erythropoietin, erythropoiesis and chronic mountain ...erythropoietin, erythropoiesis and chronic...

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Erythropoietin, Erythropoiesis and Chronic Mountain Sickness (CMS) H.-C. Gunga 1 , G. Valverde 2 , H. Spielvogel 3 , and K. Kirsch 1 1 Institut für Physiologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin 2 Universidad Mayor de San Andrés, La Paz, Bolivia 3 Instituto Boliviano de Biologia de Altura (IBBA), La Paz, Bolivia HAPPOM Symposium - LIMA 2007

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Page 1: Erythropoietin, Erythropoiesis and Chronic Mountain ...Erythropoietin, Erythropoiesis and Chronic Mountain Sickness (CMS) H.-C. Gunga1, G. Valverde2, H. Spielvogel3, and K. Kirsch1

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

Page 3: Erythropoietin, Erythropoiesis and Chronic Mountain ...Erythropoietin, Erythropoiesis and Chronic Mountain Sickness (CMS) H.-C. Gunga1, G. Valverde2, H. Spielvogel3, and K. Kirsch1

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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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Rift Valley, Human Evolution, and Altitude

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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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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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Signal Transduction Pathway - Hypoxia Inducible Factor (HIF-1 alpha)

(Wenger 2002)

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• 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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Erythropoietin and Erythropoiesis

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Physiological variables in the

etiology of CMS

CMS/EE:

Severe HypoxemiaPulmonary hypertension

ErythrocytosisConsensus Symptoms....

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! 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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•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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• 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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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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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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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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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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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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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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The distribution of hematocrit values at sea level, Cerro de Pasco, and Morococha

Winslow and Monge, 1987

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Gender differences in four common high altitude medical

conditions as reported in the literature by

Hultgren (1997)

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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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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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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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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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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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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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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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! 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

Page 32: Erythropoietin, Erythropoiesis and Chronic Mountain ...Erythropoietin, Erythropoiesis and Chronic Mountain Sickness (CMS) H.-C. Gunga1, G. Valverde2, H. Spielvogel3, and K. Kirsch1

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• 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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Physiological variables in the

etiology of CMS

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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)