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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heme-regulated eIF2alpha kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and beta-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri-/- mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri-/- mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri-/- mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri-/- macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
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PMID:The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. 1793 63

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.
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PMID:Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure. 1809 27

Erythrocytes require iron to perform their duty as oxygen carriers. Mammals have evolved a mechanism to maintain systemic iron within an optimal range that fosters erythroid development and function while satisfying other body iron needs. This chapter reviews erythroid iron uptake and utilization as well as systemic factors that influence iron availability. One of these factors is hepcidin, a circulating peptide hormone that maintains iron homeostasis. Elevated levels of hepcidin in the bloodstream effectively shut off iron absorption by disabling the iron exporter ferroportin. Conversely, low levels of circulating hepcidin allow ferroportin to export iron into the bloodstream. Aberrations in hepcidin expression or responsiveness to hepcidin result in disorders of iron deficiency and iron overload. It is clear that erythroid precursors communicate their iron needs to the liver to influence the production of hepcidin and thus the amount of iron available for use. However, the mechanism by which erythroid cells accomplish this remains unclear and is an area of active investigation.
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PMID:Iron homeostasis and erythropoiesis. 1828 20

Cancer and treatment-related anaemia is a significant clinical problem. Erythropoiesis stimulating agents (ESA) improve anaemia and ultimately enhance patients' quality of life. However, about one-third of patients do not respond to ESA administration, mostly because of the impaired supply of iron to the erythroid marrow (functional iron deficiency). Concomitant administration of intravenous (IV) iron may improve responsiveness. The use of baseline predictors of response to ESA and of indicators of appropriateness of response and iron availability should allow targeted therapeutic interventions with both ESA and IV iron. Several biochemical and haematological indicators of response and of iron balance have been studied, but firm criteria for their use have not yet been rigorously established. The commonly used early predictive markers of response to ESA, such as baseline endogenous erythropoietin levels and an increase in haemoglobin, reticulocytes, and soluble transferrin receptor levels during ESA treatment, have not proved reliable due to their low sensitivity and specificity. Traditional markers of iron availability, such as serum ferritin and transferrin saturation display interpretation pitfalls. The need for predictors and indicators of responsiveness to ESA and IV iron is still current and clinically relevant.
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PMID:Use of erythropoiesis stimulating agents and intravenous iron for cancer and treatment-related anaemia: the need for predictors and indicators of effectiveness has not abated. 1843 Jan 92

Haem-regulated eIF2alpha kinase (HRI) is essential for the regulation of globin gene translation and the survival of erythroid precursors in iron/haem deficiency. This study found that that in iron deficiency, fetal definitive erythropoiesis is inhibited at the basophilic erythroblast stage with increased proliferation and elevated apoptosis. This hallmark of ineffective erythropoiesis is more severe in HRI deficiency. Microarray gene profiling analysis showed that HRI was required for adaptive gene expression in erythroid precursors during chronic iron deficiency. The number of genes with expression affected more than twofold increased, from 213 in iron deficiency and 73 in HRI deficiency, to 3135 in combined iron and HRI deficiencies. Many of these genes are regulated by Gata1 and Fog1. We demonstrate for the first time that Gata1 expression in developing erythroid precursors is decreased in iron deficiency, and is decreased further in combined iron and HRI deficiencies. Additionally, Fog1 expression is decreased in combined deficiencies, but not in iron or HRI deficiency alone. Our results indicate that HRI confers adaptive gene expression in developing erythroblasts during iron deficiency through maintaining Gata1/Fog1 expression.
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PMID:Haem-regulated eIF2alpha kinase is necessary for adaptive gene expression in erythroid precursors under the stress of iron deficiency. 1866 38

Transferrin receptors (TfRs) are the conventional pathway by which cells acquire iron for physiological requirements. Under iron-deficient conditions there is an increased concentration of surface TfR, especially on bone marrow erythroid precursors, as a mechanism to sequester needed iron. TfRs are also present in the circulation, and the circulating serum TfR (sTfR) level reflects total body TfR concentration. Under normal conditions erythroid precursors are the main source of sTfR. Disorders of the bone marrow with reduced erythroid precursors are associated with low sTfR levels. The sTfR concentration begins to rise early in iron deficiency with the onset of iron-deficient erythropoiesis, and continues to rise as iron-deficient erythropoiesis progressively worsens, prior to the development of anemia. The sTfR level does not increase in anemia of chronic inflammation, but is increased when anemia of chronic inflammation is combined with iron deficiency. The sTfR level is also increased in patients with expanded erythropoiesis, including hemolytic anemias, myelodysplastic syndromes, and use of erythropoietic stimulating agents. The ratio of sTfR/ferritin can be used to quantify the entire spectrum of iron status from positive iron stores through negative iron balance, and is particularly useful in evaluating iron status in population studies. The sTfR/log ferritin ratio is valuable for distinguishing anemia of chronic inflammation from iron deficiency anemia, whether the latter occurs alone or in combination with anemia of chronic inflammation.
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PMID:Serum transferrin receptor. 1882 9

