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Introduction: Graves' disease (GD) is the most common cause of hyperthyroidism and can affect multiple systems of the body. Currently, commonly-used treatment methods for GD have a series of shortcomings. In contrast, traditional Chinese medicine has been proven to be effective in inhibiting the progression of GD and is expected to become a key direction for the development of new drugs in the future. Therefore, a network metaanalysis was performed to compare the impacts of different traditional Chinese medicines on the curative effect, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPOAb) and thyrotropin receptor antibody (TRAb) in patients with GD. Methods: PubMed, Embase, Cochrane Library, Web of Science, WanFang, Weipu, and CNKI were searched for the randomized controlled trials of traditional Chinese medicine on GD patients up to 19 December 2023. The quality of the included studies was evaluated regarding the risk of bias, and the data were analyzed by R software. Results: Thirty-five articles were included in the analysis, involving 2828 GD patients and traditional Chinese medicines including Bailing Capsule, Jinshuibao Capsule, Astragalus injection, Jiakangling Tablet, Jiakangling Capsule, Tripterygium Wilfordii, Sanjie Xiaoying Decoction, Prunella vulgaris (L.) Oral Liquid, P. vulgaris (L.) Granules, Xiehuo Xiaoying Recipe, Xiehuo Yangyin Powder, Yikang Pill and Yinjia Pellet. The results of network meta-analysis suggested that for GD patients, Bailing Capsule, Jiakangling Capsule, Tripterygium wilfordii, P. vulgaris (L.) Oral Liquid and Yinjia Pellet had better curative effect compared with Western medicine. Prunella vulgaris (L.) Granules and Yikang Pill could improve the TSH level. Prunella vulgaris (L.) Granules, P. vulgaris (L.) Oral Liquid and Yikang Pill could reduce FT3 level. Jiakangling Capsule, P. vulgaris (L.) Granules, P. vulgaris (L.) Oral Liquid and Yikang Pill could reduce the FT4 level. Prunella vulgaris (L.) Oral Liquid can reduce the level of TPOAb and TRAb. Besides, Yinjia Pellet was the most helpful in improving the curative effect. Yikang Pill could best improve TSH. Prunella vulgaris (L.) Granules had the best effect on reducing FT3. Prunella vulgaris (L.) Granules performed best in reducing FT4. Prunella vulgaris (L.) Oral Liquid had the most favorable effect on reducing TPOAb and TRAb. Conclusion: Based on the current research, it is safe to conclude that Chinese medicine can improve the curative effect and TSH level of patients with GD, and reduce the levels of FT3, FT4, TPOAb and TRAb. Besides, Yinjia Pellet is the most helpful in improving the curative effect. Yikang Pill can best improve TSH. Prunella vulgaris (L.) Granules have the best effect on reducing FT3. Prunella vulgaris (L.) Granules perform best in reducing FT4. Prunella vulgaris (L.) Oral Liquid has the most favorable effect on reducing TPOAb and TRAb. [ABSTRACT FROM AUTHOR]

Background: Thyroid cancer is the most common endocrine carcinoma, accounting for 3.26% of all cancers. The most histologically, well-differentiated thyroid cancer is papillary thyroid carcinoma (PTC). Although PTC is regarded as an indolent tumor, a portion of the cancer cells metastasize to lymph nodes around the thyroid gland. Lymph node metastasis (LNM) is a critical risk factor for tumor recurrence in PTC, which strongly affects disease prognosis and the quality of life. Methods: This study aims to examine how differences in the level of the thyroid profile and other risk factors may influence LNM incidence in patients with PTC in Taiwan. We carried out a single-center retrospective study. These PTC patients were retrospectively reviewed by the Department of Endocrinology from 2016 to 2019. A total of 165 patients were included in our research. Results: The findings revealed a close relationship with the level of free thyroxine (FT4), the level of the thyroid-stimulating hormone (TSH), and lymph node metastases. The correlation in terms of FT4 (p = 0.005) and TSH (p = 0.417) with LNM was found as a result of the univariate regression analysis. In the multiple regression analysis, the findings revealed a close relationship between LNM, FT4 (p < 0.001), and TSH (p = 0.008). Conclusions: Although the predictability of the TSH should be examined further, the association between LNM and FT4 or TSH should not be ignored. The results could help guide decision-making and patient counseling, using the level of serum FT4 or the TSH as a possible predictive factor of the LNM in PTC. [ABSTRACT FROM AUTHOR]

Abstract Background Understanding the relationship of thyroid hormones with the development of chronic kidney disease (CKD) has important clinical implications for managing patients with both thyroid and kidney dysfunction. In this review, our purpose was to provide a thorough comprehension of the interplay between thyroid hormones, thyroid dysfunctions, and CKD. Summary While there is evidence linking thyroid hormone levels to renal diseases, the association between thyroid hormones, specifically within the normal range, and the risk of CKD incidence is still a subject of debate. The Google Scholar, PubMed, Scopus, and Web of Science, were searched using the medical subject heading (MeSH) terms for the relevant keywords up to December 2023. Conclusion Based on the review, the development of CKD is more consistently associated with higher serum TSH and thereafter lower serum free T3 levels; however, its association with free T4 is more controversial. Furthermore, subclinical and overt hypothyroidisms were considerably associated with incident CKD. Hyperthyroidism and Hashimoto thyroiditis might increase the risk of CKD.

