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Concept: Thyroid disease

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Background: A systematic analysis of the clinical and pathologic patterns of childhood “sporadic” thyroid carcinoma in Belarus, in the absence of the “Chernobyl radioactive iodine factor,” has never been performed. The aim of this study was to establish the essential features of “sporadic” papillary thyroid carcinoma (PTC) in Belarusian children and adolescents, and the relationship of tumor pathology to extrathyroidal extension (ETE) and lymph node metastases. Methods: This was a retrospective population-based study with assessment of histological samples of 119 cases of thyroid cancer in Belarusian children and adolescents of 0-18 years old registered during 2005-2008 years. Sporadic PTC was noted in 94 children who were not exposed to the Chernobyl radiation release. None of the 119 cases of thyroid were follicular thyroid cancer. Results: The incidence rate of PTC was 1.13 per 100,000 persons. The median age at diagnosis was 15.1 years with fourfold predominance of diagnosis in female patients. Relapse was detected in 2% of cases with median follow-up of 4.2 years. Median tumor size was 12 mm. Three percent of the cases of PTC had multifocal growth. The classical variant of PTC was registered in 46% of the patients with thyroid cancer, the follicular variant of PTC was noted in 20% of the cases. The percent of rare types of PTC (tall cell and diffuse sclerosing) were equal to that for solid PTCs (13%, 12%, and 10%, respectively). Adolescents had a pure papillary carcinoma more often compared to children who represented tumors with mixed papillary/follicular patterns more frequently (p<0.05). Two-thirds of the patients with PTC had regional lymph node metastases. ETE was established in 39 of 74 patients in whom ETE could be assessed by morphology. Multivariate analysis showed that lymphatic invasion was the strongest independent factor associated with both ETE (p<0.0001) and lymph node metastases (p<0.0001). Conclusion: In 2005-2008, sporadic thyroid cancer in children of Belarus was represented by high prevalence of PTC and absence of follicular thyroid cancer. Sporadic cases of PTC in Belarus were characterized by smaller tumor size, a small number of cases with multifocal growth, an equal number of rare types and solid PTCs, a relatively high prevalence of pure papillary variant of PTC in adolescents, and a low frequency of early relapses. A high frequency of ETE and lymph node metastases was detected. The strongest morphologic factor associated with both of them was lymphatic invasion.

Concepts: Cancer, Oncology, Lymph node, Chernobyl disaster, Types of cancer, Tumor, Thyroid disease, Lymph

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

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

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Studies on the role of thyroid hormones (THs) in teleost fish physiology have deployed the synthetic goitrogens, methimazol (MMI), propilthiouracil (PTU) and thiourea (TU) that are used to treat human hyperthyroidism. However, the action of the goitrogens, MMI, PTU and TU at different levels of the hypothalamic-pituitary-thyroid (HPT) axis in teleosts is largely unknown. The central importance of the hypothalamus and pituitary in a number of endocrine regulated systems and the cross-talk that occurs between different endocrine axes makes it pertinent to characterize the effects of MMI, PTU and TU, on several endpoints of the thyroid system. The marine teleost, sea bream (Sparus auratus) was exposed to MMI, PTU and TU (1mg/kg wet weight per day), via the diet for 21days. Radioimmunoassays (RIA) of plasma THs and ELISA of the TH carrier transthyretin (TTR) revealed that MMI was the only chemical that significantly reduced plasma TH levels (p<0.05), although both MMI and PTU significantly (p<0.05) reduced plasma levels of circulating TTR (p<0.05). Histological analysis of the thyroid tissue revealed modifications in thyrocyte activity that explain the reduced circulating levels of THs. MMI also significantly (p<0.05) up-regulated transcript abundance of liver deiodinase 1 and 2 while significantly (p<0.05) decreasing TRβ expression in the pituitary, all hallmarks of HPT axis action of goitrogens in vertebrates. The results indicate that in the sea bream MMI is the most effective goitrogen followed by PTU and that TU (1mg/kg wet weight for 21days) failed to have a goitrogenic effect. The study highlights the non-uniform effect of goitrogens on the thyroid axis of sea bream and provides the basis for future studies of thyroid disrupting pollutants.

Concepts: Thyroid disease, Hyperthyroidism, Thyroid, Endocrine system, Actinopterygii, Goitrogen, Teleostei, Goitrin

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Anaplastic thyroid cancer (ATC) is an aggressive neoplasm for which a paucity of data exist about the relative role of operative procedures in disease management.

Concepts: Epidemiology, Cancer, Oncology, Patient, Types of cancer, Thyroid disease

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Carcinomas arising in the thyroglossal duct cysts are rare, accounting only for about 0.7-1.5 % of all thyroglossal duct cysts.1 (-) 3 Synchronous occurrence of thyroglossal duct carcinoma and thyroid carcinoma is reported to be even rarer.4 Traditionally, surgical treatments of such coexisting thyroglossal duct cyst carcinoma (TGDCa) and papillary thyroid carcinoma (PTC) were typically performed through a single transverse or double incisions on the overlying skin. A longer, extended cervical incision might be required if neck dissection is necessary. Though this method provides the operator with the optimal surgical view, the detrimental cosmetic effect on the patient of possessing a scar cannot be avoided, despite the effort of the surgeon to camouflage the scar by placing the incision in natural skin creases. Recently, the authors have previously reported the feasibility of robot-assisted neck dissections via a transaxillary and retroauricular (“TARA”) approach or modified face-lift approach in early head and neck cancers.5 (,) 6 On the basis of the forementioned surgical technique, we demonstrate our novel technique for robot-assisted Sistrunk’s operation via retroauricular approach as well as robot-assisted neck dissection with total thyroidectomy via transaxillary approach.

