Higher T3 Concentrations Research Articles

Large method differences for free thyroid hormone assays in the hyperthyroid range can affect assessment of hyperthyroid status: Comparison of Abbott Alinity to Roche Cobas, Siemens Centaur and equilibrium dialysis LC-MS/MS

BackgroundFree T4 (FT4) determination is one of the most commonly performed biochemical tests in endocrinology. Treatment of thyroid dysfunctions is adjusted based on the severity of symptoms and biochemical test results. For Graves’ hyperthyroidism, clinical guidelines recommend using FT4 as a (rough) guide to dose antithyroid drugs, together with other clinical information. It is well known that different platforms and methods give different FT4 results; however, large non-linear method differences at high FT4 concentrations are less well recognized. Current clinical guidelines do not make it clear that method differences in the hyperthyroid range can affect recommendations. MethodSerum samples from patients with very low (biochemically hypothyroid) to very high (hyperthyroid) concentrations of FT4 and/or free T3 (FT3) were analyzed using Abbott Alinity and compared to concentrations measured using Roche Cobas, Siemens ADVIA Centaur (FT4 only) and an in-house equilibrium dialysis liquid chromatography tandem mass spectrometry (LC-MS/MS) method. ResultsAlinity measured markedly lower FT4 and FT3 concentrations compared to the other methods, particularly at high FT4 concentrations. Regression analysis indicated that Alinity FT4 had a non-linear (curved) relationship to FT4 measured by the other methods. The method differences affected guideline-recommended treatments for hyperthyroidism. ConclusionMeasured free thyroid hormone concentrations are highly method-dependent, especially at high FT4 concentrations. Clinicians treating hyperthyroid patients should be aware that patients appear much less hyperthyroid from FT4-measurements performed using Alinity compared to Cobas or Centaur. Guideline-recommended antithyroid drug dosages based on FT4 (including multiples of the upper reference range) have to be adjusted to the FT4 method used. FT4 results from different methods should be clearly distinguished (e.g. separate lines) in medical records.

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review.

The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life. We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

T3 and glucose increase expression of phosphoenolpyruvate carboxykinase (PCK1) leading to increased β-cell proliferation

ObjectivesThyroid hormone (T3) and high glucose concentrations are critical components of β-cell maturation and function. In the present study, we asked whether T3 and glucose signaling pathways coordinately regulate transcription of genes important for β-cell function and proliferation. MethodsRNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations and in the presence or absence of T3. Gene expression was also studies in sorted human β-cells, mouse islets and Ins-1 cells by RT-qPCR. Silencing of the thyroid hormone receptors (THR) was conducted using lentiviruses. Proliferation was assessed by ki67 immunostaining in primary human/mouse islets. Chromatin immunoprecipitation and proximity ligation assay were preformed to validate interactions of ChREBP and THR. ResultsWe found glucose-mediated expression of carbohydrate response element binding protein alpha and beta (ChREBPα and ChREBPβ) mRNAs and their target genes are highly dependent on T3 concentrations in rodent and human β-cells. In β-cells, T3 and glucose coordinately regulate the expression of ChREBPβ and PCK1 (phosphoenolpyruvate carboxykinase-1) among other important genes for β-cell maturation. Additionally, we show the thyroid hormone receptor (THR) and ChREBP interact, and their relative response elements are located near to each other on mutually responsive genes. In FACS-sorted adult human β-cells, we found that high concentrations of glucose and T3 induced the expression of PCK1. Next, we show that overexpression of Pck1 together with dimethyl malate (DMM), a substrate precursor, significantly increased β-cell proliferation in human islets. Finally, using a Cre-Lox approach, we demonstrated that ChREBPβ contributes to Pck1-dependent β-cell proliferation in mouse β-cells. ConclusionsWe conclude that T3 and glucose act together to regulate ChREBPβ, leading to increased expression and activity of Pck1, and ultimately increased β-cell proliferation.

Identification by Liquid Chromatography-Tandem Mass Spectrometry and Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry of the Contributor to the Thyroid Hormone Receptor Agonist Activity in Effluents from Sewage Treatment Plants.

