S79
Pathophysiology and Epidemiology of Chronic Mountain Sickness C. Monge-C, A. Arregui, F. Leon- Velarde
Departments of Physiological Sciences (CMC and FLV) and Neurology (AA), Universidad Peruana Cayetano Heredia, Apartado 5045, Lima 100, PerO
Sa %
Abstract C. Monge-C, A. Arregui and F. Leon- Velarde,
1992. E
Chronic mountain sickness, which affects permanent residents of high altitudes, is the outcome of a
8
progressive loss of ventilatory rate which naturally occurs with age and resulting in excessive hypoxemia and polycythemia. A theoretical model predicts the progressive failure of homeostatic control of the hemoglobin concentration when the values increase above those found at sea level. This is confirmed by lack of feedback mechanism between high altitude erythrocytosis and serum erythropoietin. The results of epidemiological studies are in agreement with the physiological findings. In a male population living at 4,300 m, an increase with age of the prevalences of excessive ery-
.0
throcytosis (Hb > 213 g/l), blood oxygen saturation 213 g/l (mean 2SD of the normal distribution found in the younger group), the prevalence of EE showed a hyperbolic increase with age (3). The latter epidemiological study
cal model which uses some fundamental equations of respiratory physiology and combines them with the erythrocytic response of high altitude natives to different levels of altitude,
shows that the so called homeostatic index indicates maximum negative feedback regulation of Hb at sea level values. At higher Hb values there is a progressive loss of regulation and it
approaches 0 at values found in CMS (Figure 2). The model and Figure 1 also show that there is a positive feedback loop between 02 concentration in the blood (Ca02) and Hb and that therefore an excessive increase in Ca2 does not arrest the synthesis of hemoglobin in the bone marrow (6, 7). The model also showed a significant reduction of vital capacities as age in- therefore predicts the possibility of an increase in the variabilcreased and was in agreement with the physiological studies of ity of the hematological response as erythrocytosis increases Sime et a!. (12) which correlated ventilatory rates, Hb and age due to the progressive loss of regulation of the blood hemogloat similar altitudes. bin concentration.
An attempt to further explore the correlation
Table 1 Regressions of hemoglobin (Hb g/l) with 02 saturation (Sa02) in different age groups living at 4,300 m.
20—39 40—54 55—69
Regression
Hb = 327 (± 36) —1.61 (± 0.43) x Sa02 Hb = 316 (± 33) —1.53 (± 0.39) x Sa02 Hb = 179 (±57) 0.17 (±0.69) x Sa02
Cases
p=
168
0.000 0.000 0.803
154
56
(Source: Arregui and Leôn-Velarde, unpublished observations).
carried out in 200 male subjects living in Cerro de Pasco at 4,300 m (Arregui and León-Velarde, unpublished observations). In each individual Hb, Sa02 (by finger oxymetry) and peak ventilatory flow rates (PEFR) were measured. In addition a CMS score was obtained from ten symptoms usually seen in CMS (3). The results (Table 2) show that Hb and CMS scores increase with age while 02 saturation and height-cor-
rected PEFR decreases with age. Figure 3 shows that the An explanation for the variable response of erythrocytosis to changes in the level of hypoxemia may be found in the poorly understood regulatory function between these two important physiological parameters. A mathemati-
frequency of excessive erythrocytosis rises slightly with age to-
gether with a more pronounced increase in the frequency of
persons with headaches (2), CMS score > 21 and Sa02 Table 2 Hemoglobin (Hb; g/l), 02 saturation (Sa02; %), chronic mountain sickness (CMS) score, and height corrected peak expiratory flow rate (PEER/H) in different age groups living at 4,300 m.
35
20—39
40—54
n=88 30
z
Hb Sa02
MATHEMATICAL APPROACH TO PHYSIOLOGICAL PROBLEMS D. S. Riggs, TheM.!. 1'. Aess, 1976
CMS PEER/H
25
55—69
n=93
192.6±24.7
187.3±22.9
84.9± 4.7 17.9± 3.2 346.9 54.4
84.7± 4.2 18.3± 3.8 325.8 55.7
n=32
p=
200.0±21.0 82.3± 3.7
0.02
19.8± 3.9 275.0 58.0
0.03
0.01
0.00
(Source: Arregul and León-Velarde, unpublished observations).
