Subclinical Thyrotoxicosis and Cardiovascular Risk: Assessment of Circulating Endothelial Progenitor Cells, Proangiogenic Cells, and Endothelial Function.

Background: Subclinical thyrotoxicosis (SCT) is defined by low or undetectable thyroid-stimulating hormones and normal thyroid hormones. The treatment of SCT is uncertain despite being associated with increased cardiovascular risk (CVR) and mortality. Circulating endothelial progenitor cells (cEPCs) and circulating angiogenic cells (CACs) have been found to be reduced in conditions with CVR. We aimed to evaluate whether endothelial function and cEPC and CAC counts were reduced in SCT and to study the in vitro effect of triiodothyronine (T3) on proangiogenic cell (PAC) function from young healthy controls. Methods: cEPCs (quantified by flow cytometry, 20 SCT/20 controls), CACs following in vitro cultures (15 SCT/14 controls), paracrine function of CACs, endothelial function by flow-mediated dilation (FMD, 9 SCT/9 controls), and the effect of T3 on apoptosis and endothelial nitric oxide synthase (eNOS) expression in PACs were studied. Results: p < 0.001, CD133+/VEGFR-2+ 0.4 (0.0-0.7) vs. 0.6 (0.0-4.6), p = 0.009, CD34+/VEGFR-2+ 0.3 (0.0-1.0) vs. 0.7 (0.1-4.9), p = 0.002; while CAC count was similar. SCT predicted a lower cEPC count after adjustment for conventional CVR factors. FMD was lower in SCT subjects versus controls (% mean ± SD, 2.7 ± 2.3 vs. 6.1 ± 2.3, p = 0.005). In vitro studies showed T3 increased early apoptosis and reduced eNOS expression in PACs. Conclusions: In conclusion, SCT is associated with reduced cEPC count and FMD, confirming increased CVR in SCT. Future outcome trials are required to examine if treatment of this subclinical hyperactive state improves cardiovascular outcome. Clinical Trial Registration: http://www.controlled-trials.com/isrctn/, identifier ISRCTN70334066.

Behavioral assessment of children and adolescents with Graves' disease: A prospective study.

Previous studies have identified frequent comorbid neuropsychiatric disorders and conditions in adults with thyrotoxicosis. These studies are scarce or even lacking in pediatric population. This work aimed to study the behavior of children and adolescents with Graves' disease (GD). This study included 35 children with GD (boys = 15; girls = 25; mean age: 11.45±1.50yrs) and 40 healthy children (boys = 20; girls = 20; mean age: 12.54±1.62yrs). Behavior was assessed using Child Behavior Checklist (CBCL). Children with GD were assessed during periods of thyroid hormone elevation (active disease) and normalized thyroid hormones (with anti-thyroid drugs or ATDs). Compared to healthy children, patients during periods of thyroid hormone elevation (74.29%) and normalized thyroid hormones (31.43%) had higher frequencies of behavioral abnormalities and scorings of total CBCL scale (P = 0.01; P = 0.04, respectively) and its subscales' [Anxious/Depressed (P = 0.02; P = 0.04), Withdrawn/Depressed (P = 0.03; P = 0.04) and Somatic Complaints (P = 0.03; P = 0.127) and Social (P = 0.01; P = 0.225), Thought (P = 0.01; P = 0.128) and Attention (P = 0.01; P = 0.01) problems], indicating internalizing and externalizing problems. The majority of patients had at least two different behavioral problems. Marked improvement was found during period of normalized thyroid hormones (P = 0.001). Correlation analyses showed significant associations between total CBCL scoring and age at onset (P = 0.01; P = 0.001) and lower concentrations of thyroid stimulating hormone (TSH) (P = 0.001; P = 0.04) and higher concentrations of free thyroxine (fT4) (P = 0.01; P = 0.02), triiodothyronine (fT3) (P = 0.01; P = 0.03) and thyrotropin receptor antibodies (TRAbs) (P = 0.001; P = 0.01) during periods of thyroid hormone elevation and normalized thyroid hormones, respectively. Multiple linear regression analysis showed that "at presentation" lower concentrations of TSH (P = 0.001; P = 0.03) and higher concentrations of fT4 (P = 0.001, P = 0.01), fT3 (P = 0.01; P = 0.06) and TRAbs (P = 0.001; P = 0.001) were predictors of behavioral problems during periods of active disease and normalized thyroid hormones. We conclude that GD is associated with higher frequencies and severities of anxiety, depression and inattention during periods of thyroid hormone elevation as well as normalized thyroid hormones with ATDs. Therefore, early diagnosis and optimizing management are required to improve children's social life.

