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Iron out. Iron builds up in mice with defective HFE genes (top), but not when a hepcidin gene is added (bottom).

Ironing Out Hemochromatosis

A recently discovered peptide can prevent the iron buildup associated with a common genetic disorder, a new study finds. The disorder, called hereditary hemochromatosis, affects one in every 200 to 300 people, making it the most prominent of all known genetic maladies. The study points the way to new treatments for the disease.

Although iron deficiency is the world's worst nutritional problem, it's possible to have too much of a good thing. Patients with hereditary hemochromatosis--most of whom have two defective copies of a gene called HFE--absorb surplus iron from their diets, overloading their bodies with the metal, which can lead to widespread organ damage. Although the precise role of HFE in regulating iron flux has remained mysterious, scientists have suspected that the answer may come from some kind of "iron hormone," a molecule predicted to relay signals from the liver--which detects blood iron levels--to the gut. In particular, a hormone that can dampen iron absorption would help explain what goes wrong in hereditary hemochromatosis, because the loss of such a hormone would likely lead to the excessive iron uptake.

Now, a team led by Sophie Vaulont, a molecular biologist at the Cochin Institute in Paris, has provided strong evidence that the long-sought iron hormone is hepcidin. This small peptide is expressed at abnormally low levels in patients with hereditary hemochromatosis. Earlier work by Vaulont's group and others had shown that high iron levels trigger the liver to make hepcidin and that elevated hepcidin lowers the amount of iron in the body. In their current paper, published online this week by Nature Genetics, Vaulont, postdoctoral researcher Gaël Nicolas, and colleagues tested the importance of low hepcidin production in hereditary hemochromatosis. They treated mice, which like humans with the disease had defective copies of the HFE gene, by adding a gene for hepcidin. Mice without the added gene showed the toxic iron buildup characteristic of the disease, but livers of mice with the transgene showed "no iron accumulation whatsoever," says Vaulont. And that, she adds, means a lack of hepcidin really does cause hereditary hemochromatosis.

"It's a very interesting and important paper," says Hal Drakesmith, a molecular biologist at the Weatherall Institute of Molecular Medicine in Oxford, U.K. He agrees that hepcidin could "in theory" provide a treatment for hereditary hemochromatosis. This would be a dramatic step beyond the current therapy of choice--ancient but effective--of bloodletting, the periodic removal of blood from the patient to eliminate excess iron.

Related sites
CDC's page on iron overload and hemochromatosis
The American Hemochromatosis Society
Hemochromatosis information from the National Digestive Diseases Information Clearinghouse