Hereditary Hemochromatosis

Iron is an essential metal involved in oxygen transport mediated by hemoglobin in mammals and in the activity of various enzymes, including catalase. Both deficiency and overload may cause such serious conditions in humans as anemia and hemochromatosis, respectively.

Iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species.

Hereditary hemochromatosis is a genetic iron overload disorder that in the past was difficult to diagnose until the progressive accumulation of iron, mainly in the form of ferritin and hemosiderin, caused solid organ injury, particularly to the liver, heart, and pancreas (especially insulin-secreting Β-cells). Recently, HFE, the gene responsible for hereditary hemochromatosis, was identified by a positional cloning approach (OMIM + 235200). HFE is related to major histocompatibility complex class I proteins, and is mutated in hereditary hemochromatosis. Two point mutations, C282Y and H63D, have been linked to the majority of disease cases.

Hereditary hemochromatosis is usually inherited in an autosomal-recessive manner. Unfortunately, the exact role of HFE is still unclear at present. A mutation in the gene encoding SLC40A1 (OMIM #606069) is associated with an autosomal-dominant type of hemochromatosis. It is of note that defects in HAMP (OMIM #602390) or in transferrin receptor 2 (OMIM #604250) also induce hemochromatosis.