3,3',5-Triiodothyroacetic acid (TRIAC) was identified as a major contributor to the activity of thyroid hormone receptor (TR) agonists in environmental water. TRIAC contributed 60-148% of the TR-agonist activity in effluents from sewage treatment plants (STPs). Meanwhile, the contributions of 3,5,3'-triiodothyronine (T3), 3,3',5,5'-tetraiodothyronine (T4), and analogues were <1%. TRIAC concentrations in the range of 0.30-4.2 ng/L are likely enough to cause disruption of the thyroid system in living aquatic organisms. The origin of TRIAC in the STP effluents was investigated by analyzing both STP influents and effluents. Relatively high concentrations of T3 and T4 (2.5 and 6.3 ng/L, respectively) were found only in the influents. TRIAC was identified only in the effluents. These findings suggested that T3 and T4 in STP influents were potentially converted into TRIAC during activated sludge treatment or by other means. The evaluation of TRIAC at relevant environmental concentrations by in vivo assays and an appropriate treatment to reduce the TR activity in sewage are needed.

Electrocardiography in euthyroid individuals: a Danish general population study

Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease.We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex.Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, P<0.001 in women and 5.3 bpm/nM, P<0.001 in men) and T4 (3.7 bpm/10pM, P<0.001 in women and 3.1 bpm/10pM, P<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all P<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric, and more often had notches with higher concentrations of T4 (all P≤0.01).Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.

ФУНКЦИОНАЛЬНОЕ СОСТОЯНИЕ ЩИТОВИДНОЙ ЖЕЛЕЗЫ И НАДПОЧЕЧНИКОВ У ПАЦИЕНТОВ С ПСОРИАЗОМ

The article defines the characteristic features of thyroid and adrenal function in patients with psoriasis, taking into account the pituitary regulation and streptococcal association of dermatosis. Patients with psoriasis, regardless of the form of dermatosis and microbial association, experience a non-thyroid syndrome with a high T3 concentration, increased glucocorticoid and mineralocorticoid function of the adrenal glands.

Electrocardiography in euthyroid individuals: a Danish general population study

Thyroid hormones within the euthyroid range have been linked to mortality and differences in heart rate. However, some relations between thyroid hormone concentration and various electrocardiographic measurements remain unassessed. We aimed to investigate the association between thyroid hormone concentrations within the euthyroid range and different electrocardiographic markers in people free of thyroid disease. We obtained electrocardiograms (ECG) and blood samples of free T4, total T3, and thyrotropin (TSH) in 20,852 subjects from the general population (the GESUS study). Relations between concentrations of TSH, free T4, and total T3 and heart rate, QTc, QRS duration, PR interval, P-wave duration and T-wave morphology were assessed in a multivariate adjusted linear model stratified by sex. Roughly half of the 18,046 included participants with thyroid hormone measurements within euthyroid range were men, and the average age was 56 years. Heart rate increased with concentrations of T3 (6.4 bpm/nM, P<0.001 in women and 5.3 bpm/nM, P<0.001 in men) and T4 (3.7 bpm/10pM, P<0.001 in women and 3.1 bpm/10pM, P<0.001 in men). We found no relation between TSH and heart rate. PR interval and QRS duration decreased with higher concentrations of T3 (all P<0.01). QTc increased with higher concentrations of T4 in men (5 ms/10pM), and T waves were flatter, more asymmetric, and more often had notches with higher concentrations of T4 (all P≤0.01). Thyroid hormone concentrations within the euthyroid range in people free of thyroid disease were associated with changes in the electrocardiogram in a general population.

