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Social Bookmarking                   What's this?  Previous Article  |  Table of Contents Blood, Vol. 90 No. 8 (October 15), 1997: pp. 3234-3035 CORRESPONDENCE Nontransfusional Iron Overload in Thalassemia: Association With Hereditary Hemochromatosis     LETTER To the Editor: Hemochromatosis is inherited as an autosomal recessive trait and is manifested by excessive absorption of dietary iron in homozygotes leading to complications of iron overload and premature death.1 In 1996, a candidate gene for hemochromatosis, HLA-H, was isolated.2 A missense mutation that led to the substitution of a tyrosine for cysteine at codon 282 (Cys282Tyr) was identified in the vast majority of patients with hemochromatosis, with 80% to 100% of patients with hemochromatosis being homozygous for the HLA-H Cys282Tyr allele.2-5 A second mutation resulting in the substitution of aspartic acid for histidine at codon 63 (His63Asp)2 was also identified, but its role is uncertain. Recent surveys have shown that the Cys282Tyr allele is frequent in Northern Europeans, with a frequency of 10% in some populations, but rare in Africans and Asians.6 Although the levels of serum ferritin, serum iron, and transferrin saturation are higher than normal in heterozygotes for hemochromatosis, complications due to iron overload are extremely rare in these individuals.7 Apart from hereditary hemochromatosis, there are a number of other conditions in which nontransfusional iron loading occurs; these include sideroblastic anemia, porphyria cutanea tarda, the thalassemia syndromes, pyruvate kinase deficiency, and hereditary atransferrinemia. Among these, thalassemia is the only one that occurs commonly and is prevalent in the tropical and subtropical regions.8 Carriers for thalassemia may have a very mild anemia but rarely iron overload; heterozygosity for thalassemia also does not appear to accentuate iron loading in individuals homozygous or heterozygous for hemochromatosis.9 Unlike heterozygous thalassemia, which is clinically asymptomatic, thalassemia intermedia is manifested by a symptomatic anemia associated with increased iron absorption, but regular transfusions are not necessary.8 We have screened 81 thalassaemia intermedia patients (46 with 2 thalassemia alleles, 6 thalassemia heterozygotes with / or / genotypes, 6 with dominantly inherited thalassemia, and 23 hemoglobin [Hb] E/ thalassemia) for the Cys282Try and His63Asp mutations in the HLA-H gene. Their ages ranged from 10 to 65 years, with the following ethnic mix: Asian Indian (58%), Middle Eastern (17%), Mediterranean (15%), English (7%), and Chinese (3%). None of the patients is on a regular transfusion regime. The mutations were detected by restriction enzyme analysis of polymerase chain reaction (PCR)-amplified DNA6; the Cys282Tyr mutation creates a new Rsa I site, whereas the His63Asp mutation removes an Mbo I site. Deletional and thalassemia and rearrangement of the and globin gene complex were screened for by Southern blot hybridization. Point mutations causing thalassemia were detected by sequence analysis of PCR-amplified globin genes.10 The Cys282Tyr mutation was detected in only 1 of the 81 individuals with thalassemia intermedia. The proband presented in 1975 at the age of 42 years with joint pains. Hepatomegaly was noted with a Hb level of 9.8 g/dL and a serum iron level of 44.1 mmol/L with 71% transferrin saturation. A diagnosis of thalassemia and gout was made. He was lost to follow-up, but re-presented in 1981 with diabetes mellitus and was started on oral hypoglycemic agents, later needing insulin. Over the next decade, although his Hb level remained fairly stable, his ferritin level gradually increased with clear evidence of overload (Table 1). In 1994, his condition had worsened, with a Hb level of 6.5 g/dL and 9% reticulocytes; deep skin pigmentation and marked hepatosplenomegaly were noted. He received a single blood transfusion for the first time. In 1995, aged 62 years, he had a splenectomy and liver biopsy. Liver histology showed markedly increased iron (hepatic iron was 1.86% dry weight; normal <0.13%) and the hemosiderin granules were distributed mainly in hepatocytes with relative sparing of the Kupffer cells, features typical of primary hemosiderosis. There was background hepatitis, but autoantibody screen was negative and there was no evidence of hepatitis A, B, or C. After splenectomy, his Hb level increased to 7 to 9 g/dL. He was started on subcutaneous desferrioxamine. In 1996, he suffered a myocardial infarction and received a second blood transfusion in an attempt to improve his myocardial oxygenation.   