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

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1-28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.
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PMID:The anemia of chronic disorders: studies of marrow regulation and iron metabolism. 80 11

Erythropoietin production was studied in 30-day-old and adult rats previously injected with pharmacological doses of isoproterenol. The animals were stimulated either by hypobaric hypoxia or by a combination of hypoxia and acute anemia. The erythropoietic activity of the plasma was measured by 59Fe incorporation in total circulating red blood cells of mice made polycythemic by chronic hypoxia. The results were converted to units of erythropoietin (IRP). A significant reduction of erythropoietin production was observed only in young rats. Our interpretation of the findings is that isoproterenol induced the differentiation of the salivary glands in the young animals hence reducing hormone production at the extrarenal (submandibular) level.
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PMID:Reduced extrarenal erythropoietin production in rats treated with isoproterenol. 87 9

The plasma erythropoietic activity of anephric mice and anephric mice without submandibular glands was compared. The erythropoietin production was stimulated by anemia (phenylhydrazine) and hypobaric hypoxia (0.4 atm). The activity was measured by the 59Fe incorporation in total circulating red blood cells in mice rendered polycythemic by hypoxia. The results were also calculated in units (IRP) of erythropoietin. The plasma erythropoietic activity of anephric mice was neutralized by antiserum against normal erythropoietin. Extrarenal erythropoietin production was significantly reduced in mice deprived of submandibular glands. These data indicate that this phenomenon is not restricted to the rat and support the concept that the submandibular glands are important extrarenal sources of erythropoietin.
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PMID:The role of the submandibular glands in extrarenal erythropoietin production in mice. 89 62

Male adult mice were allowed to drink only a solution of 32% ethyl alcohol for 3 months. Hematocrit and hemoglobin concentration were lower in ethanol-treated than in control mice at the end of the experimental period. Red cell volume was not significantly different between both groups. Plasma volume was higher in experimental than in control mice. Therefore, the anemia found in ethanol-treated mice can be regarded as a dilution anemia. When ethanol-treated and control mice, both made polycythemic by hypertransfusion to suppress their endogenous erythropoietin formation, were injected with doses of erythropoietin in the range of 0.2 to 3.2 IRP units, the derived dose-response curves were markedly different because of a reduced response to the hormone by the treated mice. This finding suggests that the number of "erythropoietin-responsive cells" may be reduced as the result of ethanol, or that their response to the hormone may be delayed or inhibited. Plasma erythropoietin concentration in alcohol- treated mice, as determined in the posthypoxic polycythemic mouse bioassay, was higher than normal in both normoxic and hypoxic conditions, probably as the result of the impaired responsiveness to the hormone mentioned above.
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PMID:Effect of chronic ethanol administration on production of and response to erythropoietin in the mouse. 637 52

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage-transferrin, transferrin receptor, and ferritin-have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the "Stimulator of Fe Transport" (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.
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PMID:Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism. 1170 34

Serum erythropoietin (EPO) determination is useful in the diagnosis of renal anemia. In anemic patients with normal renal function increased EPO concentrations are typically found, however, so far hemoglobin-related reference ranges for serum EPO had not been established. In a cross-sectional manner we determined serum EPO in 280 patients with anemia and normal serum concentrations of creatinine and urea. Each 70 consecutive anemic patients with hemoglobin concentrations within four intervals were included (<8 g/dL; 8.1-9.0 g/dL; 9.1-10.0 g/dL; 10.1-11.0 g/dL). 97 patients were from surgical disciplines, 183 were from internal disciplines. Serum EPO was determined by use of an automated sandwich immunoassay that is standardized according to the WHO 2nd IRP 67/343. The ranges between the 20th and 80th percentile of EPO concentrations for the four specified hemoglobin intervals were as follows: Hb <8 g/dL, EPO 61.8-366 IU/L; Hb 8.1-9.0 g/dL, EPO 43.3-242 IU/L; Hb 9.1-10.0 g/dL, EPO 31.8-113 IU/L; Hb 10.1-11.0 g/dL, EPO 22.3-71.2 IU/L. Since no complete diagnostic evaluation of the patients' renal and respiratory functions was performed in this cross-sectional study we propose the 20th percentile of EPO concentrations as a preliminary hemoglobin-related reference range; serum EPO concentrations below this percentile speak for a contribution of EPO deficiency in the individual etiology of anemia.
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PMID:Serum erythropoietin concentrations in patients with anemia--preliminary hemoglobin-related reference ranges. 1246 43

