Pathology of chronic mountain sickness · due to chronic mountain sickness. Reategui-L6pez (1969) reported 30 cases of chronic mountain sickness studied at Cuzco (3,339 m) over a

Thorax (1973), 28, 701.

Pathology of chronic mountain sicknessJAVIER ARIAS-STELLA, HEVER KRUGER, and

SIXTO RECAVARREN

Institute for High Altitude Investigations, Universidad Peruana 'Cayetano Heredia', Lima, Peru

Arias-Stella, J., Kriiger, H., and Recavarren, S. (1973). Thorax, 28, 701-708. Pathology ofchronic mountain sickness. Pathological data on chronic mountain sickness are scarce dueto the fact that the disease is ameliorated or cured by descent to a low altitude. In this reportwe describe a case of chronic mountain sickness occurring in a woman of 48 years at Cerrode Pasco (4,300 m above sea level). The necropsy findings are compared with the limitedpathological observations reported by others. It is apparent from our findings that in fatalcases the main changes are located within the pulmonary circulation. So far histologicalstudies have been reported only in cases of the secondary form of chronic mountain sickness.The basic pathology of the primary form (Monge's disease) remains to be defined.

The terms chronic mountain sickness, chronicsoroche, high altitude disease, or Monge's diseasehave been used to define the condition of loss ofnatural or acquired acclimatization occurring inpeople living at high altitude (Monge and Monge,1966). These terms have been applied to personsnative to high altitude and to emigrants from sealevel. The disease is characterized by an accentua-tion of changes associated with hypoxaemia, suchas increased oxygen arterial unsaturation, poly-cythaemia, and pulmonary arterial hypertension.Clinical features include cyanosis, headache,insomnia, and paraesthesiae. The signs andsymptoms are progressive and eventually lead tochronic cor pulmonale and cardiac insufficiency.Hypoventilation due to a diminished response tothe stimulus of carbon dioxide and/or hypox-aemia has been suggested as the basic pathogenicmechanism (Hurtado, 1966; Severinghaus, Bain-ton, and Carcelen, 1966). While the disease isrelatively frequent above 3,500 m and is easilyrecognized on clinical grounds, a clear definitionof its pathological nature is still lacking becausethe disease is ameliorated or cured by descent tosea level.

TYPES OF CHRONIC MOUNTAIN SICKNESSIt is evident from published reports (Arias-Stella,1971) that the term 'chronic mountain sickness'is used to describe any disease which presentswith some of the signs and symptoms listed above

Requests for reprints: Professor J. Arias-Stella, Institute for HighAltitude Investigations, Universidad Peruana, 'Cayetano Heredia'.Lima, Peru

in a person living at high altitude. We proposeto distinguish three clinicopathological types ofchronic mountain sickness:TYPE 1 This occurs in subjects who, for profes-sional or other reasons, move from sea level tolive at high altitude and never adapt to thischange. Detailed reports on these cases are lack-ing. Monge (1943) specifically mentioned themwithout giving details of individual cases. Morerecently, isolated examples have been reported(Figallo, 1971; Sobrevilla, 1971). However, asimilar condition known as 'brisket disease' hasbeen described in detail by Glover and Newson(1915 and 1918) and by Hecht et al. (1962) incattle grazing at high altitude in the region ofSalt Lake City. The basic pathogenic mechanismin this type of chronic mountain sickness is afailure of homeostatic adjustment to the atmo-sphere at high altitude. Since Monge (1943) usedthe terms acute, subacute, and chronic sorochefor the illness which may occur during adaptationto high altitude, we propose that type I chronicmountain sickness be designated 'chronic soroche'.TYPE II This form of the disease is seen amongpeople from sea level who have already adaptedand have been living in good health at high alti-tudes, or among natives of the Andes in whomorganic disease exaggerates the hypoxaemic state.This may occur in patients with obesity, kypho-scoliosis, and neuromuscular disorders affectingthe thoracic cage, or any other condition thatinfluences pulmonary function such as emphy-sema, tuberculosis, and pneumoconiosis. Monge

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Pathology of chronic nmountain sickness

recognized such cases as secondary chronic moun-tain sickness (Monge and Monge, 1966), and so

we propose that this type be designated 'Monge'ssyndrome'.

