title: Advances in alpha-1-antitrypsin deficiency liver disease.
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.
authors: St. Louis University School of Medicine, Cardinal Glennon Children's Medical Center, 1465 South Grand Blvd., St. Louis, MO, 63104, USA, teckmanj@slu.edu.
authors: Jeffrey H
authors: JH
authors: Teckman
authors: Ajay
authors: A
authors: Jain
mesh_terms: D017209:Apoptosis / Q000235:genetics; D022781:Hepatocytes / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D009154:Mutation; D000515:alpha 1-Antitrypsin / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy
chemical_list: D000515:alpha 1-Antitrypsin