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

Iron balance is regulated by the rate of erythropoiesis and the size of the iron stores. Anemia that accompanies infection, inflammation, and cancer (anemia of chronic disease) features normal or increased iron stores, although patients may have functional iron deficiency, namely, an imbalance between iron requirements of the erythroid marrow and the actual supply. The proportion of hypochromic red cells and the hemoglobin content of reticulocytes are direct indicators of functional iron deficiency. Biochemical markers, especially the soluble transferrin receptor/log ferritin ratio (ferritin index), are useful indicators of the iron supply to erythropoiesis. The relationship between functional iron deficiency (reticulocyte hemoglobin content) and iron supply to erythropoiesis (ferritin index) can be described in a diagnostic plot. In normoproliferative and hypoproliferative erythropoiesis, the plot allows the differentiation of classic iron deficiency from anemia of chronic disease and the combined state of functional iron deficiency with anemia of chronic disease. The therapeutic implications of the plot are to differentiate patients into those who should be administered iron supplements, epoetin, or a combination of epoetin and iron. In patients receiving epoetin therapy, the plot is an important tool for monitoring erythropoietic activity, functional iron deficiency, and adequate iron stores for new red cell production. Enhanced erythropoiesis is reflected quantitatively by the ferritin index vector. A transgression of the 1.5 (3.2) cut-off value for the ferritin index indicates that extra doses of iron need to be administered to increase the body's iron stores. A lack of increase or a reticulocyte hemoglobin content below 28 picograms indicates functional iron deficiency. The diagnostic plot is a model for differentiating iron-deficient states and predicting those patients who will respond to epoetin therapy.
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PMID:The diagnostic plot: a concept for identifying different states of iron deficiency and monitoring the response to epoetin therapy. 1664 27

Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation.
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PMID:Interleukin-6 induces hepcidin expression through STAT3. 1683 72

Patients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and iron status of patients with EPP. We thoroughly explored these parameters in Fechm1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic hypochromic anemia without ringed sideroblasts, little or no hemolysis, and no erythroid hyperplasia. Serum iron, ferritin, hepcidin mRNA, and Dcytb levels were normal. The homozygous Fechm1Pas mutant involved no tissue iron deficiency but showed a clear-cut redistribution of iron stores from peripheral tissues to the spleen, with a concomitant 2- to 3-fold increase in transferrin expression at the mRNA and the protein levels. Erythrocyte PPIX levels strongly correlated with serum transferrin levels. At all stages of differentiation in our study, transferrin receptor expression in bone marrow erythroid cells in Fech(m1Pas) was normal in mutant mice but not in patients with iron-deficiency anemia. Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIX-liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow.
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PMID:Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice. 1700 76

During erythroid differentiation and maturation, it is critical that the 3 components of hemoglobin, alpha-globin, beta-globin, and heme, are made in proper stoichiometry to form stable hemoglobin. Heme-regulated translation mediated by the heme-regulated inhibitor kinase (HRI) provides one major mechanism that ensures balanced synthesis of globins and heme. HRI phosphorylates the alpha-subunit of eukaryotic translational initiation factor 2 (eLF2alpha) in heme deficiency, thereby inhibiting protein synthesis globally. In this manner, HRI serves as a feedback inhibitor of globin synthesis by sensing the intracellular concentration of heme through its heme-binding domains. HRI is essential not only for the translational regulation of globins, but also for the survival of erythroid precursors in iron deficiency. Recently, the protective function of HRI has also been demonstrated in murine models of erythropoietic protoporphyria and beta-thalassemia. In these 3 anemias, HRI is essential in determining red blood cell size, number, and hemoglobin content per cell. Translational regulation by HRI is critical to reduce excess synthesis of globin proteins or heme under nonoptimal disease states, and thus reduces the severity of these diseases. The protective role of HRI may be more common among red cell disorders.
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PMID:Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. 1711 Apr 56

X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by defects of the transporter ABCB7 and is characterized by mitochondrial iron deposition and excess of protoporphyrin in erythroid cells. We describe ABCB7 silencing in HeLa cells by performing sequential transfections with siRNAs. The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin. The cells showed an increase of protoporphyrin IX, a higher sensitivity to H(2)O(2) toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2), while the activity of mitochondrial enzymes, such as citrate synthase or succinate dehydrogenase, and ATP content were not decreased. In contrast, aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced. The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes. In addition, the results indicate that anemia in XLSA/A is caused by the accumulation of iron in a form that is not readily usable for heme synthesis.
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PMID:RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload. 1719 93

Anemia associated with chronic renal disease remains a major concern for nephrologists as it significantly increases the morbidity and mortality in this patient group. The introduction of erythropoietin has dramatically changed the treatment of anemia in uremic patients. However, some patients showed hyporesponsiveness to erythropoietin because of inadequate iron supply to the erythroid bone marrow. Patients undergoing chronic intermittent hemodialysis are especially vulnerable to iron deficiency due to blood loss during the hemodiaylsis sessions, gastrointestinal bleeding and compromised gastrointestinal absorption. Demand for iron is also increased by the treatment for anemia with erythropoietin. Intravenous administration is more effective than oral iron supplemantation in renal failure patients. Some studies have raised concerns of the potential serious side effects associated with intravenous iron administration. Besides anaphylactic reactions that were reported to occur in less than 1% of patients treated with iron dextran and have not been associated with other iron formulations, concerns about the long-term use of iron include the increased risk of infections and oxidative stress with consequent cardiovascular disease. Therapy with dextran-free iron formulations is an essential part of anemia treatment protocols, and was not found to be associated with either short- or long-term serious side effects.
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PMID:[Principles of iron therapy in hemodialysis patients]. 1721 2

