Zubieta-Castillo, G., Zubieta-Calleja, G., Arano, E. and Zubieta-Calleja L
High Altitude Pathology Institute (IPPA) - P.O.Box 2852 LA PAZ, BOLIVIA
E-mail:zubieta@altitudeclinic.com
http://www.altitudeclinic.com

As published in "PROGRESS IN MOUNTAIN MEDICINE AND HIGH ALTITUDE PHYSIOLOGY", May 20th-24th 1998. Matsumoto, Japan.
HidekiOhno, Toshio Kobayashi, shigeru Masuyama & Michiro Nakashima (Editors)

ABSTRACT. Aging is a common cause for the appearance of different diseases, such as presbyopia, diabetes, gout, obesity, and nephrosclerosis which are more frequent in men. Likewise aging also increases women’s chances of osteoporosis, breast cancer and rheumatism. However, aging per se, as in all kinds of disease, is not the cause of Chronic Mountain Sicknes CMS. Respiratory and ventilatory deficiencies in hypoxia, cause lower oxygen saturation. Increased polycythemia is a necessary compensatory mechanism that elevates the oxygen content, even though there is cyanosis, pulmonary hypertension, low saturation and increased blood viscosity.

The incidence of CMS (hematocrit above 55%) was 28% of 653 male patients, 11% of 1042 female patients at a hospital in La Paz (3510 m) and 52% of 429 male patients, 26% of 1070 female patients at a hospital in El Alto (4100m). More men suffer from respiratory diseases and respiratory illness with chronic mountain sickness (CMS) than women and the severity is in relation to age, magnitude of the pulmonary lesions and altitude. A moderate increased polycythemia will be more severe at higher altitude, increasing exponentially as barometric pressure decreases.

KEY WORDS: CMS, hypoxia, gender, adaptation, altitude

The experienced observer can make the diagnosis of Chronic Mountain Sickness (CMS) in several active people , walking through the streets of the bowl-shaped city of La Paz (3100-4100 m) and its neighboring city of El Alto "the high plateau" (4100 m). This shows that CMS patients (with increased hematocrit above the normal levels for each specific altitude) are actually carrying on with their regular lives and are not completely incapacitated at high altitude. They arrive to consultation either because routine blood tests show increased hematocrit; they have hypoxic symptoms and signs; they do not feel well or a physician told them that they are ill due to an increased hematocrit. In other words, some may never make a consultation and carry on with their lives.

These patients, with very increased polycythemia, have a limited cardio-pulmonary function and this becomes apparent by extensive cardio-pulmonary testing as described before [1]. All their organic systems are adapted to severe hypoxia, the increased polycythemia being the most prominent sign. Some advanced cases of CMS present an acute and temporary worsening of their long-standing hypoxic condition, which we call Triple Hypoxia Syndrome [2]. It is commonly thought that polycythemia (of unknown etiopathogenesis), affects pulmonary function in CMS. However, no broadening of the distribution of ventilation perfusion ratios was found by West et. al. in induced severe normovolemic polycythemia in dogs with hematocrits up to 76% [3]. Lately, the gender characteristics of CMS patients has also been of interest to many authors [4] [5]. In order to study gender differences and the influence of respiratory disease on CMS, we gathered information on hematocrit in both sexes.

METHODS

The laboratory hemograms of two general hospitals, one situated in La Paz at 3510 m and another in El Alto at 4100 m were sampled. In La Paz, 653 males and 1042 females and in El Alto 429 males and 1070 females were studied. All subjects were adults. We additionally studied women with CMS in our laboratory performing pulmonary function testing and blood gas analyses. We classified CMS as those subjects with hematocrit above 56 %.

RESULTS

In fig. 1, the people with hematocrit greater than 56 % at 3510 m and 4100 m are presented as a percentage of the each gender. The males had a higher incidence of CMS at both altitudes, being above 50% in the residents of El Alto.

Fig. 1. Percentage of males and females with a hematocrit greater than 56 % in hospitals of
La Paz (3510 m) and El Alto (4100 m).

It is evident from the results that men have a higher incidence of CMS than women at both altitudes. This may be explained by females suffering less of pulmonary disease (unpublished observations), which has been shown to be the primary cause of CMS. In a study, multiple correlation analysis between altitude and the number of red blood cells showed that hypoxia per-se is not the primary cause of increased polycythemia but rather a secondary trigger [6]. It has also been shown that no correlation between the severe radiological images in miners and the increased polycythemia exists. We suspect that this may be explained by the fact that the pulmonary lesions destroy both the alveoli and the capillaries, hence they do not produce shunting, which is found in a great number of cases.

Similarly, in El Alto the number of incidences of CMS in both sexes was elevated compared to La Paz. This observation may be explained by the higher incidence of cardio-respiratory disease caused by poor sanitary conditions and deficient medical assistance due to poverty.

The city of El Alto (4100 m) is located over 500 meters higher than the center of town in La Paz and around 1000 m above the bottom of the city. This poses a problem for normal values of hematocrit. Physiological changes due to altitude shifts within the city of La Paz, have been reported before in relation to the importance of blood gas interpretation [7]. There is a conflict of setting the normal values because of the daily exposure to altitude changes within the city: People living in El Alto come regularly to consultation at 3510 m, and that represents changes in situ. Hence, "normal" values of hematocrit should be considered with caution. Besides increased polycythemia is caused by multiple factors, where lung, heart or kidney anomalies, besides nutrition, overweight and very rarely hemoglobin abnormalities, play a role. It is interesting to point out that some people with CMS, who were heavy smokers and later developed cancer of the lungs gradually become anemic and die of caquexia.

Low saturation oxyhemoglobin is a characteristic of CMS and an interesting S-shaped curve has been plotted between the number of red blood cells and the oxygen saturation. Increased polycythemia of high altitude was first classified in 3 levels according to the number of red blood cells (in million/mm3): moderate (6.5 to 7.5), severe (7.5 to 8.5) and grave (greater than 8.5). (1). Since the saturation is in the steep part of the oxygen dissociation curve, variations (as previously reported, by us) of saturation by holding the breath, taking a deep inspiration and even just talking while taking a blood gas sample will give variations in the arterial oxygen tension (PaO2), that will confuse the physician [8]. This will give the impression to a lowland physician that it is an abnormal condition at high altitude.

In order to study the cause of hypoxemia the 4 basic causes (shunt, uneven ventilation, diffusion alteration and hypoventilation) have to be investigated. This is why a sole test of forced vital capacity, cannot be conclusive of pulmonary function alteration. Furthermore, at high altitude not even minimal alterations can be tolerated, although they tend to be classified as normal at sea level and at high altitude. For example, a small slope in the plateau of the single breath nitrogen washout curve is an alteration that at sea level is insignificant but at high altitude can lead to CMS. For example, several other tests of pulmonary function to be performed should be: hyperoxic shunt tests, single breath nitrogen-washout, flow-volume curved and ventilation.

The latter has shown that CMS patients hypoventilate, but some hyperventilate on oxygen administration [9]. Hypoxemia attributed to pulmonary alterations, as previously mentioned, may lead to a low PaO2. This, in turn, initially leads to increased cardio-pulmonary activity that has a high oxygen consumption, so it is suggested that the organism (as a reflex mechanism) hypoventilates in order to save "energy" and instead increases the number of red blood cells [9]. Hence, pulmonary disease causes sustained hypoxia which in turn may be compensated for by increased polycythemia.

Due to the increased polycythemia, with increased CO2, CMS patients are able to hold their breath nearly twice as long as the normals without loss of conscience or tissue lesions (see article in this same book). In clinical practice, we have had to give a blood transfusion to a heavily smoking women (age 61) with moderate increased polycythemia, who was suffering from a phlebitis, and this helped to improve her deteriorated condition . Also, some authors found that in polycythemia vera, the pulmonary diffusing capacity was greater than in normals, attributing this to increased hemoglobin. This may also be the case in CMS and may be of benefit in lung disease. Hence it appears that increased polycythemia may be beneficial.

Fig. 2. Chest x-ray (left) showing the pulmonary fibrosis and pulmonary hypertension of an intellectually and physically capable 66 year old female patient (shown at right), with hematocrit = 67% ; arterial blood gases: pH = 7.38, PaO2 = 46 mmHg, PaCO2 = 36 mmHg; FVC= 51%, FEV.1/FVC = 106%, increased slope of single breath nitrogen washout.

