Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis.

Hereditary hemochromatosis is a genetic disorder of iron metabolism leading to inappropriate iron absorption and iron loading in various organs especially the liver. Despite the genetic mutation being relatively common in those of Anglo Celtic descent, cirrhosis of the liver occurs in only a small proportion of affected individuals. The risk of hepatic fibrosis and cirrhosis relates to the degree of iron loading with threshold hepatic iron concentrations being identified from population studies. However, other environmental and possibly genetic factors appear to modify this risk. Excess alcohol consumption appears to be one of the most important cofactors with steatosis and coexistent viral infection also implicated. Genetic polymorphisms in genes associated with fibrogenesis, antioxidant activity, and inflammation have been investigated in several different forms of chronic liver disease. The variability in the expression of these genes that predispose patients with hemochromatosis to increased risk of severe liver disease is the subject of ongoing investigations. Clearly the progression of iron loading to cirrhosis marks a crucial stage in the natural history of a patient's disease and therefore therapy and prognosis. This review explores recent developments in knowledge of environmental and genetic modifiers of this process.