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.
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PMID:The role of iron regulatory proteins in mammalian iron homeostasis and disease. 1685 17

Glutaredoxin 5 (GLRX5) deficiency has previously been identified as a cause of anemia in a zebrafish model and of sideroblastic anemia in a human patient. Here we report that GLRX5 is essential for iron-sulfur cluster biosynthesis and the maintenance of normal mitochondrial and cytosolic iron homeostasis in human cells. GLRX5, a mitochondrial protein that is highly expressed in erythroid cells, can homodimerize and assemble [2Fe-2S] in vitro. In GLRX5-deficient cells, [Fe-S] cluster biosynthesis was impaired, the iron-responsive element-binding (IRE-binding) activity of iron regulatory protein 1 (IRP1) was activated, and increased IRP2 levels, indicative of relative cytosolic iron depletion, were observed together with mitochondrial iron overload. Rescue of patient fibroblasts with the WT GLRX5 gene by transfection or viral transduction reversed a slow growth phenotype, reversed the mitochondrial iron overload, and increased aconitase activity. Decreased aminolevulinate delta, synthase 2 (ALAS2) levels attributable to IRP-mediated translational repression were observed in erythroid cells in which GLRX5 expression had been downregulated using siRNA along with marked reduction in ferrochelatase levels and increased ferroportin expression. Erythroblasts express both IRP-repressible ALAS2 and non-IRP-repressible ferroportin 1b. The unique combination of IRP targets likely accounts for the tissue-specific phenotype of human GLRX5 deficiency.
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PMID:Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. 2036 84

Iron deficiency is a common condition increasingly diagnosed and treated by gastroenterologists. The most common presentation of iron deficiency is anaemia; however, it is a systemic disorder affecting multiple aspects of health in various organs. Iron is an essential element, with iron-containing proteins exerting a variety of vital functions, including oxygen transport, cellular respiration, intermediary metabolism, regulation of transcription and DNA repair. Major pathways of iron utilisation and production of iron-containing proteins include iron sulphur cluster biosynthesis, haem synthesis and storage within ferritin. The main site of iron absorption is the small intestine, but most iron is recycled by the monocyte-macrophage system via phagocytosis of senescent erythrocytes. Hepcidin, the key iron-regulating peptide binds to the iron exporter ferroportin and leads to its degradation, thereby inhibiting intestinal iron absorption and cellular export. Hepcidin levels are regulated on a transcriptional level by various stimuli, including transferrin saturation, erythropoietic activity, hypoxia and inflammation. Iron deficiency evokes adaptive responses resulting in alteration of cellular metabolism, changes in gene expression, activation of signalling pathways, cell cycle regulation, differentiation and cell death. Such responses are mediated by a number of iron-sensitive signalling pathways, including the IRE/IRP system, HIF and haem signalling. This review provides a molecular perspective for the clinician and highlights important biological aspects of iron deficiency.
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PMID:Iron sensing and signalling. 2201 65

Iron is essential for several vital biological processes. Its deficiency or overload drives to the development of several pathologies. To maintain iron homeostasis, the organism controls the dietary iron absorption by enterocytes, its recycling by macrophages and storage in hepatocytes. These processes are mainly controlled by hepcidin, a liver-derived hormone which synthesis is regulated by iron levels, inflammation, infection, anemia and erythropoiesis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Cells are able to regulate themselves the expression of the iron metabolism-related genes through different post-transcriptional mechanisms, such as the alternative splicing, microRNAs, the IRP/IRE system and the proteolytic cleavage. Whenever those mechanisms are disturbed, due to genetic or environmental factors, iron homeostasis is disrupted and iron related pathologies may arise.
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PMID:An overview of molecular basis of iron metabolism regulation and the associated pathologies. 2584 14


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