Advances in alpha-1-antitrypsin deficiency liver disease

Alpha-1-antitrypsin (a1AT) deficiency is a common, but under-diagnosed, genetic disease. In the classical form, patients are homozygous for the Z mutant of the a1AT gene (called ZZ or PIZZ), which occurs in 1 in 2,000-3,500 births. The mutant Z gene directs the synthesis of large quantities of the mutant Z protein in the liver, which folds abnormally during biogenesis and accumulates intracellularly, rather than being efficiently secreted. The accumulation mutant Z protein within hepatocytes causes liver injury, cirrhosis, and hepatocellular carcinoma via a cascade of chronic hepatocellular apoptosis, regeneration, and end organ injury. There is no specific treatment for a1AT-associated liver disease, other than standard supportive care and transplantation. There is high variability in the clinical manifestations among ZZ homozygous patients, suggesting a strong influence of genetic and environmental modifiers. New insights into the biological mechanisms of intracellular injury have led to new, rational therapeutic approaches.