What changes must the body adapt to?

Conditions at altitudes over 2500m present a unique combination of stresses on the human body. Between 2500 and 3500m, defined as high altitude, the atmospheric pressure falls to three quarters, then to two thirds of that at sea level, and at 5500 it is less than half1. As the atmospheric pressure drops, the quantity of oxygen, CO2 and water in each lungful of air decreases proportionally. Ultraviolet light is stronger, with less atmospheric shielding.

Physiological changes begin to be detectable at 1500m, while arterial oxygen saturation is still over 90%2. Between 3500 and 5500, oxygen saturation falls to well below 90%, and physiological changes are marked. Symptoms of altitude sickness are common with rapid ascent, as the body struggles to maintain oxygen levels. Above 5500m, defined as extreme altitude, hypoxaemia is universal and long term survival depends on oxygen or descent.

The body will adapt, over a period weeks, to cope with these changed conditions. Early changes involve mechanisms which can often be excessive and cause discomfort or serious illness. These pathological effects of the body’s attempts to adapt are extremely common and in some cases life threatening, and deserve consideration. Chronic changes, assuming the initial period of a few days is survived, involves alterations to metabolism and oxygen transport that will last for months even after return to sea level. Living permanently at high altitude will alter gene expression, resulting in different physiological and cellular development.

Acute Pulmonary responses to Hypoxia

The most immediate problem faced after climb to altitude is hypoxia. Maintenance of normal sea level pulmonary function will lead rapidly to unconsciousness from cerebral hypoxaemia. Hypoxaemia is detected by chemoreceptors in the carotid body, which set off a chain of reactions, including long term changes to blood composition.

The first and most basic response to falling oxygen levels is hyperventilation. An automatic increase in the rate and depth of breathing can maintain sufficient oxygen levels for normal functioning. Hyperventilation, particularly when continued for hours or days, has the effect of lowering blood CO2 levels. The control of respiratory function is heavily influenced by the partial pressure of CO2 in the blood, and very low levels can cause irregularities until acclimatisation takes place. Breathing during sleep can become extremely erratic, and may stop for fifteen seconds at a time.

Pulmonary arterioles constrict when exposed to hypoxic conditions. This was, at sea level, a mechanism to divert blood away from a badly ventilated section of lung caused by, for example, an obstructed bronchus. When it occurs in a whole lung, it causes pulmonary hypertension. Long term exposure results in mild hypertrophy of the right heart, and changes to the muscularity of pulmonary arteriole beds3.

Pulmonary complications:

Pulmonary hypertension can combine with other effects of altitude to have serious ill effects. Leukocyte migration out of blood vessels is associated with increased permeability4 of pulmonary blood vessels can result in fluid leakage and oedema. High altitude pulmonary oedema, or HAPE, is the main cause of death associated with rapid ascent to high altitude. Interstitial oedema further impairs gas exchange, making hypoxia worse.5

It has been known for some time that sodium and water clearance in the lungs is reduced by hypoxia. A 2002 study by Sartori et al6 showed that the expression of a gene producing a protein pump responsible for this Na+/water coupled clearance was inhibited by low oxygen levels. Individuals with higher copy numbers of this protein pump in their nasal epithelium at sea level were found to have lower rates of pulmonary oedema and mountain sickness, suggesting that reactions to altitude have a genetic element. It was suggested that this pump may be entirely responsible for HAPE7.

A study by Cremona et al8, however, found decreased forced expiratory volume, which they assumed to be due to increased extravascular fluid in the lung, in 75% of healthy climbers who had just undergone moderate exercise at high altitude. This indicated that three out of four healthy climbers experience some degree of mild, subclinical HAPE, suggesting it is not entirely a disease confined to a small, genetically predisposed population.

This supports the earlier theory that a mechanical and inflammatory response was responsible.7 Debate continues over the involvement of the inflammatory response, with a recent study finding no increased levels of inflammatory cells in the lungs in HAPE cases9. The pulmonary hypertensive pathway, however, appears to be an almost certain culprit.

Renal response and Dehydration

Hypoxia has the effect of triggering diuresis. Activity of the renin-aldosterone-angiotensin salt reabsorption system drops. Fluid reabsorption by the kidneys is reduced, and urination increases markedly. A reduction in blood volume has the effect of increasing the concentration of red blood cells, which provides a relative increase the oxygen carrying capability10.

Along with the increased water loss from hyperventilating in dry air, these changes can lead to dehydration. This is a contributing factor to many headaches experienced at high altitude which may be mistaken for acute mountain sickness, the general feeling of headache, tiredness and nausea associated with ascent to altitude.

Acute Cerebral Responses and Complications

Hypoxaemia promotes increased blood flow to the brain to maintain cell oxygen levels required for normal mental function. This results in brain swelling in all individuals who travel rapidly to high altitude. This swelling is associated with an increase in blood vessel permeability, possibly related to elevated NO2 levels and the creation of radical oxygen species. This increased permeability can sometimes lead to cerebral oedema.

It has been observed that individuals who have a higher ratio of cranial cerebrospinal fluid to brain experience a lower rate of acute mountain sickness. It has been suggested that this is because they are better able to compensate for this swelling. This would help explain the random nature of acute mountain sickness, which occurs with no specific distribution of age, fitness, race or gender.

Oxidative stress

Work and exercise in low oxygen conditions place enormous energy stress on the body. Attempts to maintain high levels of energy output in low oxygen conditions result in the production of highly reactive radical species, which cause widespread cellular damage and have been linked to acute mountain sickness. Higher levels of ultraviolet radiation exacerbate this problem.

