Biochemical Changes during High Altitude Mountaineering

RYAN ATKINSBIO209 XZ

Table of Contents HIGH ALTITUDE MOUNTAINEERING

ALTITUDE-RELATED ISSUES

CAUSES OF ALTITUDE-RELATED ILLNESS

ACCLIMATIZATION

BIOCHEMICAL CHANGES AT ALTITUDE

GENETIC VARIATIONS IN TIBETAN SHERPAS

WORKS CITED

What is High Altitude Mountaineering?

“Because it’s there.”

- British mountaineer George Mallory, when asked during a 1923 interview why he wanted to climb Mt. Everest.

What is High Altitude Mountaineering?

▪ The International Society of Mountain Medicine recognizes three distinct altitude brackets, although the term “high altitude mountaineering” can be loosely applied to all of them.▪ High Altitude Mountaineering is any climbing/trekking at

an altitude > 1,500 m (~4,000 ft).▪ Greater than 3,500 m (~11,500 ft) above sea level is

considered very high altitude.▪ Greater than 5,500 m (~18,000 ft) above sea level is

considered extreme altitude.

Altitude-Related Issues

▪ At elevations > 2500 m (~8,000 ft) altitude illness becomes a problem that climbers must anticipate.▪ Altitude-related illnesses include (in order of

seriousness):- Acute and Chronic mountain sickness (AMS, CMS)- High altitude pulmonary edema (HAPE)- High altitude cerebral edema (HACE)▪ If these problems are not treated promptly, they can

progress from one to the next, ultimately leading to death.▪ The best treatment, especially in the early stages of

AMS, is simply for the climber(s) to descend to a lower altitude, although Gamow bags and medications like dexamethasone may also help.

Causes of Altitude-Related Illness

▪ One of the primary (and most most widely studied) causes of altitude-related illnesses is the systemic hypoxia that mountaineers encounter at altitude.▪ This hypoxia is caused primarily by

a decrease in barometric pressure, and consequently, the partial pressure of O2 (PO2).▪ Shown to the right, the decrease of

PO2 in the ambient air, inspired air, alveolar air, and arterial blood gas as altitude increases.

Causes of Altitude-Related Illness (cont.)

▪ At sea level, (PO2) is ~159 mmHg.▪ As altitude is gained, this number continues to decrease.▪ By the time a climber reaches the summit of Mt. Everest , PO2

is only ~53 mmHg, one third of the pressure at sea level.▪ This drastic decrease in the PO2 results in the hypoxic

environment that causes AMS, CMS, HAPE, and HACE in mountaineers.▪ Hypoxia (and its related illnesses) can be staved off to a degree

by acclimatization – a number of biochemical changes that fight to maintain homeostasis in the face of decreased oxygen availability.

Acclimatization

▪ Acclimatization is the (relatively slow) process of the body adjusting to the decreased availability of oxygen at high altitude

▪ Proper acclimatization takes place over a period of days or weeks to depending on the altitude.

▪ Acclimatization aids such as hypobaric chambers, supplemental oxygen, and prophylactic medications like acetazolamide (Diamox®) can be used to lessen the physiologic changes that climbers undergo during initial exposure to altitude.

▪ Some populations are also better suited to acclimatization and high altitudes due to genetic changes.

Acclimatization (cont.)

Acclimatization (cont.)

Condition Altitude Physiological Features

Acclimatization to High Altitude

Up to 5,000 m

HyperventilationNearly complete renal compensation for respiratory alkalosisPolycythemiaIncrease in intracellular oxidative enzymesReduced intercapillary diffusion distances in some tissues

Evolutionary Adaptation Up to 5,000 m

Hyperventilation (Reduced in some populations, including Tibetans)Complete renal compensation for respiratory alkalosisPolycythemia (Reduced in some populations, including Tibetans)Changes in intracellular enzymes

Exposure to Extreme Altitude

Above 7,000 m

Extreme hyperventilationMarked respiratory alkalosis and alkalemiaIncreased O2 affinity of hemoglobin due to alkalosisDecreased VO2 MaxLarge reduction in anaerobic metabolismIncreased weight loss due to altitude-induced anorexia

Biochemical Changes - Kidneys

▪ In a hypoxic environment the kidneys increase local production of endothelin and adrenomedullin, which suppresses ADH, renin, and aldosterone – this results in a decrease in total body water of 1-3 L.

▪ The decrease in plasma volume results in a higher hemoglobin concentration prior to erythropoiesis, as well as reducing intravascular pressure.

