Congenital Hypothyroidism (CH) is the most common endocrine disorder, affecting one out of 2000-4000 newborns. Most CH are due to a defect in thyroid embryonic development and they can lead to severe phenotypes if not treated correctly. Multiple observations argue in favor of a genetic cause in a minority of thyroid dysgenesis, but to date, only few cases could be explained by a mutation in one of the genes coding for the factors known to be important in thyroid development and/or function (NKX2-1, PAX8, FOXE1, TSHR). This is the reason why it was important to develop new models allowing the discovery of new genes/mechanisms potentially implicated in the gland organogenesis. To that purpose, we set up in the laboratory a structure enabling the use of zebrafish as an animal model. The latter is indeed more and more used by developmental biologists, including by scientists interested in thyroid development.<p><p>The first step of our project consisted in a deeper characterization of the model, notably by the study of the expression patterns of the thyroid functional differentiation markers. Furthermore, the exact role of the Tsh/Tshr signaling – main regulator of thyroid growth and function in mammals – was dissected. In a second part of the project, we generated a stable transgenic line (tg(tg:mCherry)) allowing the visualization of thyroid development in living embryos and in a dynamic manner, thanks to real-time imaging techniques. On the one hand, this tool enabled us to better understand the morphological aspect of the different stages of thyroid development, such as the budding, evagination, relocalization or folliculogenesis. On the other hand, the use of double transgenic fishes obtained by crossing tg(tg:mCherry) with other lines expressing GFP in surrounding structures of interest, allowed us to highlight the contacts between the cardiovascular system and thyroid, and this along the whole gland development. The introduction of this model within the laboratory paves the way for the discovery and the study of thyroid intrinsic and extrinsic genes/mechanisms which might play a role on its development.<p><p>L’hypothyroïdie congénitale (HC) est une maladie relativement fréquente, touchant un nouveau-né sur 2000-4000. La majorité des HC sont dues à un défaut dans le développement embryonnaire de la glande, et peuvent mener à des phénotypes sévères si elles ne sont pas correctement traitées. Il existe plusieurs arguments en faveur d’une cause génétique dans une minorité de ces dysgénésies thyroïdiennes mais, à ce jour, seuls quelques cas ont pu être reliés à une mutation dans un des gènes codant pour des facteurs connus pour être importants dans le développement/la fonction de la glande (NKX2-1, PAX8, FOXE1, TSHR). C’est pour cette raison qu’il est important de développer de nouveaux modèles pouvant permettre la découverte de nouveaux gènes/mécanismes potentiellement impliqués dans l’organogénèse de la glande. A cette fin, nous avons mis en place au sein du laboratoire une structure permettant l’utilisation du poisson-zèbre comme modèle animal. Ce dernier est en effet de plus en plus utilisé par les biologistes du développement, y compris par les scientifiques qui s’intéressent au développement thyroïdien.<p><p>La première étape de notre travail a consisté en une caractérisation approfondie du modèle, notamment par l’étude du réseau d’expression des marqueurs de différenciation fonctionnelle de la glande. En outre, le rôle exact de la signalisation par la TSH – principal régulateur de la croissance et de la fonction de la thyroïde des mammifères – a été étudié. Dans la deuxième partie du projet, nous avons généré une ligne transgénique stable (tg(tg:mCherry)) permettant la visualisation du développement thyroïdien dans des embryons vivants et ce, de manière dynamique, grâce au principe d’imagerie en temps réel. D’une part, cet outil nous a permis de mieux comprendre l’aspect morphologique des différentes étapes du développement thyroïdien, telles que la formation du bourgeon, l’invagination, la relocalisation ou la folliculogénèse. D’autre part, l’utilisation de poissons doublement transgéniques obtenus par le croisement de tg(tg:mCherry) avec d’autres lignées où les structures environnantes d’intérêt expriment la GFP nous a permis de mettre en avant les contacts entre le système cardiovasculaire et la thyroïde, et ce, tout au long de son développement. La mise en place de ce modèle au sein de notre laboratoire ouvre la voie à la découverte et à l’étude de mécanismes/gènes extrinsèques à la thyroïde mais pouvant jouer un rôle sur son développement. / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished

