YPOXIA-INDUCED PULMOnary hypertensive disorders are a major cause of morbidity and mortality in respiratory and cardiac diseases and at high altitude. [1][2][3][4] Hypoxia causes pulmonary hypertension through hypoxic pulmonary vasoconstriction and vascular remodeling. 1 Convergent discoveries in the biochemistry of oxygen sensing and in cardiopulmonary physiology have recently established the importance of the hypoxia-inducible factor (HIF) family of transcription factors in regulating these processes. [5][6][7][8][9][10][11][12] Hypoxia-inducible factor controls an extensive range of transcriptional responses to hypoxia throughout the body. 5,6 Emerging evidence supports a role for HIF in regulating systemic responses to hypoxia across the principal organ systems responsible for oxygen delivery to cells, encompassing erythropoiesis as well as pulmo-See also Patient Page.

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores. (Blood. 2012;119(3):857-860) IntroductionDietary iron absorption was shown in the 1950s to be under the dual regulation of body iron stores and the prevailing rate of erythropoiesis, giving rise to the concept of the "store regulator" and the "erythroid regulator" in iron homeostasis. 1,2 The downstream mediator of both regulators was later shown to be the iron-regulatory hormone hepcidin, 3 which opposes iron absorption and recycling by binding and internalizing the cellular iron exporter ferroportin. 4 The molecular mechanisms of hepcidin regulation are not completely understood. Oral iron loading stimulates hepcidin production in healthy humans. 5,6 This may result in part from the binding of serum holotransferrin to transferrin receptor 1 in the liver, releasing the non-classical MHC class 1 molecule hereditary hemochromatosis protein (HFE) to interact with a holotransferrintransferrin receptor 2 (TfR2) complex that up-regulates hepcidin expression. [7][8][9] There is also evidence of a role for the membranebound protein hemojuvelin in the response to iron loading, 5,10 and mutations in HFE, TfR2, or hemojuvelin can all cause hemochromatosis via inadequate hepcidin production. 11 The signal linking erythropoiesis to hepcidin suppression remains unknown. Candidates include erythropoietin (EPO) itself, soluble transferrin receptor (sTfR), and growth differentiation factor-15 (GDF15), which is released by maturing erythroblasts and reduces hepcidin mRNA expression in cultured hepatocytes. 12 Excessive serum GDF15 appears to underlie the paradoxical iron overload seen in patients with ␤-thalassemia. 12 It is now known that hepcidin expression is also suppressed by hypoxia, but the mechanism is controversial. In mice, hypoxiainducible factor was reported to regulate hepcidin expression via direct transcriptional suppression, 13 but this finding has not been replicated in isolated hepatocytes. 14 Hypoxia-inducible factor may, however, contribute to hepcidin suppression indirectly via effects on the breakdown of hemojuvelin. 15,16 In vivo, hypoxia could also suppress hepcidin indirectly through erythropoiesis and enhanced iron use. Recently, a decrease in hepcidin was...

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Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.