The treatment of renal anaemia with erythropoiesis stimulating agent is often associated with a functional iron deficiency characterized by normal or elevated iron stores but insufficient iron delivered for erythropoiesis. Biological markers of iron status depend on the compartment where it is located: stored, circulating or available for erythropoiesis. Ferritin is the protein of iron storage but also a protein of the acute phase of inflammation and serum ferritin increases in case of liver cytolysis. In the circulation iron is bound to transferrin (Tf). Tf dosage is necessary to calculate transferrin saturation coefficient (TSAT) which decreases below 20% in iron deficiency but also in inflammatory states. Another Limitation is the nycthemeral variations of serum iron. The best marker of functional iron deficiency is the percentage of hypo chromic red cells (> 6%) followed by reticulocyte Hb content (< 29 pg/cell). These 2 markers measure the body capacity to donate iron to erythroid precursors but necessitate specific laboratory equipment. In all cases evaluation of iron balance should be done at least eight days after the last iron infusion.
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PMID:[How do we optimally evaluate iron stores in dialyzed patients treated with erythropoiesis stimulating agent?]. 1737 68

Recombinant human erythropoietin (rHuEPO) has transformed the management chronic renal failure (CKD) and considerably improved the outcome of patients on regular chronic dialysis. However, a significant number of patients fail to respond to high of Erythropoiesis-stimulating agents (ESAs) and several causes of inadequate response to epoetin therapy have been identified. Some factors, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as hemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be adjusted. Iron deficiency, whether functional or absolute, is the most common factor that limits the response to rHuEPO. Monitoring of iron parameters and a large use of iron supplementation result in an efficient epoetin response. Infection and inflammation have been shown to reduce responsiveness to ESAs by disrupting iron metabolism and increasing the release of pro-inflammatory cytokines that inhibit erythropoiesis. Increase dialysis dose is associated with improvements in anemia correction and reduced requirements for ESAs. Severe hyperparathyroidism and aluminum overload lead to a reduced number of responsive erythroid progenitor cells. Finally, a number of nutritional factors, such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C, are susceptible to alter erythropoiesis. Optimizing patient response to ESAs therefore requires consideration of many of well-established factors and is important for both patient outcomes and cost of treatment.
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PMID:[Factors affecting the response to erythropoiesis-stimulating agents]. 1737 70

The national and international recommendations concerning the iron management in chronic kidney disease (CKD) patient are well established. All acknowledge the fact that iron needs are increased in uremic patients. This is particularly true for CKD-5 patients treated by hemodialysis (increased losses) and when treated by an erythropoetic stimulating agent (ESA). Annual iron requirements are currently estimated between 500 mg and 3000 mg per year. The biodisponibility of oral iron isreduced and side effects are quite common. The venous supplementation of iron offers today the best safety/efficacy profile. The evaluation of iron store is mandatory in CKD patient. The assessment of iron store in kidney patient relies on three major markers: transferrin saturation (Trf Sat); ferritin; percentage of hypochromic erythroid cells. Faced to iron deficiency, it is crucial to differentiate two situations: an absolute iron deficiency (Trf Sat < 20 % ; ferritin < 100 ng/ml; percentage of hypochromic cells > 10%); a functional iron deficiency (Trf Sat < 20%; ferritin > 200-500 ng/ml; percentage of hypochromic cells > 5-10%). When intravenous iron supplementation is indicated, dosing regime should be based on a slow and a reduced dosage administration to comply with manufacturer and best practice recommendations. Regular iron infusion of 50 to 100 mg per week is able to cover the basic needs for most hemodialysis patients.
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PMID:[Recommendations of iron management in chronic kidney patients]. 1737 84

Inflammation induced anemia and resistance to erythropoietin are common features in patients with chronic kidney disease (CKD). Elevated levels of cytokines and enhanced oxidative stress, conditions associated with inflammatory states, are implicated in the development of anemia. Accumulating evidence suggests that activation of cytokine cascade and the associated acute-phase response, as it often occurs in patients with CKD, divert iron from erythropoiesis to storage sites within the reticuloendothelial system leading to functional iron deficiency and subsequently to anemia or resistance to erythropoietin. Other processes have also been shown to be involved in the pathogenesis of anemia provoked by the activated immune system including an inhibition of erythroid progenitor proliferation and differentiation, a suppression of erythropoietin production and a blunted response to erythropoietin. The present review concerns the underlying alterations in iron metabolism induced by chronic inflammation that result in anemia.
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PMID:Iron homeostasis in chronic inflammation. 1744 78


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