Hindawi

BioMed Research International

Volume 2022, Article ID 5749382, 5 pages
https://doi.org/10.1155/2022/5749382

Review Article
Ethiopian Native Highlander’s Adaptation to Chronic High-
Altitude Hypoxia

Ayechew Getu
Department of Physiology, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196, Gondar, Ethiopia

Correspondence should be addressed to Ayechew Getu; ayechew.adera@uog.edu.et

Received 14 December 2021; Revised 13 March 2022; Accepted 6 April 2022; Published 15 April 2022

Academic Editor: Kazim Husain

Copyright © 2022 Ayechew Getu. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

People living in a high-altitude environment have distinct lifelong challenges. Adaptive mechanisms have allowed high-altitude
residents to survive in a low-oxygen environment for thousands of years. The purpose of this review was to provide a brief
review of the Ethiopian native highlanders’ adaptive mechanisms to chronic hypoxia problems at high altitude. Traditionally,
an elevated hemoglobin concentration has been considered as a hallmark of lifelong adaptation to high-altitude hypoxia,
though this notion has been refuted recently as a result of the establishment of the alternative adaptive responses found in
Amhara highlanders living in the Simien Mountains of northern Ethiopia. These populations did not have elevated
hemoglobin (no erythrocytosis) but had normal hemoglobin saturation and arterial oxygen level, which alerts researchers to
explore the possibility of the presence of an alternative adaptive mechanism. Contrary to this, Oromos living in the Bale
Mountains of southern Ethiopia have elevated hemoglobin. The presence of increased nitric oxide (NO) and cyclic guanosine
monophosphate (cGMP) in native Amhara highlanders suggests the possibility of adaptation via vasodilation, which would
improve oxygen supply to metabolic tissues. Native Amhara highlanders showed no indications of chronic mountain sickness
and had a higher pulmonary blood pressure without having a higher pulmonary vascular resistance. In addition, the cerebral
circulation is sensitive to NO and carbon dioxide (CO2) but not to hypoxia, which would likely promote increased cerebral
blood flow and increase oxygen delivery to the brain, making Ethiopian high-altitude natives better suited for survival at high
altitudes. Further research is warranted to translate these background natural features of Ethiopian native highlanders to
clinical applications.

1. Background high altitude above 2500 m is usually associated with the

symptoms and signs of a decrement in oxygen supply to
High altitude is uniquely characterized by temperature vari- metabolic tissues. The degree of symptoms experienced usu-
ation, ultraviolet radiation, humidity level, nutrient compo- ally increases as the altitude level increases, and often, the
sition, and most importantly a decrease in atmospheric symptoms subside upon returning to low altitude [2].
pressure. Because of this feature of the environmental condi- Moreover, besides the observation of symptoms, attain-
tion, it is stressful and challenging not only for temporary ing altitudes high above 3000 m has been associated with
residents but also for natives. However, human beings have anatomical and physiochemical alterations. Early research
strived in this harsh environment for thousands of years by revealed that because of the presence of long-term adaptive
using genetic and phenotypic adaptive mechanisms. mechanisms, lowlanders can strive and live permanently at
Exposure to high-altitude challenges and the effects that an altitude of up to 4900 m, whereas native highlanders
follow on the body have been known for more than a cen- can reside at a maximum altitude of 5800–6000 m [3].
tury [1]. Barometric pressure, along with partial pressure It is estimated that about 82 million people live perma-
of oxygen, decreases as altitude increases, and ascent to a nently at an altitude of 2500 m or above [4]. The Amhara
2 BioMed Research International

