immunophenotyping panels. For the most appropriate interpretation, the requesting physician must provide the laboratory with: -The therapeutic monoclonal antibody being used or considered -The pertinent hematologic diseases that have been diagnosed or considered -Any pertinent protocol requirements

Useful For: Detecting cell-surface antigens on malignant cells that are potential therapeutic antibody targets Determining the eligibility of patients for monoclonal antibody therapies Monitoring response to the therapeutic antibody

Interpretation: The immunophenotyping report will summarize the pattern of antigenic expression on malignant cells and, if appropriate, the normal cellular counterparts that correspond to the therapeutic monoclonal antibody target.

Reference Values: Normal individuals have B lymphocytes, T lymphocytes, or myeloid cells that express the corresponding cell-surface antigens in question.

Clinical References: 1. Davis AT: Monoclonal antibody-based therapy of lymphoid neoplasms: what's on the horizon? Semin Hematol 2000;37(4 Suppl 7):34-42 2. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 1999;17:268-276 3. Flynn JM, Byrd JC: Campath-1H monoclonal antibody therapy. Curr Opin Oncol 2000;12:574-581 4. Kreitman RJ, Wilson WH, Bergeron K, et al: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Eng J Med 2001;345:241-247 5. Shanafelt TD, Geyer SM, Bone ND, et al: CD49D expression is an independent predictor of overall survival in patients with CLL: a prognostic parameter with therapeutic potential. Br J Haematol 2008;140:537-546

TAMV

Thermoactinomyces vulgaris, IgG Antibodies, Serum

82514

Clinical Information: Thermoactinomyces vulgaris is one of the causative agents of hypersensitivity pneumonitis (HP). Other causative microorganisms include Micropolyspora faeni and Aspergillus fumigatus. The development of HP caused by Thermoactinomyces vulgaris is accompanied by an immune response to Thermoactinomyces vulgaris antigens with production of IgG antibodies. While the immunopathogenesis of HP is not known, several immune mechanisms are postulated to play a role, including both cellular and humoral mechanisms.(1)

Useful For: Evaluation of patients suspected of having hypersensitivity pneumonitis induced by exposure to Thermoactinomyces vulgaris

Interpretation: Elevated concentrations of IgG antibodies to Thermoactinomyces vulgaris, Aspergillus Current as of August 23, 2017 7:11 am CDT


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fumigatus, or Micropolyspora faeni in patients with signs and symptoms of hypersensitivity pneumonitis may be consistent with disease caused by exposure to 1 or more of these organic antigens.

Reference Values: 0-12 years: < or =6.6 mg/L 13-18 years: < or =11.0 mg/L >18 years: < or =23.9 mg/L

Clinical References: 1. Fink JN, Zacharisen MC: Chapter 69: Hypersensitivity pneumonitis. In Allergy Principles and Practice. Vol 1. Fifth edition. Edited by E Middleton Jr, CE Reed, EF Ellis, et al. St. Louis, MO, Mosby Year Book Inc., 1998 2. Girard M, Lacasse Y, Cormier Y: Hypersensitivity pneumonitis. Allergy 2009;64:322-334 3. Grunes D, Beasley MB: Hypersensitivity pneumonitis: A review and update of histologic findings. J Clin Pathol 2013;66:888-895

TDP

Thiamine (Vitamin B1), Whole Blood

42356

Clinical Information: Thiamine (vitamin B1) is an essential vitamin required for carbohydrate metabolism, brain function, and peripheral nerve myelination. Thiamine is obtained from the diet. Body stores are limited and deficiencies can develop quickly. The total thiamine pool in the average adult is about 30 mg. An intake of 0.5 mg per 1,000 kcal per day is needed to maintain this pool. Due to its relatively short storage time, marginal deficiency can occur within 10 days and more severe deficiency within 21 days if intake is restricted. Approximately 80% of all chronic alcoholics are thiamine deficient due to poor nutrition. However, deficiency also can occur in individuals who are elderly, have chronic gastrointestinal problems, have marked anorexia, are on cancer treatment, or are receiving diuretic therapy. The signs and symptoms of mild-to-moderate thiamine deficiency are nonspecific and may include poor sleep, malaise, weight loss, irritability, and confusion. Newborns breast fed from deficient mothers may develop dyspnea and cyanosis; diarrhea, vomiting, and aphonia may follow. Moderate deficiency can affect intellectual performance and well-being, despite a lack of apparent clinical symptoms. Severe deficiency causes congestive heart failure (wet beriberi), peripheral neuropathy (dry beriberi), Wernicke encephalopathy (a medical emergency that can progress to coma and death), and Korsakoff syndrome (an often irreversible memory loss and dementia that can follow). Rapid treatment of Wernicke encephalopathy with thiamine can prevent Korsakoff syndrome. Symptoms of dry beriberi include poor appetite, fatigue, and peripheral neuritis. Symptoms of wet beriberi include cardiac failure and edema. Patients with Wernicke encephalopathy present with behavior change (confusion, delirium, apathy), diplopia (often sixth nerve palsies), and ataxia. A late stage, in which the patients may develop an irreversible amnestic confabulatory state, is referred to as the Wernicke-Korsakoff syndrome. The response to thiamine therapy in deficient patients is usually rapid. Thiamine deficiency is a treatable, yet underdiagnosed, disorder in the United States. A heightened level of awareness of the possibility of thiamine deficiency is necessary to identify, intervene, and prevent thiamine deficiency's dire consequences. It appears that no conditions are directly attributable to thiamine excess and that thiamine administration is safe except in extremely rare cases of anaphylaxis from intravenous thiamin. Whole blood thiamine testing is superior to currently available alternative tests for assessing thiamine status. Serum or plasma thiamine testing suffers from poor sensitivity and specificity, and 99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. High-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), as well as invasive carcinoma.(1,2) Patients with both negative cytology and negative HPV have been shown to be at extremely low risk for cervical neoplasia.(1,2) For women 30 years and older who have received a negative Pap test and concurrent negative HPV result, the American Cancer Society (ACS) and American College of Obstetricians and Gynecologists (ACOG) recommendations for cervical screening state that physicians may lengthen the screening interval to 3 years when using the combined tests. Patients deemed to be at high risk by the clinician should still be screened more frequently. The presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a high-grade squamous intraepithelial lesion. Current guidelines for follow-up of a cytology-negative/HPV-positive patient recommend repeat HPV testing in 12 months.(2) Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in >99% of cervical cancers worldwide. HPV is a small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8,000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high risk for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic, and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4-6) Although persistent infection with HR-HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long-term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared. In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid-based cytology methods require subjective interpretation by highly trained cytopathologists and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy and biopsy. A histologically confirmed high-grade



Page 2037

lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer. Nucleic acid (DNA) testing by PCR has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may 1) increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US). Recently, data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 and HPV-18 positive women is 11.4% (95% confidence interval [CI] 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for other HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(7) Based in part on these data, the American Society for Colposcopy and Cervical Pathology (ASCCP) now recommends that HPV 16/18 genotyping be performed on women who are positive for HR-HPV but negative by routine cytology. Women who are found to be positive for HPV-16 or HPV-18 may be referred to colposcopy, while women who are negative for genotypes 16 and 18 may have repeat cytology and HR-HPV testing in 12 months.(4)

Useful For: Detection of cervical carcinoma or intraepithelial lesions and the presence or absence of high-risk human papillomavirus (HR-HPV) in women over age 30 at risk for cervical neoplasia HPV testing detection of high risk genotypes associated with the development of cervical cancer Results can be used as an aid in triaging women with abnormal Pap smear results Individual genotyping of HPV-16 or HPV-18, if present Results of HPV-16 and HPV-18 genotyping can be used as an aid in triaging women with positive HR-HPV but negative Pap smear results

Interpretation: Cytology: Standard reporting, as defined by the Bethesda System (TBS) is utilized. Human papillomavirus (HPV): A positive result indicates the presence of HPV DNA due to 1 or more of the following genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. A negative result indicates the absence of HPV DNA of the targeted genotypes. For patients with atypical squamous cells of undetermined significance (ASC-US) Pap smear result and who are positive for high-risk HPV (HR-HPV), consider referral for colposcopy, if clinically indicated. For women aged 30 years and older with a negative Pap smear result but who are positive for HPV-16 or HPV-18, consider referral for colposcopy, if clinically indicated. For women aged 30 years and older with a negative Pap smear, positive HR-HPV test result, but who are negative for HPV-16 and HPV-18, consider repeat testing by both cytology and a HR-HPV test in 12 months.

Reference Values: ThinPrep PAP Test: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. HPV Test: Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68

Clinical References: 1. Lorincz AT, Richart RM: Human papillomavirus DNA testing as an adjunct to cytology in cervical screening programs. Arch Pathol Lab Med 2003 August;127(8):959-968 2. Wright TC, Jr, Schiffman M: Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003 February 6;348(6):489-490 3. Soloman D, Davey D, Kurman R, et al: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002 April;287(16):2114-2119 4. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposclpy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Low Genit Tract Dis 2012;16(3):175-204 5. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19 6. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-1056 7. Wright TC Jr, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV positive, cytology-negative results. Am J Clin Pathol 2011 Oct;136(4):578-586 8. Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 April;17(5 Suppl 1):S1-S27 9. Sherman ME, Lorincz A, Scott DR, et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year Current as of August 23, 2017 7:11 am CDT


Page 2038

cohort analysis. J Nat Cancer Inst 2003 January;95(1):46-52

83343

ThinPrep Diagnostic with Human Papillomavirus (HPV) Reflex Clinical Information: Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of years in most patients. Follow-up of the cervical Pap abnormality atypical squamous cells of undetermined significance (ASCUS) is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10%-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL). The majority (>99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. High-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesions and HSIL, as well as invasive carcinomas. Patients with HSIL have a greater risk for progression to carcinoma. In the setting of an abnormal Pap result, the presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a HSIL. If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, considering ordering this test, which is diagnostic, rather than the screen (83342 / ThinPrep Screen with Human Papillomavirus [HPV] Reflex). Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in >99% of cervical cancers worldwide. HPV is a small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8,000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high-risk for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic, and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4-6) Although persistent infection with HR-HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long-term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared. In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid-based cytology methods require subjective interpretation by highly trained cytopathologists and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy and biopsy. A histologically confirmed high-grade lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer. Nucleic acid (DNA) testing by PCR has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may 1) increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US). Recently, data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 or HPV-18 positive women is 11.4% (95% confidence interval [CI] 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for other HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(7) Based in part on these data, the American Society for Colposcopy and Cervical Pathology (ASCCP) now recommends that HPV 16/18 genotyping be performed on women who are positive for HR-HPV but negative by routine cytology. Women who are found to be positive for HPV-16 or HPV-18 may be referred to colposcopy, while women who are negative for genotypes 16 and 18 may have repeat



Page 2039

cytology and HR-HPV testing in 12 months.(4)

Useful For: Management and triage of patient's, age 21 or greater, with abnormal Pap results Human papillomavirus (HPV) testing detection of high-risk genotypes associated with the development of cervical cancer Results can be used as an aid in triaging women with abnormal Pap smear results Individual genotyping of HPV-16 or HPV-18, if present Results of HPV-16 and HPV-18 genotyping can be used as an aid in triaging women with positive high risk HPV (HR-HPV) but negative Pap smear results.


Reference Values: ThinPrep Pap Test: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Note: Abnormal results will be reviewed by a pathologist at an additional charge. HPV Test: Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68

Clinical References: 1. Solomon D, Schiffman M, Tarone R: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-299 2. Soloman D, Davey D, Kurman R, et al: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114-2119 3. Wright TC, Cox JT, Massad LS, et al: 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-21294. 4. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposclpy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Low Genit Tract Dis 2012;16(3):175-204 5. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19 6. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-1056 8. Wright TC Jr, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV positive, cytology-negative results. Am J Clin Pathol 2011 Oct;136(4):578-586 8. Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 April;17(5 Suppl 1):S1-S27 9. Sherman ME, Lorincz A, Scott DR, et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Nat Cancer Inst 2003 January;95(1):46-52

82039

ThinPrep Diagnostic Without Physician Interpretation Clinical Information: The ThinPrep Pap test is an alternative preparation method for the cervical Pap screening test. The method utilizes a liquid-based technique that replaces the direct smear method of the conventional Pap screen. This method is 1 of several technologies developed to improve visualization of cellular material by reducing smearing trauma, air drying artifact, and obscuring blood and inflammation. In addition, variability in smearing technique is eliminated as the majority of processing and preparation is performed in the laboratory under controlled conditions. Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of



Page 2040

years in most patients. Follow-up of the cervical Pap abnormality atypical squamous cells of undetermined significance (ASCUS) is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10%-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL). If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, this test should be ordered rather than 82037 / ThinPrep Screen, Without Physician Interpretation.

Useful For: Detection of cervical carcinoma or intraepithelial lesions when screening women for possible cervical neoplasia

Interpretation: Standard reporting, as defined by the Bethesda System (TBS) is utilized. Reference Values: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Note: Abnormal results will be reviewed by a pathologist at an additional charge.

Clinical References: 1. Austin RM, Ramzey I: Increased detection of epithelial cell abnormalities by liquid-based gynecologic cytology preparations. A review of accumulated data. Acta Cytol 1998;42:178-184 2. Guidos BJ, Selvaggi SM: Use of the ThinPrep Pap test in clinical practice. Diagn Cytopathol 1999;20:70-73 3. Kurman RJ, Solomon D: The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria, and explanatory notes for terminology and specimen adequacy. New York, NY, Springer-Verlag, 1994 4. Gay JD, Donaldson LD, Goellner JR: False-negative results in cervical cytologic studies. Acta Cytol 1985;29:1043-1046 5. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis 2012;16(3):175-204

89118

ThinPrep Screen with HPV for Women 30 Years and Older Clinical Information: The majority (>99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. High-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as invasive carcinomas.(1,2) Patients with both a negative cytology and negative HPV have been shown to be at extremely low risk for cervical neoplasia.(1,2) For women 30 years old and older who have received a negative Pap test and concurrent negative HPV result, the American Cancer Society (ACS) and American College of Obstetricians and Gynecologists (ACOG) recommendations for cervical screening state that physicians may lengthen the screening interval to 3 years when using the combined test. Patients deemed to be high risk by the clinician should still be screened more frequently. The presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a high-grade squamous intraepithelial lesion. Current guidelines for follow-up of a cytology-negative/HPV-positive patient recommend repeat HPV testing in 12 months.(2) Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in >99% of cervical cancers worldwide. HPV is a small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8,000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high risk for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4-6) Although persistent infection with HR-HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long-term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared. In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary



Page 2041

tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid-based cytology methods require subjective interpretation by highly trained cytopathologists and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy, and biopsy. A histologically confirmed high-grade lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer. Nucleic acid (DNA) testing by PCR has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may 1) increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US). Recently, data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 and HPV-18 positive women is 11.4% (95% confidence interval [CI] 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for other HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(7) Based in part on these data, the American Society for Colposcopy and Cervical Pathology (ASCCP) now recommends that HPV 16/18 genotyping be performed on women who are positive for HR-HPV but negative by routine cytology. Women who are found to be positive for HPV-16 or HPV-18 may be referred to colposcopy, while women who are negative for genotypes 16 and 18 may have repeat cytology and HR-HPV testing in 12 months.(4)

Useful For: Detection of cervical carcinoma or intraepithelial lesions and the presence or absence of high-risk human papillomavirus (HR-HPV) when screening women over the age of 30 for possible cervical neoplasia HPV testing detection of high-risk genotypes associated with the development of cervical cancer Results can be used as an aid in triaging women with abnormal Pap smear results Individual genotyping of HPV-16 or HPV-18, if present Results of HPV-16 and HPV-18 genotyping can be used as an aid in triaging women with positive HR-HPV but negative Pap smear results


Reference Values: ThinPrep PAP Test: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. HPV Test: Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68

Clinical References: 1. Lorincz AT, Richart RM: Human papillomavirus DNA testing as an adjunct to cytology in cervical screening programs. Arch Pathol Lab Med 2003 August;127(8):959-968 2. Wright TC, Jr, Schiffman M: Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med 2003 February 6;348(6):489-490 3. Soloman D, Davey D, Kurman R, et al: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002 April;287(16):2114-2119 4. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposclpy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Low Genit Tract Dis 2012;16(3):175-204 5. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19 6. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide Current as of August 23, 2017 7:11 am CDT


Page 2042

study. Lancet Oncol 2010;11:1048-1056 7. Wright TC Jr, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV positive, cytology-negative results. Am J Clin Pathol 2011 Oct;136(4):578-586 8. Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 April;17(5 Suppl 1):S1-S27 9. Sherman ME, Lorincz A, Scott DR, et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Nat Cancer Inst 2003 January;95(1):46-52

83342

ThinPrep Screen with Human Papillomavirus (HPV) Reflex Clinical Information: Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of years in most patients. Follow-up of the cervical Pap abnormality atypical squamous cells of undetermined significance (ASCUS) is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10%-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL). The majority (>99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. High-risk HPV (HR-HPV) types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesions and HSIL, as well as invasive carcinomas. Patients with HSIL have a greater risk for progression to carcinoma. In the setting of an abnormal Pap result, the presence of HR-HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a HSIL. If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, considering ordering the diagnostic test (83343 / ThinPrep Diagnostic with Human Papillomavirus (HPV) Reflex) rather than this screen. Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in >99% of cervical cancers worldwide. HPV is a small, nonenveloped, double-stranded DNA virus, with a genome of approximately 8,000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high-risk for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic, and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4-6) Although persistent infection with HR-HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long-term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared. In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid-based cytology methods require subjective interpretation by highly trained cytopathologists and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy and biopsy. A histologically confirmed high-grade lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer. Nucleic acid (DNA) testing by PCR has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may 1) increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US). Recently, data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 or HPV-18 positive women is



Page 2043

11.4% (95% confidence interval [CI] 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for other HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(7) Based in part on these data, the American Society for Colposcopy and Cervical Pathology (ASCCP) now recommends that HPV 16/18 genotyping be performed on women who are positive for HR-HPV but negative by routine cytology. Women who are found to be positive for HPV-16 or -18 may be referred to colposcopy, while women who are negative for genotypes 16 and 18 may have repeat cytology and HR-HPV testing in 12 months.(4)

Useful For: Management and triage of patients, age 21 or greater, with abnormal Pap results HPV testing detection of high-risk genotypes associated with the development of cervical cancer Results can be used as an aid in triaging women with abnormal Pap smear results Individual genotyping of HPV-16 and HPV-18, if present Results of HPV-16 and HPV-18 genotyping can be used as an aid in triaging women with positive HR-HPV but negative Pap smear results.


Reference Values: ThinPrep Pap Test: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Note: Abnormal results will be reviewed by a pathologist at an additional charge. HPV Test: Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68

Clinical References: 1. Solomon D, Schiffman M, Tarone R: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-299 2. Soloman D, Davey D, Kurman R, et al: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114-2119 3. Wright TC, Cox JT, Massad LS, et al: 2001 consensus guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-2129 4. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Low Genit Tract Dis 2012;16(3):175-204 5. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19 6. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-1056 7. Wright TC Jr, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV positive, cytology-negative results. Am J Clin Pathol 2011 Oct;136(4):578-586 8. Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 April;17(5 Suppl 1):S1-S27 9. Sherman ME, Lorincz A, Scott DR, et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Nat Cancer Inst 2003 January;95(1):46-52

82037

ThinPrep Screen, Without Physician Interpretation Clinical Information: The ThinPrep Pap test is an alternative preparation method for the cervical Pap screening test. The method utilizes a liquid-based technique that replaces the direct smear method of the conventional Pap screen. This method is 1 of several technologies developed to improve visualization of cellular material by reducing smearing trauma, air drying artifact, and obscuring blood and inflammation.



Page 2044

In addition, variability in smearing technique is eliminated as the majority of processing and preparation is performed in the laboratory under controlled conditions. Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of years in most patients. Follow-up of the cervical Pap abnormality atypical squamous cells of undetermined significance (ASCUS) is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL). If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, considering ordering the diagnostic test 82039 / ThinPrep Diagnostic Without Physician Interpretation rather than this test.

Useful For: Detection of cervical carcinoma or intraepithelial lesions when screening women for possible cervical neoplasia

Interpretation: Standard reporting, as defined by the Bethesda System (TBS) is utilized. Reference Values: Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy. Note: Abnormal results will be reviewed by a pathologist at an additional charge.

Clinical References: 1. Austin RM, Ramzey I: Increased detection of epithelial cell abnormalities by liquid-based gynecologic cytology preparations. A review of accumulated data. Acta Cytol 1998;42:178-184 2. Guidos BJ, Selvaggi SM: Use of the ThinPrep Pap test in clinical practice. Diagn Cytopathol 1999;20:70-73 3. Kurman RJ, Solomon D: The Bethesda system for reporting cervical/vaginal cytologic diagnoses: definitions, criteria, and explanatory notes for terminology and specimen adequacy. New York, NY, Springer-Verlag, 1994 4. Gay JD, Donaldson LD, Goellner JR: False-negative results in cervical cytologic studies. Acta Cytol 1985;29:1043-1046 5. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis 2012;16(3):175-204

FFTIO

Thiocyanate, serum

57708

Reference Values: Toxic Thiocyanate concentrations: Greater than 10 mg/dL

FFTHM

Thiopental and Metabolite, Serum/Plasma

90354

Reference Values: Reporting limit determined each analysis Thiopental Synonym(s): Pentothal Hypnotic range: 1 - 5 mcg/mL Therapeutic coma: 30 - 100 mcg/mL Anesthesia: 7 - 130 mcg/mL Pentobarbital Synonym(s): Thiopental Metabolite Peak serum concentrations of 1.2 - 3.1 mcg/mL were produced 0.5 - 2.0 hours after a 100 mg oral dose and peak serum concentrations of 3 mcg/mL were produced 6 min. following a 100 mg IV dose. Potentially toxic at blood concentrations greater than 10 mcg/mL.



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TPMT3 65188

Thiopurine Methyltransferase (TPMT) Activity Profile, Erythrocytes Clinical Information: Thiopurine methyltransferase (TPMT) deficiency is a condition in which patients treated with standard doses of azathioprine (AZA, Imuran), 6-mercaptopurine (6-MP, Purinethol), or 6-thioguanine (6-TG, Thioguanine Tabloid) may develop life-threatening myelosuppression or severe hematopoietic toxicity. The metabolic conversion of AZA, 6-MP, or 6-TG to purine nucleotides and the subsequent incorporation of these nucleotides into DNA play an important role in both the therapeutic efficacy and the toxicity of these drugs. A competitive catabolic route for the metabolism of thiopurines is catalyzed by the TPMT enzyme, which inactivates them by thiomethylation. A balance must be established between these competing metabolic pathways so that: 1) sufficient amounts of drug are converted to the nucleotide to act as an antimetabolite and 2) the antimetabolite levels do not become so high as to cause potentially lethal bone marrow suppression. TPMT deficiency is an autosomal recessive condition with an incidence of approximately 1 in 300 individuals homozygous for deleterious mutations in the TPMT gene; about 10% of the population are heterozygous carriers of TPMT mutations. Adverse effects of AZA, 6-MP, or 6-TG administration can be observed in individuals who are either homozygous or heterozygous for TPMT deficiency. TPMT hyperactivity is also a known phenotype. Individuals who are hypermetabolizers have therapeutic resistance to thiopurine drugs, and therefore they cannot achieve therapeutic levels. If an individual with TPMT hyperactivity is treated with higher and higher doses of thiopurine drugs, they may develop severe hepatotoxcitity. Therefore, treatment with alternative medications is recommended for hypermetabolizers. As such, knowing a patient's TPMT status prior to treatment with AZA, 6-MP, or 6-TG is important for purposes of calculating drug dosages.

Useful For: Detection of individuals with low thiopurine methyltransferase (TPMT) activity who are at risk for excessive myelosuppression or severe hematopoietic toxicity when taking thiopurine drugs Detection of individuals with hyperactive TPMT activity who have therapeutic resistance to thiopurine drugs and may develop hepatotoxicity if treated with these drugs

Interpretation: The thiopurine methyltransferase (TPMT) activity profile, RBC assay is used to detect individuals with low and intermediate TPMT activity who may be at risk for myelosuppression when exposed to standard doses of thiopurines, including azathioprine (AZA, Imuran), 6-mercaptopurine (Purinethol), or 6-thioguanine (6-TG, Thioguanine Tabloid). TPMT is the primary metabolic route for inactivation of thiopurine drugs in the bone marrow. When TPMT activity is low, it is predicted that proportionately more 6-mercaptopurine can be converted into the cytotoxic 6-thioguanine nucleotides that accumulate in the bone marrow causing excessive toxicity. This test can also detect TMPT hyperactivity. Individuals who are hypermetabolizers have therapeutic resistance to thiopurine drugs, and therefore they cannot achieve therapeutic levels. If an individual with TPMT hyperactivity is treated with higher and higher doses of thiopurine drugs, they may develop severe hepatotoxcitity. The activity of TPMT is measured by 3 different substrates. Reports include the quantitative activity level of TPMT for each of 3 different substrates and an interpretation of these results. When abnormal results are detected, a detailed interpretation is given, including an overview of results and suggestion as to whether patient has TPMT deficiency or hyperactivity, as well as discussion of treatment considerations. TPMT phenotype testing does not replace the need for clinical monitoring of patients treated with thiopurine drugs. Genotype for TPMT cannot be inferred from TPMT activity (phenotype). Phenotype testing should not be requested for patients currently treated with thiopurine drugs. Current TPMT phenotype may not reflect future TPMT phenotype, particularly in patients who received blood transfusion within 30 to 60 days of testing. TPMT enzyme activity can be inhibited by several drugs such as: naproxen (Aleve), ibuprofen (Advil, Motrin), ketoprofen (Orudis), furosemide (Lasix), sulfasalazine (Azulfidine), mesalamine (Asacol), olsalazine (Dipentum), mefenamic acid (Ponstel), thiazide diuretics, and benzoic acid inhibitors. TPMT inhibitors may contribute to falsely low results: patients should abstain from these drugs for at least 48 hours prior to TPMT testing. Falsely low results may also occur as a result of inappropriate specimen handling and hemolysis.