ncreaaed CO2 Production
16.5
17.0
17.5
18.0
18.5
19.0
0 NO
0
N)
CID
—
--
Fig. 2 The homeostatic index as a function of blood hemoglobin concentration in two different levels of altitude. The index has been calculated at sea level Pa02 (95 torr) and at high altitude (45 torr). At both altitudes the index shows maximal homeostatic regulation at sea level Hb values. The insert shows a similar plot relating the homeostatic index to alveolar PCO2 at two levels of CO2 production. It can be seen that maximal regulation is obtained at normal resting PCO2 levels.
o
-
Hb g/lcEml
____
16.0
0
5
N)
a 0
Pa
C> 0 9 u
A (rnm.Hg.)
to
15
IIcn
0
in Inirsd Air
o 0
I
&
20
Fig. 3 Frequencies (%) of low arterial oxygen saturation (SAT 213 g/l), headaches and high chronic mountain sickness scores (MMCSco > 20) in three age groups.
Downloaded by: Queen's University. Copyrighted material.
Age groups
between hypoxemia and polycythemia in a single altitude was
mt. J. Sports Med. 13(1992) S81
Pathophysiology and Epidemiology of Chronic Mountain Sickness
References
< 83%; the prevalence of excessive erythrocytosis in the adult male population was 15.6%.
Alippi R. M., Barcelo A. C., Bozzini C. E.: Enhanced erythropoie-
Studies on the concentration of erythropoietin in the serum of high altitude natives (HA) also are indicative of the lack of a simple feedback mechanism between serum immunoreactive erythropoietin (siEPO) and Hb. Winslow et al.
sis induced by hypoxia in hypertransfused, post-hypoxic mice. ExpHematolll:878—883, 1983. 2 Arregui A., Cabrera J., León-Velarde F., Paredes S., Vizcarra D.,
(13) in their study of Sherpas and Quechua natives living at
Arregui A., León-Yelarde F., Valcárcel M. Salud y minerIa. El Riesgo del Mal de Montafla Crónico entre Mineros de Cerro de Pasco. Lima, ADEC-ATC/Mosca Azul., 1990. Kryger M., Glass R., Jackson D. L., McCullough R. E., Scoggin C.
ty of HA erythrocytosis to correct tissue hypoxia. LeonVelarde et al. (5) have studied Hb, Sa02 and siEPO in Peruvian workers living at 4,300 m with normal (NE) or excessive ery-
throcytosis (EE). A comparative group studied at sea level (SL), served as control. The three parameters showed statistically significant differences between HA and SL groups, the values in SL being lower. Significant differences were also found between NE and EE groups in Hb and Sa02 but there was no statistical difference in siEPO between the two groups. The results indicated, therefore, that HA residents who develop EE are not distinguishable from residents who develop NE on the basis of estimates of siEPO. As a result, variations in EPO did not explain the striking variation in Hb at high altitudes. Alippi et al. (1) have shown in mice that a previous exposure to hypobaria blocks the inhibitory effect of transfusion-
induced polycythemia on EPO secretion during subsequent exposure. This indicated the loss of feedback control of hormone secretion and the disappearance of the inverse correlation between Hb and siEPO concentration. These findings are in agreement with the mathematical model referred to above which showed the progressive loss of feedback regulation of Hb at concentrations above the normal sea level values.
A recent review of the physiological adaptation capacity to high altitude of mammals and birds show that hypoxemic polycythemia is not necessarily an adaptive parameter at very high altitudes (8). Chronic mountain sickness is the tribute that man and phenotypically adapted animals pay to a mechanism based in an excessive increase in the hemoglobin concentration which loads the blood with oxygen without correcting tissue hypoxia. This is due to the lack of the necessary negative feedback regulation between blood oxygen pres-
sure and/or content and the erythrocytic response. The disease has not been described in genotypically adapted animals who do not develop polycythemia in their high altitude environment (8). Acknowledgements The epidemiological and clinical work described has
been supported in part by grants from IDRC (Canada) to AA and FLY.
'
H., Grover R. F., Weil J. V.: Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1:3—17, 1978. León-Velarde F., Monge-C C., Yidal A., Carcagno M., Criscuolo M., Bozzini C. E.: Serum immunoreactive erythropoietin in high altitude natives with an without excessive erythrocytosis. Exp Hematoll9:257—260, 1991.
