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Long-term results of surgical treatment in Graves' disease orbitopathy. Is there a correlation between the extent of thyroidectomy and the course of orbithopathy?
Elisabeth Maurer, R. Dãnilã, E. Dominguez, T. Osei-Agymang, A. Zielke, I. Hassan (Chirurgia, 103 (3): 295-299)

Introduction
Basedow-Graves' disease is a systemic autoimmune disease that associates thyroidal and extrathyroidal manifestations consisting of thyrotoxicosis, orbitopathy and pretibial myxedema (1). The endocrine orbitopathy (EO) is the most common extrathyroidal involvement, as clinical evident ocular signs are present in about 50% of the patients and subclinical abnormalities can be demonstrated by CT, MRI of the orbit or measurement of intraocular pressure in the majority of the remaining 50% (2). Less frequently the characteristic ocular syndrome occurs in patients with Hashimoto's thyroiditis or apparently without thyroid abnormalities (the so-called euthyroid Graves' disease) (3).
The pathogenesis of EO comprises an increase of retroocular fibroadipose tissue and swelling of extraocular muscles and connective tissues, due to an infiltration with lymphocytes, mastocytes and macrophages (4).
The management of EO should be based on both the severity and activity of the disease. In 2/3 of the cases the disease has usually a spontaneous, self limiting evolution and requires only symptomatic local measures such as topical lubricants, artificial tears, alpha-blocking eye drops and smoking cessation (3, 5). Approximately 15% of the patients will experience an aggravation of EO with chronic proptosis, diplopia and/or strabismus, inducing a significant alteration of life quality and psycho-social disorders. As no causative treatment is currently available, EO may benefit from medical decompression (high dose glucocorticoids, orbital radiation therapy) and orbital surgery (2).
The effect of thyroidectomy on the course of the disease, either as a mean to controlle thyrotoxicosis or to remove the thyroid-orbit shared antigens, remains a matter of debate and makes the subject of our study.

Patients and Methods
A retrospective cross-sectional study was performed on a series of 171 cases of Graves' disease, operated between January 1987 and January 2002 in the Department of Surgery of the Philipps University, Marburg. All patients were identified via the central electronic patient registry. Data related to diagnosis (clinical and hormonal status, thyroid auto antibodies) and medical treatment of GD prior to admission, as well as early postoperative outcome were collected from the medical files. The severity of EO at the time of operation was assessed according to NOSPECS classification (6) (table 1).
A structured telephonic interview was conducted in order to collect and appraise the long term results. The data acquired for all patients were systematized in a standardized table.
The indication for thyroidectomy consisted mainly of failure of antithyroid medication, followed by the size of the goiter (WHO III) and/or a significant or progressive EO.
Total thyroidectomy is actually the accepted standard surgical procedure in Graves' disease. According to the trend of the time, subtotal thyroidectomy was performed in the period 1987-1991, whereas in the following interval 1991-2000, unilateral lobectomy and contralateral near total lobectomy (Hartley-Dunhill) was the preferred operative procedure. In selected cases of severe endocrine ophthalmopathy or pronounced immunologic activity, a total thyroidectomy was performed. Since 2001, total thyroidectomy has become the procedure of choice. All operations were performed or supervised by consultant surgeons, experienced in thyroid and parathyroid surgery. Independent of the extent of resection, a standardized surgical technique was employed, mandating primary identification of the recurrent laryngeal nerve (RLN) as well as visualization and preservation of the parathyroid glands. Parathyroid autotransplantation was performed whenever their blood supply was compromised.
According to the NOSPECS classification of the severity of EO at the time of surgery, the patients were divided in three groups. The patients in group I had no signs of EO, group II consisted of cases with moderate EO while in group III were included the patients with significant ocular involvement.
The course of the orbitopathy after surgery was evaluated using a simplified questionnaire, the patients could answer on the telephone (7)(table 2).

