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Concept: Thyroid

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

172

Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3',5'-triiodothyronine, 3,3',5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism.

Concepts: Protein, Metabolism, Thyroid, Tyrosine, Agonist, Signal transduction, Amino acid, Hormone

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

170

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

169

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

168

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

157

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

146

83

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

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

32

Lithium is a widely used and highly effective treatment for mood disorders, but causes poorly characterised adverse effects in kidney and endocrine systems. We aimed to analyse laboratory information system data to determine the incidence of renal, thyroid, and parathyroid dysfunction associated with lithium use.

Concepts: Retrospective, Systems theory, Parathyroid gland, Renin-angiotensin system, Nephron, Kidney, Thyroid, Endocrine system