Serum Free Thyroxine Concentrations Research Articles

Exposure to PM2.5 and its constituents in relation to thyroid function of pregnant women: Separate and mixture analyses

The relationships between exposure to PM2.5 and its constituents and thyroid hormone (TH) levels in pregnant women are still uncertain, particularly regarding the impact of mixed exposure to PM2.5 constituents on thyroid function during pregnancy. This study aimed to investigate the individual and mixed effect of PM2.5 and its constituents on TH levels during pregnancy. Fluorescence and chemiluminescence immunoassays were utilized to measure serum concentrations of free thyroxine (FT4) and thyroid-stimulating hormone (TSH) in pregnant women participating in the Fujian Birth Cohort Study (FJBCS). PM2.5 and its constituents were obtained from the ChinaHighAirPollutants dataset. Generalized linear regression model and mixture analysis were applied to explore the individual and mixed effect of PM2.5 and its constituents on TH levels. 13711 participants from the FJBCS were taken into the final analysis. In the context of separate exposure, an increase of one interquartile range (IQR) in PM2.5 exposure during the 1st trimester, 2nd trimester, and entire pregnancy was associated with a decrease of −0.042 (−0.050, −0.034), −0.017 (−0.026, −0.009), and −0.011 (−0.017, −0.004) in FT4 level, respectively. As well, significant negative associations were observed between FT4 level and PM2.5 constituents. Additionally, PM2.5 and its constituents were in relation to an increased risk of hypothyroxinemia in pregnant women. It is noteworthy that, in the context of mixed exposure, the weighted quantile sum regression (WQS) indices were significantly associated with both FT4 level (1st trimester: −0.031 (−0.036, −0.026); 2nd trimester: −0.026 (−0.030, −0.023); whole pregnancy: −0.024 (−0.028, −0.020)) and hypothyroxinemia risk (1st trimester: 1.552 (1.312, 1.821); 2nd trimester: 1.453 (1.194, 1.691); whole pregnancy: 1.402 (1.152, 1.713)). PM2.5 and its chemical constituents may affect thyroid function in pregnant women individually and in combination, with the effect observed during early gestational exposure being most pronounced.

Impact of Subclinical Hypothyroidism on Lipid Profile in Jeddah: A Retrospective Cohort Study.

Background Patients with subclinical hypothyroidism (SCH) have a high serum concentration of thyroid-stimulating hormone (TSH), whereas their serum-free thyroxine concentrations are normal. Lipid metabolism is regulated in large part by thyroid hormones. It could be connected to a changed lipid profile. This study aimed to evaluate the relationship between SCH and alterations in the lipid profile. Methodology Data from 99 patients with SCH and 109 euthyroid cases were collected from King Abdulaziz Medical City, Jeddah, Saudi Arabia, from 2016 to 2022. Patients older than 18 years were included in the study. The groups were matched in terms of gender, age, and body mass index. SCH was defined as a TSH value of 4.5 to 10 mIU/L, and normal T4 as 5 to 18 μg/dL. Control cases had a normal TSH ranging from 0.45 to 4.5 mIU/L. The total serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels in both groups were examined and the results were recorded. Results In comparison to the control group, SCH patients had greater median glycated hemoglobin (HbA1C) (p = 0.001) and lower median vitamin D levels (p = 0.004) before therapy. Before therapy, SCH patients also showed considerably lower HDL levels and significantly higher LDL and TG levels (p < 0.001). Conclusions There is a substantial correlation between SCH and reduced HDL and vitamin D levels. It was linked to increased TG, LDL, and HbA1c levels. Only vitamin D and LDL were pathologically high. Treatment with levothyroxine raised total and LDL cholesterol levels. Future research should look into the affordability of treating SCH.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

Chronic Excess Iodine Intake Inhibits Bone Reconstruction Leading to Osteoporosis in Rats