A pregnant woman with an autonomously functioning thyroid nodule: a case report.

BACKGROUND: The epidemiology and natural history of autonomously functioning thyroid nodules (AFTNs) have not been elucidated. Here we report the pregnant Japanese woman with an AFTN. CASE PRESENTATION: The patient was a 31-year-old woman who was hospitalized due to the placenta previa associated with threatened abortion at the 16 weeks of her third pregnancy. At her second pregnancy, she was euthyroid but had a single, 2.3 cm nodule on her right thyroid lobe. Her thyroid hormone level was trended increased with her pregnancy progression, and the thyrotoxic state was remained after delivery. Before her third pregnancy, her hyper-vascular nodule enlarged to 3.4 cm at regular monitoring. When she visited our hospital, she was at 16 weeks of pregnancy and had thyrotoxicosis with negative TSH-receptor antibody. She delivered a baby weighing 2615 g without hypothyroidism at 39 weeks of pregnancy by natural delivery. After delivery, a 99mTc scintigram showed a hot spot in her right thyroid lobe. She was diagnosed with AFTN and treated with methimazole while nursing. CONCLUSIONS: This case showed that hCG stimulation during pregnancy caused thyroid nodule enlargement and enhanced thyroid hormone production. The pregnancy could be the pathological stimulus and provides chance to diagnosis for AFTNs.

Thyroid dysfunction following pregnancy and implications for breastfeeding.

Subclinical autoimmune thyroiditis exacerbates after delivery through immune rebound mechanisms and results in 5 types of thyroid dysfunction. The prevalence of postpartum thyroid dysfunction is around 5% in mothers in the general population. Typically, an exacerbation induces destructive thyrotoxicosis followed by transient hypothyroidism, known as postpartum thyroiditis. Late development of permanent hypothyroidism is found frequently and patients should be followed up once every one to two years. Destructive thyrotoxicosis in postpartum thyroiditis should carefully be differentiated from post-partum Graves' disease. Postpartum thyroiditis typically occurs 1-4 months after parturition whereas Graves' disease develops at 4-12 months postpartum. Anti-TSH receptor antibodies (TRAb) are typically positive and thyroid blood flow is high in Graves' disease, whereas these features are absent in postpartum thyroiditis. Postpartum Graves' disease should be treated with antithyroid drugs.

The Influence of Thyroid Hormones on Brain Structure and Function in Humans.

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.

Diagnostic testing for Graves' or non-Graves' hyperthyroidism: A comparison of two thyrotropin receptor antibody immunoassays with thyroid scintigraphy and ultrasonography.

