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Purpose Graves’ disease is the underlying diagnosis in the vast majority of Thyroid Associated Orbitopathy (TAO) cases, however patients with primary autoimmune hypothyroidism and those with no previous or current history of thyroid dysfunction occasionally develop TAO. Although the severity of TAO is influenced by high anti-TSH receptors (TRAb) titres and thyrotoxicosis, severe cases of hypo and euthyroid patients without previous documented hyperthyroidism have been described 1 . Genetic susceptibility seems to have a less important role in the pathogenesis of TAO than in autoimmune thyroid disease. Patients can be biochemically hyper-, eu- or hypothyroid at the onset of TAO. The autoimmune status, severity of the eye disease and family history at first presentation to the thyroid eye clinic in a large cohort of patients with TAO, none of whom had undergone thyroid ablation by thyroidectomy or radioactive iodine treatment were investigated (Table 1). Methods Cross sectional study conducted over 8 ½ years (January 1997 to July 2005) in the thyroid-ophthalmology clinic at the University Hspital of Wales. The analysis was performed using SPSS v11.1, including binary logistic regression. Inclusion criteria : All patients with a diagnosis of active TAO based on clinical features, confirmed when in doubt by orbital computer tomography (CT) or magnetic resonance imaging (MRI) who were biochemically euthyroid for a minimum of two months prior to attendance at the clinic. Exclusion criteria : Cases where thyroid disease had been treated by ablation (either surgically or with radioactive iodine) or patient had undergone prior surgical intervention for orbitopathy. Definitions : Mild TAO- minimal or moderate soft tissue swelling; Moderate TAO - marked soft tissue swelling and motility impairment ± diplopia; Severe TAO- sight threatening disease causing corneal exposure or optic nerve compression. Hyperthyroid TAO- previous history of hyperthyroidism or currently taking antithyroid drugs. Euthyroid TAO- normal thyroid function tests with no thyroid history, no clinical signs or symptoms of thyroid disease (except TAO) and no previous medical treatment for thyroid dysfunction. Hypothyroid TAO- Primary autoimmune hypothyroidism and no documented previous hyperthyroid episodes. THYROID ASSOCIATED ORBITOPATHY IN A LARGE SOUTH WALES COHORT I Cozma* ˜, LS Cozma”, RL Boyce^, M Ludgate˜, JH Lazarus˜, C Lane* *Dept Ophthalmology, ˜Centre for Endocrine & Diabetes Sciences, School of Medicine, Heath Park, Cardiff; ”Dept Endocrinology, Princess of Wales Hospital, Bridgend; ^ Dept Ophthalmology, Sunderland Eye Infirmary Results One hundred and forty patients without previous thyroidectomy or radioiodine treatment attended the clinic. One hundred and thirty eight were Caucasians and two were Asian. Their mean age ( + SD) was 48.5 + 4.2 years. The majority of patients (65.7%) were hyperthyroid, 20.7% were hypothyroid with no previous documented hyperthyroid episode and 13.6% have never had any thyroid dysfunction at presentation of TAO (Fig.1). There was a predominance of the severe forms of TAO (43.9%), followed by 14.6% moderate and 41.5% mild cases. Patients with moderate and severe TAO were analyzed together (Table 1, Fig.2). A combination of negative thyroid peroxidase (TPO) antibodies and positive TRAb increased the chance of developing severe TAO in hyperthyroid patients, Fisher exact p=0.032 in a model adjusted for age at diagnosis of TAO. Regarding the autoimmunity, hypothyroid patients with severe TAO were more likely to have a positive family history of thyroid disease or personal history of autoimmunity (8 out of 12, 66.5%) in contrast to the mild hypothyroid (7 out of 17, 41.2%), Fisher exact p=0.03 in the model adjusted for smoking status and age at diagnosis of TAO. Interpretation Our study shows new data regarding TAO in hypothyroid patients and the relationship between antibody status and severity. In our series of 140, 29 (20.7%) were hypothyroid and the increased proportion of these patients is probably a reflection of eliminating the patients with thyroid ablation. In the Graves’ group subjects with an association of negative TPO and positive TRAb antibodies were more prone to present with severe TAO than patients with other antibody findings (Table 2). This combination was also found by Khoo et a l 2 , in a series of 123 patients, to be associated with a higher rate of onset of any degree of TAO in patients with Graves’. We also found a higher prevalence of smokers than reported in the literature 3 in moderate and severe TAO across all thyroid status groups including pure hypothyroid patients. In conclusion our study suggests that TAO occurs quite frequently in patients who have never been hyperthyroid and the severity may be equal in the hyperthyroid and never hyperthyroid groups. ,[object Object],[object Object],[object Object],[object Object],Figure 1 Thyroid status at presentation of TAO (percentages) Figure 2 Severity of TAO in relation to thyroid status Table 1- General characteristics of all (n=140) newly referred patients with active TAO. Data are means + SD. * Student t-test. † ANOVA across all groups. ‡ Chi square or Fisher exact test Table 2 – Autoimmune status in the hyper- and hypothyroid patients NS † 22.0 + 1.3 21.4 + 0.3 24.2 + 1.1 21.2 + 0.6 24.5 + 0.4 21.6 + 0.4 Mean max proptosis moderate-severe mild NS ‡ 3 / 4 9 / 3 10 / 2 13 /4 33 / 3 52 / 4 Bilat disease (Yes/ No): moderate-severe mild NS ‡ 4 / 3 4 / 8 5 / 7 7 / 10 8 / 28 15 / 41 Family history (Yes/ No): moderate-severe mild NS ‡ 5 / 2 5 / 7 9 / 3 6 / 11 26 / 10 34 / 22 Smoker/ non-smoker moderate-severe mild NS ‡ 5 / 2 8 / 4 10 / 2 17 / 0 29 / 7 46 / 10 Sex (female/ male): moderate-severe mild NS † 48.8 + 4.0 52.5 + 3.5 52.2 + 3.8 47.1 + 3.6 47.6 + 2.2 47.7 + 2.1 Age at onset of TAO (yrs): moderate-severe mild NS* - - 50.2 + 4.1 44.7 + 3.9 46.5 + 2.4 46.7 + 2.1 Age at dg of thyroid disease (yrs): moderate-severe mild P Value Euthyroid (n= 19) Hypothyroidism (n= 29) Hyperthyroidism (n= 92) 1 0 4 0 0 3 0 0 4 3 6 2 TPO level (U/ml) : 32-100 100-400 >400 2 (10%) 4 (20%) 3 (15%) 1 (5%) 2 (5.4%) 12 (32.4%) 6(16.2%) 9(24.1%) TPO negative: severe mild 0 2 (10%) 3 (15%) 1 (5%) 4 (10.8%) 3 (8.1%) 7(18.9%) 3 (8.1%) TPO positive: severe mild TRAb negative TRAb positive TRAb negative TRAb positive Hypothyroidism Hyperthyroidism

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