Long-Term Follow-up of Graves Orbitopathy After Treatment With Short- or Long-Term Methimazole or Radioactive Iodine.

OBJECTIVE: The aim of this study was to compare long-term outcomes in terms of new onset or worsening of Graves orbitopathy (GO) in patients with Graves disease treated with different therapeutic modalities for hyperthyroidism. METHODS: A total of 1163 patients with Graves disease were enrolled in this study; 263 patients were treated with radioiodine and 808 patients received methimazole (MMI) therapy for a median of 18 months, of whom 178 patients continued MMI for a total of 96 months (long-term methimazole [LT-MMI]). The thyroid hormonal status and GO were evaluated regularly for a median of 159 months since enrollment. RESULTS: The rates of relapse, euthyroidism, and hypothyroidism at the end of follow-up were as follows: radioiodine treatment group: 16%, 22%, and 62%, respectively; short-term MMI group: 59%, 36%, and 5%, respectively; and LT-MMI group: 18%, 80%, and 2%, respectively. During the first 18 months of therapy, worsening of GO (11.5% vs 5.7%) and de novo development of GO (12.5% vs 9.8%) were significantly more frequent after radioiodine treatment (P <.004). Overall worsening and de novo development of GO from >18 to 234 months occurred in 26 (9.9%) patients in the radioiodine group and 8 (4.5%) patients in the LT-MMI group (P <.037). No case of worsening or new onset of GO was observed in patients treated with LT-MMI from >60 to 234 months of follow-up. CONCLUSION: Progression and development of GO were associated more with radioiodine treatment than with MMI treatment; GO may appear de novo or worsen years after radioiodine treatment but not after LT-MMI therapy.

Long-term thionamide antithyroid treatment of Graves' disease.

Thionamide antithyroid drugs (ATD) are the treatment of choice for Graves' hyperthyroidism. The major drawback of ATD treatment for 1-2 years is the relapse of hyperthyroidism in about 50% of patients. Recently, it has been shown that ATD treatment for more than five years is accompanied by long-term remission in majority of patients without additional major side effects in both adults and children. Compared to radioactive iodine therapy, long-term ATD results in more favorable outcomes. This review summarizes the evidence on long-term ATD therapy regarding the remission rate of hyperthyroidism, efficacy and safety, indications and mode of therapy in patients with hyperthyroidism.

Efficacy and Safety of Long-Term Methimazole versus Radioactive Iodine in the Treatment of Toxic Multinodular Goiter.

BACKGRUOUND: This study compared the degree of sustained control of hyperthyroidism in patients with toxic multinodular goiter (TMNG) treated with long-term methimazole (LT-MMI) or radioactive iodine (RAI). METHODS: In this clinical trial, 130 untreated patients with TMNG were randomized to either LT-MMI or RAI treatment. Both groups were followed for 108 to 148 months, with median follow-up durations of 120 and 132 months in the LT-MMI and RAI groups, respectively. Both groups of patients were followed every 1 to 3 months in the first year and every 6 months thereafter. RESULTS: After excluding patients in whom the treatment modality was changed and those who were lost to follow-up, 53 patients in the LT-MMI group and 54 in the RAI group completed the study. At the end of the study period, 50 (96%) and 25 (46%) patients were euthyroid, and two (4%) and 25 (46%) were hypothyroid in LT-MMI and RAI groups, respectively. In the RAI group, four (8%) patients had subclinical hyperthyroidism. The mean time to euthyroidism was 4.3±1.3 months in LT-MMI patients and 16.3± 15.0 months in RAI recipients (P<0.001). Patients treated with LT-MMI spent 95.8%±5.9% of the 12-year study period in a euthyroid state, whereas this proportion was 72.4%±14.8% in the RAI-treated patients (P<0.001). No major treatment-related adverse events were observed in either group. CONCLUSION: In patients with TMNG, LT-MMI therapy is superior to RAI treatment, as shown by the earlier achievement of euthyroidism and the longer duration of sustained normal serum thyrotropin.

Time to Normalization and Sustainable Normal Serum Thyrotropin Concentrations in Patients with Hyperthyroidism: Comparison of Methimazole and Radioactive Iodine Treatments.