Results
A group of 171 patients were operated for GD between January 1987 and January 2002. Complete data acquisition was possible in 153/171 patients (89 %). The group consisted of 123 women with a median age of 36 years (range 10-75) and 30 men with a median age of 33 years (range 22- 65).
The postoperative follow-up period ranged between 12 and 216 months (median 96 months). 42 (27.5%) patients could not be contacted for the last follow-up. Therefore, the patient's general practitioner was contacted and asked the same set of questions to obtain the relevant data. The level of TSH-receptor antibodies (TRAb) was preoperatively measured in 87/153 patients (56.8 %) and was found increased in 80/87 (92 %). In seven patients (8 %) the TSH-R-Ab level was within the normal range. In these patients clinical symptoms, measurement of endocrine orbitopathy and ultrasonography of the thyroid gland confirmed the suspected Graves´ disease.
No clinical signs of EO were found at the time of operation in 70 patients (45.8 %) - group I. The 83 (54.2 %) patients with clinical eye disease were divided in group II - 63 patients (76 %) with moderate syndrome (grade I-III according to NOSPECS-Classification) and group II - 20 patients (24 %) with marked symptoms of EO (grade IV-V). There were no statistically significant differences between the three groups, in regard to gender, age, TSH-R-Ab level and extent of resection (table 3). So, no correlation could be found between the volume of the thyroid, the level of TSH-R-Ab and the severity of the EO.
The self-assessment of the postoperative course of EO revealed an improvement of eye condition in 53 patients (63.8 %), a stationary course in 29 patients (34.9 %) and only one patient experienced an aggravation. Of the 70 patients without preoperative signs, one patient developed postoperatively the EO (table 4).

Discussion
Although the autoimmune nature of EO is generally accepted, the exact pathogenetic mechanism is not clear. The most valid hypothesis is that autoreactive T lymphocytes directed against one or more antigens common to the thyroid and orbit infiltrate and generate a increased production of glycosaminoglycans in the orbital tissue and the perimysium of extraocular muscles (8).
The most plausible autoantigen is the TSH-receptor as Graves' disease is caused by TSH-R-antibodies (TRAb) and TSH-R expression has been shown in the orbital tissue of EO patients (9,10). In addition, it has been showed a correlation between EO activity and the level of TRAb (11). Other autoantigens have been investigated, including several eye muscle antigens (12), acetylcholine receptor, thyroperoxidase, thyroglobulin (13) and alpha-fodrin (14) but with unconvincing results.
The question is if these patients with Graves' disease and EO should be treated with antithyroid drugs or ablative methods such as surgery, radioiodine therapy or both. Supporters of non-ablative thyroid treatment suggest that control of thyrotoxicosis with antithyroid drugs may be associated with a decrease of autoimmunity and consequently an improvement of ocular conditions; furthermore, once triggered, EO might proceed independently of thyroid treatment (15).
Thyroid resection may be justified by the pathogenic link between thyroid and orbit, so it makes sense to assume that removal of thyroid-orbit shared antigens and autoreactive T lymphocytes might be beneficial to the eye (16).
In our study, 64 % of the patients experienced an improvement of the EO postoperatively, but no correlation with the type of thyroidectomy could be established. These findings are supported by other studies - Witte et al noted an improvement of the EO after surgery in 74 % of the cases but no difference was noted between subtotal and total thyroidectomy (17).
A combination of thyroidectomy followed by radioiodine therapy, designed as total thyroid ablation, was shown to be associated with an improvement of clinical EO (18). Moreover, a recent randomized controlled clinical trial demonstrated that total thyroid ablation is followed by a better outcome of EO in patients given intravenous glucocorticoids, in comparison with surgery alone. (19).
The current data are not enough to support total thyroid ablation in all patients with clinically relevant ocular syndrome but it may be justified for the EO patients benefiting from thyroidectomy as the treatment of choice for their hyperthyroidism (2).
On the other hand, Perros et al followed over a period of 5 yrs the natural course of EO on 59 patients and showed a significant improvement in 20 %, a mild improvement in 40 %, no improvement in 20 % whereas in 20 % a worsening of ocular symptoms was noted (20). This high rate of spontaneous amelioration raises the question of the effectiveness of any of the treatment modalities mentioned above.
In conclusion, although the literature data are controversial, our results support the positive role of thyroidectomy in patients with Graves'orbitopathy, independent of the amount of thyroid tissue resected.

