Clinical Information

Alpha-1-antitrypsin (A1A) is a protein that inhibits the enzyme neutrophil elastase. It is predominantly synthesized in the liver and secreted into the bloodstream. The inhibition function is especially important in the lungs because it protects against excess tissue degradation. Tissue degradation due to A1A deficiency is associated with an increased risk for early onset panlobular emphysema, which initially affects the lung bases (as opposed to smoking-related emphysema, which presents with upper lung field emphysema). Patients may become symptomatic in their 30s and 40s. The most frequent symptoms reported in a National Institute of Health study of 1129 patients with severe deficiency (mean age 46 years) included cough (42%), wheezing (65%), and dyspnea with exertion (84%). Many patients were misdiagnosed as having asthma. It is estimated that approximately one-sixth of all lung transplants are for A1A deficiency.

Liver disease can also occur, particularly in children; it occurs much less commonly than emphysema in adults.

Alpha-1-antitrypsin deficiency is a relatively common disorder in the Northern European White population. The diagnosis of A1A deficiency is initially made by quantitation of protein levels in serum followed by phenotyping-determination of specific allelic variants by isoelectric focusing (IEF), genotyping-DNA based detection of specific variants, or proteotyping using liquid chromatography tandem mass spectrometry (LC-MS/MS). While there are many different alleles in this gene, only 3 are common. The 3 major alleles include M (full functioning, normal allele), S (associated with reduced levels of protein), and Z (disease-causing variant associated with liver disease and premature emphysema). The S and Z alleles account for the majority of the abnormal alleles detected in affected patients. As a codominant disorder, both alleles are expressed. An individual of SZ or S-null genotype may have a small increased risk for emphysema (but not liver disease) due to slightly reduced protein levels. On the other hand, an individual with the ZZ genotype is at greater risk for early onset liver disease and premature emphysema.

Smoking appears to hasten development of emphysema by 10 to 15 years. These individuals should be monitored closely for lung and liver function.

Historically, IEF phenotyping has been the primary method for characterizing variants, though in some cases the interpretation is difficult and prone to error. Serum quantitation is helpful in establishing a diagnosis but can be influenced by other factors. IEF phenotyping, LC-MS/MS proteotyping, and DNA-based genotyping are routinely used to test for deficiency alleles but can miss disease alleles other than the S and Z alleles. In patients suspected to have alpha-1-antitrypsin deficiency based on clinical findings or serum alpha-1-antitrypsin (AAT) levels, who do not have evidence of the SZ or ZZ genotype by routine methods, this gene analysis assay may provide useful information. Full sequencing of the SERPINA1 coding region is performed for the detection of rare non-S or non-Z disease variants.

For more information see Alpha-1-Antitrypsin-A Comprehensive Testing Algorithm.