Niveles de tirotrofina y anticuerpos antitiroperoxidasa en el primer trimestre de gestación asociados a complicaciones del embarazo en la mujer eutiroidea / Thyrotropin levels and anti-thyroid peroxidase antibodies during first trimester of pregnancy associated with maternal and foetal complications in euthyroid women

Introducción: El embarazo es una situación fisiológica que presenta cambios endócrinos e inmunológicos. La tiroides modifica su economía para proveer suficientes hormonas a la madre y al feto. La autoinmunidad y las disfunciones tiroideas tienen alta prevalencia en mujeres en edad fértil y pueden afectar el curso de la gestación, con repercusiones clínicas adversas maternas y fetales. El objetivo de este estudio fue relacionar la proporción de gestantes eutiroideas con tirotrofina (TSH) en 2 niveles del rango de referencia ( ± DS; 1,57 ± 0,82 vs. 1,16 ± 0,54 mUI/l, p = 0,001). Los niveles séricos de T4L y T4 fueron similares en ambos grupos. De la subpoblación EP, el 63% fue incluida en EP1 y el 37% en EP2, y en EN el 80% en EN1 y el 20% en EN2. Se observó un incremento significativo (p = 0,001) en las complicaciones en EP (22%) vs. EN (10%). En mujeres EP con y sin aborto espontáneo, la TSH ( ± DS) fue 1,65 ± 0,67 vs. 0,99± 0,77 mUI/l (p = 0, 014). Las mujeres EP con y sin parto prematuro presentaron niveles de TSH (X ± DS) 1,63 ± 0,70 vs. 1,15 ± 0,53 mUI/l (p = 0,012). En el grupo EN, el nivel de TSH ( ± DS) para las mujeres con y sin aborto fue 1,45 ± 0,61 vs. 0,85± 0,66 mUI/l (p = 0,001), mientras que en mujeres con y sin parto prematuro la TSH ( ± DS) fue 1,59 ± 0,71 vs. 0,83 ± 0,64 mUI/l (p = 0,001), respectivamente. Sin embargo, no hubo diferencias entre los niveles promedio de TSH encontrados en aborto vs. parto pretérmino en ambos grupos. En EP, 32 mujeres y 19 en EN desarrollaron hipotiroidismo en el curso del embarazo (ns) y 29 en EP y 10 en EN tiroiditis posparto (p = 0,005). La autoinmunidad tiroidea y los mayores niveles de TSH dentro del rango de referencia en mujeres en primer trimestre de embarazo estarían asociados a complicaciones en el transcurso de la gestación y desarrollo de disfunción tiroidea posparto.

Introduction: Pregnancy is a physiological state presenting with endocrine and immunological changes. The thyroid gland modifies its output in order to provide enough hormonesto the mother and foetus. Thyroid autoimmunity and thyroid dysfunction are prevalent in women of childbearing age and may affect the course of gestation and having maternal and foetal clinical consequences. The purpose of the present study was to establish the relationship between euthyroid pregnant women with thyrotropin (TSH) at two levels of the reference range ( ± SD; 1.57 ± 0.82 vs 1.16 ± 0.54 mIU/L, P=.01). FT4 and T4 values were similar in both groups. Out of the pregnant women in the EP group, 63% were included in EP1, and 37% in EP2. In the EN group, 80% of women were included in EN1 and 20% in EN2. A significant (P=.001) increase in pregnancy complications in EP group (22%) vs EN (10%) was observed. In the EP group, TSH levels were: 1.65 ± 0.67 vs 0.99± 0.77 ( ± SD) mIU/L (P=.014) respectively, in women with and without miscarriage. TSH levels were 1.63 ± 0.70 vs 1.15 ± 0.53 ( ± SD) mIU/L (P=.012), respectively, in women with and without preterm delivery. In the EN group TSH levels were: 1.45 ± 0.61 vs 0.85± 0.66 ( ± SD) mIU/L (P=.001), respectively, in women with and without miscarriage. TSH levels were 1.59 ± 0.71 vs 0.83 ± 0.64 ( ± SD) mIU/L (P=.001), respectively, in women with and without preterm delivery. However, TSH levels in miscarriage and preterm delivery were similar. Thirty-two EP, and 19 EN women developed hypothyroidism in pregnancy (ns), and 29 EP and 10 EN women developed post-partum thyroiditis (P=.005). Conclusion: Thyroid autoimmunity and higher TSH levels within the reference range during the first trimester of pregnancy were associated with pregnancy complications and with the development of thyroid postpartum dysfunction.

