Division of Gastroenterology & Hepatology, University Hospital Zurich, Switzerland; Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Germany.
Hepatology. 2013 Dec;58(6):2153-62. doi: 10.1002/hep.26581. Epub 2013 Oct 11.
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).
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.
本研究旨在从（1）肝组织中hepcidin 的释放，（2）肠道铁转运和（3）系统炎症和红细胞生成反应的水平，描述登山者在低氧环境下铁稳态的适应性。
研究了 25 名健康登山者。在海拔 446m 时采集血样和十二指肠活检，随后在快速上升到海拔 4559m 的第 2 天（MG2）和第 4 天（MG4）采集。通过定量逆转录聚合酶链反应（RT-PCR）和免疫组织化学分析活检标本中二价金属离子转运蛋白 1（DMT-1）、铁蛋白 1（FP-1）信使 RNA（mRNA）和蛋白表达。通过质谱法分析血清 hepcidin 水平。通过标准技术定量检测血清铁、铁蛋白、转铁蛋白、白细胞介素（IL）-6 和 C 反应蛋白（CRP）。通过酶联免疫吸附试验（ELISA）测量血清促红细胞生成素和生长分化因子 15（GDF15）水平。
在低氧环境下，促红细胞生成素在 MG2 时达到峰值（P < 0.001），同时 GDF15 在 MG2 时也增加（P < 0.001）。血清铁和铁蛋白水平在 MG2 和 MG4 时迅速下降（P < 0.001）。十二指肠 DMT-1 和 FP-1 mRNA 表达在 MG2 和 MG4 时增加到基线的 10 倍以上（P < 0.001）。MG2 和 MG4 时血浆 CRP 增加，而 IL-6 仅在 MG2 时增加（P < 0.001）。MG2 和 MG4 时血清 hepcidin 水平下降（P < 0.001）。
本研究在健康志愿者中表明，在低氧条件下，hepcidin 受到抑制，十二指肠铁转运迅速上调。这些变化可能增加膳食铁的摄取，并允许释放储存的铁，以确保在缺氧诱导的代偿性红细胞生成中获得足够的铁供应。
