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Thyroid Function and the Risk of Fibrosis of the Liver, Heart, and Lung in Humans: A Systematic Review and Meta-Analysis.
Bano, A, Chaker, L, Muka, T, Mattace-Raso, FUS, Bally, L, Franco, OH, Peeters, RP, Razvi, S
Thyroid : official journal of the American Thyroid Association. 2020;(6):806-820
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Abstract
Background: Fibrotic diseases have an unclear etiology and poor prognosis. Fluctuations in thyroid function may play a role in the development of fibrosis, but evidence is fragmented and inconclusive. This systematic review and meta-analysis aimed to investigate the association of thyroid function with fibrotic diseases of the liver, heart, and lung in humans. Methods: We searched PubMed, Medline Ovid, Embase Ovid, and Web-of-Science for studies published from inception to 14 June 2019, to identify observational studies that investigated the association of thyroid function with fibrosis of the liver, heart, and lung in humans. Study quality was evaluated by the Newcastle-Ottawa Scale. The Mantel-Haenszel method was used to pool the odds ratios (ORs) of studies investigating the association of hypothyroidism with liver fibrosis. Results: Of the 2196 identified articles, 18 studies were included in the systematic review, of which 11 studies reported on liver fibrosis, 4 on myocardial fibrosis, and 3 on pulmonary fibrosis. The population sample size ranged from 36 to 7259 subjects, with median mean age 51 years (range, 36-69) and median percentage of women 53 (range, 17-100). The risk of bias of studies was low to moderate to high. Higher serum thyrotropin and lower thyroid hormone levels were generally associated with higher likelihood of fibrosis. Compared with euthyroidism, overt and subclinical hypothyroidism was associated with a higher likelihood of fibrosis in the liver (six of seven studies), heart (three of three studies), and lung (three of three studies). Based on the results of the seven studies included in the meta-analysis, overt and subclinical hypothyroidism was associated with an increased risk of liver fibrosis (pooled OR, 2.81; 95% confidence interval [CI], 1.74-4.53; heterogeneity, I2 31.4%; pooled OR, 2.12; CI, 1.45-3.12; heterogeneity, I2 0%; respectively), without evidence of publication bias. Conclusions: This study suggests that low thyroid function is associated with increased likelihood of chronic fibrotic diseases of the liver, heart, and lung. However, the evidence is mainly based on cross-sectional data. Prospective studies and randomized clinical trials are needed to investigate the potential efficacy of thyroid hormone and its analogs on the occurrence and progression of fibrosis.
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Maternal Thyroid Function in Early Pregnancy and Child Attention-Deficit Hyperactivity Disorder: An Individual-Participant Meta-Analysis.
Levie, D, Korevaar, TIM, Mulder, TA, Bath, SC, Dineva, M, Lopez-Espinosa, MJ, Basterrechea, M, Santa-Marina, L, Rebagliato, M, Sunyer, J, et al
Thyroid : official journal of the American Thyroid Association. 2019;(9):1316-1326
Abstract
Background: Thyroid hormone is essential for optimal fetal brain development. Evidence suggests that both low and high maternal thyroid hormone availability may have adverse effects on child neurodevelopmental outcomes, but the effect on behavioral problems remains unclear. We studied the association of maternal thyrotropin (TSH) and free thyroxine (fT4) concentrations during the first 18 weeks of pregnancy with child attention-deficit hyperactivity disorder (ADHD). Methods: A total of 7669 mother-child pairs with data on maternal thyroid function and child ADHD were selected from three prospective population-based birth cohorts: INfancia y Medio Ambiente (INMA; N = 1073, Spain), Generation R (N = 3812, The Netherlands), and Avon Longitudinal Study of Parents and Children (ALSPAC; N = 2784, United Kingdom). Exclusion criteria were multiple pregnancy, fertility treatment, usage of medication affecting the thyroid, and pre-existing thyroid disease. We used logistic regression models to study the association of maternal thyroid function with the primary outcome, ADHD, assessed via the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria by parents and/or teachers at a median child age of 4.5 to 7.6 years, and with the secondary outcome, an ADHD symptom score above the 90th percentile. Effect modification by gestational age and sex was tested with interaction terms and stratified analyses. Results: Overall, 233 (3%) children met the criteria for ADHD. When analyzed continuously, neither fT4 nor TSH was associated with a higher risk of ADHD (odds ratio [OR] 1.1, 95% confidence interval [CI 1.0-1.3], p = 0.060 and OR 0.9 [CI 0.9-1.1], p = 0.385, respectively) or with high symptom scores. When investigating effect modification by gestational age, a higher fT4 was associated with symptoms above the 90th percentile but only in the first trimester (for fT4 per 1 SD: OR 1.2 [CI 1.0-1.4], p = 0.027). However, these differential effects by gestational age were not consistent. No significant effect modification by sex was observed. Conclusions: We found no clear evidence of an association between maternal thyroid function and child ADHD.
