Erythropoietin and soluble transferrin receptor concentrations in … · Erythropoietin and soluble...
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1 EPO and sTfR in altitude residents HAPPOM Erythropoietin and soluble transferrin receptor concentrations in high altitude residents with excessive erythrocytosis Guido Valverde 1 , Hilde Spielvogel 1 , Karl A. Kirsch 2 , Hanns-Christian Gunga 2 , Ivan Huanco 3 1 Universidad Mayor de San Andrés, La Paz, Bolivia, Project ALFA II (HAPPOM) 2 Institut für Physiologie, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin 3 Universidad Nacional del Altiplano, Puno, Peru. •PROJECT ALFA II–0379 FCD (HAPPOM)
Transcript of Erythropoietin and soluble transferrin receptor concentrations in … · Erythropoietin and soluble...
1EPO and sTfR in altitude residents HAPPOM
Erythropoietin and solubletransferrin receptor concentrations
in high altitude residents with excessive erythrocytosis
Guido Valverde1, Hilde Spielvogel1, Karl A. Kirsch2, Hanns-Christian Gunga2, Ivan Huanco3
1Universidad Mayor de San Andrés, La Paz, Bolivia, Project ALFA II (HAPPOM)2Institut für Physiologie, Campus Benjamin Franklin,
Charité-Universitätsmedizin Berlin3Universidad Nacional del Altiplano, Puno, Peru.
•PROJECT ALFA II–0379 FCD (HAPPOM)
2EPO and sTfR in altitude residents HAPPOM
Outlook and objectives in 2005-2007The general data base of patients with CMS and EE is scanty. Therefore it was planned:
1) To take for the ALFA Continuation Phase (LA) additional samples from patients with CMS and EE.
2) Do a careful anamnesis of these subjects which was not always possible in the previous study.
3) To associate erythropoietic markers with the iron metabolism.
4) To quantify [EPO] in healthy high altitude natives/long time residents and in subjects with EE or CMS.
3EPO and sTfR in altitude residents HAPPOM
In order to complete the data of the previous study, we looked into the clinical histories of 25 Patients.
Signs and symptoms:• Cyanosis (6)• Headache (5)• Overweight BMI> 25 kg/m2 (22)• Pulmonary Hypertension (10)• Smokers (2)• Frequent blood-letting (16) (1 per month~400 ml)
CLINICAL DATA
4EPO and sTfR in altitude residents HAPPOM
854511,39666,28[Age] [years]
80538,73468,57[Age] [years]
40,4024,304,3315830,0444[BMI] [m/kg2]
140,6532,7130,5777965,64[sTfR] [nmol·l-1]
212,968,8548,4576950,37[EPO] [U·l-1]
23,4019,801,4266921,43Hb [g·dl-1]N=18
71604,3450165,05Hct [%]Males
34,1030,401,4152231,7571[BMI] [m/kg2]
98,3039,6322,3745856,62[sTfR] [nmol·l-1]
82,3214,0624,9043038,54[EPO] [U·l-1]
22,1019,800,8602320,30Hb [g·dl-1]N=7
67602,6367461,57Hct [%]Females
MAXMINSt. DesMeanParameterN=25
5EPO and sTfR in altitude residents HAPPOM
Correlation blood-letting vs EPO• Two patients deserve special attention:
B-14: Blood-letting 4/7/2005Sample Collection: 6/7/2005[EPO]: 109,4 U/l[sTfR]: 93,51 nmol/l
B-21: Blood-letting 14/9/2005Sample Collection: 15/9/2005[EPO]: 212,96 U/l[sTfR]: 140,65 nmol/l
[EPO] cut-off 36 U·l-1 [sTfR] cut-off 28 nmol·l-1.
This fact suggests that blood letting, although used frequently in EE patients, is not recommendable.
6EPO and sTfR in altitude residents HAPPOM
Methods (I).We included 75 patients from
“ La Rinconada” in Puno-Peru.• The place, a gold mine, is located at 5,435 m• The Rinconada is the highest permanent human
settlement in the world.
Inclusion criteria:- Whole life at high altitude:(3,800 - 5,435 m).
