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Concept: Iron deficiency

11

Iron metabolism is regulated by transcriptional and post-transcriptional mechanisms. The mRNA of the iron-controlling gene, transferrin receptor 1 (TfR1), has long been believed to be negatively regulated by a yet-unidentified endonuclease. Here, we show that the endonuclease Regnase-1 is critical for the degradation of mRNAs involved in iron metabolism in vivo. First, we demonstrate that Regnase-1 promotes TfR1 mRNA decay. Next, we show that Regnase-1(-/-) mice suffer from severe iron deficiency anemia, although hepcidin expression is downregulated. The iron deficiency anemia is induced by a defect in duodenal iron uptake. We reveal that duodenal Regnase-1 controls the expression of PHD3, which impairs duodenal iron uptake via HIF2α suppression. Finally, we show that Regnase-1 is a HIF2α-inducible gene and thus provides a positive feedback loop for HIF2α activation via PHD3. Collectively, these results demonstrate that Regnase-1-mediated regulation of iron-related transcripts is essential for the maintenance of iron homeostasis.

Concepts: DNA, Iron metabolism, Iron deficiency, Iron, Transferrin, Protein, Iron deficiency anemia, Human iron metabolism

6

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

5

Current guidelines to treat iron deficiency recommend daily provision of ferrous iron divided through the day to increase absorption. However, daily dosing and split dosing might increase serum hepcidin and decrease iron absorption from subsequent doses. Our study aim was to compare iron absorption from oral iron supplements given on consecutive versus alternate days and given as single morning doses versus twice-daily split dosing.

Concepts: Knitting, Hematology, Dose, Human iron metabolism, Iron deficiency, Iron supplements, Randomized controlled trial, Iron

5

Iron supplements acutely increase hepcidin, but the duration and magnitude of the increase, its dose dependence and effects on subsequent iron absorption have not been characterized in humans. Better understanding of these phenomena might improve oral iron dosing schedules. We investigated whether the acute iron-induced increase in hepcidin influences iron absorption of successive daily iron doses and twice daily iron doses. We recruited 54 non-anemic young women with plasma ferritin ≤20 µg/l and conducted: 1) a dose-finding investigation with 40, 60, 80, 160 and 240 mg labeled Fe as [(57)Fe]-, [(58)Fe]- or [(54)Fe]-FeSO4 given at 8.00 fasting on one or on two consecutive days (study 1, n=25; study 2, n=16); and 2) a study giving three 60 mg Fe doses (twice a day dosing) within 24h (study 3, n=13). In studies 1 and 2, 24hr after doses of 60 mg or greater, serum hepcidin was increased (P<0.01) and fractional iron absorption was decreased by 35-45% (P<0.01). With increasing dose, fractional absorption decreased (P<0.001), while absolute absorption increased (P<0.001). A six-fold increase in iron dose (40 to 240 mg), resulted in only a 3-fold increase in iron absorbed (6.7 to 18.1 mg). In study 3, total iron absorbed from three doses (two mornings and afternoon) was not significantly greater than that from two morning doses. Providing lower dosages (40-80 mg Fe) and avoiding twice a day dosing maximizes fractional absorption. The duration of the hepcidin response supports alternate day supplementation, but longer-term effects of these schedules require further investigation. These clinical trials were registered at www.clinicaltrials.gov as NCT01785407 and NCT02050932.

Concepts: Fasting, Human iron metabolism, Liver, Magnesium, Iron deficiency, Iron, Iron supplements, Dose

4

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

4

Heme enzymes activate oxygen through formation of transient iron-oxo (ferryl) intermediates of the heme iron. A long-standing question has been the nature of the iron-oxygen bond and, in particular, the protonation state. We present neutron structures of the ferric derivative of cytochrome c peroxidase and its ferryl intermediate; these allow direct visualization of protonation states. We demonstrate that the ferryl heme is an Fe(IV)=O species and is not protonated. Comparison of the structures shows that the distal histidine becomes protonated on formation of the ferryl intermediate, which has implications for the understanding of O-O bond cleavage in heme enzymes. The structures highlight the advantages of neutron cryo-crystallography in probing reaction mechanisms and visualizing protonation states in enzyme intermediates.

Concepts: Oxygen, Cytochrome c oxidase, Iron deficiency, Hydrogen, Catalase, Cytochrome, Iron, Heme

3

High prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) has been reported in children with autism spectrum disorder (ASD). However, there is a limited number of studies about the association between iron deficiency parameters and clinical symptoms of ASD. This study aims to compare hemoglobin, hematocrit, iron, ferritin, MCV, and RDW levels between ASD patients and healthy controls and to investigate the correlation between these values and clinical symptoms of ASD.

Concepts: Transferrin, Iron deficiency, Iron, Autism spectrum, Mean corpuscular volume, Anemia, Hemoglobin, Iron deficiency anemia

3

Administration of ferric pyrophosphate citrate (FPC, Triferic™) via hemodialysate may allow replacement of ongoing uremic and hemodialysis-related iron losses. FPC donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration.

Concepts: Renal failure, Reticuloendothelial system, Iron deficiency anemia, Iron deficiency, Dialysis, Hemodialysis, Liver, Iron

3

Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.

Concepts: Iron deficiency anemia, Parent, Heme, Iron deficiency, Mother, Hemoglobin, Sociology, Iron

2

The prevention and treatment of iron deficiency is a major public health goal. Challenges in the treatment of iron deficiency include finding and addressing the underlying cause and the selection of an iron replacement product which meets the needs of the patient. However, there are a number of non-evidence-based misconceptions regarding the diagnosis and management of iron deficiency, with or without anaemia, as well as inconsistency of terminology and lack of clear guidance on clinical pathways. In particular, the pathogenesis of iron deficiency is still frequently not addressed and iron not replaced, with indiscriminate red cell transfusion used as a default therapy. In our experience, this imprudent practice continues to be endorsed by non-evidence-based misconceptions. The intent of the authors is to provide a consensus that effectively challenges these misconceptions, and to highlight evidence-based alternatives for appropriate management (referred to as key points). We believe that this approach to the management of iron deficiency may be beneficial for both patients and healthcare systems. We stress that this paper solely presents the Authors' independent opinions. No pharmaceutical company funded or influenced the conception, development or writing of the manuscript.

Concepts: Health care, Transferrin, Patient, Hemoglobin, Medicine, Iron deficiency, Iron, Iron supplements