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OBJECTIVE: Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. METHODS: The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. RESULTS: Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. CONCLUSION: GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.

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OBJECTIVE: We aimed to investigate the role of DIO2 polymorphisms rs225014 and rs12885300 in Graves' disease patients, mainly for controlling body weight following treatment. METHODS: We genotyped 280 GD patients by the time of diagnosis and 297 healthy control individuals using a TaqMan SNP Genotyping technique. We followed up 141 patients for 18.94 ± 6.59 months after treatment. RESULTS: There was no relationship between the investigated polymorphisms with susceptibility to GD and gain or loss of weight after GD treatment. However, the polymorphic inheritance (CC+CT genotype) of DIO2 rs225014 was associated with a lower body weight variation after GD treatment (4.26 ± 6.25 kg) when compared to wild type TT genotype (6.34 ± 7.26 kg; p = 0.0456 adjusted for the follow-up time). This data was confirmed by a multivariate analysis (p = 0.0138) along with a longer follow-up period (p = 0.0228), older age (p = 0.0306), treatment with radioiodine (p-value = 0.0080) and polymorphic inheritance of DIO2 rs12885300 (p = 0.0306). CONCLUSION: We suggest that DIO2 rs225014 genotyping may have an auxiliary role in predicting the post-treatment weight behavior of GD patients.

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ABSTRACT Objective Graves' disease (GD) is the main cause of hyperthyroidism among adults. It is an autoimmune condition classically marked by the Merserburg Triad (goiter, thyrotoxicosis, and orbitopathy), but the change in presentation of GD over time has rarely been studied. To determine changes in the clinical presentation of patients with GD in the last 30 years. Subjects and methods The study evaluated 475 patients diagnosed with GD between 1986 and 2016 in a single center. Patients were evaluated regarding epidemiological aspects, thyroid function, inflammatory activity of the eyes evaluated by the Clinical Activity Score; CAS, severity evaluated by NOSPECS classification and thyroid volume estimated by ultrasonography. Results Patients assessment identified an increase in the mean age of diagnosis of GD (p < 0.02), a reduction in thyroid volume (p < 0.001) and less intense orbital involvement from 2007-2016 compared to 1986-2006 (p = 0.04). The number of smoking patients was smaller from 2007 to 2016 (28.7%) than 1986 to 2006 (42.8% p = 0.001). The TSH and TRAb values did not had significant changes. Conclusion GD presentation appears to be changed in the last years compared to the typical initial presentation. There is a less frequent inflammatory involvement of orbital tissue, smaller goiters, a lower number of smokers and diagnosis at older age.

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OBJECTIVE: The association between coronary artery disease (CAD) and thyroid function remains controversial. We evaluated the thyroid function and graduated well-defined CAD as confirmed by quantitative coronary angiography (CA). SUBJECTS AND METHODS: We evaluated the serum TSH, free thyroxine, free triiodothyronine and thyroid antibody levels in 300 consecutive patients (age 61.6 ± 9.9 years and 54% were male) undergoing CAD diagnosis as confirmed by CA. Plaques with ≥ 50% stenosis being indicative of obstructive CAD, and patients were divided into groups according to main epicardial coronary arteries with plaques (0, 1, 2, 3). Lipid profiles and a homeostasis model assessment (HOMA-IR) were determined. RESULTS: Serum median (25% and 75% percentile) TSH levels in patients with group 2 and 3 (2.25; 1.66-3.12 mU/L and 4.99; 4.38-23.60 mU/L, respectively) had significantly higher TSH concentrations (p < 0.0001) than the group 0 (1.82; 1.35-2.51 mU/L). Furthermore, patients of group 3 had higher TSH concentration (p < 0.0001) than those of group 1 (1.60; 0.89-2.68 mU/L). Group 3 were older (64 ± 8.5 vs. 59 ± 9.5, p = 0.001), had more patients with dyslipidemia (84% versus 58%, p < 0.001), male (54% versus 44%, p = 0.01), hypertension (100% versus 86%, p < 0.001), and smoking (61% versus 33%, p < 0.001) than group 0. Multivariate stepwise logistic analysis showed TSH, age, HbA1c, and HOMA-IR were the CAD associated variables. CONCLUSIONS: In this cohort, elevated TSH levels in the high normal range or above are associated with the presence and severity of CAD besides may represent a weak CAD risk factor.