<p>Uvod: Poslednjih godina u fokusu istraživača je efekat sintetskih jednjenja na endokrini sistem. Estri ftalne kiseline se koriste u procesu plastifikacije, kao industrijski rastvarači, lubrikanti, aditivi u tekstilnoj industriji, u pesticidima, kozmetičkim proizvodima. Raste broj dokaza da je tiroidna žlezda podložna dejstvu endokrinih disruptora. Tiroidni hormoni imaju važnu ulogu u regulaciji rasta, tkivne diferencijacije, energetskog metabolizma, reprodukcije i formiranja centralnog nervnog sistema. Brojna istraživanja ukazala su da ftalati deluju kao EDs. Ciljevi istraživanja: 1. Procena izloženosti populacije mono-etilheksil-ftalatu (MEHP) i mono-etil-ftalatu (MEP). 2. Evaluacija razlika u nivou pokazatelja tirodine funkcije između ftalat pozitivnih i ftalat negativnih ispitanika i između gojaznih i normalno uhranjenih ftalat pozitivnih ispitanika. 3.Utvrđivanje razlika u serumskom nivou leptina gojaznih ispitanika sa i bez pozitivnih ftalatnih metabolita i procena povezanosti leptina sa MEP i MEHP i pokazateljima tiroidne funkcije. Izbor ispitanika i metod rada: Istraživanje je sprovedeno kao studija preseka, obuhvatilo je 201 ispitanika. Ispitanici su podeljeni u grupu MEP/MEHP pozitivnih i negativnih i na podgupe normalno uhranjenih i gojaznih. Od antropometrijskih mera određena je telesna visina, telesna masa, obim struka i indeks telesne mase. Laboratorijske analize: jutarnji uzorak urina za određivanje MEP i MEHP; na&scaron;te uzet uzorka venske krvi za FT4, FT3, TSH i leptin. Statististička analiza sprovedena je na softverskom paketu SPSS. Rezultati: Polovina stanovni&scaron;tva je izložena ftalatima. MEP dovodi do povi&scaron;enja FT4 samo u subpopulaciji gojaznih. Nije utvrđen statistički značajan uticaj MEP na FT3. Kod gojaznih MEP pozitivnih osoba ženskog pola povi&scaron;en je TSH. MEHP uzrokuje sniženje FT4 kod normalno uhranjenih ispitanika, a kod normalno uhranjenih mu&scaron;karaca snižava FT3. Nije utvrđen uticaj MEHP na tirotropin. U gojaznih nije ustanovljen uticaj DEHP i DEP na leptinsku sekreciju.Uočena je tendencija negativne korelacije leptina i FT4 kod gojaznih, dok uticaja na FT3 i TSH nema. Zaključak: Na&scaron;a populacija je u velikoj meri izložena ftalatima. Potvrđeno je da MEP i MEHP imaju uticaj na pojedine indikatore tiroidne funkcije. Ftalati u na&scaron;em istraživanju ne uzrokuju poremećaj leptinske skrecije, a leptin ima blag uticaj jedino na FT4.</p> / <p>Introduction: Effects of synthesized chemicals on endocrine system has been in the focus in the last years. Phthalates are used in plasticization, as industrial solvents, lubricants, textile industry additives, in pesticides and cosmetic products. Evidence for thyroid disruption is growing. Thyroid hormones (TH) have an important role in regulation of growth, tissue differentiation, energy metabolism, reproduction and central nervous system formation. Studies show phthalates can cause endocrine disruption. Aims: 1. Estimation of burden of mono-ethyl phthalate (MEP) and di-2-ethylheksyl phthalate(MEHP) in the population. 2. Evaluation of differences in TH and TSH in MEP/MEHP positive and negative participants, as in obese and lean MEP/MEHP positive participants. 3. Evaluation of differences in leptin in obese MEP/MEHP positive and negative subjects and evaluation of the connection between leptin, MEP, MEHP and thyroid indicators. Patients and methods: This was a cross-sectional study that comprised 201 subjects divided into MEP/MEHP positive and negative group, further subdivided in obese and lean. Anthropometric parameters done: body height, body weight, waist and body mass index. Laboratory tests done: morning urine sample analysis for MEP/MEHP and venous sample analysis for free thyroxine (FT4), free tri-iodothyronine (FT3), thyroid stimulating hormone (TSH) and leptin. Statistical analysis was done in SPSS. Results: Half of subjects were exposed to phthalates. MEP induced an increase in FT4 in obese participants and had no influence on FT3. TSH was increased in obese MEP positive female subjects. MEHP induced a decrease in FT4 in lean participants and a decrease of FT3 in lean males. There was no correlation between MEHP and TSH. Influence of MEP/MEHP on leptin secretion. A tendency for negative correlation between leptin and FT4 was seen. There was no influence of leptin on FT3 and TSH. Conclusion: Our population is greatly exposed to phthalates. MEP and MEHP influence certain thyroid indicators i.e. cause thyroid disruption. Phthalates do not influence leptin secretion in our study. There is a mild effect of leptin on FT4.</p>

Introdução: Doenças tireoidianas subclínicas incluem hipotireoidismo e hipertireoidismo subclínicos. A associação entre doença tireoidiana subclínica e morbimortalidade cardiovascular é controversa e os dados sobre a relação entre essas condições clínicas e aterosclerose subclínica são escassos. Objetivos: Este estudo objetiva avaliar a associação entre doença tireoidiana subclínica, calcificação arterial coronariana (CAC), doença arterial coronariana (DAC), índice de espessura de médio-íntima carotídea média (IMT) e velocidade de onda de pulso carotídeo-femoral (cf-VOP) no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Métodos: Incluímos sujeitos eutireóideos, definidos como tendo TSH entre 0,4 e 4,0 mUI/L e T4L entre 0,8 e 1,9ng/dL, indivíduos com hipotireoidismo subclínico, definido como TSH > 4,0 mUI/L e T4L normal, e hipertireoidismo subclínico, definido como TSH < 0,4 mUI/L e T4L normal. Excluímos os indivíduos com as demais disfunções tireoidianas, em uso de medicação que altera a função tireoidiana, e com doença cardiovascular prévia. Na análise de angiotomografia, excluímos também os sujeitos com hipertireoidismo subclínico pelo pequeno número que impedia a análise e, na análise de cf-VOP, doença renal crônica, indivíduos em uso de diuréticos e de anti-hipertensivos. As associações entre quintis de TSH, CAC > 100 e DAC foram avaliadas por regressão logística e as associações entre IMT, VOP (como variáveis contínuas ou categorizadas com ponto de corte no percentil 75 amostral) e níveis de TSH ou doenças tireoidianas subclínicas foram avaliadas por regressões logísticas e lineares multivariadas. Todos os modelos foram ajustados por variáveis demográficas e