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Blood, 2 July 2009, Vol. 114, No. 1, pp. 1-2.
Iron overload in AsiaSHAARE ZEDEK MEDICAL CENTER Abstract In a remarkable study in this issue of Blood, Lok and colleagues describe the genotypic and phenotypic characteristics of hereditary hemochromatosis in 42 cases in 8 distinct families of Asian origin.1 Hemochromatosis is a hereditary disorder characterized by excessive iron absorption in the diet, leading to iron overload and toxicity to various organs. It is a genetically heterogeneous disease. HFE hemochromatosis is the most common form of hemochromatosis in populations of Northern European origin. In addition, other non-HFE hemochromatosis mutations are increasingly being recognized in Northern Europeans. By contrast, hemochromatosis in Asia is believed to be uncommon and is not well understood. Part of the difficulty recognizing a phenotype suggestive of hereditary hemochromatosis in Asia is the high prevalence of other hemoglobin disorders such as thalassemia resulting in secondary iron overload, and, conversely, the possible masking of hereditary iron overload by a high prevalence of coexistent iron deficiency on the other.
None of the patients described by Lok et al have the common HFE hemochromatosis. Novel mutations in genes encoding hemojuvelin (HJV), hepcidin (HAMP), and ferroportin (SLC40A1) were identified in 8 families from Pakistan, Bangladesh, Sri Lanka, and Thailand (see figure). Detailed family studies show a high degree of consanguinity that increases the frequency of the recessive forms of the disease. As the authors have been unable to find a mutation in any of the known hemochromatosis genes for the remaining 24 families (out of the 32) with iron overload, it is reasonable to assume that there are other, presently unrecognized genes responsible for hemochromatosis. Likewise, the failure of previous reports from Asia of non-HFE hemochromatosis to identify the underlying mutations2 may well be because screening was for known common European mutations, rather than a comprehensive analysis of each candidate gene for new mutations. Mutations affecting the genes encoding hepcidin or hemojuvelin cause early onset severe juvenile hemochromatosis, whereas mutations of other genes involved in the hepcidin pathway, such as HFE or transferrin receptor (TFR2), cause less severe forms of hemochromatosis. Clinical genotype-phenotype correlations among the various forms of hereditary hemochromatosis and the finding that all of them are associated with abnormally low hepcidin production allowed important early predictions regarding their respective roles in hepcidin production.3,4 The recent identification of bone morphogenetic protein 6 (BMP6) as a key endogenous regulator of hepcidin expression and the description of massive iron overload in mice lacking BMP65–7 allows the prediction of BMP6 mutations to be a likely cause of non-HFE–related juvenile hemochromatosis in humans. The study by Lok et al is the product of a remarkable international collaboration involving carefully orchestrated fieldwork in major clinical centers located in Pakistan, Bangladesh, Sri Lanka, and Thailand combined with the experience and resources of a leading institute of molecular medicine and other academic centers in the United Kingdom. It is to be expected that these studies represent just the modest beginnings of a major long-term international venture. The present findings are of both academic and practical value, facilitating further research aimed at establishing the nature and prevalence of hereditary hemochromatosis in the Asian population. The observations highlight the risk of hereditary iron overload in countries of the developing world. The findings also underline the importance of early diagnosis of primary iron overload to prevent irreversible damage. In the countries involved, there is still a significant delay in recognizing hemochromatosis, and simple diagnostic measures, such as serum ferritin measurements and increased transferrin saturation, should be considered for young patients in whom diabetes and hypogonadism coexist.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
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| Copyright © 2009 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
