Chronic altitude illness


While much of the attention in clinical high altitude medicine is focused on acute forms of altitude illness that occur within the first several days of ascent to a given elevation, there are two chronic conditions that affect people who have lived at high altitude for months or years or infants born at altitude: chronic mountain sickness (CMS) and high altitude pulmonary hypertension (HAPH). Numerous terms have been used in the literature for these conditions, but following the publication of two consensus statements on the topic (León-Velarde 1998; León-Velarde et al. 2005) (Table 24.1), the term CMS will be used to refer to the condition of excessive erythrocytosis, while HAPH will be used when referring to the form where pulmonary hypertension predominates.

Table 24.1 Nomenclature for chronic high altitude diseases and previous terms or synonyms and essential features

Suggested name



Chronic mountain sickness

Monge’s disease

Excessive erythrocytosis

High altitude excessive polycythemia


Excessive erythrocytosis

Pulmonary hypertension in some cases. Right heart failure

High altitude pathologic erythrocytosis

Headache, dizziness, fatigue. Recovery on descent to low altitude

High altitude pulmonary hypertension

CMS of the vascular type

Pulmonary hypertension

High altitude heart disease

Right ventricle hypertrophy

Hypoxic cor pulmonale

Right heart failure

Infant subacute mountain sickness

Moderate hypoxemia

Pediatric high altitude heart disease. Adult subacute mountain sickness

No excessive erythrocytosis

Source: Abstracted from the ISMM Consensus statement (León-Velarde et al. 2005).

There is considerable overlap between these two conditions. Most patients with CMS also have pulmonary hypertension and may go on to develop right heart failure, while some patients with HAPH have a degree of excessive erythrocytosis. However, in most patients, one or the other response to chronic altitude hypoxia dominates, so the consensus group decided to keep the two diagnoses while recognizing that some patients had both conditions. The situation is, perhaps, analogous to that of high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE), which can occur either in isolation or in conjunction with each other in people who have recently ascended to high altitude.

CMS has been well known for many years, but HAPH has only been recognized as a clinical entity following reports from the Andes (Peñaloza 1971) and China (Chen et al. 1982). A more acute condition has also been reported by Anand et al. (1990) in Indian soldiers stationed between 5800 m and 6700 m for several months (mean 1.8 years), similar to that which had been recognized earlier in children born or brought up to altitude at an early age (Khoury and Hawes 1963).

Chronic Mountain Sickness


Carlos Monge M. reported the first cases of CMS in the 1920s, including a case of polycythemia in a patient from Cerro de Pasco (4300 m) in Peru (Monge 1925) and a series of patients with red cell counts significantly higher than normally found at high altitude (Monge and Whittembury 1976). (Note: Carlos Monge M. is the father and Carlos Monge C., the son: the M and C are the initial letters of the mothers’ names, as is Spanish custom.) This condition has come to be known also as Monge’s disease. The 1935 international expedition, led by Bruce Dill, reported one case of CMS in the English literature (Talbott and Dill 1936), while in 1942, Hurtado published detailed observations of eight cases, outlining the symptomatology and hematological changes at high altitude and the effect of descent to sea level and return to high altitude (Hurtado 1942). Outside South America, CMS was described in residents of Leadville, Colorado (3100 m), by Monge M. in the late 1940s (Winslow and Monge 1987), and Weil et al. (1971) provided subsequent studies of affected individuals beginning in the 1960s. Reports of CMS from the Himalayas indicate the condition to be prevalent in immigrant Han Chinese in Lhasa (3658 m) but less common in the indigenous Tibetan population (Pei et al. 1989; Wu et al. 1998; Xing et al. 2008).

Epidemiology of CMS

Several studies have examined the regional differences and worldwide distribution of CMS (Beall 2006; Beall 2007; Xing et al. 2008). Different degrees of severity and presentation from Africa, Asia, and North and South America provide a rich supply of information for speculation about human migration and insights into human adaptation over many generations to a constant physiological stressor, hypoxia.


CMS is found most commonly in the Andes, where it was first described mainly affecting the local Amerindians, especially the Quechuan population living on the altiplano at altitudes about 3300–4500 m. Men are affected far more commonly than women. The average age is 40 years with a range from 22 to 51 years in one reported series (Peñaloza and Sime 1971), and it is prevalent in more than 30% of Andean men more than 60 years of age (Corante et al. 2018; Monge et al. 1989). It was previously thought that CMS was virtually confined to the Andes, but this is not the case, as discussed below.

