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Concept: Thyroid-stimulating hormone

355

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

171

Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3'-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.

Concepts: Hypothalamus, Prolactin, Thyroid-stimulating hormone, Thyroid, Feedback, Negative feedback, Thyrotropin-releasing hormone, Triiodothyronine

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

169

Congenital hypothyroidism, usually of the primary and permanent variety, is an eminently preventable cause of growth retardation and mental handicap whose outlook has been transformed by newborn screening, usually involving the measurement of capillary TSH. Severe primary congenital hypothyroidism, due for example to athyreosis, may result in subtle cognitive, behavioural and sensori-motor deficits, but the extent to which these can be offset by optimal postnatal diagnosis and management remains uncertain. This is because the available adult follow-up data reflect the outcome of previous management in the 1970’s and 1980’s, and also because the accurate neuro-psychological assessment of children is difficult, particularly in the preschool population. There is an urgent need to develop new consensus guidelines and to ensure that the children managed according to such guidelines are systematically and prospectively assessed so that good quality outcome data become available. In this review, key recommendations in the management of congenital hypothyroidism include: screening at day 3 so that severely affected infants can begin treatment within the first 10 days of life; setting the thyrotropin (TSH) referral cut-off at 8-10 mU/L; adopting a disciplined diagnostic algorithm to evaluate referred cases, with measurement of venous free thyroxine (T4), TSH and thyroglobulin combined with dual ultrasound and radioisotope imaging; initial treatment with a T4 dose of 50 μg daily in infants weighing ≥ 2.5 kg and 15 μg/kg/day in infants weighing < 2.5 kg followed by weekly review until thyroid function is normalised; and maintenance of free T4 levels between 15-26 pmol/L and TSH between 0.5-5 mU/L thereafter to avoid both under- and overtreatment.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Thyroxine, Newborn screening, Congenital hypothyroidism

169

It has been proposed that neonatal thyroid-stimulating hormone (TSH) concentrations are a good indicator of iodine deficiency in the population. A frequency of neonatal TSH concentrations above 5 mU/L below 3% has been proposed as the threshold indicating iodine sufficiency. The objective of the present study was to evaluate feasibility and usefulness of nation-wide neonatal TSH concentration screening results to assess iodine status in Belgium. All newborns born in Belgium during the period 2009-2011 (n = 377713) were included in the study, except those suffering from congenital hypothyroidism and premature neonates. The frequency of neonatal TSH concentrations above 5 mU/L from 2009 to 2011 in Belgium fluctuated between 2.6 and 3.3% in the centres using the same TSH assay. There was a significant inverse association between neonatal TSH level and birth weight. The longer the duration between birth and screening, the lower the TSH level. Neonatal TSH levels were significantly lower in winter than in spring or autumn and significantly lower in spring and summer than in autumn while significantly higher in spring compared to summer. In conclusion, despite that pregnant women in Belgium are mildly iodine deficient, the frequency of neonatal TSH concentrations above 5 mU/L was very low, suggesting that the neonatal TSH threshold proposed for detecting iodine deficiency needs to be re-evaluated. Although neonatal TSH is useful to detect severe iodine deficiency, it should not be recommended presently for the evaluation of iodine status in mildly iodine deficient regions.

Concepts: Pregnancy, Childbirth, Infant, Thyroid-stimulating hormone, Hypothyroidism, Pediatrics, Winter, Cretinism

