α-1-Antitrypsin (α1AT) is a serum glycoprotein synthesized in the liver. The majority of patients with α1AT deficiency liver disease are homozygous for the Z mutant of α1AT (called ZZ or 'PIZZ'). This mutant gene directs the synthesis of an abnormal protein which folds improperly during biogenesis. Most of these mutant Z protein molecules undergo proteolysis; however, some of the mutant protein accumulates in hepatocytes. Hepatocytes with the largest mutant protein burdens undergo apoptosis, causing compensatory hepatic proliferation. Cycles of hepatocyte injury, cell death and compensatory proliferation results in liver disease ranging from mild asymptomatic enzyme elevations to hepatic fibrosis, cirrhosis and hepatocellular carcinoma. There is a high variability in clinical disease presentation suggesting that environmental and genetic modifiers are important. Management of α1AT liver disease is based on standard supportive care and liver transplant. However, increased understanding of the cellular mechanisms of liver injury has led to new clinical trials.
Keywords: apoptosis; autophagy; hepatocellular proliferation; liver; α-1-antitrypsin.