Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe iron overload has been reported in patients with the beta-thalassaemia trait. Studies performed before the discovery of the haemochromatosis gene (HFE) have yielded conflicting results: some suggest that iron overload might arise from the interaction of the beta-thalassaemia trait with heterozygosity for haemochromatosis, some with homozygosity for haemochromatosis and others that it was unrelated to haemochromatosis. We have studied the clinical phenotype, iron indices and HFE genotypes of 22 unrelated patients with the beta-thalassaemia trait and haemochromatosis, the inheritance of chromosome 6p and 1q haplotypes in families of non-homozygous C282Y probands and serum measures of iron status in relatives heterozygous for C282Y with or without the beta-thalassaemia trait. We demonstrate that the beta-thalassaemia trait aggravates the clinical picture of C282Y homozygotes, favouring higher rates of iron accumulation and the development of severe iron-related complications. We suggest that the coexistence of the beta-thalassaemia trait might also increase the risk of iron overload in patients with HFE genotypes at a mild risk of haemochromatosis. Our findings do not support the hypothesis that the association of the beta-thalassaemia trait with a single C282Y or H63D allele might lead to iron overload and suggest that other non-HFE-related inherited factors are present in haemochromatosis patients with incomplete HFE genotypes.
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PMID:Haemochromatosis in patients with beta-thalassaemia trait. 1112 55

Since 1996, the identification of the HFE gene has enabled DNA testing for hereditary haemochromatosis (HH). The range of DNA testing available includes: (1) diagnostic, (2) predictive (also called presymptomatic testing) and (3) screening. Access to DNA testing has been facilitated by an Australian Medicare rebate, the first available for genetic disorders. Despite the availability of HFE DNA testing in HH, it remains necessary to interpret results in the context of the clinical picture. Traditional markers based on phenotype (transferrin ferritinsaturation, and liver biopsy) are still required in some circumstances. We report our experience with HFE DNA testing using a semi-automated approach, which allows multiplexing for the two common mutations (C282Y and H63D). Screening a cohort of beta-thalassaemia major and sickle cell anaemia patients of predominantly Mediterranean origin showed that these individuals do not have the common C282Y mutation. This excluded C282Y as a factor in the pathogenesis of iron overload in these haemoglobinopathies. It also showed that the C282Y mutation is of limited value when investigating HH in certain ethnic groups. An Australian family studied illustrated the relative contribution of C282Y and H63D in iron overload. A recently reported third mutation (S65C) in the HFE gene was detected in a low frequency in the populations tested.
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PMID:DNA testing for haemochromatosis: diagnostic, predictive and screening implications. 1118 24

Heterozygosity for beta-thalassemia (minor) by itself does not lead into iron overload; however, when it is inherited together with a homozygous state for either the H63D or the C282Y mutations of the hereditary hemochromatosis gene (HFE gene), iron overload may ensue. We describe here a kindred in which the propositus, being heterozygote for beta-thalassemia and the H63D mutation of the HFE gene, developed severe iron overload and in turn, chronic liver failure with portal hypertension. Other members of the family with either beta-thalassemia or heterozygous for the H63D gene mutation did not develop iron overload. The interaction between beta-thalassemia and hereditary hemochromatosis is briefly discussed and speculations about other possible genetic mutations leading into familial iron loading are done.
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PMID:Heterozygosity for the H63D mutation in the hereditary hemochromatosis (HFE) gene may lead into severe iron overload in beta-thalassemia minor: observations in a thalassemic kindred. 1142 Nov 5

