Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis

Abstract

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...

Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

“…Serum hepcidin-25 levels in our Italian HFEhemochromatosis patients were low at 11.1 ± 9.2 ng/mL. The current observations of circulating hepcidin 25 confirmed the findings previously observed in urine from patients with HFE-hemochromatosis (12). Low levels of serum hepcidin 25 were also found in Japanese patients with non-HFE hemochromatosis (18).…”

“…In other words, because of the high tolerance to iron hepatotoxicity, clinical manifestation might be delayed in HFEhemochromatosis. The mean amount of iron removed from HFE hemochromatosis was reported to be 4.98 g (3.9-6.1 g in the range) (12), while that of CHC was 0.61 g (0-1.6 g in the range) (17). The results of the current study did not differ from those in the literature.…”

“…Thus, hepcidin synthesis is at a low level in patients with HFE-hemochromatosis, which is the primary explanation for the development of iron overload in these patients (10). Venesection further decreases serum and urinary hepcidin to very low levels in patients with HFEhemochromatosis, indicating that they are still able to modulate, although inappropriately, hepcidin production in response to iron stores (11,12). Investigation of hepcidin regulation has been limited due to the lack of reliable methods.…”

Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation

“…[33][34][35] After allogeneic HSCT, the HFE genotype likely reflects donor rather than patient genotype. 16 The 40% incidence of HFE mutations is in accordance with the prevalence in populations of European descent.…”

Expression of hepcidin and other iron-related genes in type 3 hemochromatosis due to a novel mutation in transferrin receptor-2

“…13,20 By contrast, patients with HFE-HH have a decreased hepcidin response to oral iron. 13 The lack of response in the proband indicates that also a defective TFR2 abrogates the acute iron sensing of transferrin saturation. This finding is intriguing if we consider that TFR2 likely participates, together with HFE, to the putative iron signaling complex that modulates hepcidin transcription by sensing changes in diferric Tf concentration.…”