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

28

AIMS: Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making. METHODS: We (1) retrospectively studied the relationship between TSH and FT(4) in a large unselected clinical sample (n=6641) of primary hypothyroid, euthyroid and hyperthyroid subjects, and (2) applied a mathematical model of thyroid hormone feedback control to assess the relation between structural parameters and TSH levels in the different functional states. RESULTS: When separately analysing total sample and untreated subjects, the correlation slope for logTSH versus FT(4) for hypothyroid subjects was significantly different from that of the euthyroid panel and hyperthyroid subjects (the latter being compromised by reaching the TSH assay’s lower detection limit). As trends between functional states changed, each functional segment appeared to become differently regulated. Theoretical modelling and sensitivity analysis revealed that the influence of various structural parameters on TSH levels also depends on the overall function of the feedback loop. CONCLUSIONS: Our data suggest that the states of hypothyroidism, euthyroidism and hyperthyroidism can be regarded as differently regulated entities. The apparent complexity could be replicated by mathematical modelling suggesting a hierarchical type of feedback regulation involving patterns of operative mechanisms unique to each condition. For clinical purposes and assay evaluation, neither the standard model relating logTSH with FT(4), nor an alternative model based on non-competitive inhibition can be reliably represented by a single correlation comparing all samples for both hormones in one all-inclusive group.

Concepts: Physics, Thyroid-stimulating hormone, Thyroid disease, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone, Triiodothyronine

28

Despite the introduction of salt iodization programmes as national measures to control iodine deficiency, several European countries are still suffering from mild iodine deficiency (MID). In iodine sufficient or mildly iodine deficient areas, iodine deficiency during pregnancy frequently appears in case the maternal thyroid gland cannot meet the demand for increasing production of thyroid hormones (TH) and its effect may be damaging for the neurodevelopment of the foetus. MID during pregnancy may lead to hypothyroxinaemia in the mother and/or elevated thyroid-stimulating hormone (TSH) levels in the foetus, and these conditions have been found to be related to mild and subclinical cognitive and psychomotor deficits in neonates, infants and children. The consequences depend upon the timing and severity of the hypothyroxinaemia. However, it needs to be noted that it is difficult to establish a direct link between maternal iodine deficiency and maternal hypothyroxinaemia, as well as between maternal iodine deficiency and elevated neonatal TSH levels at birth. Finally, some studies suggest that iodine supplementation from the first trimester until the end of pregnancy may decrease the risk of cognitive and psychomotor developmental delay in the offspring.

Concepts: Pregnancy, Infant, Thyroid-stimulating hormone, Hypothyroidism, Thyroid, Thyroid hormone, Iodine, Triiodothyronine

28

OBJECTIVE: To identify the clinical findings of Hashimoto’s encephalopathy (HE) in children and assess their neurological outcome. METHODS: In this retrospective observational study of 42 children with encephalitis dominated by acute neuro-behavioral features, eight met the diagnostic criteria of HE. Their biological, EEG and brain MRI characteristics were compared to those of the other 34 children. Their clinical outcome was also compared to that of 14 children with Hashimoto’s thyroiditis (HT). RESULTS: All eight HE children were girls and had high levels of anti-thyroid peroxidase (TPO) antibodies at onset (4043.3 ± 2969.8 IU/mL, inclusion criteria: TPO > 60 IU/mL) despite normal T4 and TSH levels in six of them. All HE children had abnormal EEG and brain MRI was abnormal in four of them. Relapses were observed in five children with a second relapse, despite steroid therapy, occurring sooner after the previous episode (median 18 days (range 17-188) vs 213 days (range 14-518)). Immunosuppressive therapy was started in all five children and two developed sequelae by the last follow-up visit (after 4 ± 1.3 years). Mean anti-TPO antibody titers were significantly higher in HE children than in those with Hashimoto’s thyroiditis (HT) (4043.3 ± 2969.8 IU/mL vs 1980.9 ± 3449.9 IU/mL, p = 0.03). Four HE children subsequently developed hypothyroidism whereas only one HT patient presented encephalitis. CONCLUSION: HE is characterized by suggestive clinical symptoms with high levels of anti-TPO antibodies and, in most cases, normal T4 and TSH titers. Despite steroid treatment, relapses and sequelae are frequent. HE may evolve toward HT, but the reverse appears to be rare.

Concepts: Observational study, Thyroid-stimulating hormone, Electroencephalography, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Immunosuppressive drug, Hashimoto's encephalopathy