▪ It is currently being debated whether this altitude-induced “dehydration” is potentially adaptive or harmful.

▪ As part of the hypoxic response, the kidneys will also begin to excrete erythropoietin to increase the number of red blood cells and the oxygen carrying capacity of the blood, although this occurs at a slower rate.

Mechanisms of Plasma Volume Reduction

Biochemical Changes – Skeletal Muscle

▪ Experienced, acclimatized mountaineers display significantly shorter phosphocreatine (PCr) recovery halftimes when compared to trekkers without prior high altitude experience.▪ This decreased halftime results in better mitochondrial

function at altitude, even in older climbers.▪ Previously well-trained mountaineers also exhibited better

O2 extraction by skeletal muscle at high altitudes than their altitude-naïve counterparts.▪ It is hypothesized that altitude exposure may induce stable

changes in phenotype through epigenetic modifications.

Biochemical Changes – Skeletal Muscle

The chart at right shows a comparison of PCr recovery times between “Climbers” – individuals that had previously acclimatized to altitudes > 6,800 m and were well trained mountaineers, and “Trekkers” – altitude-naïve individuals that had never been to high elevation. This was done during the Caudwell Xtreme Everest Expedition in 2007.

Genetic Variations in Tibetan Sherpas

Genetic Variations in Tibetan Sherpas

▪ Tibetans, when compared to lowland populations, maintain higher arterial oxygen saturation at altitude both while resting and exercising.▪ They also display a decreased loss of aerobic performance with

increasing elevation.▪ It has been hypothesized that these differences are due to

epigenetic modification and natural selection acting on a specific set of genes in high-altitude populations like the Tibetan Sherpas.▪ The most likely candidates for the modified genes that allow for

these advantages are EPAS1 (endothelial PAS domain protein 1), EGLN1 (early growth response 1), and PPARA (peroxisome proliferator activated receptor alpha).

Genetic Variations in Tibetan Sherpas (cont.)

▪ EPAS1, in particular, plays an important role in regulating erythropoiesis and hemoglobin (Hb) levels.▪ Researchers have been able to isolate three significant

Sherpa-specific allelic variations in EPAS1 - an A/G/A sequence on rs13419896/4953354/4953388 as opposed to the G/A/G that most populations exhibit, including lowland Tibetans.▪ This genetic mediation of erythropoietin levels is important

for maintaining a healthy hematocrit level, which can reduce the risk of health problems at altitude due to high blood viscosity (which would be an issue in individuals exhibiting polycythemia).

Genetic Variations in Tibetan Sherpas (cont.)

▪ In a 2004 study, it was also shown that Tibetans born and living at high altitude were, through metabolic adaptation, less prone to oxidative damage to their cells.▪ Through proteomics, the researchers also found that

Sherpa populations exhibited ratios of pyruvate kinase and lactate dehydrogenase in their muscles similar to that seen in hummingbird flight muscles.▪ This would allow for an exceptionally high ATP turnover rate

in the muscle compared to other individuals.▪ These many differences are what has made Sherpas highly

sought after as high-altitude mountaineering guides since the first summit of Everest in 1953.

Works Cited

▪ Dietz, T. "ISMM Non-Physician Altitude Tutorial." International Society of Mountain Medicine. ISMM, 29 Jan. 2006. Web. 05 May 2016

▪ Edwards, L., and Murray, A. “The Effect of High Altitude on Human Skeletal Muscle Energetics: P-MRS Results from the Caudwell Xtreme Everest Expedition.” PLoS ONE 5.5 (2010): 1-8. Web. 20 Mar. 2016

▪ Goldfarb-Rumyantzev, A., and Alper, S. "Short-term Responses of the Kidney to High Altitude in Mountain Climbers." NDT (2013): 1-8. Web. 20 Mar. 2016

▪ Masayuki, H., and Yunden, D. “Genetic Variations in EPAS1 Contribute to Adaptation to High-Altitude Hypoxia in Sherpas.” PLoS ONE 7.12 (2012) 1-8. Web. 20 Mar. 2016

▪ Reeves, J. Young, A. "Human Adaptation to High Terrestrial Altitude." Medical Aspects of Harsh Environments. Vol. 2.: Office of the Surgeon General, 2002. 645-79. Print.

▪ West, J. "Human Responses to Extreme Altitudes." Integrative and Comparative Biology 46.1 (2006): 25-34. Web. 20 Mar. 2016

▪ Wu, T., and Bengt, K. "High Altitude Adaptation in Tibetans." High Altitude Medicine & Biology 7.3 (2006): 193-208. Web. 20 Mar. 2016