Plasma Thyrotropin Concentrations Research Articles

Towards translating in vitro measures of thyroid hormone system disruption to in vivo responses in the pregnant rat via a biologically based dose response (BBDR) model

Despite the number of in vitro assays that have been recently developed to identify chemicals that interfere with the hypothalamic-pituitary-thyroid axis (HPT), the translation of those in vitro results into in vivo responses (in vitro to in vivo extrapolation, IVIVE) has received limited attention from the modeling community. To help advance this field a steady state biologically based dose response (BBDR) model for the HPT axis was constructed for the pregnant rat on gestation day (GD) 20. The BBDR HPT axis model predicts plasma levels of thyroid stimulating hormone (TSH) and the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Thyroid hormones are important for normal growth and development of the fetus. Perchlorate, a potent inhibitor of thyroidal uptake of iodide by the sodium iodide symporter (NIS) protein, was used as a case study for the BBDR HPT axis model. The inhibitory blocking of the NIS by perchlorate was associated with dose-dependent steady state decreases in thyroid hormone production in the thyroid gland. The BBDR HPT axis model predictions for TSH, T3, and T4 plasma concentrations in pregnant Sprague Dawley (SD) rats were within 2-fold of observations for drinking water perchlorate exposures ranging from 10 to 30,000 μg/kg/d. In Long Evans (LE) pregnant rats, for both control and perchlorate drinking water exposures, ranging from 85 to 82,000 μg/kg/d, plasma thyroid hormone and TSH concentrations were predicted within 2 to 3.4- fold of observations. This BBDR HPT axis model provides a successful IVIVE template for thyroid hormone disruption in pregnant rats.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations

ABSTRACTBackgroundIodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy.ObjectivesWe aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy.MethodsWe included 531 pregnant women (aged 22–40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27–33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations).ResultsMedian (IQR) micronutrient concentrations were 112 μg/L (80–156 μg/L) for UIC, 67 μg/L (58–76 μg/L) for plasma selenium, and 973 μg/L (842–1127 μg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 μg/L and 70 μg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98% < 4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and <1200 μg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 μg/L with tT3.ConclusionsPregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Could the ketogenic diet induce a shift in thyroid function and support a metabolic advantage in healthy participants? A pilot randomized-controlled-crossover trial.

BackgroundThe ketogenic diet (KD) has been shown to result in body mass loss in people with disease as well as healthy people, yet the effect of the KD on thyroid function and metabolism are unknown.ObjectiveWe aimed to determine the effects of a KD, compared with an isocaloric high-carbohydrate low-fat (HCLF) diet, on resting metabolic rate and thyroid function in healthy individuals.DesignEleven healthy, normal-weight participants (mean(SD) age: 30(9) years) completed this randomized crossover-controlled study. For a minimum of three weeks on each, participants followed two isocaloric diets: a HCLF diet (55%carbohydrate, 20%fat, 25%protein) and a KD (15%carbohydrate, 60%fat, 25% protein), with a one-week washout period in-between. Importantly, while on the KD, the participants were required to remain in a state of nutritional ketosis for three consecutive weeks. Crossover analyses and linear mixed models were used to assess effect of diet on body mass, thyroid function and resting metabolic rate.ResultsBoth dietary interventions resulted in significant body mass loss (p<0.05) however three weeks of sustained ketosis (KD) resulted in a greater loss of body mass (mean (95%CI): -2.9 (-3.5, -2.4) kg) than did three weeks on the HCLF diet (-0.4 (-1.0, 0.1) kg, p < 0.0001). Compared to pre-diet levels, the change in plasma T3 concentration was significantly different between the two diets (p = 0.003), such that plasma T3 concentration was significantly lower following the KD diet (4.1 (3.8, 4.4) pmol/L, p<0.0001) but not different following the HCLF diet (4.8 (4.5, 5.2) pmol/L, p = 0.171. There was a significant increase in T4 concentration from pre-diet levels following the KD diet (19.3 (17.8, 20.9) pmol/L, p < 0.0001), but not following the HCLF diet (17.3 (15.7, 18.8) pmol.L, p = 0.28). The magnitude of change in plasma T4 concentration was not different between the two diets (p = 0.4). There was no effect of diet on plasma thyroid stimulating hormone concentration (p = 0.27). There was a significantly greater T3:T4 ratio following the HCLF diet (0.41 (0.27, 0.55), p < 0.0001) compared to pre-diet levels but not following the KD diet (0.25 (0.12, 0.39), p = 0.80).ConclusionsAlthough the diets were isocaloric and physical activity and resting metabolic rate remained constant, the participants lost more mass after the KD than after the HCLF diet. The observed significant changes in triiodothyronine concentration suggest that unknown metabolic changes occur in nutritional ketosis, changes that warrant further investigation.Trial registrationPan African Clinical Trial Registry: PACTR201707002406306 URL: https://pactr.samrc.ac.za/.