BackgroundAlthough iodine modulates bone metabolism in the treatment of thyroid disease, the effect of iodine intake on bone metabolism remains less known. ObjectiveThis study evaluated the effect of excess iodine intake in rats on bone reconstruction in the 6th and 12th month of intervention. MethodRats were treated with different doses of iodinated water: the normal group (NI, 6.15 μg/d), 5-fold high iodine group (5HI, 30.75 μg/d), 10-fold high iodine group (10HI, 61.5 μg/d), 50-fold high iodine group (50HI, 307.5 μg/d), and 100-fold high iodine group (100HI, 615 μg/d). Thyroid hormone concentrations were determined by a chemiluminescent immunoassay. Morphometry and microstructure of bone trabecula were observed by hematoxylin and eosin staining and microcomputed tomography, respectively. Alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) staining were performed to evaluate the activity of osteoblasts and osteoclasts, respectively. ResultsThe 24-h urine iodine concentration increased with iodine intake. The rats in the HI groups had higher serum thyroid-stimulating hormone and decreased serum free thyroxine concentrations in the 12th month than the NI group (all P < 0.05). The percentage of the trabecular bone area and osteoblast perimeter in the 100HI group were significantly lower than those in the NI group (P < 0.05). Increased structure model index was observed in the 50HI and 100HI groups compared with the NI group in the 6th month and increased trabecular separation in the 12th month (all P < 0.05). ALP and TRAP staining revealed osteoblastic bone formation was reduced, and the number of TRAP+ multinucleated cells decreased with increasing iodine intake. ConclusionsExcess iodine intake may increase the risk of hypothyroidism in rats. Chronic excess iodine intake can lead to abnormal changes in skeletal structure, resulting in reduced activity of osteoblasts and osteoclasts, which inhibits the process of bone reconstruction and may lead to osteoporosis.

A machine learning-assisted system to predict thyrotoxicosis using patients’ heart rate monitoring data: a retrospective cohort study

Previous studies have shown a correlation between resting heart rate (HR) measured by wearable devices and serum free thyroxine concentration in patients with thyroid dysfunction. We have developed a machine learning (ML)-assisted system that uses HR data collected from wearable devices to predict the occurrence of thyrotoxicosis in patients. HR monitoring data were collected using a wearable device for a period of 4 months in 175 patients with thyroid dysfunction. During this period, 3 or 4 thyroid function tests (TFTs) were performed on each patient at intervals of at least one month. The HR data collected during the 10 days prior to each TFT were paired with the corresponding TFT results, resulting in a total of 662 pairs of data. Our ML-assisted system predicted thyrotoxicosis of a patient at a given time point based on HR data and their HR-TFT data pair at another time point. Our ML-assisted system divided the 662 cases into either thyrotoxicosis and non-thyrotoxicosis and the performance was calculated based on the TFT results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of our system for predicting thyrotoxicosis were 86.14%, 85.92%, 52.41%, and 97.18%, respectively. When subclinical thyrotoxicosis was excluded from the analysis, the sensitivity, specificity, PPV, and NPV of our system for predicting thyrotoxicosis were 86.14%, 98.28%, 94.57%, and 95.32%, respectively. Our ML-assisted system used the change in mean, relative standard deviation, skewness, and kurtosis of HR while sleeping, and the Jensen–Shannon divergence of sleep HR and TFT distribution as major parameters for predicting thyrotoxicosis. Our ML-assisted system has demonstrated reasonably accurate predictions of thyrotoxicosis in patients with thyroid dysfunction, and the accuracy could be further improved by gathering more data. This predictive system has the potential to monitor the thyroid function status of patients with thyroid dysfunction by collecting heart rate data, and to determine the optimal timing for blood tests and treatment intervention.

The effect of metformin therapy on serum thyrotropin and free thyroxine concentrations in patients with type 2 diabetes: a meta-analysis

Type 2 diabetes and thyroid function disorders are two common chronic endocrine disorders with the high prevalence in various populations. Metformin is well established as the first-line drug therapy for managing diabetes mellitus. In this meta-analysis, we aimed to determine the effect of metformin on serum TSH and FT4 concentrations in patients with type 2 diabetes. We searched PubMed, Scopus, web of science, Cochrane library, and google scholar to collect information on the effect of metformin on serum TSH and FT4 levels. Demographic and clinical information and serum TSH and FT4 concentrations before and after metformin treatment were extracted. Studies on patients over 18 years of age were included. A total of 11 studies including 1147 patients were selected for the final analysis. In hypothyroid patients, the TSH level decreased significantly after treatment with metformin (Hedges’s g:1.55, 95%CI 0.93–2.16, p-value < 0.001); FT4 level increased slightly after taking metformin, but the increase was not significant (Heddges’s g: − 0.30, 95%CI − 0.90,0.31, p-value = 0.34). In euthyroid subjects, the slight decrease found in TSH and FT4 concentrations was not statistically significant. Metformin reduces TSH levels in hypothyroid patients; however, it has no effect on TSH levels in euthyroid patients. Metformin does not affect serum FT4 levels in euthyroid and hypothyroid patients.