Reference Values: 3.00-6.66 nmol/mL/hr 6-Methylmercaptopurine (normal) 5.04-9.57 nmol/mL/hr 6-Methylmercaptopurine riboside (normal) 2.70-5.84 nmol/mL/hr 6-Methylthioguanine riboside (normal)

Clinical References: 1. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical pharmacogenetics Current as of August 23, 2017 7:11 am CDT


Page 2046

implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-391 2. Sandborn WJ: Pharmacogenomics and IBD: TPMT and thiopurines. Inflamm Bowel Dis 2004;10:Suppl 1 S35-S37 3. Schedel J, Godde A, Schutz E, et al: Impact of thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations in patients with chronic inflammatory diseases. Ann N Y Acad Sci 2006;1069:477-491 4. Zhou S: Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol 2006;1:119-128 5. Brouwer C, De Abreu R, Keiser-Garritsen J, et al: Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular aspects. Eur J Cancer 2005;41:613-623

GTPMT

Thiopurine Methyltransferase (TPMT) Genotyping, Blood

62753

Clinical Information: The thiopurine drugs are purine antimetabolites that are useful in the treatment of acute lymphoblastic leukemia, autoimmune disorders (eg, Crohn disease, rheumatoid arthritis), and organ transplant recipients. The thiopurine drugs, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and azathioprine (AZA) are prodrugs that require intracellular activation to 6-thioguanine nucleotides (6-TGN). This activation is catalyzed by multiple enzymes. The cytotoxic effects of thiopurine drugs are achieved mainly through incorporation of 6-TGNs into DNA and RNA. The pathway that leads to synthesis of active cytotoxic 6-TGNs is in competition with inactivation pathways catalyzed by thiopurine methyltransferase (TPMT). Evaluation of this pathway is important because the levels of 6-TGNs measured in red blood cells have been correlated with both thiopurine therapeutic efficacy and toxicity such as myelosuppression. TPMT activity is inherited as a monogenic codominant trait and variable TPMT activity is associated with TPMT genetic variants. The distribution of TPMT activity in red blood cells is trimodal in Caucasian population, with approximately 0.3% of people having deficient (undetectable) TPMT activity, 11% low (intermediate) activity, and 89% normal TPMT activity. The allele for normal TPMT activity (wild-type) has been designated TPMT*1. Four TPMT alleles, comprised of a combination of 3 different single-nucleotide substitutions (SNPs), account for the majority of inactivating alleles in some ethnicities, including Caucasians: TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C. Additional less frequent TPMT alleles TPMT*4, TPMT*5, TPMT*8, and TPMT*12 also have been implicated as deficiency alleles. There is substantial evidence linking TPMT genotype to phenotypic variability and, therefore, genotyping tests have a high likelihood of being informative in these populations. TPMT Allele cDNA Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive (normal) metabolizer *2 c.238G->C Nonfunctional, no activity *3A c.460G->A and c.719A->G Nonfunctional, no activity *3B c.460G->A Nonfunctional, no activity *3C c.719A->G Nonfunctional, no activity *4 c.626-1G->A Nonfunctional, no activity *5 c.146T->C Nonfunctional, no activity *8 c.644G->A Reduced-function/decreased activity *12 c.374C->T Reduced-function/decreased activity The US Food and Drug Administration, the Clinical Pharmacogenetics Implementation Consortium, and certain professional societies recommend consideration of TPMT genotype or TPMT erythrocyte testing prior to the initiation of therapy with thiopurine drugs. There is substantial evidence linking TPMT genotype to phenotypic variability. Dose adjustments based upon TPMT genotype have reduced thiopurine-induced adverse effects without compromising desired antitumor and immunosuppressive therapeutic effects in several clinical settings. Complementary clinical tests are available to measure TPMT enzymatic activity in erythrocytes. Genotyping is not impacted by other medications known to inhibit TPMT activity. This testing can be complimented by the TPMT erythrocyte phenotype testing if the clinician wants to check for lower TPMT enzyme activity, regardless of cause.

Useful For: Predicting potential for toxicity to thiopurine drugs (6-mercaptopurine, 6-thioguanine, and azathioprine)

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating whether results are predictive of a poor, intermediate, or extensive metabolizer phenotype. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the TPMT Nomenclature Committee.(1) For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.



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An interpretive report is provided.

Clinical References: 1. TPMT nomenclature committee. Available at www.imh.liu.se/tpmtalleles 2. Appell ML, Berg J, Duley J, et al: Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013;23(4):242-248 3. Nguyen CM, Mendes MA, Ma JD: Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. PLoS Curr 2011;3:RRN1236 4. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-391 5. Weinshilboum R: Thiopurine pharmacogenetics clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 2001 Apr;29(4 Pt 2):601-605 6. Zaza G, Cheok M, Krynetskaia N, et al: Thiopurine pathway. Pharmacogenet Genomics 2010 Sep;20(9):573-574

OTPMT

Thiopurine Methyltransferase (TPMT) Genotyping, Saliva

62751

Clinical Information: The thiopurine drugs are purine antimetabolites that are useful in the treatment of acute lymphoblastic leukemia, autoimmune disorders (eg, Crohn disease, rheumatoid arthritis), and organ transplant recipients. The thiopurine drugs, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and azathioprine (AZA), are prodrugs that require intracellular activation to 6-thioguanine nucleotides (6-TGN). This activation is catalyzed by multiple enzymes. The cytotoxic effects of thiopurine drugs are achieved mainly through incorporation of 6-TGNs into DNA and RNA. The pathway that leads to synthesis of active cytotoxic 6-TGNs is in competition with inactivation pathways catalyzed by thiopurine methyltransferase (TPMT). Evaluation of this pathway is important because the levels of 6-TGNs measured in red blood cells have been correlated with both thiopurine therapeutic efficacy and toxicity such as myelosuppression. TPMT activity is inherited as a monogenic codominant trait and variable TPMT activity is associated with TPMT genetic variants. The distribution of TPMT activity in red blood cells is trimodal in Caucasian population, with approximately 0.3% of people having deficient (undetectable) TPMT activity, 11% low (intermediate) activity, and 89% normal TPMT activity. The allele for normal TPMT activity (wild-type) has been designated TPMT*1. Four TPMT alleles, comprised of a combination of 3 different single nucleotide polymorphisms (SNPs), account for the majority of inactivating alleles in some ethnicities, including Caucasians: TPMT*2, TPMT*3A, TPMT*3B, and TPMT*3C. Additional less frequent TPMT alleles TPMT*4, TPMT*5, TPMT*8, and TPMT*12 also have been implicated as deficiency alleles. There is substantial evidence linking TPMT genotype to phenotypic variability and, therefore, genotyping tests have a high likelihood of being informative in these populations. TPMT Allele cDNA Nucleotide Change Effect on Enzyme Metabolism** *1 None (wild type) Extensive (normal) metabolizer *2 c.238G->C Nonfunctional, no activity *3A c.460G->A and c.719A->G Nonfunctional, no activity *3B c.460G->A Nonfunctional, no activity *3C c.719A->G Nonfunctional, no activity *4 c.626-1G->A Nonfunctional, no activity *5 c.146T->C Nonfunctional, no activity *8 c.644G->A Reduced-function/decreased activity *12 c.374C->T Reduced-function/decreased activity The US Food and Drug Administration, the Clinical Pharmacogenetics Implementation Consortium, and certain professional societies recommend consideration of TPMT genotype or TPMT erythrocyte testing prior to the initiation of therapy with thiopurine drugs. Dose adjustments based upon TPMT genotype have reduced thiopurine-induced adverse effects without compromising desired antitumor and immunosuppressive therapeutic effects in several clinical settings. Complementary clinical tests are available to measure TPMT enzymatic activity in erythrocytes. Genotyping is not impacted by other medications known to inhibit TPMT activity. This testing can be complimented by the TPMT erythrocyte phenotype testing if the clinician wants to check for lower TPMT enzyme activity regardless of cause.

Useful For: Predicting potential for toxicity to thiopurine drugs (6-mercaptopurine, 6-thioguanine, and azathioprine) Genotyping patients who prefer not to have their blood drawn

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating whether results are predictive of a poor, intermediate, or extensive metabolizer phenotype. The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the TPMT Nomenclature Committee.(1) For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as Current as of August 23, 2017 7:11 am CDT


Page 2048

well as potential alternate drug choices.

Reference Values: An interpretive report is provided.

Clinical References: 1. TPMT nomenclature committee. Available at www.imh.liu.se/tpmtalleles 2. Appell ML, Berg J, Duley J et al: Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013;23(4):242-248 3. Nguyen CM, Mendes MA, Ma JD: Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk. PLoS Curr 2011;3:RRN1236 4. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-391 5. Weinshilboum R: Thiopurine pharmacogenetics clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos 2001 Apr;29(4 Pt 2):601-605 6. Zaza G, Cheok M, Krynetskaia N, et al: Thiopurine pathway. Pharmacogenet Genomics 2010 Sep;20(9):573-574

FFTHO

Thiosulfate, Urine

90480

Reference Values: Reporting limit determined each analysis Creatinine (mg/L) U.S. Population (10th â€“ 90th percentiles, median) All participants: 335 - 2370 mg/L, median: 1180 (n=22,245) Males: 495 - 2540 mg/L, median: 1370 (n=10,610) Females: 273 - 2170 mg/L, median 994 (n=11,635) Thiosulfate (mcg/mL) Normal range: approximately 2.9+/-2.5 mcg/mL (based on an average creatinine concentration of 1 g/L) Thiosulfate (Creatinine corrected) (mg/g Creat) Thiosulfate was detected in urine from 29 controls at 2.9 +/- 2.5 mg/g creatinine. Exposure to 1240 nmol/L (30 ppm) for 45 minutes resulted in a urinary thiosulfate concentration of 60 mg/g creatinine. Specific Gravity Confirmation Physiologic range: 1.010 - 1.030.

FFTHI

Thiothixene (Navane)

91126

Reference Values: Reference Range: 10.0 - 30.0 ng/mL

TT

Thrombin Time (Bovine), Plasma

9059

Clinical Information: Prolonged clotting times may be associated with a wide variety of coagulation abnormalities including: -Deficiency or functional abnormality (congenital or acquired) of many of the coagulation proteins -Deficiency or functional abnormality of platelets -Specific factor inhibitors -Acute disseminated intravascular coagulation -Exogenous anticoagulants (eg, heparin, warfarin) The prothrombin time and activated partial thromboplastin time are first-order tests for coagulation abnormalities and are prolonged in many disorders. A battery of coagulation tests is often required to determine the cause of prolonged clotting times. Thrombin catalzyes the transformation of fibrinogen to



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fibrin (by cleaving fibrinpeptides A and B), which is followed by polymerization of fibrin to form a clot. The thrombin time (TT) test measures the time of clot formation when thrombin is added to citrated plasma. The phospholipid-dependent procoagulant enzyme cascades (intrinsic, extrinsic, and "common" pathway) are bypassed by the addition of exogenous thrombin. Therefore, the TT mainly reflects functions and interactions of solution-phase exogenous thrombin and endogenous fibrinogen.

Useful For: The main utility of the thrombin time test is to detect or exclude the presence of heparin or heparin-like anticoagulants (which act by enhancing antithrombin's inhibition of thrombin and other procoagulant enzymes) when used in conjunction with the reptilase time (RT) in evaluating unexplained prolonged clotting times. Identifying the cause of a prolonged prothrombin time, activated partial thromboplastin time, or dilute Russell's viper venom time when used in conjunction with the RT and fibrinogen assay

Interpretation: Prolongation of the thrombin time (TT) is consistent with the presence of heparin-like anticoagulants, hypofibrinogenemia, dysfibrinogenemia, fibrin degradation products, and antibody inhibitors of thrombin. An immeasurably prolonged TT is usually the result of heparin in the specimen or, rarely, the presence of thrombin antibodies or afibrinogenemia. When the TT test is performed with diluted bovine thrombin to achieve a normal plasma clotting time of about 20 seconds, the TT is capable of detecting unfractionated heparin at a concentration of 0.05 units/mL of heparin. Other tests useful in interpreting the significance of prolongation of the TT include: reptilase time (RT), human thrombin time, clottable fibrinogen assay, and the fibrin D-dimer assay. These tests are available as components of coagulation profile test panels. As seen in the following table, RT can help distinguish among the various causes of a prolonged TT. Thrombin Time Reptilase Time Causes Remarks Prolonged Prolonged Hypoor afibrinogenemia Ascertain by determination of fibrinogen Prolonged Prolonged Dysfibrinogenemia Ascertain by specific assay Prolonged Normal Heparin or inhibitor of thrombin Differentiate by human TT and/or heparin assays Prolonged Prolonged Fibrin(ogen) split products (FSP) Ascertain by FSP or D-dimer assay


Clinical References: 1. Koepke JA: Coagulation testing systems. In Practical Laboratory Hematology. New York, Churchill Livingston, 1991 2. Corriveau DM, Fritsma G: Hemostasis and Thrombosis in the Clinical Laboratory. Philadelphia, JB Lippincott Company, 1988 3. Galanakis DK: Plasma thrombin time and related tests. In Williams Hematology. Fifth edition. New York, McGraw-Hill Book Company, 1995, pp L91-L93 4. Greaves M, Preston FE: Approach to the bleeding patient. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by RW Colman, J Hirsh, VJ Marder, et al. Philadelphia, JB Lippincott Company, 2001, pp 783-837

FFTAT

Thrombin-Antithrombin Complex

91200



TGAB

Thyroglobulin Antibody, Serum

84382

Clinical Information: Thyroglobulin autoantibodies bind thyroglobulin (Tg), a major thyroid-specific protein. Tg plays a crucial role in thyroid hormone synthesis, storage, and release. Tg is not secreted into the systemic circulation under normal circumstances. However, follicular destruction through inflammation (thyroiditis and autoimmune hypothyroidism), hemorrhage (nodular goiter), or rapid disordered growth of thyroid tissue, as may be observed in Graves disease or follicular cell-derived thyroid neoplasms, can result in leakage of Tg into the blood stream. This results in the formation of autoantibodies to Tg (anti-Tg) in some individuals. The same processes also may result in exposure of other "hidden" thyroid antigens to the immune system, resulting in the formation of autoantibodies to other thyroid antigens, in particular thyroid peroxidase (TPO) (anti-TPO). Since anti-Tg and anti-TPO autoantibodies are observed most frequently in autoimmune thyroiditis (Hashimoto disease), they were originally considered to be of possible pathogenic significance in this disorder. However, the consensus opinion today is that they are merely disease markers. It is felt that the presence of competent immune cells at the site of thyroid tissue destruction in autoimmune thyroiditis simply predisposes the patient to form autoantibodies to hidden thyroid antigens. In individuals with autoimmune hypothyroidism, 30% to 50% will have detectable anti-Tg autoantibodies, while 50% to 90% will have detectable anti-TPO autoantibodies. In Graves disease, both types of autoantibodies are observed at approximately half these rates. The presence of anti-Tg, which occurs in 15% to 30% of thyroid cancer patients, could result in misleading Tg results. In immunometric assays, the presence of thyroid antibody can lead to false-low measurement; whereas it might lead to false-high results in competitive assays.

Useful For: As an adjunct in the diagnosis of autoimmune thyroid diseases: Hashimoto disease, postpartum thyroiditis, neonatal hypothyroidism, and Graves disease Identification of potentially unreliable serum thyroglobulin measurements by immunoassay in the follow-up of patients with differentiated follicular-cell derived thyroid carcinomas (for this application order HTG2 / Thyroglobulin, Tumor Marker, Serum or HTGR / Thyroglobulin, Tumor Marker Reflex to LC-MS/MS or Immunoassay) Current as of August 23, 2017 7:11 am CDT


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Interpretation: Diagnosis of Autoimmune Thyroid Disease: Measurements of antithyroid peroxidase (TPO) have higher sensitivity and equal specificity to antithyroglobulin (anti-Tg) measurements in the diagnosis of autoimmune thyroid disease. Anti-Tg levels should, therefore, only be measured if anti-TPO measurements are negative, but clinical suspicion of autoimmune thyroid disease is high. Detection of significant titers of anti-Tg or anti-TPO autoantibodies is supportive evidence for a diagnosis of Graves disease in patients with thyrotoxicosis. However, measurement of the pathogenic antithyroid-stimulating hormone (TSH) receptor antibodies by binding assay (THYRO / Thyrotropin Receptor Antibody, Serum) or bioassay (TSI / Thyroid-Stimulating Immunoglobulin [TSI], Serum) is the preferred method of confirming Graves disease in atypical cases and under special clinical circumstances. Positive thyroid autoantibody levels in patients with high-normal or slightly elevated serum thyrotropin levels predict the future development of more profound hypothyroidism. Patients with postpartum thyroiditis with persistently elevated thyroid autoantibody levels have an increased likelihood of permanent hypothyroidism. In cases of neonatal hypothyroidism, the detection of anti-TPO or anti-Tg in the infant suggests transplacental antibody transfer, particularly if the mother has a history of autoimmune thyroiditis or detectable thyroid autoantibodies. The neonatal hypothyroidism is likely to be transient in these cases. Thyroid Cancer Follow-up: Following therapy of differentiated follicular-cell derived thyroid cancer, patients with no residual thyroid tissue and no persistent or recurrent cancer will have undetectable or very low serum Tg levels. Persistently elevated or rising serum Tg levels, either on or off thyroxine replacement therapy, suggest possible tumor persistence or recurrence. However, if a patient also has measurable anti-Tg autoantibody levels, the results of serum Tg measurements may be unreliable. Anti-Tg may result in both falsely-low and, less commonly, falsely high serum Tg measurements. Therefore, in anti-Tg-positive patients, serum Tg measurements should not be used as the sole measurement for thyroid cancer follow-up and should be interpreted with caution. A thyroglobulin antibody result of 20 years: 0.3-4.2 mIU/L

Clinical References: 1. Fatourechi V, Lankarani M, Schryver P, et al: Factors influencing clinical decisions to initiate thyroxine therapy for patients with mildly increased serum thyrotropin (5.1-10.0 mIU/L). Mayo Clin Proc 2003 May;78(5):554-560 2. Wilson JD, Foster D, Kronenburg HM, et al: Williams Textbook of Endocrinology. Ninth edition, WB Saunders Company, 1998 3. Melmed S, Polonsky KS, Larsen PR, et al: Williams Textbook of Endocrinology. 12th edition, Elsevier Saunders Company, 2011, pp 348-414 4. Heil W, Ehrhardt V: Reference Intervals for Adults and Children 2008. Ninth edition, Roche Diagnostics Ltd, Rotkreuz, Switzerland July 2009, V9.1

TSI

Thyroid-Stimulating Immunoglobulin (TSI), Serum

8634

Clinical Information: Autoimmune thyroid disease is characterized by the presence of autoantibodies against various thyroid components, namely the thyrotropin receptor (thyroid-stimulating hormone receptor: TSHR), thyroid-peroxidase (TPO), and thyroglobulin (Tg), as well as an inflammatory cellular infiltrate of variable severity within the gland. Among the autoantibodies found in autoimmune thyroid disease, TSHR autoantibodies are most closely associated with disease pathogenesis. All forms of autoimmune thyrotoxicosis (Graves disease, Hashitoxicosis, neonatal thyrotoxicosis) are caused by the production of TSHR-stimulating autoantibodies. The role of the TPO and Tg autoantibodies in either autoimmune thyrotoxicosis or autoimmune hypothyroidism is less well established; they may merely represent epiphenomena. Detectable concentrations of anti-TPO antibodies are observed in most patients with autoimmune thyroid disease (eg, Hashimoto thyroiditis, idiopathic myxedema, and Graves disease). Autoantibodies that bind and transactivate the TSHR lead to stimulation of the thyroid gland independent of the normal feedback-regulated thyroid-stimulating hormone (TSH) stimulation. These TSHR autoantibodies also are known as long-acting-thyroid-stimulator or thyroid-stimulating immunoglobulins (TSI). Some patients with Graves disease also have TSHR-blocking antibodies, which do not transactivate the TSHR. The balance between TSI and TSHR-blocking antibodies, as well as their individual titers, are felt to be determinants of Graves disease severity. At least 20% of patients with autoimmune hypothyroidism also have evidence either of TSHR-blocking antibodies or, less commonly, TSI. TSHR autoantibodies may be found before autoimmune thyrotoxicosis becomes biochemically or clinically manifest. Since none of the treatments for Graves disease are aimed at the underlying disease process, but rather ablate thyroid tissue or block thyroid hormone synthesis, TSI may persist after apparent cure. TSI are IgG antibodies and can, therefore, cross the placental barrier, causing neonatal thyrotoxicosis. First-order tests for autoimmune thyroid disease include TPO / Thyroperoxidase (TPO) Antibodies, Serum (most suited for suspected cases of autoimmune hypothyroidism) and THYRO / Thyrotropin Receptor Antibody, Serum. Thyrotropin receptor antibody (TSHR-antibody) is a binding assay that



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detects both TSI and TSHR-blocking autoantibodies; it can be used instead of this TSI assay for most applications, as long as the results are interpreted in the clinical context. The TSHR-antibody test has a shorter turnaround time than the TSI assay, is less expensive, and if interpreted within the clinical context, has excellent correlation with the TSI assay. Specific detection of TSI is accomplished by this second-order bioassay.

Useful For: Second-order testing for autoimmune thyroid disease, including: -Differential diagnosis of etiology of thyrotoxicosis in patients with ambiguous clinical signs or contraindicated (eg, pregnant or breast-feeding) or indeterminate thyroid radioisotope scans -Diagnosis of clinically suspected Graves disease (eg, extrathyroidal manifestations of Graves disease: endocrine exophthalmos, pretibial myxedema, thyroid acropachy) but normal thyroid function tests -Determining the risk of neonatal thyrotoxicosis in a fetus of a pregnant female with active or past Graves disease -Differential diagnosis of gestational thyrotoxicosis versus first-trimester manifestation or recurrence of Graves disease -Assessing the risk of Graves disease relapse after antithyroid drug treatment A combination of TSI / Thyroid-Stimulating Immunoglobulin (TSI), Serum and THYRO / Thyrotropin Receptor Antibody, Serum is useful as an adjunct in the diagnosis of unusual cases of hypothyroidism (eg, Hashitoxicosis).

Interpretation: The sensitivity and specificity of an elevated thyroid-stimulating immunoglobulins (TSI) index for Graves disease diagnosis depends on whether patients have clinically active, untreated disease or disease treated with antithyroid drugs. Using a TSI index of 1.3 as the cutoff level in newly diagnosed, untreated patients, the sensitivity and specificity are higher than 90%. For a higher cutoff of 1.8, specificity approaches 100%, but sensitivity decreases somewhat. In patients with inactive or treated Graves disease the specificity is similar, while sensitivity is lower, ranging from 50% to 80%. Significant neonatal thyrotoxicosis is likely if a pregnant woman with a history of Graves disease has a TSI index above 3.9 during the last trimester, regardless of her remission status. Lesser elevations are only occasionally associated with neonatal thyrotoxicosis. This is particularly relevant for women who have previously undergone thyroid-ablative therapy or are on active antithyroid drug treatment and, therefore, no longer display biochemical or clinical evidence of thyrotoxicosis. Gestational thyrotoxicosis, which is believed to be due to a combination of human chorionic gonadotropin cross-reactivity on the thyroid-stimulating hormone receptor (TSHR) and transient changes in thyroid hormone protein binding, is not associated with an elevated TSI index. Finding an elevated TSI index in this setting suggests underlying Graves disease. An elevated TSI index at the conclusion of a course of anti-thyroid drug treatment is highly predictive of relapse of Graves disease. However, the converse, a normal TSI index, is not predictive of prolonged remission. In patients with thyroid function tests that fluctuate between hypoand hyperthyroidism or vice versa, a clearly elevated TSHR-antibody level (>25%) and a simultaneous TSI index that is normal or only minimally elevated (1.3-1.8) suggest a diagnosis of possible Hashitoxicosis.

Reference Values: < or =1.3 TSI index Reference values apply to all ages.