Microcytic anemia is the most commonly encountered anemia in general medical practice. Nutritional iron deficiency and beta thalassemia trait are the primary causes in pediatrics, whereas bleeding disorders and anemia of chronic disease are common in adulthood. Microcytic hypochromic anemia can result from a defect in globin genes, in heme synthesis, in iron availability or in iron acquisition by the erythroid precursors. These microcytic anemia can be sideroblastic or not, a trait which reflects the implications of different gene abnormalities. Iron is a trace element that may act as a redox component and therefore is integral to vital biological processes that require the transfer of electrons as in oxygen transport, oxidative phosphorylation, DNA biosynthesis and xenobiotic metabolism. However, it can also be pro-oxidant and to avoid its toxicity, iron metabolism is strictly controlled and failure of these control systems could induce iron overload or iron deficient anemia. During the past few years, several new discoveries mostly arising from human patients or mouse models have highlighted the implication of iron metabolism components in hereditary microcytic anemia, from intestinal absorption to its final inclusion into heme. In this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. This information could be useful in the diagnosis and classification of these microcytic anemias.
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PMID:Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis. 1918 81

Iron deficiency leads to abnormal expression and function of band 3 protein in erythrocytes, but the underlying mechanisms remain elusive. The mRNA of erythroid-specific 5-aminolevulinate synthase (eALAS) contains an iron response element and the eALAS protein is an important mediator of iron utilization by erythrocytes. In this study, we investigated the effect of short hairpin RNA (shRNA) mediated silencing of eALAS on the expression of band 3 protein induced by iron. By real-time RT-PCR and Western blot we showed that at mRNA and protein level iron-induced expression of band 3 protein was lower in eALAS-shRNA transfected K562 cells than in control cells. Of note, the lowest expression was detected in K562 cells cultured in iron deficiency condition (p < 0.01). Thus either iron deficiency or depletion of eALAS could suppress the expression of erythroid band 3 protein. These results demonstrated for the first time that iron and the iron-regulatory system regulate the expression of the erythrocyte membrane proteins.
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PMID:Erythroid 5-aminolevulinate synthase mediates the upregulation of membrane band 3 protein expression by iron. 2008 44

Human red cell differentiation requires the action of erythropoietin on committed progenitor cells. In iron deficiency, committed erythroid progenitors lose responsiveness to erythropoietin, resulting in hypoplastic anemia. To address the basis for iron regulation of erythropoiesis, we established primary hematopoietic cultures with transferrin saturation levels that restricted erythropoiesis but permitted granulopoiesis and megakaryopoiesis. Experiments in this system identified as a critical regulatory element the aconitases, multifunctional iron-sulfur cluster proteins that metabolize citrate to isocitrate. Iron restriction suppressed mitochondrial and cytosolic aconitase activity in erythroid but not granulocytic or megakaryocytic progenitors. An active site aconitase inhibitor, fluorocitrate, blocked erythroid differentiation in a manner similar to iron deprivation. Exogenous isocitrate abrogated the erythroid iron restriction response in vitro and reversed anemia progression in iron-deprived mice. The mechanism for aconitase regulation of erythropoiesis most probably involves both production of metabolic intermediates and modulation of erythropoietin signaling. One relevant signaling pathway appeared to involve protein kinase Calpha/beta, or possibly protein kinase Cdelta, whose activities were regulated by iron, isocitrate, and erythropoietin.
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PMID:Iron control of erythroid development by a novel aconitase-associated regulatory pathway. 2040 36

Iron is a trace element that is vital for life. It is a component of innumerable hemoproteins and many essential non-heme iron proteins that are involved in oxygen binding and metabolism and electron transfer. Nevertheless, iron can also be toxic to cells as it catalyses the production of oxygen radicals. Iron uptake, transport, storage and utilization are therefore strictly regulated to meet the body's iron needs and to avoid its potential toxicity. Any imbalance in iron homeostasis may lead to the development of pathological conditions associated with either iron overload or iron deficiency. In this paper, we review the current understanding of iron biology with a focus on erythroid iron demand. In addition, we will discuss molecular pathophysiology with implications for novel therapies of selected hereditary defects of iron homeostasis.
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PMID:Molecular basis of hereditary iron homeostasis defects. 2042 70


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