Effects of the abdominal fat distribution on the relationship between exposure to air pollutants and thyroid hormones among Korean adult males

BackgroundSeveral significant associations between air pollution and thyroid function have been reported, but few studies have identified whether these associations differ by obesity, particularly its regional distribution. We assessed the relationship between ambient air pollution and thyroid hormone, and whether this relationship is modified by abdominal adiposity, as indicated by the waist circumference, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and visceral-to-subcutaneous fat ratio (VSR) in Korean men.MethodsWe included 2440 male adults in the final analysis and used each person’s annual average exposure to four air pollutants: particulate matter with an aerodynamic diameter ≤ 10 μm (PM10), nitrogen dioxide, sulfur dioxide (SO2), and carbon monoxide (CO). Abdominal fat deposition was quantified by computed tomography. Serum thyrotropin (TSH) and free thyroxine (FT4) concentrations were measured for thyroid hormone. To evaluate the relationship between air pollution and thyroid hormone according to adiposity, we performed multiple linear regression analysis on the two subgroups stratified by abdominal fat level.ResultsAbdominal adiposity was significantly related to FT4 concentration. The exposures to air pollutants were associated with increased TSH and decreased FT4 concentrations. In stratified analysis using abdominal fat traits, ambient air pollution except for SO2 was significantly related to increased TSH and decreased FT4 concentrations in the high adiposity group (all p < 0.05), but not in the normal adiposity group. Among the air pollutants, PM10 showed an association with an increase of TSH concentration in all group with high adiposity, including high VAT, high SAT, and high VSR groups (all p < 0.05). In case of FT4, CO showed a similar pattern. Among the abdominal fat-related traits, the VSR in the high adiposity group had the largest effect on the relationship between exposure to air pollutants and thyroid hormone.ConclusionsThis study suggests the first clue that the relationship between air pollution exposure and thyroid hormone differs according to abdominal fat distribution among Korean adult males.

Reference Intervals of Thyroid Hormones During Pregnancy Established by Three Statistical Methods.

Monitoring the thyroid hormones during pregnancy is of great importance for fetal growth and development. Throughout the whole pregnancy, there is constant fluctuation in the thyroid hormone reference intervals (RIs). The purpose of this study is to determine method- and trimester-specific RIs for thyroid-stimulating hormone, free thyroxine, and free triiodothyronine in pregnant women in China. In this study, 2,167 women with normal pregnancies (first trimester, n = 299; second trimester, n = 1,032; third trimester, n = 836) and 4,231 healthy nonpregnant women subjects were recruited. Serum thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) concentrations were measured using electrochemiluminescence immunoassays in Abbott Alinity i analyzer. Following the exclusion of outliers, the RIs were determined using three statistical techniques: the non-parametric method, the Hoffmann method, and the Q-Q plot method. Pregnant women's levels of these three thyroid hormones differ markedly from those of healthy non-pregnant women. In addition, the concentrations of these three hormones change considerably over the course of the three phases of pregnancy. The Q-Q plot method offered more comparable RIs with the non-parametric method in healthy non-pregnant women than the Hoffmann method. Three statistical techniques were used to construct the trimester-specific RIs of thyroid hormones in pregnant women, and there was little difference between them all. The RIs by the non-parametric and Q-Q plot methods indicated closer RIs, and the RIs by the Hoffmann approach were higher and wider than those by the other two methods. For thyroid hormones, trimester-specific RIs are required. The RIs determined by non-parametric and Q⁃Q plot indirect calculation could be used as the alternative method.

