Rome Foundation Diagnostic Algorithms for Common ...

Rome Foundation Diagnostic Algorithms for Common Gastrointestinal Symptoms Editor John E. Kellow, MD Associate Editor Douglas A. Drossman, MD

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official publication of the american college of gastroenterology

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Douglas A. Drossman, MD

Introduction: A practical evidence-based approach to the diagnosis of the functional gastrointestinal disorders

John E. Kellow, MD

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Esophageal disorders

Peter J. Kahrilas, MD, and André J.P.M. Smout, MD, PhD

Recurrent heartburn Recurrent chest pain of suspected esophageal origin Dysphagia Sensation of a lump in the throat 757

Gastroduodenal disorders

Jan Tack, MD, PhD, and Nicholas J. Talley, MD, PhD

Recurrent dyspepsia

Epigastric pain

Postprandial distress

Recurrent nausea and/or vomiting Image of English garden maze with two individuals traveling the maze beginning with symptom presentation (top) to clinical diagnosis (bottom) with use of the Rome III criteria (middle rotunda). Concept by Doug Drossman, Jerry Schoendorf and John Kellow; illustration developed by Jerry Schoendorf.

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Gallbladder and sphincter of Oddi disorders

Enrico Corazziari, MD, and Peter B. Cotton, MD, FRCP, FRCS

Recurrent biliary-like pain: gallbladder in place Post-cholecystectomy biliary-like pain

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Functional abdominal pain syndrome

Ami D. Sperber, MD, and Douglas A. Drossman, MD

Constant or frequently recurring abdominal pain 775

Bowel disorders

Robin C. Spiller, MD, and W. Grant Thompson, MD

Recurrent abdominal pain/discomfort with disordered bowel habit Chronic painless diarrhea Chronic constipation 786

Anorectal disorders

Adil E. Bharucha, MD, and Arnold M. Wald, MD

Refractory constipation and difficult defecation Fecal incontinence Chronic or recurrent anorectal pain 795

Appendix A: Rome Psychosocial Alarm Questionnaire for the Functional GI Disorders

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Appendix B: Rome III Diagnostic Criteria for the Functional GI Disorders

Rome foundation diagnostic algorithms

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Rome Foundation Diagnostic Algorithm Committees PROJECT ADMINISTRATION

Coordinators/Co-Chairs John E. Kellow, MD, Co-Chair University of Sydney Sydney, Australia

Henry P. Parkman, MD, Co-Chair Temple University Philadelphia, PA, USA

Project Manager Carlar Blackman Rome Foundation

Committees

Esophageal Disorders Peter J. Kahrilas, MD Northwestern University Chicago, IL, USA

Gallbladder and Sphincter of Oddi Disorders Enrico Corazziari, MD Università “La Sapienza” Rome, Italy

André J.P.M. Smout, MD, PhD Academic Medical Center Amsterdam, The Netherlands

Gastroduodenal Disorders Jan Tack, MD, PhD University Hospitals Leuven University of Leuven Leuven, Belgium

Nicholas J. Talley, MD, PhD Mayo Clinic College of Medicine Jacksonville, FL, USA

Bowel Disorders Robin C. Spiller, MD University Hospital Nottingham, UK

W. Grant Thompson, MD Peter B. Cotton, MD, FRCP, FRCS Medical University of South Carolina Charleston, SC, USA

Functional Abdominal Pain Syndrome Douglas A. Drossman, MD UNC Center for Functional Gastrointestinal and Motility Disorders University of North Carolina at Chapel Hill Chapel Hill, NC, USA

Ami D. Sperber, MD, MSPH

University of Ottawa Ottawa, Ontario, Canada

Anorectal Disorders Adil E. Bharucha, MBBS, MD Mayo Clinic College of Medicine Rochester, MN, USA

Arnold M. Wald, MD University of Wisconsin School of Medicine and Public Health Madison, WI, USA

Department of Gastroenterology Ben-Gurion University of the Negev Tel-Aviv Medical Center Tel-Aviv, Israel

© 2010 by the American College of Gastroenterology

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Acknowledgments The reviewers were selected by the Rome Foundation for internal review of the documents. This was done in addition to the usual blinded journal peer review process.

Senior Reviewer

Henry P. Parkman, MD Philadelphia, Pennsylvania, USA Reviewers

Qasim Aziz, PhD, FRCP London, UK John Baillie, MB, ChB, FRCP, FACG Winston-Salem, North Carolina, USA Guido Basilisco, MD Milan, Italy Lin Chang, MD Los Angeles, California, USA William D. Chey, MD, FACG, FACP Ann Arbor, Michigan, USA Spencer D. Dorn, MD, MPH Chapel Hill, North Carolina, USA Dan Dumitrascu, MD Cluj, Romania Jean Paul Galmiche, MD Nantes, France Fortunée I. Habib, MD Rome, Italy Lesley A. Houghton, PhD Manchester, UK

George L. Longstreth, MD San Diego, California, USA Juan-R. Malagelada, MD, PhD Barcelona, Spain Fermín Mearin, MD, PhD Barcelona, Spain Paul Moayyedi, BSc (Bristol), MB ChB (Bristol), PhD (Leeds), MRCP, FRCP Hamilton, Ontario, Canada Bruce D. Naliboff, PhD Los Angeles, California, USA Kevin W. Olden, MD Mobile, Alabama, USA Pankaj Jay Pasricha, MD Stanford, California, USA Vincenzo Stanghellini, MD Bologna, Italy William E. Whitehead, PhD Chapel Hill, North Carolina, USA Bry Wyman, MD Madison, Wisconsin, USA The Rome Foundation is also grateful to Cathy L. Liu, Los Angeles, California, USA, for expert assistance with artwork.

Notice: The indications and dosages of all drugs in this document have been recommended in the medical literature and conform to the practices of the general medical community. The medications described do not necessarily have specific approval by the US Food and Drug Administration (FDA) for use in the diseases and dosages for which they are recommended. The package insert for each drug should be consulted for use and dosage as approved by the FDA. Because standards for usage change, it is advisable to keep abreast of revised recommendations, particularly those concerning new drugs. Copyright © 2009 by Rome Foundation The American Journal of Gastroenterology

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Preface Douglas A. Drossman, MD1, Associate Guest Editor Am J Gastroenterol 2010;105:740–741; doi:10.1038/ajg.2010.63

We are most pleased to have this opportunity to collaborate with the American Journal of Gastroenterology on this special issue. Included herein is a compendium of expert opinion and information to help the clinician diagnose the common gastrointestinal (GI) symptoms that patients present to us. The key component of this issue is the Rome Foundation’s introduction of a new clinical tool: Diagnostic Algorithms for Common Gastrointestinal Symptoms. This project evolved from the growing need for a practical, efficient, and cost-effective aid to the diagnosis of the GI symptoms that patients frequently bring to their health-care providers in both gastroenterology and primary care. Several features of this issue and of the algorithm program are worth highlighting. Algorithm development process

The Rome Foundation has for years recognized that the Rome diagnostic criteria for functional GI disorders have limitations when used by practicing clinicians. Patients don’t go to doctors complaining of IBS or sphincter of Oddi dysfunction. Rather, they present with symptoms—of abdominal pain, nausea, vomiting, and constipation, among others. Accordingly, the Foundation initiated a two-year process to address this concern by incorporating these symptom-based criteria and other diagnostic information into clinical algorithms. First, the project directors (John Kellow and Henry Parkman) and the Rome Foundation’s board identified 12 internationally recognized gastroenterologists who work in the area of functional GI and motility disorders, to work on six committees. Their first job was to compile a list of 15 common GI symptom presentations. From this entry point, we had our committees develop an evidence-based and cost-effective diagnostic pathway that would follow from the clinical presentation. These experts then developed clinically meaningful diagnostic algorithms using standard methods with “yes/no” decision trees and the use of diagnostic testing when indicated, all of which ended with specific diagnoses. This work was accomplished by e-mail for over a year and culminated in a 1½-day harmonization meeting at which the algorithms were presented to all committee members for review and modification. Each committee then selected several outside reviewers as content experts to critique their algorithms. The feedback was then incorporated into revisions of the algorithms. Finally, arti-

cles describing the use of the algorithms were sent to the journal editors for both internal and external review. What resulted is a polished set of algorithms and supportive additional information. We used the best diagnostic strategies currently available based on the consensus of numerous experts. Issue content

The Rome Foundation Diagnostic Algorithms portion of this issue of the Journal is organized into six sections that cover the primary GI regions: esophageal, gastroduodenal, biliary, bowel, anorectal, and functional abdominal pain. Each section has from one to four algorithms. For example, the bowel section has algorithms for abdominal pain associated with bowel dysfunction, chronic constipation, and chronic painless diarrhea. Next, for each algorithm we include additional features to bring the information to clinical reality: (i) extensive referenced annotations to support the decision-tree logic; (ii) detailed information on the relevant Rome III functional GI disorders and information on other GI conditions diagnosed through the algorithmic pathway; (iii) an introductory section to help the reader understand the nature of the symptoms and their underlying pathophysiology; and (iv) a case report to provide real clinical information that is linked to the algorithm and which demonstrates its proper application. Related articles

Thanks to the Journal’s Editors-in-Chief, William Chey and Paul Moayyedi, this issue is devoted to the content and process of diagnostic decision making for GI symptoms. They have included several additional peer-reviewed articles that will enrich the reader’s learning in the area of symptom-based diagnostic assessment. For example, the Red Section contains an article by W. Grant Thompson on the nature of symptoms and syndromes. There is also a Clinical Review article by William Whitehead and me on the evidence for validity of symptombased criteria, and a variety of other articles address clinical aspects of symptom-based diagnosis. Additional development features

The mission of the Rome Foundation is “to improve the lives of people with functional GI disorders” through research and education. Accordingly, we plan to disseminate the algorithms to as

President, Rome Foundation, and Co-Director, UNC Center for Functional Gastrointestinal and Motility Disorders, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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large a community of health-care practitioners as possible. To do this, we have undertaken several initiatives. (i) We will provide these algorithms for viewing on our website (http://www. theromefoundation.org) beginning in May 2010, and then for download free of charge in October 2010, and we are encouraging other organizations to link to our website as well. (ii) Beginning in October 2010, we plan to distribute CDs containing the algorithms at the annual meetings of professional associations. (iii) Offprints of this issue will be made available through the Journal and the Foundation as well as from our pharmaceutical sponsors. We also feel committed to making this a global effort, and through the Foundation’s International Liaison Committee we are translating these algorithms into several languages; as a first step they will soon be published in Spanish in Revista de Gastroenterología de México [Mexican Journal of Gastroenterology]. Finally, we are currently negotiating with a premium medical content provider to make the Rome criteria and these clinical algorithms available to a larger health-care educational environment. We are seeking to offer this information through mobile health-care and Internet providers to individuals, clinical practices, and hospitals. Certainly, with all new clinical tools, we recognize that there will be room for improvement. As with the symptom-based criteria, the work begins with consensus and proceeds to validation. Accordingly, we encourage feedback and criticism and expect to use that information to help improve our educational


tools. In addition, through our research program, we encourage investigators to apply to the Foundation with proposals that will help to validate these algorithms in clinical practice. For now we hope that this diagnostic tool will prove to be a cost-efficient and valid means for improving clinical practice and, ultimately, the lives of our patients. I would like to take this opportunity to thank the individuals who helped make this project possible. First, we are most grateful for the remarkable efforts of John Kellow, MD, the journal guest editor who developed the concept and provided the motivation, commitment, and energy to guide the committee members to completion and to meticulously edit all the documents. Additional thanks go to Henry Parkman, MD, past president of the American Neurogastroenterology and Motility Society, for his valuable insights and his work as co-coordinator of this project. We also acknowledge and congratulate our 12 committee members (listed at the front of this section) for producing the very-high-quality information herein. In addition, our gratitude goes to Carlar Blackman, who served as the project manager and handled the logistics that helped bring this project to completion. Finally, special gratitude goes to our industry sponsors (listed on our website, http://www.theromefoundation.org) who supported the committee work, and special thanks to Procter & Gamble, Synergy Pharmaceuticals, Takeda Pharmaceuticals, and Zeria Pharmaceutical, which provided sponsorship for the dissemination of these educational materials.


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Introduction: A Practical Evidence-Based Approach to the Diagnosis of the Functional Gastrointestinal Disorders John E. Kellow, MD1, Guest Editor Am J Gastroenterol 2010;105:743–746; doi:10.1038/ajg.2010.64

Diagnosis of the functional gastrointestinal disorders in clinical practice

Chronic disorders of the digestive tract often exhibit a paucity of clinical signs, and thus the diagnosis of these disorders relies on the presence of characteristic symptoms. The functional gastrointestinal disorders (FGIDs) are common chronic disorders in clinical practice that affect all regions of the digestive tract and comprise about 40% of gastroenterologists’ diagnoses (1). The best-known FGIDs are irritable bowel syndrome and functional dyspepsia. These conditions not only lack reliable clinical signs but also do not exhibit structural change or biochemical abnormalities. The FGIDs are multidetermined disorders, arising from a composite of factors affecting the gut mucosa and microflora, the enteric nervous system and its extrinsic neural connections, and signaling within the brain and spinal cord (2). These disorders are best understood from a biopsychosocial perspective; as such it would appear unlikely that any single biomarker—such as mucosal histology, cardiovascular reactivity, gut permeability, and blood, stool, or genetic markers (3)—can explain the symptoms and will emerge as a diagnostic tool for these disorders. Symptom-based criteria are therefore needed to diagnose the FGIDs; in other words, diagnosis is based on the patterns of presenting symptoms with the addition of physiological and other tests where relevant and available. The Rome III classification is the only standardized and internationally recognized symptom-based classification of the FGIDs that encompasses all regions of the gastrointestinal tract (4). The diagnostic criteria for these FGIDs have been refined and simplified from previous iterations and continue to be increasingly utilized in research publications (5). The clinical application of the Rome III classification, however—especially the clinical reasoning processes required for the diagnosis of an individual FGID in the office setting—has been the subject of considerably less discussion than the research application. Thus, in clinical practice, although many gastroenterologists are aware of the Rome diagnostic criteria, the uptake of the criteria appears to be rather limited, especially for disorders other than irritable bowel syn-

drome (6,7). Indeed, in the absence of reliable biomarkers, it is likely that many clinicians continue to avoid making a formal diagnosis of a specific FGID, either categorizing the disorder as “functional” or diagnosing a wide range of disorders and symptoms as “irritable bowel.” In primary care it is likely that many practitioners decline to make a diagnosis at all and simply list the predominant symptom. With respect to diagnosis of the FGIDs, what is important to the gastroenterologist is the clinical context of each FGID, namely its relation to other disorders presenting with similar symptoms—both “organic” disorders and recognized motility disorders. For example, when should one consider peptic ulcer relative to functional dyspepsia, or when and how should one differentiate inflammatory bowel disease from irritable bowel syndrome? This context is crucial to the gastroenterologist’s acceptance and recognition of the FGIDs, but it is this context that has often received limited attention in discussions of the FGIDs. The diagnosis of FGIDs should not be considered merely one of exclusion. Rather, diagnosis involves a guided algorithmic approach in order to move from symptoms to diagnosis, be it disease or syndrome. Why should the gastroenterologist diagnose specific FGIDs?

In most areas of clinical medicine, there are benefits for both physician and patient when a specific diagnosis is made. Most obviously, diagnosis (of a chronic disorder) informs, and therefore should precede, treatment; the diagnosis of the FGIDs is no exception. Thus, for example, diagnosis of functional heartburn may lead to a trial of a visceral analgesic agent; diagnosis of functional gallbladder disorder may indicate a case for cholecystectomy; diagnosis of mixed irritable bowel syndrome may facilitate rational use of both laxative and antidiarrheal agents; and diagnosis of a functional defecation disorder may point toward a trial of anorectal biofeedback therapy. More targeted treatment regimens, however, are not the only potential beneficial outcomes of a more precise diagnosis, even one that is largely symptom-based. Another important aspect is

Department of Medicine, Royal North Shore Hospital, Sydney Medical School, University of Sydney, Sydney, Australia. Correspondence: John E. Kellow, MD, Department of Medicine, Building 52, Royal North Shore Hospital, St Leonards NSW 2065, Australia. E-mail: [email protected]

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that a specific diagnosis sits in the center of a constructive doctor–patient relationship. A recent study (8) highlighted the gastroenterologist–patient communication gap that currently exists in the FGIDs. Because at follow-up most patients in this latter report did not acknowledge the FGID diagnosis they had been given at earlier consultations, these investigators recommended that clinicians take care to ensure that patients “own” their diagnosis before therapy is commenced. Another recent report (9), which evaluated aspects of the management of gastroesophageal reflux disease, also highlighted the importance of securing a precise diagnosis and of improving the quality of physician–patient communication, both of which influence patient satisfaction. Use of the Rome criteria in the clinic can make the diagnostic process more efficient, reducing unnecessary diagnostic procedures and related costs. The criteria also enable a specific diagnosis to be communicated to the patient and, in so doing, provide the gastroenterologist with an opportunity to inform the patient of our current understanding of the pathophysiology of that particular entity. With this more explicit recognition of the patient’s symptoms and their possible origin comes an enhanced physician–patient interaction, which in turn leads to improved clinical outcomes such as reduced symptom severity and reduced health-care seeking (10). Rome Foundation diagnostic algorithm project

The current project was conceived to help address the disconnect between the use of the Rome criteria in research and their use in clinical practice. The Rome criteria have been criticized for being too detailed and time consuming to use in clinical practice; our broad objective in constructing this series of algorithms is therefore to raise clinician awareness of the FGIDs by making the essentials of the Rome III classification more accessible for clinical practice. In other words, we wish to “translate” the criteria for the FGIDs into a practical clinical application for gastroenterologists, trainees, and primary-care physicians. The specific aims are to use standardized, practical and yet evidence-based, diagnostic algorithms to illustrate the full spectrum of the FGIDs and, in so doing, (i) assist the clinician in the appropriate recognition of these disorders; (ii) place the FGIDs in clinical context with the other important regional gut disorders that need to be considered in the diagnostic process; and (iii) demonstrate how the FGIDs, in many cases, can be identified and diagnosed on the basis of positive symptoms and other criteria. Fifteen typical symptom presentations are discussed, encompassing the six regional domains of criteria-based FGIDs and the most common and important disorders within each domain. These regional groups and disorders are: 1. The functional esophageal disorders—functional heartburn,

functional chest pain of presumed esophageal origin, functional dysphagia, and globus sensation

2. The functional gastroduodenal disorders—functional dys-

pepsia and its subgroups and functional nausea and vomiting disorders


3. The functional gall bladder and sphincter of Oddi dysfunc-

tion disorders—functional gall bladder disorder and functional biliary sphincter of Oddi disorder

4. Functional abdominal pain syndrome 5. The functional bowel disorders—irritable bowel syndrome,

functional diarrhea, and functional constipation

6. The functional anorectal disorders—functional defecation

disorders, functional fecal incontinence, and functional anorectal pain

The algorithms thus cover a wide range of differential diagnoses in luminal gastroenterology, and, where appropriate, salient information is also included regarding other important disorders. By utilizing the symptom criteria and appropriate alarm features or “red flags,” together with the judicious use of investigations, the algorithms provide recommended diagnostic pathways for these particular FGIDs. The complete Rome III classification of FGIDs is given in Appendix B, where the disorders covered in this series are indicated with a dagger symbol. Although the validity of the Rome symptom-based criteria requires further confirmation, epidemiological studies using factor analysis and other methods have provided evidence supporting the existence of discrete syndromes, particularly irritable bowel syndrome; this aspect is discussed further in the article by Whitehead and Drossman in this issue of the Journal. Why algorithms?

Algorithms have been defined as “flow diagrams that consist of branching-logic pathways which permit the application of carefully defined criteria to the task of identifying or classifying different types of an entity” (11). As Hadorn notes, diagnosis is in fact a form of classification and identification. Thus clinical diagnostic algorithms are tools that enable clinicians to approach patients with specified presentations in an effective and efficient manner (11). Clinical algorithms have been published in the English-language medical literature for more than 40 years (12) and have become an accepted part of continuing medical education. Unfortunately, more recently there has been a deviation from the optimal algorithm format—which includes “yes/no” decision boxes—toward simple descriptive flow diagrams. This is somewhat regrettable because the main strength of properly constructed flowchart algorithms can then be lost, that is, that algorithms are uniquely suited for explicitly communicating the conditional logic of the clinical reasoning process (12). Algorithms have been shown also to result in faster learning, higher retention, and better compliance with guidelines and recommendations than prose text (11). Presentation of the symptom-based Rome classification of FGIDs is well suited to the algorithm format. Format of the algorithms

The format of the algorithms in this series largely follows recommended international guidelines for clinical algorithm maps Volume 105 | April 2010 www.amjgastro.com

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(12). This format uses three different types of “boxes.” These are (i) the clinical state box (rounded rectangle), to describe the initial clinical symptom or symptoms and to describe, in the body of the algorithm, the patient status or diagnosis; (ii) the decision box (hexagon), to prompt a diagnostic decision, with an entry path and featuring “yes” and “no” exit paths; and (iii) the action box (rectangle), to designate a diagnostic (or therapeutic) action. Consecutive numbers on each box indicate the appropriate flow or pathways through the algorithm; these numbers also correspond to the associated explanatory notes to each box, contained in the figure legend. References are provided for the explanatory notes where feasible. Solid arrows indicate recommended pathways; dashed arrows denote an additional or optional potential course of action depending on clinical circumstances. We have added (i) a case history that precedes each algorithm and acts as a “cognitive hook” by illustrating one example of appropriate navigation through the relevant algorithm and (ii) an introductory discussion on aspects of the symptoms referable to that particular gut region. The project committees were asked to ensure that the algorithms conform to certain published desirable attributes (11), in other words, “standards” the committees were asked to meet— namely: validity, reproducibility, reliability, clarity, clinical applicability, clinical flexibility, cost effectiveness, and appropriate documentation. In this context, “validity” refers to the correct interpretation of available evidence (content and face validity); “reproducibility” refers to the fact that, given the same evidence, another algorithm group would produce similar recommendations; “reliability” refers to the fact that different users navigate the algorithms similarly; “clarity” refers to the use of precise definitions, unambiguous language, and a standard format; “clinical applicability” refers to the use of a well-defined target population, and the fact that sample case histories confirm smooth navigation through the algorithms; “clinical flexibility” refers to the ability of the algorithms to identify exceptions and to indicate how patient preferences are incorporated in decision making; “cost effectiveness” refers to the fact that algorithms lead to efficient diagnosis at acceptable cost; and “appropriate documentation” refers to the fact that, although the algorithms record assumptions and methods, the annotations and references link recommendations to available evidence. Finally, the different elements of the algorithms are required to be arranged for optimal flow as well as for visual appeal of the layout. Content of the algorithms

The project essentially summarizes and updates the clinical evaluation data contained in the Rome III book (13). The algorithms include clinically relevant physiological testing only when appropriate to the diagnostic process. The interfaces between standard investigations applicable in clinical practice, newer or emerging techniques with promise for clinical practice, and techniques available for clinical research are a consideration relevant to many of the algorithms. The committees determined that if an investigation was not crucial to the clinical diagnosis and differential diagnosis, even if it was available in certain centers for clin© 2010 by the American College of Gastroenterology

ical use, then it would not be included in the algorithms. In these instances the annotations indicate the utility, or lack of utility, of such additional investigations. Similarly, the algorithms do not address management of the various conditions discussed, except where therapeutic trials or maneuvers can be considered as part of the diagnostic process. We hope that in the near future we will develop therapeutic algorithms to aid the clinician in proper evidence-based decision making. It is accepted that the FGIDs result from complex interactions among biological, psychological, and social factors (14). Psychosocial disturbances in particular, such as psychological distress, recent environmental stress, and childhood trauma, can affect the onset, course, severity, and outcome of the FGIDs (4), and such disturbances are well known to clinicians seeing patients with FGIDs in referral practices. Psychosocial criteria, however, currently do not form part of the symptom-based criteria, as they are not specific to the FGIDs; for this reason psychosocial factors are not addressed specifically in the diagnostic algorithms. Notwithstanding this, Levy et al. (14) suggest that physicians should undertake a brief psychosocial assessment of patients with FGIDs. This assessment ideally should include evaluation for depression and anxiety, somatization, health beliefs and coping, and illness impact and health-related quality of life (14). The Rome III Psychosocial Alarm Questionnaire (12; see also Appendix A in this issue), the Hospital Anxiety and Depression Scale (15), and the Patient Health Questionnaire (PHQ-15) (ref. 16) are satisfactory for screening purposes. These instruments can help identify patients who may benefit from psychological evaluation and treatments, as part of management of the FGID. Patients with severe symptoms or evidence of poor coping with illness may warrant a more in-depth psychosocial assessment performed by a psychologist or psychiatrist (14). Limitations of algorithms

It is important to acknowledge that the clinical algorithm maps included in this series cannot address all possible clinical situations or scenarios and hence are guidelines only. The final diagnostic decisions, of course, rest with the physician and patient. Care has been taken in the explanatory notes to indicate contentious areas and alternative diagnostic routes. Traditional motility disorders present with symptoms similar to those of some of the FGIDs. For example, heartburn may result from gastroesophageal reflux disease or functional heartburn. We discussed with the leadership of the American Neurogastroenterology and Motility Society whether to collaborate on the development of joint algorithms that would include all the traditional motility disorders as well as the FGIDs. However, this would have made the algorithms more complex and delayed their completion. We concluded that these algorithms would have more clinical utility if they focused on the FGIDs and included traditional motility disorders only where necessary to explain the process of differential diagnosis. Geographic variations in diagnostic practices in various countries can limit the international utility of algorithms. In the construction of these algorithms, we have not undertaken a “cascade” The American Journal of Gastroenterology

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process, in which a hierarchical set of diagnostic techniques is included for any one diagnosis, these various techniques being ranked by the resources available to the practicing physician (17). The focus of this series of algorithms is thus on North American, Western European, and Asian-Pacific specialist gastroenterology practice. In conclusion, we hope these algorithms will be of value to clinical gastroenterologists and trainees as tools to help in the confident diagnosis of a variety of FGIDs and other relevant disorders in gastroenterology practice. I thank the authors for their excellent contributions and my co-chair Henry Parkman, recent president of the American Neurogastroenterology and Motility Society, for his co-coordination of this project. I also thank associate editor Doug Drossman for his expert assistance in bringing this project to fruition. We appreciate that as new knowledge becomes available, these guidelines will require modification; certainly, the algorithmic format readily enables such modifications. However, we believe these algorithms should enhance clinician awareness and knowledge of the FGIDs, render the diagnosis of FGIDs more transparent, and improve clinical outcomes. References

1. Russo MW, Gaynes BN, Drossman DA. A national survey of practice patterns of gastroenterologists with comparison to the past two decades. J Clin Gastroenterol 1999;29:339–43. 2. Kellow JE, Azpiroz F, Delvaux M et al. Principles of applied neurogastroenterology: physiology/motility sensation. In: Drossman DA (ed). Rome III: The Functional Gastrointestinal Disorders, 3rd edn. Degnon Associates: McLean, VA, 2006, pp40–63. 3. Gescse K, Roka R, Ferrier L et al. Increased faecal serine protease activity in


diarrhoeic IBS patients: a colonic luminal factor impairing colonic permeability and sensitivity. Gut 2008;57:591–8. 4. Drossman DA. The functional gastrointestinal disorders and the Rome III Process. Gastroenterology 2006;130:1377–90. 5. Drossman DA. Introduction: the Rome Foundation and Rome III. Neurogastroenterol Motil 2007;19:783–6. 6. Lea R, Hopkins V, Hastleton J et al. Diagnostic criteria for irritable bowel syndrome: utility and applicability in clinical practice. Digestion 2004;70:210–3. 7. Gladman LM, Gorard DA. General practitioner and hospital specialist attitudes to functional gastrointestinal disorders. Aliment Pharmacol Therapeut 2003;17:651–4. 8. Collins J, Farrall E, Turnbull DA et al. Do we know what patients want? The doctor-patient communication gap in functional gastrointestinal disorders. Clin Gastroenterol Hepatol 2009;7:1252–4. 9. Bytzer P. What makes individuals with gastroesophageal reflux disease dissatisfied with their treatment? Clin Gastroenterol Hepatol 2009;7:816–22. 10. Stewart M, Brown JB, Donner A et al. The impact of patient-centered care on outcomes. J Fam Pract 2000;49:796–804. 11. Hadorn DC. Use of algorithms in clinical guideline development. Agency for Health Care Policy and Research. AHCPR pub. no. 95-0009. Clinical Practice Guideline Development: Methodology Perspectives, pp93–104. Rockville, MD, January 1995. 12. Proposal for clinical algorithm standards. Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. Med Decis Making 1992;12:149–54. 13. Drossman DA (ed). Rome III: The Functional Gastrointestinal Disorders, 3rd edn. Degnon Associates: McLean, VA, 2006. 14. Levy RL, Olden KW, Naliboff BD et al. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology 2006;130:1447–58. 15. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70. 16. Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258–66. 17. Fried M, Quigley EMM, Hunt RH et al. Are global guidelines desirable, feasible and necessary? Nat Rev Gastroenterol Hepatol 2008;5:2–3.


ROME FOUNDATION DIAGNOSTIC ALGORITHMS

Esophageal Disorders Peter J. Kahrilas, MD1 and André J.P.M. Smout, MD, PhD2 Am J Gastroenterol 2010; 105:747–756; doi:10.1038/ajg.2010.65

ESOPHAGEAL SYMPTOMS Despite advances in diagnostic tests for gastrointestinal (GI) disorders, a careful clinical history remains central to the evaluation of a patient with upper GI symptoms. Most patients who present with esophageal disorders will have a relatively mild and non-life-threatening illness and in many instances a thoughtfully obtained history will lead to expedient and accurate management. Alternatively, it is also important to identify patients who carry a higher likelihood of serious underlying disease so that they can be investigated and managed expeditiously. As part of the history, physicians should inquire about the patient’s dietary habits as well as smoking and alcohol consumption. Some patients may experience symptoms only when they eat excessively, particularly if done so late at night before going to bed. Four major esophageal symptoms, each of which is associated with a functional esophageal disorder, are heartburn, chest pain, dysphagia, and globus.

morbidity and mortality associated with cardiac pain, it is always appropriate to consider carefully that option before the esophageal option (3). Esophageal pain is usually experienced as a pressure type sensation in the mid chest, radiating to the mid back, arms, or jaws. The precise etiology of esophageal chest pain is unknown but it is clearly overly simplistic to view this as indicative of esophageal spasm or a manifestation of a contractile abnormality. Rarely do such individuals objectively show spasm and no correlation could be established between minor aberrations of esophageal contractility and pain events. More likely, the similarities to cardiac pain stem from the fact that the two organs share a nerve plexus and the nerve endings in the esophageal wall have poor discriminative ability among stimuli (4). Esophageal distention or even chemostimulation (eg, with acid) will often be perceived as chest pain (5,6). In fact, GERD is a more common cause of chest pain than esophageal dysmotility (3). Dysphagia

Heartburn (pyrosis)

This is the most frequently encountered symptom of esophageal origin. Heartburn is characterized by a discomfort or burning sensation behind the sternum that arises from the epigastrium and may radiate toward the neck (1). Heartburn is an intermittent symptom, most commonly experienced within 60 min of eating, during exercise, and while lying recumbent. The discomfort is relieved with drinking water or antacid but can occur frequently and interfere with normal activities. Given the high background prevalence of gastroesophageal reflux disease (GERD), there is a very high predictive value of GERD as the diagnosis when heartburn is the dominant or exclusive symptom. The association is so strong that in such instances, empirical therapy for GERD has become an accepted management strategy (2). However, the term “heartburn” is often misused and/or referred to with other terms such as “indigestion” or “repeating” making it incumbent on the clinician to clarify the intended meaning. Chest pain

This is a surprisingly common esophageal symptom with characteristics strikingly similar to cardiac pain making this discrimination very difficult in some instances. Given the potential for

This symptom is reported to some degree by more than 30% of individuals with GERD. It can be caused by peptic stricture, a Schatzki ring, peristaltic dysfunction, or simply by the mucosal inflammation associated with esophagitis. Dysphagia also occurs in the absence of any identifiable abnormality in which case it is likely the result of abnormal sensitivity to bolus movement during peristalsis. Esophageal dysphagia is often described as a feeling of food “sticking” on the way down or even lodging in the chest for a prolonged period. Important distinctions are between uniquely solid food dysphagia as opposed to liquid and solid, episodic vs. constant dysphagia, and progressive vs. static dysphagia. If the dysphagia is for liquids as well as solid food, it suggests a motor abnormality of the esophagus such as achalasia (7). Conversely, uniquely solid food dysphagia is suggestive of a structural abnormality such as a stricture, Schatzki ring, or tumor; this should always be investigated. If the dysphagia is only episodic, it suggests only a slight compromise of the esophageal lumen. Afflicted individuals will often report an all-or-none phenomenon; either they perceive no impediment in food transit or they are completely obstructed to the point that even liquids back up. Progressive solid food dysphagia is an ominous finding, especially in association with weight loss, this being the classic

1 Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; 2Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. Correspondence: Peter J. Kahrilas, MD, Division of Gastroenterology, Department of Medicine, Feinberg School of Medicine, Northwestern University, 676 N Saint Clair, Suite 1400, Chicago, Illinois 60611-2951, USA. E-mail: [email protected]


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presentation of esophageal cancer. Of note, a patient’s perception of the locus of food hang-up in the esophagus is grossly imprecise. Approximately 30% of distal esophageal obstructions are perceived as cervical dysphagia, often prompting an evaluation for an oropharyngeal swallowing disorder. In such instances, the esophagus can usually be identified as the culprit because of the absence of concomitant symptoms generally associated with oropharyngeal dysphagia such as aspiration, nasopharyngeal regurgitation, cough, drooling, or obvious neuromuscular compromise. Globus sensation

This symptom, alternatively labeled “globus hystericus,” is the perception of a lump or fullness in the throat that is felt irrespective of swallowing (8). In fact, although such patients are frequently referred for an evaluation of dysphagia, globus sensation is often relieved by the act of swallowing. As implied by its other name (globus hystericus), globus sensation often occurs in the setting of anxiety or obsessive-compulsive disorders (9). Clinical experience teaches that it is also attributable to GERD in a substantial fraction of patients, although that experience is widely not reflected in the scientific literature (10).