TYPE III This type is seen in people who are

native to or in those who have adapted to lifeat high altitude and who later develop the featuresof chronic mountain sickness although no organicdisease is found to explain their increased hypox-aemia. These cases have been well documented(Monge, 1928; Hurtado, 1942; Pefialoza and Sime,1971) and have been attributed to a decreased sensi-tivity of the respiratory centre to carbon dioxideand/ or of the chemoreceptors to hypoxaemia.This leads to hypoventilation and thus to increas-ing systemic arterial unsaturation. We believe thatthe designation 'Monge's disease' should be re-served for this type of chronic mountain sickness.A 'primary' form of hypoventilation syndrome

has been described at sea level (Rodman andClose, 1959; Richter, West, and Fishman, 1957).In this syndrome there is no obesity nor anyunderlying pulmonary, cardiovascular, or neuro-muscular cause for the hypoventilation. There isa diminished ventilatory response to hypoxaemiaand hypercapnia so that polycythaemia andcyanosis develop. It seems likely that the primaryhypoventilation syndrome is the condition corre-

sponding to Monge's disease at sea level. At sea

level the primary hypoventilation syndrome israre whereas in the Andes Monge's disease isrelatively common. The reason for this may bethat persistent systemic arterial unsaturation athigh altitude can lead to permanent desensitiza-tion of the chemosensitive respiratory mechanism.In this respect it is interesting that Sorensen andSeveringhaus (1968) found that chronic hypoxiaduring the first two years of life desensitizesirreversibly the reflex response to acute hypoxia

mediated by peripheral chemoreceptors. On theother hand, we have found that the carotid bodiesare larger and heavier at high altitude (Arias-Stella, 1969).

PATHOLOGICAL STUDIES IN FATAL CHRONIC

MOUNTAIN SICKNESSWe have been able to find only two referencesto histopathological observations in fatal cases ofchronic mountain sickness. In 1961 Fernan-Zegarra and Lazo-Taboada reported the case ofa man of 35 years, a native of Caylloma (4,320 m),who had been admitted to hospital in Arequipaseveral times since 1954. He complained of pro-

gressive dyspnoea, oedema, and cyanosis, whichwere considered characteristic of Monge's disease.An electrocardiogram showed right ventricularpreponderance. His last admission to hospital was

on 11 August, 1958. He died 45 days after admis-sion with the clinical picture of cardiac failure.His haemoglobin level was 25 5 g/100 ml. Atnecropsy he was found to have scoliosis, hyper-trophy of the right and left ventricles, dilatationand atheroma of the pulmonary trunk, and markedcongestion of the liver and brain. Note is madeof 'thickening of the pulmonary arterioles due tofibrosis and moderate muscular hypertrophy'. Thefinal diagnosis reached was cardiac insufficiencydue to chronic mountain sickness.

Reategui-L6pez (1969) reported 30 cases ofchronic mountain sickness studied at Cuzco(3,339 m) over a period of nine years. It is ofinterest to note that half of these patients were

frankly obese. Five cases proved to be fatal, buta necropsy was carried out in only two. Such briefcomments on the findings as were given are sum-

marized in the Table.We have had the opportunity to study a third

case of chronic mountain sickness in which a

complete necropsy was carried out. A woman of

TABLEMAIN PATHOLOGICAL FEATURES IN REPORTED CASES OF FATAL CHRONIC MOUNTAIN SICKNESS

Author Heart Lungs Observation Cause of Death

Fernan-Zegarra and R. and L. ventricular Peripheral pulmonary Right Severe cardiacLazo-Taboada (1961) hypertrophy arterial intimal and medial lordoscoliosis insufficiency

