Alpha 1-antitrypsin deficiency pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Alpha-1 antitrypsin (AAT) is a type of protein called a "protease inhibitor." It is made in the liver and it works to protect the lungs and liver. AAT deficiency means there is not enough of this protein in the body. It is caused by a genetic defect in the formation of the 14th chromosome. Additional environmental factors such as smoking may influence the pathophysiologic outcome.

Pathophysiology

Alpha 1-antitrypsin (A1AT) is produced in the liver, and one of its functions is to protect the lungs from the neutrophil elastase enzyme. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of A1AT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ phenotype, A1AT levels are less than 15 % of normal, and patients are likely to develop emphysema at a young age; 50 % of these patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy in such cases will reveal Periodic acid-Shiff (PAS)-positive, diastase-negative granules.

Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha 1-antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a rate of 2000.

Genetics

The alpha-1 AT gene has been located on the long arm of chromosome 14, and has been successfully been sequenced and cloned. There have been 75 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 AT deficiency. Each allele has been given a letter code based upon electrophoretic mobility. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:

• Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
• Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that are < 35% of normal.
• Null – No detectable alpha-1 AT. Least common and most severe form of the disease.
• Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.