Abstract Background Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. Methods This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12–15.33, 15.34–18.67, and 18.68–22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration

Background: Understanding the relationship of thyroid hormones with the development of chronic kidney disease (CKD) has important clinical implications for managing patients with both thyroid and kidney dysfunction. In this review, our purpose was to provide a thorough comprehension of the interplay between thyroid hormones, thyroid dysfunctions, and CKD. Summary: While there is evidence linking thyroid hormone levels to renal diseases, the association between thyroid hormones, specifically within the normal range, and the risk of CKD incidence is still a subject of debate. The Google Scholar, PubMed, Scopus, and Web of Science, were searched using the medical subject heading (MeSH) terms for the relevant keywords up to December 2023. Conclusion: Based on the review, the development of CKD is more consistently associated with higher serum TSH and thereafter lower serum free T3 levels; however, its association with free T4 is more controversial. Furthermore, subclinical and overt hypothyroidisms were considerably associated with incident CKD. Hyperthyroidism and Hashimoto thyroiditis might increase the risk of CKD. [ABSTRACT FROM AUTHOR]

Background: Gestational hypothyroidism has been shown to be associated with adverse pregnancy outcomes as well as adverse outcomes for the child. Thyroid hormones concentrations change in gestation, especially within the first trimester, so the results of thyroid function test often are outside non-pregnant reference ranges. The objective of this study was to establish the first trimester reference ranges for thyroid stimulating hormone (TSH) and free thyroxine (FT4) for pregnant women in Barcelona (Spain). Methods: It was a prospective study in which 673 women were recruited during their first trimester of gestation (8–13 weeks). Serum TSH, FT4 and antithyroid peroxidase antibodies (TPOAb) were measured with Atellica® IM 1600 (Siemens Healthineers). After excluding 418 women, the reference ranges for TSH and FT4 were calculated by the 2.5th and 97.5th percentiles. Potential variables examined in this study were age, body mass index (BMI), ethnicity, iodine supplementation and smoking habit. Results: The reference ranges established on the Atellica® IM 1600 for the first trimester pregnancy in our population were 0.111 to 4.291 mIU/L for TSH and 11.45 to 17.76 pmol/L for FT4. No significant differences were found in thyroid hormones concentrations regarding maternal age (≤30 years vs >30 years) (p =.117), iodine supplementation (p =.683) and smoking habit (p =.363). The prevalence of TPOAb was estimated at 10.0%. Conclusions: We found that in our local population, the optimal TSH upper reference limit in the first trimester of gestation was 4.3 mIU/L, similar to that proposed by de ATA-2017 guideline (4.0 mIU/L). [ABSTRACT FROM AUTHOR]

Background: Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. Methods: This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12–15.33, 15.34–18.67, and 18.68–22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL. Results: The average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007). Conclusion: Low-normal fT4 concentrations are associated with lower ovarian reserve in infertile women. [ABSTRACT FROM AUTHOR]

Transient hyperthyrotropinemia/transient hypothyroxinaemia and congenital hypothyroidism (CH) have completely different treatment and clinical outcomes. However, a powerful, highly sensitive and cost-effective marker for the differentiation of these clinical entities in the early postnatal period is not available. Therefore, we aimed to test the potential, early predictive, diagnostic power of the thyroid-stimulating hormone (TSH)/free thyroxine (fT4) ratio for differentiation of the two clinical entities in the early period of life. TSH and fT4 levels were recorded on the postnatal day 7 of premature infants<32 weeks of gestational age. TSH/fT4 ratio was calculated. The significance degree of TSH/fT4 ratio was analyzed for the differentiation of transient hyperthyrotropinemia or transient hypothyroxinaemia and CH. The study included 1,204 preterm infants<32 weeks of gestational age. Of the 1,204 infants, 978 (81.2 %) had normal thyroid function. Eighty-eight infants (7.3 %) were diagnosed with CH and 138 (11.5 %) with transient hyperthyrotropinemia or transient hypothyroxinemia. Initial TSH/fT4 ratio>4.8 was found to be an early diagnostic warning sign with high power in favor of transient hyperthyrotropinemia or transient hypothyroxinemia (AUC value: 0.947) and TSH/fT4 ratio>12.5 (AUC value: 0.999) was found to be an early diagnostic warning sign with high power in favor of CH (p=0.0001). We found for the first time that the TSH/fT4 ratio can be used for the early differentiation of transient hyperthyrotropinemia/transient hypothyroxinaemia and CH in preterm infants without additional cost and with high power. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The primary aim of this study is to discern the association between specific clinical parameters and low muscle mass (LMM). We endeavor to elucidate the determinants of LMM and the predictive potency of individual factors. Methods: In this retrospective cross-sectional study, we encompassed 450 older adult Chinese participants (252 males and 198 females). Muscle mass quantifications were performed using bioelectrical impedance analysis. Comprehensive data encompassing demographic details (age, sex, height, and weight) and laboratory results (complete blood count, thyroid function, liver function, and renal function) were systematically recorded. Logistic regression models, coupled with receiver operating characteristic curve analytics, were employed to ascertain the variables influencing LMM and to evaluate the predictive validity of each parameter on LMM. Results: Upon confounding adjustment for age, gender, body mass index (BMI), and free thyroxine (FT4) persisted as a determinant of LMM. Specifically, individuals with an FT4 exceeding 1.105 ng/dL exhibited a 1.803-fold increased propensity for LMM relative to those with FT4 values below the specified threshold. Incorporating age, gender, BMI, and FT4 in the diagnostic algorithm enhanced the precision of LMM. The results differ between men and women. In the male population, we can still observe that FT4 has a certain value in the diagnosis of LMM, but this phenomenon is not found in the female population. Conclusions: Elevated FT4 concentrations, albeit within clinically accepted limits, are inversely associated with muscle mass. As such, FT4 could be postulated as a potential biomarker for LMM in geriatric individuals, especially in the male group.