OR01-05 Long-Term Efficacy of T3 Analogue Triac in MCT8 Deficiency

Background: MCT8 deficiency is a severe disorder caused by mutations in the thyroid hormone transporter MCT8. MCT8 deficiency is characterized by severe intellectual and motor disability and high serum T3 concentrations that result in thyrotoxic symptoms in peripheral tissues. This predisposes to substantial morbidity and mortality. Preclinical studies showed that the T3 analogue Triac can bypass defective MCT8 at the cellular level. Recently, we reported the results of an international multicenter trial, in which biochemical and clinical outcomes improved in patients with MCT8 deficiency who were treated with Triac for 12 months (1). However, long-term follow-up data of patients with MCT8 deficiency treated with Triac are lacking, particularly in young children. Therefore, we aimed to investigate the long-term efficacy of Triac therapy in a worldwide cohort of patients with MCT8 deficiency. Methods: We investigated the efficacy of oral Triac treatment in pediatric (n=78) and adult (n=5) patients with MCT8 deficiency in 20 countries. Triac dose was titrated according a predefined dose-escalation scheme aiming to normalize serum T3 concentrations (target 1.4-2.5 nmol/L). Thyroid function tests and biochemical markers of thyroid hormone action in peripheral tissues (SHBG, creatine kinase, creatinine) were measured at baseline and during control visits. Findings: In total, 83 patients with a median baseline age of 5 years (range 6 months – 66 years) were treated, including 24 patients aged 0-2.5 years and 17 patients aged 2.5-5 years. They were treated with Triac during 144 patient years, of whom the follow-up time was >5 years in 9 patients and 2-5 years in 22 patients. Mean dose was 45 µg/kg/day (range 11-107 µg/kg/day). Once a stable dose was achieved, no further dose adjustments were needed.Mean serum T3 concentrations decreased from 5.02 to 1.94 nmol/L (normal 1.4 – 2.5 nmol/L). SHBG concentrations improved from 238 to 204 nmol/L (normal 40-140 nmol/L). Mean creatine kinase and creatinine concentrations improved from 113 to 140 U/L (normal <230 U/L) and from 32 to 38 µmol/L (normal 31-68 μmol/L), respectively. No drug-related severe adverse events were reported. Interpretation: Triac is a safe treatment that results in sustainable improvements of the severe thyrotoxic state in pediatric and adult patients with MCT8 deficiency.

MCT8 Deficiency: The Road to Therapies for a Rare Disease.

Allan-Herndon-Dudley syndrome is a rare disease caused by inactivating mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8), a transmembrane transporter specific for thyroid hormones (T3 and T4). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development resulting in severe brain hypothyroidism. Patients also suffer from thyrotoxicity in other organs due to the presence of a high concentration of T3 in the serum. An effective therapeutic strategy should restore thyroid hormone serum levels (both T3 and T4) and should address MCT8 transporter deficiency in brain barriers and neural cells, to enable the access of thyroid hormones to target neural cells. Unfortunately, targeted therapeutic options are currently scarce and their effect is limited to an improvement in the thyrotoxic state, with no sign of any neurological improvement. The use of thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require MCT8 to cross cell membranes and whose controlled thyromimetic activity could potentially restore the normal function of the affected organs, are being explored to improve the cerebral availability of these analogs. Other strategies aiming to restore the transport of THs through MCT8 at the brain barriers and the cellular membranes include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis (at prenatal stages), will be key aspects to improve the devastating alterations present in these patients.

PERFORMANCE OF BROILER CHICKEN FED DIFFERENT LEVELS THYME, ADIANTUM, ROSEMARY AND THEIR COMBINATION

The objective of this study was to investigate the effects of different levels of medical plants (thymus vulgaris, Adiantum capillus-veneris L, Rosemarinus officinalis and their combination) supplemented in the diet on Physiological and Growth performance traits of broiler chicken. T1 Control (no supplemented), T2 Thyme powder 5 g/kg, T3 Thyme powder 10 g/kg, T4 Adiantum powder 3 g/kg, T5 Adiantum powder 5 g/kg, T6 Rosemary powder 5 g/kg, T7 Rosemary powder 10 g/kg and T8 Mixture (Thyme , Adiantum and Rosemary) with 7.5 g/kg +4 g/kg and 7.5 g/kg, respectively. A Total of 288 unsexed broiler chicks, were randomly distributed to eight treatments with three replicate. Medical plants at different levels added to basal diets at 7th days old. Live body weight and mortality rates were measured weekly. At the end of the experiment the following traits were measured: carcass traits, hematology, blood biochemical, hormonal responses, and serum enzymes parameters. There is a significant effect of medicinal plants on live body weight, feed intake and dressing percentage. Mortality rate in T2 and T7 was significant highest. While, feed conservation was not influenced by medicinal plants. There was a significant effect of treatments on abdominal fat and liver weights. Adiantum powder at different levels has significant effect on bursa and spleen weights compared to other groups. There was a significant effect of treatments on albumin, globulin, cholesterol and glucose concentration. Medicinal plants significantly affect hormonal response. The combination of plants (T8) investigated high concentration of T3 and T4 hormones. Also, addition of rosemary observed higher concentration of TSH and GH hormones. There was significant effect of medical plants on AST and ALT enzymes. There is none significant effect of medical plants on meat color among treatment.

Aortic effects of thyroid hormone in male mice.