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ABSTRACT Objective: The association between coronary artery disease (CAD) and thyroid function remains controversial. We evaluated the thyroid function and graduated well-defined CAD as confirmed by quantitative coronary angiography (CA). Subjects and methods: We evaluated the serum TSH, free thyroxine, free triiodothyronine and thyroid antibody levels in 300 consecutive patients (age 61.6 ± 9.9 years and 54% were male) undergoing CAD diagnosis as confirmed by CA. Plaques with ≥ 50% stenosis being indicative of obstructive CAD, and patients were divided into groups according to main epicardial coronary arteries with plaques (0, 1, 2, 3). Lipid profiles and a homeostasis model assessment (HOMA-IR) were determined. Results: Serum median (25% and 75% percentile) TSH levels in patients with group 2 and 3 (2.25; 1.66-3.12 mU/L and 4.99; 4.38-23.60 mU/L, respectively) had significantly higher TSH concentrations (p < 0.0001) than the group 0 (1.82; 1.35-2.51 mU/L). Furthermore, patients of group 3 had higher TSH concentration (p < 0.0001) than those of group 1 (1.60; 0.89-2.68 mU/L). Group 3 were older (64 ± 8.5 vs. 59 ± 9.5, p = 0.001), had more patients with dyslipidemia (84% versus 58%, p < 0.001), male (54% versus 44%, p = 0.01), hypertension (100% versus 86%, p < 0.001), and smoking (61% versus 33%, p < 0.001) than group 0. Multivariate stepwise logistic analysis showed TSH, age, HbA1c, and HOMA-IR were the CAD associated variables. Conclusions: In this cohort, elevated TSH levels in the high normal range or above are associated with the presence and severity of CAD besides may represent a weak CAD risk factor.

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BACKGROUND: Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD. METHODS: Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12-24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5-7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up. RESULTS: The mean follow-up was 80.8 ± 35.3 months for the RAI group, and 71.3 ± 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)--it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02-12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47-48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70-223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5-298], p < 0.05). Kaplan-Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up. CONCLUSIONS: The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment.

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AIM: To investigate the effectiveness of 2 fixed iodine (¹³¹I) doses for the treatment for Graves hyperthyroidism and their impact on eye disease. METHODS: We prospectively examined 76 patients who received a fixed dose of 370 MBq (group 1) and 52 patients who received 555 MBq ¹³¹I (group 2). Patients were followed up for 12 months and considered in remission when they were in a stable euthyroid or hypothyroid state in the absence of antithyroid drugs 12 months after ¹³¹I administration. Eight patients with active eye disease received a daily dose of 0.5 mg/kg prednisone per kilogram of body weight at the time of radioiodine therapy for 1 month. RESULTS: The remission rate obtained was similar in groups 1 (73.7%) and 2 (80.8%; P = 0.35). Hypothyroidism was diagnosed in 56.5% of the 370-MBq group and 71.1% of the 555-MBq group patients (P = 0.13). There was no correlation among clinical features, thyroid uptake, antibody levels, serum hormones levels, and outcome. However, logistic regression analysis demonstrated that patients with large thyroid glands had 2.4 times less chance to go into remission (odds ratio; 95% confidence interval = 1.18-4.96). None of the patients developed eye disease during any fixed-dose treatment regimen or worsened their previously diagnosed ophthalmopathy. CONCLUSIONS: Fixed doses of 370 MBq and 555 MBq ¹³¹I provided similar remission rates; however, outcome was influenced by the thyroid size. We propose that 370 MBq ¹³¹I should be the routine treatment dose for all Graves disease patients, reserving a dose of 555 MBq ¹³¹I to palpable large goiters, without any additional concern to eye disease.

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OBJECTIVE: To compare ultrasonography (US) to magnetic resonance imaging (MRI) and the clinical activity score (CAS) in Graves' ophthalmopathy. SUBJECTS AND METHODS: Nineteen patients underwent extraocular muscle thickness measurements by US and MRI, reflectivity by US and signal-intensity ratio by MRI. There were also twelve US control subjects. RESULTS: US median thicknesses were greater than in controls. Correlation was found between US and MRI in the median thickness of the left eye rectus medial muscle as well as between signal-intensity ratio (SIR) and thickness by US. An inverse correlation was found between reflectivity and SIR in the inferior and lateral rectus. On associating the tests for detecting activity the best results were obtained with CAS plus MRI (sensitivity 75%), and US and MRI (positive predictive value 77% and specificity 80%). CONCLUSION: CAS and US results showed poor correlation with MRI results suggesting that they cannot replace each other but when combined these methods can improve the evaluation of thyroid-associated ophthalmopathy.