highlanders of Ethiopia, the Andeans of South America, and The Simien Mountain regions are the northern part of
the Tibetans of Central Asia are well-known populations the western highlands, where the Amharas have lived for
that reside in the high altitudes and have thrived for thou- millennia at an altitude of 2400–3700 m [5]. Native Amhara
sands of years. Amharas in the Simien Mountains have been highlanders live harmoniously with low oxygen levels. In the
permanently inhabited for more than 70,000 years, whereas present day, researchers found three patterns of adaptations
in southern Ethiopia, Oromos inhabited the Bale Mountain to chronic hypoxia: Ethiopian, Tibetan, and Andean pat-
areas for about 500 years [5, 6]. terns of adaptations [14].
These people have been well adapted to the hypoxic This review is aimed at presenting a brief overview of the
environmental challenges for thousands of years, and Ethiopian native highlander’s adaptive mechanisms to
researchers have found different patterns of phenotypic chronic high-altitude hypoxic challenges. Relevant literature
and genotypic adaptive mechanisms that help inhabitants searches were conducted by using search engines including
live from generation to generation [5, 7]. PubMed and Google Scholar, typing the following keywords:
“Ethiopian native highlanders”, “adaptation”, “chronic hyp-
2. Chronic Effects of High-Altitude oxia”, and “Siemen Mountains”.
Environment on the Human Body
Mountaineers, tourists, and trekkers who normally reside at 3.1. Hematological Adaptations. Traditionally, a high con-
low altitudes usually experience the acute effects of the centration of hemoglobin level above the normal population
ascent to high altitudes. Acute exposure to low oxygen ini- values has been considered a hallmark of lifelong adaptation
tially changes the mechanics of breathing. There is an to high-altitude hypobaric hypoxia. Though varied among
increase in the rate and depth of breathing (hyperpnoea), different geographical locations and populations, an increase
which is eventually associated with a decrease in the level in the level of hemoglobin is an acute response (acclimatiza-
of CO2 in the blood (hypocapnia). This low blood CO2 level tion) to high-altitude hypoxia for new individuals who have
causes respiratory alkalosis, which may be indicative of acute recently moved from sea level [15]. An increase in the con-
mountain sickness (AMS) [8, 9]. The symptoms of AMS centration of hemoglobin improves blood oxygen-carrying
range from mild to severe forms and include sleeping prob- capacity and offsets the hypobaric condition [16].
lems, headache, dizziness, nausea and other gastrointestinal The landmark research done by Beall et al. on the pres-
disorders, pulmonary edema, and cerebral edema [10]. ence of possible hematological adaptations in Ethiopian
Acute alterations in heart activity have been linked to high-altitude natives revealed the presence of unique hema-
rapid exposure to high-altitude hypoxia. The initial response tological adaptations observed in the Simien Mountain areas
to hypoxia is an increase in cardiac output due to the of Amhara residents who inhabited for millennia. This
increase in heart rate and a temporary increase in arterial unique adaptation marks the presence of the third successful
blood pressure as a result of sympathetic activations [11]. pattern of body adaptations to hypoxia [15]. Amharas did
Permanently residing at a high altitude has a unique
not have elevated hemoglobin (no erythrocytosis) values as
clinical consequence, which is known as chronic mountain
compared to their seal level counterparts. There was normal
sickness (CMS). It is an indication of the failure of adapta-
hemoglobin saturation and arterial oxygen level despite
tion to chronic hypoxia and is characterized by excessive
erythrocytosis, severe hypoxemia, and, in some cases, mod- hypobaric conditions. Tibetans, unlike Amhara populations,
erate to severe pulmonary hypertension which may evolve had arterial hypoxemia but not erythrocytosis [17], whereas
into cor pulmonale, leading to right ventricular failure Andeans had both erythrocytosis and arterial hypox-
[12]. The global consensus on the diagnosis of CMS is that emia [18].
there should be an elevation of hemoglobin concentration Cheong et al. revealed the presence of an alternative
≥ 21 g/dl for males or ≥19 g/dl for females together with a adaptive mechanism for chronic hypoxia in these popula-
minimum score of symptoms [12]. tions. Amhara highlanders did not show elevation of hemo-
It has been noted that the clinical presentations of CMS globin but had elevated NO and cGMP in their blood [19],
increase with increased altitude and the signs and symptoms indicating the possibility of adaptation via vasodilatation
gradually disappear after descending to low altitude [13]. enhancing oxygen delivery to metabolic tissues. In their
study, surprisingly, contrary to Amharas, the Oromos of
3. Ethiopian Patterns of Adaptations to Chronic Ethiopians native to the Bale Mountains showed an eleva-
High-Altitude Hypoxia tion in hemoglobin concentration, highlighting the presence
of different adaptive mechanisms for similar hypobaric hyp-
Ethiopia is part of Eastern Africa with varied geographical oxia challenges. It is also worth noting that erythropoiesis
landscapes ranging from very low altitudes (Afar Triangle, genes were strongly expressed in Ethiopians at high altitude
1000 m below sea level) to high altitudes in the Simien and remained significantly higher at sea level [20].
Mountains (the highest peak in Ethiopia and fourth in Despite the presence of an unavoidable low ambient par-
Africa) in the Amhara region of North Gondar at 4550 m tial pressure of oxygen level, a maladaptation to chronic
above sea level. Ethiopia is divided into three well-defined high-altitude hypoxia, chronic mountain sickness (CMS), is
geographical regions: the western highlands, the eastern common in the Andes, occasionally found in Tibetans, but
highlands, and the rift valley with the lowland area. absent in Ethiopians [20, 21].
BioMed Research International 3