OBJECTIVE: Graves' disease (GD) is the most common cause of hyperthyroidism. In many cases, when the aetiological diagnosis of GD is not evident based on the clinical evaluation and thyroid function testing, it may become challenging to distinguish Graves' hyperthyroidism from other forms of thyrotoxicosis. The current study was primarly carried out to compare the diagnostic effectiveness of two TSH receptor antibody immunoassays (IMAs), ultrasonography and thyroid scintigraphy in hyperthyroidism scenario. METHODS: We retrospectively analysed consecutive patients with newly diagnosed and untreated thyrotoxicosis who underwent thyroid functional tests, both TRAb and TSI measurements, thyroid scintigraphy and ultrasonography. TRAb assessment was carried out by Kryptor® compact PLUS, while TSI by Immulite® . Echo pattern 3 corresponded to 'thyroid inferno', and the final diagnosis of GD vs non-Graves' hyperthyroidism was made according to the thyroid scan (qualitative scintigraphy). Receiver operating characteristic (ROC) curves were drawn using the final diagnosis as reference. Clinical sensitivity and specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all the tests. RESULTS: A total of 124 untreated hyperthyroid patients were included in our study (GD, n = 86 vs non-Graves' hyperthyroidism, n = 38). ROC curves showed that the optimal cut-off values associated with the highest diagnostic sensitivity and specificity was 0.7 IU/L for TRAb Kryptor® (93 [85.4-97.4] and 86.8 [71.9-95.5]) and 0.1 IU/L for TSI Immulite® (94.2 [86.9-98.1] and 84.2 [68.7-93.9]), respectively. For the echo pattern 3, we found a good sensitivity (92.1%) and a high PPV (95.2%) but a quite low specificity value (69.8%) and a relative low NPV (57.5%). For thyroid scintigraphy, the TcTU cut-off value of 1.3% corresponded to the best limit for sensitivity and specificity in our patients (95.3 [88.5-98.7] and 96.4 [81.6-99.4]). The Passing-Bablok regression equation and the Bland-Altman test showed a great degree of correlation and agreement existed between TRAb Kryptor® and Immulite® TSI results. CONCLUSIONS: Thyroid scintigraphy remains the most accurate method to differentiate causes of thyrotoxicosis. However, TRAb assays can be alternatively adopted in this setting, limiting the use of thyroid scintigraphy (TcTU evaluation) to TRAb-negative patients. Thyoid US is less accurate than both TRAb/TSI and thyroid scintigraphy, but the 'thyroid inferno' pattern provides a high PPV for GD.

A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans.

Background: In numerous studies based predominantly on rodent models, administration of 3,5-diiodo-L-thyronine (3,5-T2), a metabolite of the thyroid hormones (TH) thyroxine (T4) and triiodo-L-thyronine (T3), was reported to cause beneficial health effects, including reversal of steatohepatosis and prevention of insulin resistance, in most instances without adverse thyrotoxic side effects. However, the empirical evidence concerning the physiological relevance of endogenously produced 3,5-T2 in humans is comparatively poor. Therefore, to improve the understanding of 3,5-T2-related metabolic processes, we performed a comprehensive metabolomic study relating serum 3,5-T2 concentrations to plasma and urine metabolite levels within a large general population sample. Methods: Serum 3,5-T2 concentrations were determined for 856 participants of the population-based Study of Health in Pomerania-TREND (SHIP-TREND). Plasma and urine metabolome data were generated using mass spectrometry and nuclear magnetic resonance spectroscopy, allowing quantification of 613 and 578 metabolites in plasma and urine, respectively. To detect thyroid function-independent significant 3,5-T2-metabolite associations, linear regression analyses controlling for major confounders, including thyrotropin and free T4, were performed. The same analyses were carried out using a sample of 16 male healthy volunteers treated for 8 weeks with 250 µg/day levothyroxine to induce thyrotoxicosis. Results: The specific molecular fingerprint of 3,5-T2 comprised 15 and 73 significantly associated metabolites in plasma and urine, respectively. Serum 3,5-T2 concentrations were neither associated with classical thyroid function parameters nor altered during experimental thyrotoxicosis. Strikingly, many metabolites related to coffee metabolism, including caffeine and paraxanthine, formed the clearest positively associated molecular signature. Importantly, these associations were replicated in the experimental human thyrotoxicosis model. Conclusion: The molecular fingerprint of 3,5-T2 demonstrates a clear and strong positive association of the serum levels of this TH metabolite with plasma levels of compounds indicating coffee consumption, therefore pointing to the liver as an organ, the metabolism of which is strongly affected by coffee. Furthermore, 3,5-T2 serum concentrations were found not to be directly TH dependent. Considering the beneficial health effects of 3,5-T2 administration observed in animal models and those of coffee consumption demonstrated in large epidemiological studies, one might speculate that coffee-stimulated hepatic 3,5-T2 production or accumulation represents an important molecular link in this connection.