RECURRENT HEARTBURN Case history

A 34-year-old woman is referred to a gastroenterologist by her primary care physician (PCP) because of “therapy-resistant” reflux symptoms. She has experienced for about 5 years with daily episodes of heartburn that partially responded to treatment with

a proton pump inhibitor (PPI), prescribed by her PCP. An upper GI endoscopy, carried out 3 years before, had revealed no macroscopic signs of esophagitis and no hiatus hernia. When the history is taken by the gastroenterologist it becomes clear that the episodes of burning retrosternal pain (Box 1, Figure 1) experienced by the patient last from 10 min to some hours, bear no clear temporal relationship to meals, and are not posture dependent. She does not have regurgitation, or other types of chest pain. There is no dysphagia, odynophagia or other alarm features (Box 2). The use of omeprazole 40 mg daily (Box 3) seems to ameliorate the symptoms somewhat, but the result is described as unsatisfactory, even at a 40 mg twice daily dose (Box 4). The patient requests surgical treatment. The gastroenterologist decides to repeat the upper GI endoscopy (Box 6), after a period of PPI avoidance of 2 weeks. At endoscopy no macroscopic abnormalities are seen (Box 7). No biopsies are taken; 24-h esophageal pH and impedance monitoring is then undertaken (Box 9). This test is carried out after the patient discontinues omeprazole for 7 days. Esophageal acid exposure (Box 10) is found to be in the normal range (time with pH < 4: upright 3.2%, supine 0%, total 2.3%). During the 24-h recording six symptom episodes are indicated by the patient. None of these is temporally associated with the onset of a reflux episode, neither acid, nor nonacid, leading to a symptom association probability (SAP) of 0% (Box 12). Before placement of the pH/impedance catheter a manometric study was carried out, to measure the distance of the lower esophageal sphincter (LES) to the nose (Box 13). During this test, normal esophageal peristalsis and normal LES resting pressure and relaxation were observed (Box 14). A diagnosis of “functional heartburn” is made (Box 16).

Figure 1. Legend 1.

2.

3.

4.

5.

6.

It should be noted that heartburn is described quite differently between different cultures and languages. Most descriptions of this symptom include discomfort or burning sensation behind the sternum that may radiate toward the neck. Heartburn is an intermittent symptom, most commonly experienced in the early postprandial periods, during exercise, and while lying recumbent. The discomfort is relieved with drinking water or antacid. The symptom can interfere with normal activities. Epigastric pain or discomfort that does not rise to the retrosternal region should not be called heartburn (1). History and physical examination should look for alarm features suggestive of cancer. This would include evidence of persistent dysphagia, gastrointestinal (GI) bleeding, unintentional weight loss, lymphadenopathy, an epigastric mass, and evidence of anemia. There is no convention for the dosage, duration, or specific drug to be used in a proton pump inhibitor (PPI) trial for heartburn, making it reasonable to treat with a standard once daily dose for 2 weeks (11). If insufficient response is achieved with standard dose PPI, this should be increased to twice daily for at least 2 weeks before considering it a treatment failure. Once a satisfactory response has been achieved, the PPI dosage should be reduced to the lowest amount that is still associated with a satisfactory treatment effect. Biopsies should be obtained at the time of endoscopy if there are any visual abnormalities suggestive of metaplasia or eosinophilic esophagitis or if dysphagia is an additional presenting symptom. If eosinophilic esophagitis is suspected, five mucosal biopsies should


be obtained (12,13). Although histological criteria for esophagitis may also be detected (basal cell hyperplasia, rete pegs extending toward surface) these findings lack specificity for gastroesophageal reflux disease (GERD) (14). 7. Relevant abnormalities at upper GI endoscopy that would exclude a diagnosis of functional heartburn are reflux esophagitis and eosinophilic esophagitis. 8. The Los Angeles Classification of esophagitis is based on the occurrence and extent of visible mucosal breaks in the distal esophageal mucosa. Los Angeles A is the mildest with only short breaks ( < 5 mm) confined to folds of the epithelium, whereas Los Angeles D is the most severe with nearly circumferential breaks (15). Eosinophilic esophagitis is often attributable to allergy to ingested (food) or inhaled allergens and defined by finding ≥15 eosinophils per high-power field in esophageal mucosal biopsies (16). 9. pH or impedance–pH monitoring is performed after withholding PPI therapy for 7 days to obtain a meaningful assessment of esophageal acid exposure and to provide the greatest chance of finding a positive association between heartburn episodes and reflux events (17,18). 10. The cutoff for abnormal esophageal acid exposure is typically < 5%, although this value varies slightly among centers (19). 11. The Rome III definition of nonerosive reflux disease is either abnormal acid exposure or a positive symptom–reflux association in the absence of macroscopic endoscopic signs of reflux esophagitis (20,21). 12. The symptom association probability (SAP) is a statistical test to determine if the co-occurrence of symptoms and VOLUME 105 | APRIL 2010 www.amjgastro.com

Esophageal Disorders

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Patient with burning retrosternal discomfort or pain (heartburn)

Gastroesophageal reflux disease: titrate PPI therapy

yes 3

2 Alarm features?

4 Trial of proton pump inhibitor (PPI)

no

Heartburn resolved?

yes

16 Functional heartburn

no

6 Upper GI endoscopy ± biopsy

no 14

13 7

9

Any abnormality identified?

no

yes 8 LA A–D esophagitis, eosinophilic esophagitis

Meets esophageal motor disorder criteria?

Esophageal manometry

pH or impedance – pH monitoring (off PPIs)

no

yes

12

10 Abnormal esophageal acid exposure?

no

Positive symptom-association probability?

yes

yes

15 Achalasia, diffuse esophageal spasm

11 Nonerosive reflux disease

Figure 1. Recurrent heartburn.

reflux events within 2-min periods is happening by chance or because the two are likely related. An SAP > 95 % equates to a P < 0.05 that they are related ( 22 ). Although some centers use the symptom index (SI) to gauge symptom – reflux association, the SI is not a validated method and has no statistical basis ( 23 ). 13. It would be preferable to obtain a high-resolution manometry (esophageal pressure topography) study if available because of a greater sensitivity in the diagnosis of achalasia (24). 14. For the purposes of establishing a diagnosis of functional heartburn the only two exclusionary diagnoses are achalasia and diffuse esophageal spasm (DES). Other, less severe, peristaltic


abnormalities are still consistent with a diagnosis of functional heartburn. 15. Achalasia is defined by absent peristalsis and impaired deglutitive lower esophageal sphincter (LES) relaxation; DES by ≥20% of test swallows showing simultaneous or spastic contractions in the distal esophagus (25). 16. Rome III diagnostic criteria for functional heartburn are: (i) burning retrosternal discomfort or pain, and (ii) absence of evidence that GERD is the cause of the symptom, and (iii) absence of histopathology-based esophageal motility disorders, and (iv) criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis (26).



5

1

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RECURRENT CHEST PAIN OF SUSPECTED ESOPHAGEAL ORIGIN Case history

A 72-year-old retired woman consults a gastroenterologist upon referral by her cardiologist. In the past 2 years she has experienced numerous episodes of severe retrosternal pain radiating to the jaw and left arm; at times there is also radiation of the pain to the midline of the back (Box 1, Figure 2). Before the onset of the chest pain the patient has rarely had health problems. Her appendix was removed at age 22 years and she underwent hysterectomy at age 52 years because of fibroid tumors. She has no relevant family history of GI disease. The chest pain occurs at an average rate of two episodes per week, but there are large variations in its rate of occurrence; it is described as a heavy sensation. The onset of the pain is not clearly related to meal intake and there is no dysphagia, either during chest pain episodes, or in between. There is no typical heartburn, regurgitation, or odynophagia. The onset of the pain is not clearly related to exercise or body posture and physical examination of the lungs and chest wall is normal (Box 2). On

three occasions she has been admitted to the coronary care unit of a large general hospital. In all cases no evidence of myocardial ischemia or infarction was found. Chest X-ray had been normal. Coronary angiography had revealed normal coronary arteries, and exercise testing was negative (Boxes 5 and 6). Before referral to the gastroenterologist a therapeutic trial of omeprazole 40 mg twice daily had been given (Box 8). After 6 weeks of this treatment the patient reported that the chest pain had continued to occur (Box 9). The gastroenterologist performs an upper GI endoscopy (Box 11), during which a normal squamocolumnar junction is seen, positioned 1 cm proximal to the diaphragmatic impression (Box 12). At this stage the gastroenterologist decides to arrange some additional tests. Esophageal manometry (Box 18) followed by 24-h esophageal pH monitoring off a PPI (Box 14) shows normal peristalsis, normal LES function (Box 19), and physiological acid exposure (time with pH < 4 3.2%) (Box 15). During the 24-study no chest pain episode occurred, and therefore a positive SAP could not be established (Box 17). A diagnosis of “functional chest pain of presumed esophageal origin” is made (Box 21).

Figure 2. Legend 1.

Esophageal chest pain is typically described as retrosternal with radiation to the midline of the back. It can be a heavy sensation and closely mimic cardiac pain. Radiation to the jaws and to the left arm may also occur. 2. History and physical examination should seek evidence of musculoskeletal, pulmonary, or neurological etiologies of chest pain. 3. If an alternative diagnosis that is typically associated with chest pain is established this would conclude the evaluation for functional esophageal chest pain. 4. It is important to consider the adequately risk of potentially fatal cardiac conditions before pursuing an esophageal evaluation. This need not always mean cardiological referral but if doubt exists, it is best to err on the side of caution. 5. Relevant cardiological evaluation may include exercise stress testing, Holter monitoring and coronary angiography depending on symptom features and risk factors (27). 6. If a cardiological diagnosis that is typically associated with chest pain is established, this would conclude the evaluation for functional esophageal chest pain. 7. Although other cardiological diagnoses could potentially explain chest pain, the two with most immediate consequence are coronary artery disease and pericarditis. 8. For the indication of suspected reflux-related chest pain, a 4-week trial of twice daily proton pump inhibitor (PPI) is indicated (28). 9. If PPI therapy is associated with a satisfactory improvement or resolution of chest pain, this would conclude the evaluation for functional esophageal chest pain. 10. Once a satisfactory response has been achieved, the PPI dosage should be reduced to the least amount that is still associated with a satisfactory treatment effect. 11. Biopsies should be obtained at the time of endoscopy if there are any visual abnormalities suggestive of metaplasia, ulceration, infection, eosinophilic esophagitis, or if dysphagia was an additional presenting symptom. 12. Endoscopic findings diagnostic of a painful esophageal condition would conclude the evaluation for functional esophageal chest pain.


13. The most common cause of esophageal chest pain is gastroesophageal reflux disease (3) but other causes of esophageal ulceration such as caustic, infectious, or pill-induced esophagitis may be encountered. The Los Angeles Classification of esophagitis is based on the occurrence and extent of visible mucosal breaks in the distal esophageal mucosa. Los Angeles A is the mildest with only short breaks ( < 5 mm) confined to folds of the epithelium whereas Los Angeles D is the most severe with nearly circumferential breaks (15). 14. pH or impedance–pH monitoring is performed after withholding PPI therapy for 7 days to obtain a meaningful assessment of esophageal acid exposure and to provide the greatest chance of finding a positive association between heartburn episodes and reflux events. 15. The cutoff for abnormal esophageal acid exposure is typically < 5%, although this value varies slightly among centers (19). 16. Abnormal esophageal acid exposure or a positive symptom association probability is diagnostic of nonerosive reflux disease by Rome III criteria. This would then establish a diagnosis of a reflux chest pain syndrome (and exclude functional chest pain). 17. The symptom association probability (SAP) is a statistical test to determine if the co-occurrence of symptoms and reflux events within 2-min periods is happening by chance or because the two are likely related ( 22 ). An SAP > 95 % equates to a P < 0.05 that they are related. Although some centers use the symptom index (SI) to gauge symptom – reflux association, the SI is not a validated method and has no statistical basis ( 23 ). 18. If reflux cannot be identified as the cause of the chest pain, esophageal manometry is indicated. It is preferable to obtain a high-resolution manometry (esophageal pressure topography) study if available because of a greater sensitivity in the diagnosis of achalasia (24). 19. For the purposes of establishing a diagnosis of functional chest pain the only two exclusionary diagnoses are achalasia and DES. According to the Rome III criteria, other, less severe peristaltic abnormalities are still consistent with a diagnosis of functional chest pain.

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1

2 3

History and physical examination suggestive of nonesophageal etiology?

yes

Evaluate and treat as indicated

no

7

4 Risk of cardiac etiology?

yes

6

5 Cardiological evaluation

yes

Any abnorality identified?

Ischemic heart disease, pericarditis

no no

10

9

8

Chest pain resolved?

Trial of twice-daily proton pump inhibitor (PPI)

yes

Reflux disease with chest pain: titrate PPI therapy

21 Functional chest pain of presumed esophageal origin

no

11 Upper GI endoscopy± biopsy

no 19

12 Any abnormality identified?

no

14

Esophageal manometry

yes

no 15

13 LA A-D esophagitis, pill esophagitis, infectious esophagitis

Meets esophageal motor disorder criteria?

18 pH or impedance – pH monitoring (off PPIs)

yes

17

Abnormal esophageal acid exposure?

no

Positive symptom association probability?

yes

yes

20 Achalasia, diffuse esophageal spasm

16 Nonerosive reflux disease

Figure 2. Recurrent chest pain of suspected esophageal origin.

20. Achalasia is defined by absent peristalsis and impaired deglutitive lower esophageal sphincter (LES) relaxation; DES by ≥20% of test swallows showing simultaneous or spastic contractions in the distal esophagus (25). 21. Rome III diagnostic criteria for functional chest pain of presumed esophageal origin are: (i) midline chest pain that is not


of burning quality, and (ii) absence of evidence that GERD is the cause of the symptom, and (iii) absence of histopathologybased esophageal motility disorders, and (iv) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (26–29).



Patient with chest pain of suspected esophageal origin

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DYSPHAGIA


Case history

A 44-year man is referred to a gastroenterologist by his PCP because of dysphagia for solid food and liquids (Box 1, Figure 3). The symptoms had begun about a year ago. They were intermittent and mild initially, but for the past few weeks bolus hold-up at the mid-thoracic level is perceived with almost all meals. He has no chest pain or odynophagia. There are no features of oropharyngeal dysphagia, and physical examination for nonesophageal causes of dysphagia is negative (Box 2). His weight has remained constant at 92 kg. The patient experiences heartburn once a week on average. A brief therapeutic trial with an H2 receptor antagonist, initiated by his PCP, eliminated his heartburn but had not resulted in improvement of the dysphagia. His medical history is otherwise unremarkable, and he does not take any drugs. There is no family history of GI disease. Upper GI endoscopy is performed (Box 4) and excludes macroscopic esophagitis or any organic lesion causing esophageal

obstruction (Box 5), and microscopic examination of biopsies taken from the distal as well as the proximal esophagus shows that there is no evidence of eosinophilic esophagitis or other histological abnormality (Box 8). A barium swallow with marshmallow bolus challenge (Box 6) reveals no structural lesion and no impairment of transit through the esophagus (Box 7). Because of the presence of the mild reflux symptoms (Box 9), a trial of PPI, omeprazole 40 mg twice daily, is initiated (Box 10). This does not result in improvement of the patient’s dysphagia (Box 11). The gastroenterologist then arranges a manometric study of the esophagus (Box 13). This shows normal esophageal peristalsis, normal LES pressure and normal LES relaxation on swallowing (Box 14). Concomitant impedance monitoring confirms complete bolus transit with nine of ten swallows, findings within the range of normal. The patient again denies any cervical symptoms (Box 16). A diagnosis of “functional dysphagia” is made (Box 20).

Figure 3. Legend 1.

Dysphagia should be characterized as occurring with only solid food, suggesting a structural abnormality, or both solids and liquids, suggesting a motility abnormality, and whether localized as proximal or distal. The associated symptom of odynophagia is also important as this is highly suggestive of esophageal ulceration. 2. History and physical examination should explore for nonesophageal causes of dysphagia: neck masses, goiter, or neurological findings supportive of oropharyngeal dysphagia. 3. Detection of a nonesophageal condition associated with dysphagia would conclude the evaluation for functional dysphagia. 4. Biopsies should be obtained at the time of endoscopy regardless of visual abnormalities to evaluate for eosinophilic esophagitis; five mucosal biopsies should be obtained (12,13). Although histological criteria for esophagitis may also be detected (basal cell hyperplasia, rete pegs extending toward surface) these findings lack specificity for GERD (14). 5. Detection of a structural lesion would conclude the evaluation for functional dysphagia. 6. Barium swallow with solid bolus challenge (barium tablet or barium impregnated marshmallow) is useful in detecting obstructive lesions such as a subtle distal esophageal ring. In this application, this exam has superior sensitivity to upper gastrointestinal (GI) endoscopy (30). 7. Detection of a structural lesion would conclude the evaluation for functional dysphagia. 8. Dysphagia is a common symptom of a multitude of inflammatory and structural esophageal disorders, the detection of which would exclude functional dysphagia (31–33). 9. Concomitant symptoms of heartburn or regurgitation suggest that GERD may be the cause of dysphagia. 10. When used as a therapeutic trial in dysphagia proton pump inhibitors (PPIs) are usually dosed in a twice daily regimen for at least 2 weeks (34). 11. Resolution of dysphagia with PPI therapy would imply that the dysphagia was a manifestation of reflux disease and exclude a diagnosis of functional dysphagia. 12. As with all patients, once a satisfactory treatment response has been established, the dose of PPI should then be reduced to


13.

14.

15.

16.

17.

18. 19.

the minimal dose still associated with a satisfactory treatment response. If no structural abnormality is found, manometry is indicated. It may be preferable to obtain a high-resolution manometry (esophageal pressure topography) study if available because of a greater sensitivity in the diagnosis of achalasia and other motility disorders (35,36). If available, concurrent impedancebased assessment of esophageal transit may provide additional information regarding the completeness of bolus transit in the esophagus. The Rome III criteria stipulate that histopathology-based disorders, DES and achalasia, preclude the diagnosis of functional dysphagia. Achalasia is defined by absent peristalsis and impaired deglutitive lower esophageal sphincter (LES) relaxation; DES by ≥20% of test swallows showing simultaneous or spastic contractions in the distal esophagus (25). We propose that in addition to DES and achalasia, absent or severely disrupted peristalsis should also lead to exclusion of the diagnosis of functional dysphagia. High (cervical, oropharyngeal) dysphagia is reported by about 30% of individuals with distal disease. However, once distal disease has been adequately excluded the suggestion of any evidence for cervical dysphagia should prompt evaluation for proximal esophageal dysfunction. A videofluoroscopic swallowing study allows for the detailed examination of the swallow mechanism including the opening characteristics of the upper esophageal sphincter, which is often a blind spot at endoscopy or barium swallow examination because of lack of adequate distention (37). Note that if the initial barium study (Box 6) included videofluoroscopy as is performed in some institutions, this step can be omitted. The finding of proximal esophageal dysfunction would end the evaluation for functional dysphagia. A cricopharyngeal bar is caused by fibrous degeneration at the upper esophageal sphincter with resultant restricted opening and can be accepted as the cause of dysphagia once other pathology is excluded (38). This can also lead to the formation of Zenker’s



753

1

2 History and physical examination suggestive of nonesophageal etiology? no

3

yes

Evaluate and treat as indicated 15

4

Achalasia, absent peristalsis, diffuse esophageal spasm

Upper GI endoscopy with biopsies 5 no

Structural lesion?

6 Barium swallow with bolus challenge

yes 13 Esophageal manometry ± impedance measurement

7

yes yes

Structural lesion?

8 Stricture, web, ring, 1°or 2° tumor, esophagitis (reflux, infectious, eosinophilic or pill), dermatologic disorder, extrinsic compression

14 Meets esophageal motor disorder criteria?

16 no

Cervical dysphagia? 20

17

9 Reflux symptoms?

no

yes

no

Videofluoroscopic swallow study

no

Functional dysphagia

yes 10

19

Trial of proton pump inhibitor (PPI)

18 Cricopharyngeal bar, Zenker’s diverticulum

yes

Proximal dysfunction?

no

12 11 Reflux disease with dysphagia: titrate PPI therapy

yes

Dysphagia improved?

no

Figure 3. Dysphagia.

diverticulum, the mouth of which is located just proximal to the cricopharyngeus. 20. Rome III diagnostic criteria for functional dysphagia are: (1) sense of solid and/or liquid foods sticking, lodging, or passing abnormally through the esophagus; and (2) absence of


evidence that gastroesophageal reflux is the cause of the symptom; and (3) absence of histopathology-based esophageal motility disorders; and (4) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (26).



Patient with dysphagia

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SENSATION OF A LUMP IN THE THROAT

and explores whether the lump sensation is temporally related to stress, but the patient denies this association. The PCP, convinced that he is dealing with a functional disorder, explains to the patient that nothing is seriously wrong and attempts to reassure her. However, 2 weeks later the patient consults her PCP again because of a continuing lump sensation. She is then referred to an ear–nose–throat physician because, in reviewing her history, she did have substantial exposure to second-hand smoking and was quite concerned about this (Box 7). The latter does not find any abnormalities at examination, which includes nasolaryngoscopy (Box 8). Because of an association between globus and the endoscopic finding of ectopic gastric mucosa in the proximal esophagus and esophageal cancer, the patient is referred for endoscopy (Box 10). No abnormalities were found (Box 11). Because of the presence of some heartburn, 6-week trial of PPI therapy is initiated (Box 14). This does not lead to improvement of the lump sensation (Box 15). The patient is again reassured of the benign nature of her condition and a diagnosis of “globus” is made (Box 17).


Case history

A 30-year old woman consults her PCP because of a feeling of a lump in the throat (Box 1, Figure 4). She has had this symptom intermittently for about 1 year, but the intensity has increased during the past few weeks. There was no obvious precipitating event. Her swallowing is normal, and not painful. There is no dysphagia (Box 4) or odynophagia, and no hoarseness or other change in her voice (Box 6). Eating improves the symptom. Yet, the patient has the impression that something is stuck in her throat. She rarely experiences heartburn, and has had no weight loss. The patient is otherwise healthy. She is a nonsmoker and takes alcohol in moderation (Box 6). Apart from an oral contraceptive she does not use any drugs. The PCP examines the patient’s neck, throat, and oral cavity, but finds nothing abnormal (Box 2). There are no palpable masses, no enlarged lymph nodes, and the thyroid is not enlarged. The PCP has the impression that the patient is experiencing some anxiety

Figure 4. Legend 1.

3.

Globus sensation (Greek for “ball”) is the feeling of a lump or “ball” in the throat that is distinct from dysphagia in that it is experienced without swallowing and is even improved by swallowing; it is non-painful. History and physical examination, especially of the neck, throat and oral cavity, may reveal evidence of trauma or an inflammatory or other condition potentially explaining symptoms.

2.

4. 5.

Discovery of an alternative diagnosis sufficient to explain the symptom would preclude a diagnosis of globus. Globus sensation can occur in association with dysphagia in which case diagnostic efforts shift to the evaluation of dysphagia. Conditions associated with dysphagia would preclude a diagnosis of functional globus; see algorithm for dysphagia.

1 Patient with nonpainful sensation of a lump in the throat 5

4 Concomitant dysphagia?

yes

Dysphagia evaluation

no 6 no

no

Voice dysfunction, H&N cancer risks?

2 History and physical examination suggestive of alternative diagnosis?

Reflux symptoms?

Upper GI endoscopy

11

Globus

14 Trial of proton pump inhibitor


ENT evaluation

no

yes

no

yes 7

17

13

10

no

yes

yes


3

15 Globus improved?

12

no

Treat as indicated

Evaluate and treat as indicated

yes 9

yes 16

Treat as indicated

Reflux disease with globus: titrate PPI therapy

Figure 4. Sensation of a lump in the throat. The American Journal of GASTROENTEROLOGY


6.

7. 8. 9. 10.

11.

12. 13.

Globus sensation can occur in association with other symptoms of laryngeal dysfunction such as hoarseness, which should prompt ear–nose–throat (ENT) evaluation. Similarly if a patient is at risk for laryngeal cancer because of smoking he or she should have an ENT evaluation (39). ENT evaluation would likely include nasolaryngoscopy and other imaging as indicated (40,41). Identification of an abnormality on ENT evaluation would preclude a diagnosis of functional globus. Other ENT condition would prompt treatment as indicated. Endoscopy is performed to evaluate for ectopic gastric mucosa in the cervical esophagus or esophageal cancer, which can be associated with globus sensation. An abnormality identified at endoscopy would conclude the evaluation for functional globus. The finding of ectopic gastric mucosa in the proximal esophagus should prompt consideration of ablation therapy. Other conditions should be treated as indicated. Reflux disease can be a cause of globus and most gastroesophageal reflux disease (GERD) patients will not have macroscopic endo-

CONFLICT OF INTEREST

Guarantors of the article: Rome Foundation. Specific authors contribution: Peter J. Kahrilas: concept and design, analysis and interpretation of data, drafting of the paper. André J.P.M. Smout: co-authorship, together with Peter Kahrilas. Financial support: This work was supported by grant from the Rome Foundation. Potential competing interests: None. REFERENCES 1. Vakil N, Zanten van SV, Kahrilas P et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–20. 2. Tytgat GN, McColl K, Tack J et al. New algorithm for the treatment of gastro-oesophageal reflux. Aliment Pharmacol Ther 2008;27:249–56. 3. Voskuil JH, Cramer MJ, Breumelhof R et al. Prevalence of esophageal disorders in patients with chest pain newly referred to the cardiologist. Chest 1996;109:1210–4. 4. Sengupta JN. An overview of esophageal sensory receptors. Am J Med 2000;108:87S–9S. 5. Broekaert D, Fischler B, Sifrim D et al. Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a doubleblind, placebo-controlled study. Aliment Pharmacol Ther 2006;23:365–70. 6. Rao SS, Mudipalli RS, Remes-Troche JM et al. Theophylline improves esophageal chest pain—a randomized, placebo-controlled study. Am J Gastroenterol 2007;102:930–8. 7. Chen CL, Orr WC. Comparison of esophageal motility in patients with solid dysphagia and mixed dysphagia. Fall 2005;20:261–5. 8. Ali KH, Wilson JA. What is the severity of globus sensation in individuals who have never sought health care for it? J Laryngol Otol 2007;121:865–8. 9. Deary IJ, Wilson JA, Kelly SW. Globus pharyngis, personality, and psychological distress in the general population. Psychosomatics 1995;36:570–7. 10. Locke GR III, Talley NJ, Fett SL et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112:1448–56. 11. Howden CW, Chey WD. Gastroesophageal reflux disease. J Fam Pract 2003;52:240–7. 12. Gonsalves N, Policarpio-Nicolas M, Zhang Q et al. Histopathologic variability and endoscopic correlates in adults with eosinophilic esophagitis. Gastrointest Endosc 2006;64:313–9. 13. Kapel RC, Miller JK, Torres C et al. Eosinophilic esophagitis: a prevalent disease in the United States that affects all age groups. Gastroenterology 2008;134:1316–21. 14. Vieth M. Structural abnormalities of endoscopy-negative reflux disease— real or perceived? Digestion 2008;78:24–30.


14. 15.

16.

17.

scopic findings. Hence patients with symptoms such as heartburn or regurgitation should undergo a therapeutic trial of antireflux therapy. When used as a therapeutic trial in globus proton pump inhibitors (PPIs) are usually given in a twice daily regimen (42). Resolution of globus with PPI therapy would imply that the globus was a manifestation of reflux disease and exclude a diagnosis of functional globus. Once a satisfactory treatment response has been established, the dose of PPI should then be reduced to the minimal dose still associated with a satisfactory treatment response. Rome III diagnostic criteria for globus are: (i) persistent or intermittent, nonpainful sensation of a lump or foreign body in the throat, and (ii) occurrence of the sensation between meals, and (iii) absence of dysphagia or odynophagia, and (iv) absence of evidence that gastroesophageal reflux is the cause of the symptom, and (v) absence of histopathology-based esophageal motility disorders, and (vi) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (26).

15. Lundell LR, Dent J, Bennett JR et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles Classification. Gut 1999;45:172–80. 16. Moawad FJ, Veerappan GR, Wong RK. Eosinophilic esophagitis. Dig Dis Sci 2009;54:1818–28. 17. Savarino E, Zentilin O, Tutuian R et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy. Am J Gastroenterol 2008;103:2685–93. 18. Hemmink GJM, Bredenoord AJ, Weusten BLAM et al. Esophageal pHimpedance monitoring in patients with therapy-resistant reflux symptoms: “on” of “off ” proton pump inhibitor? Am J Gastroenterol 2008;103:2446–53. 19. Richter JE. Ambulatory esophageal pH monitoring. Am J Med 1997;103:130S–4S. 20. Winter JW, Heading RC. The nonerosive reflux disease—gastroesophageal reflux disease controversy. Curr Opin Gastroenterol 2008;24:509–15. 21. Hershcovici T, Zimmerman J. Functional heartburn vs non-erosive reflux disease: similarities and differences. Aliment Pharmacol Ther 2008;27:1103–9. 22. Weusten BLAM, Roelofs JMM, Akkermans LMA et al. The symptom-association probability: an improved method for symptom analysis of 24-hour esophageal ph data. Gastroenterology 1994;107:1741–5. 23. Wiener GJ, Richter JE, Copper JB et al. The symptom index: a clinically important parameter of ambulatory 24-hour esophageal pH monitoring. Am J Gastroenterol 1988;83:358–61. 24. Pandolfino JE, Kwiatek MA, Nealis T et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008;135:1526–33. 25. Spechler SJ, Castell DO. Classification of oesophageal motility abnormalities. Gut 2001;49:145–51. 26. Galmiche JP, Clouse RE, Balint A et al. Functional esophageal disorders. Gastroenterology 2006;130:1459–65. 27. Fenster PE. Evaluation of chest pain: a cardiology perspective for gastroenterologists. Gastroenterol Clin North Am 2004;33:35–40. 28. Wang WH, Huang JQ, Zheng GF et al. Is proton pump inhibitor testing an effective approach to diagnose gastroesophageal reflux disease in patients with noncardiac chest pain? Arch Intern Med 2005;165:1222–8. 29. Mudipalli RS, Remes-Troche JM, Andersen L et al. Functional chest pain: esophageal or overlapping functional disorder. J Clin Gastroenterol 2007;41:264–9. 30. Ott DJ, Kelley TF, Chen MY et al. Evaluation of the esophagus with a marshmallow bolus: clarifying the cause of dysphagia. Gastrointest Radiol 1991;16:1–4. 31. Mackenzie SH, Go M, Chadwick B et al. Eosinophilic oesophagitis in patients presenting with dysphagia—a prospective analysis. Aliment Pharmacol Ther 2008;28:1140–6. 32. Prasad GA, Talley NJ, Romero Y et al. Prevalence and predictive factors of eosinophilic esophagitis in patients presenting with dysphagia: a prospective study. Am J Gastroenterol 2007;102:2627–32. 33. Müller S, Pühl S, Vieth M et al. Analysis of symptoms and endoscopic findings in 117 patients with histological diagnoses of eosinophilic esophagitis. Endoscopy 2009;39:339–44.