Himalayas and Tibet

Fewer cases of CMS have been reported from the Himalayas and Tibet, although a large number of cases have now been described among Han Chinese who have relocated to Tibet. One of the larger series was that of Pei et al. (1989), who described 24 cases of CMS in Lhasa, Tibet, over a 12-month period, 23 of whom were Han Chinese and one of whom was from Tibet. The lowlanders, all of whom were male and most of whom were smokers, had spent a mean duration at high altitude of 26 years (a range of 9–43 years) before presentation. To understand who in the immigrant Han population was more susceptible to acquiring CMS, Li et al. (2012) found that workers living in an urban environment doing construction work had a higher prevalence of CMS than rural inhabitants, those living with oxygen-generating systems, or individuals with nonphysical jobs. Recent studies, based upon analysis of 1029 Han Chinese males who migrated to the Qinghai-Tibetan Plateau, report the prevalence of CMS as 17.8% in this population (Jiang et al. 2014).

CMS has been described in native Tibetans but the prevalence is much lower (1.2%) when compared to the Han Chinese (Wu et al. 1998). Wu et al. (1992) reported a series of 26 cases in native-born Tibetans living at between 3680 m and 4179 m with typical symptoms of CMS and hemoglobin concentration of 22.2 g dL−1 mean compared with 16.6 g dL−1 in healthy controls at the same altitude. The prevalence of CMS in Himalayan populations appears to increase with altitude. Studies from the Tibetan Plateau report the prevalence of CMS as 1.05%, 3.75%, and 11.83% at 2621–2980 m, 3128–3980 m, and 4000–5226 m, respectively (Wu et al. 1998). In Himachal Pradesh, India, CMS was not reported between 2350 m and 3000 m, but was found in 13.3% of the population at altitudes between 3000 m and 4150 m (Sahota and Panwar, 2013).

It appears that people of Tibetan ancestry are at less risk of developing CMS than Andean highlanders and certainly lowland Han Chinese who have relocated to high altitude. This difference in susceptibility may be due to genetic adaptations to altitude over very many generations, as described in Chapter 6.


Research regarding high altitude adaptation among Ethiopian highlanders is limited, and there is limited documentation of CMS among this population. The Ethiopian highlands are not quite as high as Tibet or the Andes, and there is greater genetic heterogeneity in the various peoples who inhabit Ethiopia. In the past decade and one-half, genetic studies have started to provide some insight on factors that might contribute to susceptibility. Xing et al. (2008) explored hypoxia-related genes in Ethiopians, Tibetans, and Himalayan high altitude residents. Markers of the response of the cerebral circulation and hypoxic ventilatory response were low in the Himalayas and Ethiopia, and increased expression of a single gene (PDP2) in CMS was not detected in the Ethiopians. In Amhara Ethiopians, hemoglobin concentration is associated with THRB, EPAS1, and PPARA adaptive loci (Scheinfeldt et al. 2012), as discussed in Chapter 6.

North America

CMS is well recognized in Leadville, Colorado (3100 m), although limited epidemiological data are available. Kryger et al. (1978a) described 20 cases, all male, and mentioned that, of about 60 cases known to physicians there, only two were female. One case of apparently classical CMS in a 67-year-old woman has been reported from as low as 2000 m in California (Gronbeck 1984). A larger study from 140 men and 148 women in Leadville, Colorado, showed the prevalence of CMS was 8.96% and 8.6%, respectively (Asmus 2002). In an analysis of mean pulmonary arterial pressure as a function of altitude, Peñaloza and Arias-Stella (2007) noted greater values in individuals from Leadville, Colorado, than would otherwise be expected at that elevation.

Clinical aspects of CMS

Definition of Chronic Mountain Sickness

According to the latest consensus statement, CMS is defined as: “A clinical syndrome that occurs in natives or long-life residents above 2500 m.” It is characterized by excessive erythrocytosis ([Hb] ≥19 g dL−1 for females and ≥21 g dL−1 for males), severe hypoxemia, and in some cases moderate or severe pulmonary hypertension, which may evolve into cor pulmonale, leading to congestive heart failure. The clinical picture of CMS gradually disappears after descending to low altitude and reappears after returning to high altitude (León-Velarde et al. 2005). The consensus statement excludes from the definition of CMS patients with any chronic pulmonary disease or any other chronic condition that worsens the hypoxemia of altitude, though it does allow a diagnosis of secondary CMS in such cases.

Scoring of Chronic Mountain Sickness

A symptom/sign scoring system for CMS was proposed at the 6th World Congress of Mountain Medicine in Qinghai in August 2004 and included in the consensus statement (León-Velarde et al. 2005). The purpose was to provide a means of comparing cases from one study to another. Symptoms signs are scored as 0 to 3 indicating: 0, no symptom; 1, mild; 2, moderate; and 3, severe symptoms, signs. The list of symptoms, signs is as follows: breathlessness, palpitations, sleep disturbance, cyanosis, dilatation of veins, paresthesia, headache, and tinnitus. Hemoglobin level: males >18 but <21 g dL−1 = 0; >21 g dL−1 = 3; females >16 g dL−1 but <19 g dL−1 = 0, >19 g dL−1 = 3. A summation of the scores reflects the severity of the disease (absent 0–5; mild 6–10; moderate 11–14; severe >15). This system is more important for the purposes of classifying subjects in research studies but can also inform clinical practice.

