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Levels of thyroid autoantibodies in patients with Graves' disease and graves' ophtalmopathy/ Graves hastaliginda ve Graves oftalmopatisinde tiroid otoantikor duzeyleri.

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 autoantibodies in patients diagnosed with Graves' disease (GD) with and without GO.

Materials and Methods

Patients

This is a cross-sectional retrospective study, which includes 98 patients with GD treated at the Endocrinology clinic of the Alexandrovska Hospital between 2002 and 2008. Seventy-six patients were female (mean age: 49.7 [+ or -] 10.6 years) and twenty-two were male (mean age: 42.7 [+ or -] 11.6 years). They had been referred for hospitalization mainly because of fluctuations in their thyroid function during antithyroid drug therapy or development of GO. The mean duration of GD was 1.6 [+ or -] 0.8 years. 46 patients had newly discovered hyperthyroidism. At the time of referral, the remaining 52 patients were taking antithyroid drugs. None of them had been treated previously with corticosteroids, radio-iodine or surgery. All procedures described below are part of the routine work-up of GD patients at our Endocrinology clinic and were in accordance with the ethical standards of the Committee on human experimentation at the Alexandrovska Hospital as well as on a national level. All patients gave their informed consent for data processing prior to their hospitalization.

Methods

The medical history included family history of thyroid disorders, smoking habits, symptoms of thyroid dysfunction as well as current treatment. A physical examination and anthropometric measurements were then performed. The palpation of the thyroid gland was followed by thyroid ultrasound on a Fukuda-Denshi 5.500 device (Fukuda Corp., Tokyo, Japan). The thyroid volume was calculated according to J. Brunn et al. in milliliters (13). Thyroid hormonesthyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured by a chemiluminescence method (Bayer Diagnostics,Leverkusen, Germany). Antiperoxidase (TPOAb) and TGAb were measured by an electrochemiluminescence method (Hoffmann-La Roche Ltd., Basel, Switzerland). TRAb were measured by an enzymatic-substrate method-ELISA (DRG International Inc., Mountainside, NJ, USA) and represented thyroid-binding inhibitory immunoglobulins. The upper normal limits for thyroid antibody titers were set as follows: TPOAb < 34 IU/l, TGAb < 115 IU/l and TRAb < 1.5 IU/l.

The diagnosis of GO was based mainly on the clinical picture (eyelid retraction, periorbital swelling, diplopia and others) according to the American Academy of Ophthalmology diagnostic criteria. The grade of the eye disease was estimated according to the NOSPECS classification (1) and the clinical activity score (CAS)--according to Mourits et al. (14). All patients were referred for precise workup by an experienced ophthalmologist at our University Hospital. Grade of exophthalmos, intraocular pressure, ocular motility and visual acuity were recorded. The statistical analysis was performed on a SPSS 13.0 for Windows package (SPSS Inc., Chicago, IL, USA). Descriptive statistics, two-sided Student's t-test, the Mann-Whitney U test, non-parametric Kruskal-Wallis and parametric ANOVA, and Spearman's correlation analysis were performed. Significance was set as p [less than or equal to] 0.05.

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 4.8 [+ or -] 1.2.

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.

The hormonal and thyroid autoantibody levels of the participants are displayed in Table 2. Fifty-six of all ninety-eight participants (57.1%) were hyperthyroid (low TSH, elevated fT4) at the time of evaluation (48 newly discovered and eight under antithyroid treatment). Another twelve of the fifty treated patients had low TSH despite normal fT4 levels (24%). Five of the fifty treated patients had low normal fT4 levels and TSH<10 IU/l (iatrogenic subclinical hypothyroidism in 10%).

The patients with GO were more hyperthyroid than those without GO. The levels of all three thyroidal antibodies showed significant differences in the subgroups with and without GO. The presence of GO was associated with higher levels of TRAb and TGAb and lower levels of TPOAb. There was no relevant correlation between the CAS and the levels of TRAb and TGAb (Spearman's [rho]=0.2, p=0.03) or of TPOAb (Spearman's [rho]=0.15, p=0.04). The correlations of thyroid autoantibody levels with the grade of GO were not significant.