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34. Kahrilas PJ, Shaheen NJ, Vaezi MF et al. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 2008;135:1383–91. 35. Fox MR, Bredenoord AJ. Oesophageal high-resolution manometry: moving from research into clinical practice. Gut 2008;57:405–23. 36. Pandolfino JE, Fox MR, Bredenoord AJ et al. High-resolution manometry in clinical practice: utilizing pressure topography to classify oesophageal motility abnormalities. Neurogastroenterol Motil 2009;21:796–806. 37. Langmore SE. Evaluation of oropharyngeal dysphagia: which diagnostic tool is superior? Curr Opin Otolaryngol Head Neck Surg 2003;11: 485–9.


38. Dantas RO, Cook IJ, Dodds WJ et al. Biomechanics of cricopharyngeal bars. Gastroenterology 1990;99:1269–74. 39. Harar RP, Kumar S, Saeed MA et al. Management of globus pharyngeus: review of 699 cases. J Laryngol Otol 2004;118:522–7. 40. Chung JY, Levine MS, Weinstein GS et al. Globus sensation: findings on videofluoroscopic examinations. Can Assoc Radiol J 2003;54:35–40. 41. Takwoingi YM, Kale US, Morgan DW. Rigid endoscopy in globus pharyngeus: how valuable is it? J Laryngol Otol 2006;120:42–6. 42. Sinn DH, Kim JH, So n HJ et al. Response rate and predictors of response in a short-term empirical trial of high-dose rabeprazole in patients with globus. Aliment Pharmacol Ther 2008;27:1275–81.



Gastroduodenal Disorders Jan Tack, MD, PhD1 and Nicholas J. Talley, MD, PhD2,3 Am J Gastroenterol 2010; 105:757–763; doi:10.1038/ajg.2010.66

GASTRODUODENAL SYMPTOMS A large number of patients in clinical practice present with symptoms that can be attributed to the gastroduodenal region. These include epigastric pain or burning, early satiation and postprandial fullness, excessive belching and nausea or vomiting. Epigastric symptoms are experienced in the region between the umbilicus and lower end of the sternum, and marked by the mid-clavicular lines. Postprandial fullness is an unpleasant sensation of prolonged persistence of food in the stomach. Early satiation is the sensation that the stomach is overfilled soon after starting to eat, out of proportion to the size of the meal, such that the meal cannot be finished. Epigastric pain refers to a subjective, more intense unpleasant sensation with a feeling of tissue damage. If the epigastric pain has a burning quality, it is referred to as epigastric burning. Nausea is defined as a queasiness or sick sensation; a feeling of the need to vomit. Vomiting is the forceful oral expulsion of gastric contents associated with contraction of the abdominal and chest wall muscles. It is usually preceded by nausea and often associated with retching (repetitive contractions of the abdominal wall without expulsion of gastric content) (1). Vomiting is different from regurgitation or rumination in that the material cannot ever be held in the mouth voluntarily. When these symptoms are chronic and occur in the absence of organic disease that readily explains them, the patient is considered to have a functional gastroduodenal disorder (1). These disorders are classified as functional dyspepsia (FD), belching disorders, functional nausea and vomiting disorders, and the rumination syndrome. Functional dyspepsia is defined as the presence of symptoms thought to originate in the gastroduodenal region (early satiation, postprandial fullness, epigastric pain or burning), in the absence of any organic, systemic or metabolic disease that is likely to explain the symptoms. FD is further subdivided into two diagnostic categories, namely meal-induced dyspeptic symptoms (postprandial distress syndrome (PDS), characterized by postprandial fullness and early satiation) and epigastric pain syndrome (EPS, characterized by epigastric pain and burning) (1). Nausea and vomiting may accompany or complicate a variety of organic gastrointestinal (GI) and systemic disorders. When these can be excluded as a cause, the patient is thought have a functional nausea and vomiting disorder. Functional disorders characterized

by the presence of chronic unexplained nausea and/or vomiting can be subdivided into chronic idiopathic nausea, functional vomiting, or the cyclic vomiting syndrome (1).

RECURRENT DYSPEPSIA Case history 1

A 38-year-old woman is referred to a gastroenterologist by her primary care physician (PCP) because of epigastric pain that has been present during the last year (Box 1, Figure 1). The pain is located between the umbilicus and the lower end of the sternum. It is intermittent, though present on most days of the week, and lasts between 10 min and 2 h. It is often moderately severe, and described as “nagging” in character, with no colicky component, and associated with epigastric burning (Box 1). The pain does not radiate up the sternum, nor to the right subscapular region nor through to the back. It is not related to food ingestion, is not associated with nausea or vomiting, and is not relieved by defecation or passage of flatus. Her bowel habit is normal. Occasionally the pain may prevent her from falling asleep but it does not wake her at night (Box 2). She has no dysphagia, weight loss (Box 3), or typical heartburn (Box 4). There is occasional mild postprandial fullness, but this is infrequent and does not occur at the time of the epigastric pain, and there is no early satiation (Box 1), or excessive belching, and rarely does she have upper abdominal bloating. A similar episode of pain occurred 3 years ago, which was not responsive to antacids. It only lasted for several weeks and then spontaneously disappeared. The patient does not take non-steroidal anti-inflammatory drugs (NSAIDs), is a nonsmoker, and uses alcohol only sporadically. There are no previous or current medical conditions to explain the pain (Box 2), and she reports no family history of GI disease (Box 3). Physical examination is normal (Box 2). Her PCP had arranged blood tests, including a serum test for Helicobacter pylori (Box 8), which was negative. She was treated with an H2 blocker for 6 weeks (Box 11), but this did not provide relief (Box 12). The PCP recommended metoclopramide, but there is no clear benefit with this medication. The gastroenterologist performs an upper GI endoscopy (Box 14), which does not reveal any peptic or other lesions, and biopsies from the antrum are negative for H. pylori (Boxes 15–18). A diagnosis of FD—EPS is made (Boxes 21 and 23).

1

Center for Gastroenterological Research, KU Leuven, Leuven, Belgium; 2Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA; Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. Correspondence: Jan Tack, MD, PhD, Center for Gastroenterological Research, KU Leuven, 49 Herestraat, Leuven 3000, Belgium. E-mail: [email protected] 3



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Full-dose proton pump inhibitor (PPI) therapy is prescribed for the next 8 weeks (Box 25). At the end of this period, the patient reports no improvement in the pain (Box 26), and she feels unable to function properly. She is concerned that the symptoms are continuing despite PPI treatment, and that no abnormality has been found. The condition—FD, EPS—is explained and the concept of visceral hypersensitivity is discussed as a potential underlying mechanism. The option of starting a low-dose tricyclic agent is proposed, and the disadvantages of other possible strategies such as an increase in the PPI dose (no evidence that this would provide better symptom control), a formal trial with a prokinetic agent (more likely to be effective in PDS), or undertaking additional investigations (unlikely to yield another diagnosis) are discussed (Box 28). The patient agrees to start a tricyclic agent after explanation of the concept of visceral hypersensitivity and the possible beneficial effects of this class of agents. Case history 2

A 24-year-old woman is referred to a gastroenterologist because of increasing difficulty in tolerating food. She was well until 7 months earlier, when she noticed progressively increasing symptoms of bothersome fullness, early satiation, and upper abdominal bloating after meals (Box 1, Figure 1). This was accompanied by an inability to finish a meal of normal size and composition. The fullness and bloating is reported in the region between the umbilicus and the lower end of the sternum, and the experience is clearly different from pain (Box 2). There was no gastroenteritis-like episode before the onset of the symptoms. The symptoms improved to some degree when the patient eliminated fatty and spicy foods, and switched to multiple small meals, and this allowed her to maintain a stable body weight. Currently, the symptoms are triggered by, and continue after, every normal-sized meal, and may persist for up to 4 h. There is no relief with belching, defecation,

or passage of flatus. Nausea occurs when the symptoms are most intense, but without vomiting (Box 2). She has no dysphagia or weight loss, and there is no heartburn (Boxes 3 and 4). Her bowel habit is normal and unchanged. The patient is a nonsmoker and takes alcohol only occasionally. She does not take any regular medications, including NSAIDs. She has no previous or current medical conditions that may explain the pain (Box 2), and there is no family history of GI disease (Box 3). Physical examination does not reveal any specific abnormalities (Box 2). The patient has tried over-the-counter antacids without any improvement. Her PCP arranged blood tests, which were reportedly normal. She was treated with a single-dose PPI for 8 weeks (Box 11), but this failed to provide any relief (Box 12). The PCP referred her to the gastroenterologist. The gastroenterologist performs an upper GI endoscopy (Box 14), which does not reveal any peptic disease or other lesions, and biopsies from the antrum do not reveal H. pylori (Boxes 15–18). A diagnosis of FD-PDS is made (Boxes 21 and 22). A low dose of metoclopramide is prescribed for the next 8 weeks (Box 25). At the follow-up visit, she reports no benefit from the metoclopramide (Box 26). The gastroenterologist explains that she has FD, PDS, and discusses the concept of abnormal motility (delayed emptying, impaired accommodation) as a potential underlying mechanism. A therapeutic trial with a prokinetic agent (different specific agents are available in different parts of the world: e.g. domperidone, erythromycin, clebopride) or a fundus-relaxing agent (e.g., buspirone) is proposed, and the limitations of other possible strategies such as an increase in the PPI dose (no evidence that this would provide better symptom control), a trial with a low-dose tricyclic agent (more likely to be effective in EPS), or undertaking additional investigations such as abdominal ultrasound or gastric motility testing (unlikely to yield another diagnosis or to change management) are discussed (Box 28). The patient agrees to start a prokinetic drug before meals.

Figure 1. Legend 1.

2.

3.

4.

5.

A patient with one or more of these symptoms is referred to as a patient with dyspepsia. In this context, it is assumed there are no known systemic or organic disorders such as diabetes mellitus or connective tissue disease. When no additional investigations are performed, this condition is referred to as uninvestigated dyspepsia. After additional investigations, in approximately 70% of these patients, no organic cause is identified, and these patients are referred to as patients with functional dyspepsia (FD) (see below) (1). A detailed history and clinical examination at the initial visit are essential both to detect the presence of alarm features and to accurately identify the particular dyspeptic symptom or symptoms present (1,2). Alarm features include age, unintentional weight loss, symptoms that awaken the patient at night, dysphagia, lymphadenopathy, abdominal mass, and signs of anemia. If any of these is present, prompt endoscopy is indicated, although the yield may be relatively low (3,4). Frequent heartburn is defined as heartburn several times per week. A brief description of heartburn in a few sentences may help the patient to recognize heartburn (1,2). Dyspeptic symptoms may accompany gastroesophageal disease (GERD) and may often respond to appropriate GERD management, which will generally consist of proton pump inhibitor (PPI) therapy (5). Also see “recurrent heartburn” algorithm.


6,7.

PPI therapy is expected to relieve heartburn, but may also relieve coexisting dyspeptic symptoms. If this is the case, the patient is considered to have GERD with associated dyspeptic symptoms (1,5,6). 8. The use of test-and-treat strategies for H. pylori eradication in uninvestigated dyspepsia is considered standard of care (5,6). Detection of H. pylori by a urease breath or stool antigen test (or less optimally serology) is most likely to be cost effective in the situation where there is high prevalence of H. pylori infection in the population. The yield of this approach decreases as the population prevalence of H. pylori infection decreases, especially when it falls below 20% (5,6). 9,10. If the patient responds symptomatically to eradication therapy, this does not firmly establish H. pylori as the cause of the symptoms. Confounding factors are placebo effect, effects of the PPI included in the eradication regimen, or spontaneous improvement (2,5–7). 11. Empirical therapy choice will be driven by drugs available locally and the restrictions to their use. Antacids, antisecretory drugs, or prokinetics can be considered here (5–9). 12,13. Response to empirical therapy does not confirm a diagnosis of FD. Organic causes of dyspepsia, for instance a peptic ulcer, may respond to empirical antisecretory therapy. However, resolution of symptoms abolishes the need for further investigation in most VOLUME 105 | APRIL 2010 www.amjgastro.com

Gastroduodenal Disorders

20

10

Patient with chronic or recurrent • postprandial fullness • early satiation • epigastric pain or • epigastric burning

yes

yes

Dyspepsia with H. pylori

Symptom improvement?

no

19 Eradication therapy 9 no


2

18

13 Dyspepsia not requiring further investigation

History and physical examination

H. pylori positive? 17

3

Coexisting frequent heartburn? yes

8

11 Consider testand-treat for H. pylori ?

no

14

12

no

Organic disorder that explains the symptoms?

no Empirical therapy


no

15

Upper GI endoscopy with H. pylori testing

yes Any abnormality identified? no

5

21

Manage as gastroesophageal reflux disease

Functional dyspepsia

28 Consider additional investigations

6 Symptom improvement?

yes

yes

yes

no 4

16 Peptic ulcer malignancy esophagitis

yes

Alarm features?

yes

22

no

26


yes 7

24

23

no Postprandial distress syndrome (PDS)

Initial therapy

Both PDS and EPS

Epigastric pain syndrome (EPS)

yes Gastroesophageal reflux disease

27 Long-term management

Figure 1. Recurrent dyspepsia. cases. Additional investigation may be considered if the patient is more than 50 years of age, or when there are specific risk factors present such as the use of non-steroidal anti-inflammatory drugs (NSAIDs) or risks for Barrett’s esophagus. Expectant management, without performing endoscopy, in a young patient with no alarm features, can still be considered at this point, even when symptoms have not been resolved (10). 14. According to the Rome guidelines (1), an upper gastrointestinal (GI) endoscopy not showing pathology that may explain the symptoms is the key study for helping to establish a diagnosis of FD. However, this investigation is not indicated in all cases of dyspepsia, as indicated above. Moreover, the impact of recent antisecretory therapy on endoscopic findings and the optimal time window of interrupting failed antisecretory therapy have not been defined. 15. Abnormal findings include either the presence of a relevant organic lesion, or a positive H. pylori test. 16,17. Relevant organic diseases that may present with dyspeptic symptoms include peptic ulcer disease, erosive esophagitis, and upper GI malignancy. These diseases require specific therapy. 18,19. The role of H. pylori infection and the yield of H. pylori eradication in case of negative endoscopy are areas of controversy. Metaanalyses indicate a small but statistically significant gain after eradication in those who are H. pylori positive, with an estimated number to treat around 15. However, the symptom response is often delayed (9). 20,10. If the patient responds to eradication therapy, this does not establish H. pylori as the cause of the symptoms. Confounding factors are placebo effect, effects of the PPI added to the eradication regimen, or spontaneous improvement. 21. FD is defined as the presence of one or more dyspepsia symptoms that are considered to arise from the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that © 2010 by the American College of Gastroenterology

22.

23.

24.

is likely to explain the symptoms. Rome III diagnostic criteria for FD are: (i) one or more of bothersome postprandial fullness, early satiation, epigastric pain and epigastric burning; (ii) no evidence of structural disease likely to explain the symptoms; and (iii) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). Postprandial distress syndrome (PDS) is a subgroup of FD characterized by postprandial fullness and early satiation. Rome III diagnostic criteria for PDS are: (i) one or both of (a) bothersome postprandial fullness, occurring after ordinary-sized meals, at least several times per week; (b) early satiation that prevents finishing a regular meal, at least several times per week; and (ii) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). The presence of upper abdominal bloating or postprandial nausea or excessive belching are supportive of PDS. Epigastric pain syndrome (EPS) is a subgroup of FD characterized by epigastric pain or epigastric burning. Rome III diagnostic criteria for EPS are: (i) pain or burning localized to the epigastrium of at least moderate severity, at least once per week; (ii) the pain is intermittent; (iii) not generalized or localized to other abdominal or chest regions; (iv) not relieved by defecation or passage of flatus; (v) not fulfilling criteria for gallbladder or sphincter of Oddi disorders; and (vi) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). Supportive criteria are that the pain is of a burning quality, but without a retrosternal component, and that the pain is induced or relieved by ingestion of a meal, although it may occur during fasting. Many patients have overlap of both EPS and PDS symptoms. The prevalence of overlap of both conditions has been explored in population studies as well as in patient samples, and may comprise up to 50% of the dyspepsia population. The American Journal of GASTROENTEROLOGY


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25,26. Initial therapy choice may depend on the FD subgroup but is all off-label. There is evidence for limited efficacy of PPIs in FD. On the basis of studies using the Rome II classification, it seems reasonable to suggest that response to PPIs is highest in the EPS subgroup, where this class of medication is the first choice of therapy (1,2,7,8). Evidence for the efficacy of prokinetic drugs is not conclusive, although they seem to be active in subgroups of patients. On the basis of studies using the Rome II classification, it seems reasonable to suggest that response to prokinetics is highest in the PDS subgroup (1,2,8). As there is no evidence of exclusive actions of PPIs or prokinetic in one of the FD subgroups, switching to the other class of agent or adding it can also be considered. The optimal approach for overlapping PDS and EPS has not been studied in depth, but a start with a PPI seems reasonable. It is often suggested that a low-dose tricyclic antidepressant can be prescribed for EPS symptoms that do not respond to PPI therapy. In case a prokinetic does not relieve PDS symptoms, a fundus-relaxing drug like for instance buspirone could be considered (2,11). 27. The optimal long-term strategy for FD that responds to initial therapy (maintenance therapy/on demand/interruption) has not been studied (10). 28. Additional investigations can be considered if there is a lack of symptomatic response: abdominal ultrasound may help exclude biliary, pancreatic, or vascular disease. However, there is no evidence of diagnostic gain with ultrasound, in the absence of symptoms suggestive of biliary tract pathology, like colicky abdominal pain. Routine blood tests such as full blood count, liver function tests, amylase and lipase, and kidney function

RECURRENT NAUSEA AND/OR VOMITING Case history

A 23-year-old woman is referred to a gastroenterologist for refractory, persistent nausea (Box 1, Figure 2). The history (Box 2) reveals that she had been well until 14 months ago, when she became progressively nauseated over the course of a few days. Although initially present several hours per day, over the past few months the nausea has become ever present, from the moment she wakes up until the time she goes to bed. The nausea is usually not associated with vomiting though she has vomited three or four times in the last year (Boxes 1, 13, 16, and 21). There is no heartburn (Box 1) or excessive belching. The nausea interferes with her appetite, though is not worsened after meals and is not related to bowel movements, posture, or exercise. She has lost 3 kg weight over the last 6 months. There are no other alarm symptoms (Box 3). She notes occasional mild intermittent postprandial fullness, without early satiation or epigastric pain. The patient does not take NSAIDs or other medications, is a nonsmoker, and uses alcohol only sporadically. There is no history of substance use (Box 4). There are no associated vestibular, neurological, or overt psychiatric symptoms (Box 11). There is no history of migraine and no other previous or current medical conditions that may explain the nausea. There is no relevant family history of GI disease. Clinical examination is negative, including the absence of vascular bruits over the abdomen, no neurological system abnormali-


tests can also be considered at this stage, if not already performed. There is no clear evidence of the usefulness of such testing in this setting, but many clinicians would consider this at this time. The same applies to thyroid function testing. Especially in high prevalence areas, celiac disease screening can be considered. Esophageal pH monitoring (patient off PPI) can reveal abnormal findings in a subset of FD patients, mainly those with epigastric pain and burning. However, the role of esophageal pH monitoring in clinical management, and its impact on subsequent management, has not been defined. Abdominal CT scan enables visualization of the pancreatico-biliary system and to screen for vascular disorders that may mimic FD. It is mainly indicated in case of refractory pain associated with weight loss. Repeated CT scans should be avoided. The yield of gastric emptying in FD as a group has not been established. However, it may be considered useful in refractory patients, especially if vomiting or weight loss is also present. Psychosocial problems such as anxiety or depression may also present with dyspeptic symptoms. It is important to consider these early on in the course of investigations, and to obtain expert opinion in case of refractoriness. A useful tool is the Rome III psychosocial alarm questionnaire (see Appendix A). Therapeutic trials using antidepressants can be considered with the end point of benefit being symptom improvement or improved daily functioning even in the presence of the symptoms. Augmentation therapy combining two psychotropic agents, or a psychotropic agent with psychologic treatment, may be considered in difficult cases who have failed all other therapies, have impaired quality of life, and where abdominal pain is a significant component.

ties, and no alarm signs (Boxes 2, 3, and 11). Blood tests including thyroid function tests and tests for other systemic or metabolic disorders are normal (Boxes 8 and 9). An abdominal ultrasound performed 12 months ago was reported as normal. An upper GI endoscopy performed during the last year was also normal (Boxes 8 and 9). A 24 h urinary cortisol is normal. Over the last year, she has tried several prokinetic and antiemetic agents (including metoclopramide, domperidone, ondansetron), and also was prescribed a PPI, up to two times the standard dose, without improvement. She now takes up to four 10 mg tablets of metoclopramide per day, with little or any effect, and no other medications. The gastroenterologist also confirms that there are no specific features to suggest rumination syndrome (Box 13) or cyclic vomiting syndrome (Box 16) and also refers the patient to an ophthalmological examination to rule out signs of intracranial hypertension (Box 11). A scintigraphic gastric emptying test (Box 18) is then arranged; this reveals a half emptying time for solids within the normal range (Box 19). A diagnosis of chronic idiopathic nausea is made (Box 22). A low-dose tricyclic antidepressant is then prescribed for 8 weeks, with addition of chlorpromazine as a symptomatic antiemetic agent (Box 25). The option of conducting additional diagnostic investigations, such as abdominal CT scan and MRI of the brain, in case of insufficient response to the proposed therapy, is discussed.



26

Patient with chronic or recurrent nausea and/or vomiting, without coexisting frequent heartburn

27


yes

Long-term management

no

Consider additional testing

24 Treat accordingly

2 History and physical examination 7 Drug- or substance-induced nausea/vomiting

3 yes

Alarm features?

15

23 Chronic idiopathic nausea

Cyclic vomiting syndrome

Functional vomiting

yes 5 yes Elimination of presumed causal agent

Potentially drugor substanceinduced?


no

14

no

yes

Consider manometric evaluation/ impedance

no

Upper GI endoscopy, blood tests

yes 21 Vomiting present?

yes

11


22

Rumination syndrome

no 4

8

17

13

Suggestive of psychological or neurological disorder?

no

no

Suggestive of rumination syndrome?

16 no

Suggestive of cyclic vomiting syndrome?

no

18 no

19 Severely delayed emptying?

Gastric emptying test

yes

yes yes

10

20 Organic causes, e.g., pyloric canal ulcer, hyperthyroidism, uremia

12 Appropriate testing or referral

Manage as gastroparesis

Figure 2. Recurrent nausea and/or vomiting.

Figure 2. Legend 1.

2.

3.

4.

5,6.

Nausea is a common and subjective symptom and the differential diagnosis is wide. In this context, it is assumed there are no known systemic or organic disorders such as diabetes mellitus or connective tissue disease. Nausea may accompany gastroesophageal reflux disease (GERD) and may often respond to appropriate GERD management, which will generally consist of proton pump inhibitor (PPI) therapy. Also see “Recurrent heartburn” algorithm (1). A detailed history and clinical examination at the initial visit are essential. The history should recognize nausea as an unpleasant sensation of the imminent need to vomit typically experienced in the epigastrium or throat. Vomiting should be distinguished from regurgitation or rumination (see below). During the history taking and clinical examination, a broad list of potential causes of nausea and vomiting, including organic gastrointestinal (GI) disorders, medications and toxic agents, endocrine disorders, neurological disorders, and psychogenic factors should be considered (1,11–14). Alarm features include age, unintentional weight loss, nocturnal symptoms, dysphagia, lymphadenopathy, abdominal mass, and evidence of anemia. If any of these symptoms or signs is present, prompt upper GI endoscopy is indicated, although the yield may be low (3,4). Classes of drugs that commonly cause nausea and/or vomiting include analgesics, cardiovascular medications, hormonal preparations, antibiotics, central nervous system (CNS) active medications, and cancer chemotherapy. Cannabis use/interruption of use has been implicated in chronic or recurrent nausea and vomiting (1). If potentially relevant medications can be discontinued, and symptoms improve in temporal association with this cessation, a


diagnosis of drug- or substanceinduced nausea/vomiting may be considered, although longer-term follow-up will be required (12). 7. Besides cancer chemotherapy agents, opioid analgesics and macrolide antibiotics are important causes of nausea and vomiting. A clue to cannabis hyperemesis is compulsive hot bathing or showering behavior. 8. Upper GI endoscopy serves mainly to exclude obstructive lesions and peptic ulceration, or rarely another organic lesion. In young patients without alarm features, empiric antiemetic therapy may be considered before endoscopy and other additional investigations. In the case of frequent vomiting, esophagitis may be present, but this is a consequence of vomiting caustic gastric contents and usually does not explain chronic or recurrent nausea and vomiting. Relevant blood tests to be considered in addition to routine hematology and biochemical tests, include C-reactive protein (CRP) level, thyroid function tests, blood glucose level, serum calcium, and tests to exclude Addison’s disease. Celiac disease may be screened for in high-prevalence areas. Further tests may be required depending on the results of these investigations. Imaging (small bowel X-ray or CT enterography) may be used to exclude mechanical obstruction in the upper GI tract (1,12). In the setting of recent major weight loss (e.g., recent spinal cord injury, anorexia nervosa), the superior mesenteric syndrome (SMA) may develop where there is compression of the third portion of duodenum by the aorta. CT is an excellent diagnostic modality at which time the superior mesenteric artery to abdominal aorta distance should be measured. 11,12. Neurological disorders that may cause chronic or recurrent nausea and/or vomiting include migraine, increased intracranial pressure, labyrinthine disorders, and demyelinating disorders. Usually The American Journal of GASTROENTEROLOGY


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there are neurological symptoms and signs that clue the physician into these possibilities. Psychological conditions that may cause chronic or recurrent nausea and/or vomiting include anxiety disorders, depression, eating disorders, and psychogenic vomiting. Psychogenic vomiting usually occurs in conditions of major psychological distress and is not clearly related to food ingestion. Self-induced vomiting is mainly associated with eating disorders. Appropriate testing (clinical neurological examination, exclusion of intracranial hypertension by examination of the eye fundus, or by MRI scan of the brain) and/or referral may need to be considered. 13. Rumination should be suspected when there is the effortless repeated regurgitation of food (14). A typical history is generally sufficient to make a diagnosis of rumination syndrome. Key elements are the timing during and shortly after meal ingestion, the lack of prodromal nausea, the repetitive and effortless appearance of food in the mouth, and the ability to swallow the regurgitated material back into the esophagus. 14. In case of doubt or need for additional confirmation, esophagogastric manometry with administration of a meal shows a diagnostic pattern of brief intragastric pressure rises that are transmitted to the esophagus. Simultaneous impedance monitoring may document that these abdominothoracic strains push intragastric contents up into the esophagus to the pharynx (14,15). 15. Rome III diagnostic criteria for rumination are: (i) persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or remastication and swallowing, and (ii) the regurgitation is not preceded by retching, and (iii) these criteria are fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). Supportive criteria are that regurgitation events are not usually preceded by nausea, there is cessation of the process when the regurgitated material becomes acidic, and the regurgitant contains recognizable food with a pleasant taste. 16. Cyclic vomiting should be suspected when there are episodes of vomiting with a stereotypical onset and duration. There are varying intervals of absence of vomiting in between episodes. No structural or biochemical cause can be identified (1,13). 17. Rome III diagnostic criteria for cyclic vomiting syndrome are: (i) stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week), and (ii) three or more of these episodes in the preceding year, and (iii) absence of nausea and vomiting in between episodes, and (iv) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). 18–20. Gastric emptying rates can be assessed using scintigraphy or breath test technology. Mildly delayed gastric emptying is a nonspecific sign that may partly depend on the presence of nausea

during the test. Severely delayed emptying suggests gastroparesis as a cause of nausea and/or vomiting. There is no consensus on a cutoff for “severely” delayed emptying using scintigraphy, enough to consider a diagnosis of gastroparesis, but we suggest using three times the upper limit of a large normal sample as the cutoff value. 21. Depending on the presence or absence of vomiting, likely diagnoses are now either chronic idiopathic nausea or functional vomiting. 22. Rome III diagnostic criteria for chronic idiopathic nausea are: (i) bothersome nausea, occurring at least several times a week, and (ii) not usually associated with vomiting, and (iii) absence of abnormalities at endoscopy or metabolic disease that explains the nausea, and (iv) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). 23. Rome III diagnostic criteria for functional vomiting are: (i) on average one or more episodes of vomiting per week, and (ii) absence of criteria for an eating disorder, rumination, or major psychiatric disease according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and (iii) absence of self-induced induced vomiting and chronic cannabinoid use and absence of abnormalities in the CNS or metabolic diseases to explain the recurrent vomiting, and (iv) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis (1). 24. Treatment for functional nausea and/or vomiting is based on antinauseants, prokinetics or low-dose antidepressants. Dopamine-2 receptor antagonists such as domperidone, metoclopramide and chlorpromazine can be considered first-line drugs. Metoclopramide can induce parkinsonism and irreversible tardive dyskinesia; chlorpromazine causes somnolence. Tricyclic antidepressants as well as mirtazapine have nausea- and vomiting-suppressing properties and can be considered second-line drugs (2,16). In case of cyclic vomiting syndrome, antimigraine drugs can also be considered (1,12,13). The rumination syndrome is preferentially treated by behavioral therapy (diaphragmatic breathing) (17). 25,26. The long-term management, in case of therapeutic response, has not been established for these disorders. 27. Additional tests may include abdominal CT scan, small bowel X-ray or CT enterography, antroduodenal manometry, or esophageal pH/impedance testing. Psychosocial problems such as anxiety or depression may also present with nausea or vomiting. It is important to consider these early on in the course of extensive investigations, and to obtain expert opinion in case of refractoriness. A useful tool is the Rome III psychosocial alarm questionnaire (see Appendix A) Therapeutic trials using antidepressants can be considered with the end point of benefit being symptom improvement or improved daily functioning even in the presence of the symptoms.


Guarantors of the article: Rome Foundation. Specific authors contribution: Each author contributed written sections, reviewed and edited the entire manuscript, and signed off on the final version. Financial support: This work was supported by a grant from the Rome Foundation. Potential competing interests: None.

REFERENCES 1. Tack J, Talley NJ, Camilleri M et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. 2. Tack J, Bisschops R, Sarnelli G. Pathophysiology and treatment of functional dyspepsia. Gastroenterology 2004;127:1239–55. 3. Moayyedi P, Talley NJ, Fennerty MB et al. Can the clinical history distinguish between organic and functional dyspepsia? JAMA 2006;295:1566–76.


4. Vakil N, Moayyedi P, Fennerty MB et al. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. Gastroenterology 2006;131:390–401. 5. Spiegel B, Vakil N, Ofman J. Dyspepsia management in primary care: a decision analysis of competing strategies. Gastroenterology 122;1270:2002. 6. Talley NJ, Vakil N, Practice Parameters Committee of the American College of Gastroenterology. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100:2324–37. 7. Moayyedi P, Delaney BC, Vakil N et al. The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology 2004;127:1329–37. 8. Moayyedi P, Soo S, Deeks J et al. Pharmacological interventions for nonulcer dyspepsia. Cochrane Database Syst Rev 2006, CD001960. 9. Moayyedi P, Soo S, Deeks J et al. Eradication of Helicobacter pylori for nonulcer dyspepsia. Cochrane Database Syst Rev 2006, CD002096. 10. El-Serag HB, Talley NJ. Systematic review: the prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther 2004;19:643–54.


11. Van Oudenhove L, Kindt S, Vos R et al. Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther 2008;28:1326–33. 12. Olden KW, Chepyala P. Functional nausea and vomiting. Nat Clin Pract Gastroenterol Hepatol 2008;5:202–8. 13. Abell TL, Adams KA, Boles RG et al. Cyclic vomiting syndrome in adults. Neurogastroenterol Motil 2008;20:269–84. 14. Malcolm A, Thumshirn MB, Camilleri M et al. Rumination syndrome. Mayo Clin Proc 1997;72:646–52.