It is well established that thyroid hormones are required for cardiovascular functions; however, the molecular mechanisms remain incompletely understood, especially the individual contributions of genomic and non-genomic signalling pathways. In this study, we dissected how thyroid hormones modulate aortic contractility. To test the immediate effects of thyroid hormones on vasocontractility, we used a wire myograph to record the contractile response of dissected mouse aortas to the adrenergic agonist phenylephrine in the presence of different doses of T3 (3,3',5-triiodothyronine). Interestingly, we observed reduced vasoconstriction under low and high T3 concentrations, indicating an inversed U-shaped curve with maximal constrictive capacity at euthyroid conditions. We then tested for possible genomic actions of thyroid hormones on vasocontractility by treating mice for 4 days with 1 mg/L thyroxine in drinking water. The study revealed that in contrast to the non-genomic actions the aortas of these animals were hyperresponsive to the contractile stimulus, an effect not observed in endogenously hyperthyroid TRβ knockout mice. To identify targets of genomic thyroid hormone action, we analysed aortic gene expression by microarray, revealing several altered genes including the well-known thyroid hormone target gene hairless. Taken together, the findings demonstrate that thyroid hormones regulate aortic tone through genomic and non-genomic actions, although genomic actions seem to prevail in vivo. Moreover, we identified several novel thyroid hormone target genes that could provide a better understanding of the molecular changes occurring in the hyperthyroid aorta.

T3 and Glucose Increase Expression of ChREBPß to Induce Expression of Phosphoenolpyruvate Carboxykinase (Pck1) Leading to Increased ß-Cell Proliferation

Thyroid hormone (T3) is required for islet development and function. Both T3 and high glucose concentrations are critical components of differentiation protocols of stem cells to β-cells. We previously demonstrated that in brown adipose tissue, T3 and glucose synergistically regulate carbohydrate response element binding protein (ChREBP), which in turn upregulates Ucp1, Glut4 and Fasn, resulting in increased thermogenesis, decreased body weight and improved glycemic levels. In the present study, we asked whether T3 and glucose signaling pathways can coordinately regulate transcription of genes important for β-cell function and mass. RNA-seq analysis was performed on cadaveric human islets from five different donors in response to low and high glucose concentrations (6 and 20 mM, respectively) and in the presence or absence of T3 (10 nM). We found that T3 and glucose coordinately regulate the expression of ChREBPβ and Pck1 (phosphoenolpyruvate carboxykinase-1). Typically, it is thought that Pck1 is not expressed in pancreatic β-cells, but it is a known target of T3 in hepatocytes. However, in FACS sorted adult human β-cells, we found that high concentrations of glucose (20 mM) and T3 (10 nM) induced the expression of Pck1 by 17.2±1.3 fold for mRNA levels. In addition, we found that overexpression of Pck1 together with its substrate dimethyl malate (DMM) increased β- cell proliferation in human islets (0.49±0.03% for human islets overexpressing Pck1, treated with DMM compared with 0.01±0.01% for control islets, n=4). Finally, using a sh-RNA knockdown approach, we demonstrated that in Ins-1 cells, ChREBPβ is necessary for Pck1 dependent β-cell proliferation. We conclude that T3 and glucose act together to regulate ChREBPβ which in turn upregulates expression of Pck1. In turn, Pck1 activity leads to increased β-cell mass. Disclosure L.S. Katz: None. D. Scott: None.

State‐dependent behavior alters endocrine–energy relationship: implications for conservation and management

Glucocorticoids (GC) and triiodothyronine (T3) are two endocrine markers commonly used to quantify resource limitation, yet the relationships between these markers and the energetic state of animals has been studied primarily in small-bodied species in captivity. Free-ranging animals, however, adjust energy intake in accordance with their energy reserves, a behavior known as state-dependent foraging. Further, links between life-history strategies and metabolic allometries cause energy intake and energy reserves to be more strongly coupled in small animals relative to large animals. Because GC and T3 may reflect energy intake or energy reserves, state-dependent foraging and body size may cause endocrine-energy relationships to vary among taxa and environments. To extend the utility of endocrine markers to large-bodied, free-ranging animals, we evaluated how state-dependent foraging, energy reserves, and energy intake influenced fecal GC and fecal T3 concentrations in free-ranging moose (Alces alces). Compared with individuals possessing abundant energy reserves, individuals with few energy reserves had higher energy intake and high fecal T3 concentrations, thereby supporting state-dependent foraging. Although fecal GC did not vary strongly with energy reserves, individuals with higher fecal GC tended to have fewer energy reserves and substantially greater energy intake than those with low fecal GC. Consequently, individuals with greater energy intake had both high fecal T3 and high fecal GC concentrations, a pattern inconsistent with previous documentation from captive animal studies. We posit that a positive relationship between GC and T3 may be expected in animals exhibiting state-dependent foraging if GC is associated with increased foraging and energy intake. Thus, we recommend that additional investigations of GC- and T3-energy relationships be conducted in free-ranging animals across a diversity of body size and life-history strategies before these endocrine markers are applied broadly to wildlife conservation and management.

