Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4479-4480
CORRESPONDENCE
Nontransfusional Iron Overload in Thalassemia Intermedia: Role of
the Hemochromatosis Allele
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LETTER |
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 
-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.
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Table 1.
Characteristics of Iron Overload in Two Sisters With
Thalassemia Intermedia With or Without C282Y Mutation
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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.
M.D. Cappellini
S.R. Fargion
M. Sampietro
G. Graziadei
G. Fiorelli
Dipartimento
di Medicina Interna
Centro Anemie Congenite
Ospedale Maggiore
Policlinico IRCCS
Milano, Italy
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REFERENCES |
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Rees DC, Luo LY, Thein SL, Singh BM, Wickramasinghe S:
Nontransfusional iron overload in thalassemia: Association with hereditary hemochromatosis.
Blood
90:3234, 1997[Free Full Text] (letter)
2.
Camaschella C, Roetto A, Gasparini P, Piperno A, Fortina P, Surrey S, Rappaport E:
Allelic association of microsatellites of 6p in Italian hemochromatosis patients.
Hum Genet
97:476, 1996[Medline]
[Order article via Infotrieve]
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Evidence of heterogeneity of hemochromatosis in Italy.
Gastroenterology
114:996, 1998[Medline]
[Order article via Infotrieve]
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Global prevalence of putative hemochromatosis mutations.
J Med Genet
34:275, 1997[Abstract/Free Full Text]
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Iron overload in Africa. Interaction between a gene and dietary iron content.
N Engl J Med
326:95, 1992[Abstract]
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Expert Scientific Working Group:
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Am J Clin Nutr
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