Clinical Features

Patients typically have rather vague neuropsychological complaints including headache, dizziness, paresthesia, somnolence, fatigue, difficulty in concentration, and loss of mental acuity. There may also be irritability, depression, and even hallucinations. Patients may gain weight and, although they do not typically report dyspnea on exertion, are often found to have decreased exercise tolerance. Poor sleep quality has also been described and is associated with decreased cognitive function in soldiers with polycythemia on the Tibetan plateau with a wide range of CMS scores (Kong et al. 2011). The characteristic feature of the disease is that the symptoms disappear on going down to sea level, only to reappear on return to altitude.

A symptom more recently reported in CMS is that of burning feet or hands. This was first described by León-Velarde and Arregui in 1994 (quoted by Thomas et al. 2000). In a study by Thomas et al. (2000), this symptom was present in all 10 unselected CMS patients, but also in four out of five healthy control subjects living at the same altitude. Described as intermittent burning usually confined to the feet, the symptom tended to subside with descent to lower elevation but recur on return to high altitude.

In addition, the conjunctivae are congested and the fingers may be clubbed. Due to differences in skin tone and elevation, the appearance may be less striking in Caucasians in Leadville, Colorado (3100 m), relative to other highland populations.

Laboratory and Other Investigations

The red cell count, hemoglobin concentration, and packed cell volume are increased, with hemoglobin values as high as 28 g dL−1 and hematocrits as high as 80–91% (Hurtado 1942) (Jefferson et al. 2002b). Like secondary polycythemia at sea level and unlike polycythemia rubra vera, there is no increase in the white blood cell count. When compared to healthy individuals at the same altitude, arterial blood gases demonstrate a higher PaCO2 and lower PaO2 and oxygen saturation (Peñaloza and Sime 1971; Kryger et al. 1978a). The lower PaO2 is due to hypoventilation, as indicated by the increased PaCO2 and, in many cases, an increased alveolar-arterial oxygen difference ([A–a]ΔO2). Manier et al. (1988) found a mean (A–a)ΔO2 of 10.5 mmHg in CMS patients at La Paz (3600 m) compared with the normal (A–a)ΔO2 of 2.9 mmHg at this altitude. Using the multiple inert gas technique, they attributed most of this to increased blood flow to poorly ventilated areas of the lung rather than to true shunting.

Tewari et al. (1991) found a reduced diffusing capacity (DLCO) in lowland soldiers with excessive polycythemia on return to low altitude, which improved with time at low altitude and return to a normal hematocrit. The DLCO was lower in smokers than nonsmokers, although both were well below predicted values. In some cases of CMS, standard pulmonary function tests show abnormalities indicating obstructive and/or restrictive defects, suggesting that patients have coexisting chronic lung disease. Using chest ultrasound, Pratali et al. (2012) exercised 15 patients with CMS and 20 control subjects at 3600 m altitude and found accumulation of lung water in those with CMS, which may contribute to impaired gas exchange as well.


Cardiac Function

Several reports have examined cardiac hemodynamics in CMS (Hainsworth and Drinkhill 2007; León-Velarde et al. 2010; Maignan et al. 2009; Naeije 2010; Peñaloza and Arias-Stella 2007; Richalet et al. 2009; Stuber et al. 2010). The very high hematocrit increases the viscosity of the blood. The systemic blood pressure may be moderately elevated while the pulmonary artery pressure is significantly higher than that of healthy high altitude residents. Peñaloza (1971), for example, found a mean pulmonary artery pressure of 64/33 mmHg in 10 cases of CMS compared with 34/23 mmHg in controls. Cardiac output was not significantly different, indicating that pulmonary vascular resistance was just over twice that of controls, likely due to the effects of increased viscosity as well as the effects of hypoxic pulmonary vasoconstriction.

Despite the higher pulmonary artery pressures and right ventricular hypertrophy in patients with CMS as compared to both low altitude and high altitude controls, Maignan et al. (2009) did not find any evidence for overt right-heart failure in their study population. Stuber et al. (2010) also used echocardiography in 30 patients with CMS and 32 controls at 3600 m to study the pulmonary vascular response to modest exercise. Although the patients with CMS demonstrated a modest increase in right-sided pressures at rest, they experienced a three-fold greater difference in right-sided pressure with modest exercise (50 watts on a cycle ergometer). This finding suggests these patients have very low pulmonary vascular compliance and also suggests that resting measurements may underestimate the hemodynamic differences between those with and without CMS. This concept is supported by recent work from Soria et al. (2019), who completed a meta-analysis of nine studies of individuals with CMS (N = 287) and found no PH at rest but mild PH during exercise. Estimates from their separate meta-analysis (N = 834) of CMS individuals and healthy highlanders indicated greater differences in mean systolic pulmonary artery pressure during mild exercise (48 mmHg versus 36 mmHg) compared to differences at rest (28 mmHg and 25 mmHg, respectively) (Soria et al. 2019).

