Liver injury in α1-antitrypsin deficiency: an aggregated protein induces mitochondrial injury
Authors: David H. Perlmutter
Journal: Journal of Clinical Investigation (2002)

α1-Antitrypsin (α1AT), the archetype of the Serpin supergene family, is the principal blood-borne inhibitor of destructive neutrophil proteases including elastase, cathepsin G, and proteinase 3 (reviewed in ref. 1). This glycoprotein, is secreted by liver cells and is considered an acute-phase reactant because its plasma levels increase during the host response to inflammation/tissue injury. The classical form of α1AT deficiency, which affects 1 in 1,800 live births in Northern European and North American populations, is associated with a mutant molecule termed α1ATZ, which is retained as a polymer in the endoplasmic reticulum (ER) of liver cells (reviewed in refs. 2, 3). Homozygotes are predisposed to premature development of pulmonary emphysema by a loss-of-function mechanism in which lack of α1AT in the lung permits uninhibited proteolytic damage to the connective tissue matrix (4, 5). Cigarette smoking markedly increases the risk and rate of development of emphysema (6). One mechanism for this environmental risk factor involves the functional inactivation of residual α1AT by phagocyte-derived active oxygen intermediates (4, 5). However, a growing body of evidence suggests that other environmental factors and genetic traits affect the incidence and severity of lung disease among α1AT-deficient individuals (7). It is still not entirely clear whether heterozygotes for α1ATZ are predisposed to lung disease.

Homozygotes for α1ATZ (“PIZZ” individuals) are also at risk for liver disease. In fact, α1AT deficiency is the most common genetic cause of liver disease in children (2, 3), and it predisposes adults to chronic liver disease and hepatocellular carcinoma (8). However, in contrast to the pathobiology of lung disease, liver injury in this deficiency appears to involve a gain-of-function mechanism whereby retention of the mutant α1ATZ molecule in the ER triggers a series of events that are eventually hepatotoxic. The strongest evidence for a gain-of-function mechanism comes from studies in which mice transgenic for mutant human α1ATZ develop liver injury with many of the histopathologic hallmarks of the human condition (9, 10). Because there are normal levels of anti-elastases in these mice, as directed by endogenous genes, the liver injury cannot be attributed to a loss of function.

Landmark nationwide prospective screening studies done by Sveger in Sweden have documented an extraordinary variation in the phenotypic expression of liver disease among homozygotes. In these studies, only 10–15% of the PIZZ population developed clinically significant liver disease over the first 20 years of life (11, 12). These data indicate that other genetic traits and/or environmental factors predispose a subgroup of PIZZ individuals to liver injury. Because only a subgroup of homozygotes develop liver disease and because there is an inherent bias in ascertainment in other clinical studies of α1AT deficiency, it has been very difficult to determine whether heterozygous (“PIMZ”) individuals are at increased risk for liver disease.