Thyroid function test variability and cardiovascular morbidity in hyperthyroidism.

OBJECTIVE: The variability of thyroid function tests (TFTs) during antithyroid drug (ATD) therapy and its association with adverse health outcomes have not been previously studied. The aim of this study was to evaluate the association of TFT variability and cardiovascular morbidity during ATD therapy. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Hyperthyroid patients (n = 394) treated with ATD therapy at Tampere University Hospital between March 2016 and December 2018 were followed up for a median time of 1.5 years (interquartile range 0.8-2.0). The coefficients of variation (CVs) of the follow-up thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) measurements were determined. The associations of TFT variability and baseline clinical factors with cardiovascular disease (CVD) -associated hospital visits were assessed with logistic regression analyses. RESULTS: In the multivariable analyses, age (odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.03-1.09), male gender (OR: 2.33, 95% CI: 1.03-5.28) and fT4-CV (OR: 1.02, 95% CI: 1.01-1.04) were independent risk factors for cardiovascular morbidity, whereas baseline positive thyrotropin receptor antibodies (TRAbs) were associated with lower cardiovascular morbidity (OR: 0.29, 95% CI: 0.14-0.61). When the patients with baseline TRAb positivity were studied separately, fT4-CV was associated with cardiovascular morbidity (OR: 1.03, 95% CI: 1.00-1.05). CONCLUSIONS: During ATD therapy, fT4 variability is associated with an increased cardiovascular morbidity. Although positive TRAbs are associated with a lower cardiovascular morbidity compared with hyperthyroidism with negative autoantibodies, the variability of fT4 is associated with cardiovascular morbidity also in patients with positive TRAbs.

Thyrotropin Receptor Autoantibody Assessment in Thyroid Eye Disease: Does the Assay Type Matter?

PURPOSE: Thyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only. METHODS: Retrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded. RESULTS: A significant positive correlation between TRAb and TSI (rho = 0.828, p < 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p < 0.01; TSI: r = 0.357, p < 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p < 0.01) as well as between CAS and TSI (rho = 0.329, p < 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p < 0.01) and 0.327 (p < 0.01), respectively. CONCLUSIONS: TRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship.

Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis.

A few patients with Hashimoto's thyroiditis or Graves' disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto's encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis. Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases. Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.

Extrathyroidal Manifestations of Persistent Sporadic Non-Autoimmune Hyperthyroidism in a 6-Year-Old Boy: A Case Report.

Thyroid-stimulating hormone receptor (TSHR) belongs in a subfamily of the G protein-coupled receptors. Thyroid-stimulating hormone receptor gene (TSHR), a gene encoding TSHR, is a major controller of thyroid cell metabolism, and its gain of function mutation leads to non-autoimmune hyperthyroidism (NAH), a condition of a prolonged state of hyperthyroidism. Diverse human diseases, and genetic, constitutional, or environmental factors contribute to the phenotypic variations of TSHR mutations; however, the underlying mechanisms leading to various extrathyroidal manifestations across ages are poorly understood. In 2018, the first Korean case of persistent sporadic NAH due to missense mutation of TSHR was reported, and this report highlights the extrathyroidal manifestations of NAH. Further investigation is warranted to clarify the roles of functional mutations of TSHR by investigating the correlation between G protein-dependent signaling properties and clinical phenotypes associated with persistent hyperthyroidism in order to develop novel therapies that could be provided for numerous conditions caused by NAH.

Hipotiroidismo en mujeres en la posmenopausia, prevalencia en el Eje Cafetero, Colombia, 2016-2019 / Hypothyroidism in postmenopausal women, prevalence in the Coffee Region, Colombia, 2016-2019 / Hipotiroidismo em mulheres na pós-menopausa, prevalência no Eje Cafetero, Colômbia, 2016-2019