Plasma Tsh concentration and risk of cardiovascular disease: A Mendelian randomization study of 105,224 individuals from the general population.

Background and Aims: In observational studies, the association between plasma concentration of thyroid stimulating hormone (TSH) and cardiovascular disease outcomes is conflicting. Using Mendelian randomization, we tested the hypothesis that plasma TSH concentration is associated with risk of ischemic heart disease (IHD), myocardial infarction (MI), and atrial fibrillation (AF).

Risk factors for low plasma thyroxine and high plasma thyroid-stimulating hormone concentrations in dogs with non-thyroidal diseases.

The aim of the current study was to identify independent risk factors for thyroid axis alterations in dogs with non-thyroidal diseases. In this retrospective cross-sectional study, data and plasma samples from 207 dogs with non-thyroidal diseases was used. The involvement of various factors (disease severity, sex, age, breed, category and duration of disease, and medication) in the alteration of plasma thyroxine (T4) or thyroid-stimulation hormone (TSH) concentrations was analyzed using multivariate logistic regression. Among the 207 dogs analyzed, 99 (47.8%) had low plasma T4 concentrations, while 45 (21.7%) had high TSH concentrations. Intact male sex [odds ratio (OR), 3.25; 1.67–6.35; P<0.001], Labrador Retrievers (OR, 18.70; 2.32–151.00; P=0.006), moderate (OR, 2.39; 1.21–4.74; P=0.012) and severe diseases (OR, 6.84; 2.27–20.70; P<0.001) were associated with increased risk for low plasma T4 concentrations. Meanwhile, intact male (OR, 3.93; 1.51–10.30; P=0.005), spayed female (OR, 4.22; 1.59–11.20; P=0.004), older age (OR, 2.73; 1.28–5.84; P=0.009), and Miniature Dachshunds (OR, 5.39; 2.38–12.20; P<0.001) had increased risk for high plasma TSH concentrations. Disease severity had been determined as an independent risk factor for canine NTIS. In addition, sex, age and breed were also associated with thyroid axis alterations in dogs with non-thyroidal diseases.

IS FIBROMYALGIA A SYNDROME OF HORMONAL IMBALANCE?

Objectives: The present study was conducted to estimate cortisol and thyroid-stimulating hormone (TSH) levels in patients with fibromyalgia syndrome (FMS) and to find correlation if any between hormone levels and pain duration in FMS.Methods: Plasma cortisol and TSH concentration were determined by electro chemiluminescence immunoassay in 89 female patients with FMS and 74 age-matched healthy women.Results: No significant difference in TSH level was observed between FMS and healthy subjects. Ten patients had higher cortisol levels than the standard reference range, 48 patients with reduced cortisol and 31 patients with normal cortisol levels. No significant correlation was observed between pain duration and levels of cortisol.Conclusion: The study has confirmed the equivocal data regarding cortisol/hypothalamic-pituitary-adrenal axis related dysfunction in FMS. To the best of our knowledge, it is the first Indian study on FMS which assessed the cortisol and TSH levels and their correlation with pain duration if any.

TSH and PRL, side-effect markers in aripiprazole treatment: adjunctive aripiprazole-induced thyrotropin oversuppression in a young man with schizophrenia

A 26-year-old Japanese man was admitted to our unit with exacerbated paranoid schizophrenia. Prior to his admission, daily administration of olanzapine had been sufficient to maintain a partial remission of...

A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents.

BackgroundHypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.ObjectiveThis study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.MethodsGenome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5−24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2−22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.ResultsNo novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (PDE10A (rs2983511: β = 0.112SD, p = 4.8 ∙ 10−16), FOXE1 (rs7847663: β = 0.223SD, p = 1.5 ∙ 10−20), NR3C2 (rs9968300: β = 0.194SD), p = 2.4 ∙ 10−11), VEGFA (rs2396083: β = 0.088SD, p = 2.2 ∙ 10−10)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (p<0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.ConclusionIn a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.

