Alpha 1 Antitrypsin

Alpha 1 antitrypsin (AAT) is a glycoprotein synthesized primarily by hepatocytes and transported by the bloodstream to the lungs. It is a member of the serine protease inhibitor (serpin) super-family of proteins, which are the most abundant proteinase inhibitors in plasma. Their major function is to protect tissue from damage by proteolytic enzymes. A broad range of proteases is inhibited including neutrophil elastase, proteinase 3, cathepsin G, pancreatic elastase, trypsin, chymotrypsin, and collagenases. Despite its name, AAT reacts with neutrophil elastase much more readily than with trypsin and represents a major defense mechanism against elastase produced by neutrophils in the lower respiratory tract. Alpha 1 antitrypsin deficiency can lead to the development of pulmonary emphysema, hepatic cirrhosis, and hepatocellular carcinoma in children and adults.

Alpha 1 antitrypsin deficiency is an autosomal recessive disorder. A codominant gene that is located on chromosome 14 controls the level of alpha 1 antitrypsin. Deficiency is usually attributable to a single amino acid substitution that alters carbohydrate binding and impairs release from hepatocytes. More than 100 allele variations have been discovered and more than 10 have been associated with deficient phenotypes. AAT genotypes that confer an increased risk for developing emphysema are those that result in plasma AAT levels below the protective threshold of 50 mg/dL (11 umol/L).

Phenotypes are classified by a coding system, in which the inherited alleles are usually letters that denote the migration of the molecule in an isoelectric focusing pH gradient from A (anodal variants) to Z (for slower migrating variants). The normal allele of alpha 1 antitrypsin is referred to as M and approximately 95% of Caucasians have a homozygous M genotype. Plasma levels exceed 90 mg/dL.

Clinical & Serum Concentrations of AAT Phenotypes


Prevalence %



Emphysema Risk



20 – 53

150 – 350




18 – 52

110 – 340




17 – 33

90 – 210




15 – 33

100 – 200




8 – 16

75 – 120

20 – 50%



2 – 7

20 – 45

80 – 100%

Null Null





The most common variant that causes more than 95% of the cases of severe AAT deficiency is the Z allele. Patients with the MZ genotype have a wide range of AAT levels and may be more susceptible to various pulmonary diseases. In the United States, the estimated prevalence of heterozygous Z genotypes is 2 to 4% and the prevalence of the homozygous ZZ genotype is 0.02 to 0.04%. Homozygotes have plasma AAT levels below 23 mg/dL (5 umol/L) and is associated with familial emphysema or infantile cirrhosis. Abnormal Z proteins self-aggregate and produce large complexes that accumulate in hepatoctyes and cause liver damage. They are not secreted into the bloodstream and never reach the lungs. Almost all ZZ neonates have evidence of liver disease at birth, which usually progresses to cirrhosis. In adults, 50% of PiZ (either heterozygous or homozygous) positive individuals develop cirrhosis and 31% develop hepatocellular carcinoma.

In the United States, 3 to 8% of individuals have a heterozygous S genotype and 0.05% has a homozygous genotype. Homozygous SS genotype causes less severe disease than the ZZ genotype. Homozygous individuals have plasma AAT concentration approximately 60% of normal. Some individuals may have a combination of S and Z variants (SZ genotype). SZ patients have AAT levels that are 30 to 40% of normal and are at increased risk of lung and liver disease.

MZ and MS heterozygotes usually do not develop clinical disease. They produce enough enzyme inhibitor to protect the lungs provided they do not smoke or work in a polluted environment. Heterozygotes that develop chronic liver disease are often positive for hepatitis B or C markers.

Rarely, a patient cannot synthesize any alpha 1 antitrypsin. This variant is called the null variant or PIQ0 genotype and is associated with a high risk of emphysema but not with liver disease.

Because alpha 1 antitrypsin is an acute phase reactant, serum levels may be falsely normal with infection or inflammation. Falsely low values may occur with malnutrition, protein losing disorders, or end stage liver disease.

Serum protein electrophoresis can be used to diagnose alpha 1 antitrypsin deficiency, because it comprises almost 80% of the alpha-1 globulins. Diagnosis can be confirmed by quantitation of alpha-1 antitrypsin levels in serum by nephelometry. Reference range is 110 - 200 mg/dL.

Alpha 1 antitrypsin genotyping should be ordered for patients who have levels below 125 mg/dL to determine if they have a heterozygous or homozygous deficiency. Genotyping is also indicated for patients with higher levels, who have coexisting inflammatory disorders. A deficiency may be masked during the acute phase reaction. The genotyping report includes the alleles detected.

Specimen requirement is one plain red top or SST tube of blood.

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