6 Monge-C C.: Hemoglobin regulation in hypoxemic polycythemia, in Chamberlayne E. C., Condliffe P. G. (eds): Adjustment to High Altitude. Bethesda, US Dept. Health Hum. Serv. (US NatI Inst HealthPubl83-2496), l983,pp 53—56. Monge-C C.: Regulación de la concentración de hemoglobina en Ia policitemia de altura: Modelo matemático. Bull Inst Fr Etudes Andinesl9:455—467, 1990. 8 Monge-C C., León-Yelarde F.: High altitude physiological adaptation: oxygen transport in mammals and birds. Physiol Rev 71: 1135—1172,1991.
Monge-C C., León-Yelarde F., Arregui A.: Increasing prevalence of excessive erythrocytosis in healthy high altitude miners. (Letter) NEngJMed32l: 1271, 1989. 10 Monge-C C., Lozano R., Carcelén A.: Renal excretion of bicarbonate in high altitude natives and in natives with chronic mountain sickness. J Clin In vest 43:2303—2309, 1964. Severinghaus J. W., Bainton C. R., Carcelén A.: Respiratory insen-
sitivity to hypoxia in chronically hypoxic man. Resp Physiol 1: 308—334, 1966. 12 Sime F. C., Monge-C C., Whittembury J.: Age as a cause of chronic mountain sickness (Monge's disease). IntJBiometerol 19: 93—98, 1975.
13 Winslow R. M., Chapman K. W., Gibson C. G., Samaja M. C., Monge-C C., Goldwasser E., Sherpa M., Blume F. D., Santolaya R.: Different hematologic responses to hypoxia in Sherpas and Quechua Indians. JApplPhysiol 66: 1561—1569, 1989. 14 Winslow R. M., Monge-C C.: Hypoxia, Polycythemia and chronic mountain sickness. Baltimore, Johns Hopkins University Press, 1987.
Carlos Monge-C, MD
__________________________
Professor of Physiology Universidad Peruana Cayetano Heredia Apartado 5045 Lima 100 Peru
Downloaded by: Queen's University. Copyrighted material.
3,700 m, have suggested that siEPO increased levels in subjects with polycythemia may be an indication of the limited capaci-
Arbaiza D.: High prevalence of migraine in a high altitude population.Neurology4l: 1678—1680,1991.
Pathophysiology and Epidemiology of Chronic Mountain Sickness C. Monge-C, A. Arregui, F. Leon- Velarde
Departments of Physiological Sciences (CMC and FLV) and Neurology (AA), Universidad Peruana Cayetano Heredia, Apartado 5045, Lima 100, PerO
Sa %
Abstract C. Monge-C, A. Arregui and F. Leon- Velarde,
1992. E
Chronic mountain sickness, which affects permanent residents of high altitudes, is the outcome of a
8
progressive loss of ventilatory rate which naturally occurs with age and resulting in excessive hypoxemia and polycythemia. A theoretical model predicts the progressive failure of homeostatic control of the hemoglobin concentration when the values increase above those found at sea level. This is confirmed by lack of feedback mechanism between high altitude erythrocytosis and serum erythropoietin. The results of epidemiological studies are in agreement with the physiological findings. In a male population living at 4,300 m, an increase with age of the prevalences of excessive ery-
.0
throcytosis (Hb > 213 g/l), blood oxygen saturation 213 g/l (mean 2SD of the normal distribution found in the younger group), the prevalence of EE showed a hyperbolic increase with age (3). The latter epidemiological study
cal model which uses some fundamental equations of respiratory physiology and combines them with the erythrocytic response of high altitude natives to different levels of altitude,
shows that the so called homeostatic index indicates maximum negative feedback regulation of Hb at sea level values. At higher Hb values there is a progressive loss of regulation and it
approaches 0 at values found in CMS (Figure 2). The model and Figure 1 also show that there is a positive feedback loop between 02 concentration in the blood (Ca02) and Hb and that therefore an excessive increase in Ca2 does not arrest the synthesis of hemoglobin in the bone marrow (6, 7). The model also showed a significant reduction of vital capacities as age in- therefore predicts the possibility of an increase in the variabilcreased and was in agreement with the physiological studies of ity of the hematological response as erythrocytosis increases Sime et a!. (12) which correlated ventilatory rates, Hb and age due to the progressive loss of regulation of the blood hemogloat similar altitudes. bin concentration.
An attempt to further explore the correlation
Table 1 Regressions of hemoglobin (Hb g/l) with 02 saturation (Sa02) in different age groups living at 4,300 m.