Cerebral Blood Flow

Although polycythemia (rubra vera) is associated with reduced cerebral blood flow (CBF) (Thomas et al. 1977) due to increased viscosity, the few studies of CBF in CMS have either shown no significant differences between subjects with and without CMS when awake breathing air (Sun et al. 1996). While some studies do not report the expected reduced flow in CMS patients compared with controls (Claydon et al. 2005), CBF in Andeans was reported as approximately 15–20% lower than sea-level values, possibly due to high hematocrit and blood viscosity in subjects examined at 4300 m in Cerro de Pasco, Peru (Milledge and Sørensen, 1972), and 3800 m in La Paz, Bolivia (Sørensen et al. 1974). Similarly, Bao et al. (2017) have recently shown that some Tibetan individuals with CMS develop cerebral edema and exhibit decreased cerebral blood flow and circulatory delay relative to healthy highlanders.

Other studies have revealed that lower middle cerebral arterial velocity is 20% lower in highlanders from Cerro de Pasco than individuals studied at sea level (Willie et al. 2011). Whether increased blood viscosity, changes in vasoconstriction, increased arterio venous oxygen content difference, or combinations thereof underlie these observations in Andean highlanders remains to be determined (Ainslie and Subudhi, 2014). Information regarding arterio-venous oxygen differences and cerebral metabolic rate for oxygen in Tibetan and Himalayan highlanders is lacking, and review of the limited studies to date indicates CBF was only slightly higher than in sea-level individuals and more than 20% greater than in Andeans at comparable high altitudes (Jansen & Basnyat, 2011).


While relocation to low altitude is the best preventative measure, it is not a feasible option for many high altitude residents whose family or financial livelihood depends upon their living at altitude. Avoidance of smoking and efforts to limit occupational and other exposures such as dust, air pollution and cobalt in the high altitude communities are also warranted but frequently difficult to implement. Efforts at prevention would also be aided through improved ability to predict susceptibility to CMS, but accurate predictive tools have not been identified.


Multiple options are available for treating CMS (Villafuerte and Corante 2016). As with prevention, symptoms and signs improve with descent to sea level, but this is an infeasible solution for many affected individuals due to family and economic factors.


Periodic phlebotomy lowers the hematocrit, improves many of the neuropsychological symptoms, and also improves pulmonary gas exchange (Cruz et al. 1979) and exercise performance in some subjects (Winslow and Monge 1987). Of historical interest, the blood bank in Leadville, Colorado, with about 60 patients being regularly bled for therapeutic purposes, at one time had no need of any other donors (Kryger et al. 1978a).

Respiratory Stimulants

Given the role that hypoventilation plays in development of the disease (discussed later), respiratory stimulants have been examined for the treatment of CMS. Kryger et al. (1978b), for example, demonstrated that 10 weeks of treatment with medroxyprogesterone acetate stimulated ventilation, raised PaO2 and reduced PaCO2 by a modest amount. Although the changes in blood gases were small, they suggest that the main benefit may have been with nocturnal oxygenation since hypoxemia was much greater at night than during the day. The only side effect reported was the loss of libido in four patients, which could be managed by lowering the dose to a level that still kept the hemoglobin concentration down.

More recent attention has focused on the role of acetazolamide. Using a randomized, double-blind design, Richalet et al. (2005b) randomized patients with CMS to receive acetazolamide 250 mg or 500 mg daily or placebo for three weeks and found a significant decrease in hematocrit, serum erythropoietin, and soluble transferrin and an increase in nocturnal SaO2 of 5%. The results for the 250 mg group were as good as for the 500 mg group. In a subsequent study involving six months of treatment, acetazolamide was shown to improve polycythemia and hypoxemia and reduce pulmonary vascular resistance (Richalet et al. 2008). Combining N-acetylcysteine with acetazolamide does not offer benefits over acetazolamide alone (Sharma et al. 2017).

While most of the benefit, noted at doses of both 250 and 500 mg/day−1, likely relates to its role as a respiratory stimulant (Rivera-Ch et al. 2008), other research on acetazolamide suggests that part of its benefit may derive from effects on the pulmonary circulation (Boulet et al. 2018; Hohne et al. 2007). Given the burden of CMS and the low cost and side effect profile of this intervention, acetazolamide represents a potentially significant public health intervention.

