Hypoxia causes pulmonary hypertension in disease and at altitude. Evidence suggests that hypoxia-inducible factor (HIF) regulates the response to hypoxia across organ systems responsible for oxygen delivery to cells, including erythropoiesis, pulmonary and cardiovascular function. HIF is iron-dependent, requiring Fe(II) as a cofactor.

In two studies, the effect of iron infusion and depletion on pulmonary artery pressure (PASP) was investigated at altitude. In the first, healthy men resident at sea level were studied for 1 week in Cera de Pasco, Peru (altitude 4340 m). During the first 3 days there were significant incremental increases in PASP. On day 3, participants received 200 mg iron sucrose or placebo. The iron reversed much of the increase in PASP. A mean decrease of 6 mm Hg was observed in the iron group compared with 2 mm Hg in the placebo group.

In the second study the effect of iron depletion on chronic mountain sickness was investigated. The patients were iron depleted using staged venesection. There was a mean increase in PASP of 4 mm Hg from 37 mm Hg to 41 mm Hg. Over 2 weeks there was progressive iron deficiency, with a further rise in PASP. After 19 days the patients received 400 mg iron sucrose or placebo followed by a crossover period. Following the initial infusions there was no difference between the groups, indicating that iron replacement did not acutely oppose the increase in PASP associated with iron depletion.

These studies suggest that iron may attenuate the response of the pulmonary vasculature to hypoxia and that iron deficiency may also be harmful in hypoxic pulmonary hypertension. This has implications for the management of chronic mountain sickness, where limiting red cell mass must be balanced against the risk of increasing PASP.

▶ Smith T, Talbot N, Privat C, et al. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA 2005;302:1444–50.