The relationship between thyroid dysfunction, cardiovascular morbidity and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase II

AimsIt is uncertain whether subclinical thyroid dysfunction is associated with cardiovascular disease (CVD) events and mortality in people with type 2 diabetes. The aim of this study was to determine whether undetected thyroid disease increases the risk of incident CVD and death in type 2 diabetes.MethodsOne thousand two hundred fifty participants with type 2 diabetes (mean age 65.3 years, 56.5% males, median diabetes duration 8.0 years) without known thyroid disease and not taking medications known to affect thyroid function were categorised, based on baseline serum free thyroxine (FT4) and thyrotropin (TSH) concentrations, as euthyroid, overt hypothyroid (increased TSH, low FT4), subclinical hypothyroid (increased TSH, normal FT4), overt thyrotoxic (decreased TSH, raised FT4) or subclinical thyrotoxic (decreased TSH, normal FT4). Incident myocardial infarction, incident stroke, all-cause and cardiovascular mortality were ascertained during a mean 6.2–6.7 years of follow-up.ResultsMost participants with newly-detected thyroid dysfunction had subclinical hypothyroidism (77.2%) while overt/subclinical thyrotoxicosis was infrequent. Compared to participants with TSH 0.34–2.9 mU/L, those with TSH > 5.1 mU/L were not at increased risk of incident myocardial infarction (adjusted hazard ratio (95% confidence limits) 1.77 (0.71, 2.87)), incident stroke (1.66 (0.58, 4.78)), all-cause mortality (0.78 (0.44, 1.37)) or cardiovascular mortality (1.16 (0.38, 3.58)). Independent baseline associates of subclinical hypothyroidism included estimated glomerular filtration rate and systolic blood pressure.ConclusionsSubclinical hypothyroidism was not independently associated with CVD events or mortality in community-dwelling people with type 2 diabetes despite its associations with CVD risk factors, questioning strategies to identify and/or treat mild thyroid dysfunction outside usual care.

Circulating free triiodothyronine concentration is positively associated with β-cell function in euthyroid patients with obesity and type 2 diabetes.

ObjectiveTo investigate the relationship between thyroid hormone concentrations and β-cell function in euthyroid patients with obesity and type 2 diabetes.MethodsWe performed a single-center cross-sectional study of 254 patients with type 2 diabetes mellitus aged ≥40 years. The participants were allocated to an obesity group or non-obesity group on the basis of their body mass index (BMI). Their β-cell function was assessed by measuring C-peptide concentration during a 75-g oral glucose tolerance test (OGTT); and their serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone concentrations were measured.ResultsThe serum FT3 concentration and the C-peptide concentrations at five time points of the OGTT were significantly higher in the obesity group than in the non-obesity group. FT3 was positively associated with the β-cell function of the obesity group, but not that of the non-obesity group, in multiple linear regression analysis, after adjustment for potential confounding factors. Serum FT3 concentration was also significantly associated with indices of obesity (BMI, waist circumference, body fat percentage, fat mass, fat mass/height 2 and visceral fat area).ConclusionsObesity-associated high serum FT3 concentrations might affect β-cell function in euthyroid patients with obesity and type 2 diabetes.

O-133 Association between normal-range paternal serum free thyroxine concentrations and outcomes of assisted reproductive technologies

