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

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

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

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

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Tuberculosis (TB) induces a systemic inflammatory state affecting iron homeostasis. Patients with TB often have additional comorbidities such as anemia which can result in poorer treat outcomes. We studied the contribution of anemia and the role of the iron regulatory hormone hepcidin among TB patients and household contacts.

Concepts: Poverty, Tuberculosis, Hematology, Iron deficiency anemia, Human iron metabolism, Anemia of chronic disease, Hepcidin, Diseases of poverty

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

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

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

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Anemia of chronic inflammation is the most prevalent form of anemia in hospitalized patients. A hallmark of this disease is the intracellular sequestration of iron. This is a consequence of hepcidin-induced internalization and subsequent degradation of ferroportin, the hepcidin receptor and only known iron-export protein. This study describes the characterization of the novel anti-hepcidin compound NOX H94, a structured L oligoribonucleotide that binds human hepcidin with high affinity (K(d)=0.65±0.06 nmol/L). In J774A.1 macrophages, NOX H94 blocked hepcidin-induced ferroportin degradation and ferritin expression (IC(50)=19.8±4.6 nmol/L). In an acute cynomolgus monkey model of interleukin 6-induced hypoferremia, NOX H94 inhibited serum iron reduction completely. In a subchronic model of interleukin-6-induced anemia NOX H94 inhibited the decrease in hemoglobin concentration. We conclude that NOX H94 protects ferroportin from hepcidin-induced degradation. Therefore, this pharmacological approach may represent an interesting treatment option for patients suffering from anemia of chronic inflammation.

Concepts: Immune system, Hemoglobin, Anemia, Iron deficiency anemia, Human iron metabolism, Monkey, Iron deficiency, Anemia of chronic disease

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Following publication of the original article [1], the authors reported that one of the authors' name is spelled incorrectly. In this Erratum the incorrect and correct author name are shown. The original publication of this article has been corrected.

Concepts: Randomized controlled trial, Anemia, Human iron metabolism, Author, Anemia of chronic disease