subclinical autonomic dysfunction in patients with beta-thalassemia
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RESEARCH LETTER
Subclinical autonomic dysfunction in patientswith beta-thalassemia
Elefterios Stamboulis • Nikoleta Vlachou • Konstantinos Voumvourakis • Athina Andrikopoulou •
Chrisa Arvaniti • Athanasios Tsivgoulis • Dimitrios Athanasiadis • Sotirios Tsiodras • Nikolaos Tentolouris •
Heleni Triantafyllidi • Marouso Drossou-Servou • Aphrodite Loutradi-Anagnostou • Georgios Tsivgoulis
Received: 22 July 2011 / Accepted: 8 November 2011 / Published online: 15 December 2011
� Springer-Verlag 2011
Abstract We electrophysiologically evaluated the auto-
nomic function (AF) in a consecutive series of patients
with beta-thalassemia and in normal individuals. Six
quantitative autonomic function tests (AFTs) were used:
tilt test, hand grip test and sympathetic skin response for
sympathetic function; R–R interval, inspiration–expiration
difference and 30/15 ratio for parasympathetic function.
The prevalence of impaired AF was higher in beta-thalas-
semia patients (13%, n = 5) than in control subjects (0%,
n = 0; p = 0.026). Subclinical autonomic dysfunction
appeared to be more prevalent in beta-thalassemia patients
compared to controls in our series. Further independent
validation of this finding is required in larger cohorts of
beta-thalassemia patients.
Keywords Autonomic dysfunction � Beta-thalassemia �Neuropathy � Cardiovascular reflexes
Introduction
Beta-thalassemia syndromes are a group of hereditary
disorders characterized by a genetic deficiency in the
synthesis of beta-globin chains. It has recently been shown
that cardiac autonomic function was impaired in a popu-
lation of beta-thalassemia patients with preclinical heart
disease [1]. Although there is increasing evidence indi-
cating that the peripheral nervous system may be affected
in beta-thalassemia [4], the ANS has not been systemati-
cally evaluated in patients with this hereditary hemato-
logical disorder. In view of the former considerations, we
aimed to electrophysiologically assess the autonomic
function in a consecutive series of patients with beta-thal-
assemia and in normal individuals.
E. Stamboulis � N. Vlachou � K. Voumvourakis �A. Andrikopoulou � C. Arvaniti � A. Tsivgoulis �G. Tsivgoulis (&)
Second Department of Neurology, Attikon Hospital,
University of Athens, Iras 39, 15344 Athens, Greece
e-mail: tsivgoulisgiorg@yahoo.gr
D. Athanasiadis
Vascular Unit, Third Department of Surgery,
Attikon Hospital, University of Athens, Athens, Greece
S. Tsiodras
Fourth Academic Department of Internal Medicine
and Infectious Diseases, Attikon University Hospital,
University of Athens Medical School, Athens, Greece
N. Tentolouris
First Department of Propaedeutic Medicine,
Athens University Medical School, Athens, Greece
H. Triantafyllidi
Second Department of Cardiology, Medical School,
Attikon Hospital, University of Athens, Athens, Greece
M. Drossou-Servou
Thalassemia Unit, General Hospital of Piraeus, Athens, Greece
A. Loutradi-Anagnostou
Prenatal Diagnosis Unit, Center for Thalassemia, Laikon General
Hospital, Athens, Greece
G. Tsivgoulis
Department of Neurology, Democritus University of Thrace,
University Hospital of Alexandroupolis, Alexandroupolis,
Greece
123
Clin Auton Res (2012) 22:147–150
DOI 10.1007/s10286-011-0154-2
Subjects and methods
Study population
We examined a consecutive series of patients with beta-
thalassemia diagnosed and followed up regularly at two
tertiary referral centers [4]. Patients with age over 60 years,
diabetes or other known possible causes of neuropathy
were excluded from the study. All included patients had
normal vitamin B12, folic acid, and serum protein elec-
trophoresis and immunofixation. They were also free of
cardiovascular disease as assessed by clinical history,
electrocardiography and echocardiography. No patient had
clinical evidence of visual or auditory dysfunction. The
control group consisted of healthy volunteers with no his-
tory of diabetes mellitus, or neurological or hematological
disorders. Fasting serum glucose was measured in cases
and controls. Patients with fasting serum glucose levels
[110 mg/dL (cutoff for impaired glucose tolerance) were
excluded from further evaluation.