Abstract Study question Are paternal serum free thyroxine (FT4) concentrations within the reference range associated with outcomes of assisted reproductive technologies (ART)? Summary answer Men of older reproductive age (≥ 35 years old) with low FT4 concentrations within the reference range are associated with a decreased live birth rate. What is known already The impact of maternal thyroid dysfunction on ART outcomes has been widely elucidated. However, few studies have investigated the impact of paternal thyroid dysfunction on ART outcomes. Our previous study showed a detrimental impact of paternal subclinical hypothyroidism (SCH) on the clinical outcomes of ART. Patients with SCH had relatively lower concentrations of FT4 compared to those with euthyroidism. Therefore, it remains to be determined whether the detrimental impacts of paternal SCH on ART outcomes arise from low concentrations of FT4. Study design, size, duration This retrospective cohort study included 4,066 couples who received 4,894 ART treatment cycles in our clinic between 1 April 2016 and 31 August 2021. Participants/materials, setting, methods The differences in sperm parameters and ART outcomes across the paternal FT4 tertiles were compared using generalised linear models or generalised estimation equation models. The primary outcomes were the clinical pregnancy rate (CPR) and live birth rate (LBR), and the secondary outcomes were sperm parameters, fertilisation rate, good-quality embryo rate, blastocyst formation rate, and implantation rate. Main results and the role of chance The mean ages of the males and their female partners were 33.0 and 31.0 years, respectively. No significant differences are observed in the sperm parameters and ART outcomes across the paternal FT4 tertiles in the overall population. However, stratified analysis of men aged ≥ 35 shows a non-significantly lower CPR in the lower paternal FT4 tertile (adjusted rate: 0.36, 95% CI: 0.27–0.45) relative to the middle (adjusted rate: 0.45, 95% CI: 0.38–0.53) and upper (adjusted rate: 0.43, 95% CI: 0.36–0.51) tertiles. The adjusted LBR is 0.21 (95% CI: 0.15–0.30) for men aged ≥ 35 in the lower FT4 tertile (p = 0.024, with reference to the upper tertile), 0.27 (95% CI: 0.21–0.35) for those in the middle tertile and 0.30 (95% CI: 0.23–0.38) for those in the upper tertile. No differences in these outcomes are seen among men aged &amp;lt; 35. The nonlinear smoothing curve obtained by using FT4 as a continuous variable further supports these findings. Limitations, reasons for caution Due to the retrospective design of the study, a causal relationship between paternal FT4 concentrations and ART outcomes could not be established. In addition, the study participants were patients who sought fertility treatment, which may have biased the results when we analysed the associations between FT4 concentrations and sperm parameters. Wider implications of the findings These results suggest that in older men, low paternal FT4 concentrations, although within the reference range, are associated with worse ART outcomes, especially LBR. Future prospective studies are warranted to confirm the detrimental effects of low paternal FT4 concentrations on ART outcomes. Trial registration number Not applicable

Normal-Range Paternal Serum-Free Thyroxine Concentrations and Outcomes of Assisted Reproductive Technologies

Background: A recent study showed that paternal subclinical hypothyroidism adversely affects the clinical outcomes of assisted reproductive technologies (ARTs). The aim of this study was to determine whether paternal serum-free thyroxine (fT4) concentrations within the reference range are associated with ART outcomes. Methods: This retrospective cohort study included 4066 couples who received 4894 ART treatment cycles in our clinic between April 1, 2016 and August 31, 2021. The differences in sperm parameters and ART outcomes across the paternal fT4 concentration tertiles were compared by using generalized linear models or generalized estimation equation models. The primary outcomes were clinical pregnancy rate (CPR) and live birth rate (LBR) per oocyte retrieval after the first embryo transfer cycle. Results: The mean ages of the males and their female partners were 32.8 (standard deviation, 5.0) and 30.7 (standard deviation, 4.1) years, respectively. No significant differences were observed in the sperm parameters or ART outcomes between the paternal fT4 concentration tertiles of the overall population. However, a stratified analysis of men aged ≥35 showed an adjusted CPR of 0.36 [confidence interval, CI: 0.27-0.45] for the lower paternal fT4 concentration tertile relative to the middle (adjusted rate: 0.45, CI: 0.38-0.53) and upper (adjusted rate: 0.43, CI: 0.36-0.51) tertiles (p for trend >0.05). The adjusted LBRs were 0.21 [CI: 0.15-0.30] for men aged ≥35 in the lower fT4 concentration tertile (p = 0.024, with reference to the upper tertile), 0.27 [CI: 0.21-0.35] for those in the middle tertile, and 0.30 [CI: 0.23-0.38] for those in the upper tertile. No differences in these outcomes were observed in men aged <35. The nonlinear smoothing curve obtained by using fT4 concentration as a continuous variable further supported these findings. Conclusions: Men of older reproductive age (≥35 years old) with low-normal fT4 concentrations within the reference range are associated with a decreased LBR. Future prospective studies are warranted to confirm the detrimental effects of low-normal paternal fT4 concentrations on ART outcomes.

Clinical utility of urinary levels of catecholamines and their fraction ratios related to heart rate and thyroid function.