Heart 750 g thickeningReitegui-Lopez (1969) (1) R. ventricular Peripheral pulmonary Obesity Cardiac insufficiency

hypertrophy arterial thickening(2) R. ventricular Peripheral pulmonary Obesity Cardiac insufficiency

hypertrophy arterial thickeningsemphysema

Arias-Stella, Kruger, and R. ventricular hypertrophy Peripheral pulmonary Dorsal Cardiac insufficiency dueRecavarren (1971) Heart 370 g arterial intimal and medial kyphoscolio- to chronic cor

thickening; fresh and sis pulrronaleorganized pulmonaryarterial thrombi; chronicbronchiolitis

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48 years, who was born and had lived all her lifein Cerro de Pasco (4,375 m), complained that forthree years before admission to hospital she hadbeen breathless, first on effort and finally at rest.She was unable to sleep in an upright position.During the last weeks before admission shedeveloped pitting oedema of the lower limbs. Shehad a productive cough with haemoptysis. Clini-cal examination revealed pitting oedema of theankles, cyanosis of the hands and face, and crepi-tation at the lung bases. Her systemic blood pres-sure was 110/70 mmHg.There were 7-5 million red cells/mm3, 6,600

white cells/mm3, and the differential count wasas follows: neutrophils 87%, eosinophils 1 %,lymphocytes 12%. Haemoglobin 21 6 g%. ESR2 mm per hour (Wintrobe). The urine containedred cells and traces of albumin.The following was the opinion of Monge (1967),

who first described chronic mountain sickness, onthe clinical history of this case: 'Evidently thisis a case of chronic mountain sickness, primarybecause of loss of acclimatization or secondarydue to other causes. I have seen similar cases buthave not dared to report them because of in-sufficient clinical data. I remember one patientwho developed extreme anasarca and eliminatedher oedema simply by coming down to the coast.'The patient died 13 days after admission. At

necropsy she weighed 47 kg and was 1-30 m inheight. She had generalized oedema and a deepbluish tint to the mucosae and limbs. There was

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FIG. 1. Right ventricular weight as a percentage of totalventricular weight in individuals at sea level and at highaltitude, in comparison with the case of chronic mountainsickness (high altitude: Cerro de Pasco 4,375 m): 0 highaltitude; * sea level; chronic mountain sickness.

pronounced dorsal kyphoscoliosis which deformedthe thoracic cage so that the anteroposteriordiameter was greater than the transverse. Theheart weighed 320 g. There was hypertrophy anddilatation of the right ventricle and dilatation ofthe right atrium. The Hermann and Wilson indexwas below 1-0, confirming a severe degree of rightventricular hypertrophy. Figure 1 expresses theright ventricular weight as a percentage of totalventricular weight, in comparison with the valuesfound in normal cases at sea level and at highaltitude (Recavarren and Arias-Stella, 1964).There was severe atheroma in the pulmonarytrunk and its main branches. The lungs were con-gested, the right weighing 360 g and the left 270 g.There were bilateral pleural effusions of a trans-parent yellow fluid, while the peritoneal cavityheld 6 litres of a similar fluid. The liver, kidneys,and brain were congested. The lungs were fixedby perfusion of the bronchial tree with 10%formalin followed by immersion of the lungs inthis fixative for seven days. The pulmonaryarteries were then studied morphometrically (Arias-Stella and Saldania, 1963).

Histological study of the lungs showed con-gested but otherwise unaffected alveoli (Fig. 2)and an intense muscularization of the peripheralportions of the pulmonary arterial tree (Fig. 3).There was some intimal fibrosis in small andmedium sized pulmonary arterial branches (Fig.4). Fresh and partially organized thrombi werefound in the large, medium, and small pulmonaryarteries (Figs. 5 and 6).

