Graves’ orbithopathy (GO, thyroid ophthalmopathy, thyroid eye disease, thyroid-related ophthalmopathy, orbitopathy) is an autoimmune, chronic, debilitating infiltrative eye disorder, which affects the orbit and eyelids. It is often connected with thyroid pathology. Generally it appears in patients with active or treated Graves’ disease or uncommonly with Hashimoto’s thyroiditis (HT) or even among euthyroid patients. Grave’s ophthalmopathy could be disfiguring and potentially severely disabling because of ocular suffering, as well as its influence on vision and appearance. GO influences orbital tissues in 25-50% of patients with Graves’ disease (1-3). On the other hand about 5% of patients with autoimmune thyroiditis or without clinically evident thyroid disease will develop Graves’ ophthalmopathy (4-6). It is diagnosed most commonly in women with female-to-male ratio of 5:1 and with peak occurrence of onset between the ages of 30 and 60 years, much less common in children than in adults (7). GO patients are older than patients with Graves’ hyperthyroidism without orbitopathy. The annual incidence of TAO in the general population is 16.0 per 100 000 population for women and 3 per 100 000 population for men with severe forms accounting for no more than 3-5% of the cases. Although GO is unquestionably more common in women, statistically, severe cases are slightly more common in men. The female to male ratio was 9.3:1 in patients with mild Graves’ orbithopathy, 3.2:1 in those with moderate orbitopathy, and 1.4:1 with severe cases. The severity and incidence of GO depends not only on the gender but it also appears to be significantly higher among smokers compared with nonsmokers (8, 9). Furthermore, cigarette smoking is one of the strongest modifiable risk factor for developing GO. It not only increases the risk of developing Graves’ ophthalmopathy, but also increases its severity and progression with a less beneficial response to therapy. Recently studies reported higher risk for prevalence of GO in patients with hyperthyroidism in Europeans compared to Asians (10). Bartalena at al. and some others researchers investigated relation between the therapy of hyperthyroidism due to Graves’ disease and the course of Graves’ orbitopathy. They showed that that radioiodine therapy for Grave’s disease was followed by the development or more often, the evolution of ophthalmopathy. Otherwise, the patients treated with thionamides or with radioiodine and prednisone had no progression of eye disease. The development of ophthalmopathy after radioiodine therapy could be related with liberate of thyroid antigens as an effect of radiation injury leading to stimulation of autoimmune reactions directed to antigens shared by the thyroid and the orbit. In addition, the post-treatment hypothyroidism is crucial in the development of ophtalmopathy (3, 11).

Although the pathogenic mechanism of Graves’ ophthalmopathy (GO) is still unknown, there is significant evidence for autoimmune reactions directed to orbital antigens, in particular to extraocular muscles, orbital fat, interstitial tissues or lacrymal glands which increase the volume of the orbital contents. Probably Graves’ orbitopathy is induced by an autoimmune reaction against antigens shared by orbital and thyroid fibrous and adipose tissues. The orbital autoantigen has not been conclusively identified but the most popular candidate antigen is the TSH receptor (TRAb) since GO is frequently connected with Graves’ disease and anti-TSH-receptor autoantibodies are founded in nearly 100% of patients with Graves’ orbitopathy. TRAb transcripts were presented by northern blot in orbital adipose tissue from a patient with GO, whereas transcripts in normal adipose tissue being at the limit of the detection (12-16). Recently many researchers and clinicians accepted that TRAb titers and prevalence correlate with the severity and activity of GO (14). It is known that orbital fibroblasts, which present the TSH receptor, are major participants in the pathogenesis of Graves’ ophthalmopathy. Firstly, T lymphocytes are activated by unknown mechanisms and then transit to the thyroid gland, orbit and eyelids. Subsequently, activated T lymphocytes produce cytokines to affect inflammation, local fibroblast activation and expansion of adipose tissue via cellular metaplasia. Activated orbital fibroblasts produce chemokines that recruit T lymphocytes into the orbit. These lymphocytes then cooperate with fibroblasts, probably activating each other. There is increasing evidence that orbital fibroblasts alone and interacting with lymphocytes can release excessive amounts of the of glycosaminoglycans, hyaluronic acid, chondroitin sulfate and finally collagen upon stimulation with various cytokines. In this scenario throglobulin, the TSH receptor, insulin-like growth factor-1 receptor (IGF-1R) or B cells have all been implicated. Inflammation targeted at the extraocular muscles as well as periocular tissues consists of lymphocytes, mast cells, and plasma cells. The histological changes are due to the accumulation of hydrophilic glycosaminoglycans, predominantly hyaluronan, and an increase in orbital adipose and connective tissue. Graves’ ophthalmopathy begins as an active phase (inflammatory phase) followed by partial regression of symptoms which eventually leads to spontaneously remission (inactive phase, static stage) (4, 5). The different clinical signs of active GO are induced by inflammatory processes of retroocular adipose/connective tissue with infiltration of type 1 helper T (Th1) cells but also plasma cells, B cells, mast cells or macrophages. The demonstrate of primarily Th1 cells and connected cytokines (Interferon-gamma [IFN-γ], tumour necrosis factor [TNF], interleukin-2) in early disease indicates that cell-mediated immunity predominates in initial disease. On the other hand in later phases of Graves’ ophthalmopathy predominate Th2 cells and cytokines (interleukin-5, interleukin-4, interleukin-10 and interleukin-13) which stimulating B-cells to produce autoantibodies. Accelerated production of glycosaminoglycans induces an edematous expansion of orbital connective tissue that effects in dysfunction of changed muscles like disturbances in ocular motility, increased orbital pressure and even displacement of the eye (proptosis) (6-8).

The histological changes explain the clinical manifestations of Graves’ orbitopathy which can be variable: exophthalmos, lagophthalmos (inability to close the eye), eyelid retraction, corneal exposure, periorbital and lid edema, edema of the bulbar conjunctivae, palpebral and conjunctival redness, chemosis, epiphora, photophobia, inflamed caruncle, visual changes (visual field defects, reduced visual acuity, reduced color sensitivity), orbital pain, diplopia (most commonly on up-gaze) or strabismus. They may also include loss of eyelashes and eyebrows, dermatochalazia or conjunctival injection. Superior limbic keratoconjunctivitis is known as a prognostic marker for severe disorder (9).