Background: Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC. Methods: Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis. Results: The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC). Conclusion: The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process. [ABSTRACT FROM AUTHOR]

Background: Multiple evidence suggests that thyroid function is associated with polycystic ovary syndrome (PCOS), but whether thyroid function is causally related to PCOS is unclear. To investigate whether the association reflect causality, a Mendelian randomization (MR) analysis was conducted. Methods: Single nucleotide polymorphisms (SNPs) involved in this study were acquired from The ThyroidOmics Consortium and the IEU Open Genome-wide association study (GWAS) database, respectively. In forward MR analysis, we included normal free thyroxine (FT4, n=49,269), normal thyroid-stimulating hormone (TSH, n=54,288), hypothyroidism (n=53,423) and hyperthyroidism (n=51,823) as exposure. The outcome was defined as PCOS in a sample size of 16,380,318 individuals. The exposure in the reverse MR analyses was chosen as PCOS, while the outcome consisted of the four phenotypes of thyroid function. The inverse-variance weighted (IVW) method was performed as the major analysis, supplemented by sensitivity analyses. Results: The occurrence of PCOS was associated with increased risk of hyperthyroidism (IVW, OR=1.08, 95%CI=1.02-1.13, P=0.004). No evidence suggested that other phenotypes of thyroid function were related to PCOS. Conclusions: Our findings demonstrate a cause-and-effect connection between PCOS and hyperthyroidism. The study established foundation for further investigation for interaction between thyroid function and PCOS. [ABSTRACT FROM AUTHOR]

Background The remote performance of thyroid function blood tests is complicated because it requires blood collection. Objective To compare TSH and free thyroxine (FT4) levels between capillary and venous blood and assess the adequacy of measuring each value in capillary blood. Methods This prospective intervention study was conducted at Ito Hospital and was based on the clinical research method. The participants were 5 healthy female volunteers and 50 patients (41 females and 9 males) between the ages of 23 and 81 years. To measure TSH and FT4 levels in capillary and venous blood, a digital immunoassay (d-IA) method capable of measuring trace samples was used. Chemiluminescence measurements were used as controls. Values obtained for each assay system were compared using Spearman's correlation analysis. Capillary blood was collected using an autologous device (TAP II; not approved in Japan). Results Capillary plasma volume obtained using TAP II was 125 µL or more in 26 cases, 25 µL to 124 µL in 24 cases, and less than 25 µL in 5 cases. Strong correlations were noted in the TSH and FT4 levels between capillary and venous blood, with correlation coefficients of rs = 0.99 and rs = 0.97, respectively. Conclusion Capillary TSH and FT4 levels strongly correlate with venous blood values. Trace samples can be used in high-precision d-IA methods. These results may promote telemedicine in assessing thyroid function. [ABSTRACT FROM AUTHOR]

Objective: Prevalence of subclinical thyroid disease increases with age, but optimal detection and surveillance strategies remain unclear particularly for older men. We aimed to assess thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations and their longitudinal changes, to determine the prevalence and incidence of subclinical thyroid dysfunction in older men. Design, Participants and Measurements: Longitudinal study of 994 community‐dwelling men aged ≥70 years without known or current thyroid disease, with TSH and FT4 concentrations assessed at baseline and follow‐up (after 8.7 ± 0.9 years). Factors associated with incident subclinical thyroid dysfunction were examined by logistic regression and receiver operating characteristic analyses. Results: At baseline, 85 men (8.6%) had subclinical hypothyroidism and 10 (1.0%) subclinical hyperthyroidism. Among 899 men euthyroid at baseline (mean age 75.0 ± 3.0 years), 713 (79.3%) remained euthyroid, 180 (20.0%) developed subclinical/overt hypothyroidism, and 6 (0.7%) subclinical/overt hyperthyroidism. Change in TSH correlated with baseline TSH (r =.16, p <.05). Change in FT4 correlated inversely with baseline FT4 (r = −0.35, p <.05). Only higher age and baseline TSH predicted progression from euthyroid to subclinical/overt hypothyroidism (fully‐adjusted odds ratio [OR] per year=1.09, 95% confidence interval [CI] = 1.02‐1.17, p =.006; per 2.7‐fold increase in TSH OR = 65.4, CI = 31.9‐134, p <.001). Baseline TSH concentration ≥2.34 mIU/L had 76% sensitivity and 77% specificity for predicting development of subclinical/overt hypothyroidism. Conclusions: In older men TSH concentration increased over time, while FT4 concentration showed little change. Subclinical or overt hypothyroidism evolved in one fifth of initially euthyroid men, age and higher baseline TSH predicted this outcome. Increased surveillance for thyroid dysfunction may be justified in older men, especially those with high‐normal TSH. [ABSTRACT FROM AUTHOR]

Context Previous studies on the relationship between thyroid gland function and the development of gestational diabetes mellitus (GDM) have reported different results, leading to the need for a cohort study design with a large sample size. Objective We aimed to investigate the relationship between thyroid function in early pregnancy and GDM. Methods This was a prospective cohort study based on the China Birth Cohort Study (CBCS), from February 2018 to December 2020. The study took place at a tertiary maternal and child health hospital. A total of 36 256 pregnant women were successfully recruited based on the CBCS. The main outcome measure was GDM. Results This study consisted of 26 742 pregnant women who met the inclusion criteria, of whom 3985 (14.90%) were diagnosed with GDM, and the women with GDM were older than their healthy counterparts (33.26 ± 4.01 vs 31.51 ± 3.76 years, P <.001). After removing potential influencing variables, we found that increased thyroid-stimulating hormone (TSH) (adjusted odds ratio [aOR] 1.030, 95% CI 1.007, 1.054, P =.012) and subclinical hypothyroidism (aOR 1.211, 95% CI 1.010, 1.451, P =.039), but not free thyroxine or thyroid peroxidase antibody, were associated with the occurrence of GDM. Further analysis indicated a nonlinear relationship between TSH and GDM (P <.05): when TSH ≤ 1.24 mIU/L, the occurrence of GDM was elevated with increasing TSH, but when TSH > 1.24 mIU/L, this trend was not obvious. Conclusion High TSH might be associated with increased risk of GDM. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (β = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (β = −0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required. [ABSTRACT FROM AUTHOR]