Allylpyrocatechol, isolated from betel leaf ameliorates thyrotoxicosis in rats by altering thyroid peroxidase and thyrotropin receptors.

Allylpyrocatechol (APC) was isolated from betel leaf and its possible role in L-thyroxin (L-T4)-induced thyrotoxic rats was evaluated. The disease condition, thyrotoxicosis was confirmed by higher levels of thyroid hormones and low thyrotropin (TSH) in serum. Increased hepatic activities of 5'-mono-deiodinase(5'D1), glucose-6-phospatase (G-6-Pase); serum concentrations of alanine transaminase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase(LDH) and tumour necrosis factor-alpha(TNF-α) were observed in thyrotoxic rats. Hepatic lipid peroxidation(LPO) was also increased and the endogenous antioxidants were depleted in these rats. In western blot analysis thyroid peroxidase expression was found to be reduced, whereas thyrotropin receptor(TSHR) expression was enhanced in thyroid gland of these animals. On the other hand, APC treatment in thyrotoxic rats decreased the levels of serum thyroid hormones, ALT, AST, TNF-α and LDH, as well as hepatic 5' D1 and G-6-Pase activities. However, it increased the serum TSH levels. APC also reduced the hepatic LPO and increased the cellular antioxidants in thyrotoxic rats. However, expression of TSHR was inhibited and TPO was increased by APC. The test compound also improved histological features in both liver and thyroid. Present report appears to be the first one that indicates the positive role of APC in ameliorating T4-induced thyrotoxicosis.

Thyrotoxicosis Involves ß2-Adrenoceptor Signaling to Negatively Affect Microarchitecture and Biomechanical Properties of the Femur.

Background: Thyrotoxicosis increases bone turnover, resulting in net bone loss. Sympathetic nervous system (SNS) activation, via ß2-adrenoceptor (ß2-AR) signaling, also has osteopenic effects. Because thyroid hormones (TH) interact with the SNS to regulate several physiological processes, we hypothesized that this interaction also occurs to regulate bone mass. Previous studies support this hypothesis, as α2-AR knockout (KO) mice are less susceptible to thyrotoxicosis-induced osteopenia. Here, we evaluated whether TH-SNS interactions in bone involve ß2-AR signaling. Methods: Thyrotoxicosis was induced in 120-day-old female and male mice with ß2-AR gene inactivation (ß2-AR-/-) by daily treatment with supraphysiological doses of triiodothyronine (T3) for 12 weeks. The impact of thyrotoxicosis on femoral bone microarchitecture, remodeling, fracture risk, and gene expression of the receptor activator of nuclear factor-kappa-B (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) pathway was evaluated. In addition, the effect of the ß2-AR-specific agonist clenbuterol (CL) on cAMP accumulation was determined in osteoblastic (MC3T3-E1) cells treated with T3 and/or 17ß-estradiol (E2). Results: Thyrotoxicosis negatively affected trabecular bone microarchitecture in wild-type (WT) females, but this effect was milder or nonexistent in ß2-AR-/- animals, whereas the opposite was seen in males. T3 treatment increased the femoral RANKL/OPG mRNA ratio and the endosteal perimeter and medullary area of the diaphysis in WT females and males, but not in ß2-AR-/- mice, suggesting that T3 promotes endosteal resorption in cortical bone, in a mechanism that involves ß2-AR signaling. T3 treatment increased endocortical mineral apposition rate only in WT females but not in ß2-AR-/- mice, suggesting that TH also induce bone formation in a ß2-AR signaling-dependent mechanism. T3 treatment decreased femoral resistance to fracture only in WT females, but not in KO mice. E2 and CL similarly increased cAMP accumulation in MC3T3-E1 cells; whereas T3 alone had no effect, but it completely blocked E2-stimulated cAMP accumulation, suggesting that some T3 effects on bone may involve E2/cAMP signaling in osteoblasts. Conclusions: These findings sustain the hypothesis that T3 interacts with the SNS to regulate bone morphophysiology in a ß2-AR signaling-dependent mechanism. The data also reveal sex as an important modifier of skeletal manifestations of thyrotoxicosis, as well as a modifier of the TH-SNS interactions to control bone microarchitecture, remodeling, and resistance to fracture.

