Chinese Medical Journal 2005;118(2):161-168
Chronic mountain sickness on the Qinghai-Tibetan plateau

WU Tian-yi

WU Tian-yi (High Altitude Medical Research Institute, Xining 810012, China)

Correspondence to:WU Tian-yi,High Altitude Medical Research Institute, Xining 810012, China (Tel: 86-971-6320396. Fax:86-971-6259367. E-mail:wutianyiqh@hotmail.com)
Keywords
chronic mountain sickness;hypoxic ventilation;polycythemia;pulmonary hypertension
Abstract

High Altitude Medical Research Institute, Xining 810012, China (Wu TY)
Correspondence to: Prof. WU Tian-yi, High Altitude Medical Research Institute, Xining 810012, China (Tel: 86-971-6320396. Fax: 86-971-6259367. Email: wutianyiqh@hotmail.com)

In 1925, Carlos Monge Medrano described a new illness that he called ‘erythremia syndrome of high altitude’, which is now known as ‘chronic mountain sickness’ (CMS) or ‘Monge’s disease’ in his honour. His patient was a 38-year old man who was a resident of Cerro de Pasco (4330 m), Peru, and had a red cell count of 8.86 million, much higher than the average value at that altitude.[1] Polycythemia has frequently been used as a marker of CMS, so ‘high altitude polycythemia’ is a synonym of CMS. CMS is a syndrome of loss of adaptation to life at high altitude, which occurs to indigenous or long-term residents at altitude above about 3000 m. This clinical syndrome is characterized by excessive erythrocytosis and severe hypoxemia and by reversibility on descent.[2,3] CMS is found most commonly in the Andes.[1,3] In China, the first report of ‘high altitude polycythemia’ (HAPC) was by Wu[4] of 82 cases living at altitudes between 3008 m and 4888 m in Qinghai-Tibet. The clinical features of the patients were related to erythrocytosis and were similar to those of CMS or Monge’s disease reported from Peru.[1] The average haemoglobin (Hb) concen-tration and haematocrit (Hct ) values were (228 ± 14) g/L, and (76.8 ± 3.5) %, respectively. Over the next twenty-four years, more than one thousand similar cases were reported of persons who permanently resided at high altitude.[5] However, many questions about CMS developed in residents of the Qinghai-Tibetan plateau have been raised: How to diagnose CMS in China? Does CMS really exist in indigenous Tibetans? What are the epidemiological characteristics of CMS among Tibetan populations? What are the predisposing factors that put persons at risk for CMS? What is the pathogenesis of CMS in Tibet? Based on the recent achievements of high altitude medicine attained by the Chinese researchers, these and other questions are discussed in this brief review article.

CLINICAL FEATURES AND DIAGNOSTIC CRITERIA

The most frequent symptoms and signs of CMS are headache, dizziness, tinnitus, breathlessness and/or palpitations, sleep disturbance, fatigue, anorexia, mental confusion, cyanosis, and dilation of veins. The diagnostic criteria of CMS are controversial,[3] because there is disagreement about how to define ‘excessive erythrocytosis’; because diagnosis is primarily based on Hb or Hct values above the altitude normal range. In the last 10 years, an extensive haematological study was performed on the Tibetan plateau to ascertain normal values for Hb and Hct. The sample of 5000 included both genders of healthy Tibetan and Han subjects, aged from 5 to 60 years and living at three different elevations between 2260 m and 5226 m. We thus estimated the normal ranges of Hb and Hct at high altitude, and the cutoff value for CMS.[2] Based on this and other haematological surveys and clinical observations, the criteria for the diagnosis of CMS were set by the Chinese Medical Association for High Altitude Medicine in 1996 as follows:[6] (1) Victims include indigenous highlanders and the sojourners living at altitude above 3000 m, although some susceptible subjects at lower altitudes between 2500 m and 3000 m may develop CMS; (2) typical symptoms are headache, fatigue, somnolence, and mental confusion, and marked signs are cyanosis, hyperemia and prominent capillaries of the conjunctivae; (3) laboratory diagnostic indicators are: Hb > 200 g/L, Hct >65%, and arterial oxygen saturation (SaO2) <85% in both genders; (4) a moderate or marked pulmonary artery hypertension is frequently presented; (5) pulmonary disease, polycythemia vera, and other causes of secondary polycythemia are excluded; (6) on descent to low altitude or sea level, the relief of symptoms, and the Hb/or Hct values decrease over time.