fatores de risco cardiovasculares. Resultados: A análise de CAC incluiu 3.836 sujeitos, mediana de idade de 49 anos (IQR=44-56), 1.999 (52,1%) mulheres. CAC > 100 associou-se independentemente com o primeiro quintil (OR ajustado=1,57, IC 95%=1,05-2,35, P=0,027), usando o terceiro como referência. Na análise de angiotomografia, foram incluídos 796 sujeitos, mediana de idade de 55 anos (IQR=48-60 anos), 406 (51%) mulheres. O primeiro quintil associou-se independentemente com CAC (OR ajustado=1,76, IC 95%=1,09-2,82, P= 0,02), DAC (OR ajustado=1,73, IC 95%=1,08-2,79, P=0,023), mas não com extensão de doença. Na análise de IMT, foram incluídos 8.623 sujeitos, mediana de idade de 50 anos (IQR=45-57 anos), 4.624 (53,6%) mulheres, na subanálise de hipotireoidismo subclínico, e 8.193, com mediana de idade de 50 anos (IQR=44-57 anos), 4.382 (53,5%) mulheres, na subanálise de hipertireoidismo subclínico. Hipotireoidismo subclínico, mas não hipertireoidismo subclínico, associou-se ao IMT como variável contínua (beta=0,010, IC 95%=0,0004-0,019, P=0,041) e categorizado no percentil 75 ajustado para sexo, idade e raça (OR ajustado=1,30, IC95%=1,07-1,61, P=0,010). Na análise de cf-VOP, foram incluídos 8.341 sujeitos, mediana de idade de 50 anos (IQR=44-56 anos), 4.383 (52,5%) mulheres, na subanálise de hipotireoidismo subclínico, e 7.790, mediana de idade de 50 anos (IQR=44-57 anos), 4.191 (53,8%) mulheres, na subanálise de hipertireoidismo subclínico. Cf-VOP não se associou com doença tireoidiana subclínica. Conclusões: Em análises diferentes, CAC e DAC associaram-se com primeiro quintil de TSH usando-se o terceiro como referência. O IMT associou-se com hipotireoidismo subclínico e a cf-VOP não se associou com disfunção tireoidiana subclínica / Introduction: Subclinical thyroid disease includes subclinical hypothyroidism and subclinical hyperthyroidism. Association between subclinical thyroid disease and cardiovascular morbidity and mortality is controversial and data about the relationship between those clinical conditions and subclinical atherosclerosis is scarce. Objectives: This study aims to evaluate the association between subclinical thyroid disease, coronary artery calcification (CAC), coronary artery disease (CAD), mean common carotid intima-media thickness (IMT) and carotid-femoral pulse wave velocity (cf-PWV) in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: We included euthyroid subjects, defined as TSH between 0.4 and 4.0 mIU/l and FT4 between 0.8 and 1.9 ng/dL, and individuals with subclinical hypothyroidism, defined as TSH > 4.0 mIU/l and normal FT4, and subclinical hyperthyroidism, defined as TSH < 0.4 mIU/L and normal FT4. We excluded individuals with other thyroid disorders, subjects who used medication that altered thyroid function, subjects with past of cardiovascular disease. In computed angiotomography analysis, we have excluded subjects with subclinical hyperthyroidism because of the small sample, and in cf-PWV analysis, we have excluded individuals with chronic kidney disease, use of anti-hypertensive and diuretics. The association between TSH quintiles was evaluated in logistic regression models for CAC and CAD, and the association between IMT, cf-PWV (as continuous variables or as factor, categorized at 75th sample\'s percentile) and TSH levels or subclinical thyroid diseases was evaluated by multivariate logistic and linear regression models. All models were adjusted for demographic variables and cardiovascular risk factors. Results: CAC analysis included 3,836 subjects, median of age 49 years (IQR=44-56), 1,999 (52.1%) women. CAC > 100 was independently associated with first quintile of TSH, using the third quintile as the reference (adjusted OR=1.57, 95% CI=1.05-2.35, P=0.027). Computed angiotomography analysis included 796 subjects, median of age 55 years (IQR=48-60), 406 (51%) women. CAD and CAC > 0 was independently associated with first quintile in comparison with third quintile (adjusted OR=1.73, 95% CI=1.08-2.79, P=0.023 and adjusted OR=1.76, 95% CI=1.09-2.82, P= 0.02, respectively), but not with burden of disease. In IMT analysis, 8,623 subjects were included, median of age 50 years (IQR=45-57 years), 4,624 (53.6%) women in the subclinical hypothyroidism subanalysis, and 8,193, median age 50 years (IQR = 44-57 years), 4,382 (53.5%) women, in the subclinical hyperthyroidism subanalysis. Subclinical hypothyroidism, but not subclinical hyperthyroidism, was independently associated with IMT as continuous variable (beta=0.010, IC 95%=0.0004-0.019, P=0.041) or as factor categorized at 75th percentile adjusted for age, sex and race (adjusted OR=1.30, 95% CI=1.07-1.61, P=0.010). In cf-PWV analysis, 8,341 subjects were included, median of age 50 years (IQR=44-56 years), 4,383 (52.5%) women in the subclinical hypothyroidism subanalysis, and 7,790, median age 50 years (IQR = 44-57 years), 4,191 (53.8%) women in subclinical hyperthyroidism subanalysis. Cf- PWV was not associated with subclinical thyroid disease. Conclusion: In separated analysis, CAC and CAD was independently associated with first quintile of TSH using the third as the reference; IMT was independently associated with subclinical hypothyroidism, and cf-PWV was not associated with subclinical thyroid diseases

