Wilmar M. Wiersinga

Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO

Summary of consensus a. All patients with GO should (Fig. 1):Be referred to specialist centers;Be encouraged to quit smoking;Receive prompt treatment in order to restore andmaintain euthyroidism.b. Patients with sight-threatening GO should be treatedwith i.v. GCs as the first-line treatment; if the responseis poor after 1–2 weeks, they should be submitted tourgent surgical decompression.c. The treatment of choice for moderate-to-severe GO isi.v. GCs (with or without OR) if the orbitopathy isactive;surgery(orbitaldecompression,squintsurgery,and/or eyelid surgery in this order) should beconsidered if the orbitopathy is inactive.d. In patients with mild GO, local measures and anexpectant strategy are sufficient in most cases, buttreatment may be justified if QoL is affectedsignificantly. In memoriam This document is dedicated to the memory of MarkPrummel (1956–2005), one of the founders ofEUGOGO, who greatly contributed to expanding ourunderstanding of clinical and therapeutic aspects of GO.

Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy.

Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Incidence, predictability, and pathogenesis of amiodarone-induced thyrotoxicosis and hypothyroidism

PURPOSE To determine the incidence and predictability and to elucidate the pathogenesis of amiodarone-induced thyrotoxicosis (AIT) and hypothyroidism (AIH). PATIENTS AND METHODS A prospective study was performed in 58 consecutive euthyroid patients living in an area with moderately sufficient iodine intake, who had never been treated for thyroid disease and who started amiodarone therapy for the first time. MAIN OUTCOME MEASURES Development of thyrotoxicosis or hypothyroidism. RESULTS The follow-up period was 6 to 54 months (mean, 21 months). The incidence of AIT was 12.1%. A steady occurrence of new cases was observed. The development of AIT was unpredictable and of unexplained sudden onset. The incidence of AIH was 6.9%. All AIH cases occurred early in the course of amiodarone therapy. The development of AIH was related to pre-existent thyroid disease: the relative risk for women with microsomal and/or thyroglobulin autoantibodies prior to treatment was 13.5 (95% confidence interval 3.2 to 57.4). The development of AIT or AIH was not related to the extent of iodine overload or to the occurrence of de novo thyroid autoantibodies. When a decreased thyrotropin (TSH) response to thyrotropin-releasing hormone occurred (in the absence of AIT), continuation of amiodarone medication was associated with a normalization of the TSH response in eight of 11 cases (73%); in contrast, an increased TSH response (in the absence of AIH) returned to normal in one of four cases (25%). CONCLUSION In euthyroid subjects living in an area with a moderately sufficient intake of iodine, there is a higher incidence of AIT than of AIH. AIH is an early event, occurring especially in women with thyroid autoantibodies prior to treatment. Cases of AIT continue to occur during amiodarone therapy; its development is unpredictable and of unexplained sudden onset. The value of regular thyroid function testing is therefore limited during amiodarone administration.

Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death

BACKGROUND To examine the relationship between maternal TSH and free thyroxine (FT(4)) concentrations in early pregnancy and the risk of miscarriage, fetal or neonatal death. METHOD Cohort study of 2497 Dutch women. TSH, FT(4), and thyroid peroxidase antibodies concentrations were determined at first booking. Child loss was operationalized as miscarriage, fetal or neonatal death. Women with overt thyroid dysfunction were excluded. RESULTS Twenty-seven cases of child loss were observed. The mean TSH and FT(4) level in the women with child loss was 1.48 mU/l and 9.82 pmol/l compared with 1.11 mU/l and 9.58 pmol/l in women without child loss. The incidence of child loss increased by 60% (OR=1.60 (95% confidence interval (CI): 1.04-2.47)) for every doubling in TSH concentration. This association remained after adjustment for smoking, age, parity, diabetes mellitus, hypertension, previous preterm deliveries, and previous preterm stillbirth/miscarriage (adjusted odds ratio=1.80 (95% CI: 1.07-3.03)). This was not true for FT(4) concentrations (OR=1.41 (95% CI: 0.21-9.40); P=0.724). CONCLUSION In a cohort of pregnant women without overt thyroid dysfunction, the risk of child loss increased with higher levels of maternal TSH. Maternal FT(4) concentrations and child loss were not associated.

Risk factors for and prevalence of thyroid disorders in a cross‐sectional study among healthy female relatives of patients with autoimmune thyroid disease

objective Autoimmune thyroid disease (AITD) is a common disorder especially in women, and both genetic and environmental factors are involved in its pathogenesis. We wanted to gain more insight into the contribution of various environmental factors. Therefore, we started a large prospective cohort study in subjects at risk of developing AITD, for example healthy female relatives of AITD patients. Here we report on their baseline characteristics.