In 1997, the International Society for Mountain Sickness suggested that an international diagnostic criterion of CMS should be established: thus an International CMS Consensus Working Group was formed with the aim of unifying definition and diagnostic criteria.[7] According to the further data from the Tibetan plateau, the Chinese investigators revised the above criteria and proposed a quantitative diagnostic criterion using a questionnaire scoring system as the follows:[2,7,8]

Scoring system for symptoms and signs
The ten symptoms and signs used for scoring CMS are headache, dizziness, failing memory, fatigue, breathlessness/or palpitations sleep disturbances, tinnitus, anorexia, cyanosis of lips, face or fingers, and hyperemia and prominent capillaries of conjunctivae or laryngopharynx.

Symptom and sign severity assessment
Score 0 for a negative answer. Each symptom and sign may be scored as 1, 2, 3 for mild, moderate and severe presentation, respectively.

Scoring system for blood haemoglobin concentration and arterial oxygen saturation value
Male: 180 g/L <Hb <210 g/L, score=0; Males: Hb≥210 g/L, score=3. Female: 160 g/L <Hb <190 g/L, score-0, Hb≥190 g/L, score=3. SaO2 ≤85% in both gender, score=3.

Judgment
The diagnosis and the severity of the CMS are assessed by adding up the scores as follows: No CMS, overall score <6; mild CMS, overall score=6 through 10; moderate CMS, overall score=11 through 14; severe CMS, overall score=15 or higher.

Patients with severe headache, excessive erythrocytosis (Hb ≥250 g/L), and accentuated hypoxemia (SaO2 ≤80%) with overall score ≥15 indicate severe CMS and should immediately descend to lower altitudes.The above diagnostic criteria were used extensively in field and clinic study for several years in the Tibetan region of China, and have proved very simple and precise for diagnosis of CMS. During August, 2004, the Sixth World Congress on Mountain Medicine was held in Xining, China. The International CMS Consensus Working Group considered these Chinese diagnostic criteria as an international scoring system for diagnosis of CMS.[7]

DOES ‘TRUE MONGE’S DISEASE’ REALLY
EXIST IN INDIGENOUS TIBETANS?

CMS does occur in persons who are indigenous highlanders and have been adapted successfully to life at high altitude when the other organic disease can be excluded: patients of this type would thus have ‘true Monge’s disease’[1,9] which is adaptive failure to high altitude and thus has important biological significance. CMS have been reported most commonly in Quechua and Aymara Indians living in the Andes.[1,9] However, until the early 1990s, CMS occurrence among indigenous Tibetans had not been studied and doubt had been expressed as to whether CMS did in fact exist in the Tibetan population. Some western scientists even speculated that CMS was confined to the Andes.[1,9] However, this is not the case since Wu et al[10] first noted that the condition existed in indigenous Tibetans living at altitudes exceeding 3700 m. Pei et al[11] reported 24 cases of CMS in Lhasa (3658 m) including one Tibetan woman aged 53 years. Wu et al[12] reported a series of 26 cases of CMS in indigenous Tibetans living at 3680 to 4179 m, ranging in age from 22 to 66 years with a mean age of (44.6±7.8) years. Haematological, haemodynamic, and electrocardiographic studies were performed. Data were compared with 36 healthy Tibetans living at the same altitude. In these three studies, the clinical features were similar to cases described in the Andes. Red cell concentrations were greatly increased and the mean Hb concentration was 222 g/L compared with 166 g/L in healthy controls with an average Hct of 74.7% [controls (56.6±4.8) %]. None of the patients of CMS had chronic pulmonary disease. Thus, the authors considered the indigenous Tibetan highlanders to have ‘true Monge’s disease’, and this is now accepted by western altitude scientists.[3,13] Even though an indigenous mountain population is better adapted to high altitude, the hypoxia susceptible individuals still exist in the Tibetan population.[14] Moreover, some Tibetans having lived so high and working hard for a long period of time, can still suffer from advanced severe hypoxemia and CMS.