15. Thumshirn M, Camilleri M, Hanson RB et al. Gastric mechanosensory and lower esophageal sphincter function in rumination syndrome. Am J Physiol 1998;275 (2 Part 1): G314–21. 16. Chen CC, Lin CS, Ko YP et al. Premedication with mirtazapine reduces preoperative anxiety and postoperative nausea and vomiting. Anesth Analg 2008;106:109–13. 17. Chitkara DK, Van Tilburg M, Whitehead WE et al. Teaching diaphragmatic breathing for rumination syndrome. Am J Gastroenterol 2006;101:2449–52.


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Gallbladder and Sphincter of Oddi Disorders Enrico S. Corazziari, MD1 and Peter B. Cotton, MD, FRCP, FRCS2 Am J Gastroenterol 2010; 105:764–769; doi:10.1038/ajg.2010.67

GALLBLADDER AND SPHINCTER OF ODDI SYMPTOMS The investigation and management of patients with recurrent episodes of right upper quadrant and epigastric pain is challenging, as there are numerous causes, both “organic” and “functional” (1). Symptoms of functional gallbladder (GB) and sphincter disorders must be distinguished from those due to cholelithiasis, pancreatitis, gastroesophageal reflux disease, irritable bowel syndrome, functional dyspepsia, and peptic ulcer disease. Biliary pain

The Rome III Committee (2) concluded that biliary (and pancreatic) pain classically occurs in recurrent episodes of steady, severe, pain located in the epigastrium and/or the right upper abdominal quadrant lasting ≥30 min, not relieved by bowel movements, postural changes, or antacids. In the absence of structural disease (e.g., gallstones, pancreatitis, or malignancy), such pains may be the clinical presentation of GB or sphincter of Oddi (SO) dysfunction. The assumed mechanism for biliary-like pain in patients with the GB in situ is the increased resistance to the flow of bile at the level of the cystic duct, whereas complete obstruction produces acute cholecystitis. An alternative and more recent explanation is the presence of acquired and genetically determined metabolic and neurohormonal alterations that cause poor GB contractility and result in lithogenic bile, leading to stones and cholecystitis. The assumed mechanism for biliary (pancreatic)-like pain in patients previously submitted to cholecystectomy is the increased resistance to bile and/or pancreatic secretion flow at the level of the SO. Both stenosis and dyskinesia may cause obstruction to flow through the sphincter(s), with corresponding increased pressure in the ducts. In the case of the biliary tree, this increase is aggravated by the absence of the GB reservoir function (2). When episodes of pain have been recurrent, spinal cord or other central mechanisms are also potential contributing factors to the pain, as in the other functional gastrointestinal (GI) disorders. A deliberate evidence-based approach is desirable to avoid mistakes of omission and commission, both of which can cause needless suffering. The purpose of these algorithms and associated notes is to suggest a pathway through this complex maze. Unfortunately, some of the available tests are operator dependent, and the predictive value of several (e.g., nuclear medicine studies) is controversial. “Suspected sphincter of Oddi dysfunction” is a particularly difficult

area, where data are scarce and the risks (of endoscopic retrograde cholangiopancreatography (ERCP) and manometry) are substantial (3). To reduce clinical uncertainty and to limit invasiveness, patients are traditionally subgrouped according to the presence or absence of abnormalities on initial testing. The diagnosis of SO dysfunction is easy to entertain when patients with typical pain also have objective findings, i.e., elevation of liver blood tests or pancreatic enzymes and/or dilated common bile duct. Diagnostic uncertainty is maximal when no such diagnostic clues are present. Thus, clinicians are urged to make best use of their clinical skills in advising their patients, to use noninvasive approaches and treatment trials, and, at all times, to make sure that patients are aware of the possible alternative approaches, and of the gaps in our knowledge in this area. Although there is considerable overlap in the issues and relevant approaches, in these algorithms we have chosen to separate pre- and post-cholecystectomy contexts.

RECURRENT BILIARY-LIKE PAIN: GB IN PLACE Case history

A 35-year-old nurse of Hispanic origin is referred to a gastroenterologist by her primary care physician because of several episodes of severe upper abdominal pain that have occurred over a 6-month period. When it occurs, the pain is always located in the right upper quadrant of the abdomen, builds up to a steady and intense level, lasts 30 min to 1 h, and is of sufficient severity to disrupt her normal activities (Box 1, Figure 1). It often radiates to the right subscapular region. She is unable to identify any definite precipitating factors to the pain, although on two occasions, it occurred soon after her evening meal. The pain awoke her from sleep on one occasion. On several occasions, she has experienced diaphoresis and nausea and vomiting during the episode of pain. The pain is not relieved by defecation or passage of flatus (Box 2), and she reports that it is not triggered by movements or lifting (Box 4). She has taken an antacid on two occasions during an episode of pain but this did not improve the pain (Box 6). In between attacks, she does not suffer from other GI symptoms apart from occasional heartburn, and her weight has been steady. The patient has no significant medical history. She takes no regular medications and does not smoke or drink alcohol. In her family history, the patient reports that her mother suffered from “gallbladder trouble” that had been difficult to diagnose, but had eventually been cured by cholecystectomy.

1

Dipartimento di Scienze Cliniche Policlinico, Umberto I V. le del Policlinico, Rome, Italy; 2Medical University of South Carolina, Charleston, SC, USA. Correspondence: Enrico S. Corazziari, MD, Dipartimento di Scienze Cliniche Policlinico, Umberto I V. le del Policlinico, Rome 00161, Italy. E-mail: [email protected]



The gastroenterologist obtains further history that one attack of severe pain had caused her to be taken to the emergency room, where she was found to be afebrile and to have no specific abdominal abnormalities on physical examination. The discharge summary from that hospital visit states that her white cell count was normal, as were standard liver biochemistry and serum amylase and lipase. An abdominal ultrasound (US) scan (Box 10) had also been performed and was reported as unremarkable, although the quality of the images was poor because of her body habitus and the presence of bowel gas. A physical examination conducted by the gastroenterologist does not reveal any specific abnormalities. Despite the apparent lack of response to nonprescription antacids, the gastroenterologist recommends upper GI endoscopy (Box 8). This shows no relevant abnormality. The gastroenterologist then requests a computed tomography scan to exclude any intra-abdominal lesion, and to obtain better images of the GB (Box 12). The computed tomography scan is also negative, with a normalappearing GB and normal bile duct size, and normal-appearing pancreas. The patient continues to experience similar episodes of severe abdominal pain, despite avoiding high-fat meals. A trial of antispasmodic therapy prescribed by her primary care physician does not improve the pain. The patient and her mother are both convinced that the GB is causing her symptoms, and press the gastroenterologist for a surgical referral. However, the gastroenterologist believes that further investigation is warranted; she discusses with the patient the pros and cons of several possible additional tests to more definitively exclude gallstone and GB disease, including magnetic resonance cholangiopancreatography, endoscopic US of

the GB and biliary tree, and duodenal aspiration for biliary crystals (Box 12). Endoscopic US is available only at a town 50 miles away, while the gastroenterologist is not convinced of the value of examination for biliary crystals. After discussion, she recommends a nuclear medicine diisopropyl iminodiacetic acid (DISIDA) scan, to determine the ejection fraction of the GB, having confirmed that the patient is not taking any medications that could affect the results of the test. The investigation reports her ejection fraction to be only 20% (Box 13). On this basis, the gastroenterologist makes a diagnosis of functional GB disorder (Box 15). She suggests a 2-month therapeutic trial with a low-dose tricyclic antidepressant agent (Box 16), but the pain episodes continue despite this. She then recommends that the patient see a biliary surgeon for consideration of cholecystectomy (Box 17). The surgeon had just attended a seminar, which raised doubt on the value of the DISIDA test in this setting, as several studies had shown little or no correlation with the outcome after cholecystectomy. However, he agrees with the gastroenterologist that the clinical features are strong, that the family history adds some further support, and that there is no evidence for other disorders that may explain the pain. He performs laparoscopic cholecystectomy (Box 17) without complication. Histology of the GB reveals a mild degree of “chronic cholecystitis.” The patient made a good recovery and was free of symptoms when seen a year later by her internist for a routine checkup (Box 18). Had the outcome not been satisfactory, the gastroenterologist had planned to reassess the patient for other functional GI disorders (Box 14), and to consider the possibility of SO dysfunction (Box 19) (see the section “Post-cholecystectomy biliary-like pain” algorithm).

Figure 1. Legend 1. The typical features of biliary (and pancreatic) pain have been defined (2) as: episodes of epigastric and/or right upper quadrant pain, lasting ≥30 min and occurring at different intervals (not daily), with the pain building up to a steady level, and being severe enough to interrupt the patient’s daily activities or lead to an emergency room (ER) visit. It is important to emphasize that the following diagnostic algorithm and discussion refers specifically to pain fulfilling all the above-mentioned characteristics for biliary-like pain, and especially if one or more of the additional features of the pain outlined below are present. These additional features of the pain that should be established are: whether the pain radiates to the back and/or to the subscapular region, and whether the pain awakens the patient from sleep; also, whether there is associated nausea and vomiting. Pancreatic pain is usually focused in the epigastrium, with radiation to the mid-back. 2. Abdominal pain consistently relieved by defecation or the passage of flatus, in the absence of alarm features, suggests a functional bowel disorder (1). Alarm features include unintentional weight loss, lymphadenopathy, abdominal mass, bleeding, and evidence of anemia. 3. Further evaluation should be undertaken as appropriate; see the “recurrent abdominal pain and disordered bowel habit” algorithm. 4. Pain precipitated by movement, coughing, or laughing suggests a musculoskeletal origin. 5. Right upper quadrant/costal margin pain aggravated by sitting up (Carnett’s sign) suggests costochondritis, which may respond to local therapy. 6. Pain relieved consistently by antacids or proton pump inhibitors (PPIs) suggests peptic ulceration or gastroesophageal reflux disease.


7–9.

Upper gastrointestinal (GI) endoscopy is the primary tool for diagnosing mucosal disease of the esophagus, stomach, and duodenum. It is also usually undertaken for completeness even when the pain is not relieved by acid suppression, but ultrasound (US) scanning should take precedence. It must be noted that gallbladder pain and pain from other sources may coexist; hence, it may still be appropriate to investigate further for gallbladder disease. 10,11. Abdominal US scan and relevant blood tests should be performed initially when gallbladder disease is suspected. US has high accuracy for the detection of gallstones > 3 mm in diameter, and for cholecystitis (4). The extent to which it can detect or exclude other conditions (e.g., bile duct stones, pancreatitis, and pancreatic tumors) is highly dependent on the operator, and on the size of any lesion. When symptoms are typical and especially if there are other pointers to gallbladder disease (e.g., transient liver test abnormalities or a strong family history), there should be no hesitation to repeat the US scan. Liver biochemistry and serum amylase/lipase are normal in patients with functional gallbladder disorder. 12. With a negative US scan, or scans, of good quality, the next step depends on the degree of continuing clinical suspicion for gallstones or gallbladder disease as opposed to other rarer conditions (e.g., pancreatitis). In many circumstances, abdominal computed tomography (CT) scanning will be chosen to provide a broader survey for abdominal pathology. Good-quality CT scans can detect most cases of active and chronic pancreatitis and pancreatic tumors, as well as intra- and retro-peritoneal masses. Endoscopic US (EUS) is the most sensitive test for small gallstones, bile duct stones, and pancreatic disease, but it is not universally available,


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1


Patient with recurrent episodes of pain (not daily), in the epigastrium/right upper quadrant, lasting >30 min, building to a steady level, interrupting activities, or ER visit

3 Assess for functional bowel disorder (IBS)

13

2 yes

no 5

15 DISIDA gallbladder ejection fraction 30 min (Box 1, Figure 2). At times, the pain can radiate to the right subscapular region, and she has vomiting associated with the pain on some occasions. The pain has not woken her from sleep. There are no obvious precipitating factors. She has not used codeine-containing medications and the pain is not related to, or affected by, bowel movements; the pain is not relieved by antacids, posture, or movement (Box 2). In fact, the pain is as far as she can remember, very similar to that which she experienced before undergoing cholecystectomy. The patient does not admit to any GI symptoms in the pain-free intervals. Physical examination is negative, including evaluation for an abdominal wall origin of pain (Box 2). The patient is not overweight. Blood tests to assess serum liver biochemistry and pancreatic enzymes, and an abdominal US scan, are conducted (Box 3). The blood tests are normal. The US does not show bile

cholecystectomy than those treated medically (8). An earlier analysis examining this question came to a similar conclusion (9). It is clear that further prospective randomized clinical studies are required to determine definitively the role of dynamic isotope biliary scanning in the investigation and management of acalculous biliary-like pain. 18. The diagnosis of a functional gallbladder disorder is confirmed by the relief of pain after cholecystectomy, for a period longer than 12 months. 18,19. Lack of pain relief after cholecystectomy requires reassessment, initially to rule out a complication of surgery or residual pathology (e.g., duct stones). If the pain remains the same as preoperatively, diagnostic considerations would include sphincter of Oddi dysfunction (see algorithm for “post-cholecystectomy biliary-like pain”), or a nonbiliary source, including other functional GI disorders.

duct stones (Box 4) but does show a common bile diameter of 12 mm (Box 8). At this stage, although the patient’s pain appears most consistent with a biliary origin, the gastroenterologist wants to exclude conditions such as gastroesophageal reflux disease and peptic ulcer (Box 7), and therefore performs an upper GI endoscopy (Box 6); this reveals no abnormality. The gastroenterologist considers further abdominal imaging and arranges a magnetic resonance cholangiopancreatography. This also shows no abnormality except for the dilated bile duct (Box 8). Computed tomography scan of the abdomen does not reveal any other intra-abdominal abnormality (Box 9). In the absence of structural disease, the gastroenterologist suspects that the typical biliary-like pain might be due to SO dysfunction (Box 10). Records from the patient’s previous emergency room visits reveal that her liver biochemistry and pancreatic enzymes were normal on each visit. On the basis of the lack of any abnormality on blood tests, but the presence of a dilated bile duct, a diagnosis of biliary SO dysfunction type II is made. Knowing the risks of ERCP (with or without sphincter manometry) in such cases, the gastroenterologist refers the patient to a colleague with more experience. He considers quantitative choledochoscintigraphy, but for this case is not convinced by its discriminant value, and proceeds to ERCP (Box 16). Biliary manometry is abnormal and sphincterotomy is performed. As the pancreatic duct was injected during the cannulation process, a small temporary pancreatic stent was placed to reduce the risk of pancreatitis.

Figure 2. Legend 1.

2.

This description of pain in patients previously submitted to cholecystectomy is considered to indicate a biliary-pancreatic origin, and is suggestive of sphincter of Oddi dysfunction (SOD) (1). As with the previous algorithm, it is important to emphasize that the following diagnostic algorithm and discussion refers only to pain fulfilling all the specific features outlined. These characteristics of pain are suggestive of other conditions such as functional bowel disorder, acid-related disorder, or musculoskeletal disorder (2), and should stimulate appropriate further investigation. Recurrent abdominal wall pain should be considered. Sphincter of Oddi pain and other functional gastrointestinal (GI) disorders can coexist; hence, it may be


3.

4,5.

appropriate to continue the diagnostic process according to this algorithm. Laboratory blood tests of liver biochemistry and pancreatic enzymes, as well as noninvasive ultrasound (US), are performed to assess the presence of biliary/pancreatic or liver pathology. Transient elevation of liver biochemistry and/or serum amylase/lipase within 24 h of a pain episode may suggest SOD (or stone passage). Trans-abdominal US may detect biliary tract pathology, such as duct dilation and/or stones, and can detect some pancreatic lesions, leading to appropriate treatment. The sensitivity of US in detecting common bile duct stones is low. The acceptable size of the bile duct after cholecystectomy is controversial.


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1 Patient with recurrent episodes of pain (not daily), in the epigastrium/right upper quadrant, lasting >30 min, building to a steady level, interrupting activities or ER visit, previous cholecystectomy

12

11

13

Abnormal liver tests (X2) and dilated common bile duct

SOD type I

14 Elevated pancreatic enzymes

10

2 No relief by bowel movements, postural change or antacis; appropriate exclusion of chronic abdominal wall pain

Consider sphincter of Oddi dysfunction (SOD)

Abnormal abdominal imaging?

Do liver tests, amylase/lipase, and abdominal ultrasound scan

Consider ERCP and sphincter of Oddi manometry, +/– prior dynamic biliary imaging

19

18

8

3

SOD type II Abnormal liver tests (X2) or dilated bile duct

no

16

15

17

ERCP

Normal blood tests and bile duct diameter

yes

SOD type III or other functional GI disorder

no 4

6

Ultrasound shows common bile duct stones?

no

9

Abnormal upper GI endoscopy?

yes

yes

Common bile duct stones, pancreatitis, pancreas divisum, nonpancreaticobiliary lesion

7

5 Common bile duct stones

Peptic ulcer disease, gastroesophageal reflux disease

Figure 2. Post-cholecystectomy biliary-like pain. ERCP, endoscopic retrograde cholangiopancreatography.

6,7.

8,9.

10.

Cholecystectomy itself does not increase the size, but the duct may be enlarged because of previous pathology, and it does increase slowly with age. The diameter of the common bile duct on US scanning on average is < 6 mm and does not exceed 10 mm, even after cholecystectomy. Thus, a common bile duct diameter > 10 mm is considered dilated (10). Upper GI endoscopy is unlikely to yield relevant pathology with this constellation of symptoms and when they are not alleviated by acid suppression. However, it is wise to exclude reflux esophagitis and ulcer disease, and gastric cancer, especially in older patients. Normal US findings, or the finding of a dilated bile duct only, with or without elevated liver biochemistry or abnormal pancreatic enzymes assessed after the episodes of pain, are indications to further investigate for potential structural causes with magnetic resonance cholangiopancreatography (MRCP), abdominal computed tomography (CT) scan, and/or endoscopic US (EUS) depending on the available resources and clinical suspicion. MRCP has 80–90% sensitivity for the detection of common bile duct stones. EUS has a diagnostic accuracy comparable with ERCP for the detection of common bile duct stones, with specificity of about 85–90% and sensitivity < 95% (11). EUS is the most sensitive imaging test for chronic pancreatitis, which is an important consideration in the differential of unexplained pain in this context. In older patients, it may be used to detect or exclude small tumors and intraductal papillary mucinous neoplasm (IPMN). The absence of structural abnormalities on these tests leads to consideration of biliary SOD as a cause of pain. The Rome III diagnostic criteria (1) for functional biliary sphincter of Oddi disorder are as follows: (i) episodes of epigastric and/or right upper quadrant pain, lasting ≥30 min and occurring at different intervals (not daily), with the pain building up to a steady level, being moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency room (ER) visit, and not being relieved by bowel movements, postural change, or antacids; (ii) exclusion of other structural


disease that would explain the symptoms present; and (iii) normal amylase/lipase. Supportive criteria are as follows: (i) one or more of associated nausea and vomiting, pain radiation to the back and/or to the subscapular region, and pain awakening the patient from sleep and (ii) elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporally related to at least two pain episodes. 11–13. The concomitance of transiently abnormal liver biochemistry shortly after at least two episodes of pain, with the finding of a dilated common bile duct, is diagnostic of biliary SOD type I, with an indication to consider ERCP and endoscopic sphincterotomy (12). 14–16. The presence of elevated pancreatic enzymes is suggestive of SOD, with delay in the flow of pancreatic secretion, and constitutes an indication to consider ERCP and, in the absence of structural alterations, to consider manometry of the biliary and, if clinically relevant, pancreatic sphincter of Oddi. 15–17. Patients who have either a dilated bile duct, or abnormal liver biochemistry (but not both criteria), on two or more occasions, are classified as biliary SOD type II (12). These patients should be investigated further, but there is little consensus on the best approach (3). ERCP with biliary manometry was shown to be predictive of a good outcome after biliary sphincterotomy in one randomized trial 20 years earlier (12), and this has become the standard practice in referral centers. However, cohort studies show no better than 65% good outcomes with this approach, raising questions about the value of biliary manometry, and the need to study the pancreatic sphincter also. ERCP with manometry carries a significant risk of post-procedure pancreatitis (reduced recently by temporary pancreatic stent placement); hence, there have been many attempts to develop noninvasive diagnostic tests. Evidence for and against sphincter dysfunction can be obtained by studies of dynamic biliary imaging. Several now obsolete methods have been proposed, including measurement of the bile duct size before and after a fatty meal, or after injection of cholecystokinin (CCK) (1,13). Nuclear medicine imaging, assessing choledo-


choscintigraphy with 15 or without (14) CCK provocation has been reported to offer more reliable information. The optimum method for choledochoscintigraphy, and the predictive value of the results, remain somewhat controversial (13–17). They may guide clinicians toward proceeding to sphincter manometry if positive, or away from the procedure and attending to other treatments if negative. In practice, such nuclear medicine imaging is not often undertaken, and patients with severe symptoms and these parameters are usually referred for ERCP with sphincter manometry. There are some proponents of intra-sphincteric injection of Botox as a valid therapeutic trial (18). Dynamic MR scanning may have a role in the future. The risk of causing pancreatitis by ERCP with or


Gurantors of the article: Rome Foundation. Specific author contributions: Planning and writing the part regarding biliary algorithms: Enrico Corazziari and Peter B. Cotton. Financial support: This work was supported by a grant from the Rome Foundation. Potential competing interests: None.

REFERENCES 1. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:1377–90. 2. Behar J, Corazziari E, Guelrud M et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006;130:1498–509. 3. Cohen S, Bacon BR, Berlin JA et al. National Institutes of Health Stateof-the-Science Conference Statement; ERCP for diagnosis and therapy, January 14–16, 2002. GIE 2002;56:803–9. 4. Zeman RK, Garra BS. Gallbladder imaging. Gastroenterol Clin North Am 1991;20:27–56. 5. Yap L, Wycherley AG, Morphett AD et al. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal scintigraphy. Gastroenterology 1991;101:786–93. 6. Di Baise JK, Olejnikov D. Does gall bladder ejection fraction predict outcome after cholecystectomy for suspected chronic acalculous gallbladder dysfunction? A systematic review. Am J Gastroenterol 2003;18:167–74. 7 . Delgado-Aros S , Cremonini F, Bredenoord AJ et al. Systematic review and meta-analysis: does gall-bladder ejection fraction on cholecystokinin cholescintigraphy predict outcome after cholecystectomy in suspected functional biliary pain? Aliment Pharmacol Ther 2003 ; 18 : 167 – 74 .


19.

without sphincter manometry in patients with suspected SOD can be reduced by placing a temporary pancreatic stent (3). For all of these reasons, it seems prudent to refer these patients to tertiary centers for comprehensive assessment. Those centers are encouraged to undertake research studies to advance our knowledge. With normal liver biochemistry and normal common bile duct size, a diagnosis of biliary SOD type III, or other functional GI disorder (such as functional abdominal pain syndrome or epigastric pain syndrome), is likely. A therapeutic trial with proton pump inhibitors, antispasmodic drugs, or an antidepressant agent should be considered. The role of ERCP and manometry in patients with SOD type III remains to be clarified.

8. Mahid SS, Jafri NS, Brangers BC et al. Meta-analysis of cholecystectomy in symptomatic patients with positive hepatobiliary iminodiacetic acid scan results without gallstones. Arch Surg 2009;144:180–7. 9. Ponsky TA, DeSagun R, Brody F. Surgical therapy for biliary dyskinesia: a meta- analysis and review of the literature. J Laparoendosc Adv Surg Tech A 2005;15:439–42. 10. Feng B, Song O. Does the common bile duct dilate after cholecystectomy? Sonographic evaluation in 234 patients. AJR 1995;165:859–61. 11. Stabuc B, Drobne D, Ferkolj I et al. Acute biliary pancreatitis: detection of common bile duct stones with endoscopic ultrasound. Eur J Gastroenterol Hepatol 2008;20:1171–5. 12. Geenen JE, Hogan WJ, Dodds WJ et al. Efficacy of endoscopic sphincterotomy after cholecystectomy in patients with sphincter of Oddi dysfunction. N Engl J Med 1989;32:82–7. 13. Rosenblatt ML, Catalano MF, Alcocer E et al. Comparison of sphincter of Oddi manometry, fatty meal sonography and hepatobiliary scintigraphy in the diagnosis of sphincter of Oddi dysfunction. Gastrointest Endosc 2001;54:697– 704. 14. Cicala M, Habib FI, Vavassori P et al. Outcome of endoscopic sphincterotomy in post cholecystectomy patients with sphincter of Oddi dysfunction as predicted by manometry and quantitative choledochoscintigraphy. Gut 2002;50:665–8. 15. Sostre S, Kalloo AN, Spiegler EJ et al. A noninvasive test of sphincter of Oddi dysfunction in postcholecystectomy patients: the Scintigraphic score. J Nucl Med 1992;33:1216–22. 16. Pineau BC, Knapple WL, Spicer KM et al. Cholecystokinin-stimulated mebrofenin hepatobiliary scintigraphy in asymptomatic postcholecystectomy individuals: assessment of specificity, interobserver reliability, and reproducibility. Am J Gastroenterol 2001;96:3106–9. 17. Craig AG, Peter D, Saccone GTP et al. Scintigraphy versus manometry in patients with suspected biliary sphincter of Oddi dysfunction. Gut 2003;52:352–7. 18. Wehrmann T, Seifert H, Seipp M et al. Endoscopic injection of botulinum toxin for biliary sphincter of Oddi dysfunction. Endoscopy 1998;30:702–7.


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Functional Abdominal Pain Syndrome: Constant or Frequently Recurring Abdominal Pain Ami D. Sperber, MD1 and Douglas A. Drossman, MD2 Am J Gastroenterol 2010; 105:770–774; doi:10.1038/ajg.2010.68

CHRONIC ABDOMINAL PAIN Abdominal pain is a symptom that can be either acute or chronic and has many etiologies. Physical diagnosis textbooks provide extensive tables on the differential diagnosis of acute and chronic abdominal pain, but to make a diagnosis merely by trying to fit the patient’s symptoms into a list is not enough. It is the skill of active listening and the integration of historical data into a conceptual framework that guides the diagnostic strategy; physical examination and confirmatory studies then follow (1). This is particularly true for chronic abdominal pain. In fact, clinicians approach the diagnosis and treatment of acute and chronic pain differently. Making a differential diagnosis of acute abdominal pain seems more understandable, because acute pain is usually generated from a single peripheral source. There are characteristic features regarding the symptom description, location, its time course, and the aggravating and relieving factors. Thus, clinicians are in agreement when considering the diagnosis of a peptic ulcer when the patient describes the recent onset of intermittent burning epigastric pain that is relieved by meals and antacids and associated with black stools. In contrast, it is more difficult to apply an acute pain model to patients with chronic abdominal pain. Herein, the symptoms may not behave in the expected manner, being ever present, poorly localized, associated with negative diagnostic tests, and not readily responsive to gut-acting treatments. Not only is the clinician perplexed about diagnostic and therapeutic options but also the very legitimacy of the condition may come into question. What is required is a broader biopsychosocial construct to approach the chronic gastrointestinal pain (2). There are different types of chronic abdominal pain. Many have a peripheral contribution, e.g., pain that is due to chronic pancreatitis or inflammatory bowel disease. Herein, the nature and severity of the symptoms are attributed to the underlying pathological damage. However, as the pain becomes more chronic, treatments targeted to the peripheral organ become less than optimal, particularly when there is little or no evidence for structural damage. When abdominal pain becomes a constant presence, defies a gut-associated structural etiology, and is disruptive to life, it is categorized as a functional gastrointestinal disorder. Functional abdominal pain syndrome (FAPS) is a debilitating functional gas-

trointestinal disorder characterized by continuous and persistent or frequently recurrent abdominal pain that is associated with the loss of daily functioning (3). There is no evidence of structural (biochemical) abnormalities to explain the symptom and it is not factitious. FAPS is less prevalent than irritable bowel syndrome with which it may be confused. Owing to its debilitating nature, the burden of disease in terms of absenteeism from work and utilization of health-care services is substantial (4). Although FAPS was once classified as one of the functional bowel disorders, in the Rome III classification of the functional gastrointestinal disorders, it was placed in its own separate category (3). The pain is not related to abnormal motility or even enhanced visceral signaling (5), and clinically it is not associated with change in bowel habit, or eating, nor is it relieved by defecation. The greater contribution to the pain experience relates to abnormal cingulate functioning that may be linked to psychosocial disturbances (6–8). As there is a dearth of literature on FAPS, this contention is based on data obtained from patients with severe painful irritable bowel syndrome and psychosocial disturbances, which could be considered as a surrogate condition that represents FAPS. From a pathophysiological perspective, pain can have contributions from anywhere in the neuraxis. When injuring a finger, the pain clearly arises from peripheral neural injury with increased afferent nociceptive input to the brain. This is also true for acute visceral inflammation or injury, such as acute cholecystitis or bowel obstruction. However, when a gastrointestinal disorder becomes chronic, as noted previously with inflammatory bowel disease or chronic pancreatitis, the pain experience is increasingly influenced by central nervous system function. In functional gastrointestinal disorders, the symptoms become even more associated with central dysregulation amplifying the pain, in addition to the bowel dysfunction. Finally, in FAPS, there may be little or no gastrointestinal disturbance and the major disturbance is an “abnormal perception of normal gut function,” rather than an abnormal gut function. Indeed, the main mechanism for altered pain regulation with FAPS relates to the failure to inhibit and possibly even the amplification of normal regulatory afferent input through altered central “gate control” mechanisms (originating in the prefrontal and cingulate cortex and other limbic structures) (7). This

1 Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2President, Rome Foundation, and Co-Director, UNC Center for Functional Gastrointestinal and Motility Disorders, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Correspondence: Ami D. Sperber, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. E-mail: [email protected]



impairment in homeostatic inhibition of pain (disinhibition) may relate to reduced serotonin, norepinephrine, endorphin, and other neuropeptide activity though the medial central nervous system circuitry to the dorsal horn. Thus, although the pain is experienced in (and attributed to) the abdomen, these cognitive and emotional centers regulate the perception of pain primarily through the gate control mechanisms of the brain–gut axis. Recognition of the central nervous system as the primary modulator of pain in FAPS is essential to understanding its clinical manifestations, and to the development of diagnostic and therapeutic strategies. The diagnosis of FAPS, although symptom based, reflects this understanding of central rather than gut-related disturbances. Extensive diagnostic investigations in the absence of “red flags” or alarm features (see Box 4 in Figure 1 and Legend 4) suggest that such testing is ordered by nondiscerning clinicians when patients insist that “something be done” and/or because physicians fear “missing something more serious.” Extensive diagnostic studies are unjustified not only because they are they not indicated clinically but also because they are expensive and tend to impair the physician–patient relationship and the therapeutic alliance. They may send a message to the patient that the physician is uncertain of the positive diagnosis of FAPS, and reduce overall patient confidence in the plan of care. A major objective in the care of patients with FAPS is to develop an understanding of this condition as a biopsychosocial disorder in which symptoms can be attributed to brain–gut dysfunction. A therapeutic plan should be developed and implemented with confidence and by communicating a clear understanding of the mechanisms for symptom generation and treatment. The higher frequency of psychosocial difficulties in FAPS that enhance the pain experience through these central nervous system pathways (6,9) should be elicited and addressed. This understanding can lead to effective behavioral and psychopharmacological treatments (10). The foundation of any therapeutic strategy is the patient–physician partnership, which is predicated on compassion, acknowledgment of the distress associated with the painful condition (“legitimization” of pain), and maintenance of an objective and observant stance. Other therapeutic options grow out of this basic relationship and include both pharmacological and nonpharmacological approaches. All treatment programs should be based on a multicomponent strategy, with the patient as a full partner. Realistic expectations should be agreed upon for “care” rather than for “cure” (1).

CONSTANT OR FREQUENTLY RECURRING ABDOMINAL PAIN Case history

A 33-year-old woman is referred to a gastroenterologist by her primary care physician because of a long history of constant and severe abdominal pain refractory to all previous treatments; she has associated loss of daily functioning and is unable to work (Box 1, Figure 1). She has no known systemic disease that explained the pain.


