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Concept: Anemia of chronic disease

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BACKGROUND: Growth differentiation factor 15 (GDF15), a divergent TGFβ superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH). PROCEDURES: We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children. RESULTS: Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain. CONCLUSIONS: Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.

Concepts: Regulation of gene expression, Iron deficiency anemia, Hematology, Ferroportin, Anemia of chronic disease, Hepcidin, Human iron metabolism, Gene expression

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To assess the incidence of iron deficiency (ID), and iron deficient anemia (IDA) within a cohort of highly trained runners and triathletes, and to examine the association of oral iron supplementation history with serum ferritin (sFe) and hemoglobin (Hb) concentrations.

Concepts: Anemia of chronic disease, Iron deficiency, Iron, Iron supplements, Ferritin, Hemoglobin, Anemia, Iron deficiency anemia

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Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD.

Concepts: Hepcidin, Hematology, Iron deficiency anemia, Iron, Anemia, Anemia of chronic disease, Human iron metabolism

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A relation between pica (the craving and purposive consumption of nonfood items) during pregnancy and anemia is observed frequently. However, few studies related pica behaviors to biomarkers of iron status, and little is known about pica prevalence in U.S. pregnant adolescents. To address this, we undertook a longitudinal study examining iron status and pica behaviors among a group of 158 pregnant adolescents (aged ≤18 y). Approximately two-thirds of the participants were African American and 25% were Hispanic. Maternal iron status indicators [hemoglobin, soluble transferrin receptor, serum ferritin (SF), total body iron (TBI), and serum hepcidin] were assessed during pregnancy (18.5-37.3 wk) and at delivery. Pica behavior was assessed up to 3 times across gestation. Among the 158 adolescents, 46% reported engaging in pica behavior. Substances ingested included ice (37%), starches (8%), powders (4%), and soap (3%). During pregnancy, mean SF [geometric mean: 13.6 μg/L (95% CI: 11.0, 17.0 μg/L)], TBI (mean ± SD: 2.5 ± 4.2 mg/kg), and hepcidin [geometric mean: 19.1 μg/L (95% CI: 16.3, 22.2 μg/L)] concentrations were significantly lower (P < 0.05) in the pica group (n = 72) than values observed among the non-pica group [SF, geometric mean: 21.1 μg/L (95% CI: 18.0, 25.0 μg/L); TBI, mean ± SD: 4.3 ± 3.5 mg/kg; hepcidin, geometric mean: 27.1 μg/L (95%: 23.1, 32.1 μg/L); n = 86]. Although additional studies must address the etiology of these relations, this practice should be screened for, given its association with low iron status and because many of the substances ingested may be harmful. This trial was registered at clinicaltrials.gov as NCT01019902.

Concepts: Anemia of chronic disease, Embryo, Anemia, Hemoglobin, Iron deficiency, Iron metabolism, Transferrin, Iron deficiency anemia

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The cargo receptor NCOA4 mediates autophagic ferritin degradation. Here we show that NCOA4 deficiency in a knockout mouse model causes iron accumulation in the liver and spleen, increased levels of transferrin saturation, serum ferritin, and liver hepcidin, and decreased levels of duodenal ferroportin. Despite signs of iron overload, NCOA4-null mice had mild microcytic hypochromic anemia. Under an iron-deprived diet (2-3 mg/kg), mice failed to release iron from ferritin storage and developed severe microcytic hypochromic anemia and ineffective erythropoiesis associated with increased erythropoietin levels. When fed an iron-enriched diet (2 g/kg), mice died prematurely and showed signs of liver damage. Ferritin accumulated in primary embryonic fibroblasts from NCOA4-null mice consequent to impaired autophagic targeting. Adoptive expression of the NCOA4 COOH terminus (aa 239-614) restored this function. In conclusion, NCOA4 prevents iron accumulation and ensures efficient erythropoiesis, playing a central role in balancing iron levels in vivo.