Clinical References: 1. Morris JC III, Hay ID, Nelson RE, Jiang NS: Clinical utility of thyrotropin-receptor antibody assays: comparison of radio-receptor and bioassay methods. Mayo Clin Proc 1988;63:707-717 2. Volpe R: Rational use of thyroid function tests. Crit Rev Clin Lab Sci 1997;34:405-438 3. Saravanan P, Dayan CM: Thyroid autoantibodies. Endocrinol Metab Clin North Am 2001;30(2):315-335 4. Grebe SKG: Thyroid disease. In The Genetic Basis of Common Diseases. Second edition. Edited by RA King, JI Rotter, AG Motulsky. New York, Oxford University Press, 2002, pp 397-430

TPO

Thyroperoxidase (TPO) Antibodies, Serum

81765

Clinical Information: Thyroperoxidase (TPO) is an enzyme involved in thyroid hormone synthesis, catalyzing the oxidation of iodide on tyrosine residues in thyroglobulin for the synthesis of triiodothyronine and thyroxine (tetraiodothyronine). TPO is a membrane-associated hemoglycoprotein expressed only in thyrocytes and is one of the most important thyroid gland antigens. Disorders of the thyroid gland are frequently caused by autoimmune mechanisms with the production of autoantibodies. Anti-TPO antibodies activate complement and are thought to be significantly involved in thyroid



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dysfunction and the pathogenesis of hypothyroidism. The determination of TPO antibody levels is the most sensitive test for detecting autoimmune thyroid disease (eg, Hashimoto thyroiditis, idiopathic myxedema, and Graves disease) and detectable concentrations of anti-TPO antibodies are observed in most patients with these disorders. The highest TPO antibody levels are observed in patients suffering from Hashimoto thyroiditis. In this disease, the prevalence of TPO antibodies is about 90% of cases, confirming the autoimmune origin of the disease. These autoantibodies also frequently occur (60%â€“80%) in the course of Graves disease. In patients with subclinical hypothyroidism, the presence of TPO antibodies is associated with an increased risk of developing overt hypothyroidism. Many clinical endocrinologists use the TPO antibody test as a diagnostic tool in deciding whether to treat a patient with subclinical hypothyroidism, and Mayo Medical Laboratories endorses this practice. See Thyroid Function Ordering Algorithm in Special Instructions.

Useful For: Aiding in the diagnosis of thyroid autoimmune disorders Differentiating thyroid autoimmune disorders from nonautoimmune goiter or hypothyroidism As a diagnostic tool in deciding whether to treat a patient who has subclinical hypothyroidism

Interpretation: Values above 9.0 IU/mL generally are associated with autoimmune thyroiditis, but elevations are also seen in other autoimmune diseases. In patients with subclinical hypothyroidism, the presence of thyroperoxidase (TPO) antibodies predicts a higher risk of developing overt hypothyroidism, 4.3% per year versus 2.1% per year in antibody-negative individuals. Furthermore, it raises the concern that such patients may be at increased risk of developing other autoimmune diseases, such as adrenal insufficiency and type 1 diabetes. The frequency of detectable anti-TPO observed in nonimmune thyroid disease is similar to the 10% to 12% observed in a healthy population with normal thyroid function. There is a good association between the presence of autoantibodies against TPO and histological thyroiditis. However, in view of the extensive regenerative capacity of the thyroid under the influence of thyroid-stimulating hormone, chronic thyroid disease may be present for years before the clinical manifestation of hypothyroidism becomes evident, if ever.

Reference Values: 3.25 IU/L during the last trimester, regardless of her clinical remission status. Lesser elevations are only occasionally associated with neonatal thyrotoxicosis. Gestational thyrotoxicosis, which is believed to be due to a combination of human chorionic gonadotropin cross-reactivity on the TSHR and transient changes in thyroid hormone protein binding, is only very rarely associated with an elevated TRAb test. Finding an elevated TRAb test in this setting suggests usually underlying Graves disease. An elevated TRAb test at the conclusion of a course of antithyroid drug treatment is highly predictive of relapse of Graves disease. However, the converse, a normal TRAb test, is not predictive of prolonged remission.

Reference Values: < or =1.75 IU/L

Clinical References: 1. Schott M, Hermsen D, Broecker-Preuss M, et al: Clinical value of the first automated TSH receptor autoantibody assay for the diagnosis of Graves disease: an international multicentre trial. Clin Endocrinol (Oxf) 2009 Oct;71(4):566-573 2. Hermsen D, Broecker-Preuss M, Casati M, et al: Technical evaluation of the first fully automated assay for the detection of TSH receptor autoantibodies. Clin Chim Acta 2009 Mar;401(1-2):84-89 3. Grebe SKG: Thyroid disease. In The Genetic Basis of Common Diseases. Second edition. Edited by RA King, JI Rotter, AG Motulsky. New York, Oxford University Press, 2002, pp 397-430

TBGI

Thyroxine-Binding Globulin (TBG), Serum

9263

Clinical Information: Thyroxine binding globulin (TBG) is the high-affinity serum binding protein for thyroxine and triiodothyronine. Normally, the thyroid adjusts to changing concentrations of TBG by producing more or less thyroid hormone to maintain a constant level of metabolically important free hormone. Elevated TBG levels are associated with influences such as pregnancy, genetic predisposition, oral contraceptives, and estrogen therapy. TBG levels can decrease with androgenic or anabolic steroids, large doses of glucocorticoids, hypoproteinemic states, liver disease, nephrotic syndrome, and congenital TBG variants.

Useful For: Determination of thyroxine-binding globulin levels is particularly useful for cases in which Current as of August 23, 2017 7:11 am CDT


Page 2067

total thyroid hormone levels do not correlate with the thyrometabolic status, most commonly with pregnancy or the use of contraceptive steroids

Interpretation: A change in thyroxine-binding globulin (TBG) concentration may be of hereditary, pathophysiologic, or pharmacologic origin. The TBG concentration indicates whether an abnormally high or low total thyroid hormone concentration is offset by a parallel increase or decrease in TBG concentration. In TBG deficiency, one may find euthyroid patients with extremely low total thyroxine (T4) values. Conversely, patients with high TBG levels may be clinically euthyroid with high serum total T4 values. Twenty-four specimens obtained during various stages of pregnancy yielded results ranging from 27 to 66 mcg/mL with a median of 43 mcg/mL. The literature suggests 47 to 59 mcg/mL as the range of TBG values expected during the third trimester of pregnancy.

Reference Values: Males: 12-26 mcg/mL Females: 11-27 mcg/mL

Clinical References: 1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. 2006, pp 2053-2095 2. Wenzel KW: Pharmacological interference with in vitro tests of thyroid function. Metabolism 1981;30:717-732

T4BPE

Thyroxine-Binding Protein Electrophoresis, Serum

38507

Clinical Information: Normally, almost all thyroxine (99.5%) is bound to thyroxine-binding globulin, prealbumin, and albumin. Deficiencies and aberrant forms of these binding proteins can occur, causing difficulties interpreting thyroid function test results. Such abnormalities may be identified by thyroxine-binding protein electrophoresis.

Useful For: Explaining unusual thyroxine (T4), free T4, and thyroxine-binding globulin (TBG) test results that do not correlate with the patientâ€™s clinical presentation Detecting the presence of aberrant thyroxine-binding proteins such as abnormal forms of albumin and prealbumin Detecting selective deficiency of one of the thyroxine-binding proteins Detecting antibodies to T4 An adjunct to the diagnosis of patients with high T4 concentration due to peripheral hormone resistance by ruling out thyroxine-binding abnormalities

Interpretation: Rare protein-binding abnormalities may be suspected in euthyroid patients having an elevated total thyroxine (T4) but normal thyroxine-binding globulin (TBG). The following example is from a healthy 40-year-old male with familial dysalbuminemic hyperthyroxinemia, a benign familial condition that can be confused with hyperthyroidism: -Increased T4 of 14.4 mcg/dL (normal=5.0-12.5 mcg/dL) -Normal TBG of 20.1 mcg/dL (normal=12-26 mcg/mL) The thyroxine-binding protein electrophoresis (TBPE) assay identified that of the saturating dose of (125)I-T4: -52% was bound to albumin (normal 12%-34%) -36% was bound to thyroxine-binding prealbumin (normal 49%-70%) -13% was bound to TBG (normal 10%-25%) In this example, based on the TBPE findings, this patientâ€™s increased serum T4 was due to increased binding to albumin. This was suggestive of familial dysalbuminemic hyperthyroxinemia (FDH), an inherited abnormality characterized by the presence of a variant serum albumin with preferential affinity for T4.

Reference Values: THYROXINE-BINDING PROTEIN ELECTROPHORESIS 10.3-24.9 mcg T4/dL bound to TBG 11.5-34.1 mcg T4/dL bound to albumin 48.8-70.4 mcg T4/dL bound to prealbumin T4 (THYROXINE), TOTAL ONLY Adult (> or =20 years): 4.5-11.7 mcg/dL Pediatric: 0-5 days: 5.0-18.5 mcg/dL 6 days-2 months: 5.4-17.0 mcg/dL 3-11 months: 5.7-16.0 mcg/dL Current as of August 23, 2017 7:11 am CDT


Page 2068

1-5 years: 6.0-14.7 mcg/dL 6-10 years: 6.0-13.8 mcg/dL 11-19 years: 5.9-13.2 mcg/dL

Clinical References: 1. Hay ID, Klee GG: Thyroid dysfunction. Endocrinol Metab Clin North Am 1988;17:473-509 2. Bartalena L, Robbins J: Thyroid hormone transport proteins. Clin Lab Med 1993;13(3):583-598 3. Wilson JD, Foster DW, Kronenburg MD, et al: Williams textbook of Endocrinology. Ninth edition. WB Saunders Company, 1998

60974

TIA-1, Immunostain Without Interpretation Clinical Information: T-cell intracellular antigen 1 (TIA-1) shows a granular cytoplasmic staining pattern due to its presence in cytotoxic granules. It is involved in cytotoxic cell-mediated immune responses. TIA-1 was first identified in cytotoxic T cells; it is also expressed in normal natural killer (NK) cells and granulocytes. TIA-1 antibody is useful in characterizing neoplasms of cytotoxic T cells or NK cells.

Useful For: Characterizing neoplasms of cytotoxic T cells or natural killer cells Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Felfar RE, Macon WR, Kinney MC, et al: TIA-1 Expression in Lymphoid Neoplasms. Identification of Subsets with Cytotoxic T Lymphocyte or Natural Killer Cell Differentiation. Am J Pathol 1997;150(6):1893-1900 2. Morice WG, Kurtin PJ, Tefferi A, Hanson CA: Distinct Bone Marrow Findings in T-Cell Granular Lymphocytic Leukemia Revealed by Paraffin Section Immunoperoxidase Stains for CD8, TIA-1, and Granzyme B. Blood 2002;99(1):268-274 3. Rudiger T, Ott G, Ott MM, et al: Differential Diagnosis Between Classic Hodgkinâ€™s Lymphoma, T-Cell-Rich B-Cell Lymphoma, and Paragranuloma by Paraffin Immunohistochemistry. Am J Surg Pathol 1998;22(10):1184-1191

FGTIA

Tiagabine (Gabitril), Serum

75019

Reference Values: Report Limit: Reference Range:

5.0 ng/mL or =100 Strongly positive Reference values apply to all ages.


TRAM

Tramadol and Metabolite, Random Urine

62595

Clinical Information: Tramadol, a centrally acting opioid analgesic, is utilized in the treatment of moderate to moderately severe pain. Tramadol acts as an opiate agonist through the binding of the parent drug and its O-desmethyl (M1) metabolite to mu-opioid receptors and through the weak inhibition of norepinephrine and serotonin reuptake. The active metabolite, O-desmethyltramadol, is a considerably more potent mu-opioid receptor agonist than its parent drug. In urine, approximately 30% of tramadol is excreted as unchanged drug, while approximately 60% is excreted as metabolites (N- and O-desmethyltramadol). The half-life of tramadol and O-desmethyltramadol is approximately 7 hours.

Useful For: Monitoring of compliance utilizing tramadol Detection and confirmation of the illicit use of tramadol

Interpretation: The presence of tramadol or O-desmethyltramadol levels of 25 ng/mL or higher is a strong indicator that the patient has used tramadol.

Reference Values: Cutoff: 25 ng/mL

Clinical References: 1. Grond S, Sablotzki: Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43(13):879-923 2. Dayer P, Collart L, Desmeules J: The pharmacology of tramadol. Drugs 1994;47 Suppl 1:3-7

61774

Transcription Factor E3 (TFE3), Immunostain Without Interpretation Clinical Information: Transcription factor E3 (TFE3) is a member of the microphthalmia transcription factor (MiTF)/TFE family of helix-loop-helix transcription factors. TFE3 overexpression is observed in TFE translocation-associated renal cell carcinoma and alveolar soft part sarcoma.

Useful For: Assessment of transcription factor E3 expression Current as of August 23, 2017 7:11 am CDT


Page 2095


Clinical References: 1. Komai Y, Fujiwara M, Fujii Y, et al: Adult Xp11 translocation renal cell carcinoma diagnosed by cytogenetics and immunohistochemistry. Clin Cancer Res 2009;15:1170-1176 2. Vistica DT, Krosky PM, Kenney S, et al: Immunohistochemical discrimination between the ASPL-TFE3 fusion proteins of alveolar soft part sarcoma. J Pediatr Hematol Oncol 2008;30:46-52 3. Argani P, Antonescu CR, Couturier J, et al: PRCC-TFE3 renal carcinomas: morphologic, immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the t(X;1)(p11.2;q21). Am J Surg Pathol 2002;26(12):1553-1566

TRSF

Transferrin, Serum

34623

Clinical Information: Transferrin is a glycoprotein with a molecular weight of 79570 daltons. It consists of a polypeptide strand with 2 N-glycosidically linked oligosaccharide chains and exists in numerous isoforms. The rate of synthesis in the liver can be altered in accordance with the bodyâ€™s iron requirements and iron reserves. Transferrin is the iron transport protein in serum. In cases of iron deficiency, the degree of transferrin saturation appears to be an extremely sensitive indicator of functional iron depletion. The ferritin levels are depressed when there is a deficiency of storage iron. In sideropenia, an iron deficiency can be excluded if the serum transferrin concentration is low, as in inflammation or less commonly, in cases of ascorbic acid deficiency. In screening for hereditary hemochromatosis, transferrin saturation provides a better indication of the homozygous genotype than does ferritin. The treatment of anemia with erythropoietin in patients with renal failure is only effective when sufficient depot iron is present. The best monitoring procedure is to determine transferrin saturation during therapy. Transferrin saturation in conjunction with ferritin gives a conclusive prediction of the exclusion of iron overloading in patients with chronic liver disease.

Useful For: Screening for chronic iron overload diseases, particularly hereditary hemochromatosis Interpretation: Serum iron, total iron binding capacity (TIBC), and percent saturation are useful only in screening for chronic iron overload diseases, particularly hereditary hemochromatosis. Although serum iron, TIBC, and percent saturation are widely used for the diagnosis of iron deficiency, serum ferritin is a much more sensitive and reliable means of demonstrating iron deficiency. In hereditary hemochromatosis, serum iron is usually above 150 mcg/dL and percent saturation exceeds 60%. In advanced iron overload states, the percent saturation often exceeds 90%.


Clinical References: 1. Silverman LM, Christenson RH, Grant GH: Amino acids and proteins. In Textbook of Clinical Chemistry. Edited by NW Tietz. Philadelphia, WB Saunders Company, 1986, pp 519-618 2. Ramsay WNM: The determination of the total iron binding capacity of serum. Clin Chim Acta 1957;1:221-226 3. Tsung SH, Rosenthal WA, Milewski KA: Immunological measurement of transferrin compared with chemical measurement of total iron binding capacity. Clin Chem 1975;21:1063-1066 4. Buffone GJ, Lewis SA, Losefsohn M, Hicks JM: Chemical and immunochemical measurements of total iron binding capacity compared. Clin Chem 1978;24:1788-1791 5. Markowitz H, Fairbanks VF: Transferrin assay and total iron binding capacity. Mayo Clin Proc 1983;58:827-828 6. Szoke D, Panteghini M: Diagnostic value of transferrin. Clin Chim Acta 2012 Aug 16;413(15-16):1184-1189

FGFB

Transforming Growth Factor beta, Serum

58044

Interpretation: Results are intended for research purposes or in attempts to understand the



Page 2096

pathophysiology of unusual immune or inflammatory disorders.

Reference Values: Transforming Growth Factor beta, S:

TACIF 84388

3,465 â€“ 13,889 pg/mL

Transmembrane Activator and CAML Interactor (TACI) Gene, Full Gene Analysis Clinical Information: Transmembrane activator and CAML interactor (TACI) is a member of the tumor-necrosis factor (TNF)-like receptor family, a group of receptors that regulate both survival and apoptosis of immune cells.(1) TACI is encoded by the TACI gene (official symbol, TNFRSF13B). TACI is expressed on the surface of resting B cells and activated T cells, but not resting T cells. TACI interacts with 2 ligands-BAFF (B-cell activating factor), also known as BLys (B-lymphocyte stimulator), which belongs to the TNF family, and APRIL (a proliferation-inducing ligand). The ligands for TACI are expressed on macrophages, monocytes, and dendritic cells.(2) TACI regulates isotype class-switching of immunoglobulins and also is involved in the antibody response to T-independent antigens.(3) The human TACI gene locus is located on the short arm of chromosome 17, which is a common target for variation and rearrangement.(3) The TACI gene consists of 5 exons spanning approximately 35 kb (including 1002 bp upstream of the 5' untranslated region [UTR] and 1024 bp downstream of the 3' UTR). In recent studies, 4 variants (p.L69Tfs*12, p.C104R, p.A181E, p.R202H) have been shown to be statistically significant in common variable immunodeficiency (CVID) and selective IgA deficiency (sIgAD) patients when compared to controls.(4) Two other variants, p.P251L and p.V220A, are considered to be likely benign as they are present in both controls and patients.(4-6) The TACI gene variants described so far are nonsense, missense, or frameshift variants, all of which can be detected by gene sequencing. CVID is a complex, heterogeneous disease with defects in 1 or more of these pathways: B-cell survival; circulating memory B cells (CD27+), including class-switched (CD27+IgM-IgD-), nonswitched (CD27+IgM+IgD+), and IgM-memory B cells (CD27+IgM+IgD-); B-cell activation after receptor cross-linking; T-cell signaling; and cytokine expression. CVID patients have hypogammaglobulinemia with impaired functional antibody responses among other clinical features. While the molecular basis for most cases of CVID and sIgAD remains unknown, a fraction of CVID cases (approximately 20%-25%) have been reported to be associated with variants in the TACI gene, ICOS, BAFF-R, or CD19. There are several other genes reported with CVID or CVID-like disease that are not discussed here. Most cases of CVID are sporadic, but at least 10% are familial with a predominance of autosomal dominant over autosomal recessive inheritance. TACI gene mutations account for 8% to 15% of CVID cases depending on the study population and are sporadic in the majority of cases. The familial TACI gene variants can be inherited in either an autosomal dominant or autosomal recessive fashion. TACI gene variants can also display incomplete penetrance, indicating that not all carriers of TACI gene variants develop the disease phenotype.()7) TACI gene variants appear to be strongly associated with lymphoproliferative diseases such as splenomegaly or tonsillar hypertrophy. Autoimmune thyroiditis is observed in 15% of TACI gene variant-positive CVID cases. Heterozygous TACI gene variants are associated with CVID and autoimmunity, while homozygous TACI gene variants appears to protect against autoimmunity (8, 9). The known TACI gene variants appear, in most cases, to be associated with normal protein expression with aberrant or absent functional activity. Consequently, the vast majority (approximately 95%) of cases cannot be identified by the flow cytometry analysis (see CVID / CVID Confirmation Flow Panel)). In or =100 Strongly positive Reference values apply to all ages.


TREE3

Tree Panel # 3

81704





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 2101

TREE4

Tree Panel # 4

81705





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



61206

Treponema pallidum, Immunostain Without Interpretation Clinical Information: Syphilis is caused by infection with the spirochete Treponema pallidum. Transmission of Treponema pallidum occurs via penetration of the spirochetes through mucosal membranes and abrasions on epithelial surfaces. It is primarily spread through sexual contact but can be spread by exposure to blood products and transferred in utero.

Useful For: Identification of Treponema pallidum in tissues Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If Current as of August 23, 2017 7:11 am CDT


Page 2102

a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Fernandez-Flores A: Immunostaining for Treponema pallidum: caution in its evaluation. Am J Dermatopathol 2010;32(5):523-526 2. Martin-Ezquerra G, Fernandez-Casado A, Barco D, et al: Treponema pallidum distribution patterns in mucocutaneous lesions of primary and secondary syphilis: an immunohistochemical and ultrastructural study. Hum Pathol 2009;40:624-630 3. Quatresooz P, Perard GE: Skin homing of Treponema pallidum in early syphilis-an immunohistochemical study. Appl Immunohistochem Mol Morphol 2009;17(1):47-50 4. Buffet M, Grange PA, Gerhardt P, et al: Diagnosing Treponema pallidum in secondary syphilis by PCR and immunohistochemistry. J Investig Dermatol 2007;127:2345-2350

FHAL

Triazolam (Halcion)

90119

Reference Values: Reference Range: 5.0 - 20.0 ng/mL

STRIC

Trichinella Antibody, Serum

9017

Clinical Information: Trichinosis is an infection by the nematode parasite, Trichinella spiralis. The infection is acquired by ingestion of larvae in inadequately cooked, contaminated meat, especially pork, bear, and walrus meat may also be sources of infection. After ingestion, acid-pepsin digestion in the stomach liberates the larvae, which develop into adult worms in the small intestine. After fertilization, the female worm produces larvae that penetrate the mucosa and seed the skeletal muscles via the blood stream. In muscle fibers they coil and encyst, remaining viable for up to several years. Diarrhea is the most common symptom associated with intestinal infection with adult worms. Subsequently, during systemic invasion by the larvae, fever, periorbital swelling, muscle pain and swelling, and pulmonary symptoms and rash develop.

Useful For: As an adjunct in the diagnosis of trichinosis Interpretation: A positive enzyme-linked immunosorbent assay (ELISA) suggests current infection with Trichinella spiralis. Serology should be used in conjunction with clinical, epidemiologic, and other laboratory tests to establish the correct diagnosis. The number of individuals showing positive results may vary significantly between populations and geographic regions.


Clinical References: Grove DI: Tissue nematodes. In Principles and Practice of Infectious Diseases. Fourth edition. Edited by GL Mandell, et al. New York, Churchill Livingstone, 1995

FFTRU

Trichloroacetic Acid, Urine

91099

Reference Values: Creatinine: >50 mg/dL Trichloroethane Exposure: Normal (unexposed population): None detected Exposed: Biological Exposure Index (BEI): 10 mg/L (end of workweek) Toxic: Not established



Page 2103

Trichloroethylene Exposure: Normal (unexposed population): None detected Exposed: Biological Exposure Index (BEI): 100 mg/g creat (end of workweek) Biological Tolerance Value (BAT): 100 mg/L (end of exposure or end of shift, or after several shifts for long-term exposure) Toxic: Not established Tetrachloroethylene (Perchloroethylene) Exposure: Normal (unexposed population): None detected Exposed: Biological Exposure Index (BEI): 7.0 mg/L (end of workweek) Toxic: Not established

FFTRE

Trichloroethylene, Occupational Exposure, blood

90306

Reference Values: Free Trichloroethanol Units: mg/L Normal (Unexposed Population): None Detected Exposed: Biological Exposure Index (BEI): 4.0 mg/L (end of shift at end of workweek) Biological Tolerance Value (BAT): 5.0 mg/L (end of exposure or end of shift, or after several shifts for long term exposure) Toxic: Not established Trichloroethylene Units: mg/L Normal (unexposed population): None Detected Exposed: Not established Toxic: Greater than 1.5 mg/L

TRVI

Trichoderma viride, IgE

82853




Page 2104





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



TVRNA

Trichomonas vaginalis by Nucleic Acid Amplification

61755

Clinical Information: Trichomonas vaginalis (TV) is a protozoan parasite that commonly infects the genital tract of men and women. It is now considered to be the most common curable sexually transmitted disease (STD) agent, with an estimated 3.7 million infected individuals in the United States.(1-4) Although up to 70% of infected individuals are asymptomatic, infections may be associated with vaginitis, urethritis, and cervicitis in women, and urethritis and prostatitis in men.(3) Patients that are infected with Trichomonas vaginalis have an increased risk of acquiring other sexually transmitted infections such as HIV, while infections in pregnant women are associated with premature labor, low-birth-weight offspring, premature rupture of membranes, and posthysterectomy/postabortion infection.(3) Symptoms of Trichomonas vaginalis overlap considerably with other sexually transmitted infections and, therefore, laboratory diagnosis is required for definitive diagnosis. The most commonly used method for detection is microscopic examination of a wet-mount preparation of vaginal secretions. However, this method has only 35% to 80% sensitivity compared with culture.(5) Culture also suffers from relatively low sensitivity (38%-82%) when compared to molecular methods.(5) Culture is also technically challenging and takes 5 to 7 days to complete. Molecular methods, such as the APTIMA Trichomonas vaginalis Assay, offer the highest sensitivity and specificity for detection of trichomoniasis. The APTIMA test utilizes target capture, transcription-mediated amplification (TMA), and hybridization protection assay (HPA) technologies for detection of Trichomonas vaginalis ribosomal RNA (rRNA).

