Michele Marinò

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

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.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures

Aim: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves’ orbitopathy (GO) receiving surgery for disfiguring proptosis. Method: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. Results: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. Conclusions: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

An update on medical management of Graves' ophthalmopathy.

Graves’ ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves’ disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3–5% of affected individuals, quality of life is severely impaired even in patients with mild GO. Management of severe GO can be either medical or surgical (orbital decompression, eye muscle or lid surgery). Medical management relies on the use of highdose systemic glucocorticoids or orbital radiotherapy, either alone or in combination. Studies carried out in the last 5 yr have shown that glucocorticoids are more effective through the iv route than through the oral route. However, particular attention should be paid to possible liver toxicity of iv glucocorticoids. Recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. At variance with previous encouraging data, recent randomized clinical trials have shown that currently available SS analogs are not very effective in the management of GO. Antioxidants might have a role, at least in mild forms of GO. Particular attention should be paid to correction of risk factors (cigarette smoking, thyroid dysfunction, radioiodine therapy) involved in GO progression.

Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves’ ophthalmopathy treated successfully with glucocorticoids themselves

We report a case of acute hepatitis of autoimmune origin which occurred in a 43-yr-old woman during iv glucocorticoid (GC) pulse therapy for Graves’ ophthalmopathy (GO). Prior to therapy, liver function tests were normal with no previous history of liver disorders or conditions predisposing to GC-associated liver damage. After the administration of a 4.7-g cumulative dose of methylprednisolone acetate, there was a marked increase of liver enzymes, prompting immediate discontinuation of iv GC. Nevertheless, liver enzymes increased further, reaching a peak 45 days later, with values 30- to 50-fold greater than those prior to therapy, associated with evidence of impaired liver function. Liver biopsy showed a marked lymphocytic infiltration, likely indicating an autoimmune hepatitis. Based on the assumption that following GC-induced immune suppression, autoimmune hepatitis might have been precipitated by sudden re-activation of the immune system during interpulse periods, we treated the patient with im and then oral GC, in order to re-induce immune suppression. Within three days from re-institution of GC therapy, there was a marked reduction of liver enzymes and amelioration of liver function. Complete normalization was achieved two months later, while the patient was still receiving a low maintenance dose of oral prednisone.

Thyroglobulin in orbital tissues from patients with thyroid-associated ophthalmopathy: predominant localization in fibroadipose tissue.

UNLABELLED One of the hypotheses that explains the pathogenesis of thyroid-associated ophthalmopathy (TAO) is that thyroglobulin (Tg) is transported through a retrograde lymphatic route to orbital tissues (OT), where it elicits autoimmune damage. In a previous study we demonstrated the presence of intact Tg of thyroid origin in OT from three patients with TAO. The present study was undertaken to investigate this issue further, by increasing the number of patients, by analyzing the distribution of Tg in OT, and by investigating possible relations between the presence of Tg in OT and the clinical features of patients. OT was obtained from seven patients with TAO who underwent decompressive orbitotomy via a transpalpebral approach. Patients were designated P10 to P16. Inflamed palpebral skin, retrobulbar fibroadipose tissue and extraocular muscle surgical samples were collected separately. Tissue extracts were prepared by homogenization and analyzed for the presence of Tg using two different techniques. We first performed immunoprecipitation experiments, in which a rabbit polyclonal anti-Tg antibody was used to capture Tg on protein A and a mouse monoclonal anti-Tg antibody was used to re-veal captured Tg by Western blotting. Intact 330-kd Tg was detected in retrobulbar fibroadipose tissue extracts from three patients (P10, P11, and P16), whereas no Tg was detected in retrobulbar fibroadipose tissue extracts from the remaining four patients. Tg was not detected in the extraocular muscle extracts from all patients studied. In addition, intact 330-kd Tg was found in the inflamed palpebral skin extract from one patient (P10). No Tg was detected in OT extracts from two patients without thyroid or eye disease and in abdominal adipose tissue extracts from two obese patients without thyroid or eye disease. We then searched for Tg by enzyme-linked immunosorbent assay (ELISA), using the same antibodies used for immunoprecipitation. Tg was detected in retrobulbar fibroadipose tissue extracts from four patients (P10, P11, P12, and P16) and in the inflamed palpebral skin extract from patient P10, in amounts ranging from approximately 125 to approximately 400 pg/microg of tissue protein. Again, Tg was not detected in extraocular muscle extracts. A positive gradient between Tg in OT and Tg in the serum was observed in patient P12. Using an ELISA approach, we found that Tg in OT from three TAO patients (P10, P11, and P12) contained thyroxine (T4) residues (mean T(4) CONTENT 2.42 molecules per molecule of Tg), indicating that Tg had originated in the thyroid. Combining the results obtained in our previous and present study, we found a possible relation between the presence of Tg in OT and the previous treatment with radioiodine. Thus, of the seven patients (3 in the previous and 4 in the present study) in whose OT Tg was found, six had been treated with radioiodine, whereas of the three patients with no Tg in their OT none had been treated with radioiodine. In conclusion, Tg was found in OT extracts from patients with TAO by immunoprecipitation in three of seven cases and by ELISA in four of seven cases. Tg was found in retrobulbar fibroadipose tissue, but not in extraocular muscles. There was a relation between the presence of Tg in OT and the previous treatment with radioiodine. Our results support the hypothesis that Tg may play a role as a coantigen in the pathogenesis of TAO. Further studies are needed to investigate this possibility.