The gastroenterologist obtains the history when the patient first developed recurrent episodes of abdominal pain at the age of 6 years, and these episodes led to school absence. The frequency and severity of the episodes of pain increased after menarche. Over the past 10 years, the pain has become more frequent and more severe, and for the past 5 years, has been present constantly, occurring on a daily basis. It is described as dull or cramping in character and is usually located in the mid to lower abdomen. The pain is specifically not related to or affected by bowel movements, eating, or menstrual cycle (Box 2). The patient communicates intense pain by wincing and holding her abdomen, and she requests that diagnostic studies be conducted to “find and fix” the problem (Box 1). Her records indicate that physical examinations in the past and diagnostic studies have been negative for other medical disorders (Box 3). The tests have included two colonoscopies, upper gastrointestinal endoscopy, computerized tomography scan of the abdomen, capsule endoscopy, pelvic ultrasound, and abdominal magnetic resonance imaging. An exploratory laparotomy 5 years earlier suggested endometriosis, leading to an unsuccessful trial of leuprolide acetate. She also underwent cholecystectomy 3 years earlier due to a low ejection fraction on DISIDA (isotope) scan. There are no alarm features (Box 4). The patient states that she has had > 30 emergency room visits where she usually receives intravenous morphine and phenergan, and is discharged with a week’s supply of oral narcotics, hydrocodone or oxycodone. In the letter of referral, her primary care physician states that she often needs to refill these prescriptions to prevent her from returning to the emergency room. She has had five hospitalizations for abdominal pain when emergency room treatments were unsuccessful. Further history shows that at age 16 years, the patient left home before finishing high school, and after becoming pregnant, married at age 17. After 4 years, she left her spouse when he became physically abusive. The patient and her daughter are currently living with her mother. For the past 2 years, she has been unable to work (Box 1) and is currently receiving disability payments. The gastroenterologist notes that a psychiatry consultant diagnosed major depression with posttraumatic stress disorder resulting from a childhood history of family deprivation, as well as sexual and physical abuse. The pain is considered to be consistent with a pain disorder associated with psychological factors (DSM-IV 307.80), and there is no evidence for malingering (Box 7). The psychiatrist recommended treatment with paroxetine 20 mg/day and follow-up at a local mental health center. She was discharged with paroxetine and also oxycodone 10 mg three times a day. Upon presentation on this occasion, the patient is lying on her side on the examination table with hips flexed. She complains of severe cramping abdominal pain in the mid and lower abdomen with nausea. The examination is again negative (Box 4), except for a positive Carnett’s test (see Box 5 in Figure 1 and Legend 5). She is asking to be hospitalized to determine the cause of the pain and to receive intravenous medication to relieve the pain. A diagnosis of FAPS is made (Box 8).


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Patient with constant or frequently recurring abdominal pain for at least 6 months:

7

• not associated with known systemic disease • with loss of daily function including work and socializing

Referral to mental health-care professional to exclude malingering

yes 2

4 Is pain associated with bowel movements, eating, or menses?

6 Alarm features identified on history or physical examination?

no

yes

no

Suspicion that pain is feigned?

no

yes

3 Consider IBS, EPS, and other painful FGIDs, or mesenteric ischemia. Other possible diagnoses include painful gynecological disorders, e.g., endometriosis

5

8 Do appropriate diagnostic workup for alarm features

Functional abdominal pain syndrome

Figure 1. Constant or frequently recurring abdominal pain.

Figure 1. Legend 1.

2.

3.

Constant or frequently recurring abdominal pain in this context refers to pain that is constant, nearly constant, or at least frequently recurring, with pain or discomfort occurring every day, and where the pain has been present for at least 6 months. The pain is associated with some loss of daily functioning such as work or school absenteeism and limitations in social activities. Systemic disease that may be associated with this type of pain is not known to be present. The history should also include clinical/psychosocial features (1). During history taking, symptom-reporting behaviors should be noted (3). These include verbal and nonverbal expression of varying pain intensity, urgent reporting of intense symptoms, minimizing or denying a role for psychosocial factors, requesting additional diagnostic studies, focusing attention on complete recovery, seeking health care frequently, taking limited personal responsibility for self-management, and making requests for narcotic analgesics. Although behavioral communications are not criteria for the diagnosis, they are a commonly observed feature in this context. The history should elicit specific features of the pain, especially associations with bowel movements and eating, and also any relationship to the menstrual cycle. If the pain is associated with bowel movements and leads to frequent, looser stools or infrequent harder stools with relief upon defecation (any combination of two), then a diagnosis of irritable bowel syndrome (IBS) should be considered (11) (see the “chronic or recurrent abdominal pain/discomfort with disordered bowel habit” algorithm). If the pain is located in the epigastrium or right upper quadrant, is severe, interrupts daily activities and recurs at different intervals (i.e., not daily), a diagnosis of functional gallbladder or sphincter of Oddi disorder should be considered (12) (see the “recurrent biliary-like pain” and “post-cholecystectomy biliary-like


4.

5.

pain” algorithms). If the pain is localized to the epigastrium, is intermittent, and does not fulfill criteria for gallbladder or sphincter of Oddi disorder, functional dyspepsia (specifically, epigastric pain syndrome (EPS)) should be considered (13) (see the “recurrent dyspepsia” algorithm). The diagnosis of chronic mesenteric ischemia should be considered. Characteristic features may include pain exacerbated by eating (intestinal angina) and pain out of proportion to the physical examination. This is a difficult determination to make but should be considered in the context of new onset in a patient of older age with a history of vascular disease along with symptoms of nausea, vomiting, and weight loss. Diarrhea may also be present. Upper abdominal pain may reflect celiac axis involvement. If the pain is associated with and worsened by menses, it might indicate conditions, such as endometriosis, dysfunctional uterine bleeding, or another gynecological pathology, and should be evaluated by pelvic examination, pelvic ultrasound, and/or referral to a gynecologist. A pelvic examination will help in this determination, first examining pelvic structures intra-vaginally and then comparing with bimanual examination. When in doubt, evaluation by a gynecologist is suggested. A complete physical examination should be conducted. The minimal diagnostic workup includes complete blood count (CBC), erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), biochemistry panel, and fecal occult blood (over the age of 50 years). Alarm features can include abnormal findings on physical examination, unintentional weight loss, family history of abdominal cancer, and laboratory abnormalities, such as anemia, hypoalbuminemia, abnormal liver function tests, elevated ESR, and positive fecal occult blood. If alarm features are identified by history, physical examination, or laboratory screening investigations, other sources of abdominal pain VOLUME 105 | APRIL 2010 www.amjgastro.com

6.

7.

should be considered. An appropriate level of suspicion may also be required to differentiate chronic abdominal wall pain from pain of visceral origin. The pain is usually localized and increases with contraction of the abdominal muscles. Carnett’s sign in which pain or tenderness increase with intentional tensing of the abdominal muscles can be elicited on physical examination in these cases (14). Although a positive Carnett’s sign could indicate abdominal wall pain as the source of this patient’s symptoms, and if elicited might be taken into account it makes more sense, in the context of the history and clinical course, that her pain is related to central hypersensitivity with hypervigilance. Thus, in the context of the present case, a positive Carnett’s sign would be considered as negating visceral pain as the pain source and supporting a central hypersensitivity more than abdominal wall pain. In effect, the original Carnett’s sign, in this application, is being modified to differentiate visceral from central pain mechanisms. Feigned pain or malingering relates to the intentional production of false or grossly exaggerated physical (or psychological) symptoms, motivated by external incentives. This may relate to avoiding work, obtaining financial compensation, or obtaining drugs. The DSM-IV indicates that malingering should be strongly suspected if any combination of the following is noted (15): medico-legal context of presentation (i.e., referred by an attorney to the clinician for examination); marked discrepancy between the person’s claimed stress, symptoms or disability, and the objective findings; lack of cooperation during the diagnostic evaluation and in complying with the prescribed treatment regimen; and the presence of antisocial personality disorder. On the basis of the DSM-IV criteria, three or more of the following are required for this diagnosis: a pervasive pattern of disregard for and violation of the rights of others as indicated by: (i) unlawful behaviors, (ii) deceitfulness and lying, (iii) impulsivity or failure to plan ahead, (iv) irritability and aggressiveness with physical fights or assaults, (v) reckless disregard for the safety of oneself or others, (vi) irresponsibility with failure to sustain consistent work behavior or honor financial obligations, and (vii) lack of remorse for being indifferent to having hurt, mistreated, or stolen from another. Feigned pain or malingering differs from factitious disorder in that the motivation for the symptom production in malingering is an external incentive, whereas in factitious disorder, external incentives are absent. It differs from conversion disorder or somatoform disorder as the symptoms are intentionally produced, and thus in contrast to these conditions, relief is not often obtained by suggestion or hypnosis. It is recognized that feigned pain is not easy to detect; hence, it may be appropriate to refer to a mental health professional to confirm

8.


Guarantors of the article: The Rome Foundation. Specific author contributions: Ami D. Sperber and Douglas A. Drossman coauthored and collaborated on the section on FAPS from the onset and each participated in all aspects from the initial concept through all drafts to the final version. Financial support: This work was supported by a grant from the Rome Foundation. Potential competing interests: None.

4.

5.

6.

7.

REFERENCES 1. Drossman DA. Functional abdominal pain syndrome. Clin Gastroenterol Hepatol 2004;2:353–65. 2. Drossman DA. Presidential address: gastrointestinal illness and the biopsychosocial model. Psychosom Med 1998;60:258–67. 3. Clouse RE, Mayer EA, Aziz Q et al. Functional abdominal pain syndrome. In Drossman DA, Corazziari E, Delvaux M et al. (eds). Rome III. The


8.

9.

this suspicion. It should not be presumed unless there is clear evidence for its presence. In the absence of alarm features or screening abnormalities and in the presence of long-standing stable symptoms, the diagnosis of functional abdominal pain syndrome (FAPS) is highly probable if all criteria for this diagnosis have been met. Rome III diagnostic criteria for FAPS are as follows: (i) continuous or nearly continuous abdominal pain, (ii) no or only occasional relationship of pain with physiological events (e.g., eating, defecation, or menses), (iii) some loss of daily functioning, (iv) the pain is not feigned, (v) insufficient symptoms to meet criteria for another functional gastrointestinal disorder (FGID) that would explain the pain, and (vi) criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis. If these criteria are met, reassurance regarding the diagnosis of FAPS and symptomatic treatment should be followed by reassessment in 3–6 weeks (16). Psychosocial factors including major depression or anxiety disorder, somatoform disorder, maladaptive coping, and life stress including physical, sexual, or emotional abuse are common in patients with FAPS. These disorders can be screened through the psychosocial history or in some cases through psychological testing (17). The Rome III Psychosocial Alarm Questionnaire for Functional Gastrointestinal Disorders (Appendix A), which identifies “red flags” or more serious markers of psychosocial disturbance that would prompt psychiatric or psychological referral, is a useful tool for clinical practice. These issues are discussed in detail by Creed et al. (18), including a treatment algorithm with red flags for mental health consultation. Primary treatment options for FAPS include tricyclic antidepressants (TCA) or selective serotonin reuptake inhibitors or serotoninspecific reuptake inhibitors (SSRI) therapy, or nonpharmacological therapy, such as cognitive-behavioral therapy (CBT), hypnotherapy, or dynamic or interpersonal psychotherapy (19). An algorithm to guide treatment decisions for FAPS appears in the study by Clouse et al. (3) In patients with marked disability, opiate misuse, and/or multiple and widespread pain problems in addition to FAPS, in whom little or no improvement is seen with these treatment strategies, referral to a specialized multidisciplinary chronic pain program might be considered. Another compelling issue to address that occurs in patients with FAPS is the injudicious use of narcotic agents that may lead to the development of narcotic bowel syndrome (20). This condition is characterized by the accelerated use of narcotic medications for pain relief, but which paradoxically is associated with hyperalgesia. The treatment requires detoxification from narcotics and substitution of the treatments as noted above.

Functional Gastrointestinal Disorders, 3rd edn McLean, Virginia: Degnon Associates, 2006. Maxton DG, Whorwell PJ. Use of medical resources and attitudes to health care of patients with “chronic abdominal pain”. Br J Med Econ 1992;2:75–9. Dorn SD, Palsson OS, Thiwan SI et al. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an increased tendency to report pain rather than increased neurosensory sensitivity. Gut 2007;56:1202–9. Ringel Y, Drossman DA, Leserman JL et al. Effect of abuse history on pain reports and brain responses to aversive visceral stimulation: an FMRI study. Gastroenterology 2008;134:396–404. Jones MP, Dilley JB, Drossman D et al. Brain-gut connections in functional GI disorders: anatomic and physiologic relationships. Neurogastroenterol Motil 2006;18:91–103. Drossman DA. Brain imaging and its implications for studying centrally targeted treatments in irritable bowel syndrome: a primer for gastroenterologists. Gut 2005;54:569–73. Drossman DA, Ringel Y, Vogt BA et al. Alterations of brain activity associated with resolution of emotional distress and pain in a case of severe irritable bowel syndrome. Gastroenterology 2003;124:754–61.


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10. Grover M, Drossman DA. Psychopharmacologic and behavioral treatments for functional gastrointestinal disorders. Gastrointest Endosc Clin N Am 2009;19:151–70. 11. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91. 12. Behar J, Carazziari E, Guelrud M et al. Functional gallbladder and sphincter of Oddi disorders. Gastroenterology 2006;130:1498–509. 13. Tack J, Talley NJ, Camilleri M et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466–79. 14. Carnett JB. Intercostal neuralgia as a cause of abdominal pain and tenderness. Surg Gynecol Obstet 1926;42:625. 15. First HB, Frances A, Pincus HA. DSM-IV-TR Guidebook. Washington, DC: American Psychiatric Publishing, 2004.


16. Drossman DA, Camilleri M, Mayer EA et al. AGA technical review on irritable bowel syndrome. Gastroenterology 2002;123:2108–31. 17. Levy RL, Olden KW, Naliboff BD et al. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology 2006;130:1447–58. 18. Creed F, Levy RL, Bradley LA et al. Psychosocial aspects of the functional gastrointestinal disorders. In Drossman DA, Corazziari E, Delvaux M, et al. (eds). The Functional Gastrointestinal Disorder., 3rd edn McLean, Virginia: Degnon Associates, 2006. 19. Drossman DA. Severe and refractory chronic abdominal pain: treatment strategies. Clin Gastroenterol Hepatol 2008;6:978–82. 20. Grunkemeier DM, Cassara JE, Dalton CB et al. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol 2007;5:1126–39.



Bowel Disorders Robin C. Spiller, MD1 and W. Grant Thompson, MD2 Am J Gastroenterol 2010; 105:775–785; doi:10.1038/ajg.2010.69

BOWEL SYMPTOMS The main symptoms that arise from the intestines are abdominal pain or discomfort, disordered bowel habit, abdominal bloating, and distension. Abdominal pain/discomfort

The diagnostic features of abdominal pain include site, radiation (if any), character (burning, stabbing, colicky), pattern and duration (since onset and length of attack), and precipitating and relieving factors. Abdominal pain or discomfort of functional gastrointestinal origin arises from stimulation of visceral nerves: typically it is diffuse and poorly localized, often in the central or lower abdomen. When asked to demonstrate it, the patient may use an outstretched hand placed over the area. Features that support a gastrointestinal origin of abdominal pain include exacerbation by eating and relief by defecation, the latter being part of the diagnostic criteria for irritable bowel syndrome (IBS). However, although eating increases colonic motility and can produce discomfort within a half an hour of eating, it is a feature of many gastrointestinal diseases. Therefore, pain after eating is not part of the diagnostic criteria for IBS. In contrast, when visceral disease is associated with stimulation of somatic neurons, the pain is more precisely localized. Diverticulitis and appendicitis are examples of intra-abdominal disease that initially are poorly localized because mild inflammation affects only visceral neurons. However, when the inflammation progresses and reaches the parietal peritoneum, a more precisely localized somatic abdominal pain is experienced. Other examples include the radiation to the back that is typical of pancreatic disease or of a penetrating duodenal ulcer. Abdominal wall pain due to a Spigelian hernia (hernia through the aponeurotic fascia just lateral to the rectus abdominis muscle), a rectus muscle injury, or painful rib syndrome is also more accurately localized. Pain from such causes can be identified by Carnett’s test, in which the patient folds his arms across the chest and raises his head against gentle resistance. Exacerbation of the pain by tensing the rectus muscles in this way indicates an abdominal wall disorder (1). Pain in the rib cage is also precisely localized and exacerbated by local pressure or compression. Early recognition of these less-common somatic sources of abdominal pain can save much futile investigation (2).

The abdominal pain of IBS is visceral in nature and typically episodic and unpredictable. Periods of pain recur over a median (range) of 3 (2–8) days, interspersed with a few pain-free days (3). However, in some cases painful periods may be more prolonged. A crucial feature of IBS abdominal pain is its temporal association with a disturbed bowel habit. Concurrent with the pain is a change in the frequency and consistency of bowel movements, a phenomenon used in the Manning criteria. For IBS, these features have a sensitivity for IBS ranging from 0.39–0.6 and a specificity of 0.66–0.77 with likelihood ratios that range from 1.7–2.1. Therefore, by themselves these features are of little diagnostic value, but combinations of them perform much better. A combination of any three Manning criteria— i.e., three of (a) more frequent stools with onset of pain, (b) looser stools at the onset of pain, (c) visible distension, or (d) relief by defecation—have a sensitivity of 0.84 and a specificity of 0.76, with a positive likelihood ratio of 2.9 and a negative likelihood ratio of 0.2 (4). Constipation

On the basis of surveys undertaken many years ago, “constipation” was traditionally defined as less than three bowel movements per week (5), yet many who fit this definition do not consider themselves constipated. Current evidence suggests that the effort to defecate and the consistency (form) of the stool are more important. Stool consistency, assessed using the Bristol Stool Form Scale (BSFS), adds an objective dimension to stool form observations as it correlates well with colonic transit times (6). The BSFS forms part of the Rome III criteria for recognition of IBS with constipation, as well as assisting the recognition of functional constipation (7). Thus, the Rome III criteria for “constipation” include thresholds for stool form, as well as stool frequency and effort. Patients’ criteria for constipation often differ from their physicians’, leading to potential misunderstanding between patient and doctor. A survey of 731 women in the United Kingdom found that the presence of constipation differed according to whether the individual, the gut transit time, or the Rome I criteria for functional constipation were used to define it (8). Although about 8.5% of the subjects had constipation by each of these definitions, only 2% were constipated by all three definitions. Therefore, the physician must consider all aspects of a patient’s complaint of constipation, including his or her attitude toward the symptoms. Hard

1

Nottingham Digestive Diseases Centre, University Hospital, Nottingham, UK; 2Emeritus Professor of Medicine, University of Ottawa, Ontario, Canada. Correspondence: Robin C. Spiller, MD, Nottingham Digestive Diseases Centre, University Hospital, C Floor South Block, NG7 2BB Nottingham, UK. E-mail: [email protected]



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stools correlate well with slow transit but difficulty with defecation and stool frequency do not, for they are determined by factors other than colon transit.

tional gastrointestinal disorders attributed to bowel function. The commonest functional bowel disorder is IBS. Symptom severity

Diarrhea

The term “diarrhea” suffers from definitional difficulties similar to those of constipation. Although the urgent passage of liquid stools eight times per day is diarrhea by any definition, there is a gray area between abnormal and normal. The frequent passage of hard stools is not diarrhea. For this reason, “loose (mushy) or watery stools without pain occurring in at least 75 percent of stools” is the symptom criterion for functional diarrhea (7), a feature that generally indicates fast transit through the colon. As with IBS with constipation, the BSFS also assists the recognition of IBS with diarrhea. Notwithstanding, the patient should also be asked about urgency and frequency as these symptoms are socially debilitating and prevent the patient from eating out or traveling, thereby markedly reducing the patient’s quality of life. When urgency is a marked feature, anal sphincter weakness should be considered, particularly in females with a previous difficult vaginal delivery. More than many other functional gastrointestinal disorder symptoms, diarrhea—particularly when associated with above normal stool volumes—may have an organic cause, necessitating careful questioning and more extensive investigation. Bloating and abdominal distension

Patients with a functional bowel disorder frequently report a sensation of bloating, which may be quite intrusive and close to a sensation of discomfort. Bloating is not IBS specific and therefore is not a diagnostic criterion. Some patients also describe visible abdominal distension with the need to loosen clothing. This can appear abruptly and may be due to a reflex contraction of the diaphragm combined with relaxation of abdominal muscles (9). Although bloating and distension may occur in the same patient, bloating reflects a sensory or perceptual phenomenon, whereas distension indicates an observable change in the diameter of the abdominal wall (10). Recently, objective measurements have confirmed that normally abdominal girth increases slightly during the day, falling abruptly on lying down to go to sleep and increasing on rising. The diurnal increase is greater than normal in patients with IBS and constipation (10). Only half of the IBS patients reporting the sensation of bloating show distension beyond the normal range. Those without visible distension have lower visceral pain thresholds, thus it seems likely that the sensation is due to visceral hypersensitivity (11). Functional bowel syndromes

Abdominal pain or discomfort, disturbed bowel habit with constipation or diarrhea, and bloating are common symptoms in the general population, which individually lack both sensitivity and specificity for a diagnosis. However, combinations of such symptoms are more specific. When equipped with appropriate thresholds of frequency, such combinations can be identified as syndromes. The functional bowel disorders are the group of funcThe American Journal of GASTROENTEROLOGY

Clinicians frequently make diagnostic and treatment decisions based not only on the symptom pattern, but also on the severity of the symptoms, often the pain but also the stool pattern, as reported by patients. Therefore, this is an important parameter to gauge as part of the diagnostic evaluation. For example, patients with diarrhea that is more severe and associated with incontinence may require anorectal motility testing and possible biofeedback. In general, when symptoms become more severe and interfere with daily functioning, they may often be associated with other symptoms, medical or psychological (comorbidities). In particular the clinician must consider concurrent psychological distress symptoms (anxiety or depression) or even comorbid psychiatric disorders (e.g., major depression, post-traumatic stress, somatization, or personality disorders) that may also exist. Many such patients will have a history of previous psychiatric illness (12). If these types of psychological symptoms are prominent, the clinician needs to explore their relevance. The Rome III Psychosocial Alarm Questionnaire (see Appendix A), Hospital Anxiety and Depression (13), or Personal Health Questionnaire (PHQ15) (14) scales, or their equivalents can be administered to patients in a few minutes. They may help identify those patients who may benefit from psychological evaluation and treatments, and if successful, the bowel symptoms may also improve. Patients meeting criteria for somatization disorder should be identified early as they require different management and consume more medical resources (15). Depending on the level of rapport achieved, it may be appropriate to explore more sensitive areas like childhood abuse. Treatment with antidepressants often improves patient symptoms, reduces psychological distress and enhances overall well being and daily function (16). In severe or intractable cases, one should also consider referral to a mental health professional to help the patient develop effective self-management strategies.

RECURRENT ABDOMINAL PAIN/DISCOMFORT WITH DISORDERED BOWEL HABIT Case history

A 32-year-old businesswoman is referred to a gastroenterologist because of recurrent episodes of abdominal pain associated with a disordered bowel habit (Box 1, Figure 1; Diagrams 1 and 2). The symptoms have been present intermittently for about 5 years, but have become more frequent and severe over the past 4 months. The pain occurs every 2 or 3 weeks, and lasts for several days at a time. It is usually situated in the left iliac fossa or periumbilical region, and is often brought on by eating and relieved by a bowel movement. Her stools usually become looser and more frequent at the onset of the pain. She may have up to four loose mushy stools within a period of 2 h in the morning. At other times she may not have a bowel movement for 3 or 4 days, and the stool is then hard and lumpy. She experiences urgency accompanying the loose bowel movements, straining with the hard bowel movements and VOLUME 105 | APRIL 2010 www.amjgastro.com

often experiences a sensation of incomplete evacuation. She also has an uncomfortable sensation of bloating and her abdomen is often visibly distended, especially in the afternoon and evening (Box 2). There are no alarm features, with no blood or mucus in her stools, no weight loss, nor any pain during the night. There is no family history of gastrointestinal disease (Box 3). She has no nausea, vomiting or anorexia, but feels tired for much of the time. Her periods are heavy, often lasting ≥6 days. She has no significant past medical history apart from longstanding migraine. The patient is a non-smoker and eats a balanced diet with no known food intolerances. Her milk intake is < 240 ml per day. Caffeine, fiber, and fructose intake are not excessive. Her only medications are the oral contraceptive pill and infrequent sumatriptan tablets for migraine headaches. She has not taken antibiotics recently. She has tried a number of herbal preparations for her symptoms with no improvement. Physical examination is negative with no pallor or abdominal mass. She demonstrates the loca-

tion of her pain with both hands spread open over the umbilicus. Perianal and rectal examination are normal (Boxes 2 and 3). Given her tiredness and heavy periods, the gastroenterologist arranges a complete blood count (CBC); he also suggests checking celiac serology (Box 7). The CBC is normal (hemoglobin 11.7 gm/dl, mean cell volume (MCV) 88 fl) and tissue transglutaminase is negative (Box 8). The gastroenterologist makes a diagnosis of IBS (Box 9). He discusses the diagnosis of IBS, including the possible causes and how the symptoms may occur, and reassures her that IBS does not lead to more serious disease. He uses the BSFS to help the patient describe her usual pattern of stool consistency (without laxatives or antidiarrheal preparations) (Box 10). This discussion confirms that her stool form, according to the BSFS, varies from type 1 or 2 (hard/lumpy) to type 6 or 7 (mushy/watery) in approximately equal proportions of time (at least 25% of the time for each pattern). On this basis, a diagnosis of mixed IBS (IBS-M) is made (Box 12).

1 Patient with recurrent abdominal pain/discomfort associated with disordered bowel habit

2

11 Medical and psychosocial history, physical examination

IBS with constipation (IBS-C) 10

9 7

3 Alarm features?

no

Consider limited screening tests

yes


Irritable bowel syndrome (IBS)

no

Evaluation of stool consistency (using Bristol Stool Form Scale)

yes

12 Mixed IBS (IBS-M)

13

no

IBS with diarrhea (IBS-D)

4 5

Investigations as indicated: e.g., colonoscopy, blood and stool tests, duodenal biopsy

Any abnormality identified? yes 6 Celiac disease, giardiasis, inflammatory bowel disease, microscopic colitis, small intestinal bacterial overgrowth, colorectal neoplasia

Figure 1. Recurrent abdominal pain/discomfort with disordered bowel habit.

Figure 1. Legend 1.

The features of the abdominal pain or discomfort should be further characterized in terms of frequency, site, character, duration, radiation (if any), and precipitating and relieving factors. In this context, discomfort means an uncomfortable sensation not described as


pain (7). The bowel pattern should be characterized in terms of pattern and frequency, consistency, and ease or difficulty of passage of stool. The temporal relationship, if any, between the abdominal pain and the altered bowel habit should be established. Any rectal bleed-


777

BOWEL DISORDERS

Bowel Disorders

BOWEL DISORDERS

778


ing or passage of mucus, and the presence of nocturnal symptoms, should be noted, as per alarm features outlined below. 2. A careful history of the current symptoms, including what the patient believes is causing his or her symptoms, should be obtained, together with past medical, surgical, psychosocial, and drug history. The pain of irritable bowel syndrome (IBS) is typically diffuse, poorly localized, and either central or lower abdominal in site. It typically occurs in bouts lasting several days (3) during which time the pain is intermittent. The pain is often precipitated by eating (17) and may resolve with fasting. A common feature of the bowel habit in IBS is that it is unpredictable, and that the stool frequency or form changes with the onset of pain. Some patients report that the abdominal pain is relieved by defecation, strongly suggesting it originates in the colon. The disturbance in bowel habit may include urgency, often but not always associated with loose stools or the passage of small hard stools. Characteristically, patients with mixed IBS may describe the passage of both hard and soft stools on the same day, often starting with formed stool and passing progressively softer stool as the contents are emptied in sequence from the distal to proximal colon. The physical examination includes palpation for abdominal masses and digital rectal examination to reveal evidence of inflammatory bowel disease and to assess stool consistency. Depending on the precise pattern of symptoms, particularly if there is a linkage between the abdominal pain and altered bowel habit as discussed below, the age of the patient, and the presence or absence of other alarm features (see below), a provisional diagnosis of IBS can be entertained even at this stage. 3. A systematic enquiry should be made during the initial consultation to exclude alarm features. Identification of these features indicates the need to carefully consider the differential diagnosis and undertake appropriate investigations. The American College of Gastroenterology and the British Society of Gastroenterology have recently published guidelines (18,19), which include the following “red flags”: documented weight loss, nocturnal symptoms, family history of colon cancer, blood mixed with stool, recent antibiotic use, relevant abnormalities on physical examination, age > 50 years, short history of symptoms, and male sex. Some of these red flags were first used in the Kruis scoring system for IBS (20) in which the presence of “abnormal physical findings or features suggestive of other disease”, erythrocyte sedimentation rate (ESR) > 10 mm/h, WBC > 10 ×109/l, anemia, or a history of blood in the stool generated a negative score that substantially reduced the probability of IBS. This system performed better than the Manning criteria with a positive likelihood ratio of 4.6 compared with 2.9 for any three Manning criteria (4). The value of red flags was confirmed in an outpatient study of 154 patients with symptoms suggestive of IBS who were fully investigated. The combination of Rome criteria and the absence of red flags had a sensitivity of 0.65 but a specificity of 100%. A subsequent prospective study of 95 patients who met Rome I criteria in the absence of red flags showed a true positive rate of 93% with only two false positives (21). Thus, in the absence of red flags, a clinical diagnosis of IBS is a safe one. Moreover, several series confirm that once established, this diagnosis rarely needs to be revised (22). 4–5. If one or more alarm features are present, further investigations are required. Relevant blood tests include complete blood count (CBC), ESR/C-reactive protein (CRP), together with calcium, and tissue transglutaminase (tTGA) or endomysial antibodies (EMAs), and thyroid stimulating hormone (TSH). Anemia or raised inflammatory markers (ESR/CRP) may be due to occult Crohn’s disease. In older patients, anemia may be due to a large colonic polyp or cancer. A low serum calcium level suggests malabsorption. These simple inexpensive tests are usually normal (1–2% abnormal in a patient meeting the Rome II symptom criteria for IBS who has no alarm features). A positive tTG or EMA suggests celiac disease (around 95% sensitivity and specificity in secondary care). Several studies suggest that the detection of thyroid abnormalities in IBS patients is no greater than by chance (23) and only rarely will correction of the The American Journal of GASTROENTEROLOGY

6.