Contrasting Phenotypes in Resistance to Thyroid Hormone Alpha Correlate with Divergent Properties of Thyroid Hormone Receptor α1 Mutant Proteins.

Background: Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor alpha gene mutations, is rare but probably under-recognized. This study sought to correlate the clinical characteristics and response to thyroxine (T4) therapy in two adolescent RTHα patients with the properties of the THRA mutation, affecting both TRα1 and TRα2 proteins, they harbored.Methods: Clinical, auxological, biochemical, and physiological parameters were assessed in each patient at baseline and after T4 therapy.Results: Heterozygous THRA mutations occurring de novo were identified in a 17-year-old male (patient P1; c.788C>T, p.A263V mutation) investigated for mild pubertal delay and in a 15-year-old male (patient P2; c.821T>C, p.L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies, and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition, and constipation, together with a subnormal T4/triiodothyronine (T3) ratio, low reverse T3 levels, and mild anemia. When studied in vitro, A263V mutant TRα1 was transcriptionally impaired and inhibited the function of its wild-type counterpart at low (0.01–10 nM) T3 levels, with higher T3 concentrations (100 nM–1 μM) reversing dysfunction and such dominant negative inhibition. In contrast, L274P mutant TRα1 was transcriptionally inert, exerting significant dominant negative activity, only overcome with 10 μM of T3. Mirroring this, normal expression of KLF9, a TH-responsive target gene, was achieved in A263V mutation-containing peripheral blood mononuclear cells following 1 μM of T3 exposure, but with markedly reduced expression levels in L274P mutation-containing peripheral blood mononuclear cells, even with 10 μM of T3. Following T4 therapy, growth, body composition, dyspraxia, and constipation improved in P1, whereas growth retardation and constipation in P2 were unchanged. Neither A263V nor L274P mutations exhibited gain or loss of function in the TRα2 background, and no additional phenotype attributable to this was discerned.Conclusions: This study correlates a milder clinical phenotype and favorable response to T4 therapy in a RTHα patient (P1) with heterozygosity for mutant TRα1 exhibiting partial, T3-reversible, loss of function. In contrast, a more severe clinical phenotype refractory to hormone therapy was evident in another case (P2) associated with severe, virtually irreversible, dysfunction of mutant TRα1.

Thyrotoxicosis induced by excessive 3,5,3′-triiodothyronine in a dog

CASE DESCRIPTION A 7-year-old castrated male Havanese was evaluated at a veterinary teaching hospital because of a 12-week history of hyperactivity, aggression, and progressive weight loss despite a healthy appetite. CLINICAL FINDINGS Tachycardia was the only remarkable finding during physical examination. Serum 3,5,3'-triiodothyronine (T3) and free T3 concentrations were markedly increased, and thyroxine (T4), free T4, and thyroid-stimulating hormone concentrations were at or decreased from the respective reference ranges. Thyroid scintigraphy revealed suppressed uptake of sodium pertechnetate Tc 99m by the thyroid gland but no ectopic thyroid tissue, which was indicative of thyrotoxicosis induced by an exogenous source of T3. TREATMENT AND OUTCOME The dog was hospitalized for 24 hours, and its diet was changed, after which the clinical signs rapidly resolved and serum T3 and free T3 concentrations returned to within the respective reference ranges. This raised suspicion of an exogenous source of T3 in the dog's home environment. Analysis of the commercial beef-based canned food the dog was being fed revealed a high concentration of T3 (1.39 μg/g) and an iodine (82.44 μg/g) concentration that exceeded industry recommendations. No other source of T3 was identified in the dog's environment. CLINICAL RELEVANCE To our knowledge, this is the first report of clinical thyrotoxicosis in a dog induced by exogenous T3, although the source of exogenous T3 was not identified. This case highlights the importance of measuring serum T3 and thyroid-stimulating hormone concentrations in addition to T4 and free T4 concentrations when there is incongruity between clinical findings and thyroid function test results.

