, 16:367
Date: 15 Dec 2013

Advances in Alpha-1-Antitrypsin Deficiency Liver Disease

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Abstract

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.

This article is part of the Topical Collection on Liver