7.

abnormality resolve the IBS symptoms. Stool examination may show cysts in giardiasis. However, one examination is only 65% sensitive and three samples are needed to reach 85% sensitivity (24). Fecal antigen testing of stool is superior to microscopic examination (25,26). Stool examination for other parasites in studies largely carried out in the United States have been unrewarding (27), but this may not be true in other countries where parasites are more common. Weight loss and chronic diarrhea should raise the possibility of HIV infection and the patient should be questioned about intravenous drug abuse or unprotected sexual intercourse with multiple partners. If relevant, serological testing for HIV infection and CD4 T-cell count should be performed. A history of recent antibiotic preceding the onset of symptoms should prompt consideration of the possibility of Clostridium difficile infection. Colonoscopy is indicated to exclude colon cancer or inflammatory bowel disease in a patient with one or more of the first four alarm features. During colonoscopy, biopsies should be performed even if the mucosa is macroscopically normal as these may reveal microscopic colitis or melanosis coli (indicating anthraquinone laxative use). The prevalence of microscopic colitis increases markedly with age being rare under 40 years but accounting for around 1 in 10 of unexplained diarrhea in patients aged > 70 years (28). The term microscopic colitis includes collagenous colitis, 87% of which are female, and lymphocytic colitis, which shows no obvious gender bias (28). If Crohn’s ileitis is suspected (because of, e.g., anemia, elevated CRP), the diagnosis may be confirmed by inspection or biopsy of the terminal ileum during colonoscopy. Barium follow-through or computed tomography (CT) enterography are the alternatives. Imaging should be kept to a minimum to avoid irradiation in patients of childbearing age. Capsule endoscopy should be reserved for those with a high probability of Crohn’s disease in whom other tests are unsuccessful (29). Small intestinal bacterial overgrowth (SIBO) is rare in the absence of achlorhydria, “blind loops,” diverticula, strictures, or severe small intestinal motility disorders (chronic intestinal pseudoobstruction). Proton pump inhibitors and pernicious anemia are the most common causes of achlorhydria. Whether or not primary SIBO (presumably due to abnormal motility) contributes to IBS is controversial but seems unlikely in most individuals. It may be diagnosed in specialist centers by culture of jejunal aspirate. Using this highly specific test, the incidence of SIBO in Rome criteria-positive IBS patients is only 4% (30). The glucose breath hydrogen test is much easier for the patient but much less reliable with a poor sensitivity and specificity at 41.7 and 44.4%, respectively (31). Bile acid malabsorption (BAM) is also rare and most reliably diagnosed by measuring the percent retention of Selenium75 homocholic acid taurine at 7 days after dosing (Selenium-75- Homocholic Acid Taurine (SeHCAT) test). Values < 5% are often seen with acute onset, often in postinfectious BAM and such low values predict a good response to cholestyramine (32). Values between 5 and 10% are also abnormal but only 50% respond to cholestyramine. If SeHCAT is unavailable, a trial of cholestyramine is a reasonable alternative. BAM is characterized by nocturnal symptoms with stool weights > 250 g (33). The precise incidence of celiac disease and giardiasis depends on where the patient lives or originated from, but in many countries these diseases are more prevalent than inflammatory bowel disease. Colon cancer is rare below the age of 40 years, and in Asia. If there are no alarm features, then a limited screen for disorders that may accompany or masquerade as IBS may still be required. Most guidelines (18,19) recommend a CBC, and serological testing for celiac disease especially in patients with diarrhea or mixed bowel habit. The cause of any anemia should be fully elucidated before a diagnosis of IBS is made. In many adult females, anemia will be related to menstrual loss but other causes should be excluded. In children, a CBC is highly sensitive and moderately specific for inflammatory bowel disease (34). CRP > 5 mg/l has low sensitivity (50%) but good specificity (81%) for inflammatory bowel disease and should also be measured if diarrhea is present (35). The value VOLUME 105 | APRIL 2010 www.amjgastro.com

8. 9.

of screening for celiac disease depends on the prevalence in the underlying population. In northwest Europe, the prevalence is around 1% of the population, and in an unselected IBS population meeting Rome II criteria, the prevalence was 4.6% (36). If celiac disease is present, the response to a gluten-free diet may indicate the extent to which the disease was causing the IBS-like symptoms. If the limited screen reveals one or more positive test results, then further investigations are required (as per Box #4). If the patient’s symptoms fulfill the Rome III criteria for IBS (see below), there are no alarm features (see annotation #3 above), and the results of the limited screening investigations are negative, then a diagnosis of IBS can be made. The Rome III diagnostic symptom criteria for IBS are: (1) recurrent abdominal pain or discomfort at least 3 days a month in the last 3 months with two or more of the following: (i) improvement with defecation; (ii) onset associated with a change in frequency of stool; (iii) onset associated with a change in form (appearance) of stool, and (2) criterion fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. On factor analysis of patients and the general population, these criteria cluster together (37). There are associated symptoms that occur in IBS but are not specific enough to be included in the criteria. These include the sensations of bloating, incomplete evacuation, straining or urgency, and the presence of increased passage of gas and burping. The presence of extra-intestinal symptoms, common in IBS, should also be assessed, as they must be managed as well. They include symptoms such as lethargy, headache, palpitation, dyspnea, backache, dyspareunia, and dysmenorrhea. Around 10% of IBS patients report that their symptoms began with an acute bacterial enteric infection (38). The significance of the diagnosis of IBS should be explained to the patient, emphasizing that other diagnoses are very unlikely now and/or in the future. The pattern of symptoms and their relation to certain precipitants may indicate the influence of stress or diet. Many patients ask whether their diet is important, particularly whether they might be lactose intolerant. The prevalence of lactose intolerance differs greatly by race (90% in Chinese, 60% in Asians, 40% in Eastern Mediterranean people). In northwest Europe, only 10% of people are lactose intolerant (39). Many sufferers recognize the link with dairy products and avoid them. Symptoms of lactose intolerance include abdominal pain,

flatulence, and diarrhea. However, the incidence of lactose intolerance in IBS patients is similar to that of healthy people (40). The effects of lactose are dose related and unless subjects take > 240 ml of milk or its equivalent daily, lactose intolerance is unlikely to be the cause of their symptoms (41). It is important to also consider the potential role of fructose and related substances. There has been a recent substantial increase in ingestion of fructose particularly in soft drinks. As fructose is poorly absorbed, large amounts can overwhelm the absorptive capacity of the small intestine leading to flatulence and diarrhea (42). Exclusion diets sometimes indicate that wheat and dairy products cause diarrhea or bloating and dietary adjustments can lead to long-term improvements (43,44). 10. In many cases, it is useful to determine the subtype of IBS, according to the bowel habit, at the time of the visit. In the Rome III classification, this is based on the Bristol Stool Form Scale (BSFS) (Diagram 1). The accompanying diagram (Diagram 2) illustrates how the scale may be used to identify IBS with diarrhea, IBS with constipation, mixed IBS (IBS-M), in which both are present at different times, and untyped IBS (IBS-U), in which neither are present. Patients with IBS show great variability in the timing of defecation and in the consistency of stool (45). There may be uncertainty about bowel pattern as IBS symptoms typically fluctuate with flares averaging 5 days (3). In such a case, a 2-week diary using the BSFS can help determine the predominant bowel pattern, and thus guide treatment. 11–13. The Bristol Stool Form Scale (BSFS) is used in the Rome III diagnostic criteria to identify the stool form of IBS patients. Repeated use of this scale over longer periods can identify patients whose bowel habit alternates IBS (IBS-A). The precise distribution of the IBS subtypes varies in different populations. In one large survey, the most frequent subtype was IBS-M at 46%, IBS-C 17%, IBS-D 32% and 3.9% being unclassified (46). This is important because approximately one-third of the patients switch subtypes between IBS-D and IBS-C over 1 year (IBS-A), and up to 75% switch from diarrhea or constipation to a mixed pattern (47). However, as several proposed IBS drugs target altered bowel habit, this subtyping can help the gastroenterologist choose the appropriate treatment at the time of consultation. As the subtype can change, the patient and doctor should be prepared to change the drug or other treatment over time.

Bristol Stool Form Scale Type 1 Separate hard lumps, like nuts, hard to pass Type 2 Sausage shaped, but lumpy Type 3 Like sausage, but with cracks on surface Type 4 Like sausage or snake, smooth and soft Type 5 Soft blobs with clear-cut edges Type 6 Fluffy pieces with ragged edges, a mushy stool Type 7 Watery, no solid pieces, entirely liquid

Diagram 1. This shows the Bristol stool form scoring system with both visual illustrations and verbal descriptions, which are easy for patients to use to describe their stool consistency.



779

BOWEL DISORDERS

Bowel Disorders

780


% Hard or lumpy stools

BOWEL DISORDERS

100

75

50

IBS-C

IBS-M

IBS-U

IBS-D

25

0 0

25

50

75

100

% Loose or watery stools Diagram 2. Diagram 2 illustrates how the scale may be used to identify irritable bowel syndrome (IBS) with constipation (IBS-C), IBS with diarrhea (IBS-D), IBS with a mixed pattern (IBS-M, that is, IBS with both stool types 1/2 and 6/7 > 25% of the time) and unsubtyped IBS (IBS-U, with neither > 25% of the time). This permits subtyping of patients with IBS into IBS-C, IBS-D, IBS with a mixed pattern, and an undetermined group in which no bowel habit pattern dominates. Serial observations are necessary to determine those with an alternating pattern in which bowel habit changes over weeks or months (IBS-A).

CHRONIC PAINLESS DIARRHEA Case history

A 27-year-old accountant is referred to a gastroenterologist because of a 2-year history of frequent watery stools (Box 1, Figure 2). He has a bowel movement of five to six times per day, often with marked urgency but no episodes of fecal incontinence. He usually needs to have a bowel movement immediately on waking, and then again several times in the morning at short intervals; on each occasion, there is only a small amount of stool, but it is always watery or very loose. The gastroenterologist shows the patient the BSFS, and the patient states that his stools always conform to stool type 6 or 7 of the BSFS. There are no features of steatorrhea, neither does the patient have abdominal pain, nausea, vomiting, or anorexia (Box 2). There is no blood or mucus in the stools, no abdominal pain, and he has not lost weight since the symptoms began; the urge to defecate rarely awakens him at night (Box 3). The diarrhea came on relatively suddenly without any obvious precipitant, such as an episode of gastroenteritis, a course of antibiotics, or a severe stressful event, and the pattern has not changed over the 2 years. He has no other significant illnesses and no previous surgery. There is no relevant family history of gastrointestinal or other disease. Twelve months ago his primary care physician had arranged for routine hematology and biochemistry that was normal. The patient had also tried loperamide briefly, but found it difficult to adjust the dose of this medication in order to avoid developing constipation. The patient denies using any drugs including laxatives. He does not smoke but drinks up to 30 g alcohol daily. His lactose intake is limited to one small glass of milk per day, and he does not consume The American Journal of GASTROENTEROLOGY

caffeine-containing drinks, candies, artificial sweeteners, or preserves. On questioning, he describes his job as being very stressful, and he is worried about losing his current position in the company. The worry causes him to sleep poorly and he finds it difficult to cope with his 3-year-old daughter (Box 2). Physical examination is negative. Blood pressure is 125/75, and the pulse rate 70 per min. There is loose stool present on rectal examination (BSFS 6), but anal sphincter tone appears normal with satisfactory voluntary squeeze pressure (Box 2). The gastroenterologist arranges for a further set of screening tests including CBC, erythrocyte sedimentation rate, urea and electrolytes, calcium, thyroid stimulating hormone, and celiac serology (tissue transglutaminase/endomysial antibody), as well as three stool examinations for parasites (Box 5). All these investigations are within normal limits (Box 6). Because of the length of the history and severity of the diarrhea, he decides to perform colonoscopy. This is normal and biopsy shows no colonic mucosal inflammation or melanosis coli. The patient admits to no risk factors for HIV infection. Noting that the patient remains quite anxious, the gastroenterologist asks him to complete the Rome III Psychosocial Alarm Questionnaire, which indicates the presence of anxiety. A provisional diagnosis of functional diarrhea is made and the gastroenterologist explains this diagnosis to the patient (Box 10). The gastroenterologist reassures him that there are drugs available to control the symptoms of diarrhea, and that he will follow the patient to guide treatment and be alert to any important changes. The gastroenterologist also discusses the role of anxiety in possibly contributing to his symptoms. When the patient acknowledges this VOLUME 105 | APRIL 2010 www.amjgastro.com

association, the doctor recommends counseling and/or services of a mental health professional, and the patient agrees. When the patient is no better after 1 month with regular and carefully titrated doses of antidiarrheal agents, and reduction of alcohol intake, the gastroenterologist arranges for further tests

(Boxes 11 and 12). A duodenal biopsy is negative. A trial of cholestyramine fails to improve the diarrhea. computed tomography scan of the abdomen is normal. Laxative screen is negative. The diagnosis of functional diarrhea is confirmed and continued management focuses on anxiety reduction (Box 14).

1 Patient with frequent loose, watery stools, without abdominal pain

5

2 History and physical examination including stool examination

10 Screening tests: CBC, ESR/CRP, urea and electrolytes, calcium, TSH, tTGA/ EMA, stool for ova, cysts, parasites X3, +/–colonoscopy and biopsy, excluded drugs

Provisional diagnosis of functional diarrhea


no

Reassure, explain, try lifestyle/diet advice/exclusion

14 11 Symptom improvement?

yes

Functional diarrhea

yes no

7 Further tests: 3 Alarm features?

e.g., duodenal biopsy, small bowel imaging, colonoscopy, and biopsies, if not already done

no

12 Further tests if not already done: e.g., colonoscopy, SeHCAT or trial cholestyramine, CT abdomen, test for laxatives

yes

no

8 4 Investigations as indicated: CBC, ESR/CRP, urea and electrolytes, calcium, TSH, tTGA/EMA, stool for ova,cysts,parasites X3, C. difficile, colonoscopy and colonic biopsies, duodenal biopsy, small bowel imaging, glucose hydrogen breath test, SeHCAT or trial of cholestyramine/metronidazole


13

no


yes 9

Celiac disease, giardiasis, IBD, microscopic colitis, bile acid malabsorption, SIBO, colon neoplasia / villus adenoma, neuroendocrine tumor, laxative abuse

yes

Figure 2. Chronic painless diarrhea. Figure 2. Legend 1.

2.

The pattern and type of diarrhea should be noted, with particular attention to the stool form, possible steatorrhea, an estimate of whether the stool volume is low or high, and the presence of any alarm features (see below). The presence or absence of associated abdominal pain should be established. If pain is present, one should consider the possibility of irritable bowel syndrome with diarrhea (IBS-D) (see Figure 1). The patient should be asked about the presence of urgency and/or incontinence as these have a strong impact on quality of life. Some patients may be too embarrassed to describe these symptoms. The gastroenterologist should enquire whether the diarrhea began with an acute infectious illness suggesting postinfective bowel dysfunction (38), or if any other precipitating factors can be implicated. A past history of gastrointestinal surgical procedures or a new medication including antibiotics at onset of symptoms might suggest an etiology. A dietary history should note the excessive intake of foods with laxative potential such as diets high in fiber, fruit or laxative agents such as sorbitol (in chewing gum) or certain fructose-containing fruits such as plums and cherries (48). The Bristol Stool Form Scale (BSFS) can be used to confirm the patient’s current and most usual stool form. During physical examination,


3.

4.

one should look specifically for signs of organic disease including inflammatory bowel disease (abdominal mass, anemia, clubbing) and malabsorption (anemia, peripheral edema, angular stomatitis, ridged nails, leuconychia). Digital rectal examination should include an assessment of anal sphincter tone. One should confirm the exact nature of the stool in the toilet or through rectal examination or stool collection. The presence of any alarm features, especially rectal bleeding, weight loss, nocturnal diarrhea, or family history of colon cancer should be established (18,19). Recent antibiotic use may be followed by Clostridium difficile colitis. Age > 50 years and/or recent onset of symptoms and/or an apparent high stool volume may also signal the need for further investigation. In the presence of one or more alarm features, further testing is indicated. These tests will be guided by the history, including where the patient lives or has traveled. They include complete blood count (CBC), erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), urea and electrolytes, serum calcium, thyroid stimulating hormone (TSH), celiac serology, stool examination for infections including C. difficile if there is a history of recent antibiotic use, colonoscopy and biopsy, and duodenal biopsy. The clinician should The American Journal of GASTROENTEROLOGY

781

BOWEL DISORDERS

Bowel Disorders

BOWEL DISORDERS

782


estimate the stool volume particularly if it is watery in consistency. As this can be inaccurate, if a large volume is suspected, a 3-day stool collection to measure weight and other tests (e.g., for laxatives, stool electrolytes, or fat) should be performed. If the weight is high (e.g., > 350 g/day), further stool testing and other diagnostics should be considered (33). More specialized testing may involve small bowel and other intra-abdominal imaging, glucose hydrogen breath test, or SeHCAT/trial of cholestyramine (32). For further details of these investigations, see the legend to the previous algorithm. Further studies, e.g., red cell folate, serum B12, serum proteins, or other tests, may be performed as indicated. Results of these tests may enable diagnosis of a variety of disorders (Box 9). 5. If there are no alarm features, a more limited panel of tests is appropriate, namely the blood and stool tests detailed above. It is important at this stage to firmly exclude the possibility of a drug-related diarrhea (e.g., magnesium containing antacids, lipase inhibitors such as orlistat, colchicine, misoprostil, prokinetics such as erythromycin and metoclopramide, and broad spectrum antibiotics). Colonoscopy or sigmoidoscopy, and biopsy may also be indicated at this stage depending on the particular clinical features of the case. 6 – 8. Abnormalities on the above tests may reveal a specific diagnosis, or require further investigation, such as duodenal biopsy to exclude celiac disease, or colonoscopy with terminal ileum inspection and biopsy to exclude Crohn’s disease (if not already carried out). 9. One of a number of disorders may be diagnosed based on the investigations performed to date. Further details of these disorders are provided in the legend to the previous algorithm. 10. If the results of relevant investigations are normal or negative, a provisional diagnosis of functional diarrhea is justified. The gastroenterologist should explain the implications of this diagnosis to the patient. He or she should reassure the patient that no structural disease has been found and that some cases spontaneously improve

11. 12.

13. 14.

eventually (49). Advice should be offered on reduction of potentially laxative elements from the diet (e.g., bran and certain fruits containing fructose and oligosaccharides) (50), and reduction of alcohol intake. Avoidance of dairy products may be helpful if > 240 ml of milk or its equivalent are consumed daily (41). A stool diary noting when flares occur may give a hint as to possible aggravating factors to be avoided. A trial of loperamide therapy is justified (51). If there is improvement with the above measures, the diagnosis of functional diarrhea can be made (see below, no. 14). If there is no improvement, further tests may be indicated such as the SeHCAT test for bile acid malabsorption, or colonoscopy and biopsy for microscopic colitis (28) and melanosis coli, if not already undertaken. A laxative screen should be considered, as secretive laxative abuse is a form of factitious illness and explains some cases of persistent diarrhea (52). If it has not already been undertaken, an assessment of psychological symptoms may be warranted using the Rome III Psychosocial Alarm Questionnaire (Appendix A), as anxiety, particularly about incontinence, may itself cause frequent defecation. The above investigations may provide a diagnosis, as listed in Box 9. Improvement in the diarrhea with lifestyle and dietary advice, or no abnormalities detected on further testing, support the diagnosis of functional diarrhea. The Rome III diagnostic criteria for functional diarrhea (7) are: (1) loose (mushy) or watery stools without pain occurring in at least 75% of stools, and (2) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. According to surveys using earlier versions of the Rome criteria, functional diarrhea is present in < 2% of the general population, and is uncommon in the clinic. Treatment is with loperamide and dietary restriction of foods with laxative properties. Specialized dietary advice can be helpful. Many cases remit eventually (52) but more studies are required.

CHRONIC CONSTIPATION Case history

A 40-year-old hairdresser is referred to a gastroenterologist by her primary care physician because of longstanding infrequent hard stools (Box 1, Figure 3). She defecates on average twice a week, and on most occasions this requires considerable straining. The stools consist of small hard pellets, never loose and watery unless she uses laxatives. The gastroenterologist shows the patient the BSFS, and the patient indicates that her stools usually conform to stool type 1 or 2 of the BSFS. These symptoms have been present for 8 years, but have become gradually more severe and troublesome over the last 2 years. She denies the need to manually disimpact herself, and does not describe a sensation of something blocking the passage of the stool. There is no abdominal pain, but she experiences abdominal bloating several times a week (Box 2). She has had no weight loss (Box 3). Her periods are very heavy and last 7 days. She smokes five cigarettes daily and does not drink alcohol. She takes no constipating drugs (Box 7). She has two children, both delivered vaginally without complication. She denies depression and describes an active social life. Dietary review indicates her fiber intake to be 15–20 g daily. There is nothing relevant in her past medical history, and no family history of constipation, bowel cancer, or other gastrointestinal disease. Physical examination is negative, including the abdominal examination. Small hemorrhoids are evident on anal inspection,


and digital rectal examination reveals only hard stool. In particular, anal sphincter tone is normal, and simulated evacuation is accompanied by relaxation of the puborectalis muscle with normal perineal descent (Box 2). The patient has tried a number of overthe-counter preparations, including stool softeners and herbal teas, but these have not been very effective. Recently, she has found that if she takes two bisacodyl tablets in the morning, she can sometimes have a more complete motion later in the day, but the improvement is short-lived. A CBC is normal. In the absence of evidence suggesting pelvic floor dysfunction or colonic inertia (see “refractory constipation and difficult defecation” algorithm following), the gastroenterologist makes a diagnosis of functional constipation (Box 11). He explains the possible mechanisms for the constipation, and suggests that she gradually increase her dietary fiber intake, and commence a low dose of psyllium, slowly increasing this over several months with adequate fluid intake (Box 12). He indicates that she may add a polyethylene glycol (PEG) preparation if needed. After 3 months, she reports significant improvement in her stool form and straining, and she defecates three or four times weekly (Box 13). She has been taking psyllium on a regular basis, with the addition of a PEG preparation as required, and is happy to continue to do this in the longer term (Box 14).


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Patient with infrequent, and/or hard stools and/or difficult to pass stools when not on laxatives

10 9

8 Stop drugs if possible

2 History and physical examination

yes


Drug-induced constipation

no

yes

11

7

3 Alarm features?

no

Constipating drugs?

Functional constipation

no

yes 4

12 Investigations as indicated e.g., colonoscopy, metabolic screen

Explanation physiology, modify lifestyle and diet, discuss bulking agents, simple laxatives 15


no

13 no


yes

yes

6 Colorectal cancer or other obstructing lesion, anorectal disease, hypothyroidism, hypercalcemia

Refer for consideration of physiological assessment (anorectal function, colonic transit); see “refractory constipation and difficult defecation” algorithm

14 Formulate longer-term management plan

Figure 3. Chronic constipation. Figure 3. Legend 1.

2.

3.

A detailed description of the patient’s defecation pattern should be obtained. In addition to stool frequency, form, and effort, a sensation of incomplete evacuation should be noted. The need to digitate manually to expel stool and prolonged straining are features that may suggest a defecation disorder. The Bristol Stool Form Scale (BSFS) can be used to confirm the patient’s current and most usual stool form. Furthermore, abdominal pain is not necessarily a feature of chronic constipation, but if present, the diagnosis could be irritable bowel syndrome with constipation (IBS-C) (see Figure 1). The history should include precipitating factors occurring at the onset of symptoms including any new constipating drugs, and an estimation of dietary fiber intake. Any changes in exercise or lifestyle should also be noted. General inspection of the patient may reveal evidence of anemia or occasionally hypothyroidism. A complete examination of the abdomen including digital rectal examination should be performed. Anal sphincter tone should be assessed, both at rest and during squeeze. The normal relaxation of the puborectalis muscle and perineal descent should be assessed during simulated evacuation. If relaxation of the puborectalis or perineal descent cannot be demonstrated, a defecation disorder may be present; see “Refractory Constipation and Difficult Defecation” algorithm below. The most important alarm features include a recent change in bowel habit, weight loss, family history of colorectal cancer, rectal bleeding, or age > 50 years.


4.

If there are one or more alarm features, colonoscopy is the most important investigation. Complete blood count (CBC) and erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) help exclude occult anemia or inflammation. Metabolic screening for hypothyroidism and hypercalcemia can be performed, especially if there are any clinical indicators, but rarely alters management (23). 5–6. Colon cancer is rare under the age of 50 years (53). Melanosis coli is a distinctive pigmentation of the colon mucosa that is seen in some patients at the time of colonoscopy and indicates chronic anthraquinone laxative use (54). Borderline hypothyroidism is common in the general population, but rarely presents as constipation in the absence of other features of thyroid disease such as lethargy, cold intolerance, and weight gain (55). Hypercalcemia is also associated with constipation though rarely in the absence of other symptoms of the underlying disease such as back pain or anemia in a person with myeloma (56). 7. If there are no alarm features, or no abnormalities are detected on further investigations, the potential for any drug effects should be considered. Constipating drugs include opiates such as codeine, morphine, tramadol and dihydrocodeine, tricyclic antidepressants, calcium containing antacids, iron preparations, chemotherapy (e.g., sorafenib, cladribine), and antipsychotics (e.g., chlorpromazine, sulpiride). 8–10. If a drug suspected of causing or exacerbating the constipation can be ceased, and if the constipation improves on its withdrawal, The American Journal of GASTROENTEROLOGY

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a diagnosis of drug-induced constipation is justified. Switching to non-constipating analgesics such as mefenamic acid or other NSAIDs may be helpful. Opioid detoxification may require more intensive treatment. Clonidine may aid opiate withdrawal as may the substitution of non-opiate analgesics such as pregabalin. Combining centrally acting opioids with naloxone or with peripherally acting opioid antagonists, if available, should also be considered. Recently, methylnaltrexone has been shown effective for opiate-induced constipation in malignant disease (57). 11. If there are no suspect drugs, or if drug withdrawal fails to improve the constipation, and if there are no alarm features, then a diagnosis of functional constipation can be made. Rome III diagnostic criteria for functional constipation (1) are: (1) two or more of the following: (a) straining during at least 25% of defecations, (b) lumpy or hard stools in at least 25% of defecations, (c) sensation of incomplete evacuation for at least 25% of defecations, (d) sensation of anorectal obstruction/blockage for at least 25% of defecations, (e) manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuations, support of the pelvic floor), (f) fewer than three defecations per week; (2) loose stools rarely present without the use of laxatives; (3) insufficient criteria for IBS; and (4) criteria fulfilled for at least 3 months with symptom onset at least 6 months before diagnosis. Functional constipation as defined by Rome criteria affects around 8% of the population (7). The main aim of treatment should be to minimize medication and rely in the long term on behavioral and dietary measures. Most placebo-controlled trials show that symptoms of those on placebo treatment approaches those in the treatment arm after around 3 months, suggesting that with proper


Guarantor of the article: The Rome Foundation. Specific author contributions: Writing and revising: Robin C. Spiller and W. Grant Thompson. Financial support: This work was sponsored by a grant from the Rome Foundation. Potential competing interests: None. REFERENCES 1. Costanza CD, Longstreth GF, Liu AL. Chronic abdominal wall pain: clinical features, health care costs, and long-term outcome. Clin Gastroenterol Hepatol 2004;2:395–9. 2. Gregory PL, Biswas AC, Batt ME. Musculoskeletal problems of the chest wall in athletes. Sports Med 2002;32:235–50. 3. Hahn B, Watson M, Yan S et al. Irritable bowel syndrome symptom patterns: frequency, duration, and severity. Dig Dis Sci 1998;43:2715–8. 4. Ford AC, Talley NJ, Veldhuyzen Van Zanten SJ et al. Will the history and physical examination help establish that irritable bowel syndrome is causing this patient’s lower gastrointestinal tract symptoms? JAMA 2008;300: 1793–805. 5. Connell AM, Hilton C, Irvine G et al. Variation of bowel habit in two population samples. Br Med J 1965;2:1095–9. 6. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol 1994;19:28–30. 7. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91. 8. Probert CS, Emmett PM, Cripps HA et al. Evidence for the ambiguity of the term constipation: the role of irritable bowel syndrome. Gut 1994;35:1455–8. 9. Accarino A, Perez F, Azpiroz F et al. Abdominal distention results from caudo-ventral redistribution of contents. Gastroenterology 2009;136:1544–51. 10. Houghton LA, Lea R, Agrawal A et al. Relationship of abdominal bloating to distention in irritable bowel syndrome and effect of bowel habit. Gastroenterology 2006;131:1003–10. 11. Agrawal A, Houghton LA, Lea R et al. Bloating and distention in irritable bowel syndrome: the role of visceral sensation. Gastroenterology 2008;134:1882–9. The American Journal of GASTROENTEROLOGY

instruction, constipation can be managed without drugs most of the time. Careful explanation of the importance of regular meals containing adequate amounts of dietary “fiber” or adequate amounts of small, poorly absorbed sugars such as fructose or sorbitol. Adequate time and posture for defecation should be explained to the patient as well as the optimal timing. For example, it is advantageous to attempt defecation 30–60 min after a meal when the gastrocolonic reflex may activate colonic mass movements and aid defecation. Simple bulking agents such as ispaghula husk or psyllium may help increase stool volume and soften stool. Bulkier stools are more easily passed than small ones (58). Polyethylene glycol (PEG) solutions have been shown in several randomized placebo-controlled trials to be effective even with fecal impaction (59). Stimulant laxatives such as senna or osmotic laxatives such as lactulose can cause pain (60) and may result in watery stool followed by several days with no bowel movement. This may be misinterpreted as constipation leading to further doses and excessive laxation. 14. Improving symptoms reinforce the diagnosis of functional constipation, and at this stage, a longer-term management plan should be devised. 15. If the constipation fails to improve, and the patient describes very infrequent stools and/or difficult defecation, particularly a sense of anorectal blockage and/or the need for anal digitation during defecation, he or she should be referred for a study of anorectal function and colonic transit. This may determine whether he or she has disordered defecation, or slow colonic transit, or both, underlying their constipation (see “refractory constipation and difficult defecation” algorithm).

12. Sykes MA, Blanchard EB, Lackner J et al. Psychopathology in irritable bowel syndrome: support for a psychophysiological model. J Behav Med 2003;26:361–72. 13. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983;67:361–70. 14. Kroenke K, Spitzer RL, Williams JB. The PHQ-15: validity of a new measure for evaluating the severity of somatic symptoms. Psychosom Med 2002;64:258–66. 15. North CS, Downs D, Clouse RE et al. The presentation of irritable bowel syndrome in the context of somatization disorder. Clin Gastroenterol Hepatol 2004;2:787–95. 16. Levy RL, Olden KW, Naliboff BD et al. Psychosocial aspects of the functional gastrointestinal disorders. Gastroenterology 2006;130: 1447–58. 17. Ragnarsson G, Bodemar G. Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS). Patients’ description of diarrhea, constipation and symptom variation during a prospective 6-week study. Eur J Gastroenterol Hepatol 1998;10:415–21. 18. Brandt LJ, Chey WD, Foxx-Orenstein AE et al. An evidence-based position statement on the management of irritable bowel syndrome. Am J Gastroenterol 2009;104 (Suppl 1): S1–35. 19. Spiller R, Aziz Q, Creed F et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007;56:1770–98. 20. Kruis W, Thieme C, Weinzierl M et al. A diagnostic score for the irritable bowel syndrome. Its value in the exclusion of organic disease. Gastroenterology 1984;87:1–7. 21. Vanner SJ, Depew WT, Paterson WG et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol 1999;94:2912–7. 22. Sloth H, Jorgensen LS. Chronic non-organic upper abdominal pain: diagnostic safety and prognosis of gastrointestinal and non-intestinal symptoms. A 5- to 7-year follow-up study. Scand J Gastroenterol 1988;23:1275–80. 23. Cash BD, Schoenfeld P, Chey WD. The utility of diagnostic tests in irritable bowel syndrome patients: a systematic review. Am J Gastroenterol 2002;97:2812–9. 24. Goka AK, Rolston DD, Mathan VI et al. The relative merits of faecal and duodenal juice microscopy in the diagnosis of giardiasis. Trans R Soc Trop Med Hyg 1990;84:66–7. VOLUME 105 | APRIL 2010 www.amjgastro.com

25. Weitzel T, Dittrich S, Mohl I et al. Evaluation of seven commercial antigen detection tests for Giardia and Cryptosporidium in stool samples. Clin Microbiol Infect 2006;12:656–9. 26. Nagaty IM, Hegazi MM. Dot-ELISA copro-antigen and direct stool examination in diagnosis of giardiasis patients. J Egypt Soc Parasitol 2007;37:641–8. 27. Hamm LR, Sorrells SC, Harding JP et al. Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome Criteria. Am J Gastroenterol 1999;94:1279–82. 28. Pardi DS, Loftus EV Jr, Smyrk TC et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut 2007;56:504–8. 29. Solem CA, Loftus EV Jr, Fletcher JG et al. Small-bowel imaging in Crohn’s disease: a prospective, blinded, 4-way comparison trial. Gastrointest Endosc 2008;68:255–66. 30. Posserud I, Stotzer PO, Bjornsson ES et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut 2007;56:802–8. 31. Berthold HK, Schober P, Scheurlen C et al. Use of the lactose-[13C]ureide breath test for diagnosis of small bowel bacterial overgrowth: comparison to the glucose hydrogen breath test. J Gastroenterol 2009;44:944–51. 32. Williams AJK, Merrick MV, Eastwood MA. Idiopathic bile acid malabsorption—a review of clinical presentation, diagnosis, and response to treatment. Gut 1991;32:1004–6. 33. Sinha L, Liston R, Testa HJ et al. Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. Aliment Pharmacol Ther 1998;12:839–44. 34. Cabrera-Abreu JC, Davies P, Matek Z et al. Performance of blood tests in diagnosis of inflammatory bowel disease in a specialist clinic. Arch Dis Child 2004;89:69–71. 35. Tibble JA, Sigthorsson G, Foster R et al. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123:450–60. 36. Sanders DS, Carter MJ, Hurlstone DP et al. Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358:1504–8. 37. Whitehead WE, Crowell MD, Bosmajian L et al. Existence of irritable bowel syndrome supported by factor analysis of symptoms in two community samples. Gastroenterology 1990;98:336–40. 38. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology 2009;136:1979–88. 39. Simoons FJ. The geographic hypothesis and lactose malabsorption a weighing of the evidence. Dig Dis Sci 1978;23:963–79. 40. Tolliver BA, Jackson MS, Jackson KL et al. Does lactose maldigestion really play a role in the irritable bowel? J Clin Gastroenterol 1996;23:15–7. 41. Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported severe lactose intolerance. N Engl J Med 1995;333:1–4. 42. Shepherd SJ, Parker FC, Muir JG et al. Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin Gastroenterol Hepatol 2008;6:765–71.


