Objective: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-a (TNF-a), interleukin-1b (IL-1b) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). Subjects: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. Results: Serum IL-6 concentrations were signi®cantly higher in both untreated patients (P < 0.001) and treated patients (P < 0.006), when compared with controls. Serum sIL-6R concentrations were signi®cantly affected by treatment (P 0:001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not in¯uenced by thyroid function and there was a signi®cant interaction between treatment and the presence of active TAO (P 0:003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were signi®cantly higher than in those with inactive TAO (P 0:003). In untreated GD patients there was no signi®cant effect of thyroid function and TAO activity on the serum concentrations of TNF-a and IL-1b. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-a, IL-1b and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-a and IL-1b and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. Conclusions: Our work shows that: (i) the proin¯ammatory cytokine pattern in GD is greatly in¯uenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

The relatively impaired glucose tolerance in the afternoon is associated with a delayed insulin response to the glucose load. This seems unlikely to be the sole explanation, however, and increased non-esterified fatty acid metabolism with a consequent decrease in glucose disposal may also contribute.

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.

Summary The variety of clinical presentations of eye changes in patients with Graves’ disease suggests that complex interactions between genetic, environmental, endogenous and local factors influence the development/severity of Graves’ ophthalmopathy (GO). At present, the role of genetic factors in the development of GO remains unknown. Based on small case‐control association studies with candidate genes, several susceptibility loci in GO have been proposed. These are human leucocyte antigen (HLA, 6p21·3), cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4, 2q33), tumour necrosis factor (TNF, 6p21·3), interferon‐γ (IFN‐γ, 12q14), intercellular adhesion molecule‐1 (ICAM‐1, 19p13), and thyroid stimulating hormone receptor gene (TSH‐R, 14q31). Unfortunately, these results were either not confirmed or require replication in larger studies. There are many reasons for the lack of reproducibility of association studies in GO, including poor characterization of the studied groups and small sample sizes, which may result in both false positive and negative results. Thus, the genetic background of GO remains to be elucidated in future research. However, the possibility that GO may be a genetically heterogeneous disorder, or that the development of GO may be predominantly influenced by environmental factors such as cigarette smoking, can not be disregarded.