Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum iron and ferritin concentrations were measured in 1,532 regular blood donors from South Wales who were undergoing HLA typing prior to registration on the British Bone Marrow and Platelet Donor Panel. Serum transferrin concentrations were determined for donors with serum iron concentrations > 24 mumol/l. There were 25 donors with transferrin saturations > 50% and 11 with transferrin saturations > 60%. There were five donors with serum ferritin concentrations > 200 micrograms/l (women) or > 300 micrograms/l (men). Two of the male donors had transferrin saturations > 50% and serum ferritin > 300 micrograms/l on repeat blood samples and are being treated by venesection. Donors with HLA-A3 did not differ from those without A3 in serum iron or ferritin concentrations. Even in the group of donors who were apparently homozygous for A3 there were neither abnormal serum iron nor ferritin concentrations. Although it is well established that measurements of transferrin saturation are required to detect homozygous haemochromatosis (HFE) in its earlier stages, the number of 'false-positive' results is likely to be unacceptably high for screening blood donors. Serum ferritin assays should identify donors with HFE and iron overload before the onset of liver damage. With two million regular donors and 300,000 new donors each year, a significant proportion of the U.K. population will be screened within 10 years. The assay of serum ferritin identifies donors with low levels of storage iron who are at risk of developing iron-deficiency anaemia. Furthermore, donation frequency may be increased for those donors with higher ferritin concentrations when blood supplies are low.
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PMID:Serum ferritin, blood donation, iron stores and haemochromatosis. 803 93

Hereditary hemochromatosis (HH) is a common autosomal recessive disease characterized by increased iron absorption and progressive iron storage that results in damage to major organs in the body. Recently, a candidate gene for HH called HFE encoding a major histocompatibility complex class I-like protein was identified by positional cloning. Nearly 90% of Caucasian HH patients have been found to be homozygous for the same mutation (C282Y) in the HFE gene. To test the hypothesis that the HFE gene is involved in regulation of iron homeostasis, we studied the effects of a targeted disruption of the murine homologue of the HFE gene. The HFE-deficient mice showed profound differences in parameters of iron homeostasis. Even on a standard diet, by 10 weeks of age, fasting transferrin saturation was significantly elevated compared with normal littermates (96 +/- 5% vs. 77 +/- 3%, P < 0.007), and hepatic iron concentration was 8-fold higher than that of wild-type littermates (2,071 +/- 450 vs. 255 +/- 23 microg/g dry wt, P < 0.002). Stainable hepatic iron in the HFE mutant mice was predominantly in hepatocytes in a periportal distribution. Iron concentrations in spleen, heart, and kidney were not significantly different. Erythroid parameters were normal, indicating that the anemia did not contribute to the increased iron storage. This study shows that the HFE protein is involved in the regulation of iron homeostasis and that mutations in this gene are responsible for HH. The knockout mouse model of HH will facilitate investigation into the pathogenesis of increased iron accumulation in HH and provide opportunities to evaluate therapeutic strategies for prevention or correction of iron overload.
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PMID:HFE gene knockout produces mouse model of hereditary hemochromatosis. 948 31

Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (beta2m-/-) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of beta2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and beta2m-/- mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the beta2m-/- mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and beta2m-/- mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the beta2m-/- mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the beta2m-/- mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the beta2m-/- mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.
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PMID:Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in beta2-microglobulin knockout mice. 953 20

Forty Caucasian patients with primary acquired sideroblastic anaemia (SA), were investigated for the presence of the Cys282Tyr and/or His63Asp mutation as possible cofactor(s) for iron overload. One patient was heterozygous for the Cys282Tyr mutation and 13 heterozygotes and one homozygote for the His63Asp mutation were found (no difference compared with controls). SA patients with normal codon 63 had a mean ferritin level of 923+/-815 microg/l whereas those with codon 63 mutation had 769+/-577 microg/l (P=0.64). We conclude that ineffective erythropoiesis with no associated mutation in the HFE gene can lead to iron overload in SA patients.
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PMID:Iron overload in patients with sideroblastic anaemia is not related to the presence of the haemochromatosis Cys282Tyr and His63Asp mutations. 1002 19

