Inadequate hepcidin synthesis leads to iron overload in HFE-related hemochromatosis. We explored the regulation of hepcidin by iron in 88 hemochromatosis patients (61 C282Y/C282Y, 27 C282Y/H63D) and 23 healthy controls by analyzing urinary hepcidin before and 24 hours after a 65-mg oral iron dose. Thirty-four patients were studied at diagnosis and had iron overload, and 54 patients were iron depleted. At diagnosis, hepcidin values in C282Y homozygotes were similar to controls, whereas values in C282Y/ H63D heterozygotes were higher (P ‫؍‬ .02).However, the hepcidin/ferritin ratio was decreased in both homozygotes (P < .001) and heterozygotes (P ‫؍‬ .017), confirming the inadequate hepcidin production for the iron load with both genotypes. In iron-depleted patients of both genotypes studied at a time remote from phlebotomy, basal hepcidin was still lower than in controls (P < .001 for C282Y/C282Y and P ‫؍‬ .002 for heterozygotes). After an iron challenge, mean urinary hepcidin excretion increased in controls (P ‫؍‬ .001) but not patients, irrespective of genotype and iron status. Significant hepcidin increase ( > 10 ng/mg creatinine) was observed in 74% of controls, 15% of homozygotes, and 32% of heterozygotes. The hepcidin response to oral iron is blunted in HFE IntroductionHereditary hemochromatosis (HH) is an autosomal recessive disorder of systemic iron regulation in which dietary iron absorption is inappropriately high. In some patients this may lead to progressive iron loading and damage to the liver and other parenchymal organs. Most patients of Northern European ancestry are homozygous for the C282Y mutation of the HFE gene, and a minority are compound heterozygotes for the C282Y/H63D mutations. Other HFE or other gene mutations are rare 1 . Newly available molecular tests have made it possible to accelerate the diagnosis to a preclinical stage and avoid the need for liver biopsy. In the preclinical stage, most patients display only alterations of iron parameters and/or of liver function tests. 2 Although the C282Y/C282Y genotype is frequent, the clinical disease is relatively uncommon, and its natural history is not well defined. Disease expression may be influenced by age, sex, environmental, and genetic modifiers. [3][4][5] No progression to clinical disease was reported in 2 prospective studies on a small number of C282Y homozygotes followed up for 17 and 25 years, respectively. 6,7 These observations suggest that among subjects with at-risk genotypes, only a subgroup develop enough iron overload to induce clinical complications. Since it is not feasible to predict the outcome of patients based only on blood iron studies, it is common clinical practice that all HFE mutated individuals with altered iron parameters undergo iron depletion by phlebotomy.Iron overload in all genetic types of hemochromatosis, except those due to ferroportin mutations, is explained by the insufficiency of the hepatic peptide hepcidin, 8 the key regulator of systemic iron homeostasis. Hepcidin binds to the iron exporter ferr...

In males, hypertension is characterized by a higher prevalence of increased iron stores and metabolic abnormalities that are part of the IRHIO syndrome. This finding may have clinical implications due to the increased risk of IRHIO patients to develop hepatic cirrhosis and also for the role of iron in early atherogenesis.

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By modulating hepcidin production, an organism controls intestinal iron absorption, iron uptake and mobilization from stores to meet body iron need. In recent years there has been important advancement in our knowledge of hepcidin regulation that also has implications for understanding the physiopathology of some human disorders. Since the discovery of hepcidin and the demonstration of its pivotal role in iron homeostasis, there has been a substantial interest in developing a reliable assay of the hormone in biological fluids. Measurement of hepcidin in biological fluids can improve our understanding of iron diseases and be a useful tool for diagnosis and clinical management of these disorders. We reviewed the literature and our own research on hepcidin to give an updated status of the situation in this rapidly evolving field.

The online version of this article has a Supplementary Appendix. BackgroundInadequate hepcidin production leads to iron overload in nearly all types of hemochromatosis. We explored the acute response of hepcidin to iron challenge in 25 patients with HFEhemochromatosis, in two with TFR2-hemochromatosis and in 13 controls. Sixteen patients (10 C282Y/C282Y homozygotes, 6 C282Y/H63D compound heterozygotes) had increased iron stores, while nine (6 C282Y/C282Y homozygotes, 3 C282Y/H63D compound heterozygotes) were studied after phlebotomy-induced normalization of iron stores. Design and MethodsWe analyzed serum iron, transferrin saturation, and serum hepcidin by both enzyme-linked immunosorbent assay and mass-spectrometry at baseline, and 4, 8, 12 and 24 hours after a single 65-mg dose of oral iron. ResultsSerum iron and transferrin saturation significantly increased at 4 hours and returned to baseline values at 8-12 hours in all groups, except in the iron-normalized patients who showed the highest and longest increase of both parameters. The level of hepcidin increased significantly at 4 hours and returned to baseline at 24 hours in controls and in the C282Y/H63D compound heterozygotes at diagnosis. The hepcidin response was smaller in C282Y-homozygotes than in controls, barely detectable in the patients with iron-depleted HFE-hemochromatosis and absent in those with TFR2-hemochromatosis. ConclusionsOur results are consistent with a scenario in which TFR2 plays a prominent and HFE a contributory role in the hepcidin response to a dose of oral iron. In iron-normalized patients with HFE hemochromatosis, both the low baseline hepcidin level and the weak response to iron contribute to hyperabsorption of iron.Key words: hemochromatosis, hepcidin, iron challenge, phlebotomy, transferrin receptor 2.Citation: Girelli D, Trombini P, Busti F, Campostrini N, Sandri M, Pelucchi S, Westerman M, Ganz T, Nemeth E, Piperno A, and Camaschella C. A HFE and TFR2 hemochromatosis. Haematologica 2011;96(4):500-506. doi:10.3324/haematol.2010.033449 time course of hepcidin response to iron challenge in patients with ©2011 Ferrata Storti Foundation. This is an open-access paper.A time course of hepcidin response to iron challenge in patients with HFE and TFR2 hemochromatosis