Claudio Marcocci

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

Cigarette Smoking and Treatment Outcomes in Graves Ophthalmopathy

Cigarette smoking is a risk factor for Graves ophthalmopathy [1]. Ophthalmopathy is more frequent and tends to be more severe in smokers than in nonsmokers [2]. Smoking may influence ophthalmopathy through direct irritative effects or by modulating immune reactions that occur in Graves ophthalmopathy [1]. Radioiodine therapy for Graves hyperthyroidism seems to be associated with an increased risk for progression of ophthalmopathy [3-5], but this view is not shared by all investigators [6, 7]. Discrepant results may be related to confounding variables, one of which may be smoking. Severe Graves ophthalmopathy can be treated with medical therapy, usually by glucocorticoids with or without orbital radiation therapy or by orbital decompression [8]. Results of medical treatment are not always satisfactory, and the reasons for nonuniform treatment outcome are not fully understood. We sought to determine whether cigarette smoking influences the untoward effects of radioiodine therapy on ophthalmopathy and the effectiveness of medical therapy for severe ophthalmopathy. Methods Patients Study 1 Study 1 included 300 patients receiving radioiodine treatment for Graves hyperthyroidism with mild or no ophthalmopathy. Mild ophthalmopathy was defined as proptosis less than 22 mm, intermittent or no diplopia, absence of optic neuropathy, and mild conjunctival and periorbital inflammation. Exclusion criteria were severe ophthalmopathy, large goiter requiring thyroidectomy, and contraindications to glucocorticoids. The 300 patients, who previously took part in a study analyzing the effect of radioiodine on ophthalmopathy [5], were assigned by computer-generated random numbers to treatment with radioiodine alone or radioiodine followed by a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day) [3]. Five patients in the radioiodine plus prednisone group were lost to follow-up. Smoking habits did not differ in the two groups. Study 2 This retrospective study included 150 consecutive patients with severe ophthalmopathy (110 women and 40 men; mean age, 41 years [range, 30 to 63 years]) treated from 1989 to 1995 with orbital radiation therapy (20 Gy per eye) and high-dose oral prednisone (initial dose, 80 to 100 mg) [9]. The prednisone dose was gradually tapered, and therapy was discontinued after 6 months. Severe ophthalmopathy was defined as proptosis of 22 mm or more, inconstant or constant diplopia, and marked inflammatory soft-tissue changes with or without optic neuropathy. The study was approved by the institutional review board, and informed consent was obtained from patients. Smoking Habits The number of cigarettes smoked was measured in pack-years, expressed as x = a x b/c, where a = number of cigarettes smoked per day, b = number of years of smoking, and c = 20 cigarettes per pack. Patients who had refrained from smoking for less than 1 year were considered smokers. Smokers were subdivided into light ( 10 pack-years), moderate (11 to 19 pack-years), and heavy smokers ( 20 pack-years). Ocular Evaluation Ocular evaluation, performed by one examiner who was blinded to treatment and smoking groups, included assessment of soft-tissue changes; measurement of proptosis (by Hertel exophthalmometry), ocular tension, and lid width; evaluation of eye muscle function (Hess chart or computerized perimetry); and determination of visual acuity. The activity score was determined according to the method of Mourits and colleagues [10], which includes consideration of seven manifestations (spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and swelling of the caruncle); one point was given to any manifestation, for a score from 0 (no activity) to 7 (very high activity). Each patient provided a self-assessment evaluation sheet. Appearance, progression, and alleviation of ophthalmopathy were defined according to major and minor criteria [5]. Major criteria were variations in exophthalmometer readings and lid width of 2 mm or more, diplopia (intermittent, inconstant, or constant), variations in activity score of 2 points or more, and changes in visual acuity of 1/10 or more. Minor criteria were variations in soft tissues or self-assessment. Appearance, progression, and alleviation of ophthalmopathy were defined by changes in at least two major criteria and one minor criterion [5]. Statistical Analysis Differences in the prevalence of smokers in the two studies were analyzed by using a chi-square test with Yates correction for continuity. Exact binomial 95% CIs were calculated for all proportions. Patients in study 1 were included in an intention-to-treat analysis in which the effects of radioiodine or radioiodine plus prednisone on ophthalmopathy were evaluated according to the predefined criteria outlined