Useful For: Detection of Trichomonas vaginalis Interpretation: A positive result is considered indicative of current or recent Trichomonas vaginalis infection (trichomoniasis). Current as of August 23, 2017 7:11 am CDT


Page 2105


Clinical References: 1. Weinstock H, Berman S, Cates W Jr: Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004;36(1):6-10 2. Soper D: Trichomoniasis: under control or undercontrolled? Am J Obstet Gynecol 2004;190(1):281-290 3. Centers for Disease Control and Prevention (CDC) Trichomoniasis-CDC Fact Sheet. Available from URL: http://www.cdc.gov/std/trichomonas/stdfact-trichomoniasis.htm Accessed August 2012 4. Schwebke JR, Burgess D: Trichomoniasis. Clin Microbiol Rev 2004;17(4):794-803 5. Wendel KA, Erbelding EJ, Gaydos CA, Rompalo AM: Trichomonas vaginalis polymerase chain reaction compared with standard diagnostic and therapeutic protocols for detection and treatment of vaginal trichomoniasis. Clin Infect Dis 2002;35(5):576-580

MTRNA 61756

Trichomonas vaginalis, Miscellaneous Sites, by Nucleic Acid Amplification Clinical Information: Trichomonas vaginalis (TV) is a protozoan parasite that commonly infects the genital tract of men and women. It is now considered to be the most common curable sexually transmitted disease (STD) agent, with an estimated 3.7 million infected individuals in the United States.(1-4) Although up to 70% of infected individuals are asymptomatic, infections may be associated with vaginitis, urethritis, and cervicitis in women, and urethritis and prostatitis in men.(3) Patients that are infected with Trichomonas vaginalis have an increased risk of acquiring other sexually transmitted infections such as HIV, while infections in pregnant women are associated with premature labor, low-birth-weight offspring, premature rupture of membranes, and post-hysterectomy/post-abortion infection.(3) Symptoms of Trichomonas vaginalis overlap considerably with other sexually transmitted infections, and therefore, laboratory diagnosis is required for definitive diagnosis. The most commonly used method for detection is microscopic examination of a wet-mount preparation of vaginal secretions. However, this method has only 35% to 80% sensitivity compared with culture.(5) Culture also suffers from relatively low sensitivity (38%-82%) when compared to molecular methods.(5) Culture is technically challenging and takes 5 to 7 days to complete. Molecular methods, such as the APTIMA Trichomonas vaginalis Assay, offer high sensitivity and specificity for detection of trichomoniasis. The APTIMA test utilizes target capture, transcription-mediated amplification (TMA), and hybridization protection assay (HPA) technologies for detection of Trichomonas vaginalis ribosomal RNA (rRNA).

Useful For: Detection of Trichomonas vaginalis Interpretation: A positive result is considered indicative of current or recent Trichomonas vaginalis infection (trichomoniasis).


Clinical References: 1. Weinstock H, Berman S, Cates W Jr: Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health 2004;36(1):6-10 2. Soper D: Trichomoniasis: under control or undercontrolled? Am J Obstet Gynecol 2004;190(1):281-290 3. Centers for Disease Control and Prevention (CDC) Trichomoniasis-CDC Fact Sheet. Available from URL: http://www.cdc.gov/std/trichomonas/stdfact-trichomoniasis.htm Accessed August 2012 4. Schwebke JR, Burgess D: Trichomoniasis. Clin Microbiol Rev 2004;17(4):794-803 5. Wendel KA, Erbelding EJ, Gaydos CA, Rompalo AM: Trichomonas vaginalis polymerase chain reaction compared with standard diagnostic and therapeutic protocols for detection and treatment of vaginal trichomoniasis. Clin Infect Dis 2002;35(5):576-580

TCPT

Trichophyton rubrum, IgE

82720

Clinical Information: Clinical manifestations of immediate hypersensitivity (allergic) diseases are caused by the release of proinflammatory mediators (histamine, leukotrienes, and prostaglandins) from immunoglobulin E (IgE)-sensitized effector cells (mast cells and basophils) when cell-bound IgE



Page 2106

antibodies interact with allergen. In vitro serum testing for IgE antibodies provides an indication of the immune response to allergen(s) that may be associated with allergic disease. The allergens chosen for testing often depend upon the age of the patient, history of allergen exposure, season of the year, and clinical manifestations. In individuals predisposed to develop allergic disease(s), the sequence of sensitization and clinical manifestations proceed as follows: eczema and respiratory disease (rhinitis and bronchospasm) in infants and children less than 5 years due to food sensitivity (milk, egg, soy, and wheat proteins) followed by respiratory disease (rhinitis and asthma) in older children and adults due to sensitivity to inhalant allergens (dust mite, mold, and pollen inhalants).




Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



TRPU

Trichosporon pullulans, IgE

82386


Useful For: Testing for IgE antibodies may be useful to establish the diagnosis of an allergic disease and to define the allergens responsible for eliciting signs and symptoms. Testing also may be useful to identify allergens which may be responsible for allergic disease and/or anaphylactic episode, to confirm sensitization to particular allergens prior to beginning immunotherapy, and to investigate the specificity of Current as of August 23, 2017 7:11 am CDT


Page 2107

allergic reactions to insect venom allergens, drugs, or chemical allergens.



Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



TWSS

Trichrome Water Soluble Stain (Bill Only)

9857


TGLBF

Triglycerides, Body Fluid

61647

Clinical Information: The presence of a chylous effusion, which results from lymphatic drainage into a body cavity, can be determined by identifying triglycerides and chylomicrons in the fluid. Catheter-related iatrogenic effusions can be identified by determining the presence of intravenous solution constituents in the fluid.

Useful For: Distinguishing between chylous and nonchylous effusions Determining if bleeding has occurred in a body fluid Identifying iatrogenic effusions

Interpretation: A triglyceride concentration above 110 mg/dL is highly suggestive of a chylous effusion.


Clinical References: Ellefson RD, Elveback L, Weidman W: Plasma lipoproteins of children and youths in Rochester, MN. DHEW Publication No. (NIH) 1978;1478-1472

TRIGC

Triglycerides, CDC, Serum

21090

Reference Values: Only orderable as part of a profile. For more information see LMPP / Lipoprotein Metabolism Profile.



Page 2108

TRIG

Triglycerides, Serum

8316

Clinical Information: Triglycerides are esters of the trihydric alcohol glycerol with 3 long-chain fatty acids. They are partly synthesized in the liver and partly derived from the diet. Increased plasma triglyceride levels are indicative of a metabolic abnormality and, along with elevated cholesterol, are considered a risk factor for atherosclerotic disease. Hyperlipidemia may be inherited or be associated with biliary obstruction, diabetes mellitus, nephrotic syndrome, renal failure, or metabolic disorders related to endocrinopathies. Increased triglycerides may also be medication-induced (eg, prednisone). Since cholesterol and triglycerides can vary independently, measurement of both is more meaningful than the measurement of cholesterol only.

Useful For: Evaluation of risk factors in individuals with elevated cholesterol values Interpretation: In the presence of other coronary heart disease risk factors, both borderline-high (150-199 mg/dL) and high values (>200 mg/dL) require attention. Triglyceride concentrations above 1,000 mg/dL can lead to abdominal pain and may be life-threatening due to chylomicron-induced pancreatitis.

Reference Values: The National Lipid Association and the National Cholesterol Education Program (NCEP) have set the following guidelines for lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and Non HDL cholesterol) in adults ages 18 and up: TRIGLYCERIDES Normal: or =500 mg/dL The Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents has set the following guidelines for lipids (total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and non-HDL cholesterol) in children ages 2 to 17: TRIGLYCERIDES 2-9 years: Acceptable: or =100 mg/dL 10-17 years: Acceptable: or =130 mg/dL

Clinical References: 1. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood. St. Louis, MO: Elsevier Saunders, 2012 2. Rifai N, Warnick GR: Laboratory Measurements of Lipids, Lipoproteins and Apolipoproteins. AACC Press, Washington, DC, 1994 3. Jacobson TA, Ito MK, Maki KC, et al: National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1-executive summary. J Clin Lipidol 2014;8(5):473-488 4. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Pediatrics 2011;128;S213

TMA

Trimellitic Anhydride, TMA, IgE

82867




Page 2109





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



TMP

Trimethoprim, Serum

80146

Clinical Information: Trimethoprim is coadministered with sulfamethoxazole for prophylaxis or treatment of bacterial infections. These agents are used to treat a variety of infections including methicillin-resistant Staphylococcus aureus, and for prophylaxis in immunosuppressed patients such as HIV-positive individuals. Trimethoprim has a wide therapeutic index and dose-dependent toxicity. Trimethoprim accumulates in patients with renal failure. Therapeutic drug monitoring is not commonly performed unless there are concerns about adequate absorption, clearance, or compliance. Accordingly, routine drug monitoring is not indicated in all patients.

Useful For: Monitoring trimethoprim therapy to ensure drug absorption, clearance, or compliance Interpretation: Most patients will display peak steady state serum concentrations >2.0 mcg/mL when drawn at least 1 hour after an oral dose. Target concentrations may be higher, depending on the intent of therapy.

Reference Values: >2.0 mcg/mL

Clinical References: 1. Kamme C, Melander A, Nilsson N: Serum and saliva concentrations of sulfamethoxazole and trimethoprim in adults in children: relation between saliva concentrations and in vitro activity against nasopharyngeal pathogens. Scand J Infect Dis 1983;15:107-113 2. Young T, Current as of August 23, 2017 7:11 am CDT


Page 2110

Oliphant C, Araoyinbo I, Volmink J: Co-trimoxazole prophylaxis in HIV: the evidence. S Afr Med J 2008 April;98(4):258-259 3. Avdic E, Cosgrove S: Management and control strategies for community-associated methicillin-resistant Staphylococcus aureus. Expert Opin Pharmacother 2008 June;9(9):1463-1479 4. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill Publishing, 2006, p 1112

TRMP

Trimipramine, Serum

64269

Clinical Information: Trimipramine is a tricyclic antidepressant with additional anxiety-reducing sedative activity. Daily dosages for adults range from 50 mg to 300 mg and are usually divided into 2 to 3 doses per day. Therapeutic ranges are based on serum samples collected at trough (ie, immediately before the next dose). Peak serum concentrations are typically achieved after 1 to 6 hours postdosage. Common adverse effects include hypotension, tachycardia, constipation, dizziness, somnolence, and blurred vision. Risk of toxicity increases when concentrations >500 ng/mL. Serious adverse effects include coma, seizures, and QRS prolongation with ventricular dysrhythmias.

Useful For: Monitoring serum concentration during therapy Evaluating potential toxicity The test may also be useful to evaluate patient compliance

Interpretation: Most individuals display optimal response to trimipramine with serum levels of 150 to 300 ng/mL. Risk of toxicity is increased with trimipramine levels >500 ng/mL. Some individuals may respond well outside of this range, or may display toxicity within the therapeutic range; thus, interpretation should include clinical evaluation. Therapeutic ranges are based on specimens drawn at trough (ie, immediately before the next dose).

Reference Values: Therapeutic concentration: 150-300 ng/mL Note: Therapeutic ranges are for specimens drawn at trough (ie, immediately before next scheduled dose). Levels may be elevated in non-trough specimens.

TPPTF 89540

Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Fibroblasts Clinical Information: The neuronal ceroid lipofuscinoses (NCL) comprise a group of recessively inherited neurodegenerative disorders involved in lysosomal protein catabolism. Clinically, they are characterized by vision loss, seizures, mental regression, behavioral changes, movement disorders, and the accumulation of autofluorescent storage material in the brain and tissues. Although at least 12 different genes have been identified, the NCLs have traditionally been categorized based on age of symptom onset: infantile, late-infantile, juvenile, and adult. Infantile and late-infantile NCL are caused primarily by defects in PPT1 and TPP1, respectively. Tissue damage is selective for the nervous system and many patients die in the first decade of life due to central nervous system degeneration. There is an overall incidence in the United States estimated at 1 in 12,500. Children affected by infantile NCL (CLN1) typically have normal growth and development until about 6 to 12 months of age. Slowed head growth occurs at around 9 months followed by psychomotor degeneration, seizures, and progressive macular degeneration leading to blindness by the age of 2. CLN1 is caused by a deficiency of the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1), which cleaves long-chain fatty acids (usually palmitate) from cysteine residues. Electron microscopy shows granular osmophilic deposits (GRODs) in most cell types. PPT1 is thought to play an active role in various cell processes including apoptosis, endocytosis, and lipid metabolism. Infantile NCL has an incidence of 1 in 20,000 in Finland and is rare elsewhere. The late infantile form of NCL (CLN2) is primarily caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1), which cleaves tripeptides from the N-terminus of polypeptides. Tissue damage results from the defective degradation and consequent accumulation of storage material with a curvilinear profile by electron microscopy. There is widespread loss of neuronal tissue especially in the cerebellum and hippocampal region. Disease onset occurs at 2 to 4 years of age with seizures, ataxia, myoclonus, psychomotor retardation, vision loss and speech impairment. Diagnostic strategy depends on the age of onset of symptoms. In children presenting between the ages 0 to 4 years, enzyme assay of PPT1 and TPP1



Page 2111

is an appropriate first step. In addition, molecular genetic testing of PPT1 or TPP1 may allow for identification of the disease causing mutations.

Useful For: Evaluation of patients with clinical presentations suggestive of neuronal ceroid lipofuscinoses (NCL) An aid in the differential diagnosis of infantile and late infantile NCL when fibroblasts are available NCL testing in fibroblast specimens

Interpretation: Tripeptidyl peptidase 1 (TPP1) and palmitoyl-protein thioesterase 1 (PPT1) enzyme activity below 5 nmol/h/mg of protein are highly suggestive of late infantile and infantile neuronal ceroid lipofuscinoses (NCL), respectively.

Reference Values: TRIPEPTIDYL PEPTIDASE 1 69-934 nmol/h/mg protein PALMITOYL-PROTEIN THIOESTERASE 1 30-194 nmol/h/mg protein

Clinical References: 1. Mole S, Cotman S: Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochem et Biophys Acta 2015;1852:2237-2241 2. Kavianen R: Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency. Eur J Neur 2007;14:369-372 3. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 749-750 4. Mole SE, Williams RE: Neuronal Ceroid-Lipofuscinoses. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle, 1993-2016. Updated 2013 Aug 1. Available at www.ncbi.nlm.nih.gov/books/NBK1428/

TPPTL 89494

Tripeptidyl Peptidase 1 (TPP1) and Palmitoyl-Protein Thioesterase 1 (PPT1), Leukocytes Clinical Information: The neuronal ceroid lipofuscinoses (NCL) comprise a group of recessively inherited neurodegenerative disorders involved in lysosomal protein catabolism. Clinically they are characterized by vision loss, seizures, mental regression, behavioral changes, movement disorders, and the accumulation of autofluorescent storage material in the brain and tissues. Although at least 12 different genes have been identified, the NCL have traditionally been categorized based on the age of onset of symptoms: infantile, late-infantile, juvenile, and adult. Infantile and late-infantile NCL are caused primarily by defects in PPT1 and TPP1, respectively Tissue damage is selective for the nervous system and many patients die in the first decade of life due to central nervous system degeneration. There is an overall incidence in the United States estimated at 1 in 12,500. Children affected by infantile NCL (CLN1) typically have normal growth and development until about 6 to 12 months of age. Slowed head growth occurs at around 9 months followed by psychomotor degeneration, seizures, and progressive macular degeneration leading to blindness by the age of 2. CLN1 is caused by a deficiency of the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1), which cleaves long-chain fatty acids (usually palmitate) from cysteine residues. Electron microscopy shows granular osmophilic deposits (GRODs) in most cell types. PPT1 is thought to play an active role in various cell processes including apoptosis, endocytosis, and lipid metabolism. Infantile NCL has an incidence of 1 in 20,000 in Finland and is rare elsewhere. The late infantile form of NCL (CLN2) is primarily caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1), which cleaves tripeptides from the N-terminus of polypeptides. Tissue damage results from the defective degradation and consequent accumulation of storage material with a curvilinear profile by electron microscopy. There is widespread loss of neuronal tissue especially in the cerebellum and hippocampal region. Disease onset occurs at 2 to 4 years of age with seizures, ataxia, myoclonus, psychomotor retardation, vision loss, and speech impairment. Diagnostic strategy depends on the age of onset of symptoms. In children presenting between the ages 0 to 4 years, enzyme assay of PPT1 and TPP1 is an appropriate first step. In addition, molecular genetic testing of PPT1 or TPP1 may allow for identification of the disease causing mutations.

Useful For: Evaluation of patients with clinical presentations suggestive of neuronal ceroid Current as of August 23, 2017 7:11 am CDT


Page 2112

lipofuscinoses (NCL) An aid in the differential diagnosis of infantile and late infantile NCL

Interpretation: Tripeptidyl peptidase 1 (TPP1) and palmitoyl-protein thioesterase 1 (PPT1) enzyme activity below 5 nmol/hour/mg of protein are highly suggestive of late-infantile and infantile neuronal ceroid lipofuscinoses (NCL), respectively.

Reference Values: TRIPEPTIDYL PEPTIDASE 1 85-326 nmol/hour/mg protein PALMITOYL-PROTEIN THIOESTERASE 1 20-93 nmol/hour/mg protein

Clinical References: 1. Mole S, Cotman S: Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochem et Biophys Acta 2015;1852:2237-2241 2. Kavianen R: Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency. Eur J Neur 2007;14:369-372 3. Enns GM, Steiner RD, Cowan TM: Lysosomal disorders. In Pediatric Endocrinology and Inborn Errors of Metabolism. Edited by K Sarafoglou, GF Hoffmann, KS Roth, New York, McGraw-Hill Medical Division, 2009, pp 749-750 4. Mole SE, Williams RE: Neuronal Ceroid-Lipofuscinoses. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al: University of Washington, Seattle, 1993-2016. Updated 2013 Aug 1. Available at www.ncbi.nlm.nih.gov/books/NBK1428/

FFTRP

Trofile Co-Receptor Tropism Assay

91774

Useful For: To determine the co-receptor tropism (CCR5, CXCR4, or dual/mixed) of a patient's HIV-1 strain for selection of CCR5 co-receptor antagonist therapy, when a patient's HIV-1 viral load is > or = 1,000 copies/mL.

Interpretation: CCR5 Tropic (R5) HIV-1 Virus uses CCR5 to enter CD4+ cells. CXCR4 Tropic (X4) HIV-1 Virus uses CXCR4 to enter CD4+ cells DUAL/MIXED Tropic (D/M) HIV-1 Dual-tropic viruses can use either CCR5 or CXCR4 to enter CD4+ cells. Mixed-tropic populations contain viruses with two or more tropisms. Non-reportable Co-receptor tropism could not be determined by the Trofile assay. Common causes of a non-reportable result are viral load or =11.5 ng/mL may indicate mast cell activation Current as of August 23, 2017 7:11 am CDT


Page 2119

occurring as a result of anaphylaxis or allergen challenge, or it may indicate increased number of mast cells as seen in patients with mastocytosis.

Reference Values: 80% (Although, tubular reabsorption of phosphorus levels must be interpreted in light of the prevailing plasma phosphorus and glomerular filtration rate.) TUBULAR MAXIMUM PHOSPHORUS REABSORPTION/GLOMERULAR FILTRATION RATE (TmP/GFR) 2.6-4.4 mg/dL (0.80-1.35 mmol/L) PHOSPHORUS (INORGANIC) Males 1-4 years: 4.3-5.4 mg/dL 5-13 years: 3.7-5.4 mg/dL 14-15 years: 3.5-5.3 mg/dL 16-17 years: 3.1-4.7 mg/dL > or =18 years: 2.5-4.5 mg/dL Reference values have not been established for patients that are or =18 years: 2.5-4.5 mg/dL Reference values have not been established for patients that are or =16 years: 0.8-1.3 mg/dL Reference values have not been established for patients that are or =16 years: 0.6-1.1 mg/dL Reference values have not been established for patients that are or =100 Strongly positive Reference values apply to all ages.


TURKF

Turkey Feathers, IgE

82824





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 2124


FGORG

Turkey IgG

57641



FCTUR

Turmeric (Curcuma longa) IgE

57544





Page 2126


60979

Tyrosinase (TYROS), Immunostain Without Interpretation Clinical Information: Tyrosinase is expressed in the majority of melanomas, making it a useful diagnostic marker. This antibody will detect the tyrosinase enzyme in the cytoplasm of normal melanocytes as well as cells of malignant melanoma.

Useful For: An aid in the identification of normal melanocytes and malignant melanoma Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Clarkson KS, Sturdgess IC, Molyneux AJ: The Usefulness of Tyrosinase in the Immunohistochemical Assessment of Melanocytic Lesions: A Comparison of the Novel T311 Antibody (Anti-Tyrosinase) with S-100, HMB45, and A103 (anti-Melan-A). J Clin Pathol 2001;54:196-200 2. Orchard GE: Comparison of Immunohistochemical Labelling of Melanocyte Differentiation Antibodies Melan-A, Tyrosinase and HMB 45 with NKIC3 and S100 Protein in the Evaluation of Benign Naevi and Malignant Melanoma. The Histochemical Journal 2000;32(8):475-481 3. Kaufmann O, Koch S, Gurghardt J, et al: Tyrosinase, Melan-A, and KBA62 as Markers for the Immunohistochemical Identification of Metastatic Amelanotic Melanomas on Paraffin Sections. Modern Pathology 1998;11(8):740-746 4. Torres-Mora J, Dry S, Li X, et al: Malignant Melanotic Schwannian Tumor. A Clinicopathologic, Immunohistochemical, and Gene Expression Profiling Study of 40 Cases, with a Proposal for the Reclassification of Melanotic Schwannoma: Am J Surg Pathol 2014;38(1):94-105 5. Xu X, Chu AY, Pasha T, et al: Immunoprofile of MITF, Tyrosinase, Melan-A, and MAGE-1 in HMB-45 Negative Melanomas. Am J Surg Pathol 2002;26(1):82-87

FSABI

Tysabri (Natalizumab) Immunogenicity

58004


UBE3Z

UBE3A Gene, Full Gene Analysis

35565

Clinical Information: Angelman syndrome (AS) is characterized by significant developmental delay and mental retardation, ataxia, jerky arm movements, unprovoked laughter, seizures, and virtual absence of speech. AS has several known genetic causes. About 65% to 80% of affected individuals have a de novo deletion of essentially the same region of chromosome 15 detected for Prader-Willi syndrome (PWS): 15q11.2-13. The deletion can often be identified by high-resolution chromosome analysis in conjunction with FISH analysis. Molecular testing has shown that the AS deletion occurs only on the copy of chromosome 15 inherited from the mother. In about 5% of patients with AS, the affected individuals have inherited 2 copies of chromosome 15 from their father (paternal uniparental disomy) and no copies of chromosome 15 from their mother. Thus, the individuals with AS resulting from deletion or uniparental disomy are deficient for maternally derived genes from chromosomes 15. Deletions and uniparental disomy occur as de novo events during conception, so the recurrence risk to siblings is very low. Both of these genetic alterations, along with imprinting center defects (accounting for another 2%-5% of AS cases), cause an abnormal methylation pattern in the PWS/AS region of chromosome 15. Another 10% of patients with AS have a documented mutation in the UBE3A gene located in the PW/AS



Page 2127

region on chromosome 15. Mutations can either be maternally inherited in an autosomal dominant fashion or de novo. If the mutation is inherited, the risk to all future pregnancies is 50%. If testing of the affected individual's mother confirms she does not carry the mutation, the risk to future pregnancies is low but not zero, as cases of germline mosaicism have been reported. Individuals with a UBE3A mutation will display a normal methylation pattern. No chromosomal or DNA abnormality has been identified in the remainder of clinically diagnosed AS patients (15%-25%). These patients may have genetic alterations that cannot be detected by current testing methods or alterations in as yet unidentified genes. Initial studies to rule-out AS should include high-resolution cytogenetic analysis (CMS / Chromosome Analysis, for Congenital Disorders, Blood) to identify chromosome abnormalities that may have phenotypic overlap with AS, and methylation-sensitive, multiple ligation-dependent probe amplification (PWAS / Prader-Willi/Angelman Syndrome, Molecular Analysis) to identify deletions, duplications, and methylation defects. In cases where methylation analysis is negative, sequencing of the UBE3A gene may provide additional diagnostic information.

Useful For: Confirmation of a diagnosis of Angelman syndrome in patients who have previously tested negative by methylation analysis



Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: revisions 2007. Genet Med 2008;10(4):294-300 2. Lossie AC, Whitney MM, Amidon D, et al: Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001;38:834-845 3. Van Buggenhout G, Fryns JP: Angelman syndrome (AS, MIM 105830). Eur J Hum Genet 2009;17:1367-1373 4. Williams CA, Geaudet AL, Clayton-Smith J, et al: Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet 2006;140A:413-418

60980

Ubiquitin (UBIQ), Immunostain Without Interpretation Clinical Information: Ubiquitin is a polypeptide of approximately 8.5 kD found in filamentous inclusions and cytosome-related organelles in human idiopathic neurodegenerative diseases, including Alzheimer disease, Pick disease, Lewy body dementia and Parkinson disease. Ubiquitin is also expressed in Rosenthal fibers in astrocytomas. Ubiquitin protein complexes have also been found in primary lysosome-related granules in mature neutrophils. Ubiquitin labels the periphery of senile plaques and of neurofibrillary tangles in Alzheimer disease, Lewy bodies in Parkinsonâ€™s disease, and Mallory bodies in alcoholic liver disease.