Prolonged hypothyroidism severely reduces ovarian follicular reserve in adult rats

BackgroundThere is substantial evidence both in humans and in animals that a prolonged reduction in plasma thyroid hormone concentration leads to reproductive problems, including disturbed folliculogenesis, impaired ovulation and fertilization rates, miscarriage and pregnancy complications. The objective of the present study is to examine the consequences of chronic hypothyroidism, induced in adulthood, for the size of the ovarian follicle pool. In order to investigate this, adult female rats were provided either a control or an iodide deficient diet in combination with perchlorate supplementation to inhibit iodide uptake by the thyroid. Sixteen weeks later animals were sacrificed. Blood was collected for hormone analyses and ovaries were evaluated histologically.ResultsAt the time of sacrifice, plasma thyroid-stimulating hormone concentrations were 20- to 40-fold increased, thyroxine concentrations were negligible while tri-iothyronin concentrations were decreased by 40% in the hypothyroid group, confirming that the animals were hypothyroid. Primordial, primary and preantral follicle numbers were significantly lower in the hypothyroid ovaries compared to the euthyroid controls, while a downward trend in antral follicle and corpora lutea numbers was observed. Surprisingly the percentage of atretic follicles was not significantly different between the two groups, suggesting that the reduced preantral and antral follicle numbers were presumably not the consequence of increased degeneration of these follicle types in the hypothyroid group. Plasma anti-Müllerian hormone (AMH) levels showed a significant correlation with the growing follicle population represented by the total ovarian number of primary, preantral and antral follicles, suggesting that also under hypothyroid conditions AMH can serve as a surrogate marker to assess the growing ovarian follicle population.ConclusionsThe induction of a chronic hypothyroid condition in adult female rats negatively affects the ovarian follicular reserve and the size of the growing follicle population, which may impact fertility.

Effect of L-thyroxine supplementation on very low birth weight infants with transient hypothyroxinemia of prematurity at 3 years of age.

To evaluate the effects of levothyroxine (L-T4) supplementation on growth and neurodevelopmental outcomes at 3 years of age in very low birth weight (VLBW) infants with transient hypothyroxinemia of prematurity (THOP). VLBW infants with plasma thyroid-stimulating hormone concentrations <10 mIU l-1 and free thyroxine concentrations <0.8 ng dl-1 were defined as having THOP and randomly assigned to the Treated (20 infants) or Untreated (31 infants) group. The Treated group received L-T4 at a dose of 5 μg kg-1 day-1. Growth and neurodevelopmental outcomes at 3 years of age were compared between the two groups. There were no significant differences in body length, body weight or head circumference mean s.d. scores or in neurodevelopmental outcomes between the two groups. L-T4 supplementation in VLBW infants with THOP demonstrated no beneficial effect at 3 years of age.

Relationships between leptin, the KiSS-1/GPR54 system and thyrotropic axis activity in ewe lambs predisposed to the delayed puberty

In the present study we compared body weight gains, some factors involved in the initiation of sexual maturation (pituitary expression of KiSS-1 and G protein-coupled receptors (GPR54), plasma concentrations of kisspeptin-10 (KiSS-10), leptin, thyroid-stimulating hormone (TSH), free thyroxin (fT4)) and the time of the first ovulation in ewe lambs predisposed to delayed puberty and control animals. The experiment was carried out on 114 ewes and 64 female lambs divided according to their birth type and body weight of their mothers. All ewe lambs were weighed at birth and every two weeks thereafter, until eight months of postnatal age. From four to eight months of postnatal age at monthly intervals, blood samples were collected from the jugular vein of all ewe lambs. Then, daily weight gains were recorded and plasma KiSS-10, leptin, TSH and fT4 concentrations were analysed by ELISA using species-specific antibodies. Starting from six months of age, the pituitary expression of KiSS-1/GPR54 mRNA was determined by Real Time-PCR. The activity of the ovaries was estimated using laparoscopy. The results obtained showed that the time of the onset of puberty in the ewe lambs depended on the mother’s body mass, the plasma leptin level, and the birth type (singleton/twin). It was observed that the elevation of leptin concentration up to 3.35±0.26–3.60±0.19ng/mL was associated with the initiation of puberty. Conversely, the hyperphysiological leptin levels found in ewe lambs, which were twin offspring of fatty sheep, were correlated with puberty delayed until the age of ten months. Moreover, it was found that a significant increase in pituitary KiSS-1 mRNA expression (1.40±0.12–1.63±0.22) (relative KiSS-1 mRNA expression level, ratio of KiSS-1 mRNA/GAPDH mRNA) and plasma KiSS-10 concentration (31.26±1.54ng/mL–32.24±2.25ng/mL) was connected with the occurrence of the first ovulation. On the other hand, GPR54 mRNA expression in the pituitary decreased around the time of the first ovulation. Also, the increase in thyroid gland activity was dependent on the mother’s body mass as well as birth type and occurred around the time of the first ovulation.

Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway.

Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic–pituitary–adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt/β-catenin pathway.

Impacts of oil spills on seabirds: Unsustainable impacts of non-renewable energy

Accidental spillage of oil in to the sea from shipping transport and drilling rigs results in spills that cause significant unsustainable mortality of wildlife and destroys marine ecosystem services. External oiling of seabirds causes large scale mortality within days following a spill, while survivors suffercauses long term chronic effects from the exposure to toxic polycyclic aromatic hydrocarbons (PAHs) present in ingested oil. Survival rates for rehabilitated oiled birds are very low despite investment of significant resources. PAHs disturb thyroid homeostasis which plays a vital role in the control of energy metabolism. In this study, plasma PAH and thyroid-stimulating hormone (TSH) were quantified as biomarkers of exposure and endocrine disruption in oiled guillemots (Uria aalge). Mean plasma PAH and TSH concentrations, were 98.1 ± 8.3 ng/ml and 0.13 ± 0.02 ng/ml and these parameters were found to be negatively correlated (p < 0.01) indicative of PAH-associated thyroid hormone suppression in more heavily oiled birds. Body condition and weight were also lower in birds that died compared with birds that were released. The data also show the value of measuring plasma TSH and PAH to monitor metabolic status and progress of decontamination of oiled birds in a rehabilitation setting.

P055. Prevalence of migraine in subclinical hypothyroidism: a case-control study.

Background The existence of an association between migraine and thyroid diseases is still a matter of debate. Epidemiological studies have shown a potential association between plasma TSH concentrations and migraine but results are contradictory. Subclinical hypothyroidism (SCH) is a common clinical entity defined biochemically as a normal serum free thyroxine (fT4) concentration in the presence of an elevated serum thyroid-stimulating hormone (TSH) concentration. In population-based studies, the prevalence of SCH ranges from 4 to 15 percent, the diagnosis being more common in women and in old age. Prospective data have shown that SCH is a risk factor for coronary heart disease, heart failure, and cardiovascular mortality, probably related to a mechanism of endothelial dysfunction and low grade chronic inflammation. A recent study suggested an increased prevalence of subclinical hypothyroidism in childhood migraine. The purpose of this study was to evaluate the prevalence and clinical characteristics of migraine in patients with subclinical hypothyroidism.

Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma.

Treatment with (131)I-MIBG is associated with significant thyroid damage. This study was undertaken to investigate the long-term efficacy of current thyroid prophylaxis, to explore the relationship between thyroid dysfunction and thyroid volume after exposure to (131)I-MIBG and to evaluate the possible negative effects of (131)I(-) on the parathyroid glands. Of 81 long-term surviving patients with neuroblastoma treated with (131)I-MIBG during the period 1999-2012, 24 were finally evaluated. Patients received thyroxine (T4), methimazole and potassium iodide as thyroid protection. In all patients (para)thyroid function was evaluated and ultrasound investigation of the (para)thyroid gland(s) was performed. Thyroid dysfunction was defined as a plasma thyrotropin concentration >5.0mU/L (thyrotropin elevation, TE) or as the use of T4 at the time of follow-up. Hyperparathyroidism was defined as a serum calcium concentration above the age-related reference range in combination with an inappropriately high parathyroid hormone level. At a median follow-up of 9.0years after (131)I-MIBG treatment, thyroid disorders were seen in 12 patients (50%; 9 with TE, 5 with a thyroid nodule and 1 patient was subsequently diagnosed with differentiated thyroid carcinoma). No significant risk factors for the occurrence of thyroid damage could be identified. In 14 of 21 patients (67%) in whom thyroid volume could be determined, the volume was considered small (<-2SD) for age and gender. Patients treated with T4 at the time of follow-up had significantly smaller thyroid volumes for age than patients without T4 treatment (p = 0.014). None of the patients was diagnosed with hyperparathyroidism. Thyroid protection during treatment with (131)I-MIBG needs attention and must be further improved, as thyroid disorders are still frequently seen despite current thyroid prophylaxis. Reduced thyroid volume in neuroblastoma survivors may be related to previous (131)I-MIBG therapy or current T4 treatment. No deleterious effects of (131)I-MIBG on the parathyroid glands could be found.