In Fig. 7 the distribution of the areas of peri-pheral arterial muscle by age and altitude is shownin comparison with the results in this case.There was chronic bronchitis mainly affecting

airways lined by tall columnar epithelium but notthose lined by low cuboidal epithelium or respi-ratory bronchioles; it was characterized by acellular infiltration of the bronchial wall. In onesection of the right middle lobe there was slightcentrilobular emphysema with some fibrousthickening of the alveolar walls. In the rightlower lobe there was oedema and haemorrhageinto the alveoli. There was pronounced congestionof the viscera. A nodular goitre was found, andin the adrenals there were nodular foci of glome-rular cells. A routine histological examination ofthe brain showed no obvious pathological features,It was considered that this was a case of cardiacinsufficiency secondary to chronic cor pulmonale.The degree of right ventricular hypertrophy andmuscularization of the peripheral pulmonaryarterial branches considerably exceeded the valuesnormally found at high altitudes.

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Pathology of chronic mountain sickness

FIG. 2. Panoramic view of the lung parenchyma. Focal septal congestioncan be seen. The alveolar walls are normally thin. (H and E x 80).

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FIG. 3. Pulmonary arterial branch at the level of the alveolar ducts.The vessel shows well-defined double elastic laminae. Structurally, thisis an artery and not an arteriole as normally seen in this position in theadult. (van Gieson Weigert x 250)

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FIG. 4. Fibrotic intimal thickening in small pulmonary arterial branch.(H and E x 500)

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fiG. 5. Pulmonary arterial muscular branch, of medium size, showingalmost complete occlusion by partially organized thrombus. (H and Ex 300)

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FIG. 6. Smallpulmonary arterial branch with fresh thrombus. (H andEx 350)

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FIG. 7, Area ofpulmonary arterial muscle at distal level,by age and altitude, in comparison with the case ofchronic mountain sickness. 0 high altitude; 0 sea level;a chronic mountain sickness; A high altitude new born(average of 7 cases); A sea level new born (average of8 cases) (high altitude: Cerro de Pasco 4,375 m).

DISCUSSION

In the Table the main pathological features inreported cases of fatal chronic high altitude dis-ease are summarized. It is clear that all the fatalcases reported so far are what we term Monge'ssyndrome or type II chronic mountain sickness.In two of the cases some form of scoliosis waspresent. The first problem to solve is whether thepulmonary histopathological findings correspondto those reported in kyphoscoliosis.

Studies of the lungs in kyphoscoliosis have showna variety of changes: emphysema, pneumonia,bronchitis, atelectasis or bronchiolectasis (Chap-man, Dill, and Graybiel, 1939; Fisher and Dole-hide, 1954; Reid, 1966). The changes are unevenlydistributed throughout the lung parenchyma andthere is no consistent nor characteristic lesion.The frequency of right ventricular hypertrophyhas been variously attributed to collapse, conges-tion, the small size of the pulmonary vascularbed, arterial medial hypertrophy, hypoxaemia,

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atrophy, and hypoplasia (Davies and Reid, 1971).Those who have studied the pulmonary arterialvessels in kyphoscoliosis have reported no abnor-mality at all (Fisher and Dolehide, 1954), 'hypo-plasia of the pulmonary arterial bed' (Reid, 1966),or minor to moderate degrees of muscularizationof the pulmonary arteries (Bergofsky, Turino, andFishman, 1959; Naeye, 1961). Whether theincrease in pulmonary vascular resistance leadingto cor pulmonale is due to mechanical circulatorydisturbance secondary to the chest deformity orto hypoxaemia, the fact is that those cases ofkyphoscoliosis with signs of right ventricular over-load usually show some degree of musculariza-tion in the pulmonary arterial branches (Daviesand Reid, 1971). Hasleton, Heath, and Brewer(1968) have described the morphological patternof pulmonary arterial changes associated withchronic hypoxia, including kyphoscoliosis, as fol-lows: '(1) Muscularization of the pulmonaryarterioles, which normally have a wall consist-ing of a single elastic lamina; (2) absence ofhypertrophy of the muscular pulmonary arteries;and (3) the development of intimal longitudinalmuscle in muscular pulmonary arteries and inarterioles.'The case of chronic mountain sickness that we