Useful For: Classification of neurodegenerative diseases Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request. Please contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Chu CT, Caruso JL, Cummings TJ, et al: Ubiquitin Immunochemistry as a Diagnostic Aid for Community Pathologists Evaluating Patients Who Have Dementia. Modern Pathology 2000;13(4):420-426 2. Josephs KA, Holton JL, Rossor MN, et al: Frontotemporal Lobar Degeneration and Ubiquitin Immunohistochemistry. Neuropathology and Applied Neurobiology. 2004;30:369-373 3. Katsuse O, Dickson DW: Ubiquitin Immunohistochemistry of Frontotemporal Lobar Degeneration Differentiates Cases With and Without Motor Neuron Disease. Alzheimer Dis Assoc Disord 2005;19:S37-S43 4. Lennox G, Lowe J, Landon M, et al: Diffuse Lewy Body Disease: Correlative Neuropathology Using Anti-Ubiquitin Immunocytochemistry. Journal of Neurology, Neurosurgery, and Current as of August 23, 2017 7:11 am CDT


Page 2128

Psychiatry 1989;52:1236-1247 5. Mackenzie IRA, Feldman HH: Ubiquitin Immunohistochemistry Suggests Classic Motor Neuron Disease, Motor Neuron Disease with Dementia, and Frontotemporal Dementia of the Motor Neuron Disease Type Represent a Clincopathologic Spectrum. J Neuropathol Exp Neurol 2005;64(8):730-739

GALE

UDP-Galactose 4' Epimerase (GALE), Blood

64372

Clinical Information: Galactosemia is an autosomal recessive disorder that results from a deficiency of 1 of the 3 enzymes catalyzing the conversion of galactose to glucose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE). Epimerase deficiency galactosemia can be categorized into 3 types: generalized, peripheral, and intermediate. Generalized epimerase deficiency galactosemia results in profoundly decreased enzyme activity in all tissues, whereas peripheral epimerase deficiency galactosemia results in decreased enzyme activity in red and white blood cells, but normal enzyme activity in all other tissues. This is compared to intermediate epimerase deficiency galactosemia which results in decreased enzyme activity in red and white blood cells and less than 50% of normal enzyme levels in other tissues. Clinically, infants with generalized epimerase deficiency galactosemia develop symptoms such as liver and renal dysfunction and mild cataracts when on a normal milk diet, while infants with peripheral or intermediate epimerase deficiency galactosemia do not develop any symptoms. Generalized epimerase deficiency galactosemia is treated by a galactose- and lactose-restricted diet, which can improve or prevent the symptoms of renal and liver dysfunction and mild cataracts. Despite adequate treatment from an early age, individuals with generalized epimerase deficiency galactosemia remain at increased risk for developmental delay and intellectual disability. Unlike patients with classic galactosemia resulting from a GALT deficiency, females with generalized epimerase deficiency galactosemia experience normal puberty and are not at increased risk for premature ovarian failure. Based upon reports by newborn screening programs, the frequency of epimerase deficiency galactosemia in the United States ranges from approximately 1 in 6,700 in African American infants to 1 in 70,000 infants of European ancestry. Galactose-1-phosphate (Gal-1-P) accumulates in the erythrocytes of patients with galactosemia due to either GALT or GALE deficiency. The quantitative measurement of Gal-1-P (GAL1P / Galactose-1-Phosphate (Gal-1-P), Erythrocytes) is useful for monitoring compliance with dietary therapy. Gal-1-P is thought to be the causative factor for development of liver disease in these patients and, because of this, patients should maintain low levels and be monitored on a regular basis. Newborn screening, which identifies potentially affected individuals by measuring total galactose (galactose and Gal-1-P) and/or determining the activity of the GALT enzyme, varies from state to state. The diagnosis of galactosemia is established by follow-up quantitative measurement of GALT enzyme activity. If enzyme levels are normal, but an infant has an elevated Gal-1-P, then epimerase deficiency galactosemia is to be considered. Molecular testing via sequencing of the GALE gene may be performed. See Galactosemia Testing Algorithm in Special Instructions for additional information.

Useful For: Diagnosis of UDP-galactose 4â€™ epimerase deficiency Interpretation: An interpretive report will be provided. See Galactosemia Testing Algorithm in Special Instructions for additional information. For galactokinase deficiency, see GALK / Galactokinase, Blood. For galactose-1-phosphate uridyltransferase deficiency, see GALT / Galactose-1-Phosphate Uridyltransferase, Blood.

Reference Values: >5.0 nmol/h/mg of hemoglobin

Clinical References: 1. Li Y, Huang X, Harmonay L, et al: Liquid chromatography-tandem mass spectrometry enzyme assay for UDP-galactose 4'-epimerase: use of fragment intensity ratio in differentiation of structural isomers. Clin Chem 2014;60:783-790 2. Chen J, Meyers GA, Bennett MJ: An interference-free two-step enzyme assay with UPLC-tandem mass spectrometric product measurement for the clinical diagnosis of uridine diphosphate galactose-4-epimerase deficiency. J Chromatogr B Analyt Technol Biomed Life Sci 2014;959:5-9 3. Fridovich-Keil J, Bean L, He M, et al: Epimerase Deficiency Galactosemia. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. Seattle, WA, University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK51671/ Current as of August 23, 2017 7:11 am CDT


Page 2129

UGTK 89396

UDP-Glucuronosyl Transferase 1A1 (UGT1A1) Gene, Known Mutation Clinical Information: Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia. Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) CN type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. This test is intended for analysis of a specific UGT1A1 gene variant or variants that have already been identified in an affected family member. Analysis is performed for the familial variants only.

Useful For: Identifying the presence of a UGT1A1 variant when the variant has been previously identified in a family member (carrier or affected)

Interpretation: An interpretive report will be provided. UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

UGTKO 60351

UDP-Glucuronosyl Transferase 1A1 (UGT1A1) Gene, Known Mutation, Saliva Clinical Information: Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water



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soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia. Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) Type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. This test is intended for analysis of a specific UGT1A1 gene variant or variants that have already been identified in an affected family member. Analysis is performed for the familial variants only.

Useful For: Identifying the presence of a UGT1A1 variant when the variant has been previously identified in a family member (carrier or affected) Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided. UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital- responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

UGT2 89611

UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia Clinical Information: Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in UGT1A1 may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia. Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated



Page 2131

hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) CN type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. In this assay, the promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants.(4)

Useful For: Identifying individuals who are at risk of hyperbilirubinemia Confirmation of a diagnosis of Gilbert or Crigler-Najjar syndromes Verification of carrier status for Gilbert or Crigler-Najjar syndromes

Interpretation: An interpretive report is provided. UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

UGT2O 60350

UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia, Saliva Clinical Information: Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia. Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) CN type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital treatments of CN may include: phototherapy,



Page 2132

heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. In this assay, the promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants.(4)

Useful For: Identifying individuals who are at risk of hyperbilirubinemia Confirmation of a diagnosis of Gilbert or Crigler-Najjar syndromes Verification of carrier status for Gilbert or Crigler-Najjar syndromes Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report is provided. UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

UGTI 89397

UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient due to mutations in the coding region or promoter TA (thymine, adenine) repeat polymorphisms, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.(2,3) Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice). The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. The promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants in this assay.(4)

Useful For: Identifying individuals who are at increased risk of adverse drug reactions with drugs that Current as of August 23, 2017 7:11 am CDT


Page 2133

are metabolized by UGT1A1, including irinotecan, atazanavir, nilotinib, pazopanib, and belinostat

Interpretation: An interpretive report will be provided. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyl-transferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract No: 2014 3. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41 5. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 6. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther 2015 doi: 10.1002/cpt.269. (Epub ahead of print) 7. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396 8. US Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Accessed November 2015. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm 9. UDP-Glucuronosyltransferase Alleles Nomenclature page. Accessed November 2015. Available at: http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles

UGTIO 60349

UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity, Saliva Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient due to mutations in the coding region or promoter TA (thymine, adenine) repeat polymorphisms, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.(2,3) Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice). The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. The promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants in this assay.(4)

Useful For: Identifying individuals who are at increased risk of adverse drug reactions with drugs that Current as of August 23, 2017 7:11 am CDT


Page 2134

are metabolized by UGT1A1, including irinotecan, atazanavir, nilotinib, pazopanib, and belinostat. Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158 2. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract No: 2014 3. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer 4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41 5. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 6. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther. 2015 doi: 10.1002/cpt.269. (Epub ahead of print) 7. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396 8. US Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htmhttp://ww w.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm - last accessed November 2015 9. UDP-Glucuronosyltransferase Alleles Nomenclature page. Available at: http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles - last accessed November 2015

U1A1 83949

UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1 Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for phase II conjugation of certain drugs, like irinotecan. UGT1A1 is additionally responsible for glucuronide conjugation of bilirubin, which renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine. Reduced UGT1A gene transcription due to variation in the number of thymine-adenine (TA) repeats in the TATA box of the gene promoter results in reduced enzymatic activity and an increased risk for adverse outcomes in response to drugs metabolized by UGT1A1. Such TA repeat variants are also associated with Gilbert syndrome (unconjugated hyperbilirubinemia). The TA repeat number may vary from 5 to 8 TA repeats, with 6 TA repeats being the most common allele (considered the normal allele), resulting in normal UGT1A1 expression. In addition, the rare 5 TA repeat (TA5 or *36: c.-41_-40delTA) has normal UGT1A1 expression. Individuals with 7 TA repeats (TA7 or *28: c.-41_-40dupTA) or the rare 8 TA repeats (TA8 or *37: c.-43_-40dupTATA) have decreased expression of UGT1A1. Approximately 10% to 15% of Caucasians and African Americans are homozygous for the TA7 repeat (*28/*28). UGT1A1 is involved in the metabolism of irinotecan, a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. If UGT1A1 activity is reduced or deficient, the active irinotecan metabolite (SN-38) is less efficiently conjugated with glucuronic acid, which leads to an increased concentration of SN-38. This in turn can result in severe neutropenia; and the combination of neutropenia with diarrhea can be life-threatening. Individuals who are homozygous for *28 (TA7) have a 50% higher risk of experiencing severe (grade 4 or 5) neutropenia following the administration of irinotecan. Approximately 40% of individuals treated with irinotecan are heterozygous for the TA7 repeat allele (ie, TA6/TA7 or



Page 2135

heterozygous *28). These individuals are also at increased risk of grade 4 neutropenia. The drug label for irinotecan indicates that individuals homozygous or heterozygous for TA repeat variants have a higher risk for severe or life-threatening neutropenia. The risk is thought to be greatest in individuals who receive irinotecan once every 3 weeks. Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have reduced activity alleles. Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment that indicate patients who are homozygous for a reduced activity (decreased expression) allele should be considered for an alternate medication due to the significant risk for developing hyperbilirubinemia (jaundice). Gilbert syndrome (GS), found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with usually benign, mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL). Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Homozygosity for the reduced activity alleles, TA7 and TA8, or compound heterozygosity (TA7/TA8) is consistent with a diagnosis of Gilbert syndrome. Heterozygosity for TA7 or TA8 is consistent with carrier status for Gilbert syndrome.

Useful For: Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1; especially irinotecan, but also including nilotinib, pazopanib, and belinostat Identifying individuals with Gilbert syndrome due to the presence of homozygous TA7, homozygous TA8, or compound heterozygous TA7/TA8 Identifying individuals who are carriers of Gilbert syndrome due to the presence of heterozygous TA7 or TA8

Interpretation: An interpretive report will be provided. Drug-drug interactions must be considered when predicting the UGT1A1 phenotype, especially in individuals heterozygous for the TA7 polymorphism (see Cautions). For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 2. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther. 2015 3. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396 4. U.S. Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm 5. UDP-Glucuronosyltransferase Alleles Nomenclature page. Available at www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles

U1A1O 60343

UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1, Saliva Clinical Information: Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate-glycuronosyl transferase 1A1 (UGT1A1), is responsible for phase II conjugation of certain drugs, like irinotecan. UGT1A1 is additionally responsible for glucuronide conjugation of bilirubin, which renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine. Reduced UGT1A gene transcription due to variation in the number of thymine-adenine (TA) repeats in the TATA box of the gene promoter results in reduced



Page 2136

enzymatic activity and an increased risk for adverse outcomes in response to drugs metabolized by UGT1A1. Such TA repeat variants are also associated with Gilbert syndrome (unconjugated hyperbilirubinemia). The TA repeat number may vary from 5 to 8 TA repeats, with 6 TA repeats being the most common allele (considered the normal allele), resulting in normal UGT1A1 expression. In addition, the rare 5 TA repeat (TA5 or *36: c.-41_-40delTA) has normal UGT1A1 expression. Individuals with 7 TA repeats (TA7 or *28: c.-41_-40dupTA) or the rare 8 TA repeats (TA8 or *37: c.-43_-40dupTATA) have decreased expression of UGT1A1. Approximately 10% to 15% of Caucasians and African Americans are homozygous for the TA7 repeat (*28/*28). UGT1A1 is involved in the metabolism of irinotecan, a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. If UGT1A1 activity is reduced or deficient, the active irinotecan metabolite (SN-38) is less efficiently conjugated with glucuronic acid, which leads to an increased concentration of SN-38. This in turn can result in severe neutropenia; and the combination of neutropenia with diarrhea can be life-threatening. Individuals who are homozygous for *28 (TA7) have a 50% higher risk of experiencing severe (grade 4 or 5) neutropenia following the administration of irinotecan. Approximately 40% of individuals treated with irinotecan are heterozygous for the TA7 repeat allele (ie, TA6/TA7 or heterozygous *28). These individuals are also at increased risk of grade 4 neutropenia. The drug label for irinotecan indicates that individuals homozygous or heterozygous for TA repeat variants have a higher risk for severe or life-threatening neutropenia. The risk is thought to be greatest in individuals who receive irinotecan once every 3 weeks. Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have reduced activity alleles. Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment that indicate patients who are homozygous for a reduced activity (decreased expression) allele should be considered for an alternate medication due to the significant risk for developing hyperbilirubinemia (jaundice). Gilbert syndrome (GS), found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with usually benign, mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL). Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Homozygosity for the reduced activity alleles, TA7 and TA8, or compound heterozygosity (TA7/TA8) is consistent with a diagnosis of Gilbert syndrome. Heterozygosity for TA7 or TA8 is consistent with carrier status for Gilbert syndrome.

Useful For: Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1; especially irinotecan, but also including nilotinib, pazopanib, and belinostat Identifying individuals with Gilbert syndrome due to the presence of homozygous TA7, homozygous TA8, or compound heterozygous TA7/TA8 Identifying individuals who are carriers of Gilbert syndrome due to the presence of heterozygous TA7 or TA8 Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided. Drug-drug interactions must be considered when predicting the UGT1A1 phenotype, especially in individuals heterozygous for the TA7 polymorphism (see Cautions). For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.


Clinical References: 1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733 2. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther. 2015 3. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396 4. U.S. Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm 5. Current as of August 23, 2017 7:11 am CDT


Page 2137

UDP-Glucuronosyltransferase Alleles Nomenclature page. Available at www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles

ULCH

Ulocladium chartarum, IgE

82546





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



UNIPD

Uniparental Disomy

35566

Clinical Information: Uniparental disomy (UPD) occurs when a child inherits 2 copies of a chromosome from 1 parent and no copies of that chromosome from the other parent. This error in division occurs during the formation of egg or sperm cells (meiosis). When an error causing UPD occurs during meiosis I both chromosome homologs from a single parent are transmitted, and heterodisomy results. When the error causing UPD occurs during meiosis II or as a postzygotic event, and a single parental homolog is transmitted to offspring in duplicate, isodisomy results. Meiotic recombination events within the context of UPD often result in a mixture of heterodisomy and isodisomy. UPD can involve an entire



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chromosome or only a segment. Mosaicism for UPD also occurs in combination with either chromosomally normal or abnormal cell lines. When UPD occurs, the imbalance of maternal versus paternal genetic information for the involved chromosome can be associated with clinical symptoms in the affected child. UPD does not always impart an abnormal clinical phenotype however. In fact, while isodisomy can result in disease due to a recessive allele at any location, heterodisomy is not expected to result in an abnormal clinical phenotype unless the involved chromosome or chromosomal segment includes imprinted genes. Imprinted genes demonstrate differential expression depending on parent of origin. Disorders that result from UPD of imprinted genes are not due to a defect in the imprinting mechanism itself, but rather they are due to an unbalanced parental contribution of normally imprinted alleles that results in altered expression of imprinted genes. For example, when maternal UPD 15 occurs (2 copies of the maternal chromosome 15 instead of 1 maternal and 1 paternal copy of chromosome 15), it causes Prader-Willi syndrome due to the lack of paternally expressed genes at the imprinted site. UPD has been described for many but not all chromosomes. In addition to the rare cases of autosomal recessive disease that result from isodisomy, clinical syndromes associated with UPD have been described for only a few chromosomes, including Russell-Silver syndrome (UPD 7), Prader-Willi syndrome (UPD 15), Angelman syndrome (UPD 15), transient neonatal diabetes (UPD 6), and UPD of chromosome14. UPD cannot be identified by gross cytogenetic analysis and requires DNA-based analysis using multiple polymorphic markers spanning the chromosome of interest. Specimens from both parents and the child or fetus are required.

Useful For: Evaluation of patients presenting with mosaicism, confined placental mosaicism, or Robertsonian translocations Evaluation of patients presenting with features of disorders known to be associated with uniparental disomy (eg, Russell-Silver syndrome) Evaluation of disease mechanism in individuals with rare autosomal recessive disease and only one carrier parent


Clinical References: 1. Schaffer LG, Agan N, Goldberg JD, et al: American College of Medical Genetics statement on diagnostic testing for uniparental disomy. Genet Med 2001;3:206-211 2. Kotzot D, Utermann G: Uniparental Disomy (UPD) other than 15: phenotypes and bibliography updated. Am J Med Genet 2005;136A:287-305 3. Kotzot D: Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol 2008:31:100-105 4. Engel E: A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements. Eur J Hum Genet. 2006 Nov;14(11):1158-1169

UNHB

Unstable Hemoglobin, Blood

9095

Clinical Information: Unstable hemoglobin disease is rare and may be caused by any 1 of a large number of hemoglobin variants. They are inherited as an autosomal dominant trait. The severity of the disease varies according to the hemoglobin variant; there may be no clinical symptoms or the disease may produce a mild, moderate, or severe hemolytic anemia. The stained peripheral blood smear shows anisocytosis, poikilocytosis, basophilic stippling, polychromasia and, sometimes, hypochromia. The reticulocyte count may be increased. Splenomegaly and Heinz bodies may also be present.

Useful For: Work-up of congenital hemolytic anemias Interpretation: An abnormal or unstable result is indicative of a hemoglobin variant present. Other confirmatory tests should be performed to identify the hemoglobinopathy (HBELC / Hemoglobin Electrophoresis Cascade, Blood).

Reference Values: Only orderable as part of a profile or as a reflex. For more information see HAEVP / Hemolytic Anemia Evaluation; or HBELC / Hemoglobin Electrophoresis Cascade, Blood; or THEVP / Thalassemia and Hemoglobinopathy Evaluation; or REVE / Erthrocytosis Evaluation; or MEVP / Methemoglobinemia Evaluation. Current as of August 23, 2017 7:11 am CDT


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Normal (reported as normal [stable] or abnormal [unstable])

Clinical References: Hoyer JD, Hoffman DR: The thalassemia and hemoglobinopathy syndromes. In Clinical Laboratory Medicine. Second edition. Edited by KD McMlatchey. Philadelphia, Lippincott Williams and Wilkins, 2002, pp 866-895

FURA

Uranium, Urine

90316

Reference Values: Reporting limit determined each analysis Normally: Less than 0.1 mcg/L

URAU

Urea, 24 Hour, Urine

8330

Clinical Information: Urea is a low molecular weight substance (Mol. Wt.=60) that is freely filtered by glomeruli and the majority is excreted into the urine, although variable amounts are reabsorbed along the nephron. It is the major end product of protein metabolism in humans and other mammals. Approximately 50% of urinary solute excretion and 90% to 95% of total nitrogen excretion is composed of urea under normal conditions. Factors which tend to increase urea excretion include increases in glomerular filtration rate, increased dietary protein intake, protein catabolic conditions, and water diuretic states. Factors which reduce urea excretion include low protein intake and conditions which result in low urine output (eg, dehydration).

Useful For: Assessment of protein intake and/or nitrogen balance Interpretation: Because multiple factors (glomerular filtration rate, dietary protein intake, protein catabolic rate, hydration state, etc.) can independently affect the urinary excretion of urea, all of these factors must be taken into account when interpreting the results.

Reference Values: 10-35 g/24 hours

Clinical References: Bankir L, Trinh-Trang-Tan MM: Urea and the kidney. In The Kidney. Sixth edition. Edited by BM Brenner. Philadelphia, WB Saunders Company, 2000

RURAU

Urea, Random, Urine

89845

Clinical Information: Urea is a low molecular weight substance (Mol Wt=60) that is freely filtered by glomeruli and the majority is excreted into the urine, although variable amounts are reabsorbed along the nephron. It is the major end product of protein metabolism in humans and other mammals. Approximately 50% of urinary solute excretion and 90% to 95% of total nitrogen excretion is composed of urea under normal conditions. Factors that tend to increase urea excretion include increases in glomerular filtration rate, increased dietary protein intake, protein catabolic conditions, and water diuretic states. Factors that reduce urea excretion include low protein intake and conditions which result in low urine output (eg, dehydration). Urea excretion is a useful marker of protein metabolism. In oliguric patients with a rising creatinine a fractional excretion of urea 35% are more consistent with acute kidney injury.(2) The fractional excretion of sodium is also used for this purpose, but may be more affected by diuretics. Therefore, the fractional excretion of urea may be particularly useful for patients receiving diuretics.

Useful For: Assessment of renal failure (prerenal vs acute kidney injury) Interpretation: Fractional excretion of urea or =100 Strongly positive Reference values apply to all ages.


UMM3F

Uveal Melanoma, Chromosome 3 Monosomy, FISH, Tissue

35269

Clinical Information: Uveal melanoma is the most common type of primary intraocular malignancy in adults, with an annual incidence of 6 per million. These melanomas arise within pigmented cells of the uveal tract of the eye, which consists of the choroid, ciliary body, and iris. Overall, mortality rates in patients with uveal melanoma are quite high (approximately 50%) and are due to metastatic disease. Identifying patients likely to develop metastasis is critical for establishing patient prognosis. Previous studies have demonstrated that monosomy 3 is highly correlated with the development of metastatic disease in patients with uveal melanoma.

Useful For: As an aid to prognosis in patients with uveal melanoma when used in conjunction with an anatomic pathology consultation

Interpretation: A neoplastic clone is detected when the percent of cells with an abnormality exceeds the normal reference range for chromosome 3 probe set. A positive result is consistent with monosomy 3 and a higher risk for metastatic disease in uveal melanoma patients. A negative result suggests that aneuploidy of chromosome 3 is not present.


Clinical References: 1. Tschentscher F, Prescher G, Horsman DE, et al: Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma. Cancer Res 2001 Apr 15;61(8):3439-3442 2. Prescher G, Bornfeld N, Hirche H, et al: Prognostic implications of monosomy 3 in uveal melanoma. Lancet 1996 May 4;349(9010):1222-1225 3. Cross NA, Ganesh A, Parpia M, et al: Multiple locations onchromosome 3 are the targets of specific deletions in uveal Current as of August 23, 2017 7:11 am CDT


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melanoma. Eye 2006 Apr;20(4):476-481 4. Parrella P, Fazio VM, Gallo AP, et al: Fine mapping of chromosome 3 in uveal melanoma: identification of a minimal region of deletion on chromosomal arm 3p25.1-p25.2. Cancer Res 2003 Dec 1;63(23):8507-8510 5. Onken MD, Worley LA, Person E, et al: Loss of heterozygosity of chromosome 3 detected with single nucleotide polymorphisms is superior to monosomy 3 for predicting metastasis in uveal melanoma. Clin Cancer Res 2007 May 15;13(10):2923-2927

FNSVG

Vaginitis (VG), NuSwab

75140

Clinical Information: This test is intended to be used as an aid to the diagnosis of bacterial vaginosis (BV) in women with a clinical presentation consistent with this disorder. The BV test utilizes semiquantitative PCR analysis of the three most predictive marker organisms (Atopobium vaginae, BVAB-2, and Megasphaera-1) to generate a total score that correlates directly with the presence or absence of BV. In this test system, samples with a score of 0 to 1 are considered negative for BV, samples with a score of 3 to 6 are positive for BV, and samples with a score of 2 are indeterminate for BV.

Useful For: Used to detect the presence of Candida albicans and Candida glabrata DNA in vaginal samples as an aid to the diagnosis of vulvovaginal candidiasis in symptomatic women. Also used in the diagnosis of Trichomonas vaginalis infections.