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OBJECTIVE: To compare ultrasonography (US) to magnetic resonance imaging (MRI) and the clinical activity score (CAS) in Graves' ophthalmopathy. SUBJECTS AND METHODS: Nineteen patients underwent extraocular muscle thickness measurements by US and MRI, reflectivity by US and signal-intensity ratio by MRI. There were also twelve US control subjects. RESULTS: US median thicknesses were greater than in controls. Correlation was found between US and MRI in the median thickness of the left eye rectus medial muscle as well as between signal-intensity ratio (SIR) and thickness by US. An inverse correlation was found between reflectivity and SIR in the inferior and lateral rectus. On associating the tests for detecting activity the best results were obtained with CAS plus MRI (sensitivity 75 percent), and US and MRI (positive predictive value 77 percent and specificity 80 percent). CONCLUSION: CAS and US results showed poor correlation with MRI results suggesting that they cannot replace each other but when combined these methods can improve the evaluation of thyroid-associated ophthalmopathy.

OBJETIVO: Comparar a ultrassonografia (US) à ressonância magnética nuclear (RMN) e o índice de atividade clínica (IAC) na oftalmopatia de Graves. SUJEITOS E MÉTODOS: Dezenove pacientes submetidos à medida da espessura dos músculos extraoculares por US e RMN, refletividade ao US e razão da intensidade de sinal (RIS) à RMN. Grupo controle para US de 12 indivíduos. RESULTADOS: Espessura mediana ao US foi maior que dos controles. Houve correlação entre US e RMN na espessura mediana dos músculos retos mediais dos olhos esquerdos e entre a RIS e a espessura ao US e correlação inversa entre refletividade e SIR nos retos inferior e lateral. Detectando atividade, os melhores resultados foram associando IAC e RMN (sensitividade de 75 por cento) e US e RMN (valor preditivo positivo de 77 por cento e especificidade de 80 por cento). CONCLUSÃO: Resultados do IAC e US mostraram pouca correlação com a RMN, sugerindo que não podem ser substituídos, mas, quando combinados, esses métodos podem melhorar a avaliação da oftalmopatia associada à tiroide.

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OBJECTIVE: Cytokines are involved in the pathogenesis of Graves' disease (GD), but ambiguous serum cytokine results have been described. METHODS: We studied the changes in serum interleukin (IL)-1ß, soluble IL-2 receptor (sIL-2R), IL-5, IL-6 and tumor necrosis factor (TNF)-α concentrations in 29 untreated GD patients before and after restoration of euthyroidism with methimazole (MMI) treatment compared to 25 control subjects. Eleven out of 29 GD patients had active Graves' ophthalmopathy (GO). RESULTS: Compared to controls, untreated GD patients had significantly higher median levels of serum IL-1ß (18.7 vs. 34.0 pg/ml), sIL-2R (292.5 vs. 1,585.0 pg/ml), IL-5 (1.0 vs. 9.0 pg/ml), IL-6 (3.0 vs. 5.0 pg/ml) and TNF-α (8.1 vs. 16.0 pg/ml). In euthyroidism following MMI treatment, concentrations of IL-1ß (25.0 pg/ml), sIL-2R (362.0 pg/ml), IL-5 (3.0 pg/ml), IL-6 (3.0 pg/ml) and TNF-α (5.0 pg/ml) declined significantly and were similar to controls. The greatest reductions were noted in sIL-2R (76.9%), TNF-α (68.8%) and IL-5 (66.6%) levels. Serum sIL-2R, IL-5 and TNF-α levels in active GO patients were significantly elevated, but no significant differences were observed in GD patients without GO. Using a multiple linear regression analysis, serum IL-1ß was significantly associated with free thyroxine, sIL-2R with triiodothyronine and serum thyrotropin receptor antibody (TRAb) and TNF-α with TRAb. CONCLUSION: These results support the notion that serum cytokines could be used as a marker of GD activity, and the decrease in cytokine levels might be related to the achievement of euthyroidism and the immunomodulatory effects of MMI treatment.

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