The Rinconada residents came from nearby high-altitude places and became permanent residents
- Excessive erythrocytosis : [Hct > 60 %]- CMS Score
7EPO and sTfR in altitude residents HAPPOM
! Asmus (Leadville CO. USA, 1993) EE " CMS: Hct ≥56% males
Hct ≥51% females
! Vasquez (Potosi-Bolivia, 2001)EE " Hct ≥61% Hb ≥21 g/dL males
Hct ≥56% Hb ≥19 g/dL females
! Consensus Statement high altitude diseases (Xining, China 2004).CMS " EE: Hb ≥21 g/dL males SS,SH,PH Hb ≥19 g/dL females
Excessive Erythrocytosis. (EE)
8EPO and sTfR in altitude residents HAPPOM
The Qinghai CMS score
• Breathlessness 0. Absent• Sleep disturbance 1. Mild• Cyanosis 2. Moderate• Dilatation of veins 3. Severe• Paresthesia Absent Score = 0-5• Headache Mild Score = 6-10• Tinnitus Moderate Score = 11-14• Hb Severe Score>15
9EPO and sTfR in altitude residents HAPPOM
La Rinconada 5,435 mPuno – Perú
10EPO and sTfR in altitude residents HAPPOM
La Rinconada 5,435 mPuno – Perú
The Rinconada Mine
11EPO and sTfR in altitude residents HAPPOM
# Blood samples were taken by venipuncture.
#Hemoglobin (Hb) and Hematocrit (Hct) were measured directly.
• Aliquots of serum were stored at -20°Cand sent to Charité UniversitätsmedizinBerlin for analysis.
• By ELISA we assessed concentrations of– Erythropoietin
([EPO], cut-off 36 U·l-1).– soluble Transferrin Receptor
([sTfR], cut-off 28 nmol·l-1).
Methods (II).
12EPO and sTfR in altitude residents HAPPOM
RESULTS (I) (Age)
15-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 55-60
Age_group
0
2
4
6
8
10
12
14
2
11
14 14
7
14
5
3
5
Frec
uenc
y20 30 40 50 60
0
2
4
6
8
10
12
Age
Frec
uenc
y
N = 75 MalesMean = 35,9
Min = 16Max = 58
13EPO and sTfR in altitude residents HAPPOM
RESULTS (II)
581610,335,9[Age] [years]
56,415,07,1725,12[sTfR] [nmol·l-1]
105,22,127,730,6[EPO] [U·l-1]
26,420,11,2822,3Hb [g·dl-1]
80613,9067,8Hct [%]Males
MAXMAXMINMINStandardStandardDeviationDeviationMeanMeanParameterParameterN=75
14EPO and sTfR in altitude residents HAPPOM
Distribution: Patients by CMS Score
2,7
50,7%50,7%41,3%41,3%
5,3%
MildModerate
CMSAbsent: 0 - 5Mild: 6 - 10Moderate: 11 -14Severe: >15
Severe
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RESULTS (III).No correlation between Hct and Hb with [Age]
10 20 30 40 50 60
60
65
70
75
80
R2 = 0,002
[Hct
] (%
)
[Hct
] (%
)10 20 30 40 50 60
20,0
21,0
22,0
23,0
24,0
25,0
26,0
27,0
R2 = 0,002
[Hb]
(g/d
L)
Age Age
16EPO and sTfR in altitude residents HAPPOM
RESULTS (IV).No correlation between Hct and Hb with [EPO]
60 65 70 75 80Hct (%)
0,0
20,0
40,0
60,0
80,0
100,0
120,0
R2 = 0,001
[EPO
] (U
/l)
20,0 21,0 22,0 23,0 24,0 25,0 26,0 27,0Hb (g/dL)
0,0
20,0
40,0
60,0
80,0
100,0
120,0
R2 = 0,001
EPO
] (U
/l)
17EPO and sTfR in altitude residents HAPPOM
RESULTS (V).No correlation between age with [EPO] and [sTfR]
10 20 30 40 50 60Age
0,0
20,0
40,0
60,0
80,0
100,0
120,0
R2 = 0,029
[EPO
] (U
/l)
10 20 30 40 50 60Age
10,0
20,0
30,0
40,0
50,0
60,0R2 = 1,382E-6
[sT
fR] (
nmol
/l)
18EPO and sTfR in altitude residents HAPPOM
RESULTS (VI).No correlation between Hct and Hb with [sTfR]
60 65 70 75 80Hct
10,0
20,0
30,0
40,0
50,0
60,0
R2= 0,042
20,0 21,0 22,0 23,0 24,0 25,0 26,0 27,0