Endokrin aktive Substanzen (EACs) sind exogene Substanzen natürlichen oder synthetischen Ursprungs, die mit der Feedbackregulation hormoneller Netzwerke interferieren können und somit deren Homöostase beeinflussen. Störungen der Hypothalamus-Hypophysen-Schilddrüsenachse (HPT-Achse) haben weitreichende Konsequenzen, da Schilddrüsenhormone essentiell für die Regulation von Entwicklung, Wachstum und Stoffwechsel sind. In der vorliegenden Arbeit wurde das Wirkprofil potenter Inhibitoren der thyreotropen Achse am Beispiel von 4-Methylbenzyliden-campher (4-MBC) und Genistein (GEN) untersucht. Der UV-Filter 4-MBC wurde in der ovariektomierten Ratte als goitrogene Substanz identifiziert. 4-MBC interferiert auf Ebene von Hypothalamus und Hypophyse mit der Expression Feedback-assoziierter Gene und beeinflusst daher die Feedbackregulation der thyreotropen Achse. Darüber hinaus wird die Biosynthese von Schilddrüsenhormonen durch Inhibition des Iodidtransports bei gleichzeitig erhöhter messenger RNA (mRNA)-Konzentration des Natrium-Iodid-Symporters (NIS) durch 4-MBC beeinträchtigt. Parallel dazu lässt die verstärkte Expression des Angiogenesemarkers vascular endothelial growth factor (VEGF) nach subakuter Exposition auf die Entstehung einer Hypothyreose schließen. Die damit einhergehenden Veränderungen sind auch in peripheren Organen durch die Analyse 3,3‘,5-Triiod-L-thyronin (T3)-regulierter Zielgene dokumentiert. Zudem wurden diese Effekte maßgeblich durch die Expositionszeit beeinflusst, da nach chronischer Exposition vermutlich auch kompensatorische Prozesse eine wichtige Rolle spielen. Die gezeigten speziesspezifischen Effekte lassen sich möglicherweise auf Unterschiede in der Pharmakokinetik zurückführen, z.B. in Folge differentieller Expression von Cytochrom P450-Genen. / Endocrine active compounds (EACs) can be of natural or synthetic origin and show hormone-like effects that interfere with feedback regulation of hormonal networks. Interferences with the hypothalamic-pituitary-thyroid axis (HPT-axis) result in extensive consequences as thyroid hormones are essential for regulation of development, growth, and metabolism. In the work presented here, the active profile of potent inhibitors of the HPT-axis namely 4-methylbenzylidene-camphor (4-MBC) and genistein (GEN) was investigated. 4-MBC, a UV filter used in sunscreens and various cosmetics, was identified as a goiter causing agent using ovariectomized rats. 4-MBC acts at the level of hypothalamus and pituitary gland by modulating the expression of thyrotropin-releasing hormone (TRH) as well as thyroid-stimulating hormone (TSH) that regulate feedback on the HPT-axis. Furthermore, biosynthesis of thyroid hormones was impaired by 4-MBC secondary to the inhibition of iodide transport with concomitantly increased messenger RNA (mRNA)-levels of the sodium-iodide symporter (NIS). In parallel expression of the angiogenesis marker vascular endothelial growth factor (VEGF) was increased, indicating hypothyroidism. After the application of 4-MBC the expression of L-3,3’,5-triiodothyronine (T3)-regulated target genes was reduced in the periphery both on the mRNA and protein level. The documented species-specific effects indicate a difference in pharmacokinetics, possibly secondary to differential expression of cytochrome P450 genes. GEN is contained in soy and red clover and its mechanistic analysis was carried out in thyroid hormone receptor (TR) deficient mice (TRα0/0). The gender-dependent effects of GEN on tissue specificity did not follow an obvious pattern and warrant continuative analysis. The work presented here supports the assumption that EACs can interfere with function and regulation of the HPT-axis at levels that were previously considered safe.

INTRODUÇÃO: O tratamento e o seguimento do carcinoma papilífero de tireoide (CPT) são individualizados pelos riscos de recorrência e mortalidade. A indicação do iodo radioativo (iodo-131) para ablação de remanescente tireóideo captante é controversa em casos classificados como de baixo risco. Por diminuir a massa tireóidea remanescente, a dose ablativa com iodo-131 (DAIR) facilita o seguimento pós-operatório, mas tem riscos e onera o tratamento. Não se encontrou na literatura estudo demonstrando a evolução da captação cervical do iodo-131 e da concentração sérica de tireoglobulina (TG) em pacientes submetidos à tireoidectomia total por CPT de riscos muito baixo e baixo, sem DAIR. OBJETIVO: Avaliar a evolução da captação cervical do iodo-131 e da concentração sérica de TG em pacientes com CPT de baixo e muito baixo risco, após tireoidectomia total e não submetidos a DAIR. MÉTODOS: Foi realizado estudo prospectivo não randomizado em pacientes com CPT de baixo e muito baixo risco submetidos a tireoidectomia total, atendidos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período setembro de 2008 novembro de 2011. Após a tireoidectomia foi ministrada levotiroxina na dose necessária para manter a concentração de hormônio tireo-estimulante (TSH) entre 0,5 e 1,0 U/ml. Dosagem sérica de TG, pesquisa de corpo inteiro com iodo-131 (PCI) e dosagem de iodo urinário foram realizadas sob estímulo de TSH endógeno elevado por interrupção da reposição hormonal com levotiroxina, por 30 dias, e dieta pobre em iodo por 15 dias. Foram realizadas ultrassonografias cervicais três e 12 meses após a tireoidectomia. As concentrações séricas de TSH e tiroxina livre sem supressão do TSH foram realizadas seis, nove e 12 meses após a tireoidectomia. RESULTADOS: Dos 26 pacientes incluídos, 22 eram do sexo feminino (84,6%), e quatro, do masculino (15,4%), com idade variando de 27 a 45 anos (média de 38,5 anos e mediana de 39,5 anos). Onze pacientes (42,3%) foram estratificados como de muito baixo risco, e 15 (57,7%), como de baixo risco. Todos os pacientes estavam em hipotireoidismo, no momento da avaliação inicial e final (TSH > 30?U/ml), e os exames realizados seis, nove e 12 meses após a operação, com ingestão de levotiroxina, mostraram as medianas da concentração de TSH de 3,4 ?U/mL, 0,3 ?U/mL e 1,5 ?U/mL, respectivamente. A média da captação de iodo-131 caiu de 1,9% na avaliação inicial para 0,5% na final, e a média da concentração sérica de TG estimulada caiu de 3,1 ng/mL para 1,9 ng/ml. CONCLUSÃO: Houve diminuição estatisticamente significativa da captação cervical do iodo-131 e da concentração sérica de TG sem DAIR nos pacientes submetidos a tireoidectomia total por CPT de baixo e muito baixo risco, sem supressão do TSH / INTRODUCTION: The treatment and follow-up of papillary thyroid carcinoma (PTC) are individualized according to the risk of recurrence and mortality. Radioiodine ablation of thyroid remnant is controversial in low-risk patients. By reducing the thyroid remnant, ablation with radioiodine facilitates the follow-up, but it adds risks and increases the cost of the treatment. We found no published study showing the outcome of cervical uptake of radioactive iodine and the serum concentration of thyroglobulin (TG) in patients undergoing total thyroidectomy for PTC classified as very low risk and low risk who did not undertake ablative dose of radioactive iodine. OBJECTIVE: The aim of this study was to document changes in the cervical uptake of radioiodine and changes in TG concentrations in low-risk and very low-risk PTC patients not submitted to radioiodine remnant ablation (RRA). METHODS: We conducted a prospective non-randomized study in patients with PTC classified as low risk and very low risk undergoing total thyroidectomy at the General Hospital of the University of Sao Paulo, School of Medicine, from September 2008 to November 2011. Levothyroxine was administered after thyroidectomy at a dose required to maintain the concentration of thyroid stimulating hormone (TSH) between 0.5 and 1.0 ?U/ml. Serum thyroglobulin, whole body scan with iodine-131 and urinary iodine were evaluated under high endogenous TSH stimulation after 30 days levothyroxine withdrawal and iodine-poor diet for 15 days. Neck ultrasounds were performed three and 12 months after thyroidectomy. The concentration of serum TSH and free thyroxine without TSH suppression were measured six, nine and 12 months after thyroidectomy. RESULTS: Of the 26 patients included, 22 were female (84.6%) and four were male (15.4%), aged ranged from 27 to 45 years (mean 38.5 years, median 39.5 years). Eleven patients (42.3%) were classified as very low risk and 15 (57.7%) as low risk. All subjects were hypothyroidism at the time of the initial and final evaluations (TSH> 30 ?U/ml). Tests performed six, nine and 12 months after the operation with levothyroxine showed the median concentration of TSH 3.4 ?U/ml, 0.3 U/ml and 1.5 ?U/ml, respectively. The average uptake of iodine-131 dropped 1.9% at baseline to the end of 1.5% and higher mean serum thyroglobulin fell from 3.1 ng/mL to 1.9 ng/ml. CONCLUSION: There was a statistically significant reduction in cervical radioiodine uptake and in stimulated TG level over one year\'s observation of low-risk and very low-risk papillary thyroid carcinoma patients who were not treated with RRA, even in the absence of TSH suppression

Introdução: Doenças tireoidianas subclínicas incluem hipotireoidismo e hipertireoidismo subclínicos. A associação entre doença tireoidiana subclínica e morbimortalidade cardiovascular é controversa e os dados sobre a relação entre essas condições clínicas e aterosclerose subclínica são escassos. Objetivos: Este estudo objetiva avaliar a associação entre doença tireoidiana subclínica, calcificação arterial coronariana (CAC), doença arterial coronariana (DAC), índice de espessura de médio-íntima carotídea média (IMT) e velocidade de onda de pulso carotídeo-femoral (cf-VOP) no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Métodos: Incluímos sujeitos eutireóideos, definidos como tendo TSH entre 0,4 e 4,0 mUI/L e T4L entre 0,8 e 1,9ng/dL, indivíduos com hipotireoidismo subclínico, definido como TSH > 4,0 mUI/L e T4L normal, e hipertireoidismo subclínico, definido como TSH < 0,4 mUI/L e T4L normal. Excluímos os indivíduos com as demais disfunções tireoidianas, em uso de medicação que altera a função tireoidiana, e com doença cardiovascular prévia. Na análise de angiotomografia, excluímos também os sujeitos com hipertireoidismo subclínico pelo pequeno número que impedia a análise e, na análise de cf-VOP, doença renal crônica, indivíduos em uso de diuréticos e de anti-hipertensivos. As associações entre quintis de TSH, CAC > 100 e DAC foram avaliadas por regressão logística e as associações entre IMT, VOP (como variáveis contínuas ou categorizadas com ponto de corte no percentil 75 amostral) e níveis de TSH ou doenças tireoidianas subclínicas foram avaliadas por regressões logísticas e lineares multivariadas. Todos os modelos foram ajustados por variáveis demográficas e fatores de risco cardiovasculares. Resultados: A análise de CAC incluiu 3.836 sujeitos, mediana de idade de 49 anos (IQR=44-56), 1.999 (52,1%) mulheres. CAC > 100 associou-se independentemente com o primeiro quintil (OR ajustado=1,57, IC 95%=1,05-2,35, P=0,027), usando o terceiro como referência. Na análise de angiotomografia, foram incluídos 796 