have studied showed no major structural distor-tion of the lungs, but there was a degree ofmuscularization of the peripheral pulmonaryarterial branches which exceeded that expectedfor the altitude. There was also intimal thicken-ing in small and medium sized pulmonary arterialbranches with fresh and partially organizedthrombi, and these changes are not usually foundin kyphoscoliosis at sea level. We therefore con-clude that, in the present case, the respiratoryeffects of the kyphoscoliosis were aggravated bythe hypoxic environment and that this producedthe clinical picture of chronic mountain sicknesswith severer vascular changes than those seen atsea level. Chronic bronchiolitis may also havecontributed to the hypoxaemic state. Obesity isanother condition known to lead to chronic corpulmonale as in the series reported by Reategui-L6pez (1969).The fatal cases of chronic mountain sickness

reported by Fernan-Zegarra and Lazo-Taboada(1961), by Reategui-Lopez (1969), and by thepresent authors indicate that the clinical picture ofchronic mountain sickness may develop when con-ditions known to affect the physiology of respira-tion occur at high altitudes.

It is not surprising, therefore, that Heath (1971)has questioned the existence of Monge's disease

as a primary pathological entity. He claims thatit is necessary to demonstrate the pathology ofMonge's disease before it can be accepted as adistinct condition. He suggests that some casesmay represent unrecognized centrilobularemphysema in persons living at high altitude.Hurtado (1971) has argued against this viewpointon the grounds that a similar argument could beapplied to deny the existence of certain mentaldiseases.Owing to the shape of the haemoglobin oxygen

dissociation curve, oxygen exchange in the lungstakes place, at high altitudes, on the descendingpart of the curve so that even a small decrementof Po2 produces a significant reduction in arterialoxygen saturation. Thus a moderate impairmentof ventilation at high altitude could reduce thealready low arterial oxygen saturation to intoler-able levels. On this basis it is easy to understandwhy even a minimal respiratory disorder caninduce severe hypoxaemia at high altitude. Afurther complication is that sustained hypoxaemiacan temporarily or permanently diminish thesensitivity of the chemoreceptors and/or therespiratory centre (Severinghaus et al., 1966;Sorensen and Severinghaus, 1968) and thus avicious circle is established, leading to progressivehypoventilation.The fact remains that up to the present there

are no detailed reports on the pathology of pri-mary chronic mountain sickness. Only when suchdata become available will the controversy aboutthe existence of a distinct pathological entity,Monge's disease, be resolved.

REFERENCESArias-Stella, J. (1969). The human carotid body at high

altitudes. American Journal of Pathology, 55, 82a(abstract).(1971). Chronic mountain sickness: pathology and

definition. In high altitude physiology: cardiac andrespiratory aspects: A Ciba Foundation Symposium,edited by Ruth Porter and Julie Knight, p. 31. ChurchillLivingstone, Edinburgh and London.

- and Saldafna, M. (1963). Terminal portion of thepulmonary arterial tree in people native to high altitudes.Circulation, 28, 915.

Bergofsky, E. H., Turino, G. M., and Fishman, A. P. (1959).Cardiorespiratory failure in kyphoscoliosis. Medicine,38, 263.

Chapman, E. M., Dill, D. B., and Graybiel, A. (1939).Decrease in functional capacity of the lungs and heartresulting from deformities of the chest; pulmonocardiacfailure. Medicine, 18,167.

Davies, G. and Reid, L. (1971). Effect of scoliosis on growthof alveoli and pulmonary arteries and on right ventricle,Archives of Diseases in Childhood, 46, 623.

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Fernan-Zegarra, L., and Lazo-Toboada, F. (1961). Mal demontafna cr6nico. Consideraciones anatomopatol6gicasy referencias clinicas de un caso. Revista Peruana dePatologia, 6, 49.

Figallo, M. A. (1971). Personal communication.Fisher, J. W. and Dolehide, R. A. (1954). Fatal cardiac

failure in persons with thoracic deformities. Archives ofInternal Medicine, 93, 687.

