The discovery of
hepcidin in 2000 and the subsequent unprecedented explosion of research and discoveries in the
iron field have dramatically changed our understanding of human disorders of
iron metabolism. Today, hereditary
hemochromatosis, the paradigmatic
iron-loading disorder, is recognized as an
endocrine disease due to the genetic loss of
hepcidin, the
iron hormone produced by the liver. This syndrome is due to unchecked transfer of
iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It is caused by mutations that affect any of the
proteins that help
hepcidin to monitor serum
iron, including HFE and, in rarer instances,
transferrin-receptor 2 and hemojuvelin, or make its receptor
ferroportin, resistant to the
hormone. In Caucasians, C282Y HFE homozygotes are numerous, but they are only predisposed to
hemochromatosis; complete organ disease develops in a minority, due to
alcohol abuse or concurrent genetic modifiers that are now being identified. HFE gene testing can be used to diagnose
hemochromatosis in symptomatic patients, but analyses of liver histology and full gene sequencing are required to identify patients with rare, non-HFE forms of the disease. Due to the central pathogenic role of
hepcidin, it is anticipated that nongenetic causes of
hepcidin loss (eg,
end-stage liver disease) can cause acquired forms of
hemochromatosis. The mainstay of
hemochromatosis management is still removal of
iron by phlebotomy, first introduced in 1950s, but identification of
hepcidin has not only shed new light on the pathogenesis of the disease and the approach to diagnosis, but etiologic therapeutic applications from these advances are now foreseen.