EPIDEMIOLOGICAL STUDIES

Further epidemiological studies are required to determine the extent of CMS in Qinghai-Tibet, and to elucidate what are the risk factors and who will be at risk for developing CMS at high altitude.

Prevalence
In order to study population distribution of CMS, an epidemiological study on CMS on the Qinghai-Tibetan plateau was performed from 1984 to 1993.[15] The survey was carried out on village populations of which more than 90 % were in the sample. A total of 2314 Tibetans and 2719 Han Chinese immigrants were surveyed, all above the age of 15. They were high altitude residents at moderate (2261 to 2980 m), high (3128 to 3968 m) and very high (4006 to 5226 m) altitudes. The diagnosis was based on the criteria of Chinese Medical Association for High Altitude Medicine.[6] The overall prevalence of CMS in Tibetans was 1.21 % compared with 5.57 % in Han immigrants (P<0.01). Han who have lived continuously above 3500 m for many years are affected about five times of Tibetans. Although there is a very low prevalence of CMS in Tibetans, the condition exists in the indigenous mountain population. The prevalence in the total hospital population in Lhasa (3658 m) was 2.24%-8.7%.[11] It is interesting to note that young Han soldiers, garrisoned in the Himalayas, who lived continuously above 5300 m for a relatively short time (9-21 months), also developed the syndrome of CMS, presenting as an excessive polycythemia and severe cardiac failure.[16] Chao et al[5] found the prevalence in these young soldiers to be 30.43% at 5000 m compared with 9.33% in the Han troops in Lhasa (3658 m). Therefore, it is now clear that CMS is a common altitude disease on the Qinghai-Tibetan plateau.

Predisposing factors
Altitude
CMS is uncommon and rarely occurs below 3000 m even among longtime residents. The prevalence of CMS increases gradually as altitude increases. It was 1.05% at 2980 m, 3.75% at 3128 to 3980 m, and 11.83% at 4006 to 5226 m in Han immigrants.[15]

Gender
CMS occurs largely in men. In Madou at 4300 m, the prevalence of CMS in Han women is 1.76% as compared with 7.77% in Han men. The prevalence in Tibetan women and men is 0.56% and 1.78% respectively. Men are affected four times of women.[15] Several factors may be responsible for this sex difference. In pre-menopausal women menstrual blood as a ‘natural phlebotomy’ may prevent marked erythrocytosis. It is also possible that the female sex hormones exert a stimulating effect on ventilation.[13]

Age
Studies in Peru have suggested that age is a major contributing factor for CMS, because an age-dependent polycythemia is based on an age-dependent loss of ventilation and arterial hypoxemia. Most patients of CMS are of moderate or old age.[17] However, the physiological studies in Tibet[18] which indicated that the lack of correlation between resting ventilation, Hct and age in indigenous Tibetans, also showed that there was no relation between age and CMS scores. These results lead the authors to conclude that age probably is not a significant predisposing factor to CMS in Tibetans and this might be an important difference between indigenous Andeans and Tibetans.[15,18]