References
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2. BARTALENA, L., HENNEMAN, G. - Graves' Disease: Complications. Graves'orbitopathy. in www. THYROIDMANAGER.ORG, updated February 20, 2007.
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8. BURCH, H.B.,WARTOFSKY, L. - Graves' ophthalmopathy: current concepts regarding pathogenesis and management. Endocr. Rev., 1993, 14:747.
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10. AGRETTI, P., DE MARCO, G., DE SERVI, M., MARCOCCI, C., VITTI, P., PINCHERA, A., TONACCHERA, M. - Evidence for protein and mRNA expression in fibroblasts from patients with thyroid-associated ophthalmopathy (TAO) after adipocytic differentiation. Eur. J. Endocrinol., 2005, 152: 777.
11. GERDING, M.N., VAN DER MEER, J.W., BOENINK, M., BAKKER, O., WIERSINGA, W.M., PRUMMEL, M.F. - Association of thyrotrophin receptor antibodies with clinical features of Graves' ophthalmopathy. Clin. Endocrinol. (Oxf), 2000, 52:267.
12. MIKOZAMI, T., SALVI, M., WALL, J.R. - Eye muscle antibodies in Graves'ophthalmopathy: pathogenic or secondary epiphenomenon? J. Endocrinol. Invest., 2004, 27:221.
13. MARINO, M., CHIOVATO, L., LISI, S., ALTEA, M.A., MARCOCCI, C., PINCHERA, A. - Role of thyroglobulin in the pathogenesis of Graves' ophthalmopathy: the hypothesis of Kriss revisited. J. Endocrinol. Invest., 2004, 27:230.
14. KAHALY, G.J., BANG, H., BERG, W., DITTMAR, M. - Alpha-fodrin as a putative autoantigen in Graves' ophthalmopathy. Clin. Exp. Immunol., 2005, 140:166.
15. WEETMAN, A.P., HARRISON, B.J. - Ablative or non-ablative therapy for Graves' hyperthyroidism in patients with ophthalmopathy? J. Endocrinol. Invest., 1998, 21:472.
16. MARCOCCI, C., BARTALENA, L., PINCHERA, A. - Ablative or non-ablative therapy for Graves' hyperthyroidism in patients with ophthalmopathy? J. Endocrinol. Invest., 1998, 21:468.
17. WITTE, J., GORETZKI, P.E., DOTZENRATH, C., SIMON, D., FELIS, P., NEUBAUER, M., ROHER, H.D. - Surgery for Graves´ disease: total versus subtotal thyroidectomy-results of a prospective randomized trial. World J. Surg., 2000, 24:1303.
18. MOLETI, M., MATTINA, F., SALOMONE, I., VIOLI, M.A., NUCERA, C., BALDARI, S., LO SCHIAVO, M.G., REGALBUTO, C., TRIMARCHI, F., VERMIGLIO, F. - Effects of thyroidectomy alone or followed by radioiodine ablation of thyroid remnants on the outcome of Graves' ophthalmopathy. Thyroid, 2003, 13:653.
19. MENCONI, F., MARINO, M., PINCHERA, A., ROCCHI, R., MAZZI, B., NARDI, M., BARTALENA, L., MARCOCCI, C. - Effects of total thyroid ablation vs near-total thyroidectomy alone on mild to moderate Graves' orbitopathy treated with intravenous glucocorticoids. J. Clin. Endocrinol. Metab., 2007, 92:1653.
20. PERROS, P., CROMBIE, A.L., KENDALL-TAYLOR, P. - Natural history of thyroid-associated ophthalmopathy. Clin. Endocrinol. (Oxf), 1995, 42:45.


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