αl-Antitrypsin Deficiency: An Overview

1 αl-antitrypsin is an antiprotease that inhibits the neutrophil elastase enzyme, and belongs to a family of structurally related serine proteinase inhibitors (serpins). Its methionine(358) residue determines the specificity for elastase. 2 The normal M-type al-antitrypsin is mainly synthesized in the liver parenchymal cells and transPorted to the plasma. Abnormal Z-mutant αl-antitrypsin is retained in the endoplasmic reticulum, which leads to its intracellular accumulation and to Markedly decreased plasma levels. 3 In normal conditions, al-antitrypsin protects the lungs from destruction by the proteolytic neutrophil elastase. A protease/antiprotease imbalance in the lung is responsible for the development of emphysema in severe al-antitrypsin deficiency and in cigarette smokers, and accounts for the marked acceleration of e lung disease in smoking al-antitrypsin deficient patients. Smoking has to be avoided in al-antitrypsin deficient patients. Replacement therapy with plasma-derived al-antitrypsin seems indicated in αl-antitrypsin deficient patients with emphysema. Intracellular accumulation of abnormal Z-αl-antitrypsin molecules in liver parenchymal cells may lead to liver disease, ranging from neonatal cholestasis to adulthood cirrhosis and hepatocellular carcinoma.