Thyroid homeostasis in mother\u2013child pairs in relation to maternal iodine status: the MISA study

Background/Objectives:Iodine deficiency during pregnancy may influence maternal and foetal thyroid function with the risk of causing neurocognitive and psychomotor deficits in the offspring. The objective of this study was to assess iodine status in pregnant women from Northern Norway and to investigate the influence of iodine status on maternal and infant thyroid function.Subjects/Methods:Women from the Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood and urine sample at three visits during their pregnancy and postpartum period (in second trimester, 3 days and 6 weeks after delivery. N=197). Women were assigned to iodine status groups according to urine iodine concentrations (UICs) in second trimester and mixed effects linear models were used to investigate potential associations between iodine status and repeated measurements of thyroid-stimulating hormone (TSH), thyroid hormones (THs), TH-binding proteins and thyroid peroxidase antibodies. Associations between maternal iodine status and TSH in heel prick samples from the infants were investigated with linear regression.Results:Median UIC in second trimester was 84 μg/l (range 18–522) and 80% had UIC below recommended level (<150 μg/l). Iodine-deficient women had higher concentrations of T3, FT3 and FT4 (estimated differences (confidence intervals) of 0.10 nmol/l (0.01, 0.17), 0.16 pmol/l (0.05, 0.26) and 0.45 pmol/l (0.10, 0.78), respectively) compared with iodine-sufficient women. The concentrations varied within normal reference ranges, but the majority of women with subclinical hypothyroidism were iodine deficient. Maternal iodine status did not influence infant TSH concentrations.Conclusions:This study indicate iodine deficiency among pregnant women in Norway. Iodine status during pregnancy influences maternal thyroid homeostasis and is therefore a risk factor for foetal and infant development.

Gene expression analysis and microdialysis suggest hypothalamic triiodothyronine (T3) gates daily torpor in Djungarian hamsters (Phodopus sungorus).

Thyroid hormones play an important role in regulating seasonal adaptations of mammals. Several studies suggested that reduced availability of 3,3',5-triiodothyronine (T3) in the hypothalamus is required for the physiological adaptation to winter in Djungarian hamsters. We have previously shown that T3 is involved in the regulation of daily torpor, but it remains unclear, whether T3 affects torpor by central or peripheral mechanisms. To determine the effect of T3 concentrations within the hypothalamus in regulating daily torpor, we tested the hypothesis that low hypothalamic T3 metabolism would favour torpor and high T3 concentrations would not. In experiment 1 gene expression in torpid hamsters was assessed for transporters carrying thyroid hormones between cerebrospinal fluid and hypothalamic cells and for deiodinases enzymes, activating or inactivating T3 within hypothalamic cells. Gene expression analysis suggests reduced T3 in hypothalamic cells during torpor. In experiment 2, hypothalamic T3 concentrations were altered via microdialysis and torpor behaviour was continuously monitored by implanted body temperature transmitters. Increased T3 concentrations in the hypothalamus reduced expression of torpor as well as torpor bout duration and depth. Subsequent analysis of gene expression in the ependymal layer of the third ventricle showed clear up-regulation of T3 inactivating deiodinase 3 but no changes in several other genes related to photoperiodic adaptations in hamsters. Finally, serum analysis revealed that increased total T3 serum concentrations were not necessary to inhibit torpor expression. Taken together, our results are consistent with the hypothesis that T3 availability within the hypothalamus significantly contributes to the regulation of daily torpor via a central pathway.

Genotoxicity of triiodothyronine: Effects on Salmonella typhimurium TA100 and human lymphocytes in vitro

There is increasing evidence that substances which are normally present in human or animal bodies may, under the certain circumstances, exhibit deleterious effects on genetic material, therefore acting as endogenous mutagenic agents. Since hormones represent one of the best studied endogenous mutagens, some research focused on the possible role of thyroid hormone in mutagenesis and carcinogenesis. Indeed, thyroid hormones accelerate aerobic metabolism and production of reactive oxygen species (ROS) and, therefore, may exhibit mutagenic effects in various test systems on mammalian cells. However, possible mutagenic effects on prokaryotic DNA has not been investigated so far. Hence, the aim of this research was to compare the sensitivity of TA 100 Salmonella typhimurium with and without metabolic activation with S9 fraction, and human lymphocytes to possible genotoxic effects of triiodothyronine (T3). Therefore, we used the reverse mutation assay on S. typhimurium (Ames test) and in vitro Comet assay in isolated peripheral blood human lymphocytes. In both tests-systems a broad spectrum of T3 concentrations was applied. The obtained results showed absence of genotoxic effects of T3 in bacterial reverse mutation assay and very profound genotoxic effects in human lymphocytes at concentrations higher than 15 ?M. We only observed cytotoxic effects in bacterial system at very high T3 concentrations (300 and 500 ?M). In conclusion, T3 was unable to increase the level of reverse mutations in Ames test both with and without S9 mix. Therefore, it seems that ROS production in mitochondria may be the primary cause of DNA damage caused by T3 in mammalian cells.