Our understanding of how iron transverses the intestinal epithelium has improved greatly in recent years, although the mechanism by which body iron demands regulate this process remains poorly understood. By critically examining the earlier literature in this field and considering it in combination with recent advances we have formulated a model explaining how iron absorption could be regulated by body iron requirements. In particular, this analysis suggests that signals to alter absorption exert a direct effect on mature enterocytes rather than influencing the intestinal crypt cells. We propose that the liver plays a central role in the maintenance of iron homeostasis by regulating the expression of hepcidin in response to changes in the ratio of diferric transferrin in the circulation to the level of transferrin receptor 1. Such changes are detected by transferrin receptor 2 and the HFE/transferrin receptor 1 complex. Circulating hepcidin then directly influences the expression of Ireg1 in the mature villus enterocytes of the duodenum, thereby regulating iron absorption in response to body iron requirements. In this manner, the body can rapidly and appropriately respond to changes in iron demands by adjusting the release of iron from the duodenal enterocytes and, possibly, the macrophages of the reticuloendothelial system. This model can explain the regulation of iron absorption under normal conditions and also the inappropriate absorption seen in pathological states such as hemochromatosis and thalassemia.
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PMID:The orchestration of body iron intake: how and where do enterocytes receive their cues? 1273 47

Primary iron overload may be relatively common in African Americans, but its cause is incompletely understood. Thus, we evaluated genotype and phenotype characteristics of unselected African American index patients with primary iron overload who reside in central Alabama. All had hepatic iron concentration > or =30 micromol/g dry wt or > or =2.0 g of iron mobilized by phlebotomy to achieve iron depletion. Genotype analyses were performed in African American control subjects from the same region. There were 23 patients (19 men, 4 women); mean age at diagnosis was 52 +/- 12 years (1 SD) (range 32-69 years). Nine (39.1%) reported that they consumed > or =45 g of ethanol daily; five had chronic hepatitis C. Eight had some form of hemoglobinopathy or thalassemia. Mean serum transferrin saturation was 56 +/- 28% (range 15-100%). The geometric mean serum ferritin at diagnosis was 1076 ng/mL [95% confidence interval 297-3473 ng/mL]. Increased stainable liver iron was observed in hepatocytes only in 4 patients, in macrophages only in 8 patients, and in hepatocytes and macrophages in 8 patients. The mean quantity of iron mobilized by phlebotomy (corrected for iron absorbed during treatment) was 5.3 +/- 2.0 g (range 4.0-8.4 g). Iron removed by phlebotomy was greater in patients with hemoglobinopathy or thalassemia than in those without these forms of anemia (6.6 +/- 1.3 g vs 3.9 +/- 1.6 g, respectively; P = 0.0144). Daily consumption of > or =45 g of ethanol or chronic hepatitis C was not associated with an increased or decreased amount of phlebotomy-mobilized iron, on the average. The percentage of index patients positive for HFE C282Y was greater than that of controls (P = 0.0058). The respective percentages of phenotype positivity for HFE H63D, D6S105(8), and HLA-A*03 were similar in patients and controls. HFE S65C, I105T, and G93R were not detected in index or control subjects. Two of 13 patients were heterozygous for the ferroportin allele nt 744 G-->T (Q248H), although the phenotype frequency of this allele was similar in patients and 39 controls. Synonymous ferroportin alleles were also detected in some patients. The ceruloplasmin mutation nt 1099C-->T (exon 6; Arg367Cys) was detected in 1 of 2 patients tested. Abnormal alleles of beta-2 microglobulin, Nramp2, TFR2, hepcidin, or IRP2 alleles were not detected in either of the 2 patients so tested. We conclude that primary iron overload in African Americans is not the result of the mutation of a single gene. HFE C282Y, ferroportin 744 G-->T, and common forms of heritable anemia appear to account for increased iron absorption or retention in some patients.
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PMID:Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. 1463 44

In this study, we evaluated the impact of mutations of the HFE and ferroportin gene on iron overload in thalassemia intermedia and betas/betathal patients. Neither HFE (C282Y and H63D) nor ferroportin(Val162del) mutations were determinants of total body iron status, as assessed by ferritin levels, in either group of patients.
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PMID:The impact of the mutations of the HFE gene and of the SLC11A3 gene on iron overload in Greek thalassemia intermedia and beta(s)/beta(thal) anemia patients. 1507 83