It is worth noting, though, that CMS symptoms can exist and the presence of underlying cardiorespiratory diseases.
without an elevated hemoglobin level and that an elevated The most important risk factors for HAPH were increasing
hemoglobin level can exist without CMS symptoms [22]. age, hypoxemia, and erythrocythemia [28]. Tibetans are con-
sidered to be the most adapted to the stress of high altitude
3.2. Vascular Adaptations. A common adaptive response to and have the least prevalent HAPH compared to Andeans
hypobaric hypoxia is an increase in the concentration of [29]. Chronic hypoxia promotes angiogenesis by modulating
hemoglobin, though the degree of elevation is minor in the the transcriptional regulator hypoxia-inducible factor 1 alpha
Amharas of the Simien Mountains of Ethiopia as compared (HIF-1α), which in turn triggers the upregulation of the eryth-
to other native highlanders, suggesting the presence of alter- ropoietin [30]. HIF-1α is a master regulator of the hypoxic
native means of adaptation. Investigators found that vascu- response, and its proangiogenic activities include regulation
lar response is another adaptive mechanism involved in of vascular endothelial growth factor (VEGF), but also eryth-
Amhara highlanders to compensate for their weak hemoglo-
ropoietin and its receptors (EpoR) [31, 32].
bin response [19].
Chronic hypoxia caused by the migration of native sea-
Vasodilatation is an important physiological adjustment
level dwellers to high altitudes or chronic lung disease leads
to increase the tissue blood flow in response to hypoxia [23].
to the development of increased pulmonary vascular resis-
Tibetans, like Amharas, have a dampened hemoglobin
response to hypoxia and have been recognized to have high tance and pulmonary hypertension [33]. The classical model
nitric oxide levels and enhanced tissue blood flow [17, 24]. to show the presence of pulmonary hypertension is increased
NO is a key molecule involved in vasodilation and the pre- vascular resistance. In contrast to this general consensus, the
vention of thrombosis. Hypoxic-induced systemic vasodila- Ethiopian study found that Amhara natives at 3700 m had
tion is attributed to the enhanced production of NO and elevated pulmonary artery pressure (27:9 ± 8:4 mmHg), but
has been noticed in the Tibetans. Native Amhara high- without elevated pulmonary vascular resistance. It has been
landers were also shown to have more NO and its down- suggested that the high pulmonary artery pressure could be
stream signal transducer cGMP, which was not the case for due to high pulmonary blood flow and right ventricular
their Oromo counterparts [19]. enlargement but not to vascular resistance [34]. This finding
In the Amhara highlanders, chronic hypoxia induced suggests the pulmonary vasculature may respond to hypoxia
elevated NO, enabling vasodilation and an increase in blood in a distinct way.
flow, compensating for their relatively lower hemoglobin Another yet unique feature of Amhara highlanders is the
response [19]. In addition, to ensure better and maintained sensitivity of their brains to oxygen shortages. The brain is
tissue blood flow, vascular endothelial growth factor C the most sensitive organ to a shortage of oxygen. Many
(VEGFC), which is crucial for angiogenesis in response to symptoms of chronic mountain sickness are possibly linked
hypoxia, was very high in Ethiopians both at high altitude with this neuronal hypoxia. One sign of the failure to adapt
and in the lowlands [20]. to acute or chronic hypobaric hypoxia is the presence of
At high altitudes, the entire lung is unavoidably exposed severe high-altitude cerebral edema (HACE) [35, 36]. Physi-
to lowered inspired oxygen. An immediate reaction is the ologically, CO2 has a cerebrovascular dilation effect, whereas
hypoxic pulmonary vasoconstriction reflex, measured as an oxygen has the opposite. Cerebral vasculatures exposed to
increase in pulmonary arterial blood pressure that automat- chronic hypoxia are thus at risk of constriction, resulting in
ically increases pulmonary vascular resistance in poorly aer- decreased blood flow.
ated regions of the lungs, thereby redirecting pulmonary The cerebral circulation of Amhara highlanders was
blood flow to regions richer in oxygen content [25]. This
found to be less sensitive to hypoxia, unlike in Peruvian
diversion of blood flow to better ventilated alveoli is critical
counterparts [20]. Amhara highlanders present with high
for matching ventilation with perfusion, decreasing the vol-
sensitivity of cerebral blood vessels for CO2 which would
ume of shunted blood and thereby preventing hypoxemia.
Chronic hypoxia promotes pulmonary vasoconstriction likely increase cerebral blood flow and increase oxygen deliv-
and increases pulmonary arterial pressure and arterial resis- ery to the brain. This unique feature makes them better
tance, which ultimately leads to right ventricular hypertro- suited for survival at high altitudes.
phy and eventually heart failure.
A subset of chronic mountain sickness, chronic high-
altitude pulmonary hypertension (HAPH), is a clinical syn- 4. Limitation of the Review
drome seen in individuals residing in high-altitude regions
and is characterized by increased pulmonary vascular resis- This review is not without limitations. First, I did not include
tance secondary to hypoxia-induced pulmonary vasocon- the findings regarding the genetic architecture of Ethiopians
striction and vascular remodeling of pulmonary arterioles and the influence of genetic variance on the adaptation
[26, 27]. The vascular alterations involve all elements of mechanisms. Second, I did not comprehensively present
the vessel wall and include endothelial dysfunction, smooth each and every similarity and difference between Ethiopian
muscle extension into previously nonmuscular vessels, and highland natives’ and others’ coping mechanisms for high-
adventitial thickening [27]. altitude hypoxia, for which the reader might not be satisfied.
The prevalence of HAPH is influenced by the altitude, eth- I encourage readers to approach the excellent references
nicity, and ancestral history of colonization to high altitudes cited in this paper.
4 BioMed Research International

5. Conclusion [13] D. A.-S. J. Penaloza and J. Arias-Stella, “The heart and pulmo-
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Conflicts of Interest Aymara,” The American Journal of Physical Anthropology,
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The author declares no conflict of interest to disclose.
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