Ethnicity
CMS is more common in immigrant Han than indigenous Tibetans. In comparison with the Tibetans and Andeans, Wu et al[12] using the same diagnostic criteria as Monge et al[19] that defined CMS as Hb>213 g/L, SaO2 <83%, and at the comparable altitude (Madou, 4300 m), revealed a much lower prevalence of 0.91% in the Tibetans than that of 15.6% found in Peruvian Quechuas at Cerro de Pasco (4300 m) (P<0.001).[19] Recently, important genetic differences between the ethnic groups has been found. Moore,[13] using all sources available pertaining to the duration of high altitude residence, estimated that Tibetans are likely to be the longest residing group (25000 to 50000 years), followed by Andeans (10000 years), then Europeans (200 years) and lastly Han (50 years). Indigenous Tibetans appeared to be less at risk of CMS than indigenous Andeans.[8-13] Also, as noted above, that the longest residing group (Tibetans) have the lowest prevalence of CMS whereas the shortest prevalence group (Han) have the highest prevalence.[15] This evidence suggests a strong association between ethnicity and CMS, and will undoubtedly lead to important findings about possible genetic differences in CMS.

Length of residence
CMS usually requires years of residence at high altitude to develop. A healthy Han person can develop CMS during his continuously living at altitudes for 15 to 20 years, whereas a Tibetan, the period necessary is more than 35 to 40 years.[15] As reported above, the young Han soldiers can develop CMS in a very few years above 5000 m and even within one year at 5300 m. It suggests that Han immigrants to Tibet may develop CMS within a shorter duration of residence than the indigenous Tibetan. Thus, altitude of residence, gender and ethnic background are some of the factors that are likely to influence the speed with which CMS developed.[13,15,20]

Geographic factors
Some authors suggested that the ‘geographical differences between the Andes and the Himalayas (including Tibet) could be important in the apparent difference in the incidence of CMS’, one might infer that permanent settlements can be established at lower altitude on the Tibetan side of the Himalayas than those in the Andes, the lower incidence of CMS in Tibetans is due to ‘mountain high, living low’.[1,9] Wu[20] summarized some of the features of the highest and largest Plateau in the world (Qinghai-Tibetan), with an area of over 2.5 million square kilometres. In 1990, it was estimated that over 4.5 million Tibetans live on the plateau and about 600000 reside at an altitude exceeding 4500 m. Wu argues that Tibetans live as high as Andeans in South America, therefore the apparently low incidence of CMS in Tibetans cannot be ascribed to “geographic differences”, but presumably to a genetic adaptation.

Smoking
There is also an association between the development of CMS and the smoking of cigarettes in Han men where the prevalence of CMS is three times higher in smokers than in non-smokers.[11] The mechanism of the association is unknown, but it could be through the agency of the production of accentuated hypoxemia, centrilobular emphysema and thus reducing alveolar ventilation.[9] Occupation
An interesting fact is the relation between CMS prevalence and occupational groups. Professionals, including cadres, teachers, and officers have a prevalence two to three times that of farmers and herders within each ethnic group and gender.[21] It is suggested that the high altitude residents will be at higher risk if the regions become more urbanized and industrialized.[1,10]

PATHOPHYSIOLOGICAL STUDIES

Polycythemia
In polycythemia the red cell count, Hb concentration and Hct values are markedly increased, and Hb values as high as 280 g/L and Hct up to 82% have been recorded.[4,10] Bone marrow examinations in 52 CMS patients showed an extreme hyperplasia of the erythroid cells but not of the leukocyte and platelet precursors.[4] Haematological examinations in altitude populations show that indigenous Tibetans have a lower Hb concentration than Han immigrants.[2]

Ventilation and hypoxic ventilatory response (HVR)
Fourteen Han male CMS patients were examined for ventilatory function in Xigaze (3890 m),[22] and 20 male healthy Han sojourners and 12 male healthy Tibetans were selected as control subjects. The results showed that CMS patients had the lower minute ventilation, tidal volume, alveolar ventilation, arterial pH, SaO2 and carbon monoxide diffusing capacity of the lung (DLco) values, and had higher respiratory frequency and PaCO2 values. These results suggested that the patients with CMS have impaired ventilation and gas-exchange compared to healthy sojourners and, by implication to healthy Tibetans. Sun et al[23] in Lhasa (3658 m) showed that patients with CMS compared with control subjects exhibited hypoventilation, lower tidal volume, blunted HVR, and a depressant effect of ambient hypoxia on ventilation. Naloxone infusion (0.14 mg/kg) to six patients with CMS did not change resting tidal volume, end tidal carbon dioxide pressure, HVR, or SaO2, although endogenous opioids were not implicated. Hence, the basis of CMS appears to be alveolar hypoventilation, blunted peripheral HVR and central hypoxic ventilatory depression.