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Thyroid Function and Dysfunction in Relation to 16 Cardiovascular Diseases.
Larsson, SC, Allara, E, Mason, AM, Michaëlsson, K, Burgess, S
Circulation. Genomic and precision medicine. 2019;(3):e002468
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BACKGROUND Subclinical thyroid dysfunction, defined as thyroid-stimulating hormone levels outside the reference range with normal free thyroxine levels in asymptomatic patients, is associated with alterations in cardiac hemodynamics. We used Mendelian randomization to assess the role of thyroid dysfunction for cardiovascular disease (CVD). METHODS Single-nucleotide polymorphisms associated with thyroid function were identified from a genome-wide association meta-analysis in up to 72 167 individuals. Data for genetic associations with CVD were obtained from meta-analyses of genome-wide association studies of atrial fibrillation (n=537 409 individuals), coronary artery disease (n=184 305 individuals), and ischemic stroke (n=438 847) as well as from the UK Biobank (n=367 703 individuals). RESULTS Genetically predicted thyroid-stimulating hormone levels and hyperthyroidism were statistically significantly associated with atrial fibrillation but no other CVDs at the Bonferroni-corrected level of significance ( P<7.8×10-4). The odds ratios of atrial fibrillation were 1.15 (95% CI, 1.11-1.19; P=2.4×10-14) per genetically predicted 1 SD decrease in thyroid-stimulating hormone levels and 1.05 (95% CI, 1.03-1.08; P=5.4×10-5) for genetic predisposition to hyperthyroidism. Genetically predicted free thyroxin levels were not statistically significantly associated with any CVD. CONCLUSIONS This Mendelian randomization study supports evidence for a causal association of decreased thyroid-stimulating hormone levels in the direction of a mild form of hyperthyroidism with an increased risk of atrial fibrillation but no other CVDs.
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Association Between Diethylhexyl Phthalate Exposure and Thyroid Function: A Meta-Analysis.
Kim, MJ, Moon, S, Oh, BC, Jung, D, Choi, K, Park, YJ
Thyroid : official journal of the American Thyroid Association. 2019;(2):183-192
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BACKGROUND Diethylhexyl phthalate (DEHP) is widely used in industrial products, particularly as plasticizers and softeners. Because it is used extensively, DEHP has been detected in humans worldwide. Although epidemiological studies suggest that DEHP can disrupt the function of the hypothalamic-pituitary-thyroid (HPT) axis, evidence on the association between DEHP exposure and thyroid function remains inconclusive. Therefore, a comprehensive meta-analysis was performed to investigate the association between DEHP exposure and the HPT axis in humans. METHODS A literature search of the MEDLINE, EMBASE, and Web of Science databases was conducted to search for studies in which the correlation coefficient values or regression coefficient values between three major DEHP metabolites (i.e., monoethylhexyl phthalate [MEHP], mono [2-ethyl-5-hydroxyhexyl] phthalate [MEHHP], and mono [2-ethyl-5-oxohexyl] phthalate) and thyrotropin, free thyroxine (T4), or total T4 were determined. The association between DEHPs and thyroid hormone levels were evaluated using Pearson's correlation coefficients. RESULTS Thirteen eligible articles were included. Urinary MEHP and MEHHP concentration was negatively correlated with total T4. Pooled correlation coefficients between MEHP/MEHHP and total T4 were -0.02 [confidence interval (CI) -0.05 to 0.00] and -0.03 [CI -0.05 to -0.01], respectively. Urinary mono (2-ethyl-5-oxohexyl) phthalate concentration was positively correlated with thyrotropin, and the pooled correlation coefficient was 0.02 [CI 0.00-0.04]. CONCLUSIONS The findings of this meta-analysis suggest a significant association between the exposure of DEHP metabolites and the function of the HPT axis.
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Thyroid Function in Early Pregnancy, Child IQ, and Autistic Traits: A Meta-Analysis of Individual Participant Data.
Levie, D, Korevaar, TIM, Bath, SC, Dalmau-Bueno, A, Murcia, M, Espada, M, Dineva, M, Ibarluzea, JM, Sunyer, J, Tiemeier, H, et al
The Journal of clinical endocrinology and metabolism. 2018;(8):2967-2979
Abstract
CONTEXT Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status. OBJECTIVE To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. DESIGN, SETTING, AND PARTICIPANTS Meta-analysis of individual participant data from 9036 mother-child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid-interfering medication usage, and known thyroid disease. MAIN OUTCOMES Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age. RESULTS FT4 <2.5th percentile was associated with a 3.9-point (95% CI, -5.7 to -2.2) lower nonverbal IQ and a 2.1-point (95% CI, -4.0 to -0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH. CONCLUSIONS Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay.
