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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron metabolism in mammals requires a complex and tightly regulated molecular network. The classical view of iron metabolism has been challenged over the past ten years by the discovery of several new proteins, mostly Fe (II) iron transporters, enzymes with ferro-oxydase (hephaestin or ceruloplasmin) or ferri-reductase (Dcytb) activity or regulatory proteins like HFE and hepcidin. Furthermore, a new transferrin receptor has been identified, mostly expressed in the liver, and the ability of the megalin-cubilin complex to internalise the urinary Fe (III)-transferrin complex in renal tubular cells has been highlighted. Intestinal iron absorption by mature duodenal enterocytes requires Fe (III) iron reduction by Dcytb and Fe (II) iron transport through apical membranes by the iron transporter Nramp2/DMT1. This is followed by iron transfer to the baso-lateral side, export by ferroportin and oxidation into Fe (III) by hephaestin prior to binding to plasma transferrin. Macrophages play also an important role in iron delivery to plasma transferrin through phagocytosis of senescent red blood cell, heme catabolism and recycling of iron. Iron egress from macrophages is probably also mediated by ferroportin and patients with heterozygous ferroportin mutations develop progressive iron overload in liver macrophages. Iron homeostasis at the level of the organism is based on a tight control of intestinal iron absorption and efficient recycling of iron by macrophages. Signalling between iron stores in the liver and both duodenal enterocytes and macrophages is mediated by hepcidin, a circulating peptide synthesized by the liver and secreted into the plasma. Hepcidin expression is stimulated in response to iron overload or inflammation, and down regulated by anemia and hypoxia. Hepcidin deficiency leads to iron overload and hepcidin overexpression to anemia. Hepcidin synthesis in response to iron overload seems to be controlled by the HFE molecule. Patients with hereditary hemochromatosis due to HFE mutation have impaired hepcidin synthesis and forced expression of an hepcidin transgene in HFE deficient mice prevents iron overload. These results open new therapeutic perspectives, especially with the possibility to use hepcidin or antagonists for the treatment of iron overload disorders.
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PMID:[Molecular mechanisms of iron homeostasis]. 1477 Mar 66

There have been major basic advances in the field of iron metabolism in recent years. These advances include the discoveries of the HFE-1 gene, a series of transmembrane iron transporters or cotransporters (eg, divalent metal transporter-1, duodenal cytochrome b, ferroportin-1, hephaestin, and transferrin receptor-2), and two key regulatory proteins named hepcidin and hemojuvelin. Several mutations of these various proteins have been linked to human diseases. These discoveries have led to major improvements in our understanding of iron physiology and have also profoundly modified and extended the pathologic iron field. Clinical applications have rapidly emerged with the appearance of new iron overload syndromes and the practical input of new genetic tools enabling the noninvasive diagnosis of HFE-1 hemochromatosis. These basic advances are paving the road for innovative therapeutic strategies not only in iron overload syndromes but also in the wide area of chronic disease-related anemia.
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PMID:The clinical relevance of new insights in iron transport and metabolism. 1496 86

Hepcidin is a circulating antimicrobial peptide mainly synthesized in the liver, which has been recently proposed as a factor regulating the uptake of dietary iron and its release by reticuloendothelial macrophages. Hepcidin is a potent mediator of anemia of inflammation. Disrupted hepcidin expression is thought to mediate the pathological effects of mutations in the HFE gene in hereditary hemochromatosis. Discovery of the critical role of hepcidin in iron homeostasis could help in the design of new therapies for some iron metabolism disorders in humans. The aim of this review is to summarize current knowledge about the function and regulation of hepcidin in iron metabolism.
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PMID:[Regulation of body iron homeostasis by hepcidin]. 1506 80

