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Mountains cover one-fifth of the earth’s surface; 38 million people live permanently at altitudes ≥2400 m, and 100 million people travel to high-altitude locations each year. Skiers in the Alps or Aspen; religious pilgrims to Lhasa or Kailash; trekkers and climbers to Kilimanjaro, Aconcagua, or Everest; and military personnel deployed to high-altitude locations are all at risk of developing acute mountain sickness (AMS), high-altitude cerebral edema (HACE), high-altitude pulmonary edema (HAPE), and other altitude-related problems. AMS is the benign form of altitude illness, whereas HACE and HAPE are life-threatening. Altitude illness is likely to occur above 2500 m but has been documented even at 1500–2500 m. In the Mount Everest region of Nepal, ~50% of trekkers who walk to altitudes >4000 m over ≥5 days develop AMS, as do 84% of people who fly directly to 3860 m. The incidences of HACE and HAPE are much lower than that of AMS, with estimates in the range of 0.1–4%.


Ascent to a high altitude subjects the body to a decrease in barometric pressure that results in a decreased partial pressure of oxygen in the inspired gas in the lungs. This change leads in turn to less pressure driving oxygen diffusion from the alveoli and throughout the oxygen cascade. A normal initial “struggle response” to such an ascent includes increased ventilation—the cornerstone of acclimation—mediated by the carotid bodies. Hyperventilation may cause respiratory alkalosis and dehydration. Alkalosis may depress the ventilatory drive during sleep, with consequent periodic breathing and hypoxemia. During early acclimation, renal suppression of carbonic anhydrase and excretion of dilute alkaline urine combat alkalosis and tend to bring the pH of the blood to normal. Other physiologic changes during normal acclimation include increased sympathetic tone; increased erythropoietin levels, leading to increased hemoglobin levels and red blood cell mass; increased tissue capillary density and mitochondrial numbers; and higher levels of 2,3-bisphosphoglycerate, enhancing oxygen utilization. Even with normal acclimation, however, ascent to a high altitude decreases maximal exercise capacity (by ~1% for every 100 m gained above 1500 m) and increases susceptibility to cold injury due to peripheral vasoconstriction. Finally, if the ascent is made faster than the body can adapt to the stress of hypobaric hypoxemia, altitude-related disease states can result.


image Hypoxia-inducible factor, which is important in high-altitude adaptation, controls transcriptional responses to hypoxia throughout the body and is involved in the release of vascular endothelial growth factor (VEGF) in the brain, erythropoiesis, and other pulmonary and cardiac functions at high altitudes. In particular, the gene EPAS1, which codes for transcriptional regulator hypoxia-inducible factor 2α, appears to play an important role in the adaptation of Tibetans living at high altitude, resulting in lower hemoglobin concentrations than are found in the Han Chinese. For acute altitude illness, a single gene variant is unlikely to be found, but the differences in the susceptibility of individuals and ...

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