Uso adecuado de las pruebas de laboratorio para la evaluación de la función tiroidea en pediatría / Appropriate use of laboratory tests for evaluation of thyroid function in pediatrics

Las pruebas de función tiroidea (PFT) son esenciales para el diagnóstico preciso y el seguimiento eficaz de la disfunción tiroidea. Existe un incremento progresivo y estable de los pedidos de PFT, incluso se han incorporado las mismas a los exámenes de salud anuales en niños sanos. Representan más del 60% de las pruebas realizadas en el laboratorio de endocrinología, tanto en adultos como en los laboratorios especializados en pediatría. Para hacer un uso eficiente de las PFT, antes de solicitarlas debemos preguntarnos… ¿Para quién? ¿Cuándo solicitarlas? ¿Qué pruebas solicitar? ¿Cómo solicitarlas? y ¿Cómo interpretar correctamente los resultados? Un resultado anormal en las PFT no siempre implica patología tiroidea asociada. Las PFT tienen importante variabilidad intra e interindividual lo que hace más compleja su correcta interpretación. La pesquisa de enfermedad tiroidea neonatal es un importante aporte a la prevención de la deficiencia mental en la infancia, su aplicación obligatoria posibilita un diagnóstico temprano, para asegurar su éxito debe considerarse en el marco de un programa integral de detección con estrategias de confirmación, tratamiento temprano y seguimiento a corto, mediano y largo plazo. No debe hacerse un uso indiscriminado de la prueba de estímulo con TRH en el diagnóstico de la patología tiroidea. En pediatría la estrategia de tamiz de enfermedad tiroidea es conveniente realizarla mediante la medición de por lo menos TSH y T4 libre e incluir la determinación de ATPO en grupos de riesgo, a diferencia de la determinación aislada de TSH como es recomendado en adultos. (AU)

Thyroid function tests (TFTs) are essential for accurate diagnosis and effective monitoring of thyroid dysfunction. There is a progressive and steady increase in requests for TFTs, and they have even been incorporated into annual health examinations in healthy children. They represent more than 60% of the tests performed in the endocrinology laboratory, both in adults and in specialized pediatric laboratories. To efficiently use TFTs, before requesting them we should ask ourselves... For whom? When to request them? Which tests to request? How to request them? and How to correctly interpret the results? An abnormal TFT result does not always imply thyroid disease. TFTs have significant intra- and inter-individual variability, which makes their correct interpretation more complex. Screening for newborn thyroid disease is an important contribution to the prevention of intellectual disability in childhood and its mandatory use enables early diagnosis; however, to ensure the test to be successful, it should be considered within the framework of a comprehensive screening program with strategies for confirmation, early treatment, and short-, medium-, and long-term follow-up. The TRH stimulation test in the diagnosis of thyroid disease should not be used indiscriminately. In children, the screening strategy for thyroid disease should be performed by measuring at least TSH and free T4 and include the measurement of TPO-ab in risk groups, as opposed to the isolated measurement of TSH as recommended in adults. (AU)

Association of Maternal Thyroid Function with Gestational Hypercholanemia.

Background: High bile acid concentration is associated with adverse perinatal outcomes (i.e., stillbirth and preterm birth) and experimental studies indicate that thyroid hormone regulates bile acid metabolism, but this has not yet been translated to clinical data in pregnant women. We aim to explore the association of thyroid function with bile acid concentrations and the risk of gestational hypercholanemia. Methods: This study comprised 68,016 singleton pregnancies without known thyroid or hepatobiliary diseases before pregnancy and thyroid medication based on a prospective cohort. Thyroid function and serum total bile acid (TBA) were routinely screened in both early (9-13 weeks) and late pregnancy (32-36 weeks). Hypercholanemia was defined as serum TBA concentration ≥10 µmol/L. Multiple linear regression models and multiple logistic regression models were performed. Results: A higher free thyroxine (fT4) during both early or late pregnancy was associated with a higher TBA concentration and a higher risk of hypercholanemia (all p < 0.01). A higher thyrotropin (TSH) in early pregnancy was associated with a higher TBA concentration in early pregnancy (p = 0.0155), but with a lower TBA concentration during later pregnancy (p < 0.0001), and there was no association of TSH with hypercholanemia. Overt hyperthyroidism in late pregnancy was associated with a 2.12-fold higher risk of hypercholanemia ([confidence interval; CI 1.12-4.03], p = 0.021) and subclinical hyperthyroidism during later pregnancy was associated with a 1.5-fold higher risk of hypercholanemia ([CI 1.14-1.97], p = 0.0034). Sensitivity analyses indicated that a high fT4 throughout pregnancy was associated with a higher risk of hypercholanemia rather than only in early or late pregnancy. Conclusions: A higher fT4 concentration during either early or late pregnancy, but not the TSH concentration, is associated with higher TBA and a higher risk of gestational hypercholanemia. Furthermore, hyperthyroidism during pregnancy could be a novel risk factor for hypercholanemia.