above. Role of the Study Sponsor Neither funding source had a role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Study 1 Among patients who received radioiodine alone, 23 (15.3% [95% CI, 10% to 22%]) had progression of ophthalmopathy. Ocular conditions were unchanged in the remaining 127 patients [5]. Among patients who received radioiodine plus prednisone, 0 had progression and 50 of 75 (66.7% [CI, 55% to 77%]) had alleviation of eye disease [5]. In the group that received radioiodine alone, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) (P = 0.007). In the group that received radioiodine plus prednisone, ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 22%]) (P < 0.001) (Table 1). Table 1. Smoking Behavior and Outcome of Mild Graves Ophthalmopathy Study 2 Of 150 consecutive patients, 85 (57%) were smokers. Sixty patients (40%) had an excellent or good response to therapy and 59 (39.3%) had a moderate response. Ophthalmopathy remained unchanged in 26 patients (17.3%) and progressed in 5 (4.3%). Duration of ophthalmopathy did not differ among groups. Sixty-one of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) (P < 0.001) responded to therapy (Table 2). Thirty-three of the 58 smokers who responded to therapy (56.9% [CI, 45% to 68%]) and 5 of 27 nonresponders (18.5% [CI, 9% to 29%]) were light smokers (P = 0.01). Table 2. Smoking Behavior and Outcome of Treatment of Severe Graves Ophthalmopathy with Orbital Radiation Therapy and High-Dose Glucocorticoids Discussion The results of our randomized study showed that cigarette smoking was associated with progression of mild ophthalmopathy, seen in 15% of patients after radioiodine therapy. In addition, smoking was associated with reduced efficacy of glucocorticoids given concomitantly with radioiodine. In the retrospective study, smoking and degree of smoking seemed to adversely affect the outcome of orbital radiation therapy and high-dose glucocorticoid treatment in patients with severe ophthalmopathy. Cigarette smoking is a risk factor for Graves ophthalmopathy. The prevalence of smoking is higher in patients with Graves disease who have ophthalmopathy than in those who do not have ophthalmopathy [1], and some [2, 11, 12] but not all [13] studies show a relation between degree and duration of smoking and severity of ophthalmopathy. Tallstedt and associates [4] reported that progression of ophthalmopathy after radioiodine therapy was more frequent in smokers than in nonsmokers, although differences were not statistically significant. Similarly, in a small series of Chinese women, Kung and coworkers [14] found no differences between smokers and nonsmokers in the progression of ophthalmopathy after radioiodine therapy. The differences between our results and those of previous studies may be explained by the larger number of patients and the consequent greater power of our study. Ethnic factors may also be important: Asian patients have a lower risk for ophthalmopathy, and the prevalence of smoking among Asian women is low [11]. Medical management of severe ophthalmopathy mostly relies on orbital radiation therapy or treatment with high-dose steroids, but results are not always favorable [8]. This may be related to several factors, including the long duration or limited activity of ophthalmopathy [8]. Our results suggest that smoking also negatively affects treatment outcome. Of note, several smokers in study 1 had no progression of ophthalmopathy after radioiodine therapy, and the condition improved with concomitant prednisone treatment. Similarly, in study 2, several smokers had excellent or good responses to orbital radiation therapy and high-dose glucocorticoid therapy. This implies that cigarette smoking is only one of many risk factors involved in the progression of ophthalmopathy. Identification of such risk factors should be a goal of future research so that treatment may be improved and disease may be prevented. The mechanisms by which cigarette smoking may affect the course of Graves ophthalmopathy and its response to treatment are largely unknown [1]. Besides having direct irritative effects, smoking may affect immune reactions occurring in the retro-orbital space [15]. Cytokines present in the retro-orbital tissues of patients with Graves ophthalmopathy [16] exert several actions relevant to the pathogenesis of the disease, including induction of expression of MHC class II molecules, heat-shock proteins, and adhesion molecules [16]. Cytokines also stimulate orbital fibroblasts to proliferate and to secrete glycosaminoglycans; the latter are responsible for most manifestations of the disease [15]. Smoking may intervene in cytokine-mediated paracrine and autocrine actions because smoking-induced hypoxia in the retrobulbar space stimulates the release of cytokines [17]. Interleukin-1 may play a pivotal role in this context, and interleuki

