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Letters to the Editor |
Departments of
1
Gastroenterology and Hepatology, and,
2 Clinical Chemistry, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
aAuthor for correspondence. E-mail hans.vanvlierberghe{at}rug.ac.be.
To the Editor:
We read with interest the article of Beutler et al. (1) on the haptoglobin (Hp) polymorphism and its influence on iron metabolism in hereditary hemochromatosis. In contrast to our results (2)(3)(4), they found no overrepresentation of the Hp 2-2 phenotype in hemochromatosis patients and the Hp polymorphism did not influence the iron status of patients and healthy individuals.
In healthy individuals, Beutler et al. (1) found no influence of the Hp phenotype on serum iron indices. They state that "there is no reason to believe that the haptoglobin pathway is an important limiting factor in iron hemostasis". This is supported by the facts that they found no Hp-type-dependent influence on serum ferritin and transferrin saturation values in healthy individuals and that in anhaptoglobinemia, no major disturbances in iron metabolism have been found. We agree that the rate of iron uptake through haptoglobin-hemoglobin (Hp-Hb) complexes is relatively small compared with major iron regulatory pathways. As in hemochromatosis, however, a long-term effect may have important consequences for iron status. In liver transplant patients, donor Hp phenotype determines the iron status post transplantation (5). Because of the limited numbers of healthy individuals and a higher degree of ethnic variation in the observational trial reported by Beutler et al. (1) compared with ours (4), their trial may have missed the statistical power needed to detect the Hp-type-related influence on iron metabolism. Our group investigated and needed more than 700 individuals to clearly demonstrate the higher serum iron indices in Hp 2-2 individuals. In young and middle-aged males, we saw a doubling of the serum ferritin concentrations between Hp 1-1 and 2-2 individuals (3).
The acute-phase-regulated and signal-inducing macrophage protein CD 163 has been identified as a receptor that scavenges Hb by mediating endocytosis of Hp-Hb complexes (6). Complexes of Hb and multimeric Hp 2-2 exhibit higher functional affinity for CD 163 than do complexes of Hb and dimeric Hp 1-1. In anhaptoglobinemia, serum hemopexin acts as a back-up scavenger molecule to protect the individual from the toxic effects of free Hb.
In contrast to our findings (4), Beutler et al. (1) found no overrepresentation of Hp 2-2 in hemochromatosis and no influence of this genotype on serum iron indices. However, the set-up of their study differed from that of our study. We chose patients with clinical characteristics of hereditary hemochromatosis who were homozygous for the Cys282Tyr missense mutation. This is clearly demonstrated by the younger age of our cohort and the higher serum iron indices observed. Beutler et al. examined a group of individuals homozygous for the Cys282Tyr missense mutation without requiring the presence of the clinical and biochemical characteristics of hereditary hemochromatosis. This is reflected by the wide range of serum ferritin concentrations and transferrin saturation. In the cohort studied by Beutler et al. (1), low serum ferritin concentrations (<100 µg/L) and serum transferrin saturation (<50%) were observed in a large number of cases. In individuals homozygous for the Cys282Tyr missense mutation (7), higher values would be expected.
Recently, Beutler et al. (8) estimated that <1% of individuals homozygous for the Cys282Tyr missense mutation will develop frank clinical hemochromatosis. Thus, only one to two patients in the cohort described by Beutler et al. (1) will develop clinical hemochromatosis. This clearly illustrates that their cohort and ours cannot be compared and consist of two different populations. We agree that it seems unlikely that the Hp polymorphism (having only a mild influence on iron metabolism) would be the major determining factor explaining why only 1% of the population homozygous for the Cys282Tyr missense mutation will develop clinical hemochromatosis. We could clearly demonstrate, however, that in clinical hemochromatosis, the Hp 2-2 phenotype is overrepresented and that patients with this phenotype have evidence of higher serum iron markers and a higher amount of blood donation before iron depletion. Our conclusion remains that in hereditary clinical hemochromatosis, the Hp polymorphism influences the biochemical presentation of the condition (4). This does not contradict the findings of Beutler et al. (1) because the cohorts cannot be compared.
References
A (C282Y) HFE hereditary haemochromatosis mutation in the U S A. Lancet 2002;359:211-218.[CrossRef][Web of Science][Medline]
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