Introduction: The accurate diagnosis of thyroid disease relies on the sensitivity and specificity of laboratory tests, which require specific reference intervals. Thyroid hormone levels can be influenced by factors such as age, gender, iodine intake and geographical region. Therefore, it is recommended for clinical laboratories to establish their own reference intervals. Aim: To establish reference intervals for Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Anti-thyroglobulin antibody (anti-TG), and Anti-Thyroid Peroxidase Antibody (antiTPO) in males and and females. Materials and Methods: A cross-sectional study was conducted in the Department of Biochemistry, Amrita Institute of Medical Sciences (AIMS), Kochi, India, from December 2021 to July 2022. The study included 217 apparently healthy subjects aged between 18 years and 60 years. TSH, FT4, anti-TPO, and anti-TG levels were analysed to establish reference values for males and females in the two age groups: 18-40 years and 41-60 years. Reference intervals for thyroid parameters were expressed as mean±Standard Deviation (SD), median, 2.5th and 97.5th percentiles. The Mann-Whitney U test was used to assess the statistical significance of thyroid parameters between gender and age groups. Results: The mean age in the female population was 38.24±11.64 years, while in the male population, it was 39.24±10.98 years. The reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO in females were determined as 0.80-4.12 μIU/mL, 0.99- 1.57 ngm/mL,

Purpose Congenital hypothyroidism (CH) is diagnosed with neonatal screening and is treated early in the neonatal period. Among these patients, transient CH (TCH) is included and requires re-evaluation. The purpose of this study was to find the best way to discontinue levothyroxine and to find trends in thyroid function tests (TFTs) after re-evaluation. Methods We retrospectively reviewed 388 patients diagnosed with CH. They were classified as permanent CH (PCH) and TCH. The total number of the PCH and TCH groups was 83 (51 boys and 32 girls). We compared clinical parameters to predict TCH and to identify the trends of TFT. Results The first thyroid-stimulating hormone (TSH) value after discontinuation and the average TSH value for 1, 2, and 3 years were all significantly higher in the PCH group (P

Objective To investigate the correlation between subclinical thyroid dysfunction and diabetic kidney disease （DKD） in the patients with type 2 diabetes mellitus （T2DM）. Methods A retrospective analysis was performed on 276 T2DM patients treated in Jilin Province FAW General Hospital from January 2019 to March 2021, including 154 patients with DKD and 122 patients without DKD （control group）. The body mass index （BMI）, glycated hemoglobin （HbA1c）, serum total thyroxine （TT4）, total triiodothyronine （TT3）, free triiodothyronine （FT3）, free thyroxine （FT4） and thyroid-stimulating hormone （TSH） were measured and detected for all patients. The patients were further divided into normal thyroid function group （n=188）, subclinical hypothyroidism （SCHypo） group （n=63） and subclinical hyperthyroidism （SCHyper） group （n=25） according to thyroid function. The influencing factors of DKD was analyzed by multivariate logistic regression. Results Compared with non DKD patients, DKD patients had a longer course of disease and higher levels of BMI, fasting blood glucose, Cystatin C, serum uric acid, triglyceride, and TSH (P＜0.05). The incidence of DKD was 54.3% (102 cases) in the normal thyroid function group and 69.8% (44 cases) in the SCHypo group, the difference had statistical significance (χ2=4.711，P=0.038), in the SCHyper group, 32.0% (8 cases) showed a significant decrease compared to the normal thyroid function group (χ2=4.376，P=0.036). The logistic regression analysis showed that TSH(OR=0.908, 95%CI:0.838-0.985, P＜0.05) and SCHypo（OR=1.060, 95%CI:1.020-1.101, P＜0.05） were independent factors of DKD. Conclusion TSH level and SCHypo may be independent influencing factors of DKD in T2DM patients.

Background: Thyroid cancer is the most common endocrine carcinoma, accounting for 3.26% of all cancers. The most histologically, well-differentiated thyroid cancer is papillary thyroid carcinoma (PTC). Although PTC is regarded as an indolent tumor, a portion of the cancer cells metastasize to lymph nodes around the thyroid gland. Lymph node metastasis (LNM) is a critical risk factor for tumor recurrence in PTC, which strongly affects disease prognosis and the quality of life. Methods: This study aims to examine how differences in the level of the thyroid profile and other risk factors may influence LNM incidence in patients with PTC in Taiwan. We carried out a single-center retrospective study. These PTC patients were retrospectively reviewed by the Department of Endocrinology from 2016 to 2019. A total of 165 patients were included in our research. Results: The findings revealed a close relationship with the level of free thyroxine (FT4), the level of the thyroid-stimulating hormone (TSH), and lymph node metastases. The correlation in terms of FT4 (p = 0.005) and TSH (p = 0.417) with LNM was found as a result of the univariate regression analysis. In the multiple regression analysis, the findings revealed a close relationship between LNM, FT4 (p < 0.001), and TSH (p = 0.008). Conclusions: Although the predictability of the TSH should be examined further, the association between LNM and FT4 or TSH should not be ignored. The results could help guide decision-making and patient counseling, using the level of serum FT4 or the TSH as a possible predictive factor of the LNM in PTC.