Genetic hemochromatosis (GH) is believed to be a disease restricted to those of European ancestry. In northwestern Europe, >80% of GH patients are homozygous for one mutation, the substitution of tyrosine for cysteine at position 282 (C282Y) in the unprocessed protein. In a proportion of GH patients, two mutations are present, C282Y and H63D. The clinical significance of this second mutation is such that it appears to predispose 1%-2% of compound heterozygotes to expression of the disease. The distribution of the two mutations differ, C282Y being limited to those of northwestern European ancestry and H63D being found at allele frequencies>5%, in Europe, in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent. The C282Y mutation occurs on a haplotype that extends </=6 Mb, suggesting that this mutation has arisen during the past 2,000 years. The H63D mutation is older and does not occur on such a large extended haplotype, the haplotype in this case extending </=700 kb. Here we report the finding of the H63D and C282Y mutations on new haplotypes. In Sri Lanka we have found H63D on three new haplotypes and have found C282Y on one new haplotype, demonstrating that these mutations have arisen independently on this island. These results suggest that the HFE gene has been the subject of selection pressure. These selection pressures could be due to infectious diseases, environmental conditions, or other genetic disorders such as anemia.
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PMID:Multicentric origin of hemochromatosis gene (HFE) mutations. 1009 Aug 90

Seven untransfused patients with congenital dyserythropoietic anaemia type I were investigated to assess the determinants of both iron overload and serum bilirubin levels. The serum ferritin concentration was increased in all patients and non-transferrin-bound iron (NTBI) was increased in all but one patient. None of the patients showed the C282Y mutation in the hereditary haemochromatosis gene, HFE. One patient was homozygous for the H63D mutation in this gene. The data indicated that differences in the extent of iron overload were not mediated by co-inheritance of the C282Y mutation in the HFE gene but could largely be explained by differences in the severity of anaemia and ineffective erythropoiesis, and in the age of the patient. In one patient an unusually high plasma bilirubin level was associated with the variant A[TA]7TAA configuration in the TATA box of the uridine diphosphate glucuronosyltransferase (UGT-1A) gene promoter, the mutation found in most patients with mild Gilbert's syndrome.
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PMID:Determinants of iron status and bilirubin levels in congenital dyserythropoietic anaemia type I. 1058 52

A complete data set (age, weight, diet and recent donation history; venous blood cell count, serum ferritin and soluble transferrin receptor concentrations and transferrin saturation; HFE genotype) was obtained from 113 male and 122 female blood donors. Progressive iron depletion and deficiency - most apparent from serum concentrations of soluble transferrin receptor divided by the logarithm of ferritin concentrations (the TfR-F index) - developed in men donating up to six times in 2 years, although the serum ferritin alone was also informative; however, no prediction could be made for those iron-depleted individuals who will develop iron deficiency after donation. Iron stores in the groups of donors with 'low-normal' haemoglobin (Hb) concentrations were indistinguishable from those in donors with higher Hb values, whereas donors failing the anaemia screen had reduced stores. This supports the UK policy of accepting donations from people whose Hb concentration is up to 0. 5 g/dl below the recommended European threshold. Women eating red meat once a week sustained higher ferritin concentrations, and the iron status of first-time women donors resembled that of men donating twice each year. Homozygosity for either HFE variant allowed greater iron retention in the face of regular donation, but among heterozygotes the findings were inconclusive.
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PMID:A study of the iron and HFE status of blood donors, including a group who failed the initial screen for anaemia. 1069 78