sujeitos, mediana de idade de 55 anos (IQR=48-60 anos), 406 (51%) mulheres. O primeiro quintil associou-se independentemente com CAC (OR ajustado=1,76, IC 95%=1,09-2,82, P= 0,02), DAC (OR ajustado=1,73, IC 95%=1,08-2,79, P=0,023), mas não com extensão de doença. Na análise de IMT, foram incluídos 8.623 sujeitos, mediana de idade de 50 anos (IQR=45-57 anos), 4.624 (53,6%) mulheres, na subanálise de hipotireoidismo subclínico, e 8.193, com mediana de idade de 50 anos (IQR=44-57 anos), 4.382 (53,5%) mulheres, na subanálise de hipertireoidismo subclínico. Hipotireoidismo subclínico, mas não hipertireoidismo subclínico, associou-se ao IMT como variável contínua (beta=0,010, IC 95%=0,0004-0,019, P=0,041) e categorizado no percentil 75 ajustado para sexo, idade e raça (OR ajustado=1,30, IC95%=1,07-1,61, P=0,010). Na análise de cf-VOP, foram incluídos 8.341 sujeitos, mediana de idade de 50 anos (IQR=44-56 anos), 4.383 (52,5%) mulheres, na subanálise de hipotireoidismo subclínico, e 7.790, mediana de idade de 50 anos (IQR=44-57 anos), 4.191 (53,8%) mulheres, na subanálise de hipertireoidismo subclínico. Cf-VOP não se associou com doença tireoidiana subclínica. Conclusões: Em análises diferentes, CAC e DAC associaram-se com primeiro quintil de TSH usando-se o terceiro como referência. O IMT associou-se com hipotireoidismo subclínico e a cf-VOP não se associou com disfunção tireoidiana subclínica / Introduction: Subclinical thyroid disease includes subclinical hypothyroidism and subclinical hyperthyroidism. Association between subclinical thyroid disease and cardiovascular morbidity and mortality is controversial and data about the relationship between those clinical conditions and subclinical atherosclerosis is scarce. Objectives: This study aims to evaluate the association between subclinical thyroid disease, coronary artery calcification (CAC), coronary artery disease (CAD), mean common carotid intima-media thickness (IMT) and carotid-femoral pulse wave velocity (cf-PWV) in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods: We included euthyroid subjects, defined as TSH between 0.4 and 4.0 mIU/l and FT4 between 0.8 and 1.9 ng/dL, and individuals with subclinical hypothyroidism, defined as TSH > 4.0 mIU/l and normal FT4, and subclinical hyperthyroidism, defined as TSH < 0.4 mIU/L and normal FT4. We excluded individuals with other thyroid disorders, subjects who used medication that altered thyroid function, subjects with past of cardiovascular disease. In computed angiotomography analysis, we have excluded subjects with subclinical hyperthyroidism because of the small sample, and in cf-PWV analysis, we have excluded individuals with chronic kidney disease, use of anti-hypertensive and diuretics. The association between TSH quintiles was evaluated in logistic regression models for CAC and CAD, and the association between IMT, cf-PWV (as continuous variables or as factor, categorized at 75th sample\'s percentile) and TSH levels or subclinical thyroid diseases was evaluated by multivariate logistic and linear regression models. All models were adjusted for demographic variables and cardiovascular risk factors. Results: CAC analysis included 3,836 subjects, median of age 49 years (IQR=44-56), 1,999 (52.1%) women. CAC > 100 was independently associated with first quintile of TSH, using the third quintile as the reference (adjusted OR=1.57, 95% CI=1.05-2.35, P=0.027). Computed angiotomography analysis included 796 subjects, median of age 55 years (IQR=48-60), 406 (51%) women. CAD and CAC > 0 was independently associated with first quintile in comparison with third quintile (adjusted OR=1.73, 95% CI=1.08-2.79, P=0.023 and adjusted OR=1.76, 95% CI=1.09-2.82, P= 0.02, respectively), but not with burden of disease. In IMT analysis, 8,623 subjects were included, median of age 50 years (IQR=45-57 years), 4,624 (53.6%) women in the subclinical hypothyroidism subanalysis, and 8,193, median age 50 years (IQR = 44-57 years), 4,382 (53.5%) women, in the subclinical hyperthyroidism subanalysis. Subclinical hypothyroidism, but not subclinical hyperthyroidism, was independently associated with IMT as continuous variable (beta=0.010, IC 95%=0.0004-0.019, P=0.041) or as factor categorized at 75th percentile adjusted for age, sex and race (adjusted OR=1.30, 95% CI=1.07-1.61, P=0.010). In cf-PWV analysis, 8,341 subjects were included, median of age 50 years (IQR=44-56 years), 4,383 (52.5%) women in the subclinical hypothyroidism subanalysis, and 7,790, median age 50 years (IQR = 44-57 years), 4,191 (53.8%) women in subclinical hyperthyroidism subanalysis. Cf- PWV was not associated with subclinical thyroid disease. Conclusion: In separated analysis, CAC and CAD was independently associated with first quintile of TSH using the third as the reference; IMT was independently associated with subclinical hypothyroidism, and cf-PWV was not associated with subclinical thyroid diseases