Resumen: El objetivo es determinar la prevalencia de hipotiroidismo en mujeres en la posmenopausia, en el Eje Cafetero. Materiales y métodos: Estudio de corte transversal en 469 participantes. Se ingresaron mujeres mayores de 40 años, en la posmenopausia, que asistieron a la consulta externa para atención por patología ginecológica; entre julio de 2016 y junio de 2019, en tres clínicas privadas de carácter universitario, en el Eje Cafetero, Colombia. Se excluyeron mujeres con diagnóstico previo de hipotiroidismo o que se negaron a participar. Muestreo aleatorio simple. Variables medidas: sociodemográficas, clínicas y quirúrgicas. Se aplicó estadística descriptiva. Resultados: La edad media fue de 56,47 ± 7,14 años. La media de los valores de la TSH en la población global fue de 3,71 ± 1,94 μUI/mL, con tendencia al incremento a medida del aumento de la edad. La prevalencia de hipotiroidismo en mujeres en la posmenopausia fue del 48,61 % (n = 228/469) (IC95 %: 37,83-54,15), en el Eje Cafetero; siendo más elevada en las obesas (54,41 %; IC95 %, 43,29-49,41 %) y en las mayores de 60 (52,35 %; IC95 %: 20,64-31,77). Se detectaron anticuerpos antitiroideos antiperoxidasa (AC-TPO) en el 46,05 % (n = 105/228) y los antitiroglobulina (TgAb) en el 21,05 % (n = 48/228) de las mujeres hipotiroideas, evidenciándose un fenómeno autoinmune en el 3,26 % (n = 153/469) de la población total estudiada. El sobrepeso, el incremento de la edad y la presencia de anticuerpos antitiroideos aumentan significativamente la prevalencia de hipotiroidismo (p < 0,05). Conclusiones: El 48,61 % de las mujeres del Eje Cafetero en la posmenopausia presentan hipotiroidismo.

Abstract: The aim is to determine the prevalence of hypothyroidism in postmenopausal women in the Coffee Region. Materials and methods: Cross-sectional study in 469 participants. Postmenopausal women over 40 years of age who sought outpatient care due to gynecological pathologies between July 2016 and June 2019 in three private university clinics in the Coffee Region, Colombia, were admitted. Women with a previous diagnosis of hypothyroidism or who refused to participate were excluded. Simple random sampling. Measured variables: sociodemographic, clinical, and surgical. Descriptive statistics were applied. Results: The mean age was 56.47 ± 7.14 years. The mean TSH values in the global population were 3.71 ± 1.94 μIU/mL, increasing with age. The prevalence of hypothyroidism in postmenopausal women was 48.61 % (n = 228/469) (95 % CI: 37.83-54.15) in the Coffee Region, being higher in obese women (54.41 %; 95 % CI, 43.29-49.41 %) and those over 60 (52.35 %; 95 % CI: 20.64-31.77). Anti-thyroid peroxidase antibodies (TPoAb) were detected in 46.05% (n = 105/228) and thyroglobulin antibodies (TgAb) in 21.05% (n = 48/228) of hypothyroid women, showing an autoimmune phenomenon in 3.26% (n = 153/469) of the total population studied. Overweight, older age and antithyroid antibodies increase the prevalence of hypothyroidism (p < 0.05). Conclusions: 48.61 % of postmenopausal women from the Coffee Region have hypothyroidism.

Resumo: O objetivo é determinar a prevalência de hipotiroidismo em mulheres na pós-menopausa, no Eje Cafetero (Eixo Cafeeiro). Materiais e métodos: Estudo de corte transversal em 469 participantes. Foram incluídas mulheres maiores de 40 anos, na pós-menopausa, que foram à consulta externa para o atendimento por patologia ginecológica; entre julho de 2016 e junho de 2019, em três hospitais particulares de caráter universitário, no Eje Cafetero, Colômbia. Foram excluídas mulheres com diagnóstico prévio de hipotiroidismo ou que negaram a participar. Amostragem aleatória simples. Variáveis medidas: sociodemográficas, clínicas e cirúrgicas. Foi aplicada estatística descritiva. Resultados: A idade média foi de 56,47 ± 7,14 anos. A média dos valores da TSH na população global foi de 3,71 ± 1,94 μUI/mL, com tendência à elevação à medida que a idade aumentasse. A prevalência de hipotiroidismo em mulheres na pós-menopausa foi de 48,61 % (n = 228/469) (IC95 %: 37,83-54,15), no Eje Cafetero; sendo mais elevada nas obesas (54,41 %; IC95 %, 43,29-49,41 %) e nas maiores de 60 (52,35 %; IC95 %: 20,64-31,77). Foram detectados anticorpos antitiroideus antiperoxidase (AC-TPO) em 46,05 % (n = 105/228) e os antitiroglobulina (TgAb) em 21,05 % (n = 48/228) das mulheres com hipotiroidismo, evidenciando-se um fenómeno autoimune em 3,26 % (n = 153/469) da população total estudada. O sobrepeso, o aumento da idade e a presença de anticorpos antitiroideus aumentam significativamente a prevalência de hipotiroidismo (p < 0,05). Conclusões: 48,61 % das mulheres do Eje Cafetero na pós-menopausa apresentam hipotiroidismo.