Concepts: Liver, Iron metabolism, Microcytic anemia, Hematology, Anemia of chronic disease, Iron deficiency anemia, Human iron metabolism, Anemia

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Recent reports have shown that novel phosphate binders containing iron are not only efficacious for the treatment of hyperphosphatemia but also may reduce the need for erythropoiesis-stimulating agents and intravenous (IV) iron for anemia management in patients on maintenance hemodialysis (MHD). Possible healthcare cost savings, which have not been demonstrated in a long-term study, may be an additional advantage of using such multi-pronged treatment strategies for the control of both hyperphosphatemia and iron needs. It is currently assumed that oral iron supplementation is less efficient than the IV route in patients with chronic kidney disease (CKD). The unexpected efficacy of novel iron-containing phosphate binders, such as ferric citrate, in repleting insufficient iron stores and improving the anemia of CKD could change this view. Previous assumptions of self-controlled iron uptake by ‘mucosal block’ or hepcidin, or else by impaired intestinal iron absorption due to CKD-associated inflammation cannot be reconciled with recent observations of the effects of ferric citrate administration. Citrate in the intestinal lumen may partly contribute to the acceleration of iron absorption. Animal experiments and clinical studies have also shown that oral iron overload can cause excessive iron accumulation despite high hepcidin levels, which are not able to block iron absorption completely. However, like with IV iron agents, no long-term safety data exist with respect to the effects of iron-containing phosphate binders on ‘hard’ patient outcomes. Future randomized prospective studies in patients with CKD are necessary to establish the safety of oral iron-containing phosphate binders for the control of both hyperphosphatemia and renal anemia.

Concepts: Anemia of chronic disease, Kidney, Renal failure, Effectiveness, Erythropoietin, Chronic kidney disease, Iron, Human iron metabolism

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Microcytic anemia is characterized by smaller-than-normal red cells due to decreased production of hemoglobin. This review discusses diagnosis and treatment of thalassemia, anemia of inflammation, and iron-deficiency anemia, highlighting recent findings.

Concepts: Hematology, Mean corpuscular volume, Anemia of chronic disease, Red blood cell, Microcytic anemia, Hemoglobin, Iron deficiency anemia, Anemia

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To better understand the role of iron homeostasis dysregulation in restless legs syndrome, we compared serum hepcidin and ferritin levels in drug-free patients with primary restless legs syndrome and healthy controls and studied the relationship between hepcidin level and restless legs syndrome severity.

Concepts: Iron metabolism, Iron deficiency anemia, Syndromes, Anemia of chronic disease, Human iron metabolism, Ferritin, Restless legs syndrome

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Anemia is highly prevalent in chronic kidney disease (CKD). Elevated hepcidin concentrations are an important mediator of disordered iron metabolism, a key mechanism underlying anemia of CKD. Vitamin D was recently shown to reduce serum hepcidin concentrations in healthy individuals. We examined whether treatment with calcitriol reduces serum hepcidin in individuals with CKD.

Concepts: Kidney, Hepcidin, Randomized controlled trial, Vitamin D, Anemia of chronic disease, Chronic kidney disease, Epidemiology, Human iron metabolism

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Iron overload is commonly encountered during the course of aplastic anemia (AA), but no composite animal model has been developed yet, which hinders drug research. In the present study, the optimal dosage and duration of intraperitoneal iron dextran injection for the development of an iron overload model in mice were explored. A composite model of AA was successfully established on the principle of immune-mediated bone marrow failure. Liver volume, peripheral hemogram, bone marrow pathology, serum iron, serum ferritin, pathological iron deposition in multiple organs (liver, bone marrow, spleen), liver hepcidin, and bone morphogenetic protein 6 (BMP6), SMAD family member 4 (SMAD4) and transferrin receptor 2 (TfR2) mRNA expression levels were compared among the normal control, AA, iron overload and composite model groups to validate the composite model, and explore the pathogenesis and features of iron overload in this model. The results indicated marked increases in iron deposits, with significantly increased liver/body weight ratios as well as serum iron and ferritin in the iron overload and composite model groups as compared with the normal control and AA groups (P<0.05). There were marked abnormalities in iron regulation gene expression between the AA and composite model groups, as seen by the significant decrease of hepcidin expression in the liver (P<0.01) that paralleled the changes in BMP6, SMAD4, and TfR2. In summary, a composite mouse model with iron overload and AA was successfully established, and AA was indicated to possibly have a critical role in abnormal iron metabolism, which promoted the development of iron deposits.

Concepts: Transferrin, Anemia of chronic disease, Developmental biology, Iron deficiency anemia, Bone marrow, Human iron metabolism, Iron metabolism, Anemia