Specific diseases Alpha-1-antitrypsin def		Alpha-1-antitrypsin (A1AT) is the prototype of a family of structurally related proteins called serpins (serine protease inhibitors) that includes antithrombin III, alpha-1-antichymotrypsin, C1 inhibitor and protein C inhibitor among others. A1AT's most important target is neutrophil elastase and other protease enzymes released by activated PMNs. Variants of A1AT are classified according to the protease inhibitor (PI) phenotype system. These variants are inherited as codominant alleles. They are assigned letters according to their migration on gel electrophoresis. The most common normal variant is MM; the most common deficiency variant is ZZ. The gene for A1AT is located on chromosome 14 (14q31). The mutant gene of the PI ZZ phenotype produces an A1AT with a single amino acid substitution. This, in turn, results in an abnormally folded molecule that is unable to pass through its secretory pathway and is retained in the endoplasmic reticulum (ER) of the liver, the predominant site of A1AT synthesis. There is an 85-90% reduction in serum levels, due to both the decreased secretion and decreased synthesis from the hepatotoxicity from the retained A1AT. 10-15% of the deficient ZZ population develop clinically significant liver disease in the first 20 years of life. The liver disease is thought to be due to the accumulation of A1AT in the ER of hepatocytes. It usually presents with typical cholestatic features - jaundice, hepatomegaly, dark urine, elevated direct bilirubin and LFTs - in the first 1-2 months of life. A1AT levels are significantly decreased and PI typing reveals the abnormal phenotype. Liver biopsy, while not necessary for the diagnosis, shows the distinctive PAS-positive diastase-resistant globules in the ER of hepatocytes. 65% of ZZ individuals develop clinically significant lung disease in adulthood. Characterized by emphysema, it is due to the unrestricted action of neutrophil elastase on the connective tissue of the lung. A well-known factor that aggravates and accelerates the emphysema in A1AT-deficient patients is cigarette smoking. Management of the liver disease is entirely symptomatic. If cirrhosis progresses to liver failure, liver transplant is an option. However, most patients with A1AT deficiency have only mild hepatic impairment. Even so, they should all be cautioned against cigarette smoking. Trials of synthetic androgens like danazol have been conducted in A1AT deficiency because of their effectiveness in hereditary angioedema, which is a deficiency of C1 inhibitor, also in the serpin family. However the increase in A1AT levels with treatment is small and only half of deficient patients respond. Replacement therapy with recombinant A1AT (IV or aerosol) is being used for patients with established emphysema. It results in increased serum A1AT levels and increased neutrophil elastase inhibitory activity in lung fluid. However it is NOT indicated for patients with liver disease. The decreased serum levels are secondary to the liver injury, not the cause of it. Return to top of page