Thyroid function related symptoms during levothyroxine monotherapy in athyreotic patients.

Previous reports by us and other investigators showed that among athyreotic patients on levothyroxine (LT4) following total thyroidectomy patients with normal serum thyroid-stimulating hormone (TSH) levels had mildly low serum free triiodothyronine (FT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum FT3 levels and patients with strongly suppressed serum TSH had elevated serum FT3 levels. The objective of this study was to clarify which of these three patient groups are closer to their preoperative euthyroid condition based on reported subjective symptoms. We prospectively studied 148 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy. Symptoms reflecting thyroid function documented preoperatively and following 12 months of LT4 after thyroidectomy were compared. In 65 patients with strongly suppressed TSH levels significant changes in symptoms with tendencies towards thyrotoxicosis were seen with regards to heat and cold tolerance (p < 0.01), bowel movements (p < 0.05), and hand tremors (p < 0.05). In 33 patients with normal TSH levels, significant changes in symptoms with tendencies towards hypothyroidism were seen with regards to heat and cold tolerance (p < 0.05) and activity (p < 0.05). Lastly, in 50 patients with mildly suppressed TSH levels and FT3 levels equivalent to preoperative levels, all symptom items remained equivalent to their preoperative levels. Symptoms reflecting thyroid function in patients on LT4 following total thyroidectomy suggested that patients with mildly suppressed TSH levels were closest to a euthyroid status. These data provide useful findings regarding the management of patients following total thyroidectomy.

A Case of Dynamic Evolution of Thyrotoxicosis on Follow-up.

A 55-year female patient presented with subacute thyroiditis (SAT) with a unique dynamic evolution, along with changes in the level of antithyroglobulin antibody, which has been rarely reported. Her thyrotoxicosis gradually worsened over the next three months. Severe hypothyroidism then rapidly developed and did not resolve. For the whole disease course, antithyroglobulin antibody levels were significantly increased, indicating dynamic changes in thyroid function. It has been suggested that the duration of thyrotoxicosis in SAT is highly variable, which is probably related to an underlying autoimmune mechanism. It is therefore, necessary to rule out other causes of thyroiditis.

Chavibetol corrects thyrotoxicosis through alterations in thyroid peroxidase.

Thyrotoxicosis is a clinical syndrome that commonly results from excess secretion and/or release of thyroid hormones in the circulation. It affects most of the body systems and if not treated properly may lead to serious health problems. In this investigation, we isolated a phenolic compound, chavibetol (CHV) from Piper betel leaf and evaluated its possible ameliorative effects in thyrotoxicosis of rats. Adult female rats were rendered thyrotoxic by the administration of L-thyroxine (L-T4) at 500 µg/kg/day, i.p., for 12 days, and then chavibetol (20.0 mg/kg, p.o.) was administered for 2 weeks. L-T4 administration elevated the concentration of serum thyroxine and triiodothyronine, activities of alanineaminotransferase and aspartate aminotransferase, and decreased the thyrotropin level as well as the expression of thyroid peroxidase (TPO). Further, it increased the activities of hepatic 5'mono-deiodinase-I, glucose-6--phosphatase, sodium-potasium-ATPase, and lipid peroxidation, and depleted the cellular antioxidants. However, chavibetol treatment to thyrotoxic rats normalized almost all these indices including TPO and also preserved the integrity of thyroid tissues suggesting its potential to correct thyrotoxicosis. Effects of CHV were more or less similar to a conventional antithyroid drug, propylthiouracil (PTU).