43. Atkinson W, Sheldon TA, Shaath N et al. Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial. Gut 2004;53:1459–64. 44. Nanda R, James R, Smith H et al. Food intolerance and the irritable bowel syndrome. Gut 1989;30:1099–104. 45. Heaton KW, Ghosh S, Braddon FE. How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form. Gut 1991;32:73–9. 46. Tillisch K, Labus JS, Naliboff BD et al. Characterization of the alternating bowel habit subtype in patients with irritable bowel syndrome. Am J Gastroenterol 2005;100:896–904. 47. Drossman DA, Morris CB, Hu YM et al. A prospective assessment of bowel habit in irritable bowel syndrome in women: defining an alternator. Gastroenterology 2005;128:580–9. 48. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome: guidelines for effective dietary management. J Am Diet Assoc 2006;106:1631–9. 49. Afzalpurkar RG, Schiller LR, Little KH et al. The self-limited nature of chronic idiopathic diarrhea. N Engl J Med 1992;327:1849–52. 50. Parker TJ, Naylor SJ, Riordan AM et al. Management of patients with food intolerance in irritable bowel syndrome: The development and use of an exclusion diet. J Hum Nutrit Diet 1995;8:159–66. 51. Lavo B, Stenstam M, Nielsen AL. Loperamide in treatment of irritable bowel syndrome—a double-blind placebo controlled study. Scand J Gastroenterol Suppl 1987;22:77–80. 52. Read NW, Krejs GJ, Read MG et al. Chronic diarrhea of unknown origin. Gastroenterology 1980;78:264–71. 53. Jemal A, Siegel R, Ward E et al. Cancer statistics. CA Cancer J Clin 2007;57:43–66. 54. da Silva JG, De Brito T, Cintra Damiao AO et al. Histologic study of colonic mucosa in patients with chronic diarrhea and normal colonoscopic findings. J Clin Gastroenterol 2006;40:44–8. 55. Al-Sultan AI, Larbi EB, Magbool G et al. Clinical presentation of spontaneous primary hypothyroidism in adults. Ann Saudi Med 1995;15:143–7. 56. Lamy O, Jenzer-Closuit A, Burckhardt P. Hypercalcaemia of malignancy: an undiagnosed and undertreated disease. J Intern Med 2001;250:73–9. 57. Thomas J, Karver S, Cooney GA et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med 2008;358:2332–43. 58. Bannister JJ, Davison P, Timms JM et al. Effect of stool size and consistency on defecation. Gut 1987;28:1246–50. 59. DiPalma JA, Cleveland MV, McGowan J et al. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007;102:1436–41. 60. Passmore AP, Wilson-Davies K, Stoker C et al. Chronic constipation in long stay elderly patients: a comparison of lactulose and a senna-fibre combination. BMJ 1993;307:769–71.Simoons FJ. The geographic hypothesis and lactose malabsorption a weighing of the evidence. Dig Dis Sci 1978;23:963–79.


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Anorectal Disorders Adil E. Bharucha, MD, MBBS1 and Arnold M. Wald, MD2 Am J Gastroenterol 2010; 105:786–794; doi:10.1038/ajg.2010.70

ANORECTAL SYMPTOMS Despite advances in diagnostic tests, a clinical interview is essential for characterizing the presence and severity of symptoms, establishing rapport with patients, selecting diagnostic tests, and guiding therapy. Although anorectal testing is necessary to diagnose defecatory disorders, a careful interview and examination often suffice for the initial management of fecal incontinence (FI). The emphasis here is on the patient’s dietary and bowel habits, as many anorectal symptoms are a consequence of disordered bowel habits (e.g., FI for semi-formed or liquid stools). When possible, bowel habits should be characterized by bowel diaries and by pictorial stool scales (1). Anorectal symptoms may be broadly characterized into constipation, FI, and anorectal pain. Constipation

As discussed in the section on bowel disorders, patients may refer to a variety of symptoms by the term “constipation.” Anecdotal experience and some evidence suggest that certain symptoms (e.g., sense of anorectal blockage and anal digitation during defecation) are more suggestive of a defecatory disorder than others (e.g., sense of incomplete evacuation after defecation and excessive straining) (2,3). In addition to impaired rectal emptying, the sense of incomplete evacuation may also reflect rectal hypersensitivity (e.g., irritable bowel syndrome). Other symptoms (e.g., hard and/or infrequent stools) are perhaps more suggestive of normal or slow transit constipation rather than defecatory disorders. As even normal subjects may struggle to expel small hard pellets, difficulty in evacuation of soft, formed, or more so, liquid stools is more suggestive of an evacuation disorder. However, functional defecation disorders often cannot be distinguished from other causes of chronic constipation by symptoms alone. As such, anorectal testing should be considered, particularly in patients who fail to respond to fiber supplementation and empiric laxative therapy. Fecal incontinence

Fecal incontinence refers to the recurrent uncontrolled passage of liquid or solid fecal material. Although distressing, involuntary passage of flatus alone should not be characterized as FI, because it is difficult to define when the passage of flatus is abnormal (4). Patients should be asked if they have FI, because more than 50% of patients will not disclose the symptom unless specifically asked (5). The frequency, amount (i.e., small stain, moderate amount (i.e., more than

a stain but less than a full bowel movement), or a large amount (i.e., full bowel movement)), type of leakage, and presence of urgency should be ascertained. Semi-formed or liquid stools pose a greater threat to pelvic floor continence mechanisms than formed stools, whereas incontinence for solid stool suggests more severe sphincter weakness than for liquid stool. The awareness of the desire to defecate before the incontinent episode is variable, and may also provide clues to pathophysiology. Patients with urge incontinence experience the desire to defecate, but cannot reach the toilet on time. Patients with passive incontinence are not aware of the desire to defecate before the incontinent episode. Patients with urge incontinence have reduced squeeze pressures (6), and/or squeeze duration (7), and/or reduced rectal capacity with rectal hypersensitivity (8), whereas patients with passive incontinence have lower resting pressures (6). Nocturnal incontinence occurs uncommonly in idiopathic FI, and is most frequently encountered in diabetes mellitus and scleroderma. Anorectal pain

As detailed in the algorithm, anorectal pain can be distinguished into levator ani syndrome and proctalgia fugax by distinctive clinical features. This classification system does not include coccygodynia, which refers to patients with pain and point tenderness of the coccyx (9), as a separate entity. Most patients with rectal, anal, and sacral discomfort have levator rather than coccygeal tenderness (10). There are many similarities between clinical anorectal and urogenital disorders characterized by chronic pain. Although the pathophysiology is largely unclear, tenderness to palpation of pelvic floor muscles in chronic pelvic pain and levator ani syndrome may reflect visceral hyperalgesia and/or increased pelvic floor muscle tension (11). Some patients with levator ani syndrome may have increased anal pressures (12). Finally, there is a strong association between chronic pelvic pain and psychosocial distress on multiple domains (e.g., depression and anxiety, somatisation, and obsessive-compulsive behavior) (13); whether this reflects an underlying cause or an effect of pain is unclear.

REFRACTORY CONSTIPATION AND DIFFICULT DEFECATION Case history

A 32-year-old office worker is referred to a gastroenterologist by her primary care physician because of a 3-year history of chronic consti-

1

Clinical and Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, Rochester, Minnesota, USA; 2Section of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. Correspondence: Adil E. Bharucha, MD, MBBS, Professor of Medicine, Mayo Clinic, Clinical and Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.), Rochester, Minnesota 55905, USA. E-mail: [email protected] The American Journal of GASTROENTEROLOGY


pation, which has not responded well to therapy (Box 1, Figure 1). She has on average two bowel movements weekly but these are usually small, of hard or normal consistency, and passed with considerable straining. After attempts at defecation, she is left with a sensation of incomplete evacuation. She has not used manual maneuvers to facilitate defecation. She has no abdominal pain, but does experience abdominal bloating on the day before defecation. There has been no rectal bleeding or weight loss. She is otherwise well, with no known systemic diseases associated with constipation, and has had no pregnancies or pelvic or abdominal surgery. She takes no medications for constipation. There is no family history of gastrointestinal disease. Her physical examination is normal. Digital rectal examination reveals normal anal resting tone and contractile response during squeeze. Simulated evacuation was accompanied not by relaxation but by paradoxical contraction of the puborectalis muscle and no perineal descent. Fiber supplements, polyethylene glycol (PEG) laxative and lactulose, prescribed at various times by her primary care physician, make her feel bloated and uncomfortable with no improvement in her constipation (Box 1). Bisacodyl gives her abdominal cramps, and a trial of lubiprostone made her nauseated, with neither improving her bowel habits. At times when she has not moved her bowels for several days she uses a glycerol suppository to aid evacuation. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), and biochemistry panel, including metabolic screen, arranged by her primary care physician 12 months earlier, were normal. The symptoms were significantly affecting her quality of life and the gastroenterologist decided to arrange for further diagnostic testing. These physiologic tests include assessment of colonic tran-

sit, anorectal manometry, and the rectal balloon expulsion test (Box 2). Anorectal manometry demonstrates a recto-anal profile during expulsion efforts that features an inappropriate contraction of the anal sphincter (increase in anal sphincter pressure) despite an adequate propulsive force (intrarectal pressure of 50 mm Hg). Resting and squeeze anal sphincter pressures are 60 (normal 48–90) and 100 (normal 98–220) mm Hg, respectively. Rectal sensory thresholds for first sensation, the desire to defecate, and urgency are 30, 100, and 160 ml respectively; values above approximately 100, 200, and 300 ml for these thresholds are abnormal (14). The balloon expulsion test reveals that the patient is unable to expel the water-filled (50 ml) balloon within 2 min on each of two attempts (normal < 60 s). Using the Hinton technique for measuring colonic transit, the patient swallowed a capsule containing 24 radio-opaque markers. After 5 days, an abdominal X-ray obtained in the supine position (110 keV) showed three markers remaining in the sigmoid colon and rectum (normal < 5 markers) (Box 3). Thus both anorectal manometry and the balloon expulsion test are abnormal (Boxes 3 and 7). On this basis a diagnosis of a functional defecation disorder is made (Box 8). This disorder is further characterized as functional defecation disorder with normal transit (Boxes 11 and 13). On this basis the patient is referred to the laboratory for anorectal biofeedback therapy. She undergoes five biofeedback sessions during a 5-week period with a trained therapist. Other centers provide a more intensive program with 2–3 sessions daily over 2 weeks. Using biofeedback, she learns to normalize her defecation profile. She reports significant clinical improvement and is now able to expel the balloon within 20 s.

Figure 1. Legend 1. For the initial assessment of chronic constipation, and the diagnosis of functional constipation, see the preceding algorithm “chronic constipation”. Rome III diagnostic criteria for functional constipation (1) are: (i) two or more of the following: (a) straining during at least 25% of defecations, (b) lumpy or hard stools in at least 25% of defecations, (c) sensation of incomplete evacuation for at least 25% of defecations, (d) sensation of anorectal obstruction/blockage for at least 25% of defecations, (e) manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuations and support of the pelvic floor), (f) fewer than three defecations per week; and (ii) loose stools are rarely present without the use of laxatives; (iii) insufficient criteria for irritable bowel syndrome; (iv) criteria fulfilled for at least 3 months with symptom onset at least 6 months before diagnosis. The use of a stool diary incorporating the Bristol Stool Form Scale can provide more information regarding stool frequency, consistency and passage. However, in this context as well as the above information, and the presence or absence of abdominal pain linked to the disordered bowel pattern, the history should particularly establish the presence of other relevant symptoms. These include a sensation of incomplete evacuation, any sensation of anorectal obstruction and the use of manual maneuvers to aid evacuation. The absence of “alarm” features should be confirmed, namely: age > 50 years, short history ( < 6 months), family history of colon cancer, blood in stools, and weight loss (2). Patients who fulfill the criteria for functional constipation and those who have not improved with an increase in dietary fiber and the use of simple laxatives (see “chronic constipation” algorithm), and with no alarm features, often warrant further physiological assessment. Although some physicians may, perhaps for medicolegal reasons, opt in this setting to evaluate for colon cancer with imaging or endoscopy,


there is no evidence to support this practice in the absence of alarm symptoms as the prevalence of colonic neoplastic lesions at colonoscopy is comparable in patients with vs. without chronic constipation (15). 2. The three key physiological investigations are anorectal manometry, the balloon expulsion test, and a colonic transit study. Anorectal manometry is carried out using water perfused or solid-state sensors or more recently by high-resolution manometry. At a minimum, anal-resting and -squeeze pressure, and the recto-anal inhibitory reflex should be assessed during manometry. Recto-anal pressure changes during straining, a maneuver which simulates defecation, should also be assessed when an evacuation disorder is suspected. Anal pressures should preferably be calculated by averaging all four quadrants to account for anal sphincter asymmetry. Variations in patient effort also need to be taken into account. Resting pressures are probably less susceptible to artifact than are squeeze pressures. Squeeze pressure should be measured by asking patients to squeeze (i.e., contract) the sphincter for at least 30 s, and to average pressure over this duration. As anal pressures are affected by age, gender, and technique, measurements ideally should be compared against normal values obtained in age- and gender-matched subjects by the same technique (16–18). The rectal balloon expulsion test, carried out by measuring the time required to expel a rectal balloon filled with 50 ml warm water or air, is a useful, relatively sensitive, and specific test for evacuation disorders (19,20). The balloon inflation volume for this test is not standardized; the balloon is either inflated by a fixed volume, typically 50–60 ml, or until patients experience the desire to defecate. When the balloon is inflated by a fixed volume (e.g., 50–60 ml), as in most laboratories, patients who have reduced rectal sensation may not


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2 Patient meeting criteria for functional constipation with no alarm features and no improvement with high-fiber diet and laxatives

Do physiological testing: anorectal manometry, rectal balloon expulsion, and colonic transit

3 Are anorectal manometry and rectal balloon expulsion both normal?

yes

no 7 no

5

yes

Are both tests abnormal? 8

6 4 Slow transit constipation

yes

Is colonic transit slow?

no

Functional constipation with normal transit

Functional defecation disorder

9 Assess barium or MR defecography yes

11

10 no

Is colonic transit slow?

Does defecography reveal disordered defecation?

no

yes

13

12

Functional defecation disorder with normal transit

Functional defecation disorder with slow transit

14 yes

Does slow colonic transit normalize after correction of functional defecation disorder?

no

Figure 1. Refractory constipation and difficult defecation. perceive the desire to defecate, and therefore may be unable to expel a balloon. The performance characteristics of this test vs. defecography were evaluated by a study, in which the balloon was inflated to the volume at which patients experienced the desire to defecate. The normal value depends on the technique. At most centers, > 60 s is considered as abnormal. The balloon expulsion test is a useful screening test, but does not define the mechanism of disordered defecation, nor does a normal balloon expulsion study always exclude a functional defecation disorder. Additional research is needed to standardize this test that does not always correlate with other tests of rectal emptying such as defecography and surface electromyography (EMG) recordings of the anal sphincters. Colonic transit is most readily assessed using a radio-opaque marker technique; scintigraphy and more recently, a wireless pH-pressure capsule have also been used to measure transit. Colonic transit measured by these three methods is reasonably comparable. There are several available techniques of measuring transit by radio-opaque markers. In the Hinton technique, a capsule containing 24 radio-opaque markers is given on day 1 and the remaining markers seen on a plain abdominal X-ray on day 6 are counted: < 5 markers remaining in the colon is normal, > 5 markers scattered throughout the colon = slow transit, and > 5 markers in the recto-sigmoid region with a near normal clearance of rest of colon may suggest functional defecation disorder (21). In an alternative approach, which characterizes not only overall but also regional colonic transit, a capsule containing 24 radio-opaque markers is given on days 1, 2, and 3 and remaining markers seen on a plain abdominal X-ray on days 4 and 7 are counted (22). With this technique, a total of ≤68 markers remaining in the colon is normal whereas > 68 markers is slow transit. *Note: Instruct radiology to use high penetration films


(110 keV) to reduce radiation exposure; if < 34 markers on day 4, then the second X-ray is not required. Have patient avoid laxatives and keep diary of bowel movements for 1 week before, and during, the test to correlate with transit. Colonic transit can also be measured by a wireless motility-pH capsule. In constipated patients, the correlation between colonic transit measured by radio-opaque markers (on day 5) and the capsule is reasonable (correlation coefficient of approximately 0.7) (23). The capsule can also measure colonic motor activity (24). Scintigraphy entails delivering an isotope (generally 99 mTc or 111 In) into the colon by a delayed-release capsule that has a pH-sensitive polymer (methacrylate), which dissolves in the alkaline pH of the distal ileum, releasing the radioisotope within the ascending colon. Then, gamma camera scans taken 4, 24, and, if necessary, 48 h after the isotope was ingested show the colonic distribution of isotope (25). Advantages of scintigraphy are that colonic transit can be assessed in 48 h as opposed to 5–7 days for radio-opaque markers. Also, gastric, small intestinal, and colonic transit can be simultaneously assessed by scintigraphy. 3. At anal manometry, the patterns of anal sphincter and rectal pressure changes during attempted defecation are the most relevant parameters in this context. A normal pattern is characterized by increased intrarectal pressure associated with relaxation of the anal sphincter. Abnormal patterns are characterized by lower rectal than anal pressures during expulsion effort, resulting from the inability to generate an adequate propulsive or “pushing” intra-rectal pressure, and/or impaired relaxation or paradoxical contraction of the anal sphincter. However, as a proportion of asymptomatic subjects may have an abnormal pattern, it is necessary to interpret this test in the context of clinical features and other test results.


4–6.

7,8.

9.

If both anorectal manometry and balloon expulsion are normal, the results of colonic transit testing enable characterization of the disorder as functional constipation with normal or slow transit. The normal values for the radio-opaque marker tests are given above. Some patients with slow and even normal transit constipation have colonic motor dysfunction, perhaps severe enough to be characterized by colonic inertia. On the other hand, slow transit constipation may be associated with normal colonic motor functions, as assessed by intraluminal methods (i.e., a barostat or manometry), or with defecatory disorders (26). Although the diagnostic criteria for colonic inertia are not established, this term refers to reduced contractile responses, measured by manometry and/or a barostat, to physiological (i.e., a meal), and pharmacological stimuli (e.g., bisacodyl and neostigmine) stimuli. Colonic manometry and barostat testing is available at selected centers. The clinical utility of distinguishing between colonic motor dysfunction and inertia is unknown. A hypaque enema should be considered if plain abdominal X-rays suggest megacolon. Based on results of recent studies, if both manometry and the rectal balloon expulsion test are abnormal, this is sufficient to diagnose a functional defecation disorder (20) In this circumstance imaging (e.g., barium or MR defecography) is not generally required but should be considered if it is necessary to exclude a structural abnormality e.g., enteroceles, intussusception, or clinically significant rectoceles. Although clinical features and digital rectal examination can identify a rectocele, imaging can assess its size and emptying during evacuation. The Rome III diagnostic criteria for functional defecation disorders are: (i) the patient must satisfy diagnostic criteria for functional constipation; (ii) during repeated attempts to defecate, must have at least two of the following: (a) evidence of impaired evacuation, based on balloon expulsion test or imaging, (b) inappropriate contraction of the pelvic floor muscles (i.e., anal sphincter or puborectalis) or < 20% relaxation of basal resting sphincter pressure by manometry, imaging or EMG, and (c) inadequate propulsive forces assessed by manometry or imaging; (3) criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. Inappropriate anal contraction is also referred to as dyssynergic defecation. If only one of the anorectal manometry and balloon expulsion is abnormal, further testing—barium or magnetic resonance defecography may be used to confirm or exclude the diagnosis. Defecography can detect structural abnormalities (rectocele, enterocele, rectal prolapse, and intussusception) and assess functional parameters (anorectal angle at rest and during straining, perineal descent, anal diameter, indentation of the puborectalis,

FECAL INCONTINENCE Case history

A 60-year-old telephone operator is referred to a gastroenterologist because of FI, which has been present for 2 years. Her usual bowel habit is that she passes 1–2 soft but formed bowel movements daily, feeling satisfied thereafter. Approximately once a week, however, she is incontinent for a small amount of semiformed stool, perhaps the size of a quarter, often while walking or standing (Box 1, Figure 2). She is aware of the incontinent episode approximately 50% of the time, and there is no associated urgency. She can usually differentiate between the sensation of gas and stool in her rectum, and is often incontinent for flatus. She wears a pantiliner throughout the day, everyday. These symptoms make it difficult for her to continue with her current work, and have significantly affected her quality of life. There is no blood or mucus in the stools and she has no other significant gastrointestinal symp© 2010 by the American College of Gastroenterology

and amount of rectal and rectocele emptying). Small bowel opacification is required to identify enterocoeles by barium defecography. The diagnostic value of defecography has been questioned primarily because normal ranges for quantified measures are inadequately defined and because some parameters such as the anorectal angle cannot be measured reliably because of variations in rectal contour. Moreover, similar to anorectal manometry, a small fraction of asymptomatic healthy people have features of disordered defecation during proctography. Thus, there is no true gold standard diagnostic test for defecation disorders. Nonetheless, an integrated consideration of tests (i.e., manometry, rectal balloon expulsion, and defecography) together with the clinical features generally suffices to confirm or exclude defecation disorders. Magnetic resonance defecography provides an alternative approach to image anorectal motion and rectal evacuation in real time without radiation exposure. In a controlled study, magnetic resonance defecography identified disturbances of evacuation and/or squeeze in 94% of patients with suspected defecation disorders (27). Whether magnetic resonance defecography will add a new dimension to the morphological and functional assessment of these patients in clinical practice merits appraisal. 10. If defecography reveals features of disordered defecation, a diagnosis of a functional defecation disorder can be made. Defecographic features of disordered defecation include less than complete anal opening, impaired puborectalis relaxation or paradoxical puborectalis contraction, reduced or increased perineal descent, and a large ( > 4 cm) rectocoele, particularly if emptying is incomplete. If defecography is not abnormal, then the patient does not fulfill criteria for the diagnosis of a functional defecation disorder; further diagnosis then depends on the presence or absence of colonic transit delay (see above #4–6). 11–13. The presence of a functional defecation disorder does not exclude the diagnosis of slow colonic transit. Thus, depending on the results of the colonic transit study, the patient can be characterized as suffering from a functional defecation disorder with normal or slow colonic transit. 14. As well as coexisting with it; however, slow colonic transit may result from a defecation disorder. If it is felt appropriate to distinguish between the two possibilities, the colonic transit evaluation may be repeated after correction of the defecation disorder. If transit normalizes, the presumption is that the delay was secondary to the defecation disorder; if not, the delayed colonic transit is presumed to be a comorbid condition, which may require therapy if there is no clinical improvement with the treatment of functional defecation disorder.

toms. A review of other systems is negative; in particular she has no urinary or neurological symptoms (Box 2). Her dietary history does not reveal symptoms of carbohydrate intolerance. She has no other medical conditions and is taking multivitamins only. The obstetric history is notable for two vaginal deliveries accompanied by episiotomy but no forceps assistance or anal sphincter injury. General physical examinations, including abdominal exam, are normal. Neurological examination is grossly normal. Digital rectal examination (Box 2) does not reveal any evidence of fecal impaction (Box 3), and there are no anorectal lesions detected. There is a reduced anal-resting tone, a reduced anal-squeeze response, a normal puborectalis lift to voluntary command, and normal perineal descent during simulated evacuation (Box 2). During the digital rectal examination, perineal descent is estimated by inspecting for perineal descent during simulated evacuation and normally should be < 3 cm. Perianal pinprick sensation and anal wink reflex are normal. The American Journal of GASTROENTEROLOGY

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The gastroenterologist confirmed that she did not have episodes of loose or frequent stools (Box 5), and obtained further history that she had tried loperamide (Box 7), but this did not produce any significant improvement (Box 8) and in fact caused constipation. She had also tried using a perianal cotton plug (Box 7), but was not satisfied with this (Box 8). Anal manometry is then arranged (Box 10). This reveals average anal-resting (35 mm Hg) and -squeeze (90 mm Hg) pressures at the lower limit of normal (for her age, normal values for resting and squeeze pressure are 29–85 mm Hg and 88–179 mm Hg, respectively) (Box 11). The anal cough reflex is present but weak. Although the rectal sen-

sory threshold for first sensation is normal, her maximum tolerable capacity is reduced (i.e., 60 cc). She is able to expel a rectal balloon within 20 s. Endoanal magnetic resonance imaging of the sphincters (Box 13) discloses mild anterior focal thinning of the internal and external sphincters (Box 14). Puborectalis structure and function appear normal. Dynamic MRI reveals normal puborectalis function during squeeze and evacuation. Based on these findings, anal sphincter weakness and altered stool consistency likely contribute to FI. As the abnormality of sphincter structure is minor, a diagnosis of functional FI is made (Box 12).

1 4

Patient with fecal incontinence

3

2

Manage appropriately and/or see ‘chronic constipation’ and ‘refractory constipation with difficult defecation’ algorithms

yes

Is there fecal impaction?

no

Clinical assessment: digital rectal examination to assess anorectal structure and function

6

5

7

no

Is there diarrhea?

Treat symptomatically

See chronic painless diarrhea algorithm

yes

10 8 Anorectal manometry and rectal sensation testing

no


yes Fecal incontinence not requiring further investigation

11 Are anal resting and squeeze pressures, and rectal sensation, normal?

13 no

14 Is weakness clearly explained by sphincter and/or nerve injury?

Anorectal imaging +/– anal EMG

no yes

yes

15

12

Functional fecal incontinence

Non-functional fecal incontinence

Figure 2. Fecal incontinence.

Figure 2. Legend 1. Fecal incontinence (FI) is defined as uncontrolled passage of fecal material recurring for at least 3 months in people aged 4 or more years. Leakage of flatus alone should not be characterized as FI. In this context, the FI is assumed to not be associated with known systemic or organic disorders (e.g., dementia, multiple sclerosis, and Crohn’s disease) (28,29). 2. The history should determine the duration of symptoms, type of FI, and associated bowel habits; urinary and neurological symptoms


should be evaluated (28). Consider possible undiagnosed systemic or organic disorders that can cause FI. Although a spinal cord lesion can cause FI, typically, patients with a spinal cord lesion and FI will have other neurological symptoms and signs of the underlying lesion. Severity is established by consideration of four variables, i.e., frequency, type (i.e., liquid, solid stool, or both), amount (small, moderate, or large) of leakage, and presence/absence of urgency. The physical examination should particularly evaluate the presence


of any alarm signs e.g., abdominal mass, evidence of anemia. Where indicated, a neurological examination should be carried out. A careful digital rectal examination is critical to understanding the etiology and for guiding management of FI. This should assess for stool impaction, anal resting tone (patients with markedly reduced tone may have a gaping sphincter), contraction of the external sphincter and puborectalis to voluntary command, and/or dyssynergia during simulated evacuation. In this patient, anal-squeeze response was reduced but the puborectalis lift was preserved, consistent with sphincter but not puborectalis weakness. Dyssynergia refers to impaired relaxation and/or paradoxical contraction of the anal sphincter and/or puborectalis muscle and/or reduced perineal descent during simulated evacuation. To evaluate the integrity of the sacral lower motor neuron reflex arc, perianal pinprick sensation, and the anal wink reflex should also be assessed. 3. The presence of fecal impaction at digital rectal examination suggests fecal retention and “overflow” FI. An abdominal X-ray should be considered to identify colonic fecal retention if appropriate. 4. If fecal impaction is present, see “chronic constipation” and “refractory constipation” algorithms. If FI persists after appropriate treatment of the fecal impaction, consider further evaluation for FI as described below. 5,6. Patients with FI and moderate to severe diarrhea should be investigated appropriately as detailed in “chronic painless diarrhea” algorithm. If FI persists after appropriate treatment of the diarrhea, consider further evaluation for FI as continued below. 6. Patients with mild symptoms and/or symptoms that are not bothersome will often benefit from symptomatic management of the FI and any associated bowel disturbances, often on an as-needed basis (30). Such management may include a trial of loperamide and/or bulking agents, advice regarding the role of scheduled evacuation, and if necessary, the use of perineal protective devices. Patients with passive incontinence for a small amount of stool may benefit from a perianal cotton plug to absorb moisture and also perhaps to help with uncontrolled passage of gas. 8,9. If symptoms improve and there are no features to suggest an organic disorder (e.g., neurological symptoms/signs suggestive of a spinal cord lesion), further testing may not be necessary—see comment number 10). A diagnosis of FI, without qualifying whether organic or functional as defined below, may be made. 10. If symptoms do not improve, further diagnostic testing, in particular anorectal manometry, should be considered. The extent of such testing is tailored to the patient’s age, probable etiological factors, symptom severity, effect on quality of life, response to conservative medical management, and availability of tests. Although widely available, these tests should preferably be carried out by laboratories with requisite expertise. 11. The key features at anorectal manometry are anal sphincter-resting and -squeeze pressures. As anal sphincter pressures decline with age and are lower in women, the age and gender should be taken into consideration when interpreting anal pressures (31–33). The anal cough reflex is useful, in a qualitative sense, for evaluating the integrity of the lower motor neuron innervation of the external anal sphincter. It is useful to assess rectal sensation, which may be normal, increased, or decreased in FI, as these disturbances can be modulated by biofeedback therapy (28). 12. If these pressures are normal, a diagnosis of functional FI can be made. In addition, it is increasingly recognized that anorectal assessments


may reveal disturbances of anorectal structure and/or function in patients who were hitherto considered to have an “idiopathic” or “functional” disorder. The causal relationship between structural abnormalities and anorectal function or bowel symptoms may be unclear, because such abnormalities are often observed in asymptomatic subjects (31,33). For example, up to one-third of all women have anal sphincter defects after vaginal delivery (28). As sophisticated tests (e.g., anal electromyography (EMG)) for elucidating the mechanisms of anal weakness are not widely available, the diagnosis of functional FI can also be entertained in patients, as exemplified in this case, with potentially abnormal innervation and either minor or no structural abnormalities. The Rome III diagnostic criteria for functional FI are (i) recurrent uncontrolled passage of fecal material in an individual with a developmental age of at least 4 years and one or more of the following: abnormal functioning of normally innervated and structurally intact muscles; minor abnormalities of sphincter structure and/or innervation; normal or disordered bowel habits (i.e., fecal retention or diarrhea); or psychological causes and (ii) exclusion of all of the following: abnormal innervation caused by lesion(s) within the brain (e.g., dementia), spinal cord or sacral nerve roots, or mixed lesions (e.g., multiple sclerosis), or as part of a generalized peripheral or autonomic neuropathy (e.g., diabetes); anal sphincter abnormalities associated with a multisystem disease (e.g., scleroderma); or structural or neurogenic abnormalities believed to be the major or primary cause of FI (iii) criteria fulfilled for the last 3 months. 13. If the sphincter pressures are abnormal, imaging of the anal sphincter should be considered. Endoanal ultrasound and magnetic resonance imaging are probably equivalent for imaging the internal sphincter (8,32,33). Magnetic resonance imaging is better for visualizing external sphincter and puborectalis atrophy and also visualizes pelvic floor motion in real-time without radiation exposure. Anal sphincter EMG should be considered in patients with clinically suspected neurogenic sphincter weakness, particularly if there are features suggestive of proximal (i.e., sacral root) involvement (8). 14. Diagnostic tests (e.g., endoanal ultrasound) may reveal disturbances of anorectal structure and/or function in patients with FI. The extent to which structural disturbances (e.g., anal sphincter defects, excessive perineal descent) can explain symptoms is often unclear (29). Therefore, the presence of structural abnormalities is not necessarily inconsistent with the diagnosis of functional FI. Many patients with anal sphincter weakness may have a pudendal neuropathy. However, it can be difficult to document a pudendal neuropathy because anal sphincter EMG requires considerable expertise and is not widely available (31,33). Therefore, patients with a pudendal neuropathy not attributable to a generalized disease process have not been excluded from the category of functional FI. A controlled study suggests that patients with FI who do not benefit from dietary modification and measures to regulate bowel habits may benefit from pelvic floor retraining (34). 15. The following conditions would be considered as secondary or non-functional FI: abnormal innervation caused by lesion(s) within the spinal cord or sacral nerve roots or part of a generalized peripheral or autonomic neuropathy, anal sphincter abnormalities associated with a multi-system disease (e.g. scleroderma), and structural abnormalities believed to be the major or primary cause of the FI (29).