Background: Triglyceride-glucose (TyG) index is an effective indicator in indentifying in pre-diabetes, diabetes, and coronary artery disease (CAD). However, the value of TyG index combined with thyroid hormones (THs) to affect CAD has not been fully evaluated. Here, we investigated the association between TyG index and THs and further studied the impacts of TyG index and THs on CAD in euthyroid. Methods: Subjects (1,297) with euthyroid who underwent selective coronary angiography (CAG) were enrolled in the present study, including 893 patients with CAD and 404 controls. The association between TyG index and THs were analyzed by linear regression models. Multivariate logistic regression analysis was used to evaluate the interaction of TyG and THs with the risk of CAD. According to the cutoff value of free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and TyG index, the patients were respectively separated into four groups: low TyG/FT3 (low or high), high TyG/FT3 (low or high), low TyG/FT4 (low or high), high TyG/FT4 (low or high), low TyG/TSH (low or high), high TyG/TSH (low or high). Results: The baseline analysis showed that FT4 level differs among the three groups according to the tertile of the TyG index. Multiple linear regression analysis revealed decreased serum FT3 level and serum FT4 level as an independent risk factor for elevated TyG index. After adjusting for confounding variables, multiple logistic regression analysis showed that patients with lower TyG index and higher FT3 level had an important protective effect on CAD when considering patients with lower TyG index and FT3 level as reference(OR = 0.536, 95% CI: 0.369-0.778, P = 0.001). Patients with higher TyG index and FT4 level (lower or higher) had a significantly increased risk of CAD (OR 1.656, 95% CI: 1.117-2.455; OR = 1.920, 95% CI: 1.279-2.848, respectively). The area under the curve for the combined diagnosis of CAD by TyG index and FT3 level is 0.615. Conclusions: These findings suggest that TyG is independently negatively correlated with FT3 or FT4 in euthyroid. In addition, there was a significant interaction between TyG index and THs on the risk of CAD. [ABSTRACT FROM AUTHOR]

Introduction: The accurate diagnosis of thyroid disease relies on the sensitivity and specificity of laboratory tests, which require specific reference intervals. Thyroid hormone levels can be influenced by factors such as age, gender, iodine intake and geographical region. Therefore, it is recommended for clinical laboratories to establish their own reference intervals. Aim: To establish reference intervals for Thyroid Stimulating Hormone (TSH), Free Thyroxine (FT4), Anti-thyroglobulin antibody (anti-TG), and Anti-Thyroid Peroxidase Antibody (anti-TPO) in males and and females. Materials and Methods: A cross-sectional study was conducted in the Department of Biochemistry, Amrita Institute of Medical Sciences (AIMS), Kochi, India, from December 2021 to July 2022. The study included 217 apparently healthy subjects aged between 18 years and 60 years. TSH, FT4, anti-TPO, and anti-TG levels were analysed to establish reference values for males and females in the two age groups: 18-40 years and 41-60 years. Reference intervals for thyroid parameters were expressed as mean±Standard Deviation (SD), median, 2.5th and 97.5th percentiles. The Mann-Whitney U test was used to assess the statistical significance of thyroid parameters between gender and age groups. Results: The mean age in the female population was 38.24±11.64 years, while in the male population, it was 39.24±10.98 years. The reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO in females were determined as 0.80-4.12 μIU/mL, 0.99-1.57 ngm/mL, <85.33 IU/mL and <45.13 IU/mL, respectively. In males, the reference intervals and cut-offs for TSH, FT4, anti-TG and anti-TPO were determined as 0.51-5.09 μIU/mL, 1.03-1.79 ng/mL, <87.09 IU/mL and <33.88 IU/mL, respectively. There was a significant difference in anti-TPO (p-value=0.017) in males between the two age groups. A significant difference was also observed in FT4 (p-value=0.010) and anti-TPO (p-value=0.034) between males and females. Conclusion: The study successfully established reference intervals and cut-off values for TSH, FT4, anti-TG, and anti-TPO. It was found that anti-TPO levels decrease significantly with age progression. Additionally, the reference interval for TSH was wider in the 41-60 years age group compared to the younger age group. [ABSTRACT FROM AUTHOR]

Background: Observational studies have indicated a potential association between thyroid dysfunction and the risk of sudden sensorineural hearing loss (SSNHL). However, the precise causal relationship between the two remains uncertain. The objective of our study was to assess the causal influence of thyroid function on SSNHL by employing a bidirectional and multivariable Mendelian randomization (MR) approach. Methods: Single-nucleotide polymorphisms (SNPs) associated with free thyroid (FT4) and thyroid stimulating hormone (TSH) were selected from the summary data of a large genome-wide association study (GWAS) conducted on European individuals. The summary-level data of SSNHL were also obtained from a GWAS, which included 196,592 participants (1,491 cases and 195,101 controls). The MR analysis primarily utilized the inverse variance weighted (IVW) method, with sensitivity analyses performed using the weighted median, MR-Egger, and MR-PRESSO approaches. Results: In the IVWmethod, an elevated genetically predicted FT4 level was found to e ectively reduce the risk of SSNHL (OR = 0.747, 95% CI = 0.565-0.987, P = 0.04). These findings were consistent when conducting multivariate MR analysis, which adjusted for TSH levels (OR = 0.929, 95% CI = 0.867-0.995, P = 0.036). However, genetically predicted TSH levels did not emerge as a risk factor for SSNHL (OR = 1.409, 95% CI = 0.895-1.230, P = 0.547). Furthermore, even after adjusting for FT4 levels in the multivariate MR analysis, no evidence of a direct causal relationship between TSH levels and the risk of SSNHL was observed (OR = 1.011, 95% CI = 0.880-1.161, P = 0.867). The reverse MR analysis showed that there was no evidence of a direct causal relationship between SSNHL and the risk of FT4 level (OR = 1.026, 95% CI = 0.999-1.054, P = 0.056) or TSH level (OR = 1.002, 95% CI = 0.989-1.015, P = 0.702). Conclusion: Within the normal range, genetic variants associated with higher FT4 levels demonstrate a potential protective e ect against SSNHL, whereas there is no direct causal relationship between TSH levels and the risk of SSNHL. [ABSTRACT FROM AUTHOR]