OBJECTIVE: The aim of this study was to compare the "time to euthyroidism" and "time spent in euthyroidism" following methimazole (MMI) and radioactive iodine (RAI) treatments. METHODS: Three hundred fifty-eight patients with hyperthyroidism, 178 who underwent long-term MMI treatment and 180 patients who underwent RAI treatment, were analyzed. The time to normalization of increased serum values of free thyroxine and triiodothyronine and suppressed serum thyroid-stimulating hormone (TSH) values as well as the percentage of time that the thyroid hormone levels remained within normal ranges during a mean follow-up time of 12 years were compared. RESULTS: The mean time to euthyroidism was 4.59 ± 2.63 months (range, 2-16 months) in the MMI group and 15.39 ± 12.11 months (range, 2-61 months) in the RAI group (P < .001). During follow-up, the percentage of time spent in euthyroidism was 94.5% ± 7.3% and 82.5% + 11.0% in the MMI and RAI groups, respectively (P < .001). Serum TSH values above and below the normal range were observed in 5.3% and 0.2% of patients, respectively, in the MMI group and 9.8% and 7.7% of patients, respectively, in the RAI group (P < .001). The time to euthyroidism and the percentage of time spent in euthyroidism in 40 RAI-treated patients with euthyroidism were similar to those in the MMI group and significantly shorter than those in the RAI-treated hypothyroid and relapsed subgroups. In patients who continued MMI therapy for >10 years, the percentage of time spent in euthyroidism was >99%. CONCLUSION: In our cohort of selected patients, MMI therapy was accompanied by faster achievement of the euthyroid state and more sustained normal serum TSH levels during long-term follow-up compared with RAI therapy.

Incidence of Thyroid Dysfunction Facing Metabolic Syndrome: A Prospective Comparative Study with 9 Years of Follow-Up.

BACKGROUND: Studies assessing thyroid hormones in metabolic syndrome (MetS) patients are contradictory. Also, the effect of MetS on thyroid function over time is not yet evaluated. This study investigated the prevalence and incidence of thyroid dysfunction (TD) as well as time trends of thyroid hormones in subjects with and without MetS, during a 10-year follow-up in Tehranian adult population. METHODS: This is a prospective cohort study conducted in the framework of Tehran Thyroid Study on 5,786 subjects aged ≥20 years: 4,905 eligible participants entered the study after excluding those with corticosteroid or radioactive iodine use, pregnancy, thyrotropin (TSH) <0.1 and >10 mU/L, and missing data. Physical examinations were performed and serum concentrations of TSH, free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), fasting plasma glucose, insulin, and lipid profile were assessed at baseline and 3-year intervals during the follow-up. MetS was defined according to the Joint Interim Statement Definition. RESULTS: At baseline, there were no difference in median serum concentrations of FT4 and TSH between MetS and non-MetS group after adjusting for age, sex, BMI, smoking, and TPOAb positivity. Although there was higher risk of overt (42%) and subclinical hypothyroidism (16%) in MetS compared with non-MetS subjects, no significant difference was observed in adjusted ORs for any TD between 2 groups. There were also no significant differences in time trends of TSH, FT4, TPOAb positivity, and incidence rates of TDs between MetS and non-MetS groups during 10 years, after adjustment for age, sex, BMI, smoking status, and TPOAb positivity. CONCLUSION: MetS is not associated with thyroid hypofunction considering other important confounders such as age, sex, smoking, BMI, and TPOAb positivity. There is also no difference in the trend of thyroid hormones and incidence of TD between MetS and non-MetS subjects during a 10-year follow-up.

Cumulative Effects of Thyroid Hormones Over 10 Years and Risk of General and Abdominal Obesity.

We aimed to assess if changes in thyrotropin (TSH) and free thyroxine (FT4) over 10 years of follow-up would be associated with changes in body mass index (BMI) and waist circumference (WC) or risk of obesity. We enrolled 2317 out of 4179 participants in Tehran Thyroid Study with serum TSH between 0.1-10 mU/l and without history of thyroid medication or surgery. Serum concentrations of FT4 and TSH were measured at baseline and three follow-ups (1999-2011). To account for within-subject correlation, the generalized estimating equation was used to assess the association between one standard deviation(SD) change in the main exposures [cumulative excess (CE)TSH and CEFT4] and changes in BMI and WC; calculated scores of CETSH and CEFT4 were included in models as time-varying exposures. Cumulative excess of TSH or FT4 was not associated with increased incidence of general or abdominal obesity. However, CEFT4 was negatively associated with BMI only in overweight and obese subjects. In GEE analysis, one unit increase in TSH was associated with 0.02 kg/m2 increase in BMI (95% CI: 0.01, 0.03), which remained significant only in women; although the association was not significant after adding FT4 to model. One unit increase in FT4 was associated with 1.5 kg/m2 decrease in BMI (95% CI:-1.8,-1.2) and 4.1 cm decrease in WC (95% CI:-5.1,-3.1) in both sexes independent of TSH and other confounders. Cumulative excess of TSH or FT4 indicated no risk for general or abdominal obesity. However, FT4 was negatively associated with BMI and WC independent of TSH.

Sex-Specific Incidence Rates and Risk Factors for Hypertension During 13 Years of Follow-up: The Tehran Lipid and Glucose Study.

Background: Hypertension, with a prevalence of 25.6% is a serious public health concern in Iran. Objective: To investigate the population-based incidence of hypertension and its potential risk factors in Tehranian adults during a median follow-up of 13.1 years. Methods: A total of 6,533 non-hypertensive participants (women = 3,639), aged ≥20 years participated in the study. Crude and age-standardized incidence rates per 1000 person-years were calculated for each sex, separately. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for all potential risk factors. Results: The crude and age-standardized incidence rates (95% CI) of hypertension per 1000 person-years were 29.7 (27.8-31.6) and 34.9 (32.5-37.4) among men and 25.8 (24.3-27.3) and 38.7 (35.5-42.0) among women, respectively. The incidence rate of hypertension in younger age groups was higher among men. However, after the 4th decade, the incidence rate was higher among women. Significant interactions of sex with age groups, body mass index categories, marital status, hypertriglyceridemia and glycemic categories were found in multivariable analyses (all p-values < 0.05). In the multivariable model, the risk in both sexes was found to be significantly associated with older age, obesity, and normal or high normal blood pressure (BP). Moreover, factors such as being overweight [HR: 1.20 (1.00-1.44)], former smoking [2.15 (1.52-3.04)], hypertriglyceridemia [1.23 (1.06-1.43)] and pre-diabetes status [1.19 (1.02-1.39)] were significant predictors of incident hypertension among women. Central obesity was found to be a significant predictor among men [1.26 (1.03-1.54)]. The optimism-corrected Harrell's C index (95% CI) in the categorical adjusted model was 0.75 (0.74-0.79) among men and 0.75 (0.74-0.76) among women. Conclusion: In the Tehranian population, nearly 2.7% of total participants (3% of men and 2.6% of women) develop hypertension each year. Obesity and high BP levels are the main modifiable risk factors in both sexes. Hypertriglyceridemia, prediabetes and former smoking are risk factors for hypertension among women.

Association Between Thyroid Function and Development of Different Obesity Phenotypes in Euthyroid Adults: A Nine-Year Follow-Up.