Identification of a novel mutation in thyroxine-binding globulin (TBG) gene associated with TBG-deficiency and its effect on the thyroid function.

PURPOSE: This study presents a case of familial transmission of thyroxine-binding globulin (TBG) deficiency. The SERPINA7-gene which codes for TBG is located on the X-chromosome (Xq21-22). More than 45 mutations have been reported to cause TBG- deficiency from various countries, but none from India so far. Genetic analysis of SERPINA7 gene was carried out to determine the cause of low TBG levels in one family. METHODS: DNA samples of the propositus and the family members were subjected to Polymerase Chain Reaction (PCR) followed by direct sequencing. Allele-specific PCR and Next-gen sequencing (NGS) were employed to confirm the site of the mutation. Thyroid function tests were estimated by Radioimmunoassay (RIA) and Immunoradiometric assay (IRMA) kits. X-chromosomal inactivation status was analyzed in the female members harboring the mutation. RESULTS: A mutational screening in this family revealed a novel frame-shift mutation S353Q, 354fs3X in the exon 4 of the SERPINA7 gene which will be referred to as TBG-complete deficiency-India (TBG-CD-Ind). One out of four female family members harboring the mutation showed selective X-chromosomal inactivation. The affected family members were clinically euthyroid initially, showed changes in the thyroid function when tested after a long time span. However, the changes in the thyroid function in the affected family members had an autoimmune etiology. CONCLUSION: This study presents the first report of TBG-CD from India wherein a novel frameshift mutation referred to as TBG-CD-Ind (S353Q, 354fs3X) in the SERPINA7 gene was detected. No apparent association was identified between thyroid function and the TBG-mutation in the affected subjects. A detailed biochemical and genomic testing to determine the exact cause of discordant TFT in the patients would certainly aid in the unequivocal diagnosis of the thyroid function and for the precise individualized treatment.

Thyroid Status and Brain Circulation: The Rotterdam Study.

CONTEXT: Whether thyroid dysfunction is related to altered brain circulation in the general population remains unknown. OBJECTIVE: We determined the association of thyroid hormones with different markers of brain circulation within community-dwelling elderly people. METHODS: This was a population-based study of 3 subcohorts of the Rotterdam Study, starting in 1989, 2000, and 2006. A total of 5142 participants (mean age, 63.8 years; 55.4% women), underwent venipuncture to measure serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Between 2005 and 2015, all participants underwent phase-contrast brain magnetic resonance imaging to assess global brain perfusion (mL of blood flow/100 mL of brain/minute). Arteriolar retinal calibers were assessed using digitized images of stereoscopic fundus color transparencies in 3105 participants as markers of microcirculation. We investigated associations of TSH, FT4 with brain circulation measures using (non)linear regression models. RESULTS: FT4 (in pmol/L) levels had an inverse U-shaped association with global brain perfusion, such that high and low levels of FT4 were associated with lower global brain perfusion than middle levels of FT4. The difference in global brain perfusion between high FT4 levels (25 pmol/L) and middle FT4 levels (FT4 = 15 pmol/L; P nonlinearity = .002) was up to -2.44 mL (95% CI -4.31; -0.56). Higher and lower levels of FT4, compared with middle FT4 levels, were associated with arteriolar retinal vessels (mean difference up to -2.46 µm, 95% CI -4.98; 0.05 for lower FT4). CONCLUSION: These results suggest that thyroid dysfunction could lead to brain diseases such as stroke or dementia through suboptimal brain circulation that is potentially modifiable.

Thyroid function in the subacute phase of traumatic brain injury: a potential predictor of post-traumatic neurological and functional outcomes.

