title: Adaptation of iron transport and metabolism to acute high-altitude hypoxia in mountaineers.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland; Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Goetze
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.forename: Kerstin
authors.initials: K
authors.lastname: Spliethoff
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Dorine W
authors.initials: DW
authors.lastname: Swinkels
authors.forename: Harold
authors.initials: H
authors.lastname: Tjalsma
authors.forename: Marco
authors.initials: M
authors.lastname: Maggiorini
authors.forename: Pierre
authors.initials: P
authors.lastname: Krayenbühl
authors.forename: Monika
authors.initials: M
authors.lastname: Rau
authors.forename: Heiko
authors.initials: H
authors.lastname: Fruehauf
authors.forename: Kacper A
authors.initials: KA
authors.lastname: Wojtal
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Lutz
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000188:drug therapy; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002097:C-Reactive Protein / Q000378:metabolism; D027682:Cation Transport Proteins / Q000097:blood; D003907:Dexamethasone / Q000627:therapeutic use; D004386:Duodenum / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000097:blood; D055436:Growth Differentiation Factor 15 / Q000097:blood; D064451:Hepcidins / Q000097:blood; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000378:metabolism*; D008099:Liver; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002097:C-Reactive Protein; D027682:Cation Transport Proteins; D003907:Dexamethasone; D005293:Ferritins; D055436:Growth Differentiation Factor 15; D064451:Hepcidins; D015850:Interleukin-6; D007501:Iron; D012333:RNA, Messenger; D014168:Transferrin; D000098742:Ferroportin; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2