Pathophysiology of CMS with normal lungs

Hypoxemia, Hypoventilation, and Gas Exchange

Patients with CMS have lower PaO2 and SaO2 than healthy subjects at the same altitude, which results in higher erythropoietin levels and thus greater erythrocytosis. This greater degree of hypoxemia is likely related to several factors. The fact that PaCO2 is also increased in CMS suggests that hypoventilation may play a key role (Figure 24.1). Severinghaus et al. (1966), for example, found that patients with CMS had an extremely blunted hypoxic ventilatory response (HVR) compared with healthy resident controls of the same age, suggesting that people at the low end of the spectrum for HVR in the population are predisposed to CMS if they remain for years at high altitude. Hypoventilation may also contribute to some of the hemodynamic features of CMS as it has been shown in studies of healthy individuals and CMS patients at high altitude that pulmonary artery pressure is related to the degree of hypoxemia; those individuals with lower ventilation have lower alveolar and arterial PO2 and, as a result, increased hypoxic pulmonary vasoconstriction. The fact that HVR decreases with age (Kronenberg and Drage 1973) and with duration of stay at altitude (Weil et al. 1971) further suggests that patients with CMS are those in whom the process is faster than average. Other studies, however, have suggested that differences in HVR may not be critical in all cases. Kryger et al. (1978a), for example, found no difference in HVR between patients and age-matched controls in Leadville, Colorado, but did find that their patients had a greater deadspace/tidal volume ratio and that their ventilation increased on breathing 100% oxygen. This result suggested they had hypoxic ventilatory depression rather than blunted HVR as a potential contributor to CMS.

Figure 24.1

Figure 24.1Possible mechanisms in the development of chronic mountain sickness (CMS). HVR, hypoxic ventilatory response; CBF, cerebral blood flow; PCV, packed cell volume.

The greater degree of hypoxemia seen in CMS may also relate to abnormalities in gas exchange, as suggested by the fact that CMS patients have a widened (A–a)ΔO2 compared to healthy controls (Manier et al. 1988). Pratali et al. (2012), for example, documented increased lung water after exercise in subjects with CMS, which certainly can contribute to impaired gas exchange.

Sleep Disordered Breathing

Changes in ventilation and oxygenation during sleep may also contribute to CMS pathophysiology. Sun et al. (1996), for example, have shown that CMS patients had more disordered breathing than a group of healthy controls, while a more recent study provides evidence that sleep apnea is generally more prevalent in Peruvian highlanders than lowlanders at sea level (Pham et al. 2017a). The presence of sleep apnea is significant as apneic episodes, whether central or obstructive in nature, are associated with increased hypoxemia, and the severity, frequency, and duration likely alter hypoxia-sensitive pathways and influence physiological and pathological outcomes. Coupled analyses of polysomnography and cardiometabolic markers in Andean highlanders, for example, indicate nocturnal hypoxemia and sleep apnea are associated with excessive erythrocytosis and glucose intolerance, respectively (Pham et al. 2017a; Pham et al. 2017b). Villafuerte and Corante (2016) showed serum EPO during sleep was significantly higher in CMS participants, in contrast to other findings for daytime EPO concentration (León-Velarde et al. 1991; Villafuerte et al. 2014), and that mean sleep SpO2 and the EPO-to-soluble EPO receptor (sEpoR) ratio (an Epo availability index) were significant predictors of hematocrit. A case-control study based on Andean males 18–25 years of age showed those with excessive erythrocytosis had greater apnea hypopnea index, lower nocturnal SpO2, and higher levels of oxidative stress marker 8-iso-PGF2-alpha (Julian et al. 2013).

In addition to effects on erythrocytosis, sleep disordered breathing and nocturnal hypoxemia have also been shown to be associated with daytime cognitive impairment (Kong et al. 2011), as well as increased systemic and pulmonary vascular dysfunction (Rexhaj et al. 2016). The presence of patent foramen ovale was further associated with a greater apnea hypopnea index, which correlated with systemic blood pressure and pulmonary artery pressure in individuals with CMS. Efforts to further assess the effects of sleep on these and molecular markers of intermittent and/or prolonged periods of hypoxemia during sleep (Prabhakar and Semenza 2012) will provide important clues into the development of CMS and cardiometabolic pathologies.


Premenopausal females appear to be protected from CMS possibly due to the stimulating effect of progesterone on ventilation. León-Velarde et al. (1997) compared pre- and postmenopausal females at Cerro de Pasco (4300 m) in Peru and found significantly higher hematocrit and lower SaO2 and peak expiratory flows in the postmenopausal group, supporting the protective role of female sex hormones.


