Liver Disease in α1-Antitrypsin Deficiency

Liver disease affects a subgroup of homozygotes for the classical form of α1-antitrypsin deficiency (ATD). There are at least four forms of this disease with onset in infancy, in childhood, in adolescence, and at 50–65 years of age. The liver disease is mostly slowly progressive and characterized by fibrosis and cirrhosis with minimal inflammation. These patients also have increased susceptibility to hepatocellular carcinoma (HCC). The pathobiology of liver injury in ATD is not completely understood, but we know that it involves a gain-of-function mechanism in which accumulation of misfolded α1-antitrypsin Z (ATZ) in the early compartments of the secretory pathway is proteotoxic for the liver cells. Intracellular pathways for degradation of misfolded ATZ, particularly the autophagic pathway, are believed to play a critical role, and FDA-approved drugs that enhance autophagy and can be repurposed appear to be attractive candidates for treatment. Several other promising drug-, cell-, or gene-based therapeutic strategies are being developed for this liver disease.