Recent experimental approaches attribute value to events occurring during intrauterine life as crucial in the onset of several diseases during postnatal life. Thyroid hormones (TH) are critical to the physiology of metabolism and body development. The aim of this study was to investigate the repercussions of lack of TH during pregnancy on body mass gain, metabolic profile, ingestive behavior of food, sodium (0.3M NaCl) and water in rat offspring at different postnatal ages. The experimental gestational hypothyroidism (EGH) was induced by the administration of 0.02% methimazole (MMI) in ad libitum drinking water from day 9 of gestation until delivery. Offspring (males and females) from MMI-treated dams (OMTD) were compared to their corresponding control offspring (i.e. male and female offspring from water-treated dams; OWTD). Insulin tolerance test (ITT) and glucose tolerance test (GTT) were also performed. Two- or three-way ANOVA followed by Bonferroni post-test were performed when necessary. OMTD showed lower body weight on PND 23 and 30 (p<0.0001). Similar profile was observed when the offspring were separated by gender, at least during the experimental period (PND 60, 90 and 120; p<0.0001 for both genders). However, there was no difference in the amount of food intake when males of OMTD (m-OMTD) were compared to OWTD (m-OWTD). Female of OMTD (f-OMTD) had lower ability to reduce glucose plasma level at ITT (p = 0.0224), otherwise, no change in GTT (p = 0.1313) was observed. At PND 60, glucose plasma level was higher in f-OMTD than in f-OWTD (p = 0.013). In m-OMTD, plasma cholesterol was higher in PND 60 and lower on PND 120 (p <0.0001), when compared to m-OWTD. In f-OMTD, cholesterol was lower only at PND 120 (p = 0.035). The high density lipoprotein (HDL) cholesterol was lower in OMTD on PND 15 and 30 (p = 0.04) and remained lower only in f-OMTD on PND 120 (p = 0.024). Moreover, EGH induced an increased in plasma triglycerides (TGL), as well as, in serum level of very low density lipoprotein (VLDL) cholesterol in offspring at DPN 15 (p = 0.039) and also after puberty (at DPN 60), but only the m-OMTD (p < 0.0001). The serum urea was lower in OMTD on PND 15 and 30. Interestingly, serum urea was inverted at DPN 60 in both, m- and f-OMTD (p = 0.006, and p = 0.003, respectively), when compared to their respective control groups. At PND 120, retroperitoneal fat weight was lower both in m- (p = 0.05) and f-OMTD (p = 0.009). Additionally, at all studied ages, relative kidney and liver mass was lower in m- (p = 0.001) and f-OMTD (p = 0.008). In conclusion, we demonstrated, for the first time, that maternal TH are critical to the ontogenetic development of systems that regulate energy metabolism throughout the life of the offspring, resulting in a reduction in body mass, biochemical instability throughout the life, lower sensitivity to insulin in females, and, a delay in the development of critical organs for the metabolism of macronutrients. / Recentes abordagens experimentais têm imputado valor aos eventos ocorridos durante a vida intrauterina como cruciais no aparecimento de doenças na vida pós-natal. Os hormônios tireoidianos (HTs) são críticos para fisiologia do metabolismo e desenvolvimento corporal. O objetivo do presente estudo foi investigar as repercussões da carência dos HTs em ratas prenhes na evolução ponderal da massa corporal, perfil bioquímico, comportamento ingestivo de ração, água e sódio (NaCl 0,3M) da prole em diferentes idades pós-natais. O hipotireoidismo gestacional experimental (HGE) foi induzido através da adicão de metimazol 0,02% na água de beber a partir do dia 9 de gestação até o parto. O grupo de prole (machos e fêmeas) de mães hipotireoideanas (PMH) foi comparado ao grupo controle de mães eutireoideanas (PME). Realizou-se o teste de tolerância à insulina (TTI) e o teste de tolerância à glicose (TTG). Os dados foram submetidos ao teste de ANOVA de duas ou três vias, quando necessário, seguidos do pós-teste de Bonferroni. De acordo com os resultados obtidos, observou-se que a PMH apresentou massa corporal menor aos 23 e 30 dias pós-natal (DPN) (p<0,0001). Padrão similar foi encontrado quando as proles foram separadas por gênero, aos 60, 90 e 120 DPN (p<0,0001, para ambos os gêneros). No entanto, não houve diferença significativa na ingestão de ração entre os machos PMH e PME. As fêmeas da prole de mães hipotireoideanas (f-PMH) apresentaram menor capacidade de reduzir a glicemia no TTI (p=0,0224) sem alteração no TTG. Aos 60 DPN, a concentração sérica de glicose foi maior nas f-PMH (p = 0,013) que nas f-PME. Nos machos prole de mães hipotireoideanas (m-PMH) o colesterol plasmático foi elevado aos 60 DPN e reduziu aos 120 DPN (p<0,0001), quando comparado aos machos prole de mães eutireoideanas (m-PME). Nas f-PMH o colesterol sérico foi menor somente aos 120 DPN (p=0,035). O HDL sérico foi menor na PMH aos 15 e 30 DPN (p=0,04), e continuou menor nas f-PMH aos 60, 90 e 120 DPN (p=0,024). Entretanto, o HGE elevou as concentrações séricas de TGL, bem como de VLDL, na PMH aos 15 DPN, e após a puberdade (aos 60 DPN), somente nos m-PMH (p<0,0001). A concentração sérica de ureia foi menor na PMH aos 15 e 30 DPN. Interessantemente, a ureia sérica foi invertida aos 60 DPN, se apresentando elevada tanto em m- (p=0,006) como em f-PMH (p=0,003), quando comparados aos respectivos grupos controle. Aos 120 DPN, a massa da gordura retroperitoneal foi menor tanto em m- (p=0,05) como em f-PMH (p=0,009). Adicionalmente, em todas idades estudadas, as massas relativas dos rins e do fígado foram menores tanto em m- (p=0,001) como em f- da PMH (p=0,008). Em conclusão, demonstrou-se, pela primeira vez, que os HTs maternos são críticos para o desenvolvimento ontogênico de sistemas que regulam o metabolismo de energia ao longo da vida da prole, resultando numa redução da massa corporal, instabilidade bioquímica ao longo da vida, menor sensibilidade à insulina em fêmeas, e um atraso no desenvolvimento de órgãos críticos para o metabolismo de macronutrientes.