Radical oxygen species are believed to act as chemical stimulants of many adaptive processes at altitude, but in excess they cause increased blood vessel permeability, contributing to cerebral swelling and oedema11. Oxygen radicals also hamper the efforts of red blood cell production, reducing erythrocyte flexibility and causing problems with blood flow. An increase in dietary antioxidants has been demonstrated to improve physical performance at high altitude.

Chronic responses: Oxygen transport and Metabolism

Probably the most beneficial effect of prolonged stay at high altitude is the increase in blood oxygen carrying capacity that occurs. Erythropoietin, or EPO, is a renal hormone which is released when blood oxygen levels are low. It travels to the bone marrow, where it stimulates precursor cells to develop into erythrocytes. These cells have themselves reacted to low oxygen levels by expressing EPO receptors on their surface, anticipating its release. These cells begin to mature within a week of EPO stimulus.

This pathway allows the rapid production of erythrocytes, allowing more oxygen to be carried per volume of blood. This adaptation halts the high-altitude diuresis, pulmonary hypertension, and increases metabolic performance. After several months of living at high altitude, performance will have returned to sea level rates. Haemaglobin may have increased by up to 50%.

Increased performance is partially due to increased haemocrit, partially to changes in erythrocyte chemistry, and partially to alterations in metabolism.

Chronic exposure to hypoxia creates changes to energy generation pathways in order to compensate for reduced oxygen levels. 2,3DPG is a glycolytic enzyme carried by erythrocytes. In chronic hypoxia, EPO treatment of cells triggers levels to increase. 2,3DPG binds to haemoglobin and lowers its oxygen affinity, causing the red blood cells to release more oxygen to the tissues.

The enzyme can also exist in a free form, and be released into the target tissue along with oxygen. Once there, it alters the glucose metabolism pathway, increasing efficiency and reducing its reliance on oxygen. ATP generation requires less oxygen when 2,3DPG is present in high levels, and this reduces oxidative stress and the need for further transport capability.

Developmental changes among natives to high altitude

Children born at high altitude develop to maximise their oxygen efficiency. The typically grow to smaller stature, with a much larger heart, and their cells contain more mitochondria. Blood vessel proliferation is notable, and is linked to expression of genes that are sensitive to cellular oxygen levels12.

Other genes are believed to be involved in the reduced pulmonary vasoconstriction response to hypoxia found in Tibetan natives 3 . Individuals who possess this blunted response have been found to have higher than normal NO levels in their lungs, despite the low oxygen levels. NO is associated with reduced pulmonary hypertension, and it is believed that populations adapted to life at very high altitude have an altered form of an NO synthase enzyme which is more efficient.


The most crucial environmental change involved in travel to high altitude is the reduced oxygen levels experienced. Physiological acute reactions begin with the triggering of hyperventilation by chemoreceptors sensitive to hypoxia. Diuresis via the reduction of renin-angiotensin-aldosterone levels increases blood concentration, producing a modest increase in oxygen carrying capacity. The kidney is also involved in chronic stages of adaptation with the synthesis of more red blood cells, by detecting low oxygen levels and releasing EPO. Red blood cells change to increase the amount of oxygen delivered per cell, and produce and carry an enzyme which reduces cell metabolic oxygen requirements. These changes will allow a recovery in blood oxygen levels to near sea level normals within weeks or months of arrival at altitude.


1 http://www.personal.usyd.edu.au/~gerhard/pressure.html

2 P W Barry, A J Pollard :Clinical review: Altitude illness BMJ 2003;326:915-919 ( 26 April )

3 M R Wilkins, A Aldashev and N W Morrell: Commentary Nitric oxide, phosphodiesterase inhibition, and adaption to hypoxic conditions: The Lancet Volume 359, Issue 9317 , 4 May 2002, Pages 1539-1540

4 Gonzalez NC, Wood JG: Leukocyte-endothelial interactions in environmental hypoxia. Adv Exp Med Biol. 2001;502:39-60. Review.

5 Bartsch P, Swenson ER, Paul A, Julg B, Hohenhaus E. :Hypoxic ventilatory response, ventilation, gas exchange, and fluid balance in acute mountain sickness. High Alt Med Biol. 2002 Winter;3(4):361-76.

6 Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, Nicod P, Scherrer U.:Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med. 2002 May 23;346(21):1631-6.

7 Voelkel NF: High-altitude pulmonary edema. N Engl J Med. 2002 May 23;346(21):1606-7.

8 Cremona G, Asnaghi R, Baderna P, Brunetto A, Brutsaert T, Cavallaro C, Clark TM, Cogo A, Donis R, Lanfranchi P, Luks A, Novello N, Panzetta S, Perini L, Putnam M, Spagnolatti L, Wagner H, Wagner PD.: Pulmonary extravascular fluid accumulation in climbers. Lancet. 2002 Aug 17;360(9332):570;

9 Swenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, Bartsch P Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor.. JAMA 2002 May 1;287(17):2228-35

10 www.high-altitude-medicine.com

11 E. W. Askew: Work at high altitude and oxidative stress: antioxidant nutrients Toxicology , Volume 180, Issue 2 , 15 November 2002, Pages 107-119

12 Appenzeller O, Minko T, Pozharox V, Bonfichi M, Malcovati L, Gamboa J, Bernardi L: Gene expression in the Andes; Relevance to neurology at sea level J. Neurol Sci 2003 March 15; 207 (1-2) 27-41

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