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CHRONIC ANORECTAL PAIN

by her gynecologist was normal and a pelvic ultrasound was negative (Box 2). A colonoscopic screening 2 years ago was normal. She has no other significant medical illnesses. General physical examination, including abdominal and neurological examination, is normal. Digital rectal examination discloses no perianal disease or tenderness (Box 2). Anal canal tone and squeeze are normal. Perianal pinprick sensation and anal wink reflex are normal. Palpation of the coccyx is not painful and no masses are felt. However, there is tenderness with posterior traction of the puborectalis muscle, greater on the left than right (Box 8). The gastroenterologist arranges a complete blood count and ESR and recommends flexible sigmoidoscopy and perianal imaging (Box 2), to exclude inflammation and neoplasia. These tests are normal. A diagnosis of levator ani syndrome is made (Box 9).

ANORECTAL DISORDERS

Case history

A 52-year-old woman is referred to a gastroenterologist because of rectal discomfort of 8 months duration (Box 1, Figure 3). She describes the pain as a deep, dull aching discomfort, lasting for some hours, and often precipitated or worsened by sitting (Box 2). The pain is not associated with bowel movements or eating (Box 4). The pain occurs inconsistently but is present, at a moderate level of severity, for as many as 4–5 days each week, and there are no painfree intervals (Box 6). She averages five bowel movements weekly, passed with minimal straining and, on some occasions, with a sense of incomplete evacuation; there has been no change in bowel habits and no rectal bleeding. There is no history of dyspareunia, dysuria, back pain, or trauma. She has had no pelvic surgery. A pelvic exam

1 7 Patient with chronic or recurrent anorectal pain

Proctalgia fugax

yes 2

6

4 Do history and physical exam/tests suggest structural disease?

Is pain associated with bowel movements or eating?

no

Is pain episodic and brief with pain-free intervals?

no

no

yes

yes

8 3

5 Do appropriate diagnostic workup for inflammatory bowel disease, perianal/perirectal abscesses, anal fissure, and painful gynecological disorders

Is the levator muscle tender to palpation?

Assess for painful functional gastrointestinal disorders (i.e., IBS) no 10

yes 9

Unspecified functional anorectal pain

Levator ani syndrome

Figure 3. Chronic anorectal pain.

Figure 3. Legend 1.

Pain present for at least 6 months is required for the diagnosis of functional anorectal pain syndrome. Patients with chronic anorectal pain have chronic or recurrent anorectal pain; if recurrent, pain lasts for 20 min or longer during episodes. In contrast, patients with proctalgia fugax have brief episodes of pain lasting seconds to minutes with no pain between episodes (29). 2–3. The history and physical exam should identify alarm and other features suggesting structural disease such as severe throbbing pain, sentinel piles, fistulous opening, and anal tenderness during digital examination, or while gently parting the posterior anus, The American Journal of GASTROENTEROLOGY

anal strictures, or induration (35). Relevant organic causes of pain including inflammatory bowel disease, peri-anal abscesses, anal fissure, and painful gynecological conditions should be considered and identified by tests. If pain is associated with and worsened by menses, conditions that might include endometriosis, dysfunctional uterine bleeding, or other gynecological pathology should be evaluated by pelvic examination, pelvic ultrasound, and/or referral to a gynecologist. Minimal diagnostic workup (in the absence of alarm signs) includes: CBC, ESR, biochemistry panel, flexible sigmoidoscopy, and perianal imaging with ultrasound or MRI. If there VOLUME 105 | APRIL 2010 www.amjgastro.com

is a high index of suspicion for anal fissures, anoscopy should be considered. 4–5. Pain associated with bowel movements, menses or eating, excludes the diagnosis of functional anorectal pain. If pain is associated with bowel movements and leads to frequent, looser stools, or infrequent harder stools with relief upon defecation (any combination of two), then a diagnosis of irritable bowel syndrome (IBS) should be considered. See “recurrent abdominal pain and disordered bowel habit” algorithm. 6. An important feature of the history is whether the pain is episodic, with pain-free intervals, or not. In chronic proctalgia, pain is generally prolonged (i.e., lasts for hours), is constant or frequent, and is characteristically dull. In proctalgia fugax, the pain is brief (i.e., lasting seconds to minutes), occurs infrequently (i.e., once a month or less often), and is relatively sharp. Observation of symptom-reporting behaviors is also important. These include verbal and non-verbal expression of pain, urgent reporting of intense symptoms, minimization of a role for psychosocial contributors, requesting diagnostic studies or even exploratory surgery, focusing on complete relief of symptoms, seeking health care frequently, taking limited personal responsibility for selfmanagement, and making requests for narcotic analgesics. 7. Rome III diagnostic criteria for proctalgia fugax include all of the following: (i) recurrent episodes of pain localized to the anus or lower rectum; (ii) episodes last from seconds to minutes; and (iii) there is no anorectal pain between episodes. 8. Rome III diagnostic criteria for chronic proctalgia include all of the following: (i) chronic or recurrent rectal pain or aching; (ii) episodes last 20 min or longer; (iii) exclusion of other causes of rectal pain such as ischemia, inflammatory bowel disease, cryptitis, intramuscular abscess, anal fissure, hemorrhoids, prostatitis, and coccygodynia; (iv) criteria fulfilled for last 3 months with symptom onset at least 6 months before diagnosis. In chronic proctalgia, levator ani tenderness differentiates levator ani syndrome from unspecified functional anorectal pain. Coccygodynia is characterized by pain and point tenderness of the coccyx (9). Most patients with rectal, anal, and sacral discomfort have levator rather than coccygeal tenderness (10).


Guarantors of the article: The Rome Foundation. Specific author contributions: Equal contribution toward all aspects of the paper, Adil E. Bharucha and A. Wald. Financial support: This work was supported by a grant from the Rome Foundation. Potential competing interests: Dr Bharucha has a license agreement with Medspira. REFERENCES 1. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920–4. 2. Grotz RL, Pemberton JH, Talley NJ et al. Discriminant value of psychological distress, symptom profiles, and segmental colonic dysfunction in outpatients with severe idiopathic constipation. Gut 1994;35:798–802. 3. Mertz H, Naliboff B, Mayer EA. Symptoms and physiology in severe chronic constipation. Am J Gastroenterol 1999;94:131–8. 4. Andrews CN, Bharucha AE. The etiology, assessment, and treatment of fecal incontinence. Nat Clin Pract Gastroenterol Hepatol 2005;2:516–25. 5. Leigh RJ, Turnberg LA. Faecal incontinence: the unvoiced symptom. Lancet 1982;1:1349–51. 6. Engel AF, Kamm MA, Bartram CI et al. Relationship of symptoms in faecal incontinence to specific sphincter abnormalities. Int J Colorectal Dis 1995;10:152–5. 7. Chiarioni G, Scattolini C, Bonfante F et al. Liquid stool incontinence with severe urgency: anorectal function and effective biofeedback treatment. Gut 1993;34:1576–80.


9. Rome III diagnostic criteria for levator ani syndrome include symptom criteria for chronic proctalgia and tenderness during posterior traction on the puborectalis muscle. 10. Rome III diagnostic criteria for unspecified functional anorectal pain include symptom criteria for chronic proctalgia, but no tenderness during posterior traction on the puborectalis muscle. In a patient with levator ani syndrome, anorectal manometry and rectal balloon expulsion testing should be considered. A recent study suggests that approximately 85% patients with levator ani syndrome had impaired anal relaxation during straining and approximately 85% had abnormal rectal balloon expulsion (36). It is unclear if dyssynergia is a cause of or secondary to pain. However, dyssynergia may guide management as discussed below. Treatment options to present to the patient can then be formulated. A randomized control trial showed that inhalation of salbutamol (a beta adrenergic agonist) was more effective than placebo for shortening the duration of episodes of proctalgia for patients in whom episodes lasted 20 min or longer (36). In a controlled study of 157 patients with levator ani syndrome, adequate relief of pain was more likely after biofeedback therapy for a concomitant evacuation disorder (87%) than electrogalvanic stimulation (EGS) (45%) or rectal digital massage (22%) (37). Biofeedback and EGS also improved pelvic floor relaxation in levator ani syndrome. In contrast, none of these measures benefited patients with functional anorectal pain. Although features of disordered defecation did not augment the utility of levator tenderness for predicting a response to biofeedback therapy, it is useful to assess defecatory functions because (i) the presence of dyssynergia before training and improvement thereof after training was very highly correlated with the success of biofeedback (and also EGS), and (ii) the biofeedback protocol is more logical to patients and providers in the presence of dyssynergia. Other treatment options include tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) therapy or non-pharmacological therapy such as cognitive behavioral therapy (CBT), hypnotherapy, or dynamic or interpersonal psychotherapy.

8. Bharucha AE, Fletcher JG, Harper CM et al. Relationship between symptoms and disordered continence mechanisms in women with idiopathic fecal incontinence. Gut 2005;54:546–55. 9. Thiele GH. Coccygodynia: cause and treatment. Dis Colon Rectum 1963;6:422–36. 10. Grant SR, Salvati EP, Rubin RJ. Levator syndrome: an analysis of 316 cases. Dis Colon Rectum 1975;18:161–3. 11. Tu FF, Holt JJ, Gonzales J et al. Physical therapy evaluation of patients with chronic pelvic pain: a controlled study. Am J Obstet Gynecol 2008;198:272. e1–7. 12. Grimaud JC, Bouvier M, Naudy B et al. Manometric and radiologic investigations and biofeedback treatment of chronic idiopathic anal pain. Dis Colon Rectum 1991;34:690–5. 13. Anderson RU, Orenberg EK, Chan CA et al. Psychometric profiles and hypothalamic-pituitary-adrenal axis function in men with chronic prostatitis/chronic pelvic pain syndrome.[see comment]. J Urol 2008;179:956–60. 14. Jameson JS, Chia YW, Kamm MA et al. Effect of age, sex and parity on anorectal function. Br J Surg 1994;81:1689–92. 15. Pepin C, Ladabaum U. The yield of lower endoscopy in patients with constipation: survey of a university hospital, a public county hospital, and a Veterans Administration medical center. Gastrointest Endosc 2002;56: 325–32. 16. Rao SS, Hatfield R, Soffer E et al. Manometric tests of anorectal function in healthy adults. Am J Gastroenterol 1999;94:773–83. 17. Diamant NE, Kamm MA, Wald A et al. AGA technical review on anorectal testing techniques. Gastroenterology 1999;116:735–60. 18. Fox JC, Fletcher JG, Zinsmeister AR et al. Effect of aging on anorectal and pelvic floor functions in females.[erratum appears in Dis Colon Rectum. 2007 Mar;50(3):404]. Dis Colon Rectum 2006;49:1726–35.


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19. Rao SS, Azpiroz F, Diamant N et al. Minimum standards of anorectal manometry. Neurogastroenterol Motil 2002;14:553–9. 20. Minguez M, Herreros B, Sanchiz V et al. Predictive value of the balloon expulsion test for excluding the diagnosis of pelvic floor dyssynergia in constipation. Gastroenterology 2004;126:57–62. 21. Halverson AL, Orkin BA. Which physiologic tests are useful in patients with constipation? Dis Colon Rectum 1998;41:735–9. 22. Metcalf AM, Phillips SF, Zinsmeister AR et al. Simplified assessment of segmental colonic transit. Gastroenterology 1987;92:40–7. 23. Rao SS, Kuo B, McCallum RW et al. Investigation of Colonic and Whole Gut Transit with wireless motility capsule and radioopaque markers in constipation. Clin Gastroenterol Hepatol 2009;7:537–44. 24. Hasler WL, Saad RJ, Rao SS et al. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol 2009;297: G1107–14. 25. Cremonini F, Mullan BP, Camilleri M et al. Performance characteristics of scintigraphic transit measurements for studies of experimental therapies. Aliment Pharmacol Ther 2002;16:1781–90. 26. Ravi K, Bharucha AE, Camilleri M et al. Phenotypic variation of colonic motor functions in chronic constipation. Gastroenterology 2010;138:89–97. 27. Bharucha AE, Fletcher JG, Seide B et al. Phenotypic variation in functional disorders of defecation. Gastroenterology 2009;128:1199–210.


28. Bharucha A. Fecal Incontinence. Gastroenterology 2003;124:1672–85. 29. Wald A, Bharucha AE, Enck P et al. Functional anorectal disorders. In: Drossman DA, Corazziari E, Delvaux M (eds). Rome III The Functional Gastrointestinal Disorders. McLean, Virginia: Degnon Associates, 2006, 639–86. 30. Wald A. Clinical practice. Fecal incontinence in adults. N Engl J Med 2007;356:1648–55. 31. Diamant NE, Kamm MA, Wald A. et al. American gastroenterological association medical position statement on anorectal testing techniques. Gastroenterology 1999;116:732–60. 32. Bharucha AE. Update of tests of colon and rectal structure and function. J Clin Gastroenterol 2006;40:96–103. 33. Bharucha AE, Fletcher JG. Recent advances in assessing anorectal structure and functions. Gastroenterology 2007;133:1069–74. 34. Heymen S, Scarlett Y, Jones K et al. Randomized controlled trial shows biofeedback to be superior to alternative treatments for fecal incontinence. Diseas Colon Rectum 2009;52:1730–7. 35. Bharucha AE, Trabuco E. Functional and chronic anorectal and pelvic pain disorders. Gastroenterol Clin North Am 2008;37:685–96. 36. Eckardt VF, Dodt O, Kanzler G et al. Treatment of proctalgia fugax with salbutamol inhalation. Am J Gastroenterol 1996;91:686–9. 37. Chiarioni G, Nardo A, Vantini I et al. Biofeedback is superior to electrogalvanic stimulation and massage for treatment of levator ani syndrome. Gastroenterology 2010, in press.



Appendix A: Psychosocial Alarm Questionnaire for the Functional GI Disorders Am J Gastroenterol 2010; 105:795; doi:10.1038/ajg.2010.71

INSTRUCTIONS The following questions are screening questions within a clinical context and are not designed for survey purposes. They help identify psychosocial problems commonly faced by patients with functional gastrointestinal disorders (FGIDs). For each question there are two possible recommendations: (a) There is a problem (boldfaced items) that the physician should acknowledge, discuss with the patient and agree to an appropriate action, which might include referral to a mental health specialist and/or initiation of pharmacotherapy. (b) A “more serious” situation (marked with ), which the physician is advised to either address personally or consider referral to a mental health professional (psychiatrist,

psychologist or other) simultaneous with or prior to treatment of the FGID. These are referred to as “red flag” situations to emphasize their importance. Note: Further research is needed to determine accurately the most appropriate action according to the nature and severity of psychosocial problems. This questionnaire was produced by the Psychosocial Aspects of Functional GI Disorders subcommittee for Rome III: Francis Creed, MD (Chair), Rona Levy, PhD (Co-Chair), Lawrence Bradley, PhD, Douglas A. Drossman, MD, Carlos Francisconi MD, Bruce Naliboff, PhD, and Kevin Olden, MD.

The Rome III Psychosocial Alarm Questionnaire for Functional Gastrointestinal Disorders is reprinted with permission from the source, Degnon Associates, McLean, VA. Drossman DA, Corazziari E, Delvaux M et al. Rome III: The Functional Gastrointestinal Disorders, 3rd edn. Degnon Associates: McLean, VA, 2006, pp 953–60. © 2010 by the American College of Gastroenterology


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QUESTIONNAIRE

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Rome III Psychosocial Alarm Questionnaire Am J Gastroenterol 2010; 105:796–797; doi:10.1038/ajg.2010.72

ROME III PSYCHOSOCIAL ALARM QUESTIONNAIRE Question

Answer

Scoring

1. Question for anxiety: In the last week have you felt tense or “wound up”?

l l l l

Most of the time A lot of the time Occasionally Not at all

Most of the time or A lot of the time indicates a problem (probable anxiety disorder).

Rationale for scoring This question is taken from the Hospital Anxiety and Depression scale (HADS). The answers Most of the time or A lot of the time identify the majority of depressive or anxiety disorders in this population. These patients had a mean HADS anxiety score of 13.3 (s.d.=3.6) compared with 6.0 (s.d.=2.5) for those who scored Occasionally or Not at all (1,2).

Red flag. Patients answering Most of the time represent 24% of the patients with functional gastrointestinal disorders and their HADS anxiety score was 15.7 (s.d.=3.2) (range: 10–21) (1,2). (Note: a HADS anxiety score of 10 or more indicates a probable case of anxiety. So, this level of anxiety merits referral to behavioral management for these patients before treatment of the FGID.) 2. Question for depression: In the last week have you felt downhearted and low?

l l l l

Most of the time A good bit of the time Some of the time Not at all

Most of the time and A good bit of the time indicate a problem (probable depressive disorder).

Rationale for scoring This question is taken from the Short Form-36 (question 9f). The answers Most of the time and A good bit of the time identify FGID patients, whose mean HADS depression score was 9.0 (s.d.= 3.0) compared with 5.0 (s.d.= 3.6) for the remainder (1,2). Red flag Patients answering to this question Most of the time represent 12.8% of patients with FGID and their mean HADS depression score was 9.4 (s.d.= 2.6) (1,2). In addition, nearly all the patients who scored Most of the time to this question also scored Most of the time to the anxiety question. So, by using both the anxiety and depression questions, our red flag criterion includes the top 15% of the most anxious/depressed patients with FGID. 3. Question for suicidal ideas: Have you recently felt so low that you felt like hurting or killing yourself?

l l l

Often Occasionally Not at all

Often or Occasionally indicates a problem and the physician should ask the patient to describe more fully their current feelings and any specific plans.

Rationale for scoring This question has not been tested empirically but has clinical face validity. The physician should not be frightened of asking more questions of patients who answer Often or Occasionally. All the evidence suggests that better prevention of suicide starts with the doctor’s preparedness to ask such questions.



Questionnaire

797

Question

Answer

Scoring

4. Question for pain severity: During the last four weeks how much bodily pain have you had?

l l l l l

Very severe Severe Moderate Mild None

Very severe or Severe indicates a problem.

Extremely Quite a bit Moderately A little bit Not at all

Extremely or Quite a bit indicates a problem.

Always Sometimes Never

Always or Sometimes indicates a problem.

Rationale for scoring Patients answering Severe or Very severe to this question (question 7 of SF-36) represent 24% of the patients with functional gastrointestinal disorders and their mean SF summary physical component score was 30.1 (s.d.= 8.5) (1,2), which is 2 standard deviations below the population norm.

5. Question for impairment: During the last four weeks how much did pain (or other symptoms) interfere with your normal activities (including work both outside the home and housework)?

l l l l l

Rationale for scoring Patients answering Quite a bit or Extremely to this question (question 8 of SF-36) represent 26% of the patients with functional gastrointestinal disorders and their mean SF summary physical component score is 28.9 (s.d.= 8.2) (1,2), which is 2 standard deviations below the population norm.

6. Question for impaired coping: When I have pain (or other symptoms), I say to myself “it is terrible and I feel it will never get better”:

l l l

Rationale for scoring This question is the one-item form of the Coping Strategies Questionnaire. It has been used in a study of chronic pain (3)but has yet to be validated in patients with FGID. 7. Question for abuse: It is quite common for people to have been emotionally, physically, or sexually victimized at some time in their life and this can affect how people manage with their medical condition. Has this ever happened to you?

l l

Yes Never

If the response is Yes, then the physician should ask: “Is this causing you distress in your life”, and “Would you like to see someone discuss this in more detail?” If the patient agrees that he/she is very distressed and would like to see someone, then this should be a “red flag” situation (i.e., the physician should consider early referral to a mental health professional, provided the patient agrees). This comes from a published literature review and recommendations (4).

REFERENCES 1. Biggs AM, Aziz Q, Tomenson B et al. Effect of childhood adversity on health related quality of life in patients with upper abdominal or chest pain. Gut 2004;53:180–6. 2. Fiddler M, Jackson J, Kapur N et al. Childhood adversity and frequent medical consultations. General Hospital Psychiatry 2004;26:367–77.


3. Jensen MP, Keefe FJ, Lefebvre JC et al. One- and two-item measures of pain beliefs and coping strategies. Pain 2003;104:453–69. 4. Drossman DA, Talley NJ, Olden KW et al. Sexual and physical abuse and gastrointestinal illness: review and recommendations. Ann Intern Med 1995;123:782–94.


QUESTIONNAIRE

ROME III PSYCHOSOCIAL ALARM QUESTIONNAIRE

APPENDIX B

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Appendix B: Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders Am J Gastroenterol 2010; 105:798–801; doi:10.1038/ajg.2010.73

A. FUNCTIONAL ESOPHAGEAL DISORDERS † A1. Functional heartburn Diagnostic criteria* must include all of the following: 1. Burning retrosternal discomfort or pain

5. Absence of histopathology-based esophageal motility disorders *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

2. Absence of evidence that gastroesophageal acid reflux is the cause of the symptom 3. Absence of histopathology-based esophageal motility disorders *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

† A2. Functional chest pain of presumed esophageal origin Diagnostic criteria* must include all of the following: 1. Midline chest pain or discomfort that is not of burning quality

2. Absence of evidence that gastroesophageal reflux is the cause of the symptom 3. Absence of histopathology-based esophageal motility disorders *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

† A3. Functional dysphagia Diagnostic criteria* must include all of the following: 1. Sense of solid and/or liquid foods sticking, lodging, or passing abnormally through the esophagus

2. Absence of evidence that gastroesophageal reflux is the cause of the symptom 3. Absence of histopathology-based esophageal motility disorders *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

B. FUNCTIONAL GASTRODUODENAL DISORDERS † B1. Functional dyspepsia Diagnostic criteria* must include all of the following: 1. One or more of the following: a. Bothersome postprandial fullness b. Early satiation c. Epigastric pain d. Epigastric burning 2. No evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. B1a. Postprandial distress syndrome Diagnostic criteria* must include all of the following: 1. Bothersome postprandial fullness, occurring after ordinarysized meals, at least several times per week 2. Early satiation that prevents finishing a regular meal, at least several times per week *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. Supportive criteria 1. Upper abdominal bloating or postprandial nausea or excessive belching can be present 2. Epigastric pain syndrome may coexist

† A4. Globus Diagnostic criteria* must include all of the following: 1. Persistent or intermittent, nonpainful sensation of a lump or foreign body in the throat

2. Occurrence of the sensation between meals 3. Absence of dysphagia or odynophagia 4. Absence of evidence that gastroesophageal reflux is the cause of the symptom

B1b. Epigastric pain syndrome Diagnostic criteria* must include all of the following: 1. Pain or burning localized to the epigastrium of at least moderate severity, at least once per week

2. The pain is intermittent 3. Not generalized or localized to other abdominal or chest regions

The Rome III Adult Diagnostic Criteria for Functional Gastrointestinal Disorders are reprinted by permission from Degnon Associates, McLean, VA. Drossman DA, Corazziari E, Delvaux M, Spiller R, Talley NJ, Thompson WG, Whitehead WE. Rome III: The Functional Gastrointestinal Disorders. 3rd edn. McLean, VA: Degnon Associates, 2006, pp 885–93. The American Journal of GASTROENTEROLOGY


4. Not relieved by defecation or passage of flatus

B4. Rumination syndrome in adults

5. Not fulfilling criteria for gallbladder and sphincter of Oddi disorders *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. Supportive criteria 1. The pain may be of a burning quality, but without a retrosternal component

Diagnostic criteria* must include both of the following: 1. Persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or remastication and swallowing 2. Regurgitation is not preceded by retching Supportive criteria 1. Regurgitation events are usually not preceded by nausea

2. The pain is commonly induced or relieved by ingestion of a meal, but may occur while fasting

2. Cessation of the process when the regurgitated material becomes acidic

3. Postprandial distress syndrome may coexist

3. Regurgitant contains recognizable food with a pleasant taste

B2. Belching disorders B2a. Aerophagia Diagnostic criteria* must include all of the following: 1. Troublesome repetitive belching at least several times a week 2. Air swallowing that is objectively observed or measured *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. B2b. Unspecified excessive belching Diagnostic criteria* must include all of the following: 1. Troublesome repetitive belching at least several times a week 2. No evidence that excessive air swallowing underlies the symptom *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

† B3. Nausea and vomiting disorders B3a. Chronic idiopathic nausea Diagnostic criteria* must include all of the following: 1. Bothersome nausea occurring at least several times per week

2. Not usually associated with vomiting 3. Absence of abnormalities at upper endoscopy or metabolic disease that explains the nausea *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. B3b. Functional vomiting Diagnostic criteria* must include all of the following: 1. On average one or more episodes of vomiting per week

2. Absence of criteria for an eating disorder, rumination, or major psychiatric disease according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 3. Absence of self-induced vomiting and chronic cannabinoid use and absence of abnormalities in the central nervous system or metabolic diseases to explain the recurrent vomiting *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. B3c. Cyclic vomiting syndrome Diagnostic criteria* must include all of the following: 1. Stereotypical episodes of vomiting regarding onset (acute) and duration (less than 1 week)

2. Three or more discrete episodes in the previous year 3. Absence of nausea and vomiting between episodes Supportive criterion History or family history of migraine headaches © 2010 by the American College of Gastroenterology

C. FUNCTIONAL BOWEL DISORDERS † C1. Irritable bowel syndrome Diagnostic criterion* Recurrent abdominal pain or discomfort** at least 3 days/month in the last 3 months associated with two or more of the following: 1. Improvement with defecation

2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool *Criterion fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. ** “Discomfort” means an uncomfortable sensation not described as pain. In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during screening evaluation is recommended for subject eligibility.

C2. Functional bloating Diagnostic criteria* must include both of the following: 1. Recurrent feeling of bloating or visible distension at least 3 days/month in the last 3 months 2. Insufficient criteria for a diagnosis of functional dyspepsia, irritable bowel syndrome, or other functional gastrointestinal disorder *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

† C3. Functional constipation Diagnostic criteria* 1. Must include two or more of the following: a. Straining during at least 25% of defecations b. Lumpy or hard stools in at least 25% of defecations c. Sensation of incomplete evacuation for at least 25% of defecations d. Sensation of anorectal obstruction/blockage for at least 25% of defecations e. Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) f. Fewer than three defecations per week 2. Loose stools are rarely present without the use of laxatives 3. Insufficient criteria for irritable bowel syndrome *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. The American Journal of GASTROENTEROLOGY

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Appendix B

APPENDIX B

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Appendix B

† C4. Functional diarrhea

2. Gallbladder is present

Diagnostic criterion* Loose (mushy) or watery stools without pain occurring in at least 75% of stools *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

3. Normal liver enzymes, conjugated bilirubin, and amylase/ lipase

C5. Unspecified functional bowel disorder Diagnostic criterion* Bowel symptoms not attributable to an organic etiology that do not meet criteria for the previously defined categories. *Criterion fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

† E2. Functional biliary sphincter of Oddi disorder Diagnostic criteria* must include all of the following: 1. Criteria for functional gallbladder and sphincter of Oddi disorder 2. Normal amylase/lipase Supportive criterion Elevated serum transaminases, alkaline phosphatase, or conjugated bilirubin temporarily related to at least two pain episodes

E3. Functional pancreatic sphincter of Oddi disorder

Diagnostic criteria* must include all of the following: 1. Continuous or nearly continuous abdominal pain

Diagnostic criteria* must include all of the following: 1. Criteria for functional gallbladder and sphincter of Oddi disorder 2. Elevated amylase/lipase

2. No or only occasional relationship of pain with physiological events (e.g., eating, defecation, menses) 3. Some loss of daily functioning 4. The pain is not feigned (e.g., malingering)

F. FUNCTIONAL ANORECTAL DISORDERS † F1. Functional fecal incontinence

† D. FUNCTIONAL ABDOMINAL PAIN SYNDROME

5. Insufficient symptoms to meet criteria for another functional gastrointestinal disorder that would explain the pain *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

E. FUNCTIONAL GALLBLADDER AND SPHINCTER OF ODDI DISORDERS Diagnostic criteria* must include episodes of pain located in the epigastrium and/or right upper quadrant and all of the following: 1. Episodes lasting 30 min or longer

2. Recurrent symptoms occurring at different intervals (not daily) 3. The pain builds up to a steady level 4. The pain is moderate to severe enough to interrupt the patient’s daily activities or lead to an emergency department visit 5. The pain is not relieved by bowel movements 6. The pain is not relieved by postural change 7. The pain is not relieved by antacids 8. Exclusion of other structural disease that would explain the symptoms Supportive criteria 1. The pain may present with one or more of the following: a. Associated with nausea and vomiting b. Radiates to the back and/or right infra-subscapular region c. Awakens from sleep in the middle of the night

† E1. Functional gallbladder disorder Diagnostic criteria* must include all of the following: 1. Criteria for functional gallbladder and sphincter of Oddi disorder The American Journal of GASTROENTEROLOGY

Diagnostic criteria* 1. Recurrent uncontrolled passage of fecal material in an individual with a developmental age of at least 4 years and one or more of the following: a. Abnormal functioning of normally innervated and structurally intact muscles b. Minor abnormalities of sphincter structure and/or innervation c. Normal or disordered bowel habits (i.e., fecal retention or diarrhea) d. Psychological causes

2. Exclusion of all the following: a. Abnormal innervation caused by lesion(s) within the brain (e.g., dementia), spinal cord, or sacral nerve roots, or mixed lesions (e.g., multiple sclerosis), or as part of a generalized peripheral or autonomic neuropathy (e.g., due to diabetes) b. Anal sphincter abnormalities associated with a multisystem disease (e.g., scleroderma) c. Structural or neurogenic abnormalities believed to be the major or primary cause of fecal incontinence *Criteria fulfilled for the last 3 months

† F2. Functional anorectal pain F2a. Chronic proctalgia Diagnostic criteria* must include all of the following: 1. Chronic or recurrent rectal pain or aching

2. Episodes last 20 min or longer 3. Exclusion of other causes of rectal pain such as ischemia, inflammatory bowel disease, cryptitis, intramuscular abscess, anal fissure, hemorrhoids, prostatitis, and coccygodynia *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. VOLUME 105 | APRIL 2010 www.amjgastro.com

Chronic proctalgia may be further characterized into levator ani syndrome or unspecified anorectal pain based on digital rectal examination. F2a.1. Levator ani syndrome: Diagnostic criterion Symptom criteria for chronic proctalgia and tenderness during posterior traction on the puborectalis. F2a.2. Unspecified functional anorectal pain: Diagnostic criterion Symptom criteria for chronic proctalgia but no tenderness during posterior traction on the puborectalis. F2b. Proctalgia fugax Diagnostic criteria* must include all of the following: 1. Recurrent episodes of pain localized to the anus or lower rectum

2. Episodes last from seconds to minutes 3. There is no anorectal pain between episodes For research purposes, criteria must be fulfilled for 3 months; however, clinical diagnosis and evaluation may be made before 3 months.

† F3. Functional defecation disorders Diagnostic criteria* 1. The patient must satisfy diagnostic criteria for functional constipation**

2. During repeated attempts to defecate must have at least two of the following: a. Evidence of impaired evacuation, based on balloon expulsion test or imaging b. Inappropriate contraction of the pelvic floor muscles (i.e., anal sphincter or puborectalis) or less than 20% relaxation of basal resting sphincter pressure by manometry, imaging, or EMG


c. Inadequate propulsive forces assessed by manometry or imaging *Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis. **Diagnostic criteria for functional constipation: (1) Must include two or more of the following: (a) Straining during at least 25% of defecations (b) Lumpy or hard stools in at least 25% of defecations (c) Sensation of incomplete evacuation for at least 25% of defecations (d) Sensation of anorectal obstruction/blockage for at least 25% of defecations (e) Manual maneuvers to facilitate at least 25% of defecations (e.g., digital evacuation, support of the pelvic floor) (f) Fewer than three defecations per week (2) Loose stools are rarely present without the use of laxatives (3) Insufficient criteria for irritable bowel syndrome F3a. Dyssynergic defecation Diagnostic criterion Inappropriate contraction of the pelvic floor or less than 20% relaxation of basal resting sphincter pressure with adequate propulsive forces during attempted defecation. F3b. Inadequate defecatory propulsion Diagnostic criterion Inadequate propulsive forces with or without inappropriate contraction or less than 20% relaxation of the anal sphincter during attempted defecation. Note: disorders presented in ‘†’ represent those referred to in the algorithms and associated text.


801

APPENDIX B

Appendix B