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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4096-4100.
Prepublished online as a Blood First Edition Paper on August 27, 2007; DOI 10.1182/blood-2007-06-096503.
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RED CELLS
Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis
Alberto Piperno1,
Domenico Girelli2,
Elizabeta Nemeth3,
Paola Trombini1,
Claudia Bozzini2,
Erika Poggiali4,
Yen Phung3,
Tomas Ganz3, and
Clara Camaschella4
1 Department of Clinical Medicine and Prevention, Milano-Bicocca University, San Gerardo Hospital, Monza, Italy;
2 Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy;
3 Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles (UCLA); and
4 Vita-Salute San Raffaele University and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
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-related hemochromatosis and not improved after iron depletion. The findings support the involvement of HFE in iron sensing and subsequent regulation of hepcidin.
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