Pathogenesis of hereditary hemochromatosis: genetics and beyond

Hereditary hemochromatosis (HH) comprises several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and secondary tissue iron deposition. The most common form of this disorder is called HFE-related HH and is caused by homozygosity for the C282Y mutation in the HFE gene. Recently, other less common hereditary forms of iron overload have been recognized and are designated as non-HFE-related HH. The identification and cloning of HFE and other genes involved in iron metabolism has greatly expanded our understanding of many aspects of HH. The introduction of a commercially available genetic test for the C282Y and H63D mutations of HFE allows presymptomatic diagnosis, and adds precision to studies of the population genetics of HFE-related HH. It is now recognized that a substantial proportion of C282Y homozygotes does not develop clinically significant iron overload, and modifier genes may be involved in this phenomenon. Mouse models of HH and cell culture studies have increased our understanding of the normal physiology and pathophysiology of iron homeostasis. Future investigations will refine our knowledge of the mechanisms of action of HFE protein, the phenotypic variability observed in persons homozygous for the C282Y mutation, and the mechanisms responsible for non-HFE-related HH.