Thyroid dysfunction stands as the most prevalent endocrine disorder in individuals with Down syndrome, particularly showcasing both clinical and subclinical hypothyroidism. TSH and FT4 blood values serve as common diagnostic and treatment adjustment markers. In Down syndrome (DS), hormone values may deviate from those observed in the general population, which may lead to overdiagnosis and consequent iatrogenesis of subclinical hypothyroidism. The objective of this study was to analyze the appropriateness of the replacement therapeutic approach by identifying the TSH and FT4 values that can be considered normal in these patients. Methods: A cross-sectional study was conducted in 503 subjects with DS of both sexes and without age limit drawn from the Health Program for individuals with DS in Valencia (Spain) from February 1993 to November 2021. The exclusion criteria included hyperthyroidism, nodules, tumors, or individuals under treatment with drugs influencing iodine metabolism. The normality of data distribution was assessed using the Shapiro–Wilk test. Outliers were detected using the Reed's criterion. Hormone values were estimated using quantile regression models for the 2.5th and 97.5th percentiles. Results: The normal values identified were 0.88–11.25 mIU/L for TSH and 0.71–1.63 ng/dL for FT4. The Wald test indicated no significant differences in the reference intervals based on age or sex. Conclusion: The establishment of these values, which, in people with DS, can be considered unique, is of great importance, allowing a watchful waiting attitude to be maintained before starting replacement therapy that is unnecessarily or adjusting medication in diagnosed cases. [ABSTRACT FROM AUTHOR]

Introduction: Six Sigma is a potent tool for evaluating the quality of the analytical phase by combining bias, imprecision, and Total Allowable Error (TEa). Considering the variation in TEa values from different sources, analysis on the sigma scale needs to be carefully monitored. Aim: To assess the performance of Thyroid Stimulating Hormone (TSH) and free Thyroxine (fT4) on the Sigma scale. Materials and Methods: The present observational, cross-sectional study Immunoassay laboratory at the Department of Biochemistry, IPGMER and SSKM Hospital, Kolkata, India, from February 2021 to January 2022. The study involves 12 months of tri-level (L1, L2, L3) Internal Quality (IQ) control data and External Quality Assessment (EQAS) data. The bias percentage was obtained from EQAS, and the Coefficient of Variation (CV%) was obtained from IQ Control (IQC) data run on Advia Centaur CP (CLIA) each month. Sigma (σ) was calculated applying TEa from the desirable biological variation database. Sigma values of L1, L2, L3 of TSH and fT4 have been calculated using Microsoft spreadsheet software version 2010, applying the formula σ=(TEa-bias)/CV. Results: The CV% and bias% were found to be within an acceptable range, always less than the cut-off percentage of imprecision (I%) and inaccuracy (B%) for TSH and fT4 in the desirable specifications for imprecision and inaccuracy (updated 2014). However, sigma levels are near the satisfactory mark, found to be 5σ) in tri-level IQ for TSH with a higher numeric TEa% value (23.7%) were obtained in more months, whereas for fT4 with a lower TEa% value (8%), better sigma values (>5σ) were obtained in a lesser number of months. Conclusion: The present study establishes that Sigma values are affected by the numeric values of TEa% of a particular parameter taken from the source. Sigma values showed average performance despite satisfactory CV% and bias% for fT4 and TSH, creating chaos in the laboratory’s operational routine. The Sigma matrix is a good indicator, but it is difficult to maintain a good sigma value for parameters that have low TEa%. It becomes crucial to choose appropriate TEa to plan a quality control strategy for thyroid hormones.

Objectives: The direct approach for determining reference intervals (RIs) is not always practical. This study aimed to generate evidence that a real-world data (RWD) approach could be applied to transfer free thyroxine RIs determined in one population to a second population, presenting an alternative to performing multiple RI determinations. Design and methods: Two datasets (US, n = 10,000; Europe, n = 10,000) were created from existing RWD. Descriptive statistics, density plots and cumulative distributions were produced for each data set and comparisons made. Cumulative probabilities at the lower and upper limits of the RIs were identified using an empirical cumulative distribution function. According to these probabilities, estimated percentiles for each dataset and estimated differences between the two sets of percentiles were obtained by case resampling bootstrapping. The estimated differences were then evaluated against a pre-determined acceptance criterion of ≤7.8% (inter-individual biological variability). The direct approach was used to validate the RWD approach. Results: The RWD approach provided similar descriptive statistics for both populations (mean: US = 16.1 pmol/L, Europe = 16.4 pmol/L; median: US = 15.4 pmol/L, Europe = 15.8 pmol/L). Differences between the estimated percentiles at the upper and lower limits of the RIs fulfilled the pre-determined acceptance criterion and the density plots and cumulative distributions demonstrated population homogeneity. Similar RI distributions were observed using the direct approach. Conclusions: This study provides evidence that a RWD approach can be used to transfer RIs determined in one population to another.

