Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 360-362
CORRESPONDENCE
Congenital Erythropoietin-Dependent Erythrocytosis Responsive to
Theophylline Treatment
 |
LETTER |
To the Editor:
In a recent article in BLOOD, Sergeyeva et al1 describe a
secondary form of congenital polycythemia that appears to be
particularly frequent in Chuvasia, a region in the central part of
European Russia. This erythrocytosis is transmitted as an autosomal
recessive trait and generally becomes clinically manifest in the
second decade of life. Because these individuals have elevated
erythropoietin (Epo) levels with no abnormality in hemoglobin (Hb)
dissociation curve or red blood cell 2,3-diphosphoglycerate, Sergeyeva
and coworkers1 conclude that the excessive Epo production
likely reflects an abnormal oxygen sensing mechanism.
We studied a 17-year-old girl with a history of intermittent headache
and progressive appearance of plethora. One year before admission a
blood cell count showed Hb 19.4 g/dL, hematocrit 65.6%, red
blood cell 7.65 × 1012/L, white blood cell 4.15
× 109/L, and platelet 130 × 109/L. Her
parents and a sister had normal blood counts. Spleen size was normal
and arterial saturation was 96.6%. Serum Epo (sEpo) was increased (107
mU/mL), and there was no evidence of in vitro spontaneous burst-forming
unit-erythroid growth from peripheral blood. Because Hb increased to
over 20 g/dL, in the months preceding admission to our department the
patient underwent regular phlebotomies to maintain levels around 16
g/dL.
We first excluded abnormalities in oxygen unloading of hemoglobin by
measuring Hb P50 using the Hemox-Analyzer (TCS Medical
Products Division, Southampton, PA). The oxyhemoglobin dissociation
curve was normal and P50 was 24.5 mmHg (normal values range
from 23 to 27.5 mm Hg).
Serum Epo was determined using venous blood sampled without
anticoagulant by means of an enzyme-linked immunosorbent assay
(ELISA) (CLINIGEN, Amgen Diagnostic, Thousand Oaks, CA); values
in normal reference individuals range from 6 to 20 mU/mL. Serum
transferrin receptor (sTfR), the level of which provides an estimate of
erythroid marrow activity,2 was also measured by an ELISA
(CLINIGEN); values in normal reference individuals range from 1.47 to
3.4 mg/L.
Basal sEpo was 204 mU/mL with a Hb level of 16.6 g/dL, a value 10 times
the upper normal limit. At the same time sTfR was 9.7 mg/L, ie, four
times the mean normal level. It should be noted that in this case the
elevated sTfR level was likely a result of both increased erythroid
marrow activity and iron deficient erythropoiesis. In fact, transferrin
saturation was 11%, and defective iron supply to erythropoiesis
increases both the expression of transferrin receptors on erythroid
cells and sTfR level.2 In any case, the above findings
indicated an inappropriately elevated endogenous Epo production
with secondary expansion of erythroid marrow activity. Computed
tomography scans of the chest and the abdomen, ultrasonography of the
abdomen, and magnetic resonance imaging of the brain excluded
Epo-producing tumors and/or renal disorders. In addition, sEpo
appeared to be normally influenced by oxygen-mediated feedback (107
mU/mL at a Hb level of 19.4 g/dL v 204 mU/mL at 16.6 g/dL).
We therefore concluded for a congenital form of polycythemia,
transmitted with an autosomal recessive pattern of inheritance and
caused by an upregulated oxygen sensing mechanism.3 This
condition appears to be very similar to the Chuvash
polycythemia.1
To further investigate the regulation of Epo production, we evaluated
whether Epo synthesis was normally modulated by adenosine as a second
messenger. Adenosine receptor antagonists like theophylline, in fact,
attenuate the production of Epo in both normal subjects and patients
with erythrocytosis after renal transplantation.4,5 We
therefore tested the effect of theophylline on sEpo and sTfR levels.
The patient was given intravenous theophylline, 240 mg two times a day
for 2 days; subsequently she took a long-acting preparation of
theophylline (7 mg per kg of body weight per day). The time course of
sEpo and sTfR under theophylline treatment is reported in Fig
1. There was a definite decrease in both
endogenous erythropoietin production and erythroid marrow activity
within a few days, although after 11 days values remained still
elevated. Treatment was continued with oral administration of
theophylline. Hb level declined to about 15 g/dL and remained stable
around this value for several months.
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| Fig 1.
Effects of theophylline on serum Epo and serum
transferrin receptor (TfR) in the 17-year-old girl with
erythropoietin-dependent erythrocytosis. Theophylline was given
intravenously in the first 2 days and then orally (see text for
details).
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In conclusion, we suggest to evaluate the effect of theophylline on
endogenous Epo production in Chuvash polycythemia. This may allow to
gain a deeper insight into the pathophysiology of this disorder and to
try a potentially useful therapeutic tool.
Mario Cazzola
Roberta Guarnone
Paola Cerani
Andrea Rovati
Edoardo Ascari
Department of Internal Medicine and Medical
Therapy
Section of Internal Medicine and Medical
Oncology
University of Pavia Medical School and IRCCS Policlinico S.
Matteo
Pavia, Italy
| |
ACKNOWLEDGMENT |
This study has been supported by IRCCS (Istituto di Ricovero e Cura a
Carattere Scientifico) Policlinico S. Matteo and the Ferrata Storti
Foundation, Pavia, Italy.
| |
REFERENCES |
1.
Sergeyeva A,
Gordeuk VR,
Tokarev YN,
Sokol L,
Prchal JF,
Prchal JT:
Congenital polycythemia in Chuvasia.
Blood
89:2148,
1997[Abstract/Free Full Text]
2.
Cazzola M,
Beguin Y:
New tools for clinical evaluation of erythropoiesis and iron status in man.
Br J Haematol
80:278,
1992[Medline]
[Order article via Infotrieve]
3.
Whitcomb WH,
Peschle C,
Moore M,
Nitschke R,
Adamson JW:
Congenital erythrocytosis: A new form associated with erythropoietin-dependent mechanism.
Br J Haematol
44:17,
1980[Medline]
[Order article via Infotrieve]
4.
Bakris GL,
Sauter ER,
Hussey JL,
Fisher JW,
Gaber AO,
Winsett R:
Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation.
N Engl J Med
323:86,
1990[Abstract]
5.
Barosi G:
Control of erythropoietin production in man.
Haematologica
78:77,
1993[Medline]
[Order article via Infotrieve]
