THE PATHOGENESIS OF HEREDITARY HEMOCHROMATOSIS

Abstract

Hereditary hemochromatosis (HH) is an iron overload disease which can result from mutations in HFE, transferrin receptor 2 (TfR2), hemojuvelin (HJV) or hepcidin, all of which lead to inadequate synthesis of the iron‐regulatory hormone hepcidin. Hepcidin deficiency in HH results in excessive iron absorption. In normal homeostasis, hepcidin production is increased by iron loading. In HH, however, hepcidin is inappropriately low for the degree of iron load suggesting that HFE, TfR2 and HJV may be involved in hepcidin regulation by iron.We explored hepcidin regulation by iron in three mouse models of HH: TfR2 mutants, HFE ‐/‐ and HJV‐/‐. HFE−/− and TfR2m/m had a dramatically blunted response to 1 d iron feeding. HFE‐/‐ also failed to increase hepcidin even after 21 d on iron diet but TfR2m/m increased hepcidin comparable to wt mice. This suggests there are two types of iron signals regulating hepcidin, one likely involving circulating iron and depending on both HFE and TfR2 (acute signal) and the other involving HFE but not TfR2 (chronic signal). HJV−/− mice, which had extremely low hepcidin mRNA expression, were not able to increase hepcidin after 1, 7 or 21 d of iron diet, indicating that apart from setting hepcidin baseline, HJV may also be necessary for hepcidin regulation by iron. HH can thus result from both decreased hepcidin baseline and the loss of hepcidin response to acute or chronic changes in iron levels.