Abstract
We thank Dr. Castiella and co-workers for the kind comments on our article. He asked about the characterization of HFE gene mutations of patients defined as non-HFE hereditary hemochromatosis (HH), i.e., non-C282Y homozygotes, and compound C282Y (Cys282 → Tyr282)/H63D (His63 → Asp63) and C282Y/S65C (Ser65 → Cys65) heterozygotes. Of the 114 patients with non-HFE–related hemochromatosis, 12 (10%) were homozygous for the H63D mutation, 29 (25%) were heterozygous for the C282Y mutation, and 16 (14%) were heterozygous for the H63D mutation. Of these patients, only six (5%) had established genetic determinants of iron overload. Three patients had a phenotype consistent with juvenile HH which was linked to chromosome 1q or homozygosity for hemojuvelin missense mutation, one patient had iron overload associated with a missense ferroportin-1 mutation, and two patients had homozygosity for transferrin receptor-2 missense mutation.1, 2 Only a few other patients were found to be affected by possible hereditary risk factors for iron overload: one was a heterozygous carrier of the E302K hemojuvelin mutation, and two were positive for the −72C→T hepcidin promoter mutation. Regarding patients homozygous for the C282Y mutation, we completely agree with Dr. Castiella that the coexistence of non-HFE gene mutations may cause a more severe iron overload, as reported by Island et al.,3 but we have not yet completed the characterization of our patients. The second point raised by Dr. Castiella is that patients negative for HFE mutations usually have milder iron overload. All patients included in our study had iron overload compatible with the diagnosis of HH with no significant difference between HFE and non-HFE HH. In addition, although it has recently been demonstrated that hepatitis C virus infection and alcohol may contribute to iron accumulation by interfering with hepcidin transcription,4, 5 only noncirrhotic patients with HFE-related HH had a significantly more severe iron overload when acquired risk factors coexisted. Heterogeneity of genetic and acquired determinants possibly responsible for iron overload may account for the different severity of iron overload in patients with HH. Silvia Fargion*, * Department of Internal Medicine, Universita' degli Studi di Milano, Milan, Italy.
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