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A meta-analysis of the association of serum ischaemia-modified albumin levels with human hypothyroidism and hyperthyroidism.
Reddy, VS, Bukke, S, Mahato, K, Kumar, V, Reddy, NV, Munikumar, M, Vodelu, B
Bioscience reports. 2017;(1)
Abstract
Serum levels of ischaemia-modified albumin (IMA) have been studied as a novel and simple measure of oxidative stress (OXS) in different thyroid pathologies. However, results of available studies in the literature were not consistent. This meta-analysis was attempted to quantify the overall effect size for serum IMA levels in human hypothyroidism (HT) and hyperthyroidism (HYT) and to study its associations with the thyroid profile. Databases of PubMed/Medline, EMBASE, Google Scholar, Web of Science and Science Direct were searched for articles. Data on serum IMA levels in HT, HYT patients and euthyroid controls were extracted to compute standardized mean differences (SMD) by the random-effects model. The associations between IMA and thyroid profile were computed by the meta-analysis of correlation coefficients. IMA levels in HT patients (SMD=1.12; Z=2.76; P=0.006) and HYT patients (SMD=1.64; Z=2.57; P=0.01) were significantly higher than in euthyroid controls and the thyroid treatment showed a favourble effect on serum IMA levels. There were strong and significant correlations between IMA and hormonal status in HT and HYT groups. This meta-analysis showing increased IMA level in both HT and HYT patients and its association with thyroid profile suggests that serum IMA could be used as a simple measure of increased OXS in thyroid dysfunction.
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Accuracy of thyroid nodule sonography for the detection of thyroid cancer in children: systematic review and meta-analysis.
Al Nofal, A, Gionfriddo, MR, Javed, A, Haydour, Q, Brito, JP, Prokop, LJ, Pittock, ST, Murad, MH
Clinical endocrinology. 2016;(3):423-30
Abstract
INTRODUCTION Thyroid ultrasound (US) is a widely used tool for evaluating thyroid nodules. Various US features have been suggested as predictors of thyroid cancer in children. OBJECTIVE To conduct a systematic review and meta-analysis to assess the diagnostic accuracy of different thyroid US features in detecting thyroid cancer in children. METHODS We searched multiple online databases for cohort studies that enrolled paediatric patients with thyroid nodules (age <21 years) and evaluated the accuracy of 12 relevant ultrasound features. Diagnostic measures were pooled across studies using a random effects model. RESULTS The search strategy yielded 1199 citations, of which 12 studies met the predefined inclusion criteria (750 nodules). The prevalence of thyroid cancer was 27·2% (40·8% in patients with a history of radiation exposure and 23·2% in patients without a history of exposure to radiation). The most common cancer was papillary thyroid cancer (86·7%). The presence of internal calcifications and enlarged cervical lymph nodes were the US features with the highest likelihood ratio [4·46 (95% CI: 1·87-10·64) and 4·96 (95% CI: 2·01-12·24), respectively] for thyroid cancer. A cystic nodule was the feature with highest likelihood ratio for benign nodules [1·96 (95% CI: 0·87-4·43)]. CONCLUSION Thyroid US features are not highly accurate predictors of benign or malignant aetiology of thyroid nodules in children. Internal calcification may predict malignancy, and cystic appearance may suggest benign aetiology.
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Recombinant human thyrotropin before (131)I therapy in patients with nodular goitre: a meta-analysis of randomized controlled trials.
Lee, YY, Tam, KW, Lin, YM, Leu, WJ, Chang, JC, Hsiao, CL, Hsu, MT, Hsieh, AT
Clinical endocrinology. 2015;(5):702-10
Abstract
BACKGROUND Recombinant human thyrotropin (rhTSH) can be used to enhance radioiodine therapy for shrinking multinodular goitre. The aim of this meta-analysis was to compare the effectiveness of rhTSH pretreatment and radioiodine therapy with that of radioiodine alone for treating benign nodular goitre. METHODS The PubMed, EMBASE, Cochrane Library, Scopus and ClinicalTrials.gov databases were searched to identify studies published before September 2014. A meta-analysis was performed to calculate the pooled effect size using random-effects models. The primary outcome was the reduction in thyroid volume. Secondary outcomes included thyroid function, extent of tracheal compression, radioactive iodine uptake, incidence of hypothyroidism and other complications. RESULTS Nine RCTs including 416 patients were selected. The reductions in thyroid volume were significantly greater in the rhTSH pretreatment groups than those in the radioiodine alone groups at 12 months (weighted mean difference: 14·42%; 95% CI: 4·51-24·34% in high-dose rhTSH vs radioiodine alone; weighted mean difference: 19·66%; 95% CI: 3·67-35·65% in low-dose rhTSH vs radioiodine alone). The incidence of hypothyroidism in the high-dose rhTSH groups was significantly higher than that in the radioiodine alone groups. No significant difference in the incidence of hypothyroidism occurred between the low-dose rhTSH groups and the radioiodine alone groups. CONCLUSIONS The overall results indicated that using rhTSH before radioiodine therapy resulted in a greater thyroid volume reduction than radioiodine therapy alone. An increased incidence of hypothyroidism was observed in patients receiving high-dose rhTSH. Low-dose rhTSH before radioiodine therapy is more efficacious than radioiodine therapy alone for treating nontoxic benign thyroid nodules.