Urinary catecholamines (CAs) have been examined for the screening of pheochromocytomas. The decision to perform screening is based on symptoms suggesting secondary hypertension or hyperactivities of the sympathetic nervous system. To elucidate the usefulness of urinary fractions and ratios of CAs, 79 patients in whom 24-h excretions of urinary CAs including adrenaline (AD), noradrenaline (NA) and dopamine (DA) had been examined from 2015 until 2020 were retrospectively analyzed. There were no significant differences in urinary CA levels between two age groups, gender groups and two BMI groups. Patients with histories of preexisting hypertension and diabetes showed significantly higher levels of urinary NA excretion, and the urinary ratio of NA/DA was also increased in the patients with a history of hypertension. Heart rate (HR) was significantly correlated with the urinary ratio of NA/DA. Serum free thyroxine (FT4) concentration and ratio of FT4/thyrotropin (TSH) were correlated with the level of urinary AD. The levels of TSH and FT4/TSH showed negative and positive correlations, respectively, with the urinary NA/DA ratio. Thus, increases of HR are related to the enhanced conversion of DA to NA and increased thyroid hormones are involved in the increase in urinary AD and the conversion of DA to NA. History of lifestyle-related diseases and changes of HR and thyroid functions need to be considered for the evaluation of urinary CAs and their ratios.

Cord Blood Thyroid Hormones and Neurodevelopment in 2-Year-Old Boys and Girls.

Objective: Thyroid hormones are essential for neurodevelopment in early life. However, the impact of mild alterations in neonatal thyroid hormones on infant neurodevelopment and its sex dimorphism is unclear. We aimed to assess whether mild variations in neonatal thyroid hormones of term-born newborns with maternal euthyroid are related to neurodevelopment in 2-year-old boys and girls.Methods: This study used data from 452 singleton term-born infants of mothers with normal thyroid function in Shanghai, China, and their follow-up measure at the age of 2 years. Cord serum concentrations of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and thyroid peroxidase antibody (TPOAb) were measured by chemiluminescent microparticle immunoassays and classified into three groups: the low (1st, Q1), middle (2nd−4th, Q2–Q4), and high (5th, Q5) quintiles. Neurodevelopment indices were assessed using the Ages and Stages Questionnaire, third edition (ASQ-3), at 24 months of age.Results: Compared to infants with thyroid hormones in the middle (Q2–Q4), boys with FT4 in the lowest quintile had 5.08 (95% CI: 1.37, 8.78) points lower scores in the communication domain, 3.25 (0.25,6.25) points lower scores in the fine motor domain, and 3.84 (0.04, 7.64) points lower scores in the personal-social domain, respectively. Boys with FT3 in the highest quintile had 4.46 (0.81, 8.11) points increase in the personal-social domain. These associations were not observed in girls. No associations were observed between cord blood serum TSH and ASQ-assessed neurodevelopment in the boys or the girls.Conclusions: Mild alterations in thyroid hormones of newborns were associated adversely with neurodevelopment in boys, suggesting the importance of optimal thyroid hormone status for neurodevelopment in early life.

Cardiotoxicity of Anti-PD-L1 Antibody and the Effect of Levothyroxine in Attenuating the Related Mortality in Mice

