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Erythropoietin, Erythropoiesis and Chronic Mountain Sickness
(CMS)
H.-C. Gunga1, G. Valverde2, H. Spielvogel3, and K. Kirsch1
1Institut für Physiologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin 2Universidad Mayor de San Andrés, La Paz, Bolivia
3Instituto Boliviano de Biologia de Altura (IBBA), La Paz, Bolivia
HAPPOM Symposium - LIMA 2007
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2/35Erythropoietin, Erythropoiesis and CMS
! Introduction Evolutionary backgroundOxygen sensing mechanisms
! Methods
! Human studies on EPO, sTfRNormobaric-Normoxic EnvironmentCircadian, monthly, annual variations
Hypobaric-Hypoxic EnvironmentShort, intermittent, and long-term exposure
Chronic Mountain Sickness (CMS)
! Summary and Conclusions
Contents
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3/35Erythropoietin, Erythropoiesis and CMS
Bed restBed rest
Humans in
Extreme Environments
Humans in
Extreme Environments
ComparativePhysiology
ComparativePhysiology
Tropics/Desert
Tropics/Desert
High Altitude
High Altitude
Micro-G(Space)Micro-G(Space)
PalaeophysiologyEvolutionaryAnthropology
PalaeophysiologyEvolutionaryAnthropology
History of Applied Science
History of Applied Science
Nathan Zuntz (1847 – 1920)Operation „Paperclip“
Nathan Zuntz (1847 – 1920)Operation „Paperclip“
ModerateAltitude
(<2,300 m)
ModerateAltitude
(<2,300 m)
HighAltitude
(>3,000 m)
HighAltitude
(>3,000 m)
Real Micro-g
Space (near Earth orbit)Space (near Earth orbit)
Exercise PhysiologyExercise
Physiology
Marathon-running
Marathon-running
SurvivaltrainingSurvivaltraining
HDTHDT IsolationIsolation ImmersionImmersion
GoldMiningGold
Mining
Simulated Micro-g
•Introduction
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4/35Erythropoietin, Erythropoiesis and CMS
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5/35Erythropoietin, Erythropoiesis and CMS
Rift Valley, Human Evolution, and Altitude
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6/35Erythropoietin, Erythropoiesis and CMS
Hochachka PW, Gunga HC & Kirsch K.Our ancestral physiological phenotype: An adaptation for
hypoxia tolerance and for endurance performance?PNAS 95: 1915-1920 (1998)
Adaptation and Conservation of Physiological Systems
in Evolution Human Hypoxia Tolerance
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7/35Erythropoietin, Erythropoiesis and CMS
Erythrocytes in different Species
Withers PC. Comparative animal physiology.Saunders 1992
Human red blood cells (7.5 μm; PCV 44% ~ 3.200 m2; Blood volume in mammals 6-8% - diving mammals > 8% of body mass)
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8/35Erythropoietin, Erythropoiesis and CMS
Signal Transduction Pathway - Hypoxia Inducible Factor (HIF-1 alpha)
(Wenger 2002)
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9/35Erythropoietin, Erythropoiesis and CMS
• Erythropoietin (EPO)is a glycoprotein hormone.
• EPO is produced by specialized cells in the kidneys (90 %) and the liver (10 %).
Erythropoietin
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10/35Erythropoietin, Erythropoiesis and CMS
Erythropoietin and Erythropoiesis
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11/35Erythropoietin, Erythropoiesis and CMS
Physiological variables in the
etiology of CMS
CMS/EE:
Severe HypoxemiaPulmonary hypertension
ErythrocytosisConsensus Symptoms....
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12/35Erythropoietin, Erythropoiesis and CMS
! Introduction Evolutionary backgroundOxygen sensing mechanisms
! Methods
! Human studies on EPO, sTfRNormobaric-Normoxic EnvironmentCircadian, monthly, annual variations
Hypobaric-Hypoxic EnvironmentShort, intermittent, and long-term exposure
Chronic Mountain Sickness (CMS)
! Summary and Conclusions
Contents
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13/35Erythropoietin, Erythropoiesis and CMS
•EPO (IBL)
Median: 12 mIU/ml Range: 4 -36 mIU/ml
•sTfR (R&D)
Caucasians (living <300 m above sea-level)
Median: 18,4 nmol/l Range 8.7 – 28,1 nmol/l
ELISA Tests
•Methods
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14/35Erythropoietin, Erythropoiesis and CMS
• Transferrin is a transport protein for iron (Fe).
• The diferric (2*Fe) transferrin is binding to TfR.
• During the phase of cellular proliferation iron is incorporatedinto the interior of the erythroblast.
• This is important for the synthesis of hemoglobin.
