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 deficiency (A1AD) occurs from a lack of liver production of Alpha 1-antitrypsin (A1AT). 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.