The application of molecular genetics to haemochromatosis and experimental mutagenesis in animals has transformed our capacity to investigate the unique physiology of iron homeostasis-a key problem in biology and medicine. The identification of HFE, the principal determinant of adult haemochromatosis (HFE1; OMIM 235200) and TfR2, recently implicated in a rarer form of the inherited disorder (HFE3; OMIM 604250), and the promise of candidate genes for juvenile haemochromatosis (HFE2; OMIM 602390) and neonatal haemochromatosis (OMIM 231100) provide the foundation for important studies into the control mechanism of iron balance in humans. The rare conditions atransferrinaemia (OMIM 209300) and acaeruloplasminaemia (OMIM 604290), each associated with tissue iron overload, have already implicated the iron transport ligand transferrin and the copper transporter caeruloplasmin in the control of iron homeostasis. Gene mapping studies in animal mutants with anaemia due to defects in the uptake or tissue transfer of iron have yielded novel proteins involved in iron transport: DMT1 (brush border transporter of ferrous iron) in the mk/mk mouse, hephaestin (basolateral multi-copper ferroxidase) in the sex-linked anaemic mouse (sla) and ferroportin1 (basolateral iron exporter) in zebrafish weh mutants. The discovery of genes that determine heritable defects of iron absorption and regulation in animals and humans thus holds promise for a complete mechanistic understanding of the molecular pathophysiology of iron metabolism.
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PMID:Haemochromatosis: novel gene discovery and the molecular pathophysiology of iron metabolism. 1100 92

Herein is described the case of a young woman presenting with iron overload and macrocytosis. The initial diagnosis was hereditary hemochromatosis. Severe anemia developed after a few phlebotomies, and she was also found to have congenital dyserythropoietic anemia that, though not completely typical, resembled type II. Only genetic testing allowed the definition of the coexistence of the 2 diseases, both responsible for the iron overload. This report points out the need to consider congenital dyserythropoietic anemia in patients with hemochromatosis and unexplained macrocytosis and, conversely, to check for the presence of hereditary hemochromatosis in patients with congenital dyserythropoietic anemia and severe iron overload. To the authors' knowledge, this is the first report of homozygosity for the C282Y mutation of the HFE gene in a patient affected by congenital dyserythropoietic anemia.
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PMID:Hereditary hemochromatosis in a patient with congenital dyserythropoietic anemia. 1107 69

Iron is vital for almost all living organisms by participating in a wide variety of metabolic processes, including oxygen transport, DNA synthesis, and electron transport. However, iron concentrations in body tissues must be tightly regulated because excessive iron leads to tissue damage, as a result of formation of free radicals. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload and, possibly, to neurodegenerative diseases. The molecular understanding of iron regulation in the body is critical in identifying the underlying causes for each disease and in providing proper diagnosis and treatments. Recent advances in genetics, molecular biology and biochemistry of iron metabolism have assisted in elucidating the molecular mechanisms of iron homeostasis. The coordinate control of iron uptake and storage is tightly regulated by the feedback system of iron responsive element-containing gene products and iron regulatory proteins that modulate the expression levels of the genes involved in iron metabolism. Recent identification and characterization of the hemochromatosis protein HFE, the iron importer Nramp2, the iron exporter ferroportin1, and the second transferrin-binding and -transport protein transferrin receptor 2, have demonstrated their important roles in maintaining body's iron homeostasis. Functional studies of these gene products have expanded our knowledge at the molecular level about the pathways of iron metabolism and have provided valuable insight into the defects of iron metabolism disorders. In addition, a variety of animal models have implemented the identification of many genetic defects that lead to abnormal iron homeostasis and have provided crucial clinical information about the pathophysiology of iron disorders. In this review, we discuss the latest progress in studies of iron metabolism and our current understanding of the molecular mechanisms of iron absorption, transport, utilization, and storage. Finally, we will discuss the clinical presentations of iron metabolism disorders, including secondary iron disorders that are either associated with or the result of abnormal iron accumulation.
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PMID:The roles of iron in health and disease. 1120 74


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