View this table: [in this window] [in a new window]   Table 1. Serial Data on Iron Status of Proband There is no family history of anemia, diabetes, hemochromatosis, or arthritis. The proband was born in the Punjab, India, and had never been transfused until 1994, at the age of 61 years. He is married with four children, one of whom (daughter) was accessible for investigation. Results of the investigation are summarized in Table 2. The proband has a marked globin chain imbalance with an / globin chain synthesis ratio of 4.1, which is much more severe than that encountered in thalassemia trait. However, DNA analysis could identify only a single thalassemia mutation (codon 41/42 -TCTT), but compound heterozygosity for a mild thalassemia mutant is implicated from clinical, hematologic, and family studies. His daughter has mild but significant hypochromic microcytic red blood cells, with an / globin chain synthesis ratio of 2.1 that is typical of thalassemia trait. However, extensive sequence analysis of the globin genes (from position -630 upstream of the mRNA cap site of the globin gene to 290 bp downstream of the termination site including the whole gene) showed only a single thalassemia allele in the father and no mutation in the daughter. DNA mapping of the and globin cluster in both father and daughter showed no deletions or rearrangements; in particular, there was no extra globin gene. Serum transferrin receptor (sTfR) level was markedly elevated in the proband, suggesting significant expansion of the erythron consistent with thalassemia intermedia, whereas normal levels were found in the daughter and wife. Electron microscopy of the father's bone marrow showed intraerythroblastic inclusions indistinguishable from the precipitated -globin chains seen in thalassemia. The proportion of erythroblast sections containing such inclusions (17%) was considerably higher than that in thalassemia trait and similar to that in the thalassemia intermedia syndromes caused by Hb E/ thalassemia.11   View this table: [in this window] [in a new window]   Table 2. Summary of Hematologic Data and HLA-H Status of Family Members Both father and daughter were heterozygous for the Cys282Tyr mutation in the HLA-H gene; neither had the His63Asp minor mutation. The mother was normal for both HLA-H alleles. It seems likely that the phenotype of thalassemia intermedia in the proband is produced by compound heterozygosity for the FS 41/42 (-4 bp), a common thalassemia mutation in Asian Indians,8 and a mild + thalassemia allele that has not been identified. Such uncharacterized thalassemia mutations have been described, some of which may not be linked to the globin complex.10 Other possible diagnoses for the unusually severe anemia in the proband, such as congenital dyserythropoietic anemia and sideroblastic anemia, are excluded by the electron microscopy findings. Although excessive iron absorption is well described in untransfused thalassemia intermedia,12 there are few reports of such individuals developing the complications of severe iron overload as seen in our patient. Certainly the majority of thalassemia intermedia patients present with symptoms of anemia, unlike the proband, whose manner and age of presentation is typical of homozygous hereditary hemochromatosis. This is one of the first examples of the heterozygous state for hemochromatosis expressing a disease phenotype and appears to result from the interacting effects of the chronic anemia from thalassemia intermedia and the Cys282Tyr HLA-H mutation. The nature of the interaction between these alleles is unclear, because the mechanisms for excessive iron absorption in both conditions are not established. The interaction between thalassemia intermedia and hereditary hemochromatosis must also occur in many other individuals, even if the populations in which these two traits are common do not coincide. A recent report