Concepts: Head and neck, Surgery, Epithelium, Thyroid disease, Al-Andalus, Surgical oncology, Otolaryngology, Thyroglossal cyst

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Cowden syndrome (CS) is dominantly inherited and predisposes patients to tumors in multiple organs. We characterized CS-associated malignant and benign thyroid disease.

Concepts: Cancer, Medical terms, Benign tumor, Thyroid disease, Thyroid, Graves' disease, Thyroidectomy, Cowden syndrome

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Sirtuin1 (SIRT1), a NAD+-dependent deacetylase, has been connected to beneficial effects elicited by calorie restriction. Physiological adaptation to starvation requires higher activity of SIRT1 and also the suppression of thyroid hormone (TH) action to achieve energy conservation. Here we tested the hypothesis that those two events are correlated and that TH may be a regulator of SIRT1 expression. 48h-fasting mice exhibited reduced serum TH and increased SIRT1 protein content in liver and brown adipose tissue (BAT), and physiological thyroxine replacement prevented or attenuated the increment of SIRT1 in liver and BAT of fasted mice. Hypothyroid mice exhibited increased liver SIRT1 protein, while hyperthyroid ones showed decreased SIRT1 in liver and BAT. In the liver, decreased protein is accompanied by reduced SIRT1 activity and no alteration in its mRNA. Hyperthyroid and hypothyroid mice exhibited increase and decrease in food intake and body weight gain, respectively. Food-restricted hyperthyroid animals (pair fed to euthyroid group) exhibited liver and BAT SIRT1 protein levels intermediary between euthyroid and hyperthyroid mice fed ad libitum. Mice with TH resistance at the liver presented increased hepatic SIRT1 protein and activity, with no alteration in SIRT1 mRNA. These results suggest that TH decrease SIRT1 protein, directly and indirectly, via food ingestion control and, in the liver, this reduction involves TRβ. The SIRT1 reduction induced by TH has important implication to integrated metabolic responses to fasting, since the increase in SIRT1 protein requires the fasting-associated suppression of TH serum levels.

Concepts: Hormone, Liver, Thyroid disease, Hypothyroidism, Thyroid, Thyroid hormone, Fasting, Triiodothyronine

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Context: Graves' disease (GD) and Hashimoto´s thyroiditis (HT) are the most common autoimmune thyroid diseases (AITD). The exact etiology of the immune response to the thyroid is still unknown. MicroRNAs (miRNAs) critically control gene-expression. It has become evident that some miRNAs play an important role in regulating the immune response, as well as immune cell development. However, data on the role of miRNAs in autoimmune thyroid diseases are lacking. Objective: The aim of this study was to determine levels of key immunoregulatory miRNAs in thyroid glands of AITD patients and healthy controls Design: Several miRNAs were amplified by a semiquantitative TaqMan PCR from fine needle aspiration biopsies of thyroid tissue of 28 patients with GD, HT, and healthy controls. Results: miRNA 146a1 is significantly decreased in the thyroid tissue of GD (mean relative expression 5,17 in GD group vs. 8,37 in controls, p = 0.019) whereas miRNA 200a1 is significantly decreased (mean 8,30 in HT group vs. 11,20 in controls, p = 0.001) and miRNA 155 2 is significantly increased (mean 12,02 in HT group vs. 8,01 in controls, p = 0.016) in the thyroid tissue of HT compared to controls. Conclusion: Although limited by small sample size and some other limitations (e.g. missing matching for age and medication), our preliminary data open up a new field of research concerning miRNAs in thyroid diseases. Further studies in this interesting field are clearly warranted.

Concepts: Immune system, Medicine, Immunology, Thyroid disease, Hyperthyroidism, Thyroid, Graves' disease, Needle aspiration biopsy

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Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself.

Concepts: Gene, Thyroid disease, Hyperthyroidism, Thyroid, Autoimmune disease, Graves' disease, Thyroidectomy, Graves' ophthalmopathy

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Background: The role of viruses as environmental triggers for Hashimoto’s thyroiditis (HT) is controversial. Thyroid epithelial cells express a variety of molecules involved in antiviral responses. This study combined histological, immunological and virological tests to describe changes in tissue from patients with newly diagnosed and untreated HT. To study the early events, patients with positive thyroid peroxidase antibodies (TPO-Ab) and normal thyroid function were also included. This stage was defined as “prethyroiditis”. Methods: Thyroid tissue was collected from 47 patients with high titers of TPO-Ab and from 24 controls. Seventeen patients had prethyroiditis, 17 had subclinical hypothyroidism, and 13 had overt hypothyroidism. IFN-α/β-inducible myxovirus resistance protein 1 (Myxovirus resistance protein A; MxA) was used as a surrogate marker for type I interferon (IFN) expression. Inflammation, expression of MxA, and the presence of the enteroviral capsid protein VP1 (VP1) were characterized by immunohistochemistry. The presence of enterovirus RNA was examined by in situ hybridization. Results: The density of CD4+ T cells was increased in all three patient groups, while CD8+ T cells were increased only in patients with overt hypothyroidism. The density of plasma cells increased as the disease progressed. The density of plasmacytoid dendritic cells (PDCs) and the expression of MxA were significantly increased in all patient groups compared with controls (p<0.01). Enterovirus RNA was present in 11% of HT patients but in none of the control subjects, whereas enteroviral protein was detected in 19% and 16%, respectively. Conclusion: The inflammatory reaction in the thyroid gland is a very early event in pathogenesis of HT. Increased expression of MxA in the inflamed tissue suggests that type I interferon plays a role in disease development. Whether this is virus-dependent needs to be explored in further studies.

Concepts: Immune system, Virus, Thyroid disease, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid peroxidase