Absence of primary hypothyroidism and goiter in Slc26a4 (-/-) mice fed on a low iodine diet.

Background: Mutations in the SLC26A4 gene, coding for the anion transporter pendrin, are responsible for Pendred syndrome, characterized by congenital sensorineural deafness and dyshormonogenic goiter. The physiological role of pendrin in the thyroid is still unclear and the lack of a thyroid phenotype in some patients with SLC26A4 mutations and in Slc26a4 (-/-) mice indicate the existence of environmental or individual modifiers able to compensate for pendrin inactivation in the thyroid. Since pendrin can transport iodide in vitro, variations in iodide supply have been claimed to account for the thyroid phenotype associated with pendrin defects. Aim: The Slc26a4 (-/-) mouse model was used to test the hypothesis that iodide supply may influence the penetrance and expressivity of SLC26A4 mutations. Materials and methods: Slc26a4 (-/-) and (+/+) mice were fed up to 6 months on a standard or low iodine diet and were evaluated for thyroid structural abnormalities or biochemical hypothyroidism. Results: A 27-fold iodide restriction induced similar modifications in thyroid histology, but no differences in thyroid size, T4 or TSH levels were observed between between Slc26a4 (-/-) and (+/+) mice, either in standard conditions and during iodine restriction. Conclusions: Iodide restriction is not able to induce a thyroid phenotype in Slc26a4 (-/-) mice. These experimental data, together with those coming from a review of familial Pendred cases leaving in regions either with low or sufficient iodide supply, support the idea that the expression of thyroid phenotype in Pendred syndrome is more powerfully influenced by individual factors than by dietary iodide.

PREGO (presentation of Graves’ orbitopathy) study: changes in referral patterns to European Group On Graves’ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012

Background/aims The epidemiology of Graves’ orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time. Methods Prospective observational study of European Group On Graves’ Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000. Results The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01). Conclusions These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

An update on the medical treatment of Graves’ hyperthyroidism

Medical treatment of Graves’ hyperthyroidism is based on the use of thionamides; namely, methimazole and propylthiouracil. In the past, methimazole was preferred by European endocrinologists, whereas propylthiouracil was the first choice for the majority of their North American colleagues. However, because of the recent definition of a better side-effect profile, methimazole is nowadays the first choice world while. Although thionamides are quite effective for the short-term control of Graves’ hyperthyroidism, a relatively high proportion of patients relapses after thionamide withdrawal. Other possible medical treatments, include iodine and compounds containing iodine, perchlorate, lithium (as an adjuvant in patients undergoing radioiodine therapy), β-adrenergic antagonists, glucocorticoids, and some new molecules still under investigation. Management of Graves’ hyperthyroidism using thionamides as well as the other available medical treatments is here reviewed in detail, with a special mention of situations such as pregnancy and lactation, as well as neonatal and fetal thyrotoxicosis.