Minimally invasive surgery for thyroid small nodules: preliminary report.

Cytological assessment of cold thyroid nodules cannot exclude malignancy in case of follicular tumors. Many follicular nodules undergo surgery although most of them later on prove to be benign. We report a new minimally invasive video-assisted approach (MIVA) for the treatment of thyroid lesions with a diameter minor than 3 cm. Ten females and 2 males (mean age: 37 yr) with a cold thyroid nodule and a cytological diagnosis of microfollicular tumor were selected for MIVA hemythyroidectomy. The procedure was carried out through a 15 mm incision with needlescopic instruments and a 308 5-mm endoscope. Mean operative time was 87 min (range 60-120). No complications were registered. Cosmetical result was excellent in all patients. MIVA hemythyroidectomy is safe and effective; indications and limits of this new procedure require further studies.

Minimally invasive, video-assisted parathyroid surgery for primary hyperparathyroidism

A new video-assisted surgical procedure for treatment of primary hyperparathyroidism combined with intraoperative quick PTH measurement was developed. This procedure was successfully used in 6 patients with a single parathyroid adenoma preoperatively localized by neck ultrasound examination.

More on smoking habits and Graves' ophthalmopathy.

Since a relationship between cigarette smoking and the occurrence of Graves’ ophthalmopathy has been recently postulated, we reviewed the smoking habits of 1730 women, including subjects without thyroid disease, with nontoxic goiter (NTG), toxic nodular goiter or toxic adenoma (TNG), Hashimoto’s thyroiditis (HT), Graves’ disease without ophthalmopathy (GD) or with ophthalmopathy (GO). The prevalence of smokers in NTG, TNG and HT was about 30%, not different from that of controls. Smokers were 47.9% in GD and 64.2% in GO groups. The latter figures were highly different from those of the other groups and also from each other. The percentage of heavy smokers was higher in patients with more severe ophthalmopathy. No clear explanation for this phenomenon can be offered. The absence of a high prevalence of smokers among patients with nontoxic goiter, nonautoimmune hyperthyroidism and Hashimoto’s thyroiditis, limits the impact that smoking might have had in the pathogenesis of goiter, hyperthyroidism and autoimmune phenomena of GD and GO.

Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I

CONTEXT In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. OBJECTIVES Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. DESIGN The study was designed to detect autoantibodies against interferon-alpha2 and interferon-omega in antiviral neutralization assays. SETTING AND PATIENTS Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. OUTCOME The diagnostic value of anti-interferon autoantibodies was assessed. RESULTS We found antibodies against interferon-alpha2 and/or interferon-omega in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-omega, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n=174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. CONCLUSIONS Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study

We have carried out a prospective study to investigate whether orbital radiotherapy combined with high dose systemic glucocorticoids is more effective than orbital radiotherapy alone for Graves’ ophthalmopathy. Thirty consecutive patients with relevant and active Graves’ ophthalmopathy were randomly assigned to treatment either with orbital radiotherapy combined with systemic glucocorticoids (Group 1, n =15) or with orbital radiotherapy alone (Group 2, n = 15). The final evaluation was made 6–9 months after beginning treatment. Two patients in each group were lost to follow-up. Ocular involvement and response to treatment were evaluated by the ophthalmopathy index and by clinical assessment. Mean ophthalmopathy index values were 5.85 in Group 1 and 5.46 in Group 2 (p = NS) before treatment, and 2.46 in Group 1 and 3.61 in Group 2 after treatment (p = 0.0001 and p = 0.003 vs initial value, respectively). The mean ophthalmopathy index decrease in Group 1 (−3.39) was significantly greater (p = 0.043) than that in Group 2 (−1.85). Favorable responses on clinical ground occurred in 9 patients (69%) in Group 1 and in 5 patients (38%) in Group 2. The difference was particularly evident on soft tissue changes and extraocular muscle involvement. Severe eye muscle restriction was substantially unaffected by either treatment. In conclusion, the association of orbital irradiation and high dose systemic glucocorticoids in the treatment of severe Graves’ ophthalmopathy provides more favorable responses than orbital radiotherapy alone.

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.

Cinacalcet Reduces Serum Calcium Concentrations in Patients with Intractable Primary Hyperparathyroidism

CONTEXT Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia. OBJECTIVE The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT. DESIGN This was an open-label, single-arm study comprising a titration phase of variable duration (2-16 wk) and a maintenance phase of up to 136 wk. SETTING The study was conducted at 23 centers in Europe, the United States, and Canada. PATIENTS The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter). INTERVENTION During the titration phase, cinacalcet dosages were titrated every 2 wk (30 mg twice daily to 90 mg four times daily) for 16 wk until serum calcium was 10 mg/dl or less (2.5 mmol/liter). If serum calcium increased during the maintenance phase, additional increases in the cinacalcet dose were permitted. MAIN OUTCOME MEASURE The primary end point was the proportion of patients experiencing a reduction in serum calcium of 1 mg/dl or greater (0.25 mmol/liter) at the end of the titration phase. RESULTS Mean +/- sd baseline serum calcium was 12.7 +/- 0.8 mg/dl (3.2 +/- 0.2 mmol/liter). At the end of titration, a 1 mg/dl or greater reduction in serum calcium was achieved in 15 patients (88%). Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. The most common adverse events were nausea, vomiting, and paresthesias. CONCLUSIONS In patients with intractable PHPT, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.