Affiliation: St. Louis University School of Medicine, Cardinal Glennon Children’s Medical Center, 1465 South Grand Blvd., St. Louis, MO 63104, USA.
Alpha-1-antitrypsin (a1AT) Deficiency is a common, but under recognized metabolic genetic disease in which individuals homozygous for the mutant Z a1AT gene are at risk for liver and lung disease. ZZ homozygotes occur in approximately 1 in 2000 births in North American and European populations. a1AT is a protein synthesized in large quantities by the liver, and then secreted into serum and extracellular fluid. Its physiologic function is to inhibit neutrophil proteases during periods of inflammation in order to protect host tissues from non-specific inflammatory injury. The mutant Z gene of a1AT directs the synthesis of a mutant protein which folds abnormally in the endoplasmic reticulum of hepatocytes during biogenesis and is retained intracellularly rather than being efficiently secreted. The lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. Cigarette smoking has been identified as an especially strong risk factor for the development of a1AT associated emphysema. The intracellular accumulation of a1AT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma. This liver injury is the result of an intracellular cascade which includes aspects of ER stress, caspase activation, and apoptotic cell death, which leads to compensatory hepatocellular proliferation, fibrosis and cirrhosis. There is no specific treatment for ZZ associated liver disease, other than standard liver disease supportive care and liver transplantation. There is a high degree of variability in the clinical manifestations among ZZ homozygous patients, suggesting a strong influence of genetic and environmental disease modifiers. Studies of the processes of intracellular injury, and of new therapies for this disease, are areas of intense and ongoing investigation.