Non-HFE-related hemochromatosis: The role of genetic factors
Authors: Agustin Castiella, Eva Zapata, Pedro Otazua, Leire Zubiaurre, Javier Fernandez
Journal: Hepatology (2010)

We read with interest the article by Fracanzani et al. 1 that revealed outstanding findings in an Italian cohort of 452 patients. The 269 patients with C282Y (cysteine-to-tyrosine substitution at residue 282) homozygosis and the 69 patients with compound heterozygosis (C282Y/H63D [histidine-to-aspartic acid substitution at residue 63]) were diagnosed as HFE-hemochromatosis patients. The remaining 114 patients were defined as non-HFE–related hemochromatosis. The HFE gene mutation study in this group of patients it is not reported. The H63D/H63D mutation is considered as an HFE-hemochromatosis-predisposing mutation. 2 Recently, studies developed in a Mediterranean country, Spain, revealed 7.5% 3 and 10% 4 of phenotypic hemochromatosis patients with H63D/H63D mutation. It would be convenient to know the percentage of H63D homozygotes in their series. In patients without C282Y homozygosis or compound heterozygosis (C282Y/H63D), they searched for the S65C (serine-to-cysteine substitution at residue 65) mutation (HFE), ferroportin, transferrin receptor 2 gene, hemojuvelin, and hepcidin mutations. Fracanzani and colleagues said that the search for recently reported non-HFE gene mutations was negative in almost all patients tested, but data are not shown. Recently, mutations described in the HJV (hemojuvelin) gene in patients with H63D homozygosis lead to the development of high liver iron overload. 5, 6 A heterozygous hepcidin (HAMP) promoter mutation in association with C282Y homozygosity appeared to lead to very severe iron overload. 7 Aguilar-Martinez et al. 8 described three cases (from 30 non-HFE hemochromatosis patients) of iron overload, two with H63D homozygosis and one with S65C heterozygosis, with HAMP promoter mutation nc.–153C→T. Although the HEIRS (Hemochromatosis and Iron Overload Screening) Study 9 did not detect the mutation in any of the 191 HFE C282Y homozygotes from the study and concluded that routine testing to detect this mutation for screeenig programs it is not justified, the data presented by Aguilar-Martinez et al. 8 indicated that, perhaps, in selected groups of non-HFE hemochromatosis patients, it would be interesting to perform this mutation study in order to possibly explain iron overload in some patients. Considering that non-HFE hemochromatosis is rare (but not so rare in Mediterranean countries), a careful selection of patients for this new molecular test is recommended. Finally, the data of this prospective study indicate that patients with HFE-related and non-HFE–related hemochromatosis have comparable iron overload. Cheng et al.10 have recently studied the differences between patients with HFE and non-HFE hemochromatosis. They confirmed that patients with non-HFE hemochromatosis have lower body iron stores than C282Y homozygotes. Our group 4 studied a 40-patient hemochromatosis cohort in the Basque country, with 50% C282Y/C282Y patients and 12.5% C282Y/H63D patients. In our cohort, 37.5% (15 of 40 patients) were patients with non-HFE hemochromatosis. The liver iron concentration did not reveal statistical significance between the different genotypes (probably due to the small number of patients), but the C282Y/C282Y (15 of 20) patients had a higher concentration (mean = 19,378 μg/g; standard deviation = 13,412) than H63D (3 of 3) homozygotes (mean = 10,081 μg/g; standard deviation = 6116), C282Y/H63D (5 of 5) (mean = 6991 μg/g), H63D/wildtype (9 of 10) (mean = 6910 μg/g), and wildtype/wildtype (2 of 2) (mean = 6716 μg/g). The search and discovery of new genes and mutations, as well as other yet unknown nongenetic factors, may help us to explain high iron overload in these patients. Agustin Castiella M.D.*, Eva Zapata M.D.*, Pedro Otazua M.D.*, Leire Zubiaurre M.D.*, Javier Fernandez M.D.*, * Gastroenterology Services, Mendaro, Mondragon and Zumárraga Hospitals, Spain.