PURPOSE: That thyroid hormones exert pleiotropic effects and have a contributory role in triggering seizures in patients with traumatic brain injury (TBI) can be hypothesized. We aimed at investigating thyroid function tests as prognostic factors of the development of seizures and of functional outcome in TBI. METHODS: This retrospective study enrolled 243 adult patients with a diagnosis of mild-to-severe TBI, consecutively admitted to our rehabilitation unit for a 6-month neurorehabilitation program. Data on occurrence of seizures, brain imaging, injury characteristics, associated neurosurgical procedures, neurologic and functional assessments, and death during hospitalization were collected at baseline, during the workup and on discharge. Thyroid function tests (serum TSH, fT4, and fT3 levels) were performed upon admission to neurorehabilitation. RESULTS: Serum fT3 levels were positively associated with an increased risk of late post-traumatic seizures (LPTS) in post-TBI patients independent of age, sex and TBI severity (OR = 1.85, CI 95% 1.22-2.61, p < 0.01). Measured at admission, fT3 values higher than 2.76 pg/mL discriminated patients with late post-traumatic seizures from those without, with a sensitivity of 74.2% and a specificity of 60.9%. Independently from the presence of post-traumatic epilepsy and TBI severity, increasing TSH levels and decreasing fT3 levels were associated with worse neurological and functional outcome, as well as with higher risk of mortality within 6 months from the TBI event. CONCLUSIONS: Serum fT3 levels assessed in the subacute phase post-TBI are associated with neurological and functional outcome as well as with the risk of seizure occurrence. Further studies are needed to investigate the mechanisms underlying these associations.

Association of Phthalate Exposure with Thyroid Function and Thyroid Homeostasis Parameters in Type 2 Diabetes.

AIMS: Phthalates, which are recognized environmental endocrine-disrupting chemicals, are associated with thyroid hormone disruption. We aimed to evaluate the relationship of phthalate metabolites with thyroid function and thyroid homeostasis parameters in type 2 diabetes and to explore whether thyroid autoimmunity status and metformin, the most common antidiabetic drug, may influence such associations. METHODS: Concurrent urine and blood samples were collected from 639 participants with type 2 diabetes in the METAL (Environmental Pollutant Exposure and Metabolic Diseases in Shanghai) study. We measured urinary concentrations of thirteen phthalate metabolites along with serum levels of thyroid-stimulating hormone (TSH), total T4 and T3, free T4 (FT4) and T3 (FT3), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). Four parameters of thyroid homeostasis, including the sum activity of step-up deiodinases (SPINA-GD), thyroid secretory capacity (SPINA-GT), Jostel's TSH index (TSHI), and thyrotroph thyroid hormone resistance index (TTSI), were also calculated. RESULTS: Among all participants, after full adjustment, multivariable regression analysis showed that some urine phthalate metabolites were negatively associated with TSH, TSHI, and TTSI levels and positively associated with FT3, T3, SPINA-GD, and SPINA-GT levels. None of the urine phthalate metabolites exhibited a significant association with thyroid autoimmunity. The associations of phthalate metabolites with thyroid function and thyroid homeostasis parameters differed based on thyroid autoantibody and metformin treatment status. CONCLUSIONS: Urinary phthalate metabolites may be associated with thyroid function and thyroid homeostasis parameters among participants with type 2 diabetes. Furthermore, our present study suggested that thyroid autoantibody status and metformin treatment status are potential mediators of such associations.

Seasonal Changes of Thyroid Function Parameters in Women of Reproductive Age Between 2012 and 2018: A Retrospective, Observational, Single-Center Study.

Background: Thyroid function can be influenced by external stimuli such as light and temperature. However, it is currently unknown whether there is seasonal variation of thyroid function in women of reproductive age. Adequate thyroid function in reproductive-aged women is necessary for optimal fetal-maternal outcomes. Therefore, this study aims to evaluate the seasonal changes in levels of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and TSH index (TSHI) in women of reproductive age. Methods: A large retrospective study was conducted that included women aged 20-49 years who visited our outpatient or checkup center between 2012 and 2018. Thyroid function was measured using the automated immunochemiluminescent assay kit. Subjects with overt thyroid dysfunction, pregnancy, thyroid disease, cancer, and severe infectious or psychological disease were excluded. Seasonal differences of thyroid function were analyzed using the Kruskal-Wallis test or the analysis of means with transformed ranks. Spearman's correlation was performed to evaluate the association between thyroid function parameters and age. A subset of 181 subjects was included in the longitudinal analyses. Differences in thyroid function between summer and winter were analyzed using the Wilcoxon signed-rank test. Results: A total of 48,990 women with a median age of 39 years were included. The prevalence of subclinical hypothyroidism was lower in summer but higher in winter (5.6% vs. 7.0%, p < 0.05). The TSH, FT3, and FT4 levels and TSHI reached a peak in winter, while they declined to trough in summer. The TSH concentrations (r = 0.044, p < 0.001) and TSHI (r = 0.025, p < 0.001) were positively correlated with age, whereas FT3 (r = -0.073, p < 0.001) and FT4 (r = -0.059, p < 0.001) were negatively correlated with age. The associations of thyroid parameters with age were similar between subjects with positive thyroid peroxidase antibody (TPOAb) and those with negative TPOAb. In the matched longitudinal analysis of 181 subjects, no differences were detected in the thyroid parameters between summer and winter. Conclusions: This retrospective single-center study showed that thyroid hormone levels and central sensitivity to thyroid hormones are influenced by age and seasonal fluctuations among women of reproductive age, while their impact on reproductive health remains to be elucidated in future studies.

Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Common Pitfalls in the Interpretation of Endocrine Tests.

Endocrine tests are the cornerstone of diagnosing multiple diseases that primary care physicians are frequently faced with. Some of these tests can be affected by situations that affect the proper interpretation, leading to incorrect diagnoses and unnecessary treatment, such as the interference of biotin with thyroid function test, falsely elevated prolactin values in presence of macroprolactinemia or falsely normal due to the "hook effect" in macroprolactinomas. Recognizing these situations is essential for the clinician to make an adequate interpretation of these tests as well as an accurate diagnosis that guarantees the best outcomes for the patient.

Family history of thyroid disease and risk of congenital hypothyroidism in neonates with Down síndrome.

INTRODUCTION: Family history of thyroid disease (FHTD) constitutes a possible risk factor for congenital hypothyroidism (CH) in the general population; however, FHTD possible relationship with CH in subjects with Down syndrome (DS) has not yet been explored. OBJECTIVE: To determine whether FHTD is associated with an increased incidence of CH in neonates with DS. METHOD: Hospital-based case-control study in 220 neonates with DS. Thyroid function tests of 37 infants with DS and positive FHTD (cases) were compared with those of 183 newborns with DS without FHTD (control group). Data were analyzed using multivariate logistic regression analysis and adjusted odds ratios (aORs) with their respective 95 % confidence intervals (CI) were calculated. RESULTS: Nine newborns with DS in our sample had CH (4.1 %). In the multivariate analysis, FHTD showed an association with CH in neonates with DS (aOR = 8.3, 95 % CI: 2.0-34.3), particularly in males (aOR = 9.0, 95 % CI: 1.6-49.6). In contrast, newborns with DS without FHTD were less likely to suffer from CH (aOR = 0.4, 95 % CI: 0.1-0.8). CONCLUSIONS: Newborns with DS and FHTD have an eight-fold higher risk for CH, particularly when the index case is male. FHTD detailed evaluation can be an easy and accessible strategy to identify those newborns with DS at higher risk for CH.

INTRODUCCIÓN: La historia familiar de enfermedad tiroidea (HFET) como factor de riesgo para hipotiroidismo congénito (HC), en síndrome de Down (SD) aún no ha sido explorada. OBJETIVO: Determinar si la HFET está asociada a mayor riesgo de HC en neonatos con SD. MÉTODO: Estudio de casos y controles en 220 neonatos con SD. Se compararon las pruebas de función tiroidea (PFT) de 37 con SD e HFET (casos), frente a las PFT de 183 recién nacidos con SD sin HFET (grupo de referencia). Se realizó análisis de regresión logística multivariante y se calculó la razón de momios (RM) y sus respectivos intervalos de confianza del 95 % (IC 95 %). RESULTADOS: Nueve casos HC (4.1 %). El HC mostró asociación con la HFET (RMa = 8.3, IC 95 %: 2.0-34.3), particularmente en los varones (RMa = 9.0, IC 95 %: 1.6-49.6). La ausencia de HFET tuvo una RM de protección para HC (RMa = 0.4, IC 95 %: 0.1-0.8). CONCLUSIONES: La HFET puede es una estrategia fácil y accesible para identificar pacientes con SD con mayor riesgo de HC.