A study by León-Velarde et al. (1993) at 4300 m in Peru found an increasing incidence of CMS with age. Taking a hemoglobin concentration of above 21.3 g dL−1 as “excessive erythrocytosis,” the incidence at 20–29 years was 6.8%, which increased to 33.7% at age 60–69 years. Beyond the potential role of menopause in females noted previously, the mechanisms for this observation are not clear. Part of it may relate to age-related differences in lung function. León-Velarde et al. (1993) also found more marked decreases in vital capacity with age in the CMS patients compared to healthy controls, whereas no age-related changes were seen in a group of sea level subjects. Age also has effects on ventilatory responses to hypoxia (Lhuissier et al. 2012) as well as hypoxic pulmonary vasoconstriction, which could contribute to development of CMS as well (Balanos et al. 2015). Finally, the PaO2 declines and (A-a)ΔO2 increases with age. While this has little effect on oxygen saturation at sea level, it has much more effect at altitude because subjects are already on the steep part of the oxygen dissociation curve. This may subsequently affect production of erythropoietin and the erythrocytosis that follows.


Cobalt is a mineral found in rocks around the mining areas in South American and is a known stimulant of erythropoiesis, likely as a result of its ability to stabilize HIF-1α (Nakuluri et al. 2019). It was not found in samples of drinking water tested by Jefferson et al. (2002) but perhaps leaches in at times and, therefore, may act as a risk factor for CMS in some localities by increasing the likelihood of developing polycythemia. In a review of their experience over many years, Reeves and Weil (2001) collected details of more than 750 males and 200 females with CMS. They noted that one of the contributing factors to the variation in the erythropoietic response to altitude was ingested toxins and minerals such as cobalt. Jefferson et al. (2002) found that 11 of 21 subjects with CMS in Cerro de Pasco (4300 m) had detectable cobalt levels in their serum compared with none in their controls. However, Bernardi et al. (2003) in their study also in Cerro de Pasco found normal cobalt levels in CMS patients.


There is notable variation in response to long-term, chronic hypoxia in different populations, and only a proportion of any population is susceptible to CMS. These considerations lead to the question of whether there is a genetic component to susceptibility. In a case–control study, Mejía et al. (2005) looked at a variety of candidate genes, including erythropoietin, erythropoietin-receptor, and HIF-1α (von Hippel-Lindau and others). They found no association between the polymorphisms linked to the candidate genes and severe polycythemia. In some preliminary work, León-Velarde and Mejía (2008) found insufficient information to make any consistent conclusions of hypoxia-related genes in their high altitude populations. Huicho et al. (2008) studied children of parents with CMS and looked at oxygen-responsive genes and those involved in glycolytic and mitochondrial pathways to see if there was a genetic signature that may predict future development of CMS. Markers of impaired adaptation to hypoxia were noted in defective coupling between glycolysis and the mitochondrial TCA cycle, which may predispose these children to the eventual development of CMS. Espinoza et al. (2014) studied 131 CMS and 84 non-CMS control subjects in Cerro de Pasco, Peru, and found that the two groups had differential gene markers for VEGF. This and other preliminary work (Buroker et al. 2010) could lead to the discovery of specific markers that could be predictors of those susceptible to CMS. More recent genomic comparison of 10 CMS and 10 non-CMS individuals identified SENP1 and ANP32D as potential contributors to CMS in Andeans (Zhou et al. 2013). This topic is considered in greater detail in Chapter 6.

Ge et al. (2011) looked at mediators which influence vasoreactivity and fluid balance, including B-type natriuretic peptide (BNP), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and endothelial nitric oxide synthase (eNOS), in 24 CMS patients living at 4300 m and compared their results with 50 controls. Both BNP and ET-1 correlated positively with echocardiographic pulmonary artery pressure and negatively with SaO2. VEGF was inversely correlated with SaO2, and eNOS correlated negatively with pulmonary artery pressure and positively with SaO2. These findings suggest that vasoactive mediators play an important role in the pathophysiology of CMS and may afford future opportunities for prevention and treatment. Additional efforts are necessary to further characterize the individual and population-level markers key to the development CMS.

Developmental Factors

As discussed in Chapter 4, Moore et al. (2007) looked to see if clinical conditions at birth (hypoxemia, small for gestational age, preterm, or pre-eclampsia) were present in patients who went on to develop CMS. Impaired fetal growth was associated with adult CMS. To determine whether perinatal hypoxia increased susceptibility to CMS in adulthood, Julian et al. (2015) evaluated males between the ages of 18 and 25 resident between 3600 m and 4100 m. Based on data from 66 control and 67 individuals with excessive erythrocytosis, defined as hemoglobin concentration greater than 18.3 g dl−1, men with excessive erythrocytosis were born to mothers with hypertension and hypoxia during the perinatal period. Such information could lead to counseling for children who may have alternatives to live at lower altitudes as they become adults.