Background: We aimed to study the contrast-enhanced ultrasound features and parameters of patients with benign and malignant thyroid nodules.

Introduction: Hypothyroidism, a prevalent endocrine disorder, leads to a generalised metabolic slowdown due to insufficient thyroid hormone production, potentially resulting in elevated levels of serum uric acid and creatinine, thus affecting renal function and purine metabolism. Aim: To assess serum creatinine and serum uric acid levels in hypothyroid patients while establishing correlations with their thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) levels. Materials and Methods: A comparative cross-sectional study was conducted in the Department of Biochemistry, Government Medical College, Kozhikkode, Kerala, India. The study involved 140 participants, including 70 recently diagnosed hypothyroid patients and 70 age- and sex-matched euthyroid individuals. Thyroid hormone levels (FT3, FT4) and TSH were quantified using the Cobas e411 electro-chemiluminescence technique. Serum creatinine levels were measured using the Modified Jaffe’s method, and serum uric acid levels were assessed through the Uricase method (Enzokit). Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 21.0, and tables and graphs were generated using Microsoft Word and Excel. Results: The mean age of study participants of control group was 39.02 years and of the hypothyroid group was 36.80 years. The comparative cross-sectional analysis revealed significantly higher levels of serum uric acid and serum creatinine in hypothyroid patients compared to euthyroid controls. Specifically, hypothyroid patients exhibited a mean serum uric acid level of 10.77±2.34 mg/dL, while euthyroid controls had a mean of 4.37±0.94 mg/dL. Mean serum creatinine levels for hypothyroid patients and euthyroid controls were 2.16±0.80 mg/dL and 0.75±0.14 mg/dL, respectively. Notably, a significant positive correlation was observed between serum uric acid and serum creatinine levels with TSH (r=0.42, p-value

Background: Free thyroxine (FT4) measurement is one of the most requested tests in patient care for diagnosing and treating thyroid-related illnesses. Equilibrium dialysis (ED) is considered the “gold standard” for FT4 measurement; however, several factors have a profound effect on the reliability of FT4 assays and require special consideration. Methods: In the current study, we focused on evaluating critical factors that could contribute to reporting errors, such as adsorption of thyroxine (T4) to labware surfaces, stability of serum samples, stock solutions, and calibrator storage conditions, as well as the solvents used to prepare T4 solutions. Results: The adsorption of T4 in ethanolic solutions and dialysates to labware surfaces can be reduced with the careful selection of pipette tips, test tubes, and 96-well plates. Adding pH modifiers to neat T4 solutions can improve its stability. FT4 in serum samples remains stable after exposure to four freeze–thaw cycles, 5 °C for 18–20 h, or −70 °C for a minimum of three years. Conclusion: The presented study has demonstrated that the loss of analyte due to pre-analytical and analytical factors during operation of the FT4 reference measurement procedure (RMP) can be minimized by careful selection of all labware for sample preparation. It was found that the accuracy and imprecision of FT4 assays can be influenced by different types of dialysis devices, but acceptable alternatives to ED membranes were identified. This study demonstrates approaches to establish a FT4 method that is independent from specific suppliers and addresses critical pre-analytical and analytical factors important for FT4 measurements.

Abstract Background Deriving population specific reference intervals (RIs) or at the very least verifying any RI before adoption is good laboratory practice. Siemens has provided RIs for thyroid stimulating hormone (TSH) and free thyroxine (FT4) determined on their Atellica® IM analyzer for all age groups except the neonatal age group which provides a challenge for laboratories that intend to use it to screen for congenital hypothyroidism (CH) and other thyroid disorders in neonates. We set out to determine RIs for TSH and FT4 using data obtained from neonates undergoing routine screening for CH at the Aga Khan University Hospital, Nairobi, Kenya. Methodology TSH and FT4 data for neonates aged 30 days and below were extracted from the hospital management information system for the period March 2020 to June 2021. A single episode of testing for the same neonate was included provided both TSH and FT4 were done on the same sample. RI determination was performed using a non-parametric approach. Results A total of 1243 testing episodes from 1218 neonates had both TSH and FT4 results. A single set of test results from each neonate was used to derive RIs. Both TSH and FT4 declined with increase in age with a more marked decline seen in the first 7 days of life. There was a positive correlation between logFT4 and logTSH (rs (1216) = 0.189, p =

Objective: The aim of this study was to elaborate the link of thyroid hormones (THs) and metabolic syndrome (MetS) in a Chinese euthyroid employee popul ation with MetS component(s). Methods: An annual health checkup was performed on employees in 2019. Anthropometric parameters, metabolic parameters, and thyroid function were measured. A questionnaire was used in conjunction with Zhenhai Lianhua Hospital database to receive employees' medication records and thyroid s urgical history records. Results: A total of 5486 eligible employees were included; the prevalen ce of MetS was generally higher in males than in females (38.9 vs. 30.4%, P < 0.001). Among employees with central obesity, hypertriglyceridemia, hyperglycemia, hypertension, and low high-density lipoprotein cholesterol (HDL-C), the prevalence of MetS was 68.8, 63.6, 68.2, 48.8, and 60.0% in males and 72.6, 63.3, 61.3, 42.3, and 42.3% in females, respectively. Logistic regression analysis showed that thyroid-stimulating hormone and free thyroxine (FT4) quartiles had no significant impact on MetS. Free triiodot hyronine/free thyroxine (FT3/FT4) and free triiodothyronine (FT3)) quartiles were posit ively associated with the increased odds ratio (OR) for MetS and dyslipidemia (hypertrigl yceridemia and low HDL-C), regardless of gender. In males, FT3 and FT3/FT4 quartil es were positively associated with the OR for central obesity, whereas FT4 quartil es were negatively associated; both FT3 and FT4 quartiles were positively associat ed with increased OR of hyperglycemia, while similar results were not observed in femal es. Interaction analysis indicated no significant effect of gender and TH interactions on risk of MetS. Conclusion: High FT3 and FT3/FT4 were strongly linked with MetS and dyslip idemia in our study, even in the euthyroid individuals. Tighter control of th yroid function was necessary for those with preexisting MetS component(s).