Reference Values: Candida albicans, NAA: Candida glabrata, NAA: Trich vag by NAA:

Negative Negative Negative

VALPG

Valproic Acid, Free and Total, Serum

37067

Clinical Information: Valproic acid (valproate, Depakote, or Depakene) is an effective medication for absence seizures, generalized tonic-clonic seizures, and partial seizures, when administered alone or in conjunction with other antiepileptic agents. The valproic acid that circulates in blood is 85% to 90% protein-bound under normal circumstances. In uremia or during concomitant therapy with other drugs that are highly protein-bound (such as phenytoin), valproic acid is displaced from protein, resulting in a higher free fraction of the drug circulating in blood. Since neurologic activity and toxicity of valproic acid are directly related to the unbound fraction of drug, adjustment of dosage based on knowledge of the free valproic acid concentration may be useful in the following situations: concomitant use of highly protein-bound drugs (usually >80% bound), hypoalbuminemia, pregnancy, renal or hepatic failure, and in the elderly. In these situations, the total valproic acid concentration in the blood may underestimate the disproportionately higher free valproic acid fraction.

Useful For: Monitoring both total and free valproic acid levels in therapy Assessing compliance Evaluating potential toxicity

Interpretation: The generally acceptable range for total valproic acid used as a reference to guide its therapy is 50 to 125 mcg/mL. The corresponding range of free valproic acid concentration for clinical reference is 5 to 25 mcg/mL. Low free valproic acid concentration relative to these ranges may suggest inadequate dosing, while a high free valproic acid concentration may be associated with toxic effects. Because the concentration of valproic acid fluctuates considerably depending on the time from last dose, interpretation of the clinical significance of the valproic acid concentration must take into consideration the timing of the blood specimen. For this reason, 2 collections are sometimes made to assess the trough and peak concentrations.

Reference Values: VALPROIC ACID, TOTAL Therapeutic: 50 (trough)-125 (peak) mcg/mL Critical value: > or =151 mcg/mL VALPROIC ACID, FREE Current as of August 23, 2017 7:11 am CDT


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Therapeutic: 5-25 mcg/mL Critical value: >30 mcg/mL

Clinical References: 1. Cloyd JC, Fischer JH, Kriel RL, Kraus DM: Valproic acid pharmacokinetics in children: Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 1993;53:22-29 2. Wagner ML, Graves NM, Leppik IE, et al: The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994;56:494-502 3. Dasgupta A, Volk A: Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit 1996;18:284-287 4. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. Fourth edition. WB Saunders Company. Philadelphia, 2005, pp 1237-1285

VALPF

Valproic Acid, Free, Serum

37068

Clinical Information: Valproate (valproate, Depakote, or Depakene) is an effective medication for absence seizures, generalized tonic-clonic seizures, and partial seizures, when administered alone or in conjunction with other antiepileptic agents. The valproic acid that circulates in blood is 85% to90% protein-bound under normal circumstances. In uremia or during concomitant therapy with other drugs that are highly protein-bound (such as phenytoin), valproic acid is displaced from protein, resulting in a higher free fraction of the drug circulating in blood. Since neurologic activity and toxicity of valproic acid are directly related to the unbound fraction of drug, adjustment of dosage based on knowledge of the free valproic acid concentration may be useful in the following situations: concomitant use of highly protein-bound drugs (usually >80% bound), hypoalbuminemia, pregnancy, renal or hepatic failure, and in the elderly. In these situations, the total valproic acid concentration in the blood may underestimate the disproportionately higher free valproic acid fraction.

Useful For: Monitoring free valproic acid in therapy Assessing compliance Evaluating potential toxicity

Interpretation: The generally acceptable range for total valproic acid used as a reference to guide its therapy is 50 to 125 mcg/mL. The corresponding range of free valproic acid concentration for clinical reference is 5 to 25 mcg/mL. Low free valproic acid concentration relative to these ranges may suggest inadequate dosing, whereas, a high free valproic acid concentration may be associated with toxic effects. Because the concentration of valproic acid fluctuates considerably depending on the time from last dose, interpretation of the clinical significance of the valproic acid concentration must take into consideration the timing of the blood specimen. For this reason, 2 collections are sometimes made to assess the trough and peak concentrations.

Reference Values: Therapeutic: 5-25 mcg/mL Critical value: >30 mcg/mL

Clinical References: 1. Cloyd JC, Fischer JH, Kriel RL, Kraus DM: Valproic acid pharmacokinetics in children: Effects of age and antiepileptic drugs on protein binding and intrinsic clearance. Clin Pharmacol Ther 1993;53:22-29 2. Wagner ML, Graves NM, Leppik IE, et al: The effect of felbamate on valproic acid disposition. Clin Pharmacol Ther 1994;56:494-502 3. Dasgupta A, Volk A: Displacement of valproic acid and carbamazepine from protein binding in normal and uremic sera by tolmetin, ibuprofen, and naproxen: presence of inhibitor in uremic serum that blocks valproic acid-naproxen interactions. Ther Drug Monit 1996;18:284-287

VALPA

Valproic Acid, Total, Serum

37066

Clinical Information: Valproic acid (valproate, Depakote, or Depakene) is used for treatment of simple and complex absence seizures and as combination therapy with other anticonvulsants for control of generalized seizures that include absence seizures. Valproic acid is initially dosed at 15 mg/kg/day, with dosage increases over time to a maximum of 60 mg/kg/day. The volume of distribution of valproic acid is



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0.2 L/kg and its half-life is 10 to 14 hours in adults, and shorter in children. It is approximately 90% protein bound. Hepatic failure and a Reyes-like syndrome associated with administration of valproic acid at therapeutic levels have been reported. Careful monitoring of liver function during the first 6 months of therapy is required. Major side effects such as central nervous system depression, thrombocytopenia, and hepatic dysfunction are likely to be experienced if the peak level regularly is above 125 mcg/mL. Analysis of free valproic acid levels may be useful in delineating the cause of toxicity when the total concentration is not excessive. Valproic acid exhibits substantial effects on the pharmacology of phenytoin, whereas phenytoin exhibits only a limited effect on valproic acid. This is due to the relative abundance of the 2 drugs in the body. Valproic acid is present at a 2- to 3-fold mass excess and a 5- to 7-fold molar excess.

Useful For: Monitoring total valproic acid in therapy Assessing compliance Evaluating potential toxicity

Interpretation: Optimal response is usually observed when the trough level is above 50 mcg/mL. Peak levels should not exceed 125 mcg/mL.

Reference Values: Therapeutic: 50 (trough)-125 (peak) mcg/mL Critical value: > or =151 mcg/mL

Clinical References: 1. Cotariu D, Zaidman JL: Valproic acid and the liver. Clin Chem 1988;34:890-897 2. Moyer TP: Therapeutic drug monitoring. In Tietz Textbook of Clinical Chemistry. Edited by CA Burtis, ER Ashwood. Fourth edition. WB Saunders Company. Philadelphia, 2005, pp 1237-1285

VS

Vanadium, Serum

83396

Clinical Information: The element vanadium, naturally found in minerals and rocks, is considered an essential element for mammals, although conclusive evidence for humans is lacking. Animal studies have shown that vanadium is essential for mammalian growth and reproduction, iron and lipid metabolism, and RBC production. Vanadium is recovered from minerals or as a by-product of iron, titanium, and uranium refining. Vanadium pentoxide is used in the production of special steels. Vanadium compounds are used as catalysts for polypropylene production and synthesis of inorganic and organic chemicals. Vanadium compounds are used in dyes, photography, ceramics, and in the production of special glasses. Vanadium also is a component of a fiber mesh prosthetic alloy. The main source of vanadium intake for the general population is food, with an estimated daily intake of 20 mcg, of which most is excreted in the feces, without absorption. Absorption through the inhalation route results in more effective uptake. About 90% of blood vanadium is found in serum. The half-life in serum is not well documented, but it appears to be on the order of several days. Although there is minimal evidence for the nature of vanadium complexation in the body, research suggests transferrin will bind available ionized vanadium. Currently, there is no clinical data to support the need for taking vanadium supplements such as vanadyl sulfate, vanadium colloid, or any other form. This test provides no information regarding any theoretical vanadium deficiency. Vanadium has been recognized as an occupational hazard for >20 years. Elevated atmospheric vanadium levels can result from burning fossil fuels with a high vanadium content. Inhalation and ingestion are the primary exposure routes. Vanadium exposure can result in a metallic taste and so-called "green tongue." Sensitization can result in asthma or eczema. Vanadium intoxication is effectively treated with ascorbic acid. Increased vanadium serum concentrations are observed in dialysis patients and those with compromised renal function since the kidney is primarily responsible for vanadium elimination. Elevated serum vanadium levels have been observed in patients with joint replacements; concentrations are likely to be increased above the reference range in patients with metallic joint prosthesis. Prosthetic devices produced by Zimmer Company and Johnson and Johnson typically are made of aluminum, vanadium, and titanium. Prosthetic devices produced by Depuy Company, Dow Corning, Howmedica, LCS, PCA, Osteonics, Richards Company, Tricon, and Whiteside typically are made of chromium, cobalt, and molybdenum. This list of products is incomplete, and these products change occasionally; see prosthesis product information for each device for composition details.

Useful For: Detecting vanadium toxicity Monitoring metallic prosthetic implant wear Current as of August 23, 2017 7:11 am CDT


Page 2155

Interpretation: Values 5.0 ng/mL indicate probable exposure. Prosthesis wear is known to result in increased circulating concentration of metal ions.(2-3) Modest increase (1-2 ng/mL) in serum vanadium concentration is likely to be associated with a prosthetic device in good condition. Serum concentrations >5 ng/mL in a patient with a vanadium-based implant suggest significant prosthesis wear. Increased serum trace element concentrations in the absence of corroborating clinical information do not independently predict prosthesis wear or failure.

Reference Values: Normal: 4 g/dL, IgA >5 g/dL, or IgG >6 g/dL should be tested for hyperviscosity. Serum viscosity and electrophoresis are recommended before and after plasmapheresis in order to correlate viscosity and M-spike with patient symptoms. This correlation may be useful for anticipating the need for repeat plasmapheresis.

Useful For: Detection of increased viscosity Monitoring patients with hyperviscosity syndrome Interpretation: Although viscosities >1.5 centipoises (cP) are abnormal, hyperviscosity is rarely present unless the viscosity is >3 cP.

Reference Values: > or =16 years: < or =1.5 centipoises Reference values have not been established for patients that are 15 mg per day, and in children who ingest >6 mg per day of vitamin A over a period



Page 2176

of several months. Manifestations are various and include dry skin, cheilosis, glossitis, vomiting, alopecia, bone demineralization and pain, hypercalcemia, lymph node enlargement, hyperlipidemia, amenorrhea, and features of pseudotumor cerebri with increased intracranial pressure and papilledema. Liver fibrosis with portal hypertension and bone demineralization may also result. Congenital malformations, like spontaneous abortions, craniofacial abnormalities, and valvular heart disease have been described in pregnant women taking vitamin A in excess. Consequently, in pregnancy, the daily dose of vitamin A should not exceed 3 mg. Vitamin E: Vitamin E contributes to the normal maintenance of biomembranes, the vascular system, and the nervous systems; and provides antioxidant protection for vitamin A. The level of vitamin E in the blood plasma or serum after a 12- to 14-hour fast reflects the individual's reserve status. Currently, the understanding of the specific actions of vitamin E is very incomplete. The tocopherols (vitamin E and related fat-soluble compounds) function as antioxidants and free-radical scavengers, protecting the integrity of unsaturated lipids in the biomembranes of all cells and preserving retinol from oxidative destruction. Vitamin E is known to promote the formation of prostacyclin in endothelial cells and to inhibit the formation of thromboxanes in thrombocytes, thereby minimizing the aggregation of thrombocytes at the surface of the endothelium. Those influences on thrombocyte aggregation may be of significance in relation to risks for coronary atherosclerosis and thrombosis. Deficiency of vitamin E in children leads to reversible motor and sensory neuropathies; this problem also has been suspected in adults. Premature infants who require an oxygen-enriched atmosphere are at increased risk for bronchopulmonary dysplasia and retrolental fibroplasia. Supplementation with vitamin E has been shown to lessen the severity of, and may even prevent, those problems. In addition, low blood levels of vitamin E may be associated with abetalipoproteinemia, presumably as a result of a lack of the ability to form very low-density lipoproteins and chylomicrons in the intestinal absorptive cells of affected persons. Vitamin E toxicity has not been established clearly. Chronically excessive ingestion has been suspected as a cause of thrombophlebitis, although this has not been definitively verified. Deficiencies of vitamins A and E may arise from poor nutrition or from intestinal malabsorption. Persons, especially children, at risk include those with bowel disease, pancreatic disease, chronic cholestasis, celiac disease, cystic fibrosis, and intestinal lymphangiectasia. Infantile cholangiopathies that may lead to malabsorption of vitamins A and E include intrahepatic dysplasia and rubella-related embryopathy.

Useful For: Diagnosing vitamin A deficiency and toxicity Evaluating persons with intestinal malabsorption of lipids Evaluating individuals with motor and sensory neuropathies for vitamin E deficiency Monitoring vitamin E status of premature infants requiring oxygenation

Interpretation: Vitamin A: The World Health Organization recommendations supplementation when vitamin A levels fall below 20.0 mcg/dL. Severe deficiency is indicated at levels 120.0 mcg/dL suggest hypervitaminosis A and associated toxicity. Vitamin E (alpha-tocopherol): -Values that indicate need for supplementation: -Premature: or =10 mg/dL ETHANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =400 mg/dL ISOPROPANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL ACETONE Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL

Clinical References: 1. Caplan YH: Forensic Science Handbook. Vol 1. Edited by R Saferstein. Englewood Cliffs, Prentice Hall, 1982 2. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. Seventh edition. Edited by TW Rall, F Murad. New York, McMillan Publishing, 1985 3. Porter WF, Moyer TP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1993, pp 1155-1235 4. Principles of Forensic Toxicology. Edited by B Levine. Washington DC, AACC Press, 1999

VLTBX

Volatile Screen, Chain of Custody, Blood

62745

Clinical Information: Volatile substances in the blood include ethanol, methanol, isopropanol, and acetone. Acetone is generally elevated in metabolic conditions such as diabetic ketoacidosis. Methanol and isopropanol are highly toxic and result from exogenous ingestion. Ethanol is the single most important substance of abuse in the United States. It is the active agent in beer, wine, vodka, whiskey, rum, and other liquors. Ethanol acts on cerebral function as a depressant similar to general anesthetics. This depression causes most of the typical symptoms such as impaired thought, clouded judgment, and changed behavior. As the level of alcohol increases, the degree of impairment progressively increases. In



Page 2184

most jurisdictions in the United States, the per se blood level for being under the influence of alcohol (ethanol) for purposes of driving a motor vehicle is 80 mg/dL. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detection and quantitation of acetone, methanol, isopropanol, and ethanol in whole blood Quantification of the concentration of ethanol in blood which correlates with the degree of intoxication Evaluation of toxicity to the measured volatile substances Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; this control implies that the opportunity for specimen tampering would be limited.

Interpretation: Methanol: The presence of methanol indicates exposure which may result in intoxication, central nervous system (CNS) depression, and metabolic acidosis. Ingestion of methanol can be fatal if patients do not receive immediate medical treatment. Ethanol: The presence of ethanol indicates exposure which may result in intoxication, CNS depression, and metabolic acidosis. Isopropanol: The presence of isopropanol indicates exposure which may result in intoxication and CNS depression. Ingestion of isopropanol can be fatal if patients do not receive immediate medical treatment. Acetone: The presence of acetone may indicate exposure to acetone; it is also a metabolite of isopropanol and may be detected during ketoacidosis.

Reference Values: METHANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL ETHANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =400 mg/dL ISOPROPANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL ACETONE Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL

Clinical References: 1. Langman, LJ, Bechtel L, Holstege CP: Chapter 35: Clinical toxicology. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. Philadelphia, PA, WB Saunders Co. 2011, pp 1109-1188 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th edition. Edited by LL Brunton, DK Blumenthal, N Murr, et al, New York, McGraw-Hill, 2011 3. Principles of Forensic Toxicology. Third edition, Edited by B Levine, Washington DC, AACC Press, 2010

VLTUX

Volatile Screen, Chain of Custody, Urine

62746

Clinical Information: Urine provides a medium for easy screening for methanol, ethanol, isopropanol, and acetone. Chain of custody is a record of the disposition of a specimen to document who collected it, who handled it, and who performed the analysis. When a specimen is submitted in this manner, analysis will be performed in such a way that it will withstand regular court scrutiny.

Useful For: Detecting the presence of acetone, methanol, isopropanol, or ethanol in urine with subsequent quantitation Chain of custody is required whenever the results of testing could be used in a court of law. Its purpose is to protect the rights of the individual contributing the specimen by demonstrating that it was under the control of personnel involved with testing the specimen at all times; Current as of August 23, 2017 7:11 am CDT


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this control implies that the opportunity for specimen tampering would be limited.


Reference Values: METHANOL Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL ETHANOL Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL ISOPROPANOL Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL ACETONE Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL

Clinical References: 1. Langman, LJ, Bechtel L, Holstege CP: Chapter 35: Clinical toxicology. In Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Edited by CA Burtis, ER Ashwood, DE Bruns. Philadelphia, PA, WB Saunders Co. 2011, pp 1109-1188 2. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th edition. Edited by LL Brunton, DK Blumenthal, N Murr, et al, New York, McGraw-Hill, 2011 3. Principles of Forensic Toxicology. Third edition, Edited by B Levine, Washington DC, AACC Press, 2010

VLTS

Volatile Screen, Serum

8632

Clinical Information: Volatile substances in the blood include ethanol, methanol, isopropanol, and acetone: -Ethanol is the single most important substance of abuse in the United States. It is the active agent in beer, wine, vodka, whiskey, rum, and other liquors. -Methanol and isopropanol are highly toxic; toxicity results from ingestion (exogenous). -Acetone is generally elevated in metabolic conditions such as diabetic ketoacidosis (endogenous). It also is a metabolite of isopropanol. Ethanol acts on cerebral function as a depressant similar to general anesthetics. This depression causes most of the typical symptoms such as impaired thought, clouded judgment, and changed behavior. As the level of alcohol increases, the degree of impairment progressively increases. On average, the serum or plasma concentration of the alcohols is 1.2-fold higher than blood concentration. For example, the serum or plasma would contain approximately 0.10 g/dL of ethanol in a blood specimen that contains 0.08 g/dL ethanol. Due to potential variations in the serum to whole blood ratio, serum should not be used in a medico-legal context. However, in the context of medical/clinical assessment, serum or plasma may be submitted for analysis.

Useful For: Detection and quantitation of acetone, methanol, isopropanol, and ethanol in serum Quantification of the concentration of ethanol in serum correlates with degree of intoxication Evaluation of toxicity to the measured volatile substances Current as of August 23, 2017 7:11 am CDT


Page 2186


Reference Values: METHANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL ETHANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =400 mg/dL ISOPROPANOL Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL ACETONE Not detected (Positive results are quantitated.) Toxic concentration: > or =10 mg/dL

Clinical References: 1. Caplan YH: Forensic Science Handbook. Vol 1. Edited by R Saferstein. Englewood Cliffs, Prentice Hall, 1982 2. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. Seventh edition. Edited by TW Rall, F Murad. New York, McMillan Publishing, 1985 3. Porter WF, Moyer TP: Clinical toxicology. In Tietz Textbook of Clinical Chemistry. Fourth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 1993, pp 1155-1235 4. Principles of Forensic Toxicology. Edited by B Levine. Washington DC, AACC Press, 1999

VLTU

Volatile Screen, Urine

8826

Clinical Information: Urine provides a medium for easy screening for methanol, ethanol, isopropanol, and acetone.

Useful For: Detecting the presence of acetone, methanol, isopropanol, or ethanol in urine with subsequent quantitation


Reference Values: METHANOL Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL ETHANOL Not detected (Positive results are quantitated.) Current as of August 23, 2017 7:11 am CDT


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Cutoff concentration: 10 mg/dL ISOPROPANOL Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL ACETONE Not detected (Positive results are quantitated.) Cutoff concentration: 10 mg/dL Toxic concentration: > or =10 mg/dL

Clinical References: Unpublished Mayo information

VWD2N

von Willebrand Disease 2N (Subtype Normandy), Blood

81662

Clinical Information: Hemophilia A (HA) and von Willebrand disease (VWD) are bleeding disorders caused by quantitative or qualitative defects in factor VIII (FVIII) or von Willebrand factor (VWF), respectively, and constitute 2 of the most common bleeding disorders. Hemophilia A is inherited as an X-linked recessive disorder while most subtypes of VWD are inherited as autosomal dominant disorders. VWF plays 2 essential roles in hemostasis. VWF mediates platelet adhesion to damaged blood vessel walls and VWF is a carrier protein for FVIII. Noncovalent binding of FVIII to VWF is necessary for normal survival of FVIII in the blood circulation. In patients with severe VWD, the circulating half-life of endogenous or infused FVIII is shortened. Mutations within the VWF gene regions encoding for the FVIII binding domain of VWF may produce a phenotype of isolated FVIII "deficiency" associated with a clinically mild-to-moderate bleeding disorder which may be misdiagnosed as HA. This mild VWD phenotype was first described in patients from the Normandy region of France, VWD Normandy (VWD Type 2N). VWD Type 2N inheritance pattern is autosomal recessive. In an international survey, VWD Normandy was detected in 58 (4.8%) of 1,198 patients previously diagnosed as having mild hemophilia A. Three VWF gene mutations (VWF Thr791Met, Arg816Trp, and Arg854Gln) accounted for 96% of patients with mutations in the FVIII binding domain of VWF.(3) Patients who are homozygous for 1 of the 3 common mutations have reduced levels of FVIII activity, whereas patients who are heterozygous typically have normal FVIII activity. However, patients who are heterozygous for 1 of the 3 common VWD Type 2N mutations may have decreased FVIII activity in the presence of a second (compound heterozygous) mutation in the VWF gene that typically results in a Type 1 or Type 3 VWD (quantitative defect). VWD Type 2N also has been associated with a more severe bleeding phenotype among patients who are homozygous for other mutations (VWF Glu24Lys) within the FVIII binding domain of VWF.(1,2) Additional studies suggest that 1.5% (3/199) to 13.8% (5/36) of patients with vWD Type 1 have a FVIII binding defect.(2,4) The diagnosis of VWD Type 2N is important for appropriate genetic counseling, because the inheritance of VWD Type 2N is autosomal recessive (as opposed to the X-linked recessive inheritance of HA). Optimal treatment or prophylaxis of bleeding requires products containing functional VWF.

Useful For: Diagnosis of von Willebrand disease (VWD) Type 2N Evaluation and genetic counseling of patients with mild-to-moderate hemophilia A with an atypical inheritance pattern Evaluation of hemophilia A patients with a shortened survival of infused factor VIII (FVIII) (not caused by a specific FVIII inhibitor) Evaluation of female patients with low FVIII activity and no prior family history of hemophilia A Evaluation of patients with Type 1 or Types 2A, 2B, or 2M VWD with FVIII activity discordantly-lower than the von Willebrand factor antigen level

Interpretation: Interpretive report will include specimen information, assay information, background information, and conclusions based on the test results. Clinical information and results of patient testing (factor VIII coagulant activity, von Willebrand factor antigen, and ristocetin cofactor activity) are useful for test interpretation.



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Clinical References: 1. Tuley EA, Gaucher C, Jorieux S, et al: Expression of von Willebrand factor "Normandy": an autosomal mutation that mimics hemophilia A. Proc Natl Acad Sci USA 1991;88:6377-6381 2. Schneppenheim R, Budde U, Krey S, et al: Results of a screening for von Willebrand disease type 2N in patients with suspected hemophilia A or von Willebrand disease type 1. Thromb Haemost 1996;76:598-602 3. Mazurier C, Meyer D: Factor VIII binding assay of von Willebrand factor and the diagnosis of type 2N von Willebrand disease-results of an international survey. On behalf of the Subcommittee on von Willebrand Factor of the Scientific and Standardization committee of the ISTH. Thromb Haemost 1996;76:270-274 4. Nesbitt IM, Goodeve AC, Guilliatt AM, et al: Characterization of type 2N von Willebrand disease using phenotypic and molecular techniques. Thromb Haemost 1996;75:959-964

VWFX

von Willebrand Factor Activity, Plasma

89792

Clinical Information: von Willebrand factor (VWF) is a multimeric adhesive glycoprotein that is important for platelet-platelet and platelet-vessel hemostatic interactions. In addition, plasma VWF serves as a carrier protein for coagulation factor VIII, stabilizing its procoagulant activity. VWF circulates in the blood in 2 distinct compartments, plasma VWF and platelet VWF. Plasma VWF mainly reflects VWF synthesis and release from vascular endothelial cells. Platelet VWF (about 10% of the blood VWF) reflects VWF synthesis by bone marrow megakaryocytes with storage primarily in the alpha granules of circulating platelets. VWF antigen measurement assesses the mass of plasma VWF protein, but does not measure platelet VWF protein. The major function of VWF (mediating platelet-platelet or platelet-vessel interaction) is most commonly assessed by measurement of plasma VWF activity. Patients with congenital severe type 3 von Willebrand disease (VWD) have markedly decreased or immeasurably low VWF antigen in the plasma (and in the platelets), and plasma VWF activity is very low or not detectable. Patients with types 2A and 2B variants of VWD (with abnormal plasma VWF function and multimeric structure) may have normal or decreased plasma VWF antigen, but typically have decreased plasma VWF activity, and decreased higher molecular weight VWF multimers in the plasma. Patients with type 2M or type 2N VWD have normal levels of antigen, but either decreased VWF activity not caused by absence of higher molecular weight VWF multimers (type 2M VWD), or decreased factor VIII coagulant activity (type 2N VWD). Patients with type 1 VWD (with decreased but normally functioning plasma VWF) have concordantly decreased plasma VWF antigen and activity. Patients with acquired von Willebrand syndrome (AVWS) may have either normal or decreased plasma VWF antigen, and decreased VWF activity. Note: This activity assay is most effective when it is combined with measurement of von Willebrand factor: VWF antigen and factor VIII coagulant activity, preferably as a panel of tests with reflexive testing and interpretive reporting [eg, VWPR / von Willebrand Profile]).

Useful For: Diagnosis of von Willebrand disease (VWD) and differentiation of VWD subtypes or differentiation of VWD from hemophilia A Monitoring therapeutic efficacy of treatment with DDAVP (desmopressin) or VWF concentrates in patients with VWD

Interpretation: von Willebrand factor (VWF) activity is reduced in parallel with VWF antigen in von Willebrand disease (VWD), except in types 2A, 2B, and 2M, and some cases of acquired von Willebrand syndrome (AVWS) in which the VWF activity is disproportionately decreased relative to the level of VWF antigen. The VWF activity may be decreased in congenital VWD or AVWS that may be associated with are variety of disorders including monoclonal gammopathies, lymphoproliferative disorders, autoimmune disorders, hypothyroidism, severe aortic stenosis, left ventricular assist device, and arteriovenous malformation. The VWF activity may be increased in association with pregnancy or estrogen use (including oral contraceptives), acute ("acute-phase reactant") or chronic inflammation, exercise or stress, liver disease, vasculitis, and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Such increases in VWF activity may obscure the laboratory diagnosis of mild VWD.

Reference Values: 55-200% Normal, full-term newborn infants may have mildly increased levels which reach adult levels by 90 days postnatal. Healthy, premature infants (30-36 weeks gestation) may have increased levels that reach adult levels by 180 days. Current as of August 23, 2017 7:11 am CDT


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Note: Individuals of blood group "O" may have lower plasma von Willebrand factor (VWF) activity than those of other ABO blood groups, such that apparently normal individuals of blood group "O" may have plasma VWF activity as low as 40% to 50%, whereas the lower limit of the reference range for individuals of other blood groups may be 60% to 70%.

Clinical References: 1. Montgomery RR: Structure and function of von Willebrand factor. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by Colman RW, Hirsh J, Marder VJ, et al. Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 249-274 2. Sadler JE, Blinder M: von Willebrand disease: diagnosis, classification, and treatment. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fourth edition. Edited by Colman RW, Hirsh J, Marder VJ, et al. Philadelphia, PA, Lippincott Williams and Wilkins, 2001, pp 825-837 3. Tefferi A, Nichols WL: Acquired von Willebrand's disease: concise review of occurrence, diagnosis, pathogenesis and treatment. Am J Med 1997;103:536-540 4. Salem RO, Van Cott EM: A new automated screening assay for the diagnosis of von Willebrand Disease. Am J Clin Pathol 2007;127:730-735

VWAG

von Willebrand Factor Antigen, Plasma

9051

Clinical Information: The von Willebrand factor (VWF) is a multimeric adhesive glycoprotein that is important for platelet-platelet and platelet-vessel hemostatic interactions. In addition, plasma VWF serves as a carrier protein for coagulation factor VIII, stabilizing its procoagulant activity. VWF circulates in the blood in 2 distinct compartments; plasma VWF mainly reflects VWF synthesis and release from vascular endothelial cells, and platelet VWF (about 10% of the blood VWF) reflects VWF synthesis by bone marrow megakaryocytes with storage primarily in the alpha granules of circulating platelets. VWF antigen measurement assesses the mass of plasma VWF protein, but does not reflect VWF functions or platelet VWF. The major function of VWF (mediating platelet-platelet or platelet-vessel interaction) is most commonly assessed by measurement of plasma ristocetin cofactor activity. Decreased VWF antigen may be seen in: -Congenital von Willebrand disease -Acquired VWD that may be associated with monoclonal gammopathies, lymphoproliferative disorders, autoimmune disorders, and hypothyroidism Increased VWF antigen may be seen in association with: -Pregnancy and/or estrogen use -Inflammation (acute-phase reactant) -Exercise or stress -Liver disease -Vasculitis -Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome von Willebrand factor (VWF) antigen measurement is most effective when it is combined with measurement of VWF ristocetin cofactor activity and factor VIII coagulant activity, preferably as a panel of tests with reflexive testing and interpretive reporting. Within this context, VWF antigen measurement can be useful for: -Diagnosis of von Willebrand disease (VWD) and differentiation of VWD subtype -Differentiation of VWD from hemophilia A (in conjunction with factor VIII coagulant assay)

Useful For: Diagnosis of von Willebrand disease (VWD) and differentiation of VWD subtype (in conjunction with von Willebrand factor ristocetin cofactor activity and factor VIII coagulant activity) -Differentiation of VWD from hemophilia A (in conjunction with factor VIII coagulant assay) Monitoring therapeutic efficacy of treatment with DDAVP (desmopressin) or VWF concentrates in patients with VWD

Interpretation: von Willebrand factor (VWF) antigen assay results generally must be used together with assays of VWF ristocetin cofactor activity and factor VIII coagulant activity, for optimum clinical utility and diagnostic efficiency. The diagnosis of von Willebrand disease (VWD) requires a combination of clinical and laboratory information. We suggest ordering VWPR / von Willebrand Profile. Patients with congenital severe type III VWD have a markedly decreased or undetectable level of VWF antigen in the plasma (and in the platelets), in addition to a plasma ristocetin cofactor activity that is very low, or not detectable. Patients with types IIA and IIB variants of VWF (with abnormal plasma VWF function and multimeric structure) may have normal or decreased plasma VWF antigen. However, they typically have decreased plasma ristocetin cofactor activity, along with decreased higher molecular-weight VWF multimers in the plasma. Patients with types IIM or IIN VWD have normal levels of VWF antigen. In spite of this, they either have decreased vWF ristocetin cofactor activity, not caused by absence of higher molecular weight vWF multimers (type IIM VWD), or decreased factor VIII coagulant activity (type IIN VWD) Patients with type I VWD (with decreased but normally functioning plasma VWF) have concordantly decreased plasma VWF antigen and ristocetin cofactor activity. Patients with acquired VWD Current as of August 23, 2017 7:11 am CDT


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may have either normal or decreased plasma VWF antigen.

Reference Values: 55-200% Note: Individuals of blood group "O" may have lower plasma von Willebrand factor (VWF) antigen than those of other ABO blood groups, such that apparently normal individuals of blood group "O" may have plasma VWF antigen as low as 40% to 50%, whereas the lower limit of the reference range for individuals of other blood groups may be 60% to 70%. Children: Neonates, infants, and children have normal or mildly increased plasma VWF antigen, with respect to the adult reference range.

Clinical References: 1. Sadler JE, Blinder M: von Willebrand disease: diagnosis, classification and treatment. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Fifth edition. Edited by RW Colman, VJ Marder, AW Clowes, et al. Baltimore, MD, Lippincott Williams and Wilkins, 2006, pp 905-921 2. Eby C, Chance D, Oliver D: A multicenter evaluation of ATA-LIATEST VWF: A new latex particle immunoassay for von Willebrand factor antigen. Clin Hemostasis Rev 1997;11:16-17 3. Rodeghiero F, Castaman G, Tosetto A: Von Willebrand factor antigen is less sensitive then ristocetin cofactor for the diagnosis of type K von Willebrand disease â€“ Results based on an epidemiological investigation. Thromb Haemost 1990;64:349-352 4. Triplett DA: Laboratory diagnosis of von Willebrandâ€™s disease. Mayo Clin Proc 1991;66:832-840

VWFM2

von Willebrand Factor Multimer Analysis, Plasma

8844

Clinical Information: von Willebrand factor (VWF) is a large multimeric plasma glycoprotein that has essential roles in primary hemostasis. Wild type VWF molecules are series of multimers varying in size from dimers to multimers over 40 subunits (>10 million Daltons). The largest multimers provide multiple binding sites that can interact with both platelet receptors and subendothelial matrix sites of injury, and are the most hemostatically active form of VWF. The biological functions of VWF are as follows: 1. VWF is a ligand and mediates platelet adhesion to the subendothelial collagen at the site of vessel wall injury by binding to the platelet receptor glycoprotein (GP)-Ib, V, IX complex and subendothelial collagen 2. VWF binds and stabilizes procoagulant factor VIII in the circulation 3. Under conditions of high shear, VWF also mediates platelet-platelet cohesion by binding to the platelet receptor GP-IIb/IIIa (integrin alpha IIb beta3) Von Willebrand disease (VWD) is the most common hereditary bleeding disorder that is caused by quantitative or qualitative VWF defect. VWD manifests clinically as easy bruising, mucocutaneous bleeding (eg, epistaxis, menorrhagia), and bleeding after trauma or surgery. VWD has been classified into 3 major types: -Type 1, typically an autosomal dominant disease, is the most common, accounting for approximately 70% of VWD patients. It represents a quantitative deficiency of VWF of variable severity. -Type 2, which is usually an autosomal dominant disease, is characterized by several qualitative abnormalities of VWF. Four subtypes have been identified: 2A, 2B, 2M, and 2N. -Type 3, an autosomal recessive disorder, leads to severe disease with virtually undetectable levels of VWF, as well as very low levels of factor VIII. Acquired von Willebrand syndrome (AVWS) is associated with a number of different disease states and is caused by several different pathophysiological mechanisms, including antibody formation, proteolysis, binding to tumor cells with increased clearance, and decreased synthesis. AVWS is most frequently described in patients with dysproteinemias (including monoclonal gammopathy of undetermined significance [MGUS], multiple myeloma, and macroglobulinemia), lymphoproliferative disorders, myeloproliferative disorders (eg, essential thrombocythemia), autoimmune diseases (eg, systemic lupus erythematosus), high-shear stress cardiovascular conditions such as severe aortic stenosis, gastrointestinal angiodysplasia, and hypothyroidism.

Useful For: Subtyping of von Willebrand factor (VWF): -When results of complementary laboratory tests (eg, F8A / Coagulation Factor VIII Activity Assay, Plasma; VWFX / von Willebrand Activity, Plasma; and VWAG / von Willebrand Factor Antigen, Plasma) are abnormally low or discordant. -Primarily used to identify variants of type 2 VWF. -An aid in determining appropriate treatment

Interpretation: The plasma von Willebrand factor (VWF) multimer analysis is a qualitative visual assessment of the size spectrum and the banding pattern of VWF multimers. This test is used to identify variants of type 2 von Willebrand disease that have fewer of the largest multimers, have unusually large Current as of August 23, 2017 7:11 am CDT


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multimers, or have qualitatively abnormal "bands" that indicate an abnormal VWF structure.


Clinical References: 1. Budde U, Schneppenheim R: von Willebrand Factor and von Willebrand Disease. Rev Clin Exp Hematol 2001;5.4:335-368 2. Ruggeri ZM: Structure and function of von Willebrand factor: Relationship to von Willebrandâ€™s disease. Mayo Clinic Proc 1991;66:847-861 3. Sadler JE: A revised classification of von Willebrand disease. Thromb Haemost 1994;71:520-525 4. Laffan M, Brown SA, Collins PW, et al: The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organization. Haemophilia 2004;10:199-217 5. Mannucci PM: Treatment of von Willebrandâ€™s disease. N Engl J Med 2004;351:683-694 6. Pruthi RKl: Plasma von Willebrand factor multimer quantitative analysis by in-gel immunostaining and infrared fluorescent imaging. Thromb Res 2010;126:543-549

VWPR

von Willebrand Profile

83099

Clinical Information: von Willebrand factor (VWF) is synthesized by the endothelial cell and megakaryocyte and is present in these cells, as well as in platelets, subendothelial tissue, and plasma. VWF serves as an adhesive protein important in adhering platelets to subendothelial tissue at the site of vascular injury and for adhering platelets to each other (aggregation). Platelet adhesion and aggregation are essential to form a mechanical hemostatic "plug" and as the focus for interaction of clotting factors and phospholipid required for the formation of the fibrin platelet clot. VWF also stabilizes plasma factor VIII by binding it and protecting it from proteolysis and serves as a carrier protein for that clotting factor. VWF circulates in the blood in 2 distinct compartments. Plasma VWF mainly reflects VWF synthesis and release from vascular endothelial cells. Platelet VWF (about 10% of the blood VWF) reflects VWF synthesis by bone marrow megakaryocytes with storage primarily in the alpha granules of circulating platelets. Plasma VWF circulates normally in multimeric forms with molecular weights ranging from 500,000 to as much as 20,000,000. The high-molecular-weight (HMW) forms of VWF are the most effective components for interaction with platelets. This primary activity of plasma VWF is measured in the laboratory with the VWF activity assay, whereas VWF antigen testing measures the amount of VWF protein, and factor VIII coagulant activity indirectly reflects VWF interaction with factor VIII. VWF multimer analysis visualizes the distribution of VWF multimers and is useful as a reflexive test for subtyping von Willebrand disease (VWD). Levels of factor VIII, VWF antigen, and VWF activity may vary greatly within each individual over time and also with blood type (normal type "O" individuals may have VWF lower than normals of other blood groups). VWF levels (and factor VIII) can be elevated in liver disease, pregnancy, estrogen therapy, inflammation, and after exercise (acute-phase reactant). VWF levels in hemophilia are normal. VWF antigen measurement assesses the mass of plasma VWF protein but does not reflect VWF functions or platelet VWF. The function of VWF (mediating platelet-platelet or platelet-vessel interaction) is most commonly assessed by measurement of plasma VWF activity. VWD is the most common inherited bleeding disorder, affecting up to 1% of the population. It can also occur as an acquired bleeding disorder. Bleeding symptoms in all types of VWD are primarily mucosal, including epistaxis, menorrhagia, gastrointestinal bleeding, and ease of bruising, but surgical or posttraumatic bleeding can also occur. Subtypes of inherited VWD are: Type 1 VWD: VWF plasma levels (antigen and activity) typically are both concordantly reduced in type 1 VWD. Because of this reduction, the level of coagulation factor VIII is often secondarily reduced also. type 1 VWD is the most common VWD variation, representing 70% to 80% of clinical VWD. It is typically inherited in autosomal dominance fashion, although recessively inherited VWD also occurs (eg, type 3 VWD). Clinical severity ranges from mild or minimal to a moderately severe bleeding diathesis and tends to correlate most closely with VWF activity. Severe Type 1 disease is also called type 3 VWD, but the distinction between the 2 may sometimes be difficult. Type 2 VWD: Type 2 VWD variants represent 20% to 30% of clinical VWD, typically autosomal dominant in inheritance. There are 4 subtypes of type 2 VWD: 2A, 2B, 2M, and 2N. Abnormal plasma HMW VWF function and multimeric structure with decreased or absent HMW multimers are characteristic of types 2A and 2B, but are normal in type 2M or 2N. VWF activity is decreased in types 2A, 2B, and 2M and typically is discordantly lower than VWF antigen. Type 2N (Normandy) has substantially decreased factor VIII coagulant activity (typically 5%-30% of mean normal), with normal VWF antigen and activity and normal VWF multimers with clinical manifestation



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as autosomally inherited mild hemophilia (in contrast to classical X chromosome-linked hemophilia A). Type 2A is the most common of the 4. Type 2B manifests thrombocytopenia, either persistent or transient, and is distinguished from type 2A by abnormally heightened aggregation response of patient platelets and plasma to low dose ristocetin stimulation. Type 2M typically demonstrates hypofunctional VWF with decreased VWF activity discordantly lower than VWF antigen not due to loss of HMW multimers. One variant of type 2M, Vicenza variant VWD, has ultralarge VWF multimers in plasma. Type 3 VWD: VWF is absent or markedly decreased in type 3 VWD (VWF antigen and activity either undetectably low or below 5% to 10% of mean normal, with secondary decrease of factor VIII coagulant activity (5%-30%). VWF multimers may be undetectable or, if present, have a normal distribution. Platelet VWF may also be absent. Acquired VWD: VWD can also occur on an acquired basis by a variety of mechanisms not well understood. Disorders associated with acquired VWD include certain myeloproliferative or lymphoproliferative disorders, plasma cell dyscrasias including monoclonal gammopathy of undetermined significance, autoimmune disorders (eg, rheumatoid arthritis, systemic lupus erythematosus), and a variety of other diseases. In some cases, no associated disorder is detected. Laboratory testing currently cannot distinguish between congenital and acquired VWD; clinical correlation is required. Useful For Detection of deficiency or abnormality of von Willebrand factor and related deficiency of factor VIII coagulant activity Subtyping von Willebrand disease as type 1 (most common), type 2 variants (less common), or type 3 (rare) This test is not useful for detection of hemophilia carriers.

Useful For: Detection of deficiency or abnormality of von Willebrand factor and related deficiency of factor VIII coagulant activity Subtyping von Willebrand disease as type 1 (most common), type 2 variants (less common), or type 3 (rare) This test is not useful for detection of hemophilia carriers.

Interpretation: An interpretive report will be provided when testing is complete. Reference Values: FACTOR VIII ACTIVITY 55-200% von WILLEBRAND FACTOR ACTIVITY 55-200% von WILLEBRAND FACTOR ANTIGEN 55-200%

Clinical References: 1. Federici AB, Mannucci PM: Advances in the genetics and treatment of von Willebrand disease. Curr Opin Pediatr 2002 Feb;14(1):23-33 2. Budde U, Schneppenheim R: von Willebrand factor and von Willebrand disease. Rev Clin Exp Hematol 2001 Dec;5(4):335-368 3. Kumar S, Pruthi RK, Nichols WL: Acquired von Willebrand disease. Mayo Clin Proc 2002 Feb;77(2):181-187

VORI

Voriconazole, Serum

88698

Clinical Information: Voriconazole (Vfend) is an antifungal agent approved for treatment of invasive aspergillosis and candidemia/candidiasis, as well as for salvage therapy for infections in patients refractory to or intolerant of other antifungal therapy. The drug inhibits the fungal enzyme 14a-sterol demethylase, a critical step in ergosterol biosynthesis. Voriconazole is metabolized in the liver primarily by CYP2C19; CYP2C9 and CYP3A4 play limited roles. The primary metabolite is voriconazole N-oxide, which has no antifungal activity. Drug clearance is primarily dependent on hepatic metabolism. The pharmacokinetics of voriconazole is highly variable and nonlinear, which results in an increased dose leading to a greater than proportional increase in serum concentration. The bioavailability of oral voriconazole is greater than 95%. Approximately 60% of the drug in serum is protein bound. Voriconazole has a volume of distribution of 4.6 L/kg. Most (80%) of the drug is excreted in the urine, exclusively as metabolites. Adverse effects of voriconazole include visual disturbances, skin rashes, and elevated liver enzyme levels.

Useful For: Monitoring trough levels of voriconazole is suggested in individuals with reduced liver function, individuals with CYP2C19 polymorphisms associated with poor metabolic function, patients Current as of August 23, 2017 7:11 am CDT


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taking other medications that affect CYP2C19 activity, and in patients experiencing potential toxicity Monitoring trough levels may be reasonable in patients who are not responding optimally or have drug interactions that may decrease voriconazole levels, or to ensure adequate oral absorption

Interpretation: Trough levels above 6 mcg/mL (and especially >10 mcg/mL) have been associated with toxicity in several reports. Trough levels below 1 mcg/mL have been associated with suboptimal response in several reports.

Reference Values: 1.0-5.5 mcg/mL Trough level (ie, immediately before next dose) monitoring is recommended.

Clinical References: 1. Andes D, Pascual A, Marchetti O: Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother 2009;53(1):24-34 2. Hope WW, Billaud EM, Lestner J, Denning DW: Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis 2008;21:580-586 3. Donnelly JP, De Pauw BE: Voriconazole-a new therapeutic agent with an extended spectrum of antifungal activity. Clin Microbiol Infect 2004;10:107-117 4. Physicians Desk Reference, (PDR) 60th edition. Medical Economics Company, Montvale, NJ, 2006 update to 2008 5. Goodman and Gilman's The Pharmacological Basis of Therapeutics. Edited by LL Brunton, 11th edition. New York, McGraw-Hill Book Company, 2006

FWALP

Wall Eyed Pike (Sander vitreus)(Stizostedium vitreum) IgE

57561

Interpretation: Class IgE (kU/L) Comment 0 100 Very High Positive



WARFB

Warfarin Sensitivity Genotype by Sequence Analysis, Blood

36451

Clinical Information: Warfarin is a Coumarin-based drug commonly utilized in anticoagulation therapy to prevent thrombosis due to inherited and acquired hemostatic disorders. The drug is also used in a number of other medical conditions and treatments including atrial fibrillation and hip replacement surgery. Warfarin acts by interfering with the metabolism of vitamin K, which is necessary for production of key coagulation factors. Warfarin inhibits vitamin K recycling by blocking its metabolism at the vitamin K-epoxide intermediate, thereby decreasing the amount of available vitamin K. Warfarin has a narrow therapeutic window; under medicating increases the risk for thrombosis and overmedicating increases the risk for cerebrovascular accidents. Warfarin therapy has one of the highest rates of severe adverse drug reactions. Warfarin is dosed using nongenetic factors including gender, weight, and age, and is monitored by coagulation testing in order to maintain the international normalized ratio (INR) within specific limits. However, warfarin metabolism is highly variable and dependent upon genetic factors. Variants within 2 genes are known to affect the metabolism of warfarin and the dose needed to maintain the correct serum drug level and degree of anticoagulation. The CYP2C9 gene encodes the cytochrome P450 2C9 (CYP2C9) enzyme that primarily metabolizes the more active isomer of warfarin (S-warfarin) to inactive products. Some CYP2C9 variants result in decreased enzymatic activity and may lead to increases in serum warfarin and overmedicating, driving the INR above the therapeutic target. The second gene (VKORC1) encodes vitamin K epoxide reductase complex subunit-1 (VKORC1), a small transmembrane protein of the endoplasmic reticulum that is part of the vitamin K cycle and the target of warfarin therapy.(1) Vitamin K epoxide, a by-product of the carboxylation of blood coagulation factors, is reduced to vitamin K by VKORC1. A VKORC1 promoter variant leads to decreased expression of the gene, resulting in reduced availability of vitamin K. This may cause increases in serum warfarin and overmedicating, driving the INR above the therapeutic target. Thus, the presence of CYP2C9 and/or VKORC1 variants may result in the need for a reduced warfarin dose and more careful monitoring in order to maintain the target INR. CYP2C9: CYP2C9 metabolizes a wide variety of drugs including warfarin and phenytoin. A number of specific CYP2C9 variants result in enzymatic deficiencies. The following information outlines the relationship between the variants detected in this assay and their effect on the activity of the enzyme: CYP2C9 Allele cDNA Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive metabolizer (normal) *2 430C->T Reduced activity *3 1075A->C Minimal activity *4 1076T->C Reduced activity *5 1080C->G Reduced activity *6 818delA No activity *8 449G->A Substrate specific *9 752A->G Reduced activity *11 1003C->T Reduced activity VKORC1: The c.-1639 promoter variant is located in the second nucleotide of an E-Box (CANNTG) and its presence disrupts the consensus sequence, reducing promoter activity. In vitro experiments show a 44% higher transcription level of the G versus the A allele.(1) The c.-1639 G>A nucleotide change results in decreased gene expression and reduced enzyme activity. Warfarin dosing may require adjustment dependent on CYP2C9 and VKORC1 genotype and predicted phenotype. Patients who are CYP2C9 poor metabolizers (reduced activity) may benefit from warfarin dose reductions or by being switched to other



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comparable drugs that are not metabolized primarily by CYP2C9. Refer to the drug label for additional information, available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=558b7a0d-5490-4c1b-802e-3ab3f1efe760

Useful For: Identifying patients who may require warfarin dosing adjustments(2,3) including: -Patients who have previously been prescribed warfarin and have required multiple dosing adjustments to maintain the international normalized ratio in the target range -Patients with a history of thrombosis or bleeding when taking warfarin -Patients being started on a first prescription for warfarin

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating the patientâ€™s predicted warfarin sensitivity. The CYP2C9 genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(4) Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C9*1/*1. Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance. The c. -1639A variant reduces VKORC1 expression. The VKORC1 GA or AA genotype leads to a significant decrease in VKORC1 expression compared with the GG genotype. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Individuals who have variants in both the VKORC1 promoter (GA or AA) and also in CYP2C9 should receive a reduced dose of warfarin and more frequent monitoring of international normalized ratio (INR) to maintain the INR in the target range; dosing adjustments are required when variants in both genes are present. Drug-drug interactions and drug/metabolite inhibition must be considered in the case of intermediate metabolism. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Oldenburg J, Bevens CG, Muller CR, Watzka M: Vitamin K epoxide reductase complex subunit I (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal 2006;8(3-4):347-353 2. Yuan HY, Chen JJ, Lee MT, et al: A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005;14:1745-1751 3. Sconce EA, Khan TI, Wynne HA, et al: The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-2333 4. Human Cytochrome P450 (CYP) Allele Nomenclature Database. Accessed 9/29/15. Available at www.cypalleles.ki.se/cyp1a2.htm 5. Johnson JA, Gong L, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90(4):625-629

WARFC

Warfarin Sensitivity Genotype by Sequence Analysis, Saliva

36457

Clinical Information: Warfarin is a Coumadin-based drug commonly utilized in anticoagulation therapy to prevent thrombosis due to inherited and acquired hemostatic disorders. The drug is also used in a number of other medical conditions and treatments including atrial fibrillation and hip replacement surgery. Warfarin acts by interfering with the metabolism of vitamin K, which is necessary for production of key coagulation factors. Warfarin inhibits vitamin K recycling by blocking its metabolism at the vitamin K-epoxide intermediate, thereby decreasing the amount of available vitamin K. Warfarin has a narrow therapeutic window; undermedicating increases the risk for thrombosis and overmedicating increases the risk for cerebrovascular accidents. Warfarin therapy has one of the highest rates of severe adverse drug reactions. Warfarin is dosed using nongenetic factors including gender, weight, and age, and is monitored by coagulation testing in order to maintain the international normalized ratio (INR) within specific limits. However, warfarin metabolism is highly variable and dependent upon genetic factors. Variants within 2 genes are known to affect the metabolism of warfarin and the dose needed to maintain the correct serum drug level and degree of anticoagulation. The CYP2C9 gene encodes the cytochrome P450 2C9 (CYP2C9) enzyme that primarily metabolizes the more active isomer of warfarin (S-warfarin) to inactive products. Some CYP2C9 variants result in decreased enzymatic activity and may lead to



Page 2197

increases in serum warfarin and overmedicating, driving the INR above the therapeutic target level. The second gene (VKORC1) encodes vitamin K-epoxide reductase complex subunit-1 (VKORC1), a small transmembrane protein of the endoplasmic reticulum that is part of the vitamin K cycle and the target of warfarin therapy.(1) Vitamin K epoxide, a by-product of the carboxylation of blood coagulation factors, is reduced to vitamin K by VKORC1. A VKORC1 promoter variant leads to decreased expression of the gene, resulting in reduced availability of vitamin K. This may cause increases in serum warfarin and overmedicating, driving the INR above the therapeutic target. Thus, the presence of CYP2C9 or VKORC1 variants may result in the need for a reduced warfarin dose and more careful monitoring in order to maintain the target INR. CYP2C9: CYP2C9 metabolizes a wide variety of drugs including warfarin and phenytoin. A number of specific CYP2C9 variants result in enzymatic deficiencies. The following information outlines the relationship between the variants detected in this assay and their effect on the activity of the enzyme: CYP2C9 Allele cDNA Nucleotide Change Effect on Enzyme Metabolism *1 None (wild type) Extensive metabolizer (normal) *2 430C->T Reduced activity *3 1075A->C Minimal activity *4 1076T->C Reduced activity *5 1080C->G Reduced activity *6 818delA No activity *8 449G->A Substrate specific *9 752A->G Reduced activity *11 1003-C>T Reduced activity VKORC1: The c.-1639 promoter variant is located in the second nucleotide of an E-Box (CANNTG) and its presence disrupts the consensus sequence, reducing promoter activity. In vitro experiments show a 44% higher transcription level of the G versus the A allele.(1) The c.-1639 G->A nucleotide change results in decreased gene expression and reduced enzyme activity. Warfarin dosing may require adjustment dependent on CYP2C9 and VKORC1 genotype and predicted phenotype. Patients who are CYP2C9 poor metabolizers (reduced activity) may benefit from warfarin dose reductions or by being switched to other comparable drugs that are not metabolized primarily by CYP2C9. Refer to the drug label for additional information, available at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=558b7a0d-5490-4c1b-802e-3ab3f1efe760.