In Monge Medrano's original paper [10], he thought that he identified polycythemia vera of high altitude (1928). Subsequently, he came to the conclusion that it was a different entity, now known as CMS, and considered this as a "loss of adaptation" (1937 & 1943) [11]. The clinical description and observation of increased polycythemia was an important contribution to high altitude pathology, made 70 years ago. Since some of the participants in the CMS discussion affirm that they have found people with CMS but without anatomical or functional alterations (see article by J. Reeves in this book), it gives us the impression that this is another kind of pathology. If the disease exists at high altitude, as described originally, we have not been able to see it in over 40 years of medical practice, neither have we seen a single case of polycythemia vera. Rather we have observed CMS patients suffering from diverse pulmonary diseases, as well as hypertension (implying vascular or kidney disease) some even with finger clubbing (even in a 21 year old). In broncho-pulmonary lesions of smokers, for example, there can be severe cyanosis, low saturation, increased polycythemia and pulmonary hypertension. If they stop smoking there is significant improvement. This is the same as at sea level, but in chronic hypoxia they reach lower saturation. Another example are some patients with asthma. This shows that CMS patients have a different etiopathogenesis, as in fig. 2. If all these examples are not included, are they going to be considered a different kind of disease? It does not seem so.

Let us suppose that 3 individuals, apparently normal, one 20 years old, and two 40 years old, move from the lower part of La Paz, (3100 m) to El Alto (4100 m) where they remain 3 months. The blood tests will probably show that the 20 years old and one of the 40 years old have normal hemoglobin and hematocrit at El Alto. The other 40 years old has increased hemoglobin levels to around 20 gm% and has therefore developed CMS. In fact, this scenario is commonly observed. Can we say that this last one has "lost his adaptation"? and that the other two have adapted?. Do we call this: "adaptation" or "loss of adaptation" ?. Furthermore, if he has "lost his adaptation", is he unable to live there any longer ?.

Here, we are at the most critical point in terms of health problems. Should this man go to the lowlands, even though he feels well intellectually and physically?. When he becomes aware that he has CMS, it turns into a substantial economical and social problem. Of course, he will, from time to time, suffer from colds with headaches, lassitude, sleep disturbance and so on (as any healthy subject with a cold) that will be diagnosed by physicians as the CMS alteration, but in reality it is the triple hypoxia syndrome in CMS that is transitory and treatable. The Triple Hypoxia Syndrome is described as a temporary reduction of the basal low saturation of patients with CMS. Three hypoxias are superimposed: High altitude hypoxia, CMS hypoxia and an acute and reversible hypoxia resultant from an acute respiratory infection or cold. It was shown that it was reversible by oxygen administration, because it improved the pulmonary hypertension and tissue oxygenation [8]. This shows that CMS is not a stable disease and that the patient suffers different degrees of increased polycythemia periodically. At altitude, "cyanotic pulmonary diseases and asymptomatic high altitude polycythemia" as defined by Hultgren are, in our experience, CMS, and the latter approaches more exactly CMS present at moderate altitude.

CMS is therefore no "loss of adaptation of life at altitude", but rather an adaptation of pulmonary, cardiac, renal or other disease to the hypoxia at high altitude. CMS patients do remarkably well, provided their basic disease is treated or looked after. Many authors agree that the disorder regresses on descent to sea level, in around one month. Patients who reascend to high altitude, and are exposed again to hypoxia, develop CMS once more. The patients from low lands with chronic pulmonary diseases commonly unnoticed at sea level, develop CMS at altitude.

There is an altitude at which everyone gets CMS. When the respiratory frequency and ventilatory capacity are unable to compensate for the extreme hypoxia, the last resort for humans is severe pulmonary hypertension (right heart hypertrophy) and an increase the number of the red cells. All permanent residents will suffer from CMS at 5500 m, but it is necessary to consider that people do not have adequate housing, heating and live in deficient hygienic and nutritional conditions at such altitudes. Since not everyone has equal capacity of adaptation, the CMS will be more severe in some than in others, and still they will survive, although in miserable conditions. This genetic predisposition is most prevalent in individuals who have a tendency to gain weight after reaching 40 years of age, but this is probably linked to the predisposition to get ill from some form of respiratory disorders.

The patient with respiratory disease at high altitude has 3 distinct possibilities: first, he can go to a lower altitude, second, he can use permanent oxygen or third he can increase his number of red blood cells. Due to social and economical problems, the natural solution is to increase the number of red blood cells.

CMS or Monge's disease is found in residents at high altitude with some abnormal pulmonary function (increased shunt, impaired diffusion, uneven ventilation and/or hypoventilation), sequelae of diseases of diverse etiopathogenesis. These lead to a sustained (and variable) low oxygen saturation and cyanosis, giving rise to pulmonary hypertension and increased polycythemia as compensatory mechanisms of adaptation to the disease under chronic hypoxic conditions. The symptoms and signs are reversible by descent to sea level or by increasing the PIO2.

ACKNOWLEDGMENT
To Eva Hoffmann for the English correction of the manuscript.