Excessive erythrocytosis with lung disease

In cases of EE with definite lung disease, it is easy to understand that the combination of altitude with fairly mild lung disease precipitates polycythemia and cor pulmonale. At high altitude, these patients are more hypoxemic because of their lung disease, hence their stimulus to erythrocytosis via erythropoietin secretion is greater, and they become abnormally polycythemic. The importance of lower respiratory tract disease is emphasized in a study by León-Velarde et al. (1994) which shows that subjects with chronic lower respiratory tract disease had higher hemoglobin concentrations, lower SaO2, and higher CMS symptom scores than healthy controls or subjects with chronic upper respiratory tract disease. Descent to lower elevations is sufficient to reverse these problems but, as noted, is not feasible for many affected individuals.

Morbidity and mortality of CMS

Data regarding the morbidity and mortality of CMS are lacking, although efforts to quantify the burden of disease in Han Chinese migrants to Tibet are underway (Pei et al. 2012). Various downstream consequences have been reported including metabolic and vascular dysfunction as well as proinflammatory and oxidative damage that may contribute to increased risk of cardiovascular outcomes. Gonzales and Tapia (2013) reported associations between increased hematocrit and total, low-density lipoprotein, and non-high density lipoprotein cholesterol and triglycerides, but not glucose, in 158 males and 384 females at 4100 m. Rimoldi et al. (2012) studied 23 CMS patients and 27 individuals without CMS at 3600 m and identified impaired flow-mediated dilation, greater arterial stiffness, and carotid intima-media thickness in CMS patients. Other work indicated markers of oxidative-nitrosative stress (i.e., increased levels of ascorbate radical and lower nitrite) were exaggerated in individuals with CMS compared to those without and lowlanders at altitude (Bailey et al. 2013); furthermore, worsened oxidative-inflammatory-nitrosative stress was associated with blunted cerebral perfusion and vasoreactivity and cognitive decline and depression in individuals with CMS (Bailey et al. 2019).


Of the two major forms of chronic altitude illness, CMS is by far the more widely known and reported, affecting primarily Andean highlanders but also large numbers of Han Chinese who have relocated to Tibet and a smaller segment of native Tibetans. Due to the effects of excessive erythrocytosis and the associated downstream effects on cardiopulmonary function and cerebral blood flow, affected individuals develop a variety of neurophysiological complaints, decreased exercise tolerance, poor sleep, paresthesias, and cyanosis. The precise mechanisms underlying development of the clinical syndrome are unclear but likely relate to alterations in daytime and nocturnal ventilation as well as gas exchange abnormalities that worsen hypoxemia and increase erythropoiesis. Genetic factors affecting HIF-mediated responses to hypoxia that contribute to such processes are starting to be identified and may further enhance understanding of disease pathophysiology. Although no effective preventive measures have been identified aside from the largely infeasible tactic of relocating to lower elevation, more effective treatment strategies include use of the respiratory stimulant acetazolamide as an alternative to the older practices of phlebotomy and medroxyprogesterone.

High Altitude Pulmonary Hypertension


It has been known for more than than 70 years that exposure to hypoxia results in pulmonary hypertension. This was first demonstrated by von Euler and Liljestrand (1946) in cats and shortly afterward by Motley et al. (1947) in man. This hypoxic pressor response, commonly referred to as hypoxic pulmonary vasoconstriction (HPV), is important in the fetus since blood must be diverted away from the nonfunctioning lung through the ductus arteriosus to the rest of the body. Its effect in life after birth may be to improve ventilation-perfusion ratios in the lung, as can occur with bronchiolar occlusion in asthma or lobar consolidation in pneumonia. In these situations, HPV reduces blood flow to the poorly ventilated areas and diverts it to other better ventilated parts of the lung. At high altitude, however, global alveolar hypoxia triggers HPV throughout the lung with no benefit to gas exchange apart from possibly some slight improvement in the upright lung due to rather more even perfusion. It is of note that animals adapted to high altitude, such as the yak (Harris 1986) or pika (Ge et al. 1998), do not have this pressor response.

As early as 1956, Rotta et al. (1956) found pulmonary hypertension in acclimatized lowlanders and residents at high altitude. In 1962, Peñaloza et al. (1963) and Arias-Stella and Saldaña (1962) presented their data on pulmonary hypertension and pulmonary artery pathology, respectively, showing hypertension and muscularization of the pulmonary arterioles in healthy people resident at high altitude in the Andes. This remodeling results in sustained pulmonary hypertension even when hypoxia is relieved by oxygen breathing or descent to low altitude, although after some months or years at low altitude, pulmonary hypertension does remit.