Effects of sodium ions on rat thyrocyte (FRTL-5 cells) swelling- and thyrotropin-activated taurine efflux dependent on cAMP and Epac.

Cellular osmolyte release is important in preventing water accumulation and swelling. However, the signaling pathways that detect volume increase and activate solute efflux are still not fully understood. We investigated efflux activation of the osmolyte taurine which is actively accumulated in rat thyrocytes (FRTL-5). Efflux of accumulated [(3)H]taurine was stimulated by cellular swelling and thyrotropin (TSH). These effects were significantly diminished in cells having reduced TSH receptor concentrations. Phosphodiesterase inhibitors (IBMX, Rolipram) enhanced both responses. An analog of forskolin (FSK; 7-deacetyl-7-[O-(N-methylpiperazino)-γ-butyryl] dihydrochloride) and an analog of cAMP, specific for activating exchange protein activated directly by cAMP (Epac; 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate, acetoxymethyl ester), significantly stimulated [(3)H]taurine efflux. A cAMP analog specific for activating protein kinase A (PKA; N6-benzoyladenosine-3',5'-cyclic monophosphate, acetoxymethyl ester) had no significant stimulatory effect on [(3)H]taurine efflux rate. The amiloride analog, 5-(N-ethyl-N-isopropyl)-amiloride, which inhibits a TSH-stimulated Na(+)/H(+) exchanger, enhanced (100 %) and ouabain inhibited (50 %) the TSH-stimulated [(3)H]taurine efflux rate. The effect of FSK on efflux was strongly potentiated by Na(+)-free iso-osmotic conditions and by osmolality/cell volume that affected also the db-cAMP-stimulated efflux. The TSH receptors and downstream elements of the signaling pathway comprising adenylyl cyclase, cAMP and Epac appeared to mediate the hormone-induced signal for [(3)H]taurine efflux from FRTL-5 cells. With less evidence, the cell volume/osmolality-induced [(3)H]taurine efflux cascade appeared to share some of the hormone signaling elements and to modulate the hormone signaling pathway at two levels through cellular Na(+).

Hipotireoidismo subclínico: uma revisão para o médico clínico / Subclinical hypothyroidism: a review for the clinic physician

O hipotireoidismo subclínico é uma alteração frequente, definida como condição oligossintomática ou assintomática, com níveis séricos elevados do hormônio estimulador da tireoidee níveis normais de tiroxina livre. Pode representar o estágio inicial de uma deterioração progressiva da função tireoidiana, sendo que, em alguns casos, esta função pode permanecer inalterada ou mesmo normal. O objetivo deste estudo foi revisara literatura para os aspectos epidemiológicos, diagnósticos, indicações do tratamento e o procedimento terapêutico aplicado ao hipotireoidismo subclínico. Os clínicos generalistas devem ser capazes de diagnosticar, indicar a terapia em situações adequadas e dar seguimento aos casos. Será discutido o conceito de hipotireoidismo subclínico, rastreio e epidemiologia.Serão abordadas evidências presentes em relação às alterações provocadas pelo hipotireoidismo subclínico: na dislipidemia,na resposta cardiovascular ao esforço físico e recuperação, no risco cardiovascular, em distúrbios psiquiátricos e em grupos especiais de idosos e gestantes, descrevendo-se o tratamento. Oh ipotireoidismo subclínico é uma condição frequente nos ambulatórios de clínica médica e por muitas vezes é assintomático ou apresentado por sintomas sutis e inespecíficos tais como: a disfunção sexual, parestesias, fadiga crônica, mialgia, sintomas psiquiátricos e disfunção cognitiva leve. É papel de o médico generalista estar capacitado para diagnosticar, analisar as variáveis que se impõem para decisão quanto ao início do tratamento e realizar acompanhamento periódico destes pacientes.

