Alpha-1 Antitrypsin Deficiency Liver Disease

Abstract

Liver disease in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency occurs due to the accumulation of large quantities of AAT mutant Z protein polymers in the liver. The mutant Z protein folds improperly during biogenesis and is retained within the hepatocytes rather than appropriately secreted. These intracellular polymers trigger an injury cascade, which leads to liver injury. However, the clinical liver disease is highly variable and not all patients with this same homozygous ZZ genotype develop liver disease. Evidence suggests that genetic determinants of intracellular protein processing, among other unidentified genetic and environmental factors, likely play a role in liver disease susceptibility. Advancements made in development of new treatment strategies using siRNA technology, and other novel approaches, are promising, and multiple human liver disease trials are underway.

Keywords: Autophagy; ERAD; Protein polymer; Proteolysis; siRNA.