20—39 40—54 55—69
Regression
Hb = 327 (± 36) —1.61 (± 0.43) x Sa02 Hb = 316 (± 33) —1.53 (± 0.39) x Sa02 Hb = 179 (±57) 0.17 (±0.69) x Sa02
Cases
p=
168
0.000 0.000 0.803
154
56
(Source: Arregui and Leôn-Velarde, unpublished observations).
carried out in 200 male subjects living in Cerro de Pasco at 4,300 m (Arregui and León-Velarde, unpublished observations). In each individual Hb, Sa02 (by finger oxymetry) and peak ventilatory flow rates (PEFR) were measured. In addition a CMS score was obtained from ten symptoms usually seen in CMS (3). The results (Table 2) show that Hb and CMS scores increase with age while 02 saturation and height-cor-
rected PEFR decreases with age. Figure 3 shows that the An explanation for the variable response of erythrocytosis to changes in the level of hypoxemia may be found in the poorly understood regulatory function between these two important physiological parameters. A mathemati-
frequency of excessive erythrocytosis rises slightly with age to-
gether with a more pronounced increase in the frequency of
persons with headaches (2), CMS score > 21 and Sa02 Table 2 Hemoglobin (Hb; g/l), 02 saturation (Sa02; %), chronic mountain sickness (CMS) score, and height corrected peak expiratory flow rate (PEER/H) in different age groups living at 4,300 m.
35
20—39
40—54
n=88 30
z
Hb Sa02
MATHEMATICAL APPROACH TO PHYSIOLOGICAL PROBLEMS D. S. Riggs, TheM.!. 1'. Aess, 1976
CMS PEER/H
25
55—69
n=93
192.6±24.7
187.3±22.9
84.9± 4.7 17.9± 3.2 346.9 54.4
84.7± 4.2 18.3± 3.8 325.8 55.7
n=32
p=
200.0±21.0 82.3± 3.7
0.02
19.8± 3.9 275.0 58.0
0.03
0.01
0.00
(Source: Arregul and León-Velarde, unpublished observations).
ncreaaed CO2 Production
16.5
17.0
17.5
18.0
18.5
19.0
0 NO
0
N)
CID
—
--
Fig. 2 The homeostatic index as a function of blood hemoglobin concentration in two different levels of altitude. The index has been calculated at sea level Pa02 (95 torr) and at high altitude (45 torr). At both altitudes the index shows maximal homeostatic regulation at sea level Hb values. The insert shows a similar plot relating the homeostatic index to alveolar PCO2 at two levels of CO2 production. It can be seen that maximal regulation is obtained at normal resting PCO2 levels.
o
-
Hb g/lcEml
____
16.0
0
5
N)
a 0
Pa
C> 0 9 u
A (rnm.Hg.)
to
15
IIcn
0
in Inirsd Air
o 0
I
&
20
Fig. 3 Frequencies (%) of low arterial oxygen saturation (SAT 213 g/l), headaches and high chronic mountain sickness scores (MMCSco > 20) in three age groups.
Downloaded by: Queen's University. Copyrighted material.
Age groups
between hypoxemia and polycythemia in a single altitude was
mt. J. Sports Med. 13(1992) S81
Pathophysiology and Epidemiology of Chronic Mountain Sickness
References
< 83%; the prevalence of excessive erythrocytosis in the adult male population was 15.6%.
Alippi R. M., Barcelo A. C., Bozzini C. E.: Enhanced erythropoie-
Studies on the concentration of erythropoietin in the serum of high altitude natives (HA) also are indicative of the lack of a simple feedback mechanism between serum immunoreactive erythropoietin (siEPO) and Hb. Winslow et al.
sis induced by hypoxia in hypertransfused, post-hypoxic mice. ExpHematolll:878—883, 1983. 2 Arregui A., Cabrera J., León-Velarde F., Paredes S., Vizcarra D.,
(13) in their study of Sherpas and Quechua natives living at
Arregui A., León-Yelarde F., Valcárcel M. Salud y minerIa. El Riesgo del Mal de Montafla Crónico entre Mineros de Cerro de Pasco. Lima, ADEC-ATC/Mosca Azul., 1990. Kryger M., Glass R., Jackson D. L., McCullough R. E., Scoggin C.