Discussion

Graves' ophtalmopathy can develop in 2540% 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.

Eckstein et al. assessed 108 patients with GO after steroid therapy or orbital irradiation (23). The simultaneous presence of thyroid-binding inhibitory immunoglobulins and thyroid-stimulating antibodies was associated with significantly higher activity and severity of GO. Only TRAb, but not TPOAb or TGAb medians, demonstrated statistically significant increase with CAS or NOSPECS scores. Another study tested the hypothesis that TRAb are independent risk factors for GO and can help to predict the severity and the outcome of the disease (6). A significant association between elevated initial thyroid-stimulating immunoglobulins and GO was also found in pediatric patients with GD (20). S.Y. Goh et al. studied the autoantibody profile in patients with GD referred to ophthalmologic or thyroid units (17). Patients with dominant GO had significantly higher stimulating TRAb (p=0.003), but lower TPOAb (p= 0.008) and TgAb levels (p<0.001). In contrast, patients with dominant GD had higher fT4 (p =0.048) and higher thyroid-binding inhibitory immunoglobulin (TBII) levels. An association between smoking and low TPOAb levels was also noted.

In our study, the levels of TRAb and TgAb did not correlate with the grade or clinical activity of GO. Correlations of different grades have been reported by other investigators (4,6). In the study by M.N. Gerding et al., the authors reported that TBII or thyroid-stimulating immunoglobulin titers did not correlate with thyroidal or orbital disease duration, or with TPOAb levels (4). In contrast, they found a striking and highly significant correlation between the CAS of the eye disease and both types of thyroid antibodies (r = 0.54; p<0.0001, and r=0.50; p<0.0001). TRAb might also be regarded as a surrogate marker for autoimmune activity in GO (21) and their levels are influenced by corticosteroid treatment (24). Bulgarian authors have also investigated the possible link between the levels of TRAb and the presence or severity of GO in GD (25).

We feel that the major contribution of this study lies in the measurement of TGAb and TPOAb levels in GD associated with GO. We were able to show higher levels of TGAb and lower ones of TPOAb in our patients with GO as compared with those without ocular involvement. TGAb and TPOAb appear to be secondary responses to the thyroid injury and are not thought to cause the disease themselves. Our conclusion is that these two auto-antibodies might open new perspectives in studying the pathogenesis of GO.

A link between the serum levels of TG, TGAb and the presence of GO has been investigated in a few studies (9-11,13). T. Kuroki et al. reported that the TG-shared antigen site of ocular connective tissue membranes appeared not to be native thyroglobulin (9).

Concerning the anticholinesterase antibodies, J. Geen et al. concluded from their data that the lack of patients with clinically apparent GO militated against a possible causal role of such antibodies (8).

Our study has a number of limitations. First, the small study size and cross-sectional design are far from the ideal large prospective study design. Because of low statistical power, we were unable to apply the ROC-analysis and show a threshold of high risk for GO for all three thyroid antibodies. Our correlation data with the disease severity are also inconclusive. Second, our study population consisted of patients referred to a hospital clinic, which might have introduced a bias toward more aggressive forms of GD and GO. Almost half of the patients were currently hyperthyroid, which could be a reason why antibody titers were higher. Previous studies have shown that euthyroid or primarily hypothyroid patients develop milder and more asymmetrical GO (15). Third, we only measured TRAb levels and did not apply any functional assay for testing their thyroid-stimulating or thyroid-blocking activity. There are accumulated data demonstrating that the characteristics of TRAb are of clinical significance for the progression and severity of GD and GO (26,27).