4-22
Transferrin and Transferrin-receptor
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15/35Erythropoietin, Erythropoiesis and CMS
Transferrin Receptor
• Transferrin Receptor (TfR)is a transmembranal protein, expressed mainly on the surface of erythroid cells
Cell interior
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16/35Erythropoietin, Erythropoiesis and CMS
! Introduction Evolutionary backgroundOxygen sensing mechanisms
! Methods
! Human studies on EPO, sTfRNormobaric-Normoxic EnvironmentCircadian, monthly, annual variations
Hypobaric-Hypoxic EnvironmentShort, intermittent, and long-term exposure
Chronic Mountain Sickness (CMS)
! Summary and Conclusions
Contents
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17/35Erythropoietin, Erythropoiesis and CMS
Circadian Variations of Serum Erythropoietin
Gunga HC, Kirsch K, Baartz F, Maillet A, Gharib C, Nalishiti W, Rich I & Röcker L.Erythropoietin under real and simulated microgravity conditions in humans.
Journal of Applied Physiology 81: 761-773 (1996)
•Epo-Studies
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18/35Erythropoietin, Erythropoiesis and CMS
Gunga HC, Kirsch K, Baartz F, Maillet A, Gharib C, Nalishiti W, Rich I & Röcker L.Erythropoietin under real and simulated microgravity conditions in humans.
Journal of Applied Physiology 81: 761-773 (1996)
Erythropoietin during Isolation and Confinement
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19/35Erythropoietin, Erythropoiesis and CMS
Gunga H.C. et al. Erythropoietin regulations in humans under different environmental and experimental conditions. Respiration and Neurobiology. Epub ahead, March 12, 2007
Annual variations of serum erythropoietin concentrations
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20/35Erythropoietin, Erythropoiesis and CMS
Erythropoietin before, during and after moderate
hypobaric-hypoxic exposure (2,315 m)
Gunga HC, Kirsch K, Röcker L & Schobersberger W .Time course of erythropoietin, triiodothyronine, throxine,
and thyroid-stimulating hormone at 2,315 m.Journal of Applied Physiology 76: 1068-1072 (1994)
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21/35Erythropoietin, Erythropoiesis and CMS
Erythropoietin and intermittent
hypobaric�hypoxic exposure(3,600 m)
Gunga HC, Röcker L, Behn C, Hildebrandt W, Koralewski E, Rich I, Schobersberger W & Kirsch K.
Shift working in the Chilean Andes (3,600 m) and its influence on erythropoietin and the low-pressure system.
Journal of Applied Physiology 81: 846-852 (1996)
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22/35Erythropoietin, Erythropoiesis and CMS
The distribution of hematocrit values at sea level, Cerro de Pasco, and Morococha
Winslow and Monge, 1987
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23/35Erythropoietin, Erythropoiesis and CMS
Gender differences in four common high altitude medical
conditions as reported in the literature by
Hultgren (1997)
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24/35Erythropoietin, Erythropoiesis and CMS
N = 105
Females (N = 34)63.5 ± 9.4, min 37.0, max. 80 yrs
Males (N = 71)62.1 ± 11.0, min 35.0, max 89.0 yrs
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
80-84
85-89
age_group
0
2
4
6
8
10
12
14
16
18
20
22
10
12
8
4
11
23
2
0
2
1
6
8
11
13
10
10 8
0
2
sexfemalemale
Age distribution
Inclusion criteria:
•Whole life at high altitude: (3,600 - 4,100
•Excessive erythrocytosis: [Hct > 60 %]
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25/35Erythropoietin, Erythropoiesis and CMS
Differences between females and males for Hct (p=0.011) and Hb (p=0.011)
female male
55
60
65
70
75
80
Hct
(%)
80
female male
19,0
20,0
21,0
22,0
23,0
24,0
25,0
26,0
Hb
(g/d
l)
80
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26/35Erythropoietin, Erythropoiesis and CMS
No differences between females and males for age, EPO and sTfR
p=0.50
female male
30
40
50
60
70
80
90
year
s
27
p=0.52
female male
0,00
50,00
100,00
150,00
200,00
250,00
[EPO
] (U
/l
2
54
51
67
53
10149
p=0.47
female male
25,00
50,00
75,00
100,00
125,00
150,00
sTf-R
(nm
ol/L
101
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27/35Erythropoietin, Erythropoiesis and CMS
No correlation between the hematological parameters (Hct, Hb) and EPO
55 60 65 70 75 80Hct (%)
0.00
50.00
100.00
150.00
200.00
250.00
[EPO
] (U
/l)
femalesmales
19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0
Hb (g/dl)
0.00
50.00
100.00
150.00
200.00
250.00
[EPO
] (U
/l)
15-22
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28/35Erythropoietin, Erythropoiesis and CMS
No correlation between the hematological parameters (Hct, Hb) and sTfR
55 60 65 70 75 80Hct (%)
25.00
50.00
75.00
100.00
125.00
150.00
sTf-R
(nm
ol/l
19.0 20.0 21.0 22.0 23.0 24.0 25.0 26.0Hb (g/dl)
25.00
50.00
75.00
100.00
125.00
150.00
sTf-R
(nm
ol/l)
femalesmales
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29/35Erythropoietin, Erythropoiesis and CMS
No correlation between age, EPO, and sTfR
years30 40 50 60 70 80 90
0.00
50.00
