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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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Submitted June 18, 2007
Accepted August 17, 2007
Blunted hepcidin response to oral iron challenge in HFE-hemochromatosis
Alberto Piperno, Domenico Girelli, Elizabeta Nemeth, Paola Trombini, Claudia Bozzini, Erika Poggiali, Yen Phung, Tomas Ganz, and Clara Camaschella*
Dept of Clinical Medicine, Prevention and Biotechnologies, Milano Bicocca University, Milan, Italy
Dept of Clinical and Experimental Medicine, University of Verona, Verona, Italy
Depts of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States
Dept of Internal Medicine, Vita-Salute San Raffaele University and IRCCS, Milan, Italy
* Corresponding author; email: camaschella.clara{at}hsr.it.
Inadequate hepcidin synthesis leads to iron overload in HFE-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 65mg 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=0.02). However, the hepcidin/ferritin ratio was decreased in both homozygotes (p<0.0001) and heterozygotes (p=0.017), 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<0.0001 for C282Y/C282Y and p=0.002 for heterozygotes). After an iron challenge, mean urinary hepcidin excretion increased in controls (p=0.001) but not patients, irrespective of genotype and iron status. Significant hepcidin increase ( 10ng/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-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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