Effect of l-thyroxine supplementation on infants with transient hypothyroxinemia of prematurity at 18 months of corrected age: randomized clinical trial.

Our objective was to evaluate effects of levothyroxine (l-T4) supplementation against neurodevelopmental outcomes at 18 months of corrected age in very-low-birth-weight (VLBW) infants with hypothyroxinemia but without elevated thyroid-stimulating hormone (TSH) concentration. VLBW infants who had plasma TSH concentrations <10 μU/mL and free thyroxine (FT4) concentrations <0.8 ng/dL between 2 and 4 weeks of age were enrolled. They were randomly assigned to either the Treated (n=25) or Untreated group (n=45). The Treated group received l-T4 at a dose of 5 μg/kg/day. We compared growth and neurodevelopmental outcomes at 18 months of corrected age in the two groups. There were no significant differences in growth, the incidences of developmental delay, cerebral palsy, visual impairment, and hearing impairment in the two groups. In such infants, l-T4 supplementation at a dose of 5 μg/kg/day did not affect FT4 levels and showed no beneficial effect at 18 months of corrected age.

Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism.

BackgroundIatrogenic hypothyroidism is associated with an increased incidence of azotemia after treatment of hyperthyroidism, and decreased survival time in azotemic hyperthyroid cats.HypothesisRestoration of euthyroidism will decrease plasma creatinine concentrations.AnimalsNineteen client‐owned, methimazole‐ or carbimazole‐treated, hyperthyroid cats with documented iatrogenic hypothyroidism (based on subnormal plasma total thyroxine concentrations [TT4] and increased plasma thyroid‐stimulating hormone concentrations).MethodsProspective interventional study. Doses of antithyroid medication were reduced until euthyroidism was restored (TT4 10–40 nmol/L). Plasma creatinine concentration and selected other clinicopathologic variables were evaluated before and after restoration of euthyroidism and compared by nonparametric statistics. Data are presented as median [25th, 75th percentile].ResultsRestoration of euthyroidism was associated with a significant decrease in plasma creatinine concentrations (2.61 [1.90, 3.26] mg/dL versus 2.07 [1.42, 2.82] mg/dL; P < .001) and body weight (4.03 [3.59, 4.53] kg versus 3.89 [3.34, 4.18] kg; P = .019), and a significant increase in packed cell volume (30 [28, 39]% versus 34 [29, 39]%; P = .038), heart rate (174 [163, 201] bpm versus 190 [164, 202] bpm; P = .009), and plasma alkaline phosphatase activity (26.6 [17.0, 33.0] IU/L versus 38.0 [23.5, 46.5] IU/L; P < .001).Conclusions and Clinical ImportanceRestoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism causes a reduction in plasma creatinine concentrations, and thus might improve renal function; however, this could be influenced by concurrent changes in body weight.

A genome-wide association study on thyroid function and anti-thyroid peroxidase antibodies in Koreans.

Genetic factors are thought to be an important determinant of thyroid function and autoimmunity. However, there are limited data on genetic variants in Asians. In this study, we performed a genome-wide association study on plasma thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentration and anti-thyroid peroxidase (anti-TPO) antibody positivity in 4238 Korean subjects. In the Stage 1 genome scan, 3396 participants from the Ansung cohort were investigated using 1.42 million genotyped or imputed markers. In the Stage 2 follow-up, 10 markers were genotyped in 842 participants from the Korean Longitudinal Study on Health and Aging cohort. An intronic variant in VAV3, rs12126655, which has been reported in Europeans, was significantly associated with plasma TSH concentration in the joint Stages 1 and 2 analyses (P = 2.2 × 10(-8)). We observed that a novel variant, rs2071403, located 75 bp proximal to the translational start site of TPO was significantly associated with plasma anti-TPO antibody positivity in the joint Stages 1 and 2 analyses (P = 1.3 × 10(-10)). This variant had a marginal sex-specific effect, and its association was more significant in females. Subjects possessing the rs2071403A allele, associated with an absence of the anti-TPO antibody, had decreased TPO mRNA expression in their thyroid tissue. Another intronic variant of HLA-DPB2, rs733208, had a suggestive association with anti-TPO antibody positivity (P = 4.2 × 10(-7)). In conclusion, we have identified genetic variants that are strongly associated with TSH level and anti-TPO antibody positivity in Koreans. Further replications and meta-analysis are required to confirm these findings.