BackgroundTriglyceride-glucose (TyG) index is an effective indicator in indentifying in pre-diabetes, diabetes, and coronary artery disease (CAD). However, the value of TyG index combined with thyroid hormones (THs) to affect CAD has not been fully evaluated. Here, we investigated the association between TyG index and THs and further studied the impacts of TyG index and THs on CAD in euthyroid.MethodsSubjects (1,297) with euthyroid who underwent selective coronary angiography (CAG) were enrolled in the present study, including 893 patients with CAD and 404 controls. The association between TyG index and THs were analyzed by linear regression models. Multivariate logistic regression analysis was used to evaluate the interaction of TyG and THs with the risk of CAD. According to the cutoff value of free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and TyG index, the patients were respectively separated into four groups: low TyG/FT3 (low or high), high TyG/FT3 (low or high), low TyG/FT4 (low or high), high TyG/FT4 (low or high), low TyG/TSH (low or high), high TyG/TSH (low or high).ResultsThe baseline analysis showed that FT4 level differs among the three groups according to the tertile of the TyG index. Multiple linear regression analysis revealed decreased serum FT3 level and serum FT4 level as an independent risk factor for elevated TyG index. After adjusting for confounding variables, multiple logistic regression analysis showed that patients with lower TyG index and higher FT3 level had an important protective effect on CAD when considering patients with lower TyG index and FT3 level as reference(OR = 0.536, 95% CI: 0.369–0.778, P = 0.001). Patients with higher TyG index and FT4 level (lower or higher) had a significantly increased risk of CAD (OR 1.656, 95% CI: 1.117–2.455; OR = 1.920, 95% CI: 1.279–2.848, respectively). The area under the curve for the combined diagnosis of CAD by TyG index and FT3 level is 0.615.ConclusionsThese findings suggest that TyG is independently negatively correlated with FT3 or FT4 in euthyroid. In addition, there was a significant interaction between TyG index and THs on the risk of CAD.

BackgroundHypothyroidism and hyperthyroidism are observationally associated with rheumatoid arthritis (RA), but causality is unclear. To evaluate the causal relationship between thyroid function and RA, we conducted a two-Sample bidirectional Mendelian Randomization (MR) study.MethodsSingle nucleotide polymorphisms associated with six phenotypes were selected from the FinnGen biobank database, The ThyroidOmics Consortium database, and the IEU Open GWAS database. For the forward MR analysis, we selected hypothyroidism (N=213,390), Graves’ disease (GD) (N=199,034), other types of hyperthyroidism (N=190,799), free thyroxine (FT4, N=49,269), and thyroid-stimulating hormone (TSH, N=54,288) as the five related thyroid function phenotypes for exposure, with RA (N=58,284) as the outcome. Reverse MR analysis selected RA as the exposure and five phenotypes of thyroid function as the outcome. The Inverse variance weighting (IVW) method was used as the primary analysis method, supplemented by weighted median (WM) and MR-Egger methods. Cochran’s Q test, MR-PRESSO, MR-Egger regression methods, and leave-one-out analysis were employed to assess sensitivity and pleiotropy.ResultsForward MR evidence indicates that genetic susceptibility to hypothyroidism is associated with an increased risk of RA (ORIvw=1.758, P=7.61×10-5). Reverse MR evidence suggests that genetic susceptibility to RA is associated with an increased risk of hypothyroidism (ORIvw=1.274, P=3.88×10-20), GD (ORIvw=1.269, P=8.15×10-05), and other types of hyperthyroidism (ORIvw=1.141, P=1.80×10-03). There is no evidence to support a forward or reverse causal relationship between genetic susceptibility to RA and FT4, TSH.ConclusionOur results provide genetic evidence supporting bidirectional causal relationships between thyroid function and RA. These findings inform preventive strategies and interventions targeting RA and thyroid dysfunction.

Purpose: Thyroid hormones sensitivity is a newly proposed clinical entity closely related with metabolic health. Prior studies have reported the cross-sectional relationship between thyroid hormones sensitivity and diabetes; however, the longitudinal association is unclear to date. We aimed to explore the relationship between impaired thyroid hormone sensitivity at baseline and diabetes onset using a cohort design. Methods: This study enrolled 7283 euthyroid participants at the first visit between 2008 and 2009, and then annually followed until diabetes onset or 2019. Thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were measured to calculate thyroid hormone sensitivity by thyroid feedback quantilebased index (TFQI), Chinese-referenced parametric thyroid feedback quantilebased index (PTFQI), thyrotropin index (TSHI), thyrotroph thyroxine resistance index (TT4RI) and FT3/FT4 ratio. Cox proportional hazard model and crosslagged panel analysis were used. Results: The mean baseline age was 44.2 ± 11.9 years, including 4170 (57.3%) male. During a median follow-up of 5.2 years, 359 cases developed diabetes. There was no significant association between thyroid hormones sensitivity indices and diabetes onset, and adjusted hazard ratios per unit (95% CIs) were 0.89 (0.65-1.23) for TFