Hereditary hemochromatosis.

The advent of the genetics era has profoundly changed the way we look at iron related diseases, particularly hemochromatosis. New discoveries have challenged historical concepts about the disease, such as its monogenic nature, intestinal origin or complete phenotypic penetrance. This review presents a new concept of hemochromatosis which stems from the idea that, beyond their genetic diversities, all known hemochromatoses have in common the same metabolic abnormality: the genetically determined failure to prevent unneeded iron from entering the circulatory pool. Inappropriate levels of hepcidin, the iron hormone, appear now as the central pathogenic event in all forms of hemochromatosis: depending on the protein involved, and its effect on hepatic production of hepcidin, the phenotype varies, ranging from massive early-onset iron loading with severe organ disease (e.g., associated with homozygous mutations of hemojuvelin or hepcidin itself) to the milder late-onset phenotype characterizing the classic and highly prevalent HFE-related form or the rare transferrin receptor 2-related form. In vitro and in vivo studies will be needed to dissect the consequences of each hereditary hemochromatosis allele and increase our understanding of the precise contribution of each gene to the hereditary hemochromatosis phenotype.