Development of a disease specific quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL

AIM To develop a reliable and valid disease specific quality of life questionnaire (the GO-QOL) for patients with Graves’ ophthalmopathy (GO), that can be used to describe the health related quality of life and changes in health related quality of life over time as a consequence of disease and treatment. METHODS 70 consecutive GO patients (age >18 years) who were referred for the first time to the combined outpatient clinic of the orbital centre and the department of endocrinology completed the 16 questions of the GO-QOL. Additional information on general quality of life and disease characteristics was obtained. Construct validity and internal consistency of the disease specific questionnaire was determined, based on principal component analysis, Cronbach alphas and correlations with MOS-24, three subscales of the SIP, demographic, and clinical measures. RESULTS The a priori expected subdivision of the questionnaire in two subscales, one measuring the consequences of double vision and decreased visual acuity on visual functioning, and one measuring the psychosocial consequences of a changed appearance, was confirmed in the principal component analysis. Both scales had a good reliability and high face validity. Correlations with other measures supported construct validity. Mean scores (range 0–100) were 54.7 (SD 22.8) for visual functioning and 60.1 (24.8) for appearance (higher score = better health). CONCLUSION The GO-QOL is a promising tool to measure disease specific aspects of quality of life in patients with GO and provides additional information to traditional physiological or biological measures of health status.

DETERMINANTS OF THYROID VOLUME AS MEASURED BY ULTRASONOGRAPHY IN HEALTHY ADULTS IN A NON‐IODINE DEFICIENT AREA

Thyroid volume was measured by ultrasonography in 50 healthy adults (25 males, 25 females, age 20‐70 years) living in the non‐iodine deficient area of Amsterdam. Thyroid volume was 10‐7 ± 4–6 ml (mean ± SD, range 2.7‐20.4 ml). No relation was found between thyroid volume and any of the following parameters: plasma TSH, T4, T3, thyroglobulin (Tg), urinary iodine excretion, tobacco and alcohol consumption. Thyroid volume in males (12.7 ± 4.4 ml) was greater than in females (8.7 ± 3.9 ml, p = 0.0014), but no sex difference was observed in the ratio of thyroid volume to body weight (males, 0.16 ± 005 ml/ kg; females 013 ± 0.06 ml/kg; NS). Thyroid volume was positively related to body weight, but not to age. We conclude that the sex difference in thyroid volume is due to the difference in body weight between males and females. Lean body mass is presumably the most important physiological determinant of thyroid size in subjects living in a non‐iodine deficient area.

Association of the TSHR gene with Graves' disease: the first disease specific locus

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD ‘blocks’ and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 × 10−6, OR 1.7) with Graves’ disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1366 AITD cases and 1061 controls (GD, P=2 × 10−6, OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.

Smoking and thyroid

Current smoking in population surveys is associated with a slight dose‐dependent fall of serum TSH, likely secondary to a rise of serum FT4 and FT3 induced by activation of the sympathetic nervous system; it is independent of iodine intake. In contrast, the slightly greater thyroid size in smokers is observed in iodine‐deficient but not in iodine‐sufficient areas and caused by competitive inhibition of thyroidal iodide uptake by thiocyanate. Smokers have an increased prevalence of nontoxic goitre and thyroid multinodularity, at least in iodine‐deficient areas. Current smoking reduces dose dependently the risk of thyroid cancer, which is more pronounced for papillary than for follicular types; the risk in former smokers approaches that of never smokers. The lower TSH and lower body mass index in smokers might contribute to this reduced risk. Current smoking lowers the risk of developing thyroid peroxidase and thyroglobulin antibodies and subclinical and overt autoimmune hypothyroidism; the effect is dose dependent, but disappears within 3 years after quitting smoking. There is evidence from an animal model of experimental autoimmune thyroiditis that anti‐inflammatory effects of nicotine are involved. In contrast, smoking is a dose‐dependent risk factor for Graves’ hyperthyroidism and especially for Graves’ ophthalmopathy. Smoking is related to a higher recurrence rate of Graves’ hyperthyroidism, a higher risk on Graves’ ophthalmopathy after 131I therapy and a less favourable outcome of GO treatment with steroids or retrobulbar irradiation. The observed associations with smoking likely indicate causal relationships in view of consistent associations across studies, the presence of dose–response effects and disappearance of associations after cessation of smoking.

Clinical Features of Dysthyroid Optic Neuropathy: A European Group on Graves Orbitopathy (EUGOGO) Survey

Background: This study was performed to determine clinical features of dysthyroid optic neuropathy (DON) across Europe. Methods: Forty seven patients with DON presented to seven European centres during one year. Local protocols for thyroid status, ophthalmic examination and further investigation were used. Each eye was classified as having definite, equivocal, or no DON. Results: Graves’ hyperthyroidism occurred in the majority; 20% had received radioiodine. Of 94 eyes, 55 had definite and 17 equivocal DON. Median Clinical Activity Score was 4/7 but 25% scored 3 or less, indicating severe inflammation was not essential. Best corrected visual acuity was 6/9 (Snellen) or worse in 75% of DON eyes. Colour vision was reduced in 33 eyes, of which all but one had DON. Half of the DON eyes had normal optic disc appearance. In DON eyes proptosis was > 21 mm (significant) in 66% and visual fields abnormal in 71%. Orbital imaging showed apical muscle crowding in 88% of DON patients. Optic nerve stretch and fat prolapse were infrequently reported. Conclusion: Patients with DON may not have severe proptosis and orbital inflammation. Optic disc swelling, impaired colour vision and radiological evidence of apical optic nerve compression are the most useful clinical features in this series.