ty of HA erythrocytosis to correct tissue hypoxia. LeonVelarde et al. (5) have studied Hb, Sa02 and siEPO in Peruvian workers living at 4,300 m with normal (NE) or excessive ery-
throcytosis (EE). A comparative group studied at sea level (SL), served as control. The three parameters showed statistically significant differences between HA and SL groups, the values in SL being lower. Significant differences were also found between NE and EE groups in Hb and Sa02 but there was no statistical difference in siEPO between the two groups. The results indicated, therefore, that HA residents who develop EE are not distinguishable from residents who develop NE on the basis of estimates of siEPO. As a result, variations in EPO did not explain the striking variation in Hb at high altitudes. Alippi et al. (1) have shown in mice that a previous exposure to hypobaria blocks the inhibitory effect of transfusion-
induced polycythemia on EPO secretion during subsequent exposure. This indicated the loss of feedback control of hormone secretion and the disappearance of the inverse correlation between Hb and siEPO concentration. These findings are in agreement with the mathematical model referred to above which showed the progressive loss of feedback regulation of Hb at concentrations above the normal sea level values.
A recent review of the physiological adaptation capacity to high altitude of mammals and birds show that hypoxemic polycythemia is not necessarily an adaptive parameter at very high altitudes (8). Chronic mountain sickness is the tribute that man and phenotypically adapted animals pay to a mechanism based in an excessive increase in the hemoglobin concentration which loads the blood with oxygen without correcting tissue hypoxia. This is due to the lack of the necessary negative feedback regulation between blood oxygen pres-
sure and/or content and the erythrocytic response. The disease has not been described in genotypically adapted animals who do not develop polycythemia in their high altitude environment (8). Acknowledgements The epidemiological and clinical work described has
been supported in part by grants from IDRC (Canada) to AA and FLY.
'
H., Grover R. F., Weil J. V.: Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1:3—17, 1978. León-Velarde F., Monge-C C., Yidal A., Carcagno M., Criscuolo M., Bozzini C. E.: Serum immunoreactive erythropoietin in high altitude natives with an without excessive erythrocytosis. Exp Hematoll9:257—260, 1991.
6 Monge-C C.: Hemoglobin regulation in hypoxemic polycythemia, in Chamberlayne E. C., Condliffe P. G. (eds): Adjustment to High Altitude. Bethesda, US Dept. Health Hum. Serv. (US NatI Inst HealthPubl83-2496), l983,pp 53—56. Monge-C C.: Regulación de la concentración de hemoglobina en Ia policitemia de altura: Modelo matemático. Bull Inst Fr Etudes Andinesl9:455—467, 1990. 8 Monge-C C., León-Yelarde F.: High altitude physiological adaptation: oxygen transport in mammals and birds. Physiol Rev 71: 1135—1172,1991.
Monge-C C., León-Yelarde F., Arregui A.: Increasing prevalence of excessive erythrocytosis in healthy high altitude miners. (Letter) NEngJMed32l: 1271, 1989. 10 Monge-C C., Lozano R., Carcelén A.: Renal excretion of bicarbonate in high altitude natives and in natives with chronic mountain sickness. J Clin In vest 43:2303—2309, 1964. Severinghaus J. W., Bainton C. R., Carcelén A.: Respiratory insen-
sitivity to hypoxia in chronically hypoxic man. Resp Physiol 1: 308—334, 1966. 12 Sime F. C., Monge-C C., Whittembury J.: Age as a cause of chronic mountain sickness (Monge's disease). IntJBiometerol 19: 93—98, 1975.
13 Winslow R. M., Chapman K. W., Gibson C. G., Samaja M. C., Monge-C C., Goldwasser E., Sherpa M., Blume F. D., Santolaya R.: Different hematologic responses to hypoxia in Sherpas and Quechua Indians. JApplPhysiol 66: 1561—1569, 1989. 14 Winslow R. M., Monge-C C.: Hypoxia, Polycythemia and chronic mountain sickness. Baltimore, Johns Hopkins University Press, 1987.
Carlos Monge-C, MD
__________________________
Professor of Physiology Universidad Peruana Cayetano Heredia Apartado 5045 Lima 100 Peru
Downloaded by: Queen's University. Copyrighted material.
3,700 m, have suggested that siEPO increased levels in subjects with polycythemia may be an indication of the limited capaci-
Arbaiza D.: High prevalence of migraine in a high altitude population.Neurology4l: 1678—1680,1991.