Although it generally does not improve performance, iron is often used by elite athletes. The physiologic changes induced by exercise can mimic iron deficiency and decrease hemoglobin and ferritin concentrations. Determination of serum transferrin receptor concentrations may identify true iron deficiency, which occurs particularly in young athletes. In contrast, increased iron stores in the body are a frequent finding in elite athletes who have used long-term iron supplementation. Elite runners have increased intestinal blood loss, but this usually can be compensated by enhanced absorption of dietary iron. The combination of exercise-induced hemolysis with enhanced intestinal blood loss in various endurance sports leads to severe abnormalities of routine tests, and extreme physical activity may be responsible for positive fecal occult blood determinations. Indiscriminate iron supplementation carries the risk of inducing hemochromatosis in individuals homozygous for the widespread C282Y allele of the HFE gene. This polymorphism is common and can be found in about 1% of individuals of Northern European descent; moreover, iron supplementation can modify the presentation of important underlying diseases such as celiac disease or colon carcinoma. In conclusion, iron supplements should be prescribed for athletes with iron-deficiency anemia and carefully monitored if given for prophylaxis; unless a therapeutic response occurs, investigations to establish the cause of iron deficiency should be initiated.
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PMID:Iron supplementation in athletes--first do no harm. 1521 43

The diagnosis of congenital dyserythropioetic anemia-type II (CDA-II) was established in 1974 in three siblings aged 20, 18 and 5 years, respectively. Liver biopsy performed in two elder siblings on admission revealed liver siderosis. Anemia showing haemolytic component with destruction of erythrocytes in the spleen was corrected after splenectomy. Increased number of erythrocytes showing "the double membrane phenomenon" was found in the peripheral blood after splenectomy. All three siblings developed cholecystolithiasis with choledocholithiasis and obstructive jaundice in two of them. Two patients at the age of 49 and 34 years (the third died in an accident at the age of 40 years) developed 29 years after the diagnosis of CDA-II had been established signs of iron overload with transferin saturation 99%, serum ferritin 1450.4 microg/l and 1131.7 microg/l respectively, and hepatic iron concentration (dry weight) 14,843 microg/g and 15,415 microg/g (norm 70-1400 microg/g) respectively. No mutations of HFE gene (C282Y and H63D) were found. Liver biopsy showed heavy accumulation of hemosiderin in hepatocytes and reticuloendothelial cells. The structure of the liver tissue was not changed, only mild fibrosis in portal area was present in the older patient. Because of iron overload therapy with phlebotomy once monthly (400 ml) has been started in both patients. In peripheral blood films excess of Pappenheimer bodies was found.
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PMID:[Congenital dyserythropoietic anemia--type II (CDA-II) in 3 siblings with long-term follow up and iron overload]. 1574 56

At age of 3.2 years routine blood analysis showed the presence of a beta-thalassemic trait with unexpected high level of serum iron and high transferrin saturation. Hematological follow-up confirmed the moderate degree of anemia and persisting high levels of iron indices throughout the years with a progressive increase of serum ferritin. At the age of 19 years the patient was diagnosed homozygous for HC63D HFE. The patient referred by us confirm the possibility of precocious alteration of iron indices in patients with heterozygosity for beta-thalassemia inherited together with HFE mutations. This observation suggests that any children with thalassemic trait with increased transferrin saturation and/or serum ferritin might be investigated for the presence of the hemocromatosis genes in order to detect the disease before any clinical manifestation and even before organ iron loading.
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PMID:Heterozygous beta-thalassemia and homozygous H63D hemochromatosis in a child: an 18-year follow-up. 1580 2

We report the case of an African American woman with sickle cell anemia and iron overload incompletely explained by erythrocyte transfusion who is heterozygous for a promoter mutation in the X-linked erythroid-specific 5-aminolevulinate synthase gene (ALAS2): a C to G transversion at nucleotide -206 from the transcription start site, as defined by primer extension (-258 from the start ATG). This mutation has previously been associated with sideroblastic anemia and iron overload in members of a Welsh kinship. No coding region mutation of HFE, FPN1, TFR2, HAMP, or HJV genes was detected. The mother of the proband has mild, chronic anemia and is also heterozygous for the same proximal promoter region mutation of ALAS2. However, she has no evidence of iron overload. We conclude that an ALAS2 promoter region mutation could partly account for iron overload in the present proband, and that this or other ALAS2 mutations could explain the occurrence of iron overload in other whites or blacks with or without anemia. The occurrence of anemia and iron overload may be discordant in women heterozygous for ALAS2 mutations.
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PMID:Iron overload in an African American woman with SS hemoglobinopathy and a promoter mutation in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene. 1588 6