100.00
150.00
200.00
250.00
[EPO
] (U
/l)
femalesmales
30 40 50 60 70 80 90years
25.00
50.00
75.00
100.00
125.00
150.00
sTf-R
(nm
ol/l)
17-22
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30/35Erythropoietin, Erythropoiesis and CMS
No correlation between EPO and sTfR in the majority of the subjects with high sTfR
25.00 50.00 75.00 100.00 125.00 150.00sTf-R (nmol/l)
0.00
50.00
100.00
150.00
200.00
250.00
[EPO
] (U
/l)
femalesmales
28nmol/l
36 U/l
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31/35Erythropoietin, Erythropoiesis and CMS
! Introduction Evolutionary backgroundOxygen sensing mechanisms
! Methods
! Human studies on EPO, sTfRNormobaric-Normoxic EnvironmentCircadian, monthly, annual variations
Hypobaric-Hypoxic EnvironmentShort, intermittent, and long-term exposure
Chronic Mountain Sickness (CMS)
! Summary and Conclusions
Contents
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32/35Erythropoietin, Erythropoiesis and CMS
• Males are more frequently affected by EE than females
• Males with EE show higher Hct and [Hb]
• High [sTfR] in the majority of the subjects with EE but no correlation to [EPO]
• Effects of blood letting on circulating [EPO] have to be clarified in patients with EE
• Effects of iron status/metabolism on hematopoiesis in patients with EE are unclear
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33/35Erythropoietin, Erythropoiesis and CMS
Physiological variables in the
etiology of CMS
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34/35Erythropoietin, Erythropoiesis and CMS
Winslow, Statham and Gibson, 1979
Changes induced by decreasing the hematocrit in eight patients with CMS
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Arterial oxygen saturation (SaO2) in long-term high altitude residents while awake (A) and during stages of sleep (1-REM) at 3,100 m
During sleep hypoxemia occurs in polycythemics but not in normals. Ear oximeter data.
Kryger and Grover, 1983
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Arterial PCO2 in normal high altitude residents (N=159) and patients with CMS (N=22)Differences in the height of the curves represent different numbers of subjects and patients studied
Cruz and Recavarren, 1982
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Richalet et al, 2005
Mean nocturnal O2 saturation (A) and apnea-hypopnea index (B) in groups of patients before and after treatment with 250 (D250) or 500 (D500) mg of Acetazolamide
compared with a CMS placebo-treated group (Placebo) and normal control subjects (Nb = number of events)
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Erythropoietin during long-term simulated micro-g conditions (Head-down tilt �6°)
Gunga HC, Kirsch K, Baartz F, Maillet A, Gharib C, Nalishiti W, Rich I & Röcker L.Erythropoietin under real and simulated microgravity conditions in humans.
Journal of Applied Physiology 81: 761-773 (1996)
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Modulation of Erythropoietin Regulation in Dogs
Ehmke J, Just A, Eckhardt KU, Persson PB, Bauer C & Kirchheim HR.Modulation of erythropoietin formation by changes in blood volume in conscious dogs.
Journal of Physiology 488: 181-191 2 (1996)
•Conclusions
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Vásquez R., and Villena M. (2001). Normal Hematological Valuesfor Healthy Persons Living at 400 Meters in Bolivia. High AltitudeMedicine & Biology 3:361-367
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The morphology of red blood cells at high altitudes
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Red-cell indexes in subjects at low and high altitudes
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Two main Groups: �normal� [EPO] (< 36 U·l-1) and with very high [EPO] (> 100 U·l-1). What about the �intermediates� (36≤[EPO]≤100)
Hct (%)
Cut-off EPO � HA ?
55 60 65 70 75 80
0.00
50.00
100.00
150.00
200.00
250.00[E
PO] (
U/l)
femalesmales
36 Ul
100.0 Ul
????
B
A
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At least two groups with excessive erythrocytosis (EE):
• “normal” [EPO] (< 36 U·l-1)• very high [EPO] (> 100 U·l- 1)
No studies before evaluated “normal” reference levels for [EPO] and [sTfR]in altitude residents
" can the published cut-off values be adopted ?
18-22
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Effect of high altitude (4,300 m) on hematocrit levels of men and woman
Hannon et al. 1966
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Normal hematocrit values at sea level as a function of age for 7,426 normal males and 7,704 normal females in the United States
(Fulwood 1982)
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Vásquez R., and Villena M.Normal Hematological Values for Healthy Persons Living at 400 Meters in Bolivia.
High Altitude Medicine & Biology 3:361-367 (2001)
Histograms of showing frequency (counts) for
hematocrit values and the mean and 2 standard deviation (SD) values
observed in 1934, 15- to 29 healthy male and female residents in
Potosi, Bolivia (4,000 m)