has suggested that the HLA-H Cys282Tyr mutation is an important predisposing factor in spontaneous porphyria cutanea tarda.13 Our study supports the emerging importance of genetic screening for hereditary hemochromatosis in other iron-loading conditions. D.C. Rees L.Y. Luo S.L. Thein MRC Molecular Haematology Unit Institute of Molecular Medicine Oxford, UK B.M. Singh Wolverhampton Diabetes Centre New Cross Hospital Wolverhampton, UK S. Wickramasinghe Department of Haematology Imperial College School of Medicine at St Mary's London, UK        ACKNOWLEDGMENT The authors thank Liz Rose and Milly Graver for preparation of the manuscript and Prof Sir D.J. Weatherall for his continuing encouragement and support. D.C.R. is an MRC Training Fellow.     REFERENCES 1. Powell LW, Jazwinska E, Halliday JW: Primary iron overload, in Brock JH, Halliday JW, Pippard MJ, Powell LW (eds): Iron Metabolism in Health and Disease. London, UK, Saunders, 1994, p 227 2. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr., Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drauna DT, Risch NJ, Bacon BR, Wolff RK: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399, 1996[Medline] [Order article via Infotrieve] 3. Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Ten Elshof AE, Gerhard GS, Chorney M: Mutation analysis in hereditary hemochromatosis. Blood Cell Mol Dis 22:187, 1996[Medline] [Order article via Infotrieve] 4. Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LW, Morris CP, Walsh TP: Haemochromatosis and HLA-H. Nat Genet 14:249, 1996[Medline] [Order article via Infotrieve] 5. Jouanolle AM, Gandon G, Jézéquel P, Blayau M, Campion ML, Mosser J, Fegelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Gicquel I, Le Gall J-Y, David V: Haemochromatosis and HLA-H. Nat Genet 14:251, 1996[Medline] [Order article via Infotrieve] 6. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJH: Global prevalence of putative haemochromatosis mutations. J Med Genet 34:275, 1997[Abstract/Free Full Text] 7. Bulaj ZJ, Griffen LM, Jorde LB, Edwards CQ, Kushner JP: Clinical and biochemical abnormalities in people heterozygous for hemachromatosis. N Engl J Med 335:1799, 1996[Abstract/Free Full Text] 8. Higgs DR, Weatherall DJ: Bailliére's Clinical Haematology. International Practice and Research: The Haemoglobinopathies. London, UK, Baillière Tindall, 1993 9. Edwards CQ, Skolnick MH, Kushner JP: Coincidental nontransfusional iron overload and thalassemia minor: Association with HLA-linked hemochromatosis. Blood 58:844, 1981[Abstract/Free Full Text] 10. Thein SL, Wood WG, Wickramasinghe SN, Galvin MC: -Thalassemia unlinked to the -globin gene in an English family. Blood 82:961, 1993[Abstract/Free Full Text] 11. Wickramasinghe SN, Hughes M: Globin chain precipitation, deranged iron metabolism and dyserythropoiesis in some thalassaemia syndromes. Haematologia 17:35, 1984[Medline] [Order article via Infotrieve] 12. Pippard MJ, Callender ST, Warner GT, Weatherall DJ: Iron absorption and loading in -thalassaemia intermedia. Lancet 2:819, 1979[Medline] [Order article via Infotrieve] 13. Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH: Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 349:321, 1997[Medline] [Order article via Infotrieve] © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Franchini, G. Gandini, M. de Gironcoli, A. Vassanelli, C. Borgna-Pignatti, and G. Aprili Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload Blood, May 1, 2000; 95(9): 2776 - 2779. [Abstract] [Full Text] [PDF] M.D. Cappellini, S.R. Fargion, M. Sampietro, G. Graziadei, and G. Fiorelli Nontransfusional Iron Overload in Thalassemia Intermedia: Role of the Hemochromatosis Allele Blood, December 1, 1998; 92(11): 4479 - 4480. [Full Text] [PDF] P. J. Ho, G. W. Hall, S. Watt, N. C. West, J. W. Wimperis, W. G. Wood, and S. L. Thein Unusually Severe Heterozygous beta -Thalassemia: Evidence for an Interacting Gene Affecting Globin Translation Blood, November 1, 1998; 92(9): 3428 - 3435. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rees, D.C. Articles by Thein, S.L. Search for Related Content PubMed PubMed Citation Articles by Rees, D.C. 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	Copyright © 1997 by American Society of Hematology         Online ISSN: 1528-0020