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Urinary thyroid hormone parameters test for evaluating the thyroid function during pregnancy.
Cai, J, Zhao, X, Lei, T, Meng, Q, Zhou, H, Zhang, M
Systems biology in reproductive medicine. 2014;(3):171-6
Abstract
It is necessary to regularly monitor thyroid function status during pregnancy. The repeated tests on serum thyroid hormones are invasive and can be uncomfortable. Sampling urine may provide an effective alternative. The primary aim of this study was to investigate if there is a correlation between the serum and urine levels of thyroid hormones during pregnancy. The secondary aim was to investigate their variation during pregnancy. This study collected the serum specimens of 30 healthy pregnant women at 9-12, 14-17, 23-26, and 37-40 weeks of gestation, respectively, simultaneously along with random urine specimens. This study compared the median levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) in serum and urine among four gestational stages. The differences were statistically significant (p < 0.05). There were positive correlations between serum FT3 (sFT3) and uFT3/uRBP (the ratio of urine FT3(uFT3) and urine retinol binding protein (uRBP)), r = 0.38 (I(2) = 0%, 95% CI: 0.21 ∼ 0.54), serum FT4 (sFT4) and uFT4/uRBP (the ratio of urine FT4 (uFT4) and uRBP), r = 0.29 (I(2) = 68.9%, 95% CI: 0.07 ∼ 0.51), and no correlation between serum TSH (sTSH) and uTSH/uRBP (the ratio of urine TSH (uTSH) and uRBP), r = 0.11 (I(2) = 86.7%, 95% CI: -0.24 ∼ 0.45). In conclusion, the levels of sFT3, sFT4, uFT3/uRBP, and uFT4/uRBP continued to decrease until the 27th week of gestation, when it was almost invariant. The levels of uFT3/uRBP and uFT4/uRBP correlated well with the sFT3 and sFT4 during pregnancy, which may provide a more convenient and secure way to monitor the maternal thyroid function status during pregnancy.
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Iodine intake and maternal thyroid function during pregnancy.
Rebagliato, M, Murcia, M, Espada, M, Alvarez-Pedrerol, M, Bolúmar, F, Vioque, J, Basterrechea, M, Blarduni, E, Ramón, R, Guxens, M, et al
Epidemiology (Cambridge, Mass.). 2010;(1):62-9
Abstract
BACKGROUND An adequate iodine intake during pregnancy is essential for the synthesis of maternal thyroid hormones and normal brain development in the fetus. Scant evidence is available on the effects and safety of iodine supplementation during pregnancy in areas with adequate or mildly deficient iodine intake. We examined the association of maternal iodine intake and supplementation with thyroid function before 24 weeks of gestation in population-based samples from 3 different areas in Spain. METHODS A cross-sectional study of 1844 pregnant women (gestational age range 8-23 weeks) was carried out in 3 areas in Spain (Guipúzcoa, Sabadell, Valencia), during the period 2004-2008. We measured levels of free thyroxine and thyroid-stimulating hormone (TSH) in serum, iodine in a spot urine sample, and questionnaire estimates of iodine intake from diet, iodized salt and supplements. Adjusted associations were assessed by multiple linear regression and logistic regression analyses. RESULTS There was an increased risk of TSH above 3 muU/mL in women who consumed 200 microg or more of iodine supplements daily compared with those who consumed less than 100 microg/day (adjusted odds ratio = 2.5 [95% confidence interval = 1.2 to 5.4]). We observed no association between urinary iodine and TSH levels. Pregnant women from the area with the highest median urinary iodine (168 microg/L) and highest supplement coverage (93%) showed the lowest values of serum free thyroxine. (geometric mean = 10.09 pmol/L [9.98 to 10.19]). CONCLUSIONS Iodine supplement intake in the first half of pregnancy may lead to maternal thyroid dysfunction in iodine-sufficient or mildly iodine-deficient populations.