mm for Iranians, 18.6 mm for Chinese, and 17.7 mm for Japanese [13]. The figures must be interpreted with caution as the studies vary in design and methodology.
What Are the Risk Factors for the Occurrence of Graves’ Orbitopathy?
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].
Can Particular Drugs Trigger or Modify Graves’ Orbitopathy and Its Course?
GO is governed by complex pathogenic mechanisms. A number of drug interferences with these pathways have been described, resulting in clinically visible modifications of the disease process.
Antidiabetic thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands known to stimulate adipogenesis. The expression of PPAR-γ was significantly increased in orbital tissue samples from patients with GO compared with normal orbital tissue [21]. According to case reports and cohort studies, TZDs can worsen GO and trigger proliferative proptosis in isolated cases without thyroid dysfunction [22]. On the other hand, PPAR-γ agonists suppress TGF-β-induced hyaluronan biosynthesis in human orbital fibroblasts and exert antifibrotic and anti-inflammatory activity [23]. Complexity of PPAR-γ activation and orbital fibroblast heterogeneity might explain divergent responses to TZD administration, and further research is needed to select PPAR-γ activities to benefit GO.
Alemtuzumab is a humanized anti-CD52 monoclonal antibody used in the treatment of multiple sclerosis. Up to 30% of the treated patients develop thyroid autoimmunity, and several cases of mild-to-moderate GO have been described [24]. Dysbalance of regulatory T cells, increased IL-21 receptor-positive effector T cells, and depletion of intrathyroid natural killer cells after alemtuzumab are presumably involved.
Lithium carbonate is the most common drug used for treating bipolar disorder. Lithium may induce both hypothyroidism and thyrotoxicosis by several mechanisms including triggering of autoimmunity with resultant thyroiditis, abnormal iodine kinetics, Jod-Basedow-like phenomenon, and direct toxicity to thyroid follicles resulting in release of thyroglobulin [25]. GO improvement after lithium withdrawal is a rare finding [26].
Patients treated with IFN-α, mostly for hepatitis C, may develop hypo- or hyperthyroidism and GO [27]. Thyroid antibodies in this group of patients occur in 40% and clinical thyroid disease in 15%. Management of GO cases could be difficult if liver dysfunction does not allow steroid or antithyroid medication use.
Is Tobacco Bad for Graves’ Orbitopathy?
Cigarette smoking is the strongest modifiable risk factor for developing GO. Despite various limitations and difficulties in comparing available studies, there is a strong evidence for a causal association between smoking and development of GO [28, 29].
A positive association between smoking and GO is found in 4 case-control studies in which control patients had Graves’ hyperthyroidism but no orbitopathy (odds ratio 1.94–10.1) and in 7 case-control studies in which control subjects did not have thyroid disease (odds ratio 1.22–20.2) [30].
About 40% of GO patients are smokers [10]. Among patients with orbitopathy, smokers are more likely to have severe disease than non-smokers. The severity of GO is related to the number of cigarettes smoked per day. The volume of intraorbital fat/connective tissue also correlates well with cumulative smoking [31]. Current smokers are also more likely to experience disease progression or poorer outcome of treatment [32, 33]. The effect of immunosuppressive treatment of GO may be attenuated in cigarette smokers [34]. Among patients with mild GO, eye disease progression after radioiodine treatment seems to be significantly higher in smokers than in non-smokers.