Patients with CMS often also had pulmonary hypertension and, in some cases, right heart failure, but the severe erythrocytosis had been described earlier and, since blood counts were so much easier to carry out than cardiac catheterization, the hypertension tended to be dismissed and attributed mainly to the increased viscosity due to high hematocrit rather than to ongoing HPV and subsequent vascular remodeling. This early work in Peru has been thoughtfully reviewed by Reeves and Grover (2005).

Other work subsequently suggested that some individuals suffered from isolated pulmonary hypertension and right heart disease in the absence of excessive erythrocytosis. In 1988, Sui et al. published their experience with infants born at low altitude and taken to high altitude in Tibet, referring to the condition subacute infantile mountain sickness (Sui et al. 1988). Shortly afterwar, Anand et al. (1990) reported a similar condition in adult soldiers stationed for some months or more at extreme altitude, referring to it as “adult subacute mountain sickness.” Both conditions were essentially right heart failure due to chronic pulmonary hypertension and are now called HAPH according to the nomenclature suggested by the consensus statement (Table 24.1). Since then, there have been numerous reports of this condition from high altitude regions of Asia (Aldeshev et al. 2002; Ge and Helun 2001; Wu 2005), as well as considerable interest worldwide (León-Velarde and Villafuerte 2011; Lopes et al. 2010; Pasha and Gassman 2010; Peñaloza and Arias-Stella 2007; Xu and Jing 2009; Zhai et al. 2010).

High altitude pulmonary hypertension in infants

The Spaniards who first colonized the Andes became well aware that their infants did not thrive if born at high altitude. They made it their practice to arrange delivery at low altitude and not to bring their babies to high altitude before one year of age. The lowland Han Chinese who relocated to Tibet faced the same problem. Wu and Liu (1995) described a Chinese infant of 11 months of age born in Lhasa (3658 m) who presented with dyspnea, cyanosis, and congestive heart failure. At postmortem, marked right ventricular hypertrophy and muscular thickening of the peripheral pulmonary artery tree were found. There was no other pathology such as congenital heart disease and the authors called the condition “high altitude heart disease.” Sui et al. (1988) had reported the postmortem findings of 15 infants who died in Lhasa of a syndrome they called “infantile subacute mountain sickness.” The presenting symptoms were commonly dyspnea and cough, with often sleeplessness, irritability, and signs of cyanosis, edema of the face, oliguria, tachycardia, liver enlargement, rales in the lungs, and fever. The majority of infants had been born at low altitude but two were born at high altitude, one of Han and one of Tibetan ancestry. The condition was usually fatal in a matter of weeks or months. The postmortem findings were extreme medial hypertrophy of muscular pulmonary arteries and muscularization of pulmonary arterioles. There was massive hypertrophy and dilatation of the right ventricle and of the pulmonary trunk.

High altitude pulmonary hypertension in adults

Anand et al. (1990) described a condition, referred to as “adult subacute mountain sickness,” in 21 soldiers who, after a full acclimatization period, were posted to between 5800 m and 6700 m for several months (mean 1.8 years) and subsequently developed a syndrome marked by dyspnea, cough, exertional angina, and dependent edema. They were treated at high altitude with diuretics with improvement and, after evacuation to low altitude by aircraft, were found to have cardiomegaly with right ventricular enlargement and, in most cases, pericardial effusion. The mean pulmonary artery pressure was elevated (26 mmHg) and rose significantly on mild exercise to 40 mmHg. Recovery was rapid after descent from high altitude. Investigations showed a generalized increase in the volume of the fluid compartments of the body and total body sodium, even in subjects without overt disease at these altitudes for this length of time (Anand et al. 1993). A similar condition was described by Wu (2005) in his review of CMS on the Qinghai-Tibetan plateau. Of note, the condition described in these reports is similar to that affecting cattle taken to high altitude, which is known as “brisket disease” (Hecht et al. 1959). The brisket is the dependent, loose skin area of the cow’s neck that becomes swollen with edema fluid in those animals with excessive increases in pulmonary artery pressure while at high altitude.


Some populations are more susceptible than others (Table 24.2), as demonstrated by data from Qinghai and Tibet, in which Han Chinese immigrants were found to be more susceptible than Tibetans by a factor of three to four. Children are more susceptible than adults by a factor of about three.

Table 24.2 Prevalence (percentage of population) of high altitude heart disease (HAPH) at various altitudes of residence in Han and Tibetan children and adults

Altitude (m)























Note: Children are more susceptible than adults and Han Chinese than Tibetans. The prevalence increases with altitude. Data of Wu and Ge, quoted in Ge and Helun (2001).

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Jul 25, 2021 | Posted by in RESPIRATORY | Comments Off on Chronic altitude illness
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