The Association of Thyroid Hormones and Tsh with the Metabolic Syndrome in Euthyroid Taiwanese Individuals

There are conflicting studies in euthyroid males and females regarding associations between thyroidrelated hormones and parameters of the metabolic syndrome (MetS). We investigated the association between serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations and MetS in euthyroid men and women. Taiwanese subjects aged 20 to 65 years who had undergone a voluntary health examination at a preventive examination agency in Taipei were enrolled in this cross-sectional study. The definition of MetS was suggested by the Bureau of Health Promotion, Department of Health, Taiwan. Euthyroidism was defined as TSH and free thyroxine (FT4) levels within the normal reference ranges while not taking any thyroid medication. We conducted multiple logistic regression to identify the ability of serum triiodothyronine (T3), FT4, and TSH concentrations to identify the relative risk for the presence of MetS and components of the MetS in euthyroid Taiwanese individuals. A total of 8,207 Taiwanese subjects (mean age: men, 45.3 ± 9.9 years; women, 43.5 ± 9.3 years) were enrolled in this study. A total of 1,672 subjects (20.4%) were defined as having MetS; these subjects had significantly higher (P<.0001) mean age (48.4 ± 9.1 years vs. 43.6 ± 10.7 years), prevalence of men (78.7% vs. 53.4%), and smoking (16.8% vs. 11.6%) than those without MetS. The median TSH, FT4, and T3 levels in all subjects were 1.70 mIU/L, 1.41 ng/dL, and 1.20 ng/mL, respectively. Higher T3 and lower FT4 values rather than TSH increased the odds ratio for MetS in men and women after adjusting for smoking and age, particularly for the association of T3 and MetS in women (uppermost quartile versus lowermost quartile: odds ratio, 2.4; 95% confidence interval, 1.6 to 3.5; P for trend <.0001). In euthyroid Taiwanese men and women, relatively high serum T3 concentrations was most strongly associated with the presence of the MetS; relatively low serum T4 was less strongly related, and serum TSH levels were not associated with the MetS. It is not known if the relationship of serum T3 and T4 to the MetS is causal. BMI = body mass index FT4 = free thyroxine MetS = metabolic syndrome OR = odds ratio T3 = triiodothyronine TSH = thyroid-stimulating hormone WC = waist circumference.

Effects of glucose, insulin and triiodothyroxine on leptin and leptin receptor expression and the effects of leptin on activities of enzymes related to glucose metabolism in grass carp (Ctenopharyngodon idella) hepatocytes.

Leptin is an important regulator of appetite and energy expenditure in mammals, but its role in fish metabolism control is poorly understood. Our previous studies demonstrated that leptin has an effect on the regulation of food intake and energy expenditure as well as lipid metabolism (stimulation of lipolysis and inhibition of adipogenesis) in the grass carp Ctenopharyngodon idella. To further investigate the role of leptin in fish, the effects of glucose, insulin and triiodothyroxine (T3) on the expression levels of leptin and leptin receptor (Lepr) and the effects of leptin on the activities of critical glucose metabolism enzymes in grass carp hepatocytes were evaluated in the present study. Our data indicated that leptin gene expression was induced by glucose in a dose-dependent manner, while Lepr gene expression exhibited a biphasic change. A high dose of insulin (100ng/mL) significantly up-regulated the expression of leptin and Lepr. Leptin expression was markedly up-regulated by a low concentration of T3 but inhibited by a high concentration of T3. T3 up-regulated Lepr expression in a dose-dependent manner. Together, these data suggest that leptin had a close relationship with three factors (glucose, insulin and T3) and might participate in the regulation of glucose metabolism in grass carp. In addition, we also found that leptin affected the activities of key enzymes that are involved in glucose metabolism, which might be mediated by insulin receptor substrate-phosphoinositol 3-kinase signaling.