Co-inheritance of HFE mutations has a substantial role in iron overload in beta-thalassaemia carriers in north European populations where two HFE mutations, C282Y and H63D, are prevalent. In Thailand, there was little information about the allele frequency of HFE mutations. It is of interest to determine whether such determinants represent a potential risk in developing iron overload as nearly 40% of the Thai population carry either one of thalassaemia or haemoglobinpathy alleles. A total of 380 normal controls from five different regions including Bangkok were screened for the HFE C282Y, H63D and IVS5+1 G-->A alleles. In addition, 70 individuals with homozygous haemoglobin E (Hb EE) were also tested and their genotypes were correlated with levels of serum ferritin. H63D is the major HFE mutation found in the Thai population with an average allele frequency of 3% (range 1-5%). One individual was heterozygous for the splice site mutation IVS5 + 1 G --> A, and the C282Y allele was not detected. In the Hb EE group, five individuals had iron deficiency (ferritin <12 microg/L) and the remaining 65 individuals had a wide range of serum ferritin levels of 16-700 microg/L. Four individuals with Hb EE were heterozygous for the H63D allele. No significant difference in serum ferritin level was detected in this group with or without the HFE mutation (137.2 +/- 78 vs. 116.3 +/- 128 microg/L). HFE mutations are relatively uncommon among the Thai population, and the average allele frequency of the ancient H63D mutation is similar to that of other countries in this region. Because of their paucity, it appears that these alleles are less likely to be responsible for high ferritin levels and iron loading in individuals with Hb E related disorders.
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PMID:Prevalence of HFE mutations among the Thai population and correlation with iron loading in haemoglobin E disorder. 1518 37

Hereditary hemochromatosis (HH) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and progressive storage resulting in organ damage. HFE gene mutations C282Y and H63D are responsible for the majority of HH cases. A third HFE mutation, S65C, has been associated with the development of a mild form of hemochromatosis. The beta-thalassemia trait is characterized by mild, ineffective erythropoiesis that can induce excess iron absorption and ultimately lead to iron overload. The aim of this study was to evaluate the effect of genetic markers (HFE mutations C282Y, H63D, and S65C) on the iron status of beta-thalassemia carriers. A total of 101 individuals heterozygous for beta-thalassemia and 101 normal control individuals were studied. The allelic frequencies of C282Y (1.5 versus 3.5%), H63D (15.3 versus 18.3%), and S65C (1.0 versus 1.5%) did not differ significantly between beta-thalassemia carriers and normal controls. Serum iron (P=0.029) and transferrin saturation (P=0.009) were increased in beta-thalassemia carriers heterozygous for H63D mutation. The number of subjects carrying C282Y or S65C mutations was too low to conclude their effect on the iron status. These results suggest that the beta-thalassemia trait tends to be aggravated with the coinheritance of H63D mutation, even when present in heterozygosity.
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PMID:The role of HFE mutations on iron metabolism in beta-thalassemia carriers. 1553 48

We present the molecular analysis of HFE gene in 400 Southwest Iranian individuals. We have studied 43 newborn, selected for the presence of HbBart's at birth, 203 normal adult and 154 transfused patients affected with beta-thalassemia. Mutation analysis consisted of amplification and direct sequencing using two different pairs of forward and reverse primers. The C282Y and S65C mutations were not found. The H63D mutation was present with an allele frequency of 0.10 in newborns, 0.082 in normal adults and 0.080 in the beta-thalassemia major populations, respectively. No differences were found between normal adults and thalassemia major patients suggesting that this mutation does not increase mortality in beta-thalassemia. The H63D mutation was found associated with haplotype VI in 41% of the chromosomes. Other haplotypes were found suggesting a multicentric origin rather than a single mutation of European origin. While sequencing exon 4, a G --> A transition was found in the proximity of the C282Y mutation. The effect of this single base substitution (E277K) previously reported in an Asian individual and now found in homozygous form in a young transfused and chelated homozygous beta-thalassemia patient is not yet known.
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PMID:Spectrum and haplotypes of the HFE hemochromatosis gene in Iran: H63D in beta-thalassemia major and the first E277K homozygous. 1557 Feb 96

Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin-ferroportin interaction in iron homeostasis.
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PMID:Hepcidin in iron overload disorders. 1567 38


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