Historia familiar de enfermedad tiroidea y riesgo de hipotiroidismo congénito en neonatos con síndrome de Down / Family history of thyroid disease and risk of congenital hypothyroidism in neonates with Down syndrome

Resumen Introducción: La historia familiar de enfermedad tiroidea (HFET) como factor de riesgo para hipotiroidismo congénito (HC), en síndrome de Down (SD) aún no ha sido explorada. Objetivo: Determinar si la HFET está asociada a mayor riesgo de HC en neonatos con SD. Método: Estudio de casos y controles en 220 neonatos con SD. Se compararon las pruebas de función tiroidea (PFT) de 37 con SD e HFET (casos), frente a las PFT de 183 recién nacidos con SD sin HFET (grupo de referencia). Se realizó análisis de regresión logística multivariante y se calculó la razón de momios (RM) y sus respectivos intervalos de confianza del 95 % (IC 95 %). Resultados: Nueve casos HC (4.1 %). El HC mostró asociación con la HFET (RMa = 8.3, IC 95 %: 2.0-34.3), particularmente en los varones (RMa = 9.0, IC 95 %: 1.6-49.6). La ausencia de HFET tuvo una RM de protección para HC (RMa = 0.4, IC 95 %: 0.1-0.8). Conclusiones: La HFET puede es una estrategia fácil y accesible para identificar pacientes con SD con mayor riesgo de HC.

Abstract Introduction: Family history of thyroid disease (FHTD) as risk factor for congenital hypothyroidism (CH) in patients with Down syndrome (DS) has not yet been explored. Objective: To determine whether FHTD is associated with an increased risk for CH in DS. Method: Case-control study in 220 neonates with DS. Thyroid function tests of 37 infants with DS and FHTD (cases) were compared with those of 183 DS newborns without FHTD (reference group). Data were analyzed using multivariate logistic regression analysis and adjusted odds ratios (aORs) with their respective 95 % confidence intervals (CI) were calculated. Results: Nine newborns with DS in our sample had CH (4.1 %). FHTD showed an association with CH in neonates with DS (aOR = 8.3, 95 % CI: 2.0-34.3), particularly in males (aOR = 9.0, 95 % CI: 1.6-49.6). In contrast, newborns with DS without FHTD were less likely to suffer from CH (aOR = 0.4, 95 % CI: 0.1-0.8). Conclusions: FHTD detailed evaluation can be an easy and accessible strategy to identify those newborns with DS at higher risk for CH.

Hipotiroidismo consuntivo en paciente con hipotiroidismo primario previo / Consumptive hypothyroidism in patient with previous primary hypothyroidism

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Baseline serum TSH levels predict the absence of thyroid dysfunction in cancer patients treated with immunotherapy.

PURPOSE: Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the development of thyroid dysfunction during immunotherapy. METHODS: This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibitors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. RESULTS: Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibodies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). CONCLUSIONS: Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs.

Maternal thyroid profile in first and second trimester of pregnancy is correlated with gestational diabetes mellitus through machine learning.

There is evidence about a possible relationship between thyroid abnormalities and gestational diabetes mellitus (GDM). However, there is still no conclusive data on this dependence, since no strong correlation has been proved. In this work, we used machine learning to determine whether there is a correlation between maternal thyroid profile in first and second trimester of pregnancy and GDM. Using principal component analysis, it was possible to find an evident correlation between both, which could be used as a complement for a more sensitive GDM diagnosis.

Thyroid Laboratory Testing and Management in Women on Thyroid Replacement Before Pregnancy and Associated Pregnancy Outcomes.

