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Concept: Hyperthyroidism

361

Background The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. Methods We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). Results The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. Conclusions Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Concepts: Clinical trial, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone, Placebo

172

The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known. It is to be stressed that the clinical course of thyroid diseases in the elderly differs essentially from that observed in younger individuals, because symptoms are more subtle and are often attributed to normal aging. Subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, require special attention in elderly subjects. Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels – progressively shifting to higher values with age – may contribute to the increased lifespan.This short review focuses on recent findings concerning the alterations in thyroid function during aging, including these which may potentially lead to extended longevity, both in humans and animals.

Concepts: Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Graves' disease, Endocrine system, Triiodothyronine

171

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Concepts: Genetics, Atrial fibrillation, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone, Endocrine system, Triiodothyronine

171

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto’s thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

Concepts: Bioinformatics, Single-nucleotide polymorphism, Thyroid disease, Genetic genealogy, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Minor allele frequency

170

C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice.

Concepts: DNA, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid hormone, Förster resonance energy transfer, HEK cell

168

BACKGROUND: We would like to investigate the if IMRT produced better target coverage and dose sparing to adjacent normal structures as compared with 3DCRT and LOF for patients with Graves' ophthalmopathy treated with retro-orbital irradiation. METHODS: Ten consecutive patients diagnosed with Graves' ophthalmopathy were prospectively recruited into this study. An individual IMRT, 3DCRT and LOF plan was created for each patient. Conformity index (CI), homogeneity index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) generated by IMRT were compared with the other two techniques. RESULTS: Mann–Whitney U test demonstrated that CI generated by IMRT was superior to that produced by 3DCRT and LOF (p=0.005 for both respectively). Similarly HI with IMRT was proven better than 3DCRT (p=0.007) and LOF (p=0.005). IMRT gave rise to better dose sparing to some OARs including globes, lenses and optic nerves as compared with 3DCRT but not with LOF. CONCLUSIONS: IMRT, as compared with 3DCRT and LOF, was found to have a better target coverage, conformity and homogeneity and dose sparing to some surrounding structures, despite a slight increase but clinically negligible dose to other structures. Dosimetrically it might be a preferred treatment technique and a longer follow up is warranted to establish its role in routine clinical use.

Concepts: Hospital, Thyroid disease, Hyperthyroidism, Target Corporation, Graves' ophthalmopathy

145

Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSH in vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI, and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.

Concepts: Protein, Metabolism, Endoplasmic reticulum, Thyroid-stimulating hormone, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone

137

Background and objectives : Subclinical hypothyroidism is an asymptomatic condition with normal thyroxin and raised thyroid stimulating hormone (TSH) level. The objective of the study was to determine the prevalence of subclinical hypothyroidism in primary health care (PHC) settings in Riyadh and explore the relationship of TSH level with age, gender, family history, body mass index, and co-morbid conditions.Subjects and methods: A cross-sectional study of adult visitors to nine satellites PHC clinics in military housing in Riyadh was carried out. TSH concentration and free T4 levels were measured. Data were collected by nurses and physicians during routine clinical practice in primary care. Descriptive analysis was performed on all variables in study, and relationships were explored using chi-square,t-test, analysis of variance, and linear regression.Results: A total of 340 out of 394 participants in the study gave blood samples. Subclinical hyperthyroidism was identified in 2.1% (p = .001) and subclinical hypothyroidism in 10.3% (p = .001) of the PHC visitors. TSH levels were found to be significantly higher (p = .047) in elderly population of ≥60 years and those with family history of thyroid disease. Non-significant upward trends were noted in TSH levels with hyperlipidemia and increasing blood pressure. No overt hyperthyroidism or hypothyroidism was found in our study sample.Conclusion: Subclinical hypothyroidism has a prevalence of 10% of adults visiting PHC’s. TSH levels are higher in the elderly, which warrants screening of those aged 60 years and above.

Concepts: Health, Thyroid-stimulating hormone, Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone

80

 To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism.

Concepts: Childbirth, Prolactin, Thyroid disease, Constipation, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone

29

The elevated fluoride from drinking water impacts on T3, T4 and TSH hormones. The aim was study impacts of drinking water fluoride on T3, T4 and TSH hormones inYGA (Yazd Greater Area). In this case- control study 198 cases and 213 controls were selected. Fluoride was determined by the SPADNS Colorimetric Method. T3, T4 and TSH hormones tested in the Yazd central laboratory by RIA (Radio Immuno Assay) method. The average amount of TSH and T3 hormones based on the levels of fluoride in two concentration levels 0-0.29 and 0.3-0.5 (mg/L) was statistically significant (P = 0.001 for controls and P = 0.001 for cases). In multivariate regression logistic analysis, independent variable associated with Hypothyroidism were: gender (odds ratio: 2.5, CI 95%: 1.6-3.9), family history of thyroid disease (odds ratio: 2.7, CI 95%: 1.6-4.6), exercise (odds ratio: 5.34, CI 95%: 3.2-9), Diabetes (odds ratio: 3.7, CI 95%: 1.7-8), Hypertension (odds ratio: 3.2, CI 95%: 1.3-8.2), water consumption (odds ratio: 4, CI 95%: 1.2-14). It was found that fluoride has impacts on TSH, T3 hormones even in the standard concentration of less than 0.5 mg/L. Application of standard household water purification devices was recommended for hypothyroidism.

Concepts: Statistics, Water purification, Thyroid disease, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone, Drinking water