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ANEMIA

Expression of the Iron Hormone Hepcidin Distinguishes Different Types of Anemia in African Children

Sant-Rayn Pasricha, Sarah H. Atkinson, Andrew E. Armitage, Shivani Khandwala, Jacobien Veenemans, Sharon E. Cox, Lucy A. Eddowes, Theodore Hayes, Conor P. Doherty, Ayse Y. Demir, Edwin Tijhaar, Hans Verhoef, Andrew M. Prentice [email protected], and Hal Drakesmith [email protected]
Science Translational Medicine • 7 May 2014 • Vol 6, Issue 235 • p. 235re3 • DOI: 10.1126/scitranslmed.3008249
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Hepcidin Guides Iron Supplementation in African Children

Anemia affects 300 million preschool children worldwide and has multiple causes including iron deficiency or infection. Dietary iron supplementation is used to combat anemia, but substantial concerns exist that iron can be harmful, in part by promoting infection. Iron is likely to preferentially benefit children with iron deficiency anemia, but identification of such children is challenging. Hepcidin is the hormone that regulates body iron levels and inhibits absorption of iron from the diet. Hepcidin concentrations are generally low in iron deficiency but are raised in iron-replete individuals and are also increased by infection. In a new study, Pasricha et al. set out to investigate whether hepcidin measurements would enable targeting of interventions to children who need iron but who are also able to absorb it. They tested this by measuring hepcidin in three cohorts of preschool African children from The Gambia and Tanzania. Single cutoffs of hepcidin concentrations efficiently identified children with iron deficiency, distinguished between iron deficiency anemia and anemia due to infection and inflammation, and predicted which children would incorporate >20% of an oral iron dose into their red blood cells. Thus, hepcidin is a critical determinant of iron homeostasis and may be a useful marker to guide diagnosis of anemia and enable screen-and-treat iron supplementation programs.

Abstract

Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non–iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.
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Supplementary Material

Summary

Fig. S1. Stability of the performance of hepcidin as an index of iron deficiency in children of different sex, age, wasting, anemia, malaria, or hemoglobinopathy status.
Fig. S2. Comparison of characteristics of hepcidin with other indices of iron status.
Fig. S3. Hepcidin compared to other indices as a test for >20% of EII.
Table S1. Characteristics of the Gambia-2003, Gambia-2001, Tanzania-2008, and combined Gambia-2001/Tanzania-2008 study populations.
Table S2. Cutoffs for hepcidin to diagnose iron deficiency and distinguish iron deficiency anemia from anemia of inflammation/infection.

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Science Translational Medicine
Volume 6 | Issue 235
May 2014

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Copyright © 2014, American Association for the Advancement of Science.

Submission history

Received: 11 December 2013
Accepted: 18 April 2014

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Acknowledgments

Supported by a National Health and Medical Research Council Early Career Fellowship (Australia) and the Haematology Society of Australia and New Zealand New Investigator Award (S.-R.P.), MRC/Oxford University Clinical Academic Graduate School/Academy of Medical Sciences (S.H.A.), The Wellcome Trust (S.E.C.), INSTAPA project and European Union’s Seventh Framework Programme (FP7/2007-2013, no. 211484) (H.V.), the MRC UK (A.E.A., A.M.P., and H.D.), and The Netherlands Organisation for Scientific Research/WOTRO (grants W93-413 and WAO93-441), United Nations International Children’s Emergency Fund, Cornelis Visser Foundation and Wageningen University (Interdisciplinary Research and Education Fund), The Wellcome Trust (094780), MRC UK (MC-A760-5QX00), NIHR Oxford Biomedical Research Centre, and the Bill and Melinda Gates Foundation (“Hepcidin and Iron in Global Health”, OPP1055865). Author contributions: S.-R.P., S.H.A., A.E.A., A.M.P., and H.D. conceived and designed the study; S.H.A., J.V., S.E.C., C.P.D., A.Y.D., E.T., H.V., and A.M.P. collected the field samples; S.K., A.E.A., A.Y.D., and E.T. measured hepcidin on the samples; S.-R.P., S.H.A., L.A.E., A.E.A., A.M.P., and H.D. designed the statistical analysis; S.-R.P. and S.H.A. undertook the statistical analysis; S.-R.P., S.H.A., A.E.A., T.H., H.V., A.M.P., and H.D. drafted the manuscript; all authors edited and approved the final manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: The data for this study are available from the authors upon request.

Authors

Affiliations

Sant-Rayn Pasricha*
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Sarah H. Atkinson*
Department of Paediatrics, Oxford University Hospitals, University of Oxford, Oxford OXS 9DU, UK.
Oxford University Clinical Academic Graduate School, Oxford OX3 9DU, UK.
Kenya Medical Research Institute/Wellcome Trust Research Programme, Centre of Geographic Medicine Research-Coast, Kilifi 230-80108, Kenya.
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Andrew E. Armitage
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Shivani Khandwala
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Jacobien Veenemans
Cell Biology and Immunology Group, Wageningen University, Wageningen 6700 AH, the Netherlands.
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Sharon E. Cox
MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
MRC Keneba, P. O. Box 273, Keneba, The Gambia.
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Lucy A. Eddowes
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Theodore Hayes
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Conor P. Doherty
Royal Hospital for Sick Children, Glasgow G3 8SJ, UK.
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Ayse Y. Demir
Laboratory for Clinical Chemistry and Haematology, Meander Medical Centre, Postbox 1502, Amersfoort 3800 BM, the Netherlands.
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Edwin Tijhaar
Cell Biology and Immunology Group, Wageningen University, Wageningen 6700 AH, the Netherlands.
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Hans Verhoef
Cell Biology and Immunology Group, Wageningen University, Wageningen 6700 AH, the Netherlands.
MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
MRC Keneba, P. O. Box 273, Keneba, The Gambia.
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Andrew M. Prentice*,† [email protected]
MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
MRC Keneba, P. O. Box 273, Keneba, The Gambia.
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Hal Drakesmith*,† [email protected]
Medical Research Council (MRC) Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
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Notes

*
These authors contributed equally to this work.
†Corresponding author. E-mail: [email protected] (H.D.); [email protected] (A.M.P.)

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