Importancia de la detección de ATPO y ATg en pacientes con TSH entre 2, 5 a 4, 5 mU/L y su prevalencia en el Hospital Aeronáutico Córdoba / Importance of detection of anti-TPO and ATG in patients with TSH values between 2.5 and 4.5 mU/l and their prevalence at the Hospital Aeronáutico Córdoba

Introducción: La enfermedad tiroidea autoinmune (EAT) causa daño celular y altera la función tiroidea por acción de los anticuerpos antitiroperoxidasa (ATPO) y antitiroglobulina (ATg).Estudios longitudinales demuestran que personas con tirotrofina (TSH) entre 2,5 a 4,5 mU/L y autoanticuerpos tiroideos (ATPO y ATg) positivos tienen un riesgo aumentado de desarrollar hipotiroidismo franco, definiendo a esta población como una categoría de riesgo intermedio. Objetivo: destacar la importancia de la detección de anticuerpos antitiroideos en la población con TSH entre 2,5 a 4,5 mU/L y conocer su prevalencia en la población del Hospital Aeronáutico Córdoba. Materiales y métodos: se midió ATPO y ATg a 216 muestras depacientes mayores a 20 años con TSH entre 2,5 a 4,5 mU/L que concurrieron al laboratorio del Hospital Aeronáutico Córdoba y se excluyeron a las mujeres embarazadas, aquellos pacientes condopajes previos de TSH mayores a 2,5 mU/L y aquellos bajo tratamiento con levotiroxina. Las determinaciones se realizaron por el inmunoanálisis quimioluminiscente de micropartículas (CMIA). Resultados: se observó mayor prevalencia del sexo femenino, aumentando con la edad y la presencia de un 30% de pacientes con anticuerpos antitiroideos positivos en la población estudiada Se demostró que es más frecuente la presencia de ATPO que de ATg y que no hay diferencia significativa entre el dosaje de ATPOy ATg en conjunto y ATPO como única medida. Conclusiones: se recomienda valorar la presencia de anticuerpos antitiroideos, principalmente ATPO, en las poblaciones más susceptibles: pacientes con TSH entre 2,5 – 4,5mU/L, mujeres mayores a 60 años y embarazadas.

Introduction: Autoimmune thyroid disease (EAT) causes cellulardamage and alters thyroid function by the action of anti thyroid peroxidase antibodies (ATPO) and anti thyroglobulin(ATg). Longitudinal studies show that people with thyrotropin (TSH) between 2.5 to 4.5 mU/L and positive thyroid autoantibodies (ATPO and ATg) have an increased risk of developing overthypothyroidism, defined this population as intermediate risk category.Objective: Highlight the importance of the detection of antithyroid antibodies in the population with TSH between 2.5 to 4.5 mU/L and determine their prevalence in the population of HospitalAeronáutico Córdoba. Materials and methods: We measured ATg and ATPO in 216 samples of patients aged over 20 years with TSH between 2.5 to 4.5 mU/L who attended the Hospital Aeronáutico Córdoba laboratory and excluded pregnant women, patients with previousdoping TSH greater than 2.5 mU/L and those treated with levothyroxine. Determinations were performed by thechemiluminescent microparticle immunoassay (CMIA). Results: We observed a higher prevalence of female gender, increasing with age and the presence of 30% of patients withpositive antithyroid antibodies in this population. We proved that ATPO is more frequent than ATg and there was no significant.

