To the Editor:
Recently Rees et al reported in Blood1 the results of a screening for the gene of genetic hemochromatosis (GH) (gene HFE) in a group of patients with thalassemia intermedia. They studied 81 patients of Asian-African and Middle Eastern origin and found that the main mutation associated to GH (C282Y) was present in only one patient. None of the patients was positive for the second mutation H63D. The patient positive for the C282Y mutation had a more severe iron overload than that usually observed in untransfused or occasionally transfused thalassemia intermedia patients, and his clinical presentation resembled that of classic homozygous GH, with arthritis and diabetes being the major complaints. The investigators suggested that the severe iron overload of this patient was the result of the interacting effect of the chronic anemia from thalassemia intermedia (other hematological diseases had been ruled out by bone marrow, including electron microscopy examination) and the main HFE mutation, even if present on only one chromosome. They concluded that subjects with thalassemia intermedia and heterozigosity for GH develop a more severe iron overload than expected from thalassemia intermedia by itself.
Because of the high prevalence of GH in whites (including Mediterranean populations), it is extremely important for the possible therapeutical implications to establish whether a fortuitous association of thalassemia and GH is common and if it is really affecting the severity of iron overload. We agree that the patient presented by Rees et al had an unexpectedly severe iron overload for a subject with thalassemia intermedia, but we have two major concerns about the interpretation given by the investigators: (1) the old age of the patient at presentation (he had a diagnosis of thalassemia intermedia at 48 years) with a thalassemia genotype not fully defined (only one β-thalassemia mutation) makes the diagnosis of thalassemia intermedia doubtful; (2) the presence of a single C282Y allele does not exclude the diagnosis of homozygous GH. In Italy, only 63% of the patients with GH are homozygous for the C282Y mutation, despite the presence of HLA-identical siblings with “classic” GH phenotype.2,3 This could be true also in African and Asian populations, in whom a very low prevalence of the C282Y mutation in controls has been reported.4 In addition, the existence of an African non–HLA-linked genetic hemochromatosis has been recently hypothesized.5 Thus, other unknown iron-related gene(s) or HFE mutations could be involved in determining the GH phenotype in populations with a low prevalence of the known HFE mutations.
We recently analyzed 37 Italian patients with thalassemia intermedia and found that heterozygosity for the C282Y mutation does not modify the iron status of thalassemia intermedia patients. Among this group we encountered two sisters with identical thalassemia genotype and phenotype (never transfused) but only one with the C282Y mutation. The iron status of the patient with C282Y mutation (including liver iron) was similar to that of the sister with the wild genotype for the main HFE mutation (Table 1). Thus, the presence of heterozygosity for C282Y mutation does not seem to affect the iron status of patients with thalassemia intermedia, although the young age and female gender of these two patients could partly explain the results, and only follow-up of well-characterized cases will better define the influence of a single GH gene in thalassemia intermedia.
In our series we also identified a 27-year-old woman with thalassemia intermedia genotype (cod 39/IVS1-6), homozygous for the C282Y mutation who, from biochemical indirect tests, did not present a more severe iron overload than the other patients studied with identical thalassemia genotype. However, she was very recently submitted to liver biopsy during surgery for cholecystectomy, and both the severity of siderosis and the cell iron distribution reflected the coexistence of GH with thalassemia intermedia. Thus, homozygous GH can lead, in thalassemia intermedia, as expected, to severe iron overload that can be underestimated by indirect iron biochemical tests. This can occur more easily in fertile age women because, even under normal conditions, they frequently develop iron deficiency from menstrual loss and pregnancy.6 For the same reasons diagnosis of GH in women may be difficult with GH manifesting later than in men, usually at menopausal age. In conclusion, our present data do not support the hypothesis that heterozygous GH increases the iron overload of patients with thalassemia intermedia who have, independently from GH, augmented iron absorption because of severe ineffective erythropoiesis. In contrast, the coexistence of homozygous GH seems to increase liver iron overload of thalassemia intermedia patients. Our results suggest that the patient described by Rees et al has homozygous GH with coexisting mild thalassemia intermedia.
