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Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers

Authors

  • Oliver Goetze,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany
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    • These authors contributed equally to the study.

  • Johannes Schmitt,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany
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    • These authors contributed equally to the study.

  • Kerstin Spliethoff,

    1. Institute of Veterinary Physiology, University of Zurich, Switzerland
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  • Igor Theurl,

    1. Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Austria
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  • Günter Weiss,

    1. Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Austria
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  • Dorine W. Swinkels,

    1. Department of Laboratory Medicine, Laboratory of Genetic & Metabolic Diseases, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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  • Harold Tjalsma,

    1. Department of Laboratory Medicine, Laboratory of Genetic & Metabolic Diseases, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
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  • Marco Maggiorini,

    1. Department of Internal Medicine, Intensive Care Unit, University Hospital Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
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  • Pierre Krayenbühl,

    1. Department of Internal Medicine, Intensive Care Unit, University Hospital Zurich, Switzerland
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  • Monika Rau,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany
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  • Heiko Fruehauf,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
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  • Kacper A. Wojtal,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
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  • Beat Müllhaupt,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Swiss Hepatopancreatobiliary (HPB)-Centre, University of Zurich, Switzerland
    3. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
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  • Michael Fried,

    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
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  • Max Gassmann,

    1. Institute of Veterinary Physiology, University of Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
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  • Thomas Lutz,

    1. Institute of Veterinary Physiology, University of Zurich, Switzerland
    2. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
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  • Andreas Geier

    Corresponding author
    1. Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland
    2. Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany
    3. Swiss Hepatopancreatobiliary (HPB)-Centre, University of Zurich, Switzerland
    4. Zurich Centre for Integrative Human Physiology (ZIHP), University Hospital Zurich, Switzerland
    • Address reprint requests to: Andreas Geier, M.D., Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Oberdürrbacherstrasse 6, D-97080 Würzburg, Germany. E-mail:geier_a2@medizin.uni-wuerzburg.de; fax: +49 931 201 640201.

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  • Potential conflict of interest: Nothing to report.

  • Supported by Zurich Centre for Integrative Human Physiology (ZIHP).

Abstract

Human iron homeostasis is regulated by intestinal iron transport, hepatic hepcidin release, and signals from pathways that consume or supply iron. The aim of this study was to characterize the adaptation of iron homeostasis under hypoxia in mountaineers at the levels of (1) hepatic hepcidin release, (2) intestinal iron transport, and (3) systemic inflammatory and erythropoietic responses. Twenty-five healthy mountaineers were studied. Blood samples and duodenal biopsies were taken at baseline of 446 m as well as on day 2 (MG2) and 4 (MG4) after rapid ascent to 4559 m. Divalent metal-ion transporter 1 (DMT-1), ferroportin 1 (FP-1) messenger RNA (mRNA), and protein expression were analyzed in biopsy specimens by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Serum hepcidin levels were analyzed by mass spectrometry. Serum iron, ferritin, transferrin, interleukin (IL)−6, and C-reactive protein (CRP) were quantified by standard techniques. Serum erythropoietin and growth differentiation factor 15 (GDF15) levels were measured by enzyme-linked immunosorbent assay (ELISA). Under hypoxia, erythropoietin peaked at MG2 (P < 0.001) paralleled by increased GDF15 on MG2 (P < 0.001). Serum iron and ferritin levels declined rapidly on MG2 and MG4 (P < 0.001). Duodenal DMT-1 and FP-1 mRNA expression increased up to 10-fold from baseline on MG2 and MG4 (P < 0.001). Plasma CRP increased on MG2 and MG4, while IL-6 only increased on MG2 (P < 0.001). Serum hepcidin levels decreased at high altitude on MG2 and MG4 (P < 0.001). Conclusion: This study in healthy volunteers showed that under hypoxemic conditions hepcidin is repressed and duodenal iron transport is rapidly up-regulated. These changes may increase dietary iron uptake and allow release of stored iron to ensure a sufficient iron supply for hypoxia-induced compensatory erythropoiesis. (Hepatology 2013; 58:2153–2162)

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