Hepcidin, which has been recently identified both by biochemical and genomic approaches, is a 25 amino acid polypeptide synthesized mainly by hepatocytes and secreted into the plasma. Besides its potential activity in antimicrobial defense, hepcidin plays a major role in iron metabolism. It controls two key steps of iron bioavailability, likely through a hormonal action: digestive iron absorption by enterocytes and iron recycling by macrophages. In humans, this could explain that low levels of hepcidin found during juvenile haemochromatosis and HFE-1 genetic haemochromatosis are associated with an iron overload phenotype. Conversely, an increase of hepcidin expression is suspected to play a major role in the development of anemia of chronic inflammatory diseases. However, the regulatory mechanisms of hepcidin expression are multiple, including iron-related parameters, anemia, hypoxia, inflammation and hepatocyte function. Therefore, many physiological and pathological situations may modulate hepcidin expression and subsequently iron metabolism. A better knowledge of the biological effects of hepcidin and of its expression regulatory mechanisms will clarify the place of hepcidin in the diagnosis and treatment of iron-related diseases.
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PMID:Hepcidin in iron metabolism. 1597 53

Patients with chronic renal insufficiency (CRI) have reduced hemoglobin levels, mostly as a result of decreased kidney production of erythropoietin, but the relation between renal insufficiency and the magnitude of hemoglobin reduction has not been well defined. Hereditary hemochromatosis is an inherited disorder of iron metabolism. The importance of the association of hemochromatosis with treatment for anemia among patients with CRI has not been well described. We analyzed the frequency of the C282Y and H63D mutations in the HFE gene in 201 Brazilian individuals with CRI undergoing hemodialysis. The analysis of the effects of HFE mutations on iron metabolism and anemia with biochemical parameters was possible in 118 patients of this study (hemoglobin, hematocrit, ferritin levels, transferrin saturation, and serum iron). A C282Y heterozygous mutation was found in 7/201 (3.4%) and H63D homozygous and heterozygous mutation were found in 2/201 (1.0%) and 46/201 (22.9%), respectively. The allelic frequencies of the HFE mutations (0.017 for C282Y mutation and 0.124 for H63D mutation) did not differ between patients with CRI and healthy controls. Regarding the biochemical parameters, no differences were observed between HFE heterozygous and mutation-negative patients, although ferritin levels were not higher among patients with the H63D mutation (P = 0.08). From what we observed in our study, C282Y/H63D HFE gene mutations are not related to degrees of anemia or iron stores in CRI patients receiving intravenous iron supplementation (P > 0.10). Nevertheless, the present data suggest that the H63D mutation may have an important function as a modulating factor of iron overload in these patients.
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PMID:Hemochromatosis (HFE) gene mutations in Brazilian chronic hemodialysis patients. 1613 14

The defensin-like circulatory peptide hepcidin is the iron-regulatory hormone that links innate immunity and iron metabolism. In response to inflammatory stimuli, the liver produces hepcidin: this antimicrobial peptide then limits the iron that is vital to invading pathogens, by decreasing iron release/transfer from enterocytes and macrophages and causing secondary hypoferremia. This may lead, however, to reduced iron availability for erythropoiesis and therefore to anemia (and anemia of chronic disease). When iron is scarce, the rate at which it is released into the bloodstream must be enhanced: indeed, iron starvation and hypoxia readily abrogate hepcidin expression. Conversely, if excess iron enters the circulation, hepcidin transcription is turned on and iron release from the intestine and macrophages abrogated. Circumstantial evidence indicates that the effect of circulatory iron on hepcidin requires functional HFE and hemojuvelin, two proteins of unknown function that have recently been linked to human hereditary hemochromatosis. In this disease it is likely that inadequate levels of circulating hepcidin lead to the uncontrolled release of iron from the intestine and macrophages, followed by tissue iron overload and organ damage. Given its role as the iron-regulatory hormone, the modulation of hepcidin activity using agonists or antagonists might offer new treatment opportunities in different human iron-dependent disorders.
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PMID:Mechanisms of disease: The role of hepcidin in iron homeostasis--implications for hemochromatosis and other disorders. 1626 43


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