Subclinical hypothyroidism is a frequent pathology defined as an oligosymptomatic or asymptomatic condition with high serum levels of thyroid stimulating hormone, and normal free thyroxine levels. It can represent the initial stage of a progressive deterioration of thyroid function, and in some cases this function may remain unchanged or even become normal. The objective of this study is to review the literature for the epidemiological aspects, diagnosis, treatment indications and treatment procedure applied to subclinical hypothyroidism. Generalist physicians should be able to diagnose, indicate the therapy in appropriate situations and follow the cases. The concept, screening and epidemiology of subclinical hypothyroidism will be discussed. We will approach the current evidence regarding changes caused by the subclinical hypothyroidism in dyslipidemia, cardiovascular response to physical exercise and recovery, cardiovascular risk, psychiatric disorders, and in the special groups: elderly and pregnant women. The treatment will also be described. The subclinical hypothyroidism is a common condition in the outpatient clinica nd is often asymptomatic or presented with subtle and nonspecific symptoms such as sexual dysfunction, paresthesias, chronic fatigue, myalgia, psychiatric symptoms and mild cognitive impairment. The generalist physician must be able to diagnose, analyze the variables that are needed for decision on the initiation of treatment, and regularly monitor the thyroid function of these patients.

Coexistence of Graves' disease, papillary thyroid carcinoma and unilateral benign struma ovarii: case report and review of the literature.

BACKGROUND: Struma ovarii is a rare cause of hyperthyroidism, while coexistence with Graves' disease has been scarcely reported. PATIENT FINDINGS: We report a patient with Graves' disease and unilateral benign functioning struma ovarii, accompanied by ascites, pleural effusion and elevated cancer antigen-125 (CA-125) levels. In subsequent thyroidectomy, incidental papillary thyroid carcinoma was also identified. The functionality of struma ovarii tissue in our patient was supported by the immunohistochemical identification of TSH receptors (TSHR), which may stimulate growth and thyroid hormone production in the presence of circulating TSHR stimulating antibodies (TSHR-Ab). REVIEW OF THE LITERATURE: A systematic review of reported cases of coexistent Graves' disease and struma ovarii was performed. CONCLUSIONS: The diagnosis of struma ovarii may be masked by Graves' disease and, therefore, be delayed for several years. Furthermore, ascites, pleural effusion and increased CA-125 may result from a benign struma ovarii. The presence of TSHR in the struma ovarii tissue along with their absence in the surrounding ovarian tissue indirectly suggests that struma ovarii is functional. It is unclear whether TSHR-Ab play a role in the development of thyroid carcinomas in such patients.

Diagnóstico y tratamiento de los trastornos tiroideos durante el embarazo: un enfoque para el cuidado integral del binomio madre-hijo / Diagnosis and management of thyroid disorders during pregnancy: an approach to comprehensive care of mother and child

Los trastornos tiroideos son frecuentes en mujeres en edad reproductiva. Sin embargo, a menudo no se diagnostican porque su sintomatología se confunde con el estado hipermetabólico característico del embarazo. A los cambios fisiológicos en el embarazo de índole cardiovascular, pulmonar, hematológica, inmunológica, etc., se añaden las modificaciones en el eje tiroideo que a lo largo de la gestación presenta diferentes estados, lo que hace aún más difícil el diagnóstico y tratamiento correctos en los casos patológicos. Los trastornos del eje tiroideo tienen repercusiones negativas sobre la madre y el feto, entre otras: preeclampsia, aborto, parto prematuro y trastornos del sistema nervioso central del feto. El tratamiento se debe dirigir a contrarrestar los efectos del aumento o la disminución del funcionamiento de la glándula teniendo en cuenta las diferencias en cuanto a requerimientos y seguridad de los fármacos en el feto. Actualmente es motivo de controversia la tamización de rutina en gestantes para trastornos tiroideos, pues hasta el momento se destinan las pruebas a mujeres embarazadas de alto riesgo.