Insulinorresistencia asociada a cambios en los niveles de tirotrofina en pacientes eutiroideos o con disfunción tiroidea subclínica / Insulin Resistance and Changes in thyrotropin levels in patients with euthyroidism or subclinic thyroid dysfunction

La relación entre síndrome metabólico y disfunción tiroidea subclínica es un tema aun controvertido. Por tal motivo, el objetivo principal de nuestro trabajo fue tratar de establecer la existencia de una asociación entre la insulinorresistencia medida por el HOMA-IR (Homeostasis Model Assessment) con los niveles de TSH en pacientes eutiroideos o con disfunción tiroidea subclínica. A su vez, y en forma secundaria, se valoraron cambios en el perfil lipídico. Se analizaron los niveles de T4L, TSH, insulina, glucemia, colesterol total, HDL colesterol, triglicéridos e índice de masa corporal en 233 pacientes eutiroideos o con disfunción tiroidea subclínica y se dividieron en tres grupos según su nivel de TSH: Grupo A: TSH < de 0,4; Grupo B: TSH entre 0,4 y 2,5 y Grupo C: TSH > de 2,5 mUI/L. Encontramos que, los niveles de insulina y el HOMA-IR en el grupo B fueron significativamente menores que en el grupo C (7,91 ± 0,67 mUI/L vs. 10,23 ± 0,91 mUI/L - p = 0,0073 y 1,84 ± 0,17 vs. 2,49 ± 0,27 - p = 0,0113, respectivamente). Esta diferencia fue independiente de la edad y del IMC. Además, se encontró una leve pero significativa disminución de los niveles de HDL-colesterol en el grupo C respecto al B (48,3 ± 0,5 vs. 46,3± 0,7 mg/dl; p = 0,0455) y un incremento de los triglicéridos (146,9 ± 11,9 vs. 112,3 ± 5,6 mg/dl; p = 0,0162). La prevalencia de insulinorresistencia definida como un valor de HOMA-IR > de 2,5 fue superior en el grupo C comparado con el B (39,5 % vs. 23,9 %; OR de 2,06 - IC 95 %: 1,19-3,63 - p = 0,013). Por último, se observó una débil pero significativa correlación negativa entre HOMA-IR y T4L (r - 0,2336; p = 0,0047) y positiva entre HOMA-IR y TSH (r = 0,1909; p = 0,0066) en toda la cohorte analizada. Concluimos que en la población analizada, los pacientes con TSH > de 2,5 mUI/L presentaron: a) niveles de HDL colesterol más bajos, b) triglicéridos y HOMA-IR más elevados, independientemente de la edad y del IMC, y c) un aumento significativo del riesgo de tener insulinorresistencia medida por HOMA-IR. Los autores declaran no poseer conflictos de interés.