BACKGROUND: Considering inconsistent and conflicting data on associations of thyroid function, within the reference range, with anthropometric measures and metabolic syndrome, this study aimed to investigate the relationship between thyroid function and different obesity phenotypes over nine years of follow-up. METHODS: This study was conducted on 1938 individuals from an ongoing population-based cohort study, the Tehran Thyroid Study. Participants were categorized into four obesity phenotypes based on body mass index and metabolic status. To investigate the associations of thyrotropin and free thyroxine (fT4) with incidence of different obesity phenotypes across the study period, a multivariate approach based on a generalized estimating equation method was used. RESULTS: At baseline, individuals with the metabolically healthy normal weight (MHNW) phenotype had higher serum fT4 levels (1.2 ± 0.16 ng/dL vs. 1.14 ± 0.14 ng/dL, 1.16 ± 0.14 ng/dL, and 1.17 ± 0.15 ng/dL in metabolically healthy obese [MHO], metabolically unhealthy normal weight, and metabolically unhealthy obese individuals, respectively). The results of the generalized estimating equation analysis after multivariate adjustment for age, sex, smoking, physical activity, education level, thyroid peroxidase antibody status, and homeostasis model assessment-insulin resistance showed that each 1 ng/dL increment in fT4 levels within the reference range was accompanied with a 1.65-fold [confidence interval (CI) 1.09-2.5] increase of developing the MHNW phenotype during 9.2 years of follow-up. Moreover, each 1.0 ng/dL increment in fT4 within the reference range was associated with a 50% decreased risk of developing the MHO phenotype (odds ratio = 0.50 [CI 0.32-0.76]). Meanwhile, a significant positive association was found between serum thyrotropin levels and development of the metabolically unhealthy normal weight phenotype (odds ratio = 1.22 [CI 1.01-1.48]). CONCLUSIONS: Serum fT4 concentrations within the reference range are associated with the development of some obesity phenotypes, including the MHNW and MHO phenotypes, after consideration of potential confounders.

Association between Thyroid Function and Body Mass Index: A 10-Year Follow-Up.

BACKGROUND/AIMS: We aimed to evaluate the association between change in thyroid function tests within the euthyroid range and body mass index (BMI) in persons with normal weight at baseline. METHODS: This study investigated 1,100 normal-weight euthyroid persons in a population-based cohort study, Tehran Thyroid Study. BMI was calculated and serum concentrations of thyrotropin (TSH) and free T4 (FT4) were assayed at baseline and after 10 years of follow-up. We evaluated the relationship between thyroid and obesity based on 2 definitions for outcome: (1) a binary outcome as BMI <25 or ≥25 kg/m2, and (2) a multinomial outcome as normal BMI, overweight, and obese. RESULTS: A total of 569 women and 531 men, aged 36.3 ± 13.5 years, were included. Modified Poisson regression analysis for binary outcome, after adjustment for age, sex, smoking, and anti-thyroid peroxidase antibody status, revealed a negative association between delta serum FT4 and follow-up BMI (relative risk 0.55 [95% CI 0.37-0.80]) without any significant association between change in serum TSH and follow-up BMI. However, in multinomial logistic regression analysis, we found no relationship between delta serum FT4 or TSH and follow-up BMI categories, for either overweight or obese vs. normal-weight participants. CONCLUSIONS: In normal-weight euthyroid individuals, changes in serum concentrations of FT4, but not TSH, may contribute to change in body weight.

Divergent pathway of lipid profile components for cardiovascular disease and mortality events: Results of over a decade follow-up among Iranian population.

BACKGROUND: Data regarding the impact of different lipid measures on cardiovascular diseases (CVD) and mortality events is not consistent. We aimed to evaluate the relationship between different lipid parameters and incident CVD and mortality events in an Iranian population over a median follow-up of 11.9 years. METHODS: The study was conducted on 2532 men and 2986 women aged ≥ 40 years. Multivariate adjusted hazard ratios (HRs), using age as time scale, were calculated for every 1 standard deviation (SD) increase in total cholesterol (TC), logarithm-transformed triglycerides (ln-TGs), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), non-HDL-C, TC/HDL-C and ln-TGs/HDL-C. Covariates included gender (female as reference), body mass index, education status, low physical activity, smoking, blood pressure status (normotension, prehypertension and hypertension), glucose tolerance status (normal glucose tolerance, prediabetes and diabetes) and lipid lowering drugs. The same analyses were also repeated for tertiles of all lipid measures. Considering the absence of interaction between gender and lipid parameters, we used a sex-adjusted analysis. For analyses of mortality events, prevalent CVD was adjusted as well (All p for interactions > 0.1). RESULTS: A total of 789 new CVD events, 279 cardiovascular (CV) and 270 non-CV deaths occurred. In multivariate analysis, all lipid measures except HDL-C showed significant risk for new CVD events with HRs ranged from 1.14 to 1.27 for ln-TGs/HDL-C and LDL-C, respectively (all p-values ≤ 0.001). Considering CV mortality, there were significant positive associations between TC, LDL-C, non-HDL-C, TC/HDL-C and CV mortality events in sex-adjusted analysis; however after multivariate analysis, these associations attenuated and reached to null. Applying lipid measures as categorical variables, only TC displayed a positive association with CV mortality in multivariate analysis [TC ≥ 6.14 mmol/L: HR 1.43 (1.04-1.98)]. In multivariate analysis, there were negative significant associations between all lipid measures except HDL-C and non-CV mortality; every 1-SD increase in TC, LDL-C, non-HDL-C, ln-TGs ,TC/HDL-C and ln-TGs/HDL-C was associated with 24, 25, 27, 19, 23 and 17 % decreased risk in non-CV mortality (all p-values ≤ 0.01). CONCLUSIONS: These findings indicate divergent associations of TC, LDL-C, non-HDL-C, TC/HDL-C, TGs and TGs/HDL-C with CVD vs non-CV mortality, demonstrating a higher risk for the former and lower risk for the latter.