Background: Women with hypothyroidism before pregnancy often require an increase in their levothyroxine dosage to maintain a euthyroid state during pregnancy. The objectives of this study were to investigate: (i) the frequency and distribution of thyrotropin (TSH) testing and levothyroxine dosage adjustment by gestational age, (ii) the magnitude of levothyroxine increase by the underlying etiology of hypothyroidism, and (iii) the relationship of overtreatment or undertreatment during pregnancy with adverse pregnancy outcomes among women using thyroid replacement before pregnancy. Methods: A retrospective cohort study of pregnancies in women on thyroid replacement before pregnancy in Alberta, Canada, was performed. Women using thyroid replacement anytime during the two years before pregnancy who delivered between October 2014 and September 2017 were included. Delivery records, physician billing, and laboratory and pharmacy administrative data were linked. Outcomes included characteristics of TSH testing, levothyroxine dosing, and pregnancy outcomes. The frequency and gestational timing of TSH testing and levothyroxine adjustments were calculated. Multiple logistic regression was used to test whether pregnancies with TSH <0.10 mIU/L (overtreatment) or TSH ≥10.00 mIU/L (undertreatment) compared with control pregnancies (TSH 0.10-4.00 mIU/L) were associated with adverse pregnancy and neonatal outcomes. Results: Of the 10,680 deliveries, 8774 (82.2%) underwent TSH testing at least once during pregnancy, at a median gestational age of six weeks. An adjustment of levothyroxine dosage was made for 4321 (43.7%) during pregnancy. TSH in pregnancy below 0.10 mIU/L increased the odds of preterm delivery when compared with control pregnancies (adjusted odds ratio, 2.14 [95% confidence interval 1.51-2.78]). TSH ≥10.00 mIU/L during pregnancy was not associated with any adverse pregnancy or neonatal outcomes in the multivariable analysis. Conclusions: Although most women on thyroid replacement before conception had TSH measured at some point during pregnancy, it is concerning that 17.8% did not. Levothyroxine overtreatment in pregnancy was associated with preterm delivery. These findings suggest that clinicians should be careful to avoid overtreatment with levothyroxine in pregnancy.

Universal screening for thyroid disease SHOULD NOT be recommended before and during pregnancy.

Thyroid dysfunction in pregnancy is strongly associated with adverse maternal and foetal outcomes. The effects of treatment are less clear. There is ongoing discussion on whom to treat, when to treat and whether treatment is beneficial. Although universal screening for thyroid disease during pregnancy increases diagnosis and treatment of thyroid dysfunction, there is currently insufficient evidence demonstrating a positive effect of screening on maternal and foetal outcomes. We therefore, at present, recommend against universal screening for thyroid disease before and during pregnancy.

Características epidemiológicas del hipotiroidismo en un área del sur de España (Sevilla) / Epidemiological characteristics of hypothyroidism in an área in southern Spain (Seville)

OBJETIVO: Determinar la incidencia y prevalencia del hipotiroidismo, estratificándolas por sexo y edad; así como el coste por dosis diaria definida (cDDD) de levotiroxina. DISEÑO: Estudio observacional, descriptivo, longitudinal y retrospectivo. EMPLAZAMIENTO: Área Sanitaria Aljarafe-Sevilla Norte. PARTICIPANTES: Pacientes de cualquier edad y sexo residentes en este Área Sanitaria, que tuvieran prescrita levotiroxina en los años 2015-2017 y al menos dos analíticas consecutivas para el control tiroideo entre 2014-2017. MEDICIONES PRINCIPALES: Se determinaron los valores de tirotropina, tiroxina y anticuerpos antiperoxidasa tiroidea facilitados por la Unidad de Laboratorio del Hospital San Juan de Dios. También los datos de prescripción de levotiroxina y su coste por dosis diaria definida, aportados por la Unidad de Farmacia del Distrito Sanitario Sevilla-Norte. Se consideró el coste del valor medio por dosis diaria definida de levotiroxina. RESULTADOS: Se analizaron 45.224 analíticas tiroideas. El 78,4 % pertenecían a mujeres. La edad media fue 49,04 (DE: 21,24) años. La prevalencia (2017) de hipotiroidismo fue del 5,54 % (IC 95 %: 5,45-5,62), la incidencia acumulada de hipotiroidismo clínico fue 2,67 casos/1.000 personas-año (IC 95 %: 2,67-2,68) y del subclínico 52,04 casos/1.000 personas-año (IC 95 %: 52,01-52,06). El coste medio anual asociado al consumo de levotiroxina fue de 153.081,13 € (DE:12.662,03) (IC 95 %:152.964,43-153.197,83). CONCLUSIONES: El presente estudio establece los primeros datos de incidencia acumulada de hipotiroidismo en un área de España y presenta una prevalencia mayor en comparación con la mayoría de estudios previos. Asimismo, muestra el coste por dosis diaria definida (cDDD) de levotiroxina, que tuvo una tendencia ascendente en el período 2015-2017