Introduction: The association between alterations of the thyroid function and an increased risk of developing cardiovascular diseases has been established for several years. Strong published evidence supports the notion that clinical hypothyroidism increases the levels of LDL cholesterol, induces arterial hypertension, and increases the levels of homocystein. However, the relationship between all these well-known risk factors for coronary disease and subclinical thyroid dysfunction remains a controversial topic. In addition, the presence of Metabolic Syndrome, known as an association of cardiovascular risk factors including: central obesity, insulin resistance, dyslipidemia and arterial hypertension, increases the possibility of developing cardiovascular diseases, to such an extent that the main cause of death in patients with type 2 diabetes, who generally present all the aforementioned factors plus hyperglycemia, is myocardial infarction. Objective: The main objective of our study was to investigate the existence of an association between insulin resistance measured by HOMA-IR and TSH levels in euthyroid patients or subclinical thyroid dysfunction. Secondarily, we evaluated changes in the lipid profile of the groups studied. Methods: This was a retrospective study. We analyzed the levels of free T4, TSH, insulin, basal plasma glucose, total and HDL cholesterol, triglycerides and body mass index in 233 patients with euthyroidism or diagnosed with subclinical thyroid dysfunction. Patients were divided into three groups according to TSH levels: Group A (n = 31) with values of TSH less than 0.4 mIU/L; Group B (n = 136) with TSH between 0.4 and 2.5 mIU/L, and Group C (n = 66) with TSH above 2.5 mIU/L. Free T4, TSH and insulin were measured with immunochemiluminescence assays (Immulite 2000). Basal plasma glucose, total cholesterol, HDL cholesterol and triglycerides were measured with automated methods (Technicon/Bayer RA 1000 Chemistry Analyzer). All measurements were performed from the same blood sample, obtained early in the morning after a minimum fasting period of 12 hours. Results: We found that the levels of insulin and HOMA-IR in group B were significantly lower that in group C (7.91 ± 0.67 mIU/L vs. 10.23 ± 0.91 mIU/L - p = 0.0073 and 1.84 ± 0.17 vs. 2.49 ± 0.27 - p = 0.0113, respectively). This difference was independent of age and BMI. In addition, we observed a slight but significant decrease in HDL-cholesterol levels in group C as compared to group B (48.3 ± 0.5 vs. 46.3 ± 0.7 mg/dl; p = 0.0455) and an increase in triglycerides (146.9 ± 11.9 vs. 112.3 ± 5.6 mg/dl; p = 0.0162). The prevalence of insulin resistance defined as a value of HOMA-IR higher than 2.5 was greater in group C compared to B (39.5 % vs. 23.9 %; OR 2.06 - IC 95 %: 1.19-3.63 - p = 0.013). Finally, a weak but significant negative correlation was observed between HOMA-IR and free T4 (r - 0.22276; p = 0.0059) and a positive correlation was observed between HOMA-IR and TSH (r = 0.1909; p = 0.0066) in the whole cohort. Conclusions: We conclude that in the studied population, patients with TSH above 2.5 mIU/L vs. those with TSH between 0.4 and 2.5 mIU/L presented: 1) lower levels of HDL cholesterol, 2) higher levels of triglycerides, insulin and HOMA-IR, independently of age and BMI and, 3) a significant increase in the risk of having insulin resistance measured by HOMA-IR.

Niveles de Tirotrofina y Hormonas Tiroideas en el Paciente Renal Crónico en Hemodiálisis / Thyrotropin and thyroid hormone levels in chronic renal patients under hemodyalisis

Las enfermedades críticas presentan cambios en el eje hipotálamo-hipófiso-tiroideo que dependen de la patología y de la gravedad de la misma. La Insuficiencia Renal Crónica es una patología grave con un alto índice de morbimortalidad. El objetivo del presente trabajo fue evaluar las hormonas del eje tiroideo en pacientes renales crónicos en hemodiálisis (HD) y su utilidad como pronosticadores de morbilidad. Se estudiaron pacientes renales crónicos de un Servicio de nefrología y hemodiálisis y se comparó con un grupo control (CT) sin enfermedad renal y/o tiroidea. Se monitoreó al enfermo pre (pre-DL) y posdiálisis (pos-DL), se realizó un seguimiento durante un año y se lo agrupó según el tiempo de permanencia bajo HD. Se evaluaron concentraciones de tirotrofina (TSH), triiodotironina (T3), tiroxina (T4) y tiroxina libre (T4L) y parámetros bioquímicos sensibles al estado del paciente: urea, creatinina, albúmina y proteínas totales. Las muestras pre-DL evidenciaron un aumento significativo en los niveles de TSH (p<0.05), con un descenso también significativo de T3 y de T4 y T4L aunque de menor magnitud (p<0.05) con respecto al CT. En el procedimiento de diálisis se observó una fluctuación transitoria de los niveles de las hormonas tiroideas (p<0.05), con una concentración máxima en la muestra pos-DL y mínima en la pre-DL, sin modificación en TSH. Durante el seguimiento de los pacientes detectamos una tendencia descendente de T3. Además, se constató un aumento de TSH y una disminución de T3 (p<0.05) en pacientes con mayor tiempo de permanencia en HD. Además, comprobamos una correlación directa entre TSH y urea e inversa entre TSH y albúmina, y correlaciones inversa entre T3 y urea y directa entre T3 y albúmina. Nuestro estudio muestra las modificaciones hormonales en el eje tiroideo debido a la enfermedad y al procedimiento de diálisis y la posible utilidad de T3 como otro indicador de morbilidad en estos pacientes.

