Hereditary hemochromatosis is an iron storage disease that results in the impairment of organ structure and function. The iron is stored predominantly as hemosiderin. The liver, heart, pancreas, endocrine organs, skin, and joints are principally affected. Cirrhosis, cardiomyopathy, diabetes mellitus, hypogonadism, skin pigmentation, and arthritis may occur with full clinical expression.

The iron enters the body via the gastrointestinal tract, because of a failure of the mechanism controlling the absorption of dietary iron. Hereditary hemochromatosis is most commonly the consequence of mutations in a gene that has been designated HFE, located approximately 4 megabases telomeric to the HLA-A locus on the short arm of chromosome 6; the gene defect causes the absorption of more iron than is required. Some patients with hereditary hemochromatosis have some other defect, as yet unknown, not linked to the HLA loci. A clinical and pathologic state of iron loading, similar to that of hereditary hemochromatosis, also occurs as a result of the iron burden caused by red cell transfusion and increased gastrointestinal iron absorption in patients with refractory anemias and thalassemia. African iron overload also resembles hereditary hemochromatosis in some respects; it is due to drinking indigenous beers containing large amounts of iron, possibly combined with a non-HLA-linked genetic abnormality.

The nature of the metabolic defect caused by mutations of HFE has not been elucidated. The normal protein appears to bind to the transferrin receptor and to change its affinity for transferrin, but the physiological significance of this interaction is not yet fully understood. Three mutations are known. One of these, 845G→A (C282Y;845A), prevents the formation of a disulfide bond essential for the binding to β2-microglobulin. This prevents transport of the HFE protein to the cell surface. The 187C→G (H63D) mutation appears to affect the binding of HFE to the transferrin receptor. A third, less common mutation, 193A→T (S65C), is less well studied and of unknown importance, at present. A condition closely resembling human hereditary hemochromatosis can be produced by targeted disruption of a homologous gene in mice.

The frequency of heterozygotes for the 845A (C282Y) mutations in central, northern, and western Europe ranges between 8 percent to 18 percent, indicating that 1 in 100 to 1 in 625 persons are homozygotes. The clinical manifestation rate (penetrance) and natural history of hemochromatosis among homozygotes for the 845A (C282Y) mutation are not yet known. The 845A (C282Y) mutation is absent from Asian and African populations, and is less frequent among southern Europeans and Ashkenazi Jews. The 187C→G (H63D) mutation is more common (about 24 percent heterozygotes among Europeans) and has a more widespread population distribution than the 845A (C282Y) mutation. The 845A (C282Y) mutation distribution suggests Celtic origin and it may have reached a high frequency because of survival and fertility advantages of 845G (C282Y) heterozygotes vis-a-vis iron deficiency.

About 75 to 85 percent of clinically recognized hemochromatosis patients of central, northern, and western European origin are homozygotes for the 845A (C282Y) mutation. The penetrance of the compound heterozygous state for the 845A/187G (282Y/463D) mutation is only about 1 percent of that of the homozygotes. An occasional 187G (H63D) homozygote with hemochromatosis has been reported. Some patients with hereditary hemochromatosis have some other defect not linked to the HLA loci and as yet of unknown origin.

Once clinical manifestations have appeared, hemochromatosis can be fatal unless the iron is removed. If untreated, death may occur as a result of cirrhosis, hepatoma, cardiac failure, arrhythmias, overwhelming infection, or diabetes. Removal of the iron is most conveniently achieved in hereditary hemochromatosis by weekly venesections of 400 to 500 ml of blood. These must be continued until a state of mild iron deficiency is achieved. Thereafter, a venesection every 3 to 4 months or less frequently is sufficient to prevent reaccumulation of iron. In refractory anemias the iron can be eliminated only by administering deferoxamine, which is infused over 10 to 12 h out of every 24, usually subcutaneously.

Removal of the iron in hereditary hemochromatosis prolongs survival, cures the cardiomyopathy and the skin pigmentation, and arrests the liver damage. Diabetes may improve, but hypogonadism and arthropathy do not, and hepatoma may complicate cirrhosis even years later.

Because hereditary hemochromatosis is a potentially lethal disease, every effort should be made to achieve early diagnosis. In particular, physicians who specialize in hepatology, cardiology, diabetes, endocrinology, and rheumatology should cultivate a high index of clinical suspicion. It is even more important to diagnose affected homozygotes before the development of significant iron overload. If venesections can be instituted before organ damage has occurred, the consequences of organ damage can be avoided. In this context, appropriate case detection and genetic counseling, especially in sibs, is mandatory.