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

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(9.) Kuroki T, Ruf J, Whelan L, Miller A, Wall JR. Antithyroglobulin monoclonal and autoantibodies cross-react with an orbital connective tissue membrane antigen: a possible mechanism for the association of ophthalmopathy with autoimmune thyroid disorders. Clin Exp Immunol 1985;62:361-70.

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(15.) Eckstein AK, Losch C, Glowacka D, Schott M, Mann K, Esser J, Morgenthaler NG. Euthyroid and primarily hypothyroid patients develop milder and significantly more asymmetrical Graves ophthalmopathy. Br J Ophthalmol 2009;93:1052-6.

(16.) Eckstein A, Mann K, Kahaly GJ, Grussendorf M, Reiners C, Feldkamp J, Quadbeck B, Bockisch A, Schott M. Role of TSH receptor autoantibodies for the diagnosis of Graves disease and for the prediction of the course of hyperthyroidism and ophthalmopathy. Recommendations of the Thyroid Section of the German Society of Endocrinology. Med Klin (Munich) 2009;104:343-8.

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(23.) Eckstein AK, Plicht M, Lax H, Hirche H, Quadbeck B, Mann K, Steuhl KP, Esser J, Morgenthaler NG. Clinical results of anti-inflammatory therapy in Graves ophthalmopathy and association with thyroidal autoantibodies. Clin Endocrinol Oxf 2004;61:612-8.

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Mihail Boyanov, Deniz Bakalov, Galina Sheinkova Endocrinology Clinic, Department of Internal Medicine, Alexandrovska University Hospital, Medical University Sofia, Sofia, Bulgaria

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.
Table 1. Displayed are the clinical data of the participants and
the corresponding thyroid volume (means [+ or -] standard deviation)

 Age, Duration of Current
 years GD, years smoking

Men 42.1 [+ or -] 11.0 1.6 [+ or -] 1.2 50.0%
Women 50.2 [+ or -] 10.4 2.2 [+ or -] 1.8 39.4%

Men + women

With GO 46.0 [+ or -] 10.3 2.4 [+ or -] 2.6 51.3%
Without GO 47.8 [+ or -] 11.1 1.4 [+ or -] 4.7 35.6%

P-value n.s. 0.03 0.002
(T-tests)

 Thyroid
 volume, [cm.sup.3]

Men 27.5 [+ or -] 15.3
Women 22.9 [+ or -] 13.3

Men + women

With GO 24.9 [+ or -] 11.9
Without GO 23.2 [+ or -] 12.9

P-value n.s.
(T-tests)

Table 2. Displayed are the hormonal levels and the thyroid
autoantibodies of the participants--medians and ranges (in
parentheses)

 TSH, IU/I fT4, pmol/I TRAb, IU/I

Men 0.010 28.6 13.3
 (0.001-7.22) (10.1-42.4) (1.9-40.0)

Women 0.140 36.4 15.7
 (0.001-8.11) (10.8-54.7) (2.2-34.4)

Men + women

With GO 0.079 33.7 22.1
 (0.001-8.11) (17.2 -54.7) (3.2- 40.0)

Without GO 0.420 23.2 10.4
 (0.005-6.42) (10.1-34.6) (1.9-22.1)

P value 0.04 0.02 <0.001
(Mann-Whit-ney
tests)

 TPOAb, IU/I TGAb, IU/I

Men 924.4 486.1
 (15-4500) (52-1510)

Women 700.5 296.7
 (10-6000) (24-820)

Men + women

With GO 390.6 412.5
 (10-1200) (90-1500)

Without GO 690.4 190.6
 (34-6000) (52-520)

P value <0.001 <0.001
(Mann-Whit-ney
tests)
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Title Annotation:Original Article/ Orijinal Makale
Author:Boyanov, Mihail; Bakalov, Deniz; Sheinkova, Galina
Publication:Turkish Journal of Endocrinology and Metabolism
Article Type:Report
Geographic Code:4EXBU
Date:Sep 1, 2010
Words:3225
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