Severe illness induces various hormonal changes in the hypothalamic-pituitary-thyroid axis. Chronic renal failure is a serious condition showing a high mortality index. The aim of this work was to evaluate thyroid hormone level in chronic renal patients under hemodialysis in order to estimate its potential use as morbidity / mortality indicator. We studied chronic renal patients from Nephrology and Hemodialysis Units of our Hospital and compared them with a control group (CT) without renal or thyroid pathology. We evaluated patients before (pre-dialysis) and after dialysis (post-dialysis) during one year. We then classified patients according to the duration of their hemodialysis treatment. We assessed Thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4) and free thyroxine (T4L) levels and other biochemical indicators: urea, creatinine, albumin, and total protein. Pre-dialysis samples showed higher TSH levels (p<0.05), a significant decrease in T3, and a lower decrease in T4 and T4L than CT. During the dialysis procedure, we observed a fluctuation in thyroid hormone levels (p<0.05), higher in post-dialysis samples, and no changes in TSH levels. The one- year follow- up showed a low decrease in T3 levels in pre- and post-dialysis samples. An increase in TSH levels and a decrease in T3 levels (p<0.05) was observed in patients after long hemodialysis treatment. Renal patients showed a direct correlation between TSH and urea and inverse correlation between TSH and albumin. However, an inverse correlation between T3 and urea and a direct correlation between T3 and albumin was observed. This study shows that thyroid-hormonal changes are induced by pathology and dialysis treatment. We suggest T3 measurement as a useful morbidity indicator for chronic renal patients.

TSH signalling and cancer

Thyroid cancers are the most frequent endocrine neoplasms and mutations in the thyrotropin receptor (TSHR) are unusually frequent. Here we present the state-of-the-art concerning the role of TSHR in thyroid cancer and discuss it in light of the cancer stem cell theory or the classical view. We briefly review the gene and protein structure updating the cancer related TSHR mutations database. Intriguingly, hyperfunctioning TSHR mutants characterise differentiated cancers in contrast to undifferentiated thyroid cancers which very often bear silenced TSHR. It remains unclear whether TSHR alterations in thyroid cancers play a role in the onset or they appear as a consequence of genetic instability during evolution, but the presence of functional TSHR is exploited in therapy. We outline the signalling network build up in the thyrocyte between TSHR/PKA and other proliferative pathways such as Wnt, PI3K and MAPK. This networks integrity surely plays a role in the onset/evolution of thyroid cancer and needs further research. Lastly, future investigation of epigenetic events occurring at the TSHR and other loci may give better clues for molecular based therapy of undifferentiated thyroid carcinomas. Targeted demethylating agents, histone deacetylase inhibitors combined with retinoids and specific RNAis may help treatment in the future.

Os cânceres de tiróide são as neoplasias endócrinas mais frequentes e as mutações no receptor de tirotrofina (TSHR) são incomumente frequentes. Nesta revisão nós apresentamos o "estado da arte" com relação ao papel do TSHR no câncer de tiróide e o discutimos à luz da teoria da célula matriz do câncer ou a visão clássica. Revisamos brevemente a estrutura do gene e da proteína, atualizando a base de dados das mutações do TSHR relacionadas ao câncer. Curiosamente, mutações do TSHR com hiperfunção caracterizam cânceres diferenciados, em contraste com os cânceres de tiróide indiferenciados, os quais muito comumente mostram TSHR silenciados. Permanece obscuro se as alterações do TSHR em cânceres de tiróide têm algum papel no surgimento ou se elas aparecem como conseqüência da instabilidade genética durante seu desenvolvimento, mas a presença de TSHR funcional é explorada na terapia. Nós delineamos a rede de sinalizacão desenvolvida no tirócito entre TSHR/PKA e outras vias proliferativas como a Wnt, PI3k e MAPK. A integridade desta rede certamente tem um papel no surgimento/evolução do câncer de tiróide e necessita de novas pesquisas. Finalmente, novas investigacões sobre os eventos epigenéticos que ocorrem no TSHR e outros locais poderão trazer novas informações para uma terapia de base molecular nos carcinomas indiferenciados de tiróide. Agentes demetilantes direcionados, inibidores da histona-deacetilase, combinados com retinóides e RNAs específicos poderão auxiliar no tratamento futuro.