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Both genetic and environmental factors may increase the risk to develop GO in patients with Graves’ hyperthyroidism. Specifically, advanced age, male sex, tobacco use, biochemically more severe hyperthyroidism and high TSH receptor antibodies have been identified as risk factors, as well as ¹³¹I therapy.

Several susceptibility loci for Graves’ hyperthyroidism (like HLA, CTLA-4, TNF, IFN-γ, ICAM-1, TSH receptor) have been proposed to be associated with an additional risk for developing GO, but the results of these small association studies with candidate genes are either not confirmed or require replication in larger studies [14, 15]. Recent studies found a higher frequency of particular polymorphisms in IL-1α, IL-1RA genes among Graves’ patients with GO than in Graves’ patients without GO [16]. It seems that in Graves’ hyperthyroidism the risk of developing GO depends more on environmental factors (especially smoking) than on a peculiar genetic context.

GO, like hyperthyroidism, is more common in women than men. However, men are at risk for more severe GO [1–4].

TSH-R autoantibodies are involved in the disease process of GO, and their detection may be of clinical benefit. TSH-binding inhibitory immunoglobulin levels are significantly higher in patients with a severe course of GO compared with patients with a mild course, and they are a risk factor independent from age and smoking. However, this observational study must be confirmed by a prospective study [17].

The type of treatment given for Graves’ hyperthyroidism may be a risk factor for GO. Thyroidectomy and antithyroid drugs do not appear to have a negative influence on the course of GO. In comparison, most studies suggest that radioiodine treatment might lead to the development or worsening of GO [1, 18].

Other possible risk factors for GO include advanced age. Neck irradiation makes susceptible patients prone to develop Graves’ hyperthyroidism and thereby sometimes also GO [19]. Older patients with restricted ocular motility, strabismus, and active GO are at higher risk of dysthyroid optic neuropathy [20].