10,0
20,0
30,0
40,0
50,0
60,0
R2 = 0,042
[sT
fR] (
nmol
/l)
[sT
fR] (
nmol
/l)
Hb
19EPO and sTfR in altitude residents HAPPOM
RESULTS (VII)
0,0 20,0 40,0 60,0 80,0 100,0 120,0
10,0
20,0
30,0
40,0
50,0
60,0
R2 = 0,001
[sT
fR] (
nmol
/l)
[EPO] (U/l)
20EPO and sTfR in altitude residents HAPPOM
Group A) with �normal” [EPO] (≤ 38 U·l-1) Group B) with very high [EPO] (≥ 78 U·l-1)
60 65 70 75 80
Hct (%)
0,0
20,0
40,0
60,0
80,0
100,0
120,0
[EPO
] (U
/l)
A
B
21EPO and sTfR in altitude residents HAPPOM
Differences between two high- altitude populations in LA. ( male subjects)
• El Alto � Bolivia ( 4100 m) (n=71)
• La Rinconada � Peru (5500 m).(n= 75)
22EPO and sTfR in altitude residents HAPPOM
RESULTS (A).No Significant differences between Males from El Alto and
La Rinconada for Hct (p=0.122) and Hb (p=0.055).
El_Alto RinconadaPopulation
55
60
65
70
75
80140
[Hct
]
20,0
22,0
24,0
26,0
140
[Hb]
PopulationEl_Alto Rinconada
23EPO and sTfR in altitude residents HAPPOM
RESULTS (B).Significant differences between Males from El Alto and La Rinconada
for Age (p=0.000); EPO (p=0,002); sTfR (p=0.000)
20
40
60
80
[Age
]
0,00
50,00
100,00
150,00
200,00
250,00
137113114
35
33
45
34
6831
[EPO
]
0,00
30,00
60,00
90,00
120,00
150,00
81
68
74[sT
fR]
Population Population PopulationEl_Alto El_Alto El_AltoRinconada Rinconada Rinconada
24EPO and sTfR in altitude residents HAPPOM
DISCUSSION (I).Possible explanation of the differences between the two populations.
HYPOTHESIS:The expression of high [sTfR] in subjects from El Alto could be related to low levels of IRON (iron deficiency) in plasma caused by frequent blood letting.On the other hand, normal [sTfR] in subjects from La Rinconada could explain a normal iron metabolism related with age in spite of the altitude level.
25EPO and sTfR in altitude residents HAPPOM
• Since the males from El Alto were significantly older than the males from La Rinconada, we must presume a relatively high prevalence of Chronic Obstructive Pulmonary Disease (COPD)among these people.
• Unfortunately, no data on the prevalence of COPD in LA PAZ/El Alto exist.
• The only study on prevalence of COPD available, was carried out by Dr. Ingrid Melgarejo in 5 hospitals in La Paz with the result of 12,09 %.
(Ingrid Melgarejo, IIBA-2005, personal communication)
DISCUSSION (II).
26EPO and sTfR in altitude residents HAPPOM
• Serum soluble transferrin receptor increases in iron deficiency as reported in literature.
• In general, to increase sensitivity and specificity, the measurement of serum sTfRshould be performed in combination with other tests:
• iron status • ferritin • TIBC • serum iron
DISCUSION (III)
27EPO and sTfR in altitude residents HAPPOM
• The subjects of La Rinconada had never been submitted to blood-letting, which could be the reason for the normal [EPO] values found in this population.
• We found normal [sTfR] in the majority of the subjects without correlation to [EPO].
• Measurements of [EPO]+[sTfR] in high-altitude residents with normal Hb and Hctvalues are necessary in order to establish a cut-off parameter for high-altitude.
CONCLUSIONS
28EPO and sTfR in altitude residents HAPPOM