Pulmonary haemodynamics
Selected data from the cardiac catheterizations suggested that the pulmonary artery pressure (PAP) in CMS patients is slightly or moderately higher than healthy high altitude residents from the same altitude. Pei et al[11] found a mean PAP of (5.3±1.5) kPa [(39.6±11.1) mmHg] in five cases of CMS in Lhasa (3658 m). Yang et al[24] reported six Han male patients with CMS at the local county hospital of Chengdu (3950 m), four of six had pulmonary hypertension with a mean PAP of 4.1 kPa (30.8 mmHg). Wu et al[25] found only 5 of 18 (27.8%) patients with CMS presented pulmonary hypertension, one patient revealed a marked pulmonary hypertension [10.0/4.8 (6.4) kPa, 75/36 (48) mmHg], the remain four had a mild pulmonary hypertension. These patients, who developed CMS at 3719 m to 4280 m but were catheterized at 2261 m, indicated that hypoxic vasoconstriction is an important cause, since the PAP is rapidly lowered by descent. However, because oxygen inhalation does not lower the PAP to normal levels, an anatomic increase in pulmonary artery resistance is probably also present.[9,11] The healthy young Tibetan men living in Lhasa (3658 m) presented an unusually small degree of hypoxic pulmonary vasoconstriction compared with other high altitude residents.[26] In addition, Tibetans have a thin-walled small pulmonary arteries,[9,14]and this may be one of the reasons why Tibetans are protected against CMS.

Sleep studies
To investigate the quality of sleep and sleep-related breathing disorders in patients with CMS, Zhang et al[27] performed full polysomnography in 15 Han subjects with HAPC [mean age was (44±6) years with a mean Hb of (232±24)g/L] living in Kuolok at an altitude of 3730 m. Eight healthy Han male volunteers [mean age (38.6±7) years] from the same altitude were controls. Compared with the controls, the number of arousals/awakenings increased and the total sleep time was decreased in HAPC group (P<0.001). Five patients presented periodic breathing and sleep apnea, periodic breathing aggravated arterial oxygen saturation, mean minimum SaO2 was (65±10)% and (78±9)% in HAPC and controls respectively. Desaturation in the polycythemic subjects was more pronounced than in the controls (P<0.01). Subsequently, the authors[28] selected 8 from the above 15 polycythemic subjects evacuated them to Suzhou (15 m). After staying at sea level for two weeks, their mean Hb concentration decreased to (163±14)g/L. Another sleep study revealed an improvement of sleep quality, an increase in total sleep time and sleep efficiency index, a decrease in total arousal’s time and the frequency of periodic breathing as compared with the same subjects at high altitude. Sun et al[29] found that CMS patients had more disordered breathing and lower mean SaO2 values when asleep than a group without CMS. Our own data show that Tibetans have a better sleep quantity, higher sleep ventilation and less sleep hypoxemia than Han immigrants at a simulated altitude of 5000 m.[30,31]This may be one of the important factors giving Tibetans relative immunity against CMS.

Erythropoietin (EPO) and 2,3- diphosphogly-ceric acid (2,3-DPG)
Although plasma immunoreactive EPO in polycythemic subjects was higher than in healthy controls both in the Han and the Tibetans, 59% of the polycythemics had values within the 95% confidence limits of normal plasma EPO values.[32] In six patients with high altitude excessive polycythemia, only one’s serum EPO was increased significantly, EPO was maintained a steady normal level in latter stage of CMS.[33] These results are consistent with the observations in patients with HAPC in Peru.[34] Perhaps, during the chronic exposure to altitude hypoxia, the expression of EPO is not at the plasma level, but may be at the receptors of the bone marrow. One glycolytic intermediate in the red cell that binds to Hb to decrease its O2 affinity is 2,3-DPG. Ge et al,[35] using ultraviolet spectrophotometry to measure the 2,3-DPG in both whole blood and erythrocytes (18 Han newcomers, 24 healthy Tibetans and 21 subjects with CMS) at an altitude of 4300 m, showed that red cell 2,3-DPG was 19% higher in the polycythemic patients than in the healthy Tibetans and Han. It was argued that a moderate increase in 2,3-DPG was an important feature of the acclimatization process of lowlanders and of the adaptation to high altitude by the highlanders. However, an extremely increased 2,3-DPG appears to be related with significantly decreased O2 affinity and accentuated hypoxemia.

