Graves’ disease have subclinical evidence of GO at imaging, under the clinical point of view a discrete proportion of them does not have overt clinical signs or symptoms of GO. Studies aimed at investigating the prevalence of GO in Graves’ disease have raised rather discordant findings, presumably due to different definitions of GO, absence of standardized eye assessment methods, time-related or geographical variations of GO frequency, and selection biases. Taking these limitations into account, the proportion of hyperthyroid Graves’ disease patients having GO has been reported to range from 13 to 69% [3]. A recent meta-analysis of 12 different studies performed in various countries showed an approximately 33% GO proportion in patients with Graves’ hyperthyroidism [3]. Based on the available studies, there seems to be a progressive decrease in GO prevalence over the years [3, 6], a possible explanation of which is the decrease in smoking in Western countries, where the vast majority of studies was performed.
Are There Any Relationships between Hyperthyroidism, Hypothyroidism, and Graves’ Orbitopathy?
In the majority of cases GO is observed in patients with Graves’ hyperthyroidism and, as shown in Figure 1, there is a close temporal relationship between the onset of hyperthyroidism and the onset of GO [2]. In support of a relationship between GO and hyperthyroidism, GO seems to be more severe in patients with untreated hyperthyroidism [7, 8], to worsen more often in Graves’ disease patients undergoing radioiodine treatment more than once [7], and to deteriorate more frequently in patients who undergo relapse of hyperthyroidism after a course of antithyroid drugs [7]. An explanation of how hyperthyroidism may influence GO is related to tissue oxidative stress induced by the excess of thyroid hormones, oxidative stress being one of the factors contributing to the inflammatory changes of the orbit [9]. However, it is also possible that, at least to some extent, the relationship between hyperthyroidism and GO reflects the fact that GO and hyperthyroidism are due to the same alteration of the immune system against thyroid and orbital antigens [7]. In this regard, each autoimmune activation or reactivation against these antigens may correspond to a temporal association between activation or reactivation of both hyperthyroidism and GO. In line with this interpretation, GO can appear in patients who are euthyroid on antithyroid drugs [2], and, as mentioned above, although rarely, GO can occur in the absence of hyperthyroidism, indicating that the latter condition is not necessary for GO to develop [4].
In addition to hyperthyroidism, also hypothyroidism is believed to affect the course of GO. Thus, progression of GO following radioiodine therapy can be to some extent prevented or at least reduced in frequency, if L-thyroxine replacement for hypothyroidism is initiated early [10, 11]. Hypothyroidism may affect GO because it may worsen orbital deposition of glycosaminoglycans, or because of the action of TSH on its receptor in orbital fibroblasts [9, 12].
Is Graves’ Orbitopathy Related to Thyroid Autoimmunity?
It is widely accepted that GO is an autoimmune condition. A hypothesis on the pathogenesis of GO implies that the responsible autoantigens would be molecules expressed by thyroid cells that are also present in orbital tissues. TSH-R is regarded as the most suitable candidate. TSH-R is expressed and functionally active in orbital tissues [9, 12]. TSH, TSH-R-stimulating antibodies, and a monoclonal anti-TSH-R antibody are capable of upregulating the synthesis of hyaluronic acid and adipogenesis in orbital fibroblasts [13–15]. GO is almost invariably associated with circulating anti-TSH-R antibodies [7, 9, 12], and the severity and the activity of GO correlate with anti-TSH-R antibodies [16]. Finally, a recent animal model resembling to some extent GO was developed by genetic immunization of mice with TSH-R [17]. Recent studies have suggested that, by acting in concert with TSH-R, the insulin-like growth factor 1 receptor, which is also expressed by orbital fibroblasts, may be necessary for TSH-R-driven autoimmunity [18]. Another hypothesis involves thyroglobulin (Tg), the precursor of thyroid hormone, which implies that GO would follow deposition and accumulation of Tg following its release from the thyroid. Once in the orbit, Tg would trigger an autoimmune reaction thereby giving origin or contributing to the development and maintenance of GO [19]. As a matter of fact, Tg of thyroid origin (containing thyroid hormone residues) was found in orbital tissues of GO patients, but no Tg-anti-Tg immune complexes were detected, and no signs of GO have been reported in experimental models of autoimmune thyroiditis obtained in mice by immunization with Tg [19]. Thus, whether Tg is involved in the pathogenesis of GO remains to be established.
Are There Other Extrathyroidal Manifestations of Graves’ Disease apart from Graves’ Orbitopathy?
In addition to GO, patients with Graves’ disease may have localized myxedema and thyroid acropachy [20]. Myxoedema is characterized by a usually restricted and well-delimited area of skin thickening, colouration (from red to brown) (Fig. 2a), pruritus, and occasionally pain. In addition to the pretibial area, its most typical location, the lesion can be rarely seen also on the feet, toes and upper extremities as well as on the forehead and ear. In severe, proliferative cases, the skin can assume an elephantiasic aspect (Fig. 2b). Myxoedema can be treated with local steroids, being quite responsive in the non-proliferative, fortunately most common, variants. Treatments with systemic steroids and other immunosuppressive medications, or with surgery, have also been used, although no clear-cut data on the outcomes are available. Thyroid acropachy is characterized by digital clubbing of fingers (but not toes) and swelling of digits and toes together with a periosteal reaction of extremity bones. Both myxoedema and acropachy are due to proliferation of fibroblasts and deposition of glycosaminoglycans,
