[Alpha-1 antitrypsin deficiency: cause and cofactor for liver disease]

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder arising due to mutation in alpha1-antitrypsin (AAT). AAT mutations interfere with the AAT production/secretion, cause decreased AAT serum levels and accumulation of AAT in the liver. The excess AAT leads to a proteotoxic liver disease, while the lack of AAT in systemic circulation predisposes to lung injury. While AATD related lung disease is well understood, liver disease needs further awareness. Non-invasive liver stiffness measurement constitutes a useful method to estimate the extent of liver fibrosis. Significant liver fibrosis occurs in 20-35 % of individuals with the classic, severe genotype Pi*ZZ. Genotype Pi*SZ, also known as the compound heterozygous form, confers an increased risk of both liver fibrosis and liver neoplasia. Even the heterozygous genotype Pi*MZ increases the odds of fibrosis in presence of further risk factors such as obesity, male sex, metabolic syndrome and diabetes mellitus. In individuals with non-alcoholic fatty liver disease or alcohol misuse it promotes the development of liver cirrhosis. While no drug treatment exists for AATD-related liver disease, there are several compounds in clinical phase II/III-trials. These either silence the AAT production via siRNA or facilitate the secretion of AAT from the liver due to an improved folding.