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50
Abstract
Objective: Previous studies in patients with Graves disease (GD) and Graves ophtalmopathy (GO) have focused mainly on the levels of
TSH-receptor antibodies (TRAb). Our aim was to investigate the levels of TRAb, thyroid peroxidase (TPOAb) and thyroglobulin antibodies (TGAb)
in patients with GD with and without GO.
Materials and Methods: 98 patients with GD were included in this retrospective study-76 women and 22 men. Thirty-nine patients had
manifested GO - 28 women, 11 men. The serum levels of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured by a
chemiluminescence assay; TPOAb and TGAb - by an electrochemiluminescence method, and TRAb - by an enzymatic-substrate method-ELISA.
Results: Median serum levels of TSH and fT4 were 0.079 IU/l and 37.7 pmol/l in patients with GD + GO versus 0.420 IU/l and 23.2 pmol/l in
patients with GD without GO (p=0.04 for TSH and p=0.02 for fT4). In GD + GO, we found higher levels of TRAb (22.1 versus 10.4 IU/L, p<0.001)
and TGAb (412.5 vs. 190.6 IU/l, p<0.001), and lower levels of TPOAb (390.6 vs. 690.4 IU/l, p=0.001) than in GD alone.
Conclusion: Higher levels of TGAb and TRAb, and lower levels of TPOAb are found in patients with GD with GO compared to patients without
ophtalmopathy. These findings might open new perspectives in studying the pathogenesis of GO. Turk Jem 2010; 14: 50-3
Key words: Graves disease, graves ophtalmopathy, thyroid antibodies
zet
Ama: Graves hastal (GH) ve Graves oftalmopati (GO) hastalar zerinde daha nce yaplm olan almalar, genel olarak TSH-reseptr
antikoru (TRAb) dzeylerine odaklanmtr. Bu almann amac GH ve GO hastalarnn TRAb, tiroid peroksidaz (TPOAb) ve tiroglobulin (TGAb)
dzeylerini aratrmaktr.
Gere ve Yntemler: GH tansyla izlenen 98 hasta, (76 kadn, 22 erkek) bu resrospektif almaya dahil edildi. 39 hastada (28 kadn, 11 erkek)
GO grld. Tiroid stimulan hormon (TSH) ve serbest tiroksin (FT4) dzeyleri kemiluminesan yntemi, TPOAb ve TGAb dzeyleri elektrokemiluminesan
yntemi ile, TRAb dzeyi ise enzim-substrat metodu-ELISA ile lld.
Bulgular: GH+GO hastalarnda medyan serum TSH ve FT4 dzeyleri srasyla 0.079 IU/I ve 37,7 pmol/I iken GO bulunmayan GH hastalarnda
TSH ve FT4 dzeylerinin srasyla 0,420IU/I ve 23,2 pmol/I olduu grlmtr (TSH iin p=0,04, FT4 iin p=0,02). GH+GO hastalarnn TRAb ve
TGAb dzeyleri yalnzca GH mevcut hastalara gre daha yksek iken (srasyla 22,1 e karn 10,4IU/L, p<0,001 ve 412,5 e karn 190.6IU/I,
p<0,001), TPOAb dzeyleri daha dkt (390,6 ya karn 690,4IU/I, p=0,001).
Sonu: GO nun elik ettii GH hastalar oftalmopati bulunmayan GH hastalar ile kyaslandnda, TGAb ve TRAb dzeylerinin daha yksek,
TPOAb dzeyinin daha dk olduu grld. Bu bulgular GO patogenezi zerinde yaplacak almalar iin yeni perspektifler sunabilir. Trk
Jem 2010; 14: 50-3
Anahtar kelimeler: Graves hastal, graves of talmopati, tiroid otoantikor
Address for Correspondence: Mihail A. Boyanov MD, DMSci Endocrinology Clinic, Alexandrovska Hospital 1, G. Sofiiski Str., Sofia 1431 Bulgaria
Phone: + 3592 9230 784 E-mail: mihailboyanov@yahoo.com Recevied: 28.11.2010 Accepted: 07.12.2010
Turkish Journal of Endocrinology and Metabolism, published by Galenos Publishing.
Boyanov et al.
Thyroid Antibodies in Graves Ophtalmopathy
Introduction
Graves ophtalmopathy (GO) is a potentially serious ocular
complication of the auto-immune thyroid disease (AITD). The
treatment of GO is not always successful and the disease can
cause constant damage to the anatomy and function of the eye.
Close observation of subjects with AITD at high risk of GO would
facilitate early preventive measures against this debilitating
complication. Little is known about the risk factors for GO such as
age, male gender, type of antithyroid treatment and smoking (1).
The precise pathological processes, which link both autoimmune
diseases are still under debate (2,3). Auto-antibodies to thyroidal
antigens might be involved in the disease progress of GO per se.