Free radical metabolism
The altitude-hypoxia influences the free radical metabolism: erythrocyte superoxide dismutase (RBC-SOD) decreased with increasing altitude whereas the plasma content of malondialdehyde increased when the altitude gradually increases.[36] However, as compared with Han at 4300 m, Tibetans presented a higher level of RBC-SOD, a higher level of glutathione peroxidase and a lower plasma malondialdehyde, thus suggesting that the metabolism of free radical in indigenous Tibetans is more stable.[37] Lipid superoxidation in patients with HAPC was increased significantly with increased altitudes, and the activity of RBC-SOD in the HAPC group was significantly lower than that of the healthy controls from the same altitude, which may be an important cause of decreasing erythrocyte deformability.[38]

PREVENTION AND TREATMENT

Descent to low altitude without return is a sure preventive but not an ideal option, because many patients want to remain at altitude for family or economic reasons, especially amongst the indigenous people. In these cases, phlebotomy can be done alone or with volume replacement-the latter being the better choice because the improvement of symptoms is long-lasting.[7] However, occasionally we have been observed that there was a rebound effect several days or weeks after venesection when the Hb concentration rose significantly. Oxygen supplementation improved blood oxygenation and reduced blood EPO. Medroxyprogesterone acetate increased ventilation and PaO2 and reduced PaCO2 with a parallel drop in Hct and improved many of the symptoms, but sometimes in male patients loss of libido has been reported. Chinese or Tibetan herbs promise good preventive and treatment effects for CMS. Honjingtian (Rhodiola Eoccinea) may help sleep at high altitude and thus increase oxygenation at night since hypoxemia may be much greater then.[39] Other Tibetan herbs, such as Dracocephalum Tanguticum Maxim and the total sapnins Panax ginseng also procuded some effects.

CONCLUSION

The report of CMS from the Qinghai-Tibetan plateau indicates the condition to be prevalent in Han immigrants but rare in indigenous Tibetans, suggesting that people of Tibetan ancestry are better adapted whereas the people of Han ancestry form a population relatively susceptible to CMS. Recently, a quantitative diagnostic criterion using a questionnaire scoring system proposed by Chinese investigators has been accepted by the International Society for Mountain Medicine and recommend as international diagnostic criteria for CMS. The pathogenetic studies suggest that there are some differences between the Andean Indians and the Han populations. For example, there is a high frequency of pulmonary hypertension among Han CMS patients in Tibet, possibly because the Han newcomers are more susceptible to hypoxic pulmonary constructive response. In addition, Hb concentration increase with age is not pronounced in indigenous Tibetans. This may be related to Tibetans at altitude having a brisk HVR, higher ventilation and greater arterial oxygenation whereas the Andeans presented a blunted HVR, lower ventilation and a lower saturation. It has been suggested that these differences reflect different genetic adaptation to high altitude.[13,14,18,40] Finally, as a result of great development in this western region of China, a large number of lowlanders have migrated to the highlands, no doubt CMS will increase in prevalence. The total high altitude populations living on the Qinghai-Tibetan plateau is around 10-12 million, have, by a rough estimate that CMS occurs in approximately 4% of the high altitude inhabitants, some 250 000 persons with CMS.[40] This review article identifies CMS as a serious health problem for high altitude populations in Qinghai-Tibet to which more attention should be paid and much further investigations are required.

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