背景与目的免疫检查点抑制剂在肿瘤治疗中表现出了显著的疗效，但也可能会引起免疫相关的不良反应（immune-related adverse events, irAEs）。近来国际上报道了数百例免疫检查点抑制剂相关心肌炎，患者死亡率达50%。本研究目的是在动物水平重现临床情况，通过多次静脉注射抗程序性细胞死亡受体1（programmed cell death 1, PD-1）抗体、抗程序性细胞死亡受体配体1（programmed cell death ligand 1, PD-L1）抗体，观察药物对正常小鼠所产生的心脏毒性，并探讨L-甲状腺素的保护作用。方法通过尾静脉向6周龄-8周龄的C57BL/6小鼠分别注射抗PD-1抗体（剂量为12.5 μg/g，每5天注射1次，共6次）、抗PD-L1抗体（10 μg/g，每周注射1次，共6次）、抗PD-L1抗体（用法用量同上）联合L-甲状腺素（注射抗体前30 min腹腔注射，剂量为0.25 μg/g）或同型对照免疫球蛋白IgG（10 μg/g，每周1次，共6次）。通过超声心动图检测小鼠心脏射血功能；通过无创鼠尾动脉测压仪、小动物生命体征监护仪检测小鼠血压、心电特征与体温；通过酶联免疫标记法检测小鼠血清中游离甲状腺素浓度。结果小鼠心脏表达不同水平的PD-L1。12只接受同型对照免疫球蛋白、12只接受抗PD-1抗体的小鼠无一发生死亡。12只接受3次-6次抗PD-L1抗体注射的小鼠的心重胫骨比显著升高，心肌细胞出现变性、透明化及血管外炎症细胞浸润等改变。心脏超声及心电图检测结果显示，小鼠的心脏射血功能严重受损、心肌缺血。此外，小鼠注射抗PD-L1抗体后血压下降、体温异常降低，血清甲状腺素（tetraiodothyronine, T4）水平降至对照组的1/3。这些小鼠中有8只死亡，死亡率达66.7%。在注射抗PD-L1抗体前30 min经腹腔注射L-甲状腺素可明显降低小鼠死亡率。结论抗PD-1抗体不会引起小鼠心脏毒性及小鼠死亡。抗PD-L1抗体可引起心脏毒性导致小鼠死亡，而L-甲状腺素有明显的保护作用。

Early Follow-up of Atypical Thyroiditis Induced by SARS-CoV-2

Background: In Spring 2020 the severe acute respiratory syndrome coronavirus 2 pandemic disease (Covid-19) badly affected Northern Italy. We have described for the first time the occurrence of thyrotoxicosis due to atypical subacute thyroiditis in 15% of patients hospitalised for Covid-19 pneumonia, compared with only 1% among patients hospitalised in the same wards during Spring 2019, thus before the Covid-19 pandemic. The whole group of Covid-19 patients also had median serum TSH concentrations significantly lower compared with the control group. The atypical thyroiditis induced by Covid-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome. Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients. Methods: Longitudinal follow-up study of survived Covid-19 patients without previous known history of thyroid disorders and/or medications, assessing serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC) and thyroid ultrasound (US) every 3 months. Patients showing baseline (at hospitalisation for Covid-19) thyroid dysfunction and/or focal hypoechoic areas suggestive for subacute thyroiditis at US performed 3 months post-infection, also underwent thyroid 99mTc or I123uptake. Results: To date, 53 patients have been included in the follow-up study. At 3 months post-infection, all of them presented with increased median (IQR) serum TSH concentrations compared with baseline: 1.3 (0.9–2.0) mIU/L versus 0.9 (0.5–1.8) mIU/L (p=0.0001). Similarly, serum concentrations of free-thyroxine, free-triiodothyronine, CRP and FBC had normalised compared with baseline. All patients had negative autoantibodies to TSH receptor; autoantibodies to thyroglobulin and to thyroid peroxidase were positive in 6/53 (11%) and 5/53 (9%) of patients, respectively. The thyroid US showed the presence of focal hypoechoic areas of thyroiditis in 16/51 (32%) patients, with thyroid uptake normal in 6/16 (37%), focally reduced in 8/16 (50%) and diffusely reduced in 2/16 (12%). Conclusions: At 3 months after Covid-19 disease all patients had a normalised thyroid function, however imaging findings suggestive for subacute thyroiditis were still present in about one third of cases. The thyroid dysfunction induced by Covid-19 seems not mediated by autoimmunity. It is important to continue to follow these patients since they might develop thyroid dysfunction during the following months.

The effect of ketogenic diet on thyroid functions in children with drug-resistant epilepsy.