Autonomic function testing (AFT)
All AFTs were performed in the laboratory under stan-
dardized conditions by the same two experienced investi-
gators who were blinded to the medical history of the
patients. All measurements were performed between 8.00
a.m. and 11.00 a.m. in a silent room at a temperature of
22–25�C. The subject lay on a tilt table in the supine
position and rested for at least 15 min before each inves-
tigation. Patients were not permitted to have food, alcohol,
caffeine or nicotine for at least 12 h before the study. All
medication was discontinued 12 h before the examination.
The sympathetic function was tested using the following
battery of tests: tilt test, hand grip test and sympathetic skin
response. The parasympathetic function was tested using
the R–R interval during deep breathing, the Valsalva ratio
and responses to standing. The methodology used by our
group for assessing autonomic dysfunction in our electro-
physiology laboratory has been previously described in
detail [3].
Nerve conduction studies
In all patients, the electrophysiological studies were per-
formed by the same investigator and standard procedures
were used as previously described [3, 4].
Statistical analyses
Comparisons between patients and controls were per-
formed using the v2 test, Fisher’s exact test, unpaired t test
and Mann–Whitney U test as indicated. The Statistical
Package for Social Sciences (SPSS Inc., version 10.0 for
Windows) was used for statistical analyses.
Results
We evaluated a consecutive series of 39 patients (19 men,
mean age 29.2 ± 8.5 years) with beta-thalassemia fulfill-
ing our inclusion criteria and 40 control subjects (12 men,
mean age 26.6 ± 8.0 years). A total of 34 patients had
homozygous beta-thalassemia and 5 had thalassemia
intermedia. The baseline characteristics of the study pop-
ulation are presented in Table 1.
The findings of AFTs in beta-thalassemia patients and
controls are summarized in Table 2. We documented three
patients with impaired sympathetic function in the thalas-
semia group (8%) and no subject with abnormal sympa-
thetic function in the control group (0%; p = 0.116 by
Fisher’s exact test). There were two patients with impaired
parasympathetic function in the thalassemia group (5%)
compared to none in the control group (0%; p = 0.241 by
Fisher’s exact test). The prevalence of impaired autonomic
function was higher in thalassemia patients (n = 5; 13%)
compared to controls (0%; p = 0.026 by Fisher’s exact
test).
Pathological nerve conduction studies indicating an
axonal sensorimotor neuropathy were more frequent in
patients than controls (49 vs. 0%; p \ 0.001 by Fisher’s
exact test; Table 2). After excluding patients with thalas-
semia intermedia (n = 5), we repeated all statistical anal-
yses and documented a higher prevalence of impaired
autonomic function in patients with thalassemia major
Table 1 Baseline characteristics in cases and controls
Characteristic Cases
(n = 39)
Controls
(n = 40)
p
Age, years (mean ± SD) 29.2 ± 8.5 26.6 ± 8.0 0.160
Male sex 49% 30% 0.110
Hematocrit % (mean ± SD) 28.7 ± 2.8 NA NA
Ferritin, ng/mL (median, IQR) 1686
(916, 2841)
NA NA
Intermediate phenotype 13% NA NA
HCV-Abs (?) % 18 NA NA
Splenectomy 54% NA NA
Transfusions (%) 87 NA NA
Duration of transfusions
(mean ± SD, years)
233 ± 5.6 NA NA
Desferrioxamine treatment (%) 74 NA NA
Duration of desferrioxamine
treatment (mean ± SD, years)
12.9 ± 5.6 NA NA
NA not applicable, IQR interquartile range
148 Clin Auton Res (2012) 22:147–150
123
(4/34; 12%) than controls (0/40, 0%; p = 0.040 by Fisher’s
exact test).
Beta-thalassemia patients with impaired (n = 5) and
normal (n = 34) autonomic function did not differ in terms
of age (p = 0.176), gender (p = 0.999), genotype (p =
0.517), ferritin (p = 0.736) and hematocrit (p = 0.512)
levels, splenectomy (p = 0.999), HCV-Abs (p = 0.999)
and duration of transfusion (p = 0.954) or desferrioxamine
(p = 0.441) treatment. Peripheral neuropathy tended to be
more prevalent (p = 0.182 by Fisher’s exact test) in thal-
assemia patients with impaired [80%; (4/5)] than with
normal [44%; (15/34)] autonomic function.