Long-term follow-up of the thyroid gland after treatment with 131 I-Metaiodobenzylguanidine in children with neuroblastoma: Importance of continuous surveillance

Thyroid dysfunction has been reported in up to 52% of patients 1.4 years after treatment with (131) I-Metaiodobenzylguanidine (MIBG) in children with neuroblastoma (NBL), despite the use of potassium-iodide (KI). Our aim was to investigate if the incidence and severity of thyroid damage increases in time. All long-term survivors of childhood NBL treated with (131) I-MIBG in the period 1989-1999 in our center (n = 16 of 43) were evaluated. During exposure to (131) I-MIBG, patients received 100 mg KI per day as thyroid protection. All MIBG images were evaluated for thyroid uptake of radio-iodine. Thyroid dysfunction was defined as a plasma thyrotropin concentration above the institutional age-related reference ranges (thyrotropin elevation, TE) or using thyroxine at last moment of follow-up. In all, ultrasound investigation of the thyroid was performed. Fifteen years after treatment with (131) I-MIBG, in 81% (n = 13) thyroid disorders were diagnosed. Eight survivors (50%) were treated with thyroxine. Thyroid nodules were found in nine survivors, of which two were diagnosed with papillary thyroid carcinoma. In 28% of (131) I-MIBG-images radio-iodine uptake in the thyroid gland was seen, but no correlation was found between thyroidal radio-iodine uptake and thyroid disorders. Despite protection with KI during exposure to (131) I-MIBG in childhood, the occurrence of thyroid disorders is high and increases in time. Continuous screening for thyroid dysfunction and nodules in these survivors is recommended. Other ways to protect the thyroid gland should be further evaluated.

Central neuropeptide Y infusion and melanocortin 4 receptor antagonism inhibit thyrotropic function by divergent pathways

Weight loss inhibits thyrotropic function and reduces metabolic rate, thereby contributing to weight regain. Under negative energy balance there is an increase in the hypothalamic expression of both neuropeptide Y (NPY) and agouti related peptide (AgRP), the endogenous antagonist of melanocortin 4 (MC4) receptors. Both NPY and MC4 receptor antagonism reduce thyrotropic function centrally, but it is not known whether these pathways operate by similar or distinct mechanisms. We compared the time-course of effects of acute or chronic intracerebroventricular (ICV) administration of NPY (1.2 nmol acute bolus, or 3.5 nmol/day for 6 days) or the MC4 receptor antagonist HS014 (1.5 nmol bolus, or 4.8 nmol/day) on plasma concentrations of thyroid stimulating hormone (TSH) or free thyroxine (T4) in male rats pair-fed with vehicle-infused controls. These doses equipotently induced hyperphagia in acute studies, reduced latency to feed, and increased white adipose tissue mass after 6 days of infusion. Acute central NPY but not HS014 administration significantly reduced plasma TSH concentrations within 30-60 min and plasma free T4 levels within 90-120 min. These inhibitory effects were sustained for up to 5-6 days of continuous NPY infusion. HS014 induced a transient decrease in plasma free T4 levels that was observed only after 1-2 days of continuous ICV infusion. While both NPY and HS014 significantly increased corticosteronemia within an hour after ICV injection, the effect of NPY was significantly more pronounced and was sustained for up to 4 days of administration. Both NPY and HS014 significantly decreased the brown adipose tissue protein levels of uncoupling protein-3. We conclude that central NPY and MC4 antagonism decrease thyrotropic function via partially distinct mechanisms with different time courses, possibly involving glucocorticoid effects of NPY. MC4 receptor antagonism increases adiposity via pathways independent of increased food intake or changes in circulating concentrations of TSH, free T4 or corticosterone.