Ketogenic diet (KD) remains a valuable treatment option for children with drug-resistant epilepsy. However, it may cause many well-known adverse effects such as dyslipidemia or kidney stones. But, its effects on thyroid functions are largely unknown. The aim of this study was to investigate the effects of the KD on thyroid functions in children with drug-resistant epilepsy. A total of 66 children (35 females) aged 3-193 months (median, 52 months) with drug-resistant epilepsy who received a KD for at least 12 months were enrolled in the study. All children were started on KD with 3:1 ratio which was then adjusted as clinically necessary. Serum free-thyroxine (FT4) and thyroid stimulating hormone (TSH) concentrations were measured before starting treatment and at the first, sixth and twelfth months of treatment. Changes in FT4 and TSH concentrations over 12 months were analyzed. Median serum FT4 and TSH concentrations, and the frequencies of patients with low FT4 and high TSH concentrations did not change significantly in the study sample over the 12-month study period. Serum FT4 levels increased significantly and TSH concentrations decreased insignificantly in four patients receiving L-thyroxine replacement therapy. During the 12-month treatment period, BMI-SDS increased, and the number of antiepileptic drugs decreased significantly. It appears that KD therapy does not impair thyroid functions in children with drug-resistant epilepsy. KD can be used safely along with L-thyroxine replacement even in children with pre-existing subclinical hypothyroidism.

Characteristics and Risk Factors of Pulmonary Hypertension in Patients With Hyperthyroidism

ObjectiveThis study aimed to comprehensively assess the characteristics and risk factors of hyperthyroidism with pulmonary hypertension (PH). MethodsThis was a retrospective cross-sectional analysis of 315 consecutive patients with hyperthyroidism admitted to the endocrinology department of Tongji Hospital from February 2016 to December 2017. PH was defined as a pulmonary arterial systolic pressure above 35 mm Hg measured by echocardiography. ResultsAmong the 315 patients, 208 were females, the median age was 42 (30-51) years, and the median disease duration was 12 (3-48) months. Thirty-five percent (111/315) of patients were identified with PH. Patients with hyperthyroidism and PH showed significantly higher serum concentrations of free thyroxine (FT4), free triiodothyronine, thyroid receptor antibodies, total bilirubin (TB), direct and indirect bilirubin, lower serum levels of hemoglobin and creatinine, and more severe cardiac load (P < .05 for each) compared with patients without PH. Levels of serum FT4, free triiodothyronine, thyroid receptor antibodies, and thyroid peroxidase antibody were different among groups of patients with different levels of pulmonary arterial systolic pressure (P < .05 for each). Multivariate logistic regression analysis indicated that serum FT4 (odds ratio, 1.02; 95% CI, 1.01-1.04; P = .004) and TB (OR, 1.03; 95% CI, 1.00-1.06; P = .030) were independent risk factors for PH in patients with hyperthyroidism. ConclusionElevated serum FT4 and TB levels may be independent risk factors for PH in patients with hyperthyroidism and valuable indicators for the identification and treatment of patients with PH and hyperthyroidism.

Control of Graves\u2019 hyperthyroidism with very long-term methimazole treatment: a clinical trial

BackgroundLong-term antithyroid drug therapy has become one of the options for treatment of Graves’ hyperthyroidism. The aim of this study was to compare thyroid status in those who discontinued methimazole (MMI) treatment after 12.8 years with those who continued MMI as long as 24 years.MethodsFifty nine patients with Graves’ disease on long-term MMI for 14.2 ± 2.9 years were recruited; 32 patients (54%) decided to discontinue MMI and 27 (46%) preferred additional years of MMI treatment. All patients were followed for a mean of 6 additional years.ResultsOf 27 patients who continued MMI up to 24 years, suppressed serum thyrotropin (TSH) was not observed in any patient after the seventh year of treatment. Serum free thyroxine, triiodothyronine, TSH and TSH receptor antibody concentrations remained normal up to the length of the study. Mean daily dose of MMI to maintain TSH in the reference range decreased gradually and reached to 2.8 ± 1.7 mg by 24 years of MMI treatment. No adverse reaction related to MMI occured during additional years of therapy. In 32 patients who discontinued MMI, hyperthyroidism relapsed in 6 patients (19%), one left follow-up and 25 (78%) remained euthyroid during the study.ConclusionsLong-term low dose MMI treatment may be a lifelong effective and safe therapeutic modality in patients with Graves’ hyperthyroidism for prevention of relapse, if studies from other centers confirm findings of this research.Trial registrationIRCT201009224794N1, 2010-10-25. Retrospectively registered.https://www.irct.ir/trial/5143.

Thermal Treatment Options for Benign Thyroid Nodules—The Role of Radio-Frequency Ablation and Laser Therapy

Thermal Treatment Options for Benign Thyroid Nodules—The Role of Radio-Frequency Ablation and Laser Therapy