Risk factors for cardiovascular disease and mortality events in adults with type 2 diabetes - a 10-year follow-up: Tehran Lipid and Glucose Study.

BACKGROUND: To identify risk factors for cardiovascular disease (CVD) and mortality events in patients with type 2 diabetes and to calculate their population attributable fraction among a representative Iranian population. METHODS: A total of 1198 patients with type 2 diabetes (504 men and 694 women), aged ≥30 years, without prevalent CVD, with a median follow-up of 10 years were included in current study. To examine the association between risk factors and their outcomes, multivariate sex-adjusted Cox proportional hazard regression models were used. RESULTS: During the study, 281 and 172 participants experienced CVD and all-cause mortality events, respectively. Regarding CVD events, fasting plasma glucose (FPG) level of 7.22-<10 mmol/L [hazard ratio (HR): 1.46, 95% CI 1.12-1.96], FPG level ≥10 mmol/L (HR 2.04, 1.53-2.72), hypertension (HR 1.65, 1.28-2.13), hypercholesterolaemia (HR 1.96, 1.40-2.75) and high waist to hip ratio (HR 1.30, 0.99-1.70; p = 0.051) were significant predictors, and corresponding population attributable fractions were 9.76, 17.84, 23.26, 41.63 and 14.76%, respectively. Considering all-cause mortality events, hypertension (HR 1.70, 1.23-2.36), FPG level ≥10 mmol/L (HR 2.31, 1.55-3.20) and smoking (HR 1.45, 1.03-2.04) were significant predictors, and corresponding population attributable fractions were 25.81, 20.88 and 11.18%, respectively. Meanwhile, being overweight or obese was associated with lower all-cause and CVD mortality events. CONCLUSIONS: Among modifiable risk factors in patients with type 2 diabetes, hypercholesterolaemia and central adiposity for CVD, smoking for mortality events and hypertension and poor glycaemic control for both outcomes need to be paid most attention by healthcare professionals. Copyright © 2016 John Wiley & Sons, Ltd.

Multiple endocrine neoplasia type 2A in an Iranian family: clinical and genetic studies.

Multiple endocrine neoplasia (MEN) type 2A, a dominant inherited syndrome caused by germline activating mutations in the RET protooncogene, is characterized by association of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. There is limited data on this disease in the Middle East region. In this paper, we present clinical and genetic studies of an Iranian patient and her family members. The patient was a 49-year old Iranian woman who presented with hypertension due to bilateral pheochromocytoma. She had history of a medullary carcinoma of thyroid which had been operated 28 years ago. Analysis of the RET gene in the family revealed a C634R mutation in codon 11 and 3 polymorphisms, G691S, S836S and S904S in codons 11, 14 and 15, respectively, that might have been important in modifying the clinical picture. Due to paucity of information on MEN type 2 in the area, this study can be helpful in portraying the clinical and cytogenetic characteristics of the disease in the region.