Glover, H. and Newson, I. E. (1915). Brisket disease(dropsy of high altitudes). The Agricultural ExperimentStation of the Colorado Agricultural College Bulletin,204.

(1918). Further studies on brisket disease.Journal ofAgricultural Research, 15, 409.

Hasleton, P. S., Heath, D., and Brewer, D. B. (1968).Hypertensive pulmonary vascular disease in states ofchronic hypoxia. Journal of Pathology and Bacteriology,95,431.

Heath, D. (1971). In: Discussion-Cor Pulmonale in chronicmountain sickness: present concept of Monge's diseasein High Altitude Physiology: Cardiac and RespiratoryAspects. A Ciba Foundation Symposium, edited by RuthPorter and Julie Knight, p. 52. Churchill Livingstone,Edinburgh and London.

Hecht, H. H., Kuida, H., Lange, R. L., Thorne, J. L., andBrown, A. M. (1962). Brisket disease. II. Clinicalfeatures and hemodynamic observations in altitude-dependent right heart failure of cattle. American Journalof Medicine, 32, 171.

Hurtado, A. (1942). Chronic mountain sickness. Journal ofthe American Medical Association, 120, 1278., (1966). Aclimataci6n a la altura. Conferencias EduardoBraun Menendez. Companlia Impresora Argentina S.A.,Buenos Aires.(1971). In: Discussion-Cor Pulmonale in chronic

mountain sickness: present concept of Monge's diseasein High Altitude Physiology: Cardiac and RespiratoryAspects. A Ciba Foundation Symposium, edited by RuthPorter and Julie Knight, p. 52. Churchill Livingstone,Edinburgh and London.

Monge, M., C. (1928). La enfermedad de los Andes, sindromeseritremicos. Anales de la Facultad de Medicina de Limia,11, 314.(1943). Chronic mountain sickness. PhysiologicalReviews, 23, 166.(1967). Personal communication.and Monge, C., C. (1966). In: High Altitude Diseases.Mechanism and Management. Thomas, Springfield,Illinois.

Naeye, R. L. (1961). Kyphoscoliosis and cor pulmonale: astudy of the pulmonary vascular bed. American JournalofPathology, 38, 561.

Pefialoza, D. and Sime, F. (1971). Chronic cor pulmonaledue to loss of altitude acclimatization (chronic mountainsickness). American Journal ofMedicine, 50, 728.

Reategui-L6pez, L .(1969). Soroche cr6nico. Observacionesrealizadas en el Cuzco en 30 casos. Revista Peruana deCardiologia, 15,45.

Recavarren, S. and Arias-Stella, J. (1964). Right ventricularhypertrophy in people born and living at high altitudes.British Heart Journal, 26, 806.

Reid, L. (1966). Autopsy studies of the lungs in kyphosco-liosis. In: Proceedings of a Symposium on Scoliosis,edited by P. A. Zorab, pp. 71-78. National Fund forResearch into Poliomylitis and other Crippling Disease,London.

Richter, T. West, J. R., and Fishman, A. P. (1957). Thesyndrome of alveolar hypoventilation and diminishedsensitivity of the respiratory center. New EnglandJournal ofMedicine, 256, 1165.

Rodman T. and Close, H. P. (1959). The primary hypo-ventilation syndrome. American Journal of Medicine,26, 808.

Severinghaus, J. W., Bainton, C. R., and Carcelen, A. (1966).Respiratory insensitivity to hypoxia in chronicallyhypoxic man. Respiration Physiology, 1, 308.

Sobrevilla, L. (1971). Personal communication.Sorensen, S. C. and Severinghaus, J. W. (1968). Irreversible

respiratory insensitivity to acute hypoxia in man bornat high altitude. Journal of Applied Physiology, 25, 217.

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Pathology of chronic mountain sickness · due to chronic mountain sickness. Reategui-L6pez (1969) reported 30 cases of chronic mountain sickness studied at Cuzco (3,339 m) over a