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Evidence-Based Laboratory Medicine. Test Utilization Recommendations. From. Metropolitan Medical Laboratory, PLC. Alpha-1-Antitrypsin Deficiency:.
Evidence-Based Laboratory Medicine Test Utilization Recommendations From Metropolitan Medical Laboratory, PLC Alpha-1-Antitrypsin Deficiency: A clinically under-recognized, but NOT rare diagnosis • • • • •

Alpha-1-antitrypsin (A1AT) deficiency is not uncommon, in fact it is one of the most common genetic disorders in Caucasians, and is reported to be one of the most common, serious, single-locus genetic diseases in the world. Its frequency is similar to that of Cystic Fibrosis. One in ten patients with chronic obstructive pulmonary disease (COPD) are either deficient in A1AT or a carrier of the gene that causes the condition. A1AT deficiency is the major known genetic risk factor for the 4th leading cause of death in the USA, chronic obstructive lung disease. This deficiency is the most common reason for liver transplant in the pediatric population. Cirrhosis and liver carcinoma in adults affects about 30-40% of those with A1AT deficiency. The WHO has recently strongly recommended that all individuals with COPD, early onset emphysema, asthma, chronic bronchitis and/or chronic liver disease be tested for A1AT deficiency.

Establishing the diagnosis of A1AT deficiency is important because: 1. Specific, effective therapy is available. There are three commercial FDA approved protein replacement products that can be used to prevent further damage to the lungs. 2. A1AT-deficient individuals are uniquely susceptible to exposure to chemical and particulate environmental agents. 3. Recent studies have demonstrated that significant positive effects are associated with identification of A1AT-deficient individuals. Increased willingness to stop cigarette smoking occurred in 75% of the study participants. 4. It may provide important information for family members.

What is A1AT deficiency? A1AT deficiency is a genetic disorder characterized by accumulation of A1AT in the liver. The accumulation within the liver cells occurs because of a structural abnormality of the A1AT protein that prevents normal secretion from the hepatocyte, with resultant deficiency of A1AT in the blood. The role of A1AT is to defend the lung against breakdown by the degradative enzyme, neutrophil elastase (an enzyme released in response to inflammatory or infectious insults). Deficiency of blood levels of A1AT below a protective threshold value will predispose the affected individual to emphysema. This usually by 40 years of age. Testing for A1AT deficiency A1AT Quantification: The diagnosis is initially made by quantitation of A1AT protein levels in plasma which can be reflexed to a genotype determination. The lower the level of A1AT – the greater the risk of developing emphysema. (A low concentration of abnormal A1AT in blood may also lead to liver disease because of the buildup of dysfunctional A1AT in the liver cells.) A1AT Genotyping: There are three important alleles: M Normal allele S Associated with reduced levels of A1AT Z Disease causing mutation associated with liver disease and premature emphysema The Z and S account for the majority of the abnormal alleles detected in affected patients and these two will be specifically tested for by Genotyping. When Quantification and Genotyping are discordant, A1AT Phenotyping is recommended.

Phenotype MM MZ MS SS SZ ZZ

Plasma Level of AAT (mg/dL)) 150-350 90-210 90-210 100-140 75-120 20-45

Emphysema Risk No increase Mild increase Mild increase Mild increase Moderate increase HIGH RISK

NOTE: A1AT is an acute phase reactant. Inflammation, infection or trauma can cause elevation of result and obscure abnormally low value.

3 Review of Metro’s Alpha-1-Antitrypsin (A1AT) Orders •

1,037 Patients Tested for A1AT Level

531 Males 506 Females Ages: 4-89 years 28% of Males