Useful For: Identifying patients who may require warfarin dosing adjustments(2,3) including: -Patients who have previously been prescribed warfarin and have required multiple dosing adjustments to maintain the international normalized ratio in the target range -Patients with a history of thrombosis or bleeding when taking warfarin -Patients being started on a first prescription for warfarin Genotyping patients who prefer not to have venipuncture done

Interpretation: An interpretive report will be provided that includes assay information, genotype, and an interpretation indicating the patientâ€™s predicted warfarin sensitivity. The CYP2C9 genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Human Cytochrome P450 (CYP) Allele Nomenclature Database Committee.(4) Individuals without a detectable gene alteration will have the predicted phenotype of an extensive drug metabolizer and are designated as CYP2C9*1/*1. Novel variants will be classified based on known, predicted, or possible effect on gene function and reported with interpretive comments detailing their potential or known significance. The c.-1639A variant reduces VKORC1 expression. The VKORC1 GA or AA genotype leads to a significant decrease in VKORC1 expression compared with the GG genotype. For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices. Individuals who have variants in both the VKORC1 promoter (GA or AA) and also in CYP2C9 should receive a reduced dose of warfarin and more frequent monitoring of international normalized ratio (INR) to maintain the INR in the target range; dosing adjustments are required when variants in both genes are present. Drug-drug interactions and drug/metabolite inhibition must be considered in the case of intermediate metabolism. It is important to interpret the results of testing and dose adjustments in the context of hepatic and renal function and patient age.


Clinical References: 1. Oldenburg J, Bevens CG, Muller CR, Watzka M: Vitamin K epoxide reductase complex subunit I (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal 2006;8(3-4):347-353 2. Yuan HY, Chen JJ, Lee MT, et al: A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005;14:1745-1751 3. Sconce EA, Khan TI, Wynne HA, et al: The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005;106:2329-2333 4. Human Cytochrome P450 (CYP) Allele Current as of August 23, 2017 7:11 am CDT


Page 2198

Nomenclature Database. Accessed 9/29/15. Available at: www.cypalleles.ki.se/cyp1a2.htm 5. Johnson JA, Gong L, Whirl-Carrillo M, et al: Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011;90(4):625-629

WRF

Warfarin, Serum

8760

Clinical Information: Warfarin (Coumadin) is an anticoagulant that acts by antagonizing the action of vitamin K resulting in the same coagulation abnormalities produced by vitamin K deficiency. Warfarin reduces the levels of prothrombin and factors VII, IX, and X, thereby prolonging the prothrombin and partial thromboplastin times. Warfarin produces its anticoagulant effect within 36 to 72 hours of initiating therapy, and the duration of action may persist for 4 to 5 days following withdrawal of drug. Warfarin circulates almost completely bound to albumin (>98%), and its half-life ranges from 20 to 60 hours. Abnormal bleeding is the chief complication of overdose.

Useful For: Monitoring patients whose prothrombin time is inconsistent with the prescribed warfarin dose, particularly when failure to comply or surreptitious drug use is suspected. Note: This test is not useful for evaluation of the patient with prolonged bleeding time suspected of exposure to rat poisons.

Interpretation: Therapeutic concentration: 2.0 to 5.0 mcg/mL Toxic concentration: > or =10.0 mcg/mL

Reference Values: Therapeutic concentration: 2.0-5.0 mcg/mL Toxic concentration: > or =10.0 mcg/mL

Clinical References: Gallus A, Jackaman J, Tillett J, et al: Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986;2:1293-1296

WSPV

Wasp Venom, IgE

82659





Negative



Page 2199

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



FWATG

Watermelon IgG

57677



WEED1

Weed Panel # 1

81882





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6




Page 2201


WEED2

Weed Panel # 2

81883





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



WEED3

Weed Panel # 3

81884




Page 2202





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



WEED4

Weed Panel # 4

81885



Interpretation: Detection of IgE antibodies in serum (Class 1 or greater) indicates an increased likelihood of allergic disease as opposed to other etiologies and defines the allergens that may be Current as of August 23, 2017 7:11 am CDT


Page 2203

responsible for eliciting signs and symptoms. The level of IgE antibodies in serum varies directly with the concentration of IgE antibodies expressed as a class score or kU/L.


Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6



WNVCI

West Nile CSF Interpretation

36779

Clinical Information: West Nile virus (WNV) is a mosquito-borne flavivirus (single-stranded RNA) that primarily infects birds but can also infect humans and horses. WNV was first isolated in 1937 from an infected person in the West Nile district of Uganda. Until the viral infection was recognized in 1999 in birds in New York City, WNV was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe.(1-3) Most recently, in 2012, a total of 5,674 cases of WNV were reported to the Centers for Disease Control and Prevention (CDC), among which 2,873 (51%) were classified as neuroinvasive disease (eg, meningitis or encephalitis) and 286 (5%) cases resulted in death.(2) Most people who are infected with WNV will not develop clinical signs of illness. It is estimated that about 20% of those who become infected will develop West Nile fever with mild symptoms, including fever, headache, myalgia, and occasionally a skin rash on the trunk of the body. Case fatality rates among patients hospitalized during recent outbreaks have ranged from 4% to 14%. Advanced age is the most important risk factor for death, and patients older than 70 years of age are at particularly high risk.(1) Laboratory diagnosis is best achieved by demonstration of specific IgG and IgM class antibodies in serum specimens. PCR (LCWNV / West Nile Virus, Molecular Detection, PCR) can detect WNV RNA in specimens from patients with recent WNV infection (ie, 3-5 days following infection) when specific antibodies to the virus are not yet present. However, the likelihood of detection is relatively low as the sensitivity of PCR detection is approximately 55% in cerebrospinal fluid and approximately 10% in blood, from patients with known WNV infection.

Useful For: Laboratory diagnosis of infection with West Nile virus Interpretation: IgM: A positive result is consistent with the acute phase of West Nile virus (WNV) meningitis or encephalitis. In the very early stages of acute WNV infection, IgM may be detectable in cerebrospinal fluid (CSF) before it becomes detectable in serum. A negative result may indicate absence of disease. However, specimens drawn too early in the acute phase may be negative for IgM-class antibodies to WNV. If WNV central nervous system infection is suspected, a second specimen should be collected in 1 to 2 weeks and tested. IgG: A positive result is consistent with CNS infection with WNV sometime in the past. This assay is unable to distinguish between intrathecal antibody synthesis and serum antibodies introduced into the CSF at the time of lumbar puncture or from a breakdown in the blood-brain barrier. Positive results should be interpreted with other laboratory and clinical data prior to a diagnosis of central nervous system infection.



Page 2204

Only orderable as part of a profile. See WNC / West Nile Virus Antibody, IgG and IgM, Spinal Fluid.

Clinical References: 1. Petersen LR, Marafin AA: West Nile Virus: a primer for the clinician. Ann Intern Med 2002;137:173-179 2. MMWR: West Nile Virus and Other Arboviral Diseases-United States, 2012. 2013;62(25):513-517 3. Brinton MA: The molecular biology of West Nile Virus: a new invader of the western hemisphere. Ann Rev Microbiol 2002;56:371-402 4. Centers for Disease Control and Prevention (CDC). Provisional Surveillance Summary of the West Nile Virus epidemic. United States, January-November 2002. MMWR Morb Mortal Wkly Rep 2002;51(50):1129-1133 5. Centers for Disease Control and Prevention (CDC). Investigations of West Nile Virus infections in recipients of blood transfusions. MMWR Morb Mortal Wkly Rep 2002;51(43):973-974

WNVSI

West Nile Serum Interpretation

36778

Clinical Information: West Nile virus (WNV) is a mosquito-borne flavivirus (single-stranded RNA) that primarily infects birds but can also infect humans and horses. WNV was first isolated in 1937 from an infected person in the West Nile district of Uganda. Until the viral infection was recognized in 1999 in birds in New York City, WNV was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe.(1-3) Most recently, in 2012, a total of 5,674 cases of WNV were reported to the Centers for Disease Control and Prevention (CDC), among which 2,873 (51%) were classified as neuroinvasive disease (eg, meningitis or encephalitis) and 286 (5%) cases resulted in death.(2) Most people who are infected with WNV will not develop clinical signs of illness. It is estimated that about 20% of those who become infected will develop West Nile fever with mild symptoms, including fever, headache, myalgia, and occasionally a skin rash on the trunk of the body. Case fatality rates among patients hospitalized during recent outbreaks have ranged from 4% to 14%. Advanced age is the most important risk factor for death, and patients older than 70 years of age are at particularly high risk.(1) Laboratory diagnosis is best achieved by demonstration of specific IgG and IgM class antibodies in serum specimens. PCR (WNVP / West Nile Virus (WNV), Molecular Detection, PCR, Plasma) can detect WNV RNA in plasma specimens from patients with recent WNV infection (ie, 3 to 5 days following infection) when specific antibodies to the virus are not yet present. However, the likelihood of detection is relatively low as the sensitivity of PCR detection is approximately 55% in cerebrospinal fluid and approximately 10% in blood, from patients with known WNV infection.

Useful For: Laboratory diagnosis of infection with West Nile virus Interpretation: IgG: The presence of IgG-class antibodies to West Nile virus (WNV) in serum indicates infection with WNV at some time in the past. By 3 weeks postinfection, virtually all infected persons should have developed IgG antibodies to WNV. If acute-phase infection is suspected, serum specimens drawn within approximately 7 days postinfection should be compared with a specimen drawn approximately 14 to 21 days after infection to demonstrate rising IgG antibody levels between the 2 serum specimens. IgM: Presence of specific IgM-class antibodies in a serum specimen is consistent with acute-phase infection with WNV. By the 8th day of illness, most infected persons will have detectable serum IgM antibody to WNV; in most cases it will be detectable for at least 1 to 2 months following disease resolution and in some cases will be detectable for 12 months or longer. The absence of IgM antibodies to WNV is consistent with lack of acute-phase infection with this virus. Specimens drawn too early in the acute phase (eg, before 8 to 10 days post-infection) may be negative for IgM-specific antibodies to WNV. If WNV is suspected, a second specimen drawn approximately 14 days postinfection should be tested. In the very early stages of WNV infection, IgM may be detectable in cerebrospinal fluid (CSF) before it becomes detectable in serum.

Reference Values: Only orderable as part of a profile. For more information see WNS / West Nile Virus Antibody, IgG and IgM, Serum.

Clinical References: 1. Petersen LR, Marafin AA: West Nile Virus: a primer for the clinician. Ann Intern Med 2002;137:173-179 2. MMWR: West Nile Virus and Other Arboviral Diseases-United States, 2012. MMWR. 2013;62(25):513-517 3. Brinton MA: The molecular biology of West Nile Virus: a new invader of the western hemisphere. Ann Rev Microbiol 2002;56:371-402 4. Centers for Disease Control and Prevention (CDC). Provisional Surveillance Summary of the West Nile Virus epidemic. United Current as of August 23, 2017 7:11 am CDT


Page 2205

States, January-November 2002. MMWR Morb Mortal Wkly Rep 2002;51(50):1129-1133 5. Centers for Disease Control and Prevention (CDC). Investigations of West Nile Virus infections in recipients of blood transfusions. MMWR Morb Mortal Wkly Rep 2002;51(43):973-974

WNV

West Nile Virus (WNV) Antibody, IgG and IgM, Serum

800264

Clinical Information: West Nile virus (WNV) is a mosquito-borne flavivirus (single-stranded RNA) that primarily infects birds but occasionally infects horses and humans. WNV was first isolated in 1937 from an infected person in the West Nile district of Uganda. Until the viral infection was recognized in 1999 in birds in New York City, WNV was found only in the Eastern Hemisphere, with wide distribution in Africa, Asia, the Middle East, and Europe.(1-3) In 2002, a total of 3,389 human cases of WNV infection were reported from 37 states (794 cases in Illinois); 2,354 (69%) presented with meningoencephalitis, 704 (21%) had West Nile fever, and 331 (10%) had an unspecified illness.(2) Overall, the WNV epidemic in the United States was the largest arboviral meningoencephalitis outbreak documented in the Western hemisphere. In addition, 33 cases of probable WNV infection occurred among persons who had received blood components in the month before illness onset.(3) Most people who are infected with WNV will not have any type of illness. It is estimated that about 20% of those who become infected will develop West Nile fever with mild symptoms, including fever, headache, myalgia, and occasionally a skin rash on the trunk of the body. About 1 of 150 WNV infections (50% of identified disease alleles in the Northern European Caucasian population. See Wilson Disease Testing Algorithm in Special Instructions for additional information.

Useful For: Diagnostic confirmation of Wilson disease Interpretation: All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.


Clinical References: 1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards of interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10(4):294-300 2. Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD): Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47(6):2089-2111 3. Mak CM, Lam CW: Diagnosis of Wilson's disease: a comprehensive review. Crit Rev Clin Lab Sci 2008;45(3):263-290

FWING

Wingscale (Atriplex Canescens) IgE

57955




BUCCF

X and Y Aneuploidy Detection, Buccal Smear, FISH

35261

Clinical Information: Aneuploidy of the sex chromosomes is common among recognized congenital syndromes. For example, the majority (80%) of individuals with Klinefelter syndrome have 2 X chromosomes and 1 Y chromosome; the remainder are mosaics or variants. Individuals with Turner syndrome have a single X chromosome in 55% of cases; the remaining 45% are either variants or mosaics. Conventional cytogenetic analysis should be performed for confirmation, especially when the



Page 2228

results are abnormal. Structural abnormalities of X and Y chromosomes will be missed by this technique, as will low-level mosaicism. This test can detect between 50% to 70% of Turner syndrome cases (only those caused by complete lack of 1 sex chromosome [45,X] or high-level mosaicism for a 45,X). Congenital blood chromosome analysis (CMS / Chromosome Analysis, for Congenital Disorders, Blood) should always be performed for Turner syndrome. The test does not rule out numeric or structural cytogenetic anomalies involving chromosomes other than X and Y.

Useful For: Diagnosis of mosaic sex chromosome aneuploidy as a supplement to conventional chromosome studies in patients with normal or uncertain chromosome results or when an alternative tissue needs to be studied.

Interpretation: Specimens that contain >5% cells with a signal pattern other than XX in females and XY in males have a very high likelihood of having a clone of cells with an abnormal complement of sex chromosomes. Specimens with or =100 Strongly positive Reference values apply to all ages.


YJV

Yellow Jacket Venom, IgE

82661





Negative

1

0.35-0.69 Equivocal

2

0.70-3.49 Positive

3

3.50-17.4 Positive

4


5


6





Page 2233

FYERS 57374

Yersinia enterocolitica Antibodies, IgA, IgG and IgM by Immunoblot Reference Values: Yersinia enterocolitica, IgA by Immunoblot Yersinia enterocolitica, IgG by Immunoblot Yersinia enterocolitica, IgM by Immunoblot

62489

Negative Negative Negative

Yes Associated Protein (YAP), Immunostain Without Interpretation Clinical Information: Yes-associated protein (YAP) is a downstream regulatory target in the Hippo signaling pathway that is upregulated in sonic hedgehog-associated medulloblastomas and medulloblastomas with activation of the Wnt signaling pathway and is expressed on lung, placenta, prostate, ovary, and testis.

Useful For: Identification and differentiation of medulloblastomas Interpretation: This test includes only technical performance of the stain (no pathologist interpretation is performed). If diagnostic consultation by a pathologist is required, order 70012 / Pathology Consultation. The positive and negative controls are verified as showing appropriate immunoreactivity. If a control tissue is not included on the slide, a scanned image of the relevant quality control tissue is available upon request; contact 1-855-516-8404. Interpretation of this test should be performed in the context of the patient's clinical history and other diagnostic tests by a qualified pathologist.

Clinical References: 1. Ellison DW, Dalton J, Kocak M, et al: Medulloblastoma clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 2011;121:381-396 2. Northcott PA, Korshunov A, Witt H, et al: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 2011 Apr 10;29(11):1408-1414 3. Thompson MC, Fuller C, Hogg TL, et al: Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol 2006;24:1924-931

FYABS

Yo Antibody Screen with Reflex to Titer and Western Blot

57847

Reference Values: Yo Ab, IFA:

Negative

Purkinje cells cytoplasmic antibody (Yo) can be found in approximately 50% of patients with paraneoplastic cerebellar degeneration (PCD). The presence of Yo antibody strongly suggests underlying gynecological cancer primarily of ovarian or breast origin. A negative assay for Yo antibody does not exclude the possibility of a malignant tumor.

FYOG

Yogurt (Lactobacillus bulgaricus) IgE

57915


Reference Values: or =11 years: 0.66-1.10 mcg/mL

Clinical References: 1. Tucker SB, Schroeter AL, Brown PW Jr, McCall JT: Acquired zinc deficiency: cutaneous manifestations typical of acrodermatitis enteropathica. JAMA 1976;235:2399-2402 2. Skelton JA, Havens PL, Werlin SL. Nutrient deficiencies in tube-fed children. Clin Pediatr 2006;45(1):37-41 3. Zorbas YG, Kakuris KK, Neofitov IA, Afoninos NI: Zinc utilization in zinc-supplemented and -unsupplemented healthy subjects during and after prolonged hypokinesis. Tr Elem Electro 2008;25:60-68

ZNCRU

Zinc/Creatinine Ratio, Random, Urine

60527

Clinical Information: Zinc is an essential element; it is a critical cofactor for carbonic anhydrase, alkaline phosphatase, RNA and DNA polymerases, alcohol dehydrogenase, and many other physiologically important proteins. Zinc also is a key element required for active wound healing. Zinc depletion occurs either because it is not absorbed from the diet or it is lost after absorption. Dietary deficiency may be due to absence (parenteral nutrition) or because the zinc in the diet is bound to fiber and not available for absorption. Once absorbed, the most common route of loss is via exudates from open wounds such as third-degree burns or gastrointestinal loss as in colitis. Hepatic cirrhosis also causes excess loss of zinc by enhancing renal excretion. The peptidase, kinase, and phosphorylase enzymes are most sensitive to zinc depletion. Zinc excess is not of major clinical concern. The popular American habit of taking mega-vitamins (containing huge doses of zinc) produces no direct toxicity problems. Much of this zinc passes through the gastrointestinal tract and is excreted in the feces. The excess fraction that is absorbed is excreted in the urine. The only known effect of excessive zinc ingestion relates to the fact that zinc interferes with copper absorption, which can lead to hypocupremia.

Useful For: Identifying the cause of abnormal serum zinc concentrations using a random urine specimen

Interpretation: Fecal excretion of zinc is the dominant route of elimination. Renal excretion is a minor, secondary elimination pathway. Normal daily excretion of zinc in the urine is in the range of 89 to 910 mcg/g creatinine. High urine zinc associated with low serum zinc may be caused by hepatic cirrhosis, neoplastic disease, or increased catabolism. High urine zinc with normal or elevated serum zinc indicates a large dietary source, usually in the form of high-dose vitamins. Low urine zinc with low serum zinc may be caused by dietary deficiency or loss through exudation common in burn patients and those with gastrointestinal losses.

Reference Values: 0-17 years: not established > or =18 years: 89-910 mcg/g Creatinine Current as of August 23, 2017 7:11 am CDT


Page 2240

Clinical References: 1. Sata F, Araki S, Murata K, et al: Behaviour of heavy metals in human urine and blood following calcium disodium ethylenediamine tetraacetate injection: Observations in heavy metal workers. J Tox Environ Health 1998;54:167-178 2. Afridi HI, Kazi TG, Kazi NG, et al: Evaluation of cadmium, lead, nickel and zinc status in biological samples of smokers and nonsmokers hypertensive patients. J Hum Hypertens 2010 Jan;24(1):34-43 3. Zorbas YG, Kakuris KK, Neofitov IA, Afoninos NI: Zinc utilization in zinc-supplemented and-unsupplemented healthy subjects during and after prolonged hypokinesia. Tr Elem Electro 2008;25(2):60-68

FZIP

Ziprasidone (Geodone, Zeldox)

57107


ng/mL

Expected plasma concentrations in patients taking Recommended Daily Dosages: Up to 220 ng/mL

FZOLP

Zolpidem (Ambien), serum or plasma

57738


ng/mL

Expected hypnotic zolpidem concentrations in patients taking recommended daily dosages: up to 250 ng/mL. Toxic range has not been established.

ZONI

Zonisamide, Serum

83685

Clinical Information: Zonisamide (Zonegran) is approved as adjunctive therapy for partial seizures refractory to therapy with traditional anticonvulsants. Zonisamide is the pharmacologically active agent; metabolites are not active. Essentially 100% of the zonisamide dose is absorbed. Zonisamide binds to erythrocytes; approximately 88% of circulating zonisamide is bound in erythrocytes. Because the erythrocyte-bound zonisamide is inactive, and binding varies with blood concentration, the relationship between serum level and dose is not linear. Time to peak zonisamide concentration is 2 to 4 hours; time to peak is delayed by co-administration with food to 4 to 6 hours. Zonisamide is metabolized by N-acetyl transferase (NAT1), cytochrome P4503A4 (CyP3A4), and uridine diphosphate glucuronidation (UDPG). Zonisamide is eliminated in the urine predominantly as the parent drug (35%), N-acetyl zonisamide (15%), and as the glucuronide ester of reduced zonisamide (50%). Co-administration of drugs that affect NAT1, CyP3A4, and UDPG activity, such as phenytoin and carbamazepine, will decrease zonisamide concentration. A typical zonisamide dose administered to an adult is 400 to 600 mg/day, administered in 2 divided doses. The apparent volume of distribution of zonisamide is 1.5 L/kg. Approximately 40% of the zonisamide circulating in the serum is bound to proteins. Zonisamide protein binding is unaffected by other common anticonvulsant drugs. The elimination half-life from plasma is 50 to 60 hours; the elimination half-life from erythrocytes is >100 hours. Since zonisamide is cleared predominantly by the kidney, the daily dosage of zonisamide given to patients with creatinine clearance