The classic form of α1-antitrypsin (α1-AT) deficiency is the most common genetic cause of liver disease in childhood. It also causes chronic liver disease and hepatocellular carcinoma in adults. The protein that is altered in this deficiency is a secretory glycoprotein predominantly derived from the liver and predominantly functioning as an inhibitor of neutrophil elastase. In the deficiency, a point mutation in the α1-AT Z molecule leads to altered folding and polymerization/aggregation such that soluble and insoluble α1-AT Z accumulate in the endoplasmic reticulum of liver cells. Liver inflammation and carcinogenesis are caused by a gain-of-toxic function mechanism involving the toxic effects of polymerized/aggregated mutant α1-AT retained within liver cells. Nevertheless, only 8% of the homozygous population develops clinically significant liver disease in the first 30 years of life, indicating that genetic and/or environmental modifiers determine the incidence and severity of liver disease in α1-AT deficiency. Altered migration of the abnormal α1-AT molecule in isoelectric focusing gels is the basis of the diagnosis of this deficiency. Although several new concepts for pharmacologic treatment are currently being investigated management of this liver disease is mostly supportive. Liver replacement therapy has been used successfully for severe liver disease.
- Aggregation-prone proteins
- Chronic obstructive pulmonary disease
- Hepatocellular carcinoma
- Proteasomal degradation pathway
- Protein homeostasis