Neonatal Thyrotoxicosis.

Neonatal thyrotoxicosis (hyperthyroidism) is less prevalent than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. Most cases are transient, secondary to maternal autoimmune hyperthyroidism (Graves disease [GD]). This article summarizes recommendations for screening and management of hyperthyroidism in both the fetal and neonatal periods, with a focus on neonatal thyrotoxicosis secondary to maternal GD. Early monitoring and treatment are crucial for optimizing short-term and long-term patient outcomes.

Thyroid diseases and bone health.

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

BACKGROUND: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. METHODS: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. RESULTS: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. CONCLUSIONS: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Decreased anxiety- and depression-like behaviors and hyperactivity in a type 3 deiodinase-deficient mouse showing brain thyrotoxicosis and peripheral hypothyroidism.

Hypo- and hyperthyroid states, as well as functional abnormalities in the hypothalamic-pituitary-thyroid axis have been associated with psychiatric conditions like anxiety and depression. However, the nature of this relationship is poorly understood since it is difficult to ascertain the thyroid status of the brain in humans. Data from animal models indicate that the brain exhibits efficient homeostatic mechanisms that maintain local levels of the active thyroid hormone, triiodothyronine (T3) within a narrow range. To better understand the consequences of peripheral and central thyroid status for mood-related behaviors, we used a mouse model of type 3 deiodinase (DIO3) deficiency (Dio3 -/- mouse). This enzyme inactivates thyroid hormone and is highly expressed in the adult central nervous system. Adult Dio3 -/- mice exhibit elevated levels of T3-dependent gene expression in the brain, despite peripheral hypothyroidism as indicated by low circulating levels of thyroxine and T3. Dio3 -/- mice of both sexes exhibit hyperactivity and significantly decreased anxiety-like behavior, as measured by longer time spent in the open arms of the elevated plus maze and in the light area of the light/dark box. During the tail suspension, they stayed immobile for a significantly shorter time than their wild-type littermates, suggesting decreased depression-like behavior. These results indicate that increased thyroid hormone in the brain, not necessarily in peripheral tissues, correlates with hyperactivity and with decreases in anxiety and depression-like behaviors. Our results also underscore the importance of DIO3 as a determinant of behavior by locally regulating the brain levels of thyroid hormone.

Hyperthyroidism.

Hyperthyroidism is characterised by increased thyroid hormone synthesis and secretion from the thyroid gland, whereas thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones, irrespective of the source. The most common cause of hyperthyroidism is Graves' disease, followed by toxic nodular goitre. Other important causes of thyrotoxicosis include thyroiditis, iodine-induced and drug-induced thyroid dysfunction, and factitious ingestion of excess thyroid hormones. Treatment options for Graves' disease include antithyroid drugs, radioactive iodine therapy, and surgery, whereas antithyroid drugs are not generally used long term in toxic nodular goitre, because of the high relapse rate of thyrotoxicosis after discontinuation. ß blockers are used in symptomatic thyrotoxicosis, and might be the only treatment needed for thyrotoxicosis not caused by excessive production and release of the thyroid hormones. Thyroid storm and hyperthyroidism in pregnancy and during the post-partum period are special circumstances that need careful assessment and treatment.

Prolonged and Severe Gestational Thyrotoxicosis Due to Enhanced hCG Sensitivity of a Mutant Thyrotropin Receptor.

CONTEXT: Gestational thyrotoxicosis, whether associated with hyperemesis gravidarum or not, is thought to be due to excessive human chorionic gonadotropin (hCG) secretion. CASE DESCRIPTION: We report here the second case of gestational thyrotoxicosis associated with hyperemesis gravidarum due to a mutation of the TSH receptor, providing thyroid hypersensitivity to hCG. CONCLUSION: Severe and lasting gestational thyrotoxicosis with normal hCG concentration should lead to sequencing of the TSH receptor gene.