Hemochromatosis: discovery of the HFE gene

Abstract

Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about 1 in 250 individuals. HH results in an increased absorption of iron at the baso-lateral surface of the enterocyte with aberrant regulation of ferroportin-mediated transfer of iron in turn brought on by a decrease in circulating hepcidin. The medical literature describes a colorful history of HH with important contributions from faculty at Saint Louis University.

Figure 1

In the duodenal enterocyte, dietary iron is reduced to the ferrous state by duodenal ferric reductase (Dcytb), transported into the cell by divalent metal transporter 1 (DMT1), and released by way of ferroportin into the circulation. Hephaestin facilitates enterocyte iron release. Hepatocytes take up iron from the circulation either as free iron or transferrin-bound iron (through transferrin receptor 1 and transferrin receptor 2). Transferrin receptor 2 may serve as a sensor of circulating transferrin-bound iron, thereby influencing expression of the iron regulatory hormone hepcidin. The hepcidin response is also modulated by HFE and hemojuvelin. Hepcidin is secreted into the circulation, where it down-regulates the ferroportin-mediated release of iron from enterocytes, macrophages, and hepatocytes (dashed red lines).

Figure 2

Low power view of liver biopsy sample from a patient with C282Y homozygous hemochromatosis. Iron stains blue and is found in hepatocytes with a periportal to pericentral gradient (Perls’ Prussian blue, x 100).