INTRODUÇÃO: O tratamento e o seguimento do carcinoma papilífero de tireoide (CPT) são individualizados pelos riscos de recorrência e mortalidade. A indicação do iodo radioativo (iodo-131) para ablação de remanescente tireóideo captante é controversa em casos classificados como de baixo risco. Por diminuir a massa tireóidea remanescente, a dose ablativa com iodo-131 (DAIR) facilita o seguimento pós-operatório, mas tem riscos e onera o tratamento. Não se encontrou na literatura estudo demonstrando a evolução da captação cervical do iodo-131 e da concentração sérica de tireoglobulina (TG) em pacientes submetidos à tireoidectomia total por CPT de riscos muito baixo e baixo, sem DAIR. OBJETIVO: Avaliar a evolução da captação cervical do iodo-131 e da concentração sérica de TG em pacientes com CPT de baixo e muito baixo risco, após tireoidectomia total e não submetidos a DAIR. MÉTODOS: Foi realizado estudo prospectivo não randomizado em pacientes com CPT de baixo e muito baixo risco submetidos a tireoidectomia total, atendidos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo no período setembro de 2008 novembro de 2011. Após a tireoidectomia foi ministrada levotiroxina na dose necessária para manter a concentração de hormônio tireo-estimulante (TSH) entre 0,5 e 1,0 U/ml. Dosagem sérica de TG, pesquisa de corpo inteiro com iodo-131 (PCI) e dosagem de iodo urinário foram realizadas sob estímulo de TSH endógeno elevado por interrupção da reposição hormonal com levotiroxina, por 30 dias, e dieta pobre em iodo por 15 dias. Foram realizadas ultrassonografias cervicais três e 12 meses após a tireoidectomia. As concentrações séricas de TSH e tiroxina livre sem supressão do TSH foram realizadas seis, nove e 12 meses após a tireoidectomia. RESULTADOS: Dos 26 pacientes incluídos, 22 eram do sexo feminino (84,6%), e quatro, do masculino (15,4%), com idade variando de 27 a 45 anos (média de 38,5 anos e mediana de 39,5 anos). Onze pacientes (42,3%) foram estratificados como de muito baixo risco, e 15 (57,7%), como de baixo risco. Todos os pacientes estavam em hipotireoidismo, no momento da avaliação inicial e final (TSH > 30?U/ml), e os exames realizados seis, nove e 12 meses após a operação, com ingestão de levotiroxina, mostraram as medianas da concentração de TSH de 3,4 ?U/mL, 0,3 ?U/mL e 1,5 ?U/mL, respectivamente. A média da captação de iodo-131 caiu de 1,9% na avaliação inicial para 0,5% na final, e a média da concentração sérica de TG estimulada caiu de 3,1 ng/mL para 1,9 ng/ml. CONCLUSÃO: Houve diminuição estatisticamente significativa da captação cervical do iodo-131 e da concentração sérica de TG sem DAIR nos pacientes submetidos a tireoidectomia total por CPT de baixo e muito baixo risco, sem supressão do TSH / INTRODUCTION: The treatment and follow-up of papillary thyroid carcinoma (PTC) are individualized according to the risk of recurrence and mortality. Radioiodine ablation of thyroid remnant is controversial in low-risk patients. By reducing the thyroid remnant, ablation with radioiodine facilitates the follow-up, but it adds risks and increases the cost of the treatment. We found no published study showing the outcome of cervical uptake of radioactive iodine and the serum concentration of thyroglobulin (TG) in patients undergoing total thyroidectomy for PTC classified as very low risk and low risk who did not undertake ablative dose of radioactive iodine. OBJECTIVE: The aim of this study was to document changes in the cervical uptake of radioiodine and changes in TG concentrations in low-risk and very low-risk PTC patients not submitted to radioiodine remnant ablation (RRA). METHODS: We conducted a prospective non-randomized study in patients with PTC classified as low risk and very low risk undergoing total thyroidectomy at the General Hospital of the University of Sao Paulo, School of Medicine, from September 2008 to November 2011. Levothyroxine was administered after thyroidectomy at a dose required to maintain the concentration of thyroid stimulating hormone (TSH) between 0.5 and 1.0 ?U/ml. Serum thyroglobulin, whole body scan with iodine-131 and urinary iodine were evaluated under high endogenous TSH stimulation after 30 days levothyroxine withdrawal and iodine-poor diet for 15 days. Neck ultrasounds were performed three and 12 months after thyroidectomy. The concentration of serum TSH and free thyroxine without TSH suppression were measured six, nine and 12 months after thyroidectomy. RESULTS: Of the 26 patients included, 22 were female (84.6%) and four were male (15.4%), aged ranged from 27 to 45 years (mean 38.5 years, median 39.5 years). Eleven patients (42.3%) were classified as very low risk and 15 (57.7%) as low risk. All subjects were hypothyroidism at the time of the initial and final evaluations (TSH> 30 ?U/ml). Tests performed six, nine and 12 months after the operation with levothyroxine showed the median concentration of TSH 3.4 ?U/ml, 0.3 U/ml and 1.5 ?U/ml, respectively. The average uptake of iodine-131 dropped 1.9% at baseline to the end of 1.5% and higher mean serum thyroglobulin fell from 3.1 ng/mL to 1.9 ng/ml. CONCLUSION: There was a statistically significant reduction in cervical radioiodine uptake and in stimulated TG level over one year\'s observation of low-risk and very low-risk papillary thyroid carcinoma patients who were not treated with RRA, even in the absence of TSH suppression