OBJECTIVE: To determine the incidence and prevalence of hypothyroidism, stratifying by sex and age, as well as the cost per defined daily dose (cDDD) of levothyroxine. DESIGN: Observational, descriptive, longitudinal, retrospective study. SETTING: Aljarafe-Sevilla Norte Health Area. PARTICIPANTS: Patients of any age and either sex living in this Health Area, who were treated with levothyroxine in 2015-2017 and who had at least two consecutive blood tests for thyroid control between 2014-2017. MAIN MEASURES: Levels of thyrotropin, thyroxine, and anti-thyroid peroxidase antibodies were determined, provided by the Laboratory Unit of the Hospital San Juan de Dios. Data on levothyroxine prescription and its cost per defined daily dose were also determined, provided by the Pharmacy Unit of the Distrito Sanitario Sevilla-Norte. We considered the cost of the mean value per defined daily dose of levothyroxine. RESULTS: 45,224 thyroid tests were analysed. 78.4% belonged to women. The average age was 49.04 (SD: 21.24). The prevalence (2017) of hypothyroidism was 5.54% (95% CI: 5.45-5.62), the cumulative incidence of clinical hypothyroidism was 2.67 cases/1000 persons-year (95% CI: 2.67-2.68) and of subclinical hypothyroidism was 52.04 cases/1000 persons-year (95% CI: 52.01-52.06). The annual average cost associated with levothyroxine use was 153,081.13 € (SD: 12,662.03) (95% CI: 152,964.43-153,197.83). CONCLUSIONS: This study establishes the first data on cumulative incidence of hypothyroidism in a Spanish area and presents a higher prevalence compared to most of the previous studies. Likewise, it shows a cost per defined daily dose (cDDD) of levothyroxine which followed an upward trend in the period 2015-2017

Reference Values of Thyroid Hormones During the First Trimester of Pregnancy in Valencian Community (Spain) and Their Relationship with Iodine Intake.

Thyroid hormones require special monitoring during the first trimester of gestation. Local reference values should be applied if available, especially in iodine-deficient areas, as generalized iodine supplementation is controversial. The aim of the present study was to establish thyroid stimulating hormone (TSH) and free thyroxine (FT4) reference values in the first trimester of gestation in the Valencian community (Spain) and relate them to iodine intake. A total of 261 healthy pregnant women participated in the study. The calculated reference values were 0.128-4.455 mIU/L for TSH and 0.9-1.592 ng/dL for FT4. The upper TSH reference value for pregnant women in the first trimester in our environment was similar to the latest American Thyroid Association (ATA) recommendation (4 mIU/L). The mean TSH value was significantly lower in smokers, and there were no significant differences when analyzing the influence of iodine supplementation, although the low duration of supplement intake needs to be taken into consideration. Ioduria levels (median 57 µg/L) confirmed iodine deficiency. We found statistically significant differences in ioduria levels among patients who consumed iodized salt and iodine supplements and those who did not. It is essential to focus on recommending adequate consumption of iodized salt and iodine supplements prior to gestation and at least during the first trimester to avoid possible maternal thyroid dysfunction and perinatal complications.

Thyroid Dysfunction is Prevalent in Autoimmune Hepatitis: A Case Control Study.

BACKGROUND: Autoimmune hepatitis (AIH) may be associated with other autoimmune diseases. Autoantibodies are common in AIH suggesting their potential role in the pathogenesis of the disease. Among these autoantibodies, thyroid autoantibodies have been reported in patients with chronic hepatitis, with greater prevalence in patients with chronic hepatitis C infection. OBJECTIVES: To assess the prevalence of thyroid dysfunction among patients with AIH. METHODS: In this case-control, retrospective study, we examined patients diagnosed with AIH according to both the original and revised international AIH group scoring systems. Patients with other hepatic pathologies were excluded AIH was evaluated as an independent risk factor for thyroid disease by a logistic regression model. Univariate and multivariate regression analyses were conducted using hypothyroidism and hyperthyroidism as the dependent variables. RESULTS: Our cohort comprised 163 patients diagnosed with AIH and 1104 healthy age- and gender-matched controls. Hypothyroidism was more prevalent among those with AIH compared to controls (17.7% vs. 5%, respectively, 95% confidence interval [95%CI] 1.68-2.48, P < 0.001). Hyperthyroidism was more prevalent in AIH patients compared to controls (odds ratio 3.2% and 1.2%, respectively, 95%CI 1.68-2.47, P < 0.001). Using a multivariate logistic analysis, we found an independent association between AIH and hypothyroidism but not with hyperthyroidism. CONCLUSIONS: Thyroid dysfunction is more prevalent in patients with AIH. Whether thyroid dysfunction is the cause or a risk factor for AIH, or vice versa, is still unclear. Screening for thyroid dysfunction is warranted after AIH is diagnosed.