Discussion
Our study showed that autonomic function was subclini-
cally affected in approximately 1 out of 13 patients with
beta-thalassemia. However, the prevalence of impaired
parasympathetic and sympathetic function was 5 and 10%,
respectively, and this difference was not significant com-
pared to control individuals.
Our findings are in line with the results of a recent study
that evaluated autonomic functions of the heart using time
domain heart variability analysis in a group of beta-thal-
assemia patients with a preclinical stage of heart disease
[1]. The authors documented an impaired sympatho-vagal
activity and concluded that diminished heart rate variability
may be an underlying electrophysiological substrate
predisposing to cardiac dysfunction in patients with
beta-thalassemia. Similarly, QTc dispersion, which is a
measure of the duration of ventricular depolarization and
repolarization, was increased in a group of beta-thalasse-
mia patients without any clinical, electrocardiographic or
echocardiographic signs of cardiac disease [5]. Finally, a
recent study from Italy has suggested that intestinal
dysmotility may constitute the underlying factor for bile
stasis and pigment gallstone formation in patients with
beta-thalassemia major [2]. Interestingly, the investigators
documented an independent correlation between impaired
autonomic function and abnormal gallbladder and small
bowel motility in their study population.
Certain limitations of the present report need to be
acknowledged. First, the case–control design of the present
study does not allow us to establish a cause–effect rela-
tionship between autonomic dysfunction and beta-thalas-
semia major. Similarly, given the present sample size, we
should interpret with caution the trend toward a higher
prevalence of autonomic dysfunction in beta-thalassemia
patients with peripheral nervous system involvement. More
specifically, there were only five patients with abnormal
autonomic function tests. These findings indicate that the
degree of autonomic dysfunction in patients with beta-
thalassemia appears to be relatively mild and may be
associated with the presence of peripheral neuropathy.
Finally, subtle cardiac dysfunctions which may influence
cardiac responses to autonomic control are not necessarily
identified on the measures used (echocardiography and
electrocardiography) and therefore remain a plausible
explanation for the moderate autonomic impairment doc-
umented in patients with beta-thalassemia.
In conclusion, subclinical autonomic dysfunction
appears to be more prevalent in beta-thalassemia patients
compared to controls. Given the relative low prevalence of
impaired AF (13%) documented in our series, further
independent validation of this finding is required in larger
cohorts of beta-thalassemia patients.
Acknowledgments Dr Elefterios Stamboulis and Dr Georgios
Tsivgoulis had full access to all of the data in the study and take
responsibility for the integrity of the data and the accuracy of the data
analysis.
Conflict of interest There are no conflict of interest to disclose.
References
1. Gurses D, Ulger Z, Levent E, Aydinok Y, Ozyurek AR (2005)
Time domain heart rate variability analysis in patients with
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Palasciano G (2004) Impaired gallbladder motility and delayed
Table 2 Autonomic function tests and nerve conduction studies
(NCS) in cases and controls
Variable Cases
(n = 39)
Controls
(n = 40)
P*
Impaired sympathetic function,
% (n)
8 (3) 0 (0) 0.116
Tilt test (abnormal/normal) 2/36 0/37
Hand grip test (abnormal/normal) 0/39 0/1/39
SSR (abnormal/normal) 1/38 0/40
Impaired parasympathetic function,
% (n)
5 (2) 0 (0) 0.241
30/15 ratio (abnormal/borderline/
normal)
0/4/35 0/0/40
Valsalva ratio(abnormal/borderline/
normal)
1/14/24 0/0/40
I–E difference (abnormal/borderline/
normal)
1/10/28 0/1/39
Impaired autonomic function, % (n) 13 (5) 0 (0) 0.026
Abnormal NCS, % (n) 49 (19) 0 (0) \0.001
* Fisher’s exact test
Clin Auton Res (2012) 22:147–150 149
123
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150 Clin Auton Res (2012) 22:147–150
123
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