Alpha-1-antitrypsin deficiency: diagnosis, pathophysiology, and management

Alpha-1-antitrypsin deficiency is a relatively common but under-recognized genetic disease in which individuals homozygous for the mutant Z disease-associated allele are at risk for the development of liver disease and emphysema. The protein product of the mutant Z gene is synthesized in hepatocytes but accumulates intracellularly rather than being appropriately secreted. The downstream effects of the intracellular accumulation of the mutant Z protein include the formation of unique protein polymers, activation of autophagy, mitochondrial injury, endoplasmic reticulum stress, and caspase activation, which subsequently progress in a cascade, causing chronic hepatocellular injury. The variable clinical presentations among affected individuals suggest an important contribution of genetic and environmental disease modifiers, which are only now being identified. The heterozygous carrier state for the mutant Z gene, found in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.