Thyroid disorders are frequent in women of reproductive age. However, they are often overlooked because their manifestations may be confused with those of the hypermetabolic state that is characteristic of pregnancy. To the physiological changes that occur during pregnancy –cardiovascular, pulmonary, hematological, immunological, etc., it is necessary to add modifications in the thyroid axis that presents different situations during pregnancy; those variations make it difficult to correctly diagnose and treat pathological situations. Disorders of thyroid axis have negative consequences on both mother and fetus, among them: preeclampsia, abortion, premature delivery and disorders of the fetal central nervous system. Treatment must be oriented to counteract the effects of either increased or diminished thyroid function; for that purpose, differences concerning requirements and safety of medicines must be taken into account. Presently there is controversy concerning routine screening of pregnant women for thyroid disorders; so far, the available tests are usually performed only in high-risk women.

The relationship between expression of the sodium/iodide symporter gene and the status of hormonal receptors in human breast cancer tissue.

PURPOSE: It has been reported that the sodium/iodide symporter (NIS) gene is expressed in several breast cancer tissues, suggesting the possibility of radionuclide imaging and therapy. However, the regulatory mechanism of NIS gene expression in breast cancer is not yet understood. To assess the relationship between the hormonal status and the NIS expression in breast cancer tissue, we investigated the NIS expression and correlated it to the expression of the thyrotropin receptor (thyroid stimulating hormone receptor, TSH-R), the estrogen receptor (ER) and the progesterone receptor (PR) in human breast cancer tissues. MATERIALS AND METHODS: Breast cancer tissues were obtained from 44 patients. Pathological examination showed 2 cases of Grade I, 17 of Grade II, 22 of Grade III, and 3 of unknown grade. We measured the expression of NIS and TSH-R genes by using RT-PCR and we measured the status of ER and PR by using immunohistochemistry. RESULTS: The NIS gene was expressed in 15 (34%) of the 44 breast cancer tissues. The NIS gene was expressed in 32% of the cases with TSH-R gene expression. The NIS gene was expressed in 40% of the breast cancer tissues with a positive PR and in 31% with a negative PR (p>0.05). It was positive for PR in 18% of the cases and negative for PR in 39% of the cases (p>0.05). CONCLUSION: The NIS gene is expressed in approximately one-third of the human breast cancer tissues. Its expression was not related to the presence of the TSH-R gene or hormonal receptors, ER and PR.

The Relationship between Expression of the Sodium/iodide Symporter Gene and the Status of Hormonal Receptors in Human Breast Cancer Tissue / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: It has been reported that the sodium/iodide symporter (NIS) gene is expressed in several breast cancer tissues, suggesting the possibility of radionuclide imaging and therapy. However, the regulatory mechanism of NIS gene expression in breast cancer is not yet understood. To assess the relationship between the hormonal status and the NIS expression in breast cancer tissue, we investigated the NIS expression and correlated it to the expression of the thyrotropin receptor (thyroid stimulating hormone receptor, TSH-R), the estrogen receptor (ER) and the progesterone receptor (PR) in human breast cancer tissues. MATERIALS AND METHODS: Breast cancer tissues were obtained from 44 patients. Pathological examination showed 2 cases of Grade I, 17 of Grade II, 22 of Grade III, and 3 of unknown grade. We measured the expression of NIS and TSH-R genes by using RT-PCR and we measured the status of ER and PR by using immunohisto-chemistry. RESULTS: The NIS gene was expressed in 15 (34%) of the 44 breast cancer tissues. The NIS gene was expressed in 32% of the cases with TSH-R gene expression. The NIS gene was expressed in 40% of the breast cancer tissues with a positive PR and in 31% with a negative PR (p>0.05). It was positive for PR in 18% of the cases and negative for PR in 39% of the cases (p>0.05). CONCLUSION: The NIS gene is expressed in approximately one-third of the human breast cancer tissues. Its expression was not related to the presence of the TSH-R gene or hormonal receptors, ER and PR.