The leading role of TSH-receptor antibodies (TRAb) is now accepted
by many thyroidologists and their measurement might be of
clinical use (4-7). Other potential orbital antigens include
thyroglobulin and cholinesterase epitopes, the flavoprotein
subunit of the mitochondrial succinate dehydrogenase, a 55 kDa
protein (G2s), calsequestrin and others (8-11). Thyroglobulin (TG)
might be produced in small amounts by the orbital fat tissue,
so antithyroglobulin antibodies (TGAb) seem to be of practical
interest in GO (9-12). However, most publications have been
focused on the measurement of TRAb in GO.
The aim of the present study was to investigate thyroid function
and auto-antibodies in patients diagnosed with Graves disease
(GD) with and without GO.
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Results
Thirty-nine study participants had manifested GO-28 women
and 11 men. Therefore, the prevalence of GO in our sample of
ninety-eight patients with GD was 36.8% in women and 50% in
men. According to the NOSPECS classification, three patients
(7.7%) had grade 1 GO, seven patients (17.9%) had grade 2,
eleven patients (28.2%)-grade 3, fifteen patients (38.4%)-grade 4,
two patients (5.1%)-grade 5 and one (2.6%)-grade 6. Twenty-five
patients with GO had a CAS score above 4 (an active disease)
and the mean CAS score for the GO group as a whole was
4.81.2.
The clinical data of the participants including the thyroid volume
measured by ultrasound are summarized in Table 1. Smoking
was more common in patients with GD + GO than in those
without GO. The odds ratio for current smoking in the presence
of GO was 1.44. Thyroid volume did not show significant
differences between the GO+and the GO-subgroups.
Table 1. Displayed are the clinical data of the participants and the
corresponding thyroid volume (meansstandard deviation)
Men
Women
Men + women
With GO
Without GO
P-value
(T-tests)
Age,
years
42.111.0
50.210.4
Duration of
GD, years
1.61.2
2.21.8
46.010.3
47.811.1
n.s.
2.42.6
1.44.7
0.03
Current
smoking
50.0%
39.4%
Thyroid
volume, cm3
27.515.3
22.913.3
51.3%
35.6%
0.002
24.911.9
23.212.9
n.s.
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Boyanov et al.
Discussion
Graves ophtalmopathy can develop in 25-40% of hyperthyroid
patients with GD and much rarely in euthyroid or hypothyroid
patients with autoimmune thyroiditis as well as in euthyroid
subjects without evidence of thyroid disease (15). The immune
mechanisms underlying the thyroid eye disease imply a possible
role of a number of auto-antigens and their specific auto-antibodies.
The most likely candidate antigen still remains the TSH-receptor
(16). A number of authors have found a positive correlation
between the levels of TRAb and the presence or severity of GO
(4,6,17-21). The correlations between the levels of TGAb and GO
are less well validated. A number of studies reported such a
relationship (8-10), while others have not (12). Similarly, data
accumulated about the TPOAb levels are also contradictory
(11,17,19,22).
Our study was performed in patients with newly discovered GD
and in patients already treated with antithyroid drugs. We were
able to prove that the presence of GO was associated with higher
levels of TRAb and TGAb and lower levels of TPOAb and TSH as
compared with patients without GO. The thyroid volume or the
duration of AITD showed no association with the presence of GO.
A collateral finding was that smokers were more prevalent
among patients with GD and GO than among those without GO.
Similar findings have been reported by other authors. A.K.
Table 2. Displayed are the hormonal levels and the thyroid autoantibodies of the participants - medians and ranges (in parentheses)
Men
Women
Men + women
With GO
Without GO
P value
(Mann-Whit-ney
tests)
TSH, IU/l
0.010
(0.001-7.22)
0.140
(0.001-8.11)
fT4, pmol/l
28.6
(10.1-42.4)
36.4
(10.8-54.7)
0.079
(0.001-8.11)
0.420
(0.0056.42)
0.04
33.7
(17.2 -54.7)
23.2
(10.1-34.6)
0.02
TRAb, IU/l
13.3
(1.9-40.0)
15.7
(2.2-34.4)
22.1
(3.2- 40.0)
10.4
(1.9-22.1)
<0.001
TPOAb, IU/l
924.4
(15-4500)
700.5
(10-6000)
TGAb, IU/l
486.1
(52-1510)
296.7
(24-820)
390.6
(10-1200)
690.4
(34-6000)
<0.001
412.5
(90-1500)
190.6
(52-520)
<0.001
Conclusion
In summary, we performed a pilot study in patients with GD with
and without GO and found different levels of TRAb, TGAb and
TPOAb in case of presence or absence of GO. Our study should
be regarded as an urge for conducting further large prospective
studies relating thyroid autoimmunity with the clinical course of
GO in GD and for further elucidation of the pathogenesis of GO.
Acknowledgments
The authors wish to thank Assoc. Prof. V. Christov, former Head
of the Endocrinology Clinic, for his encouragement in this work
and Dr. L. Wezenkova and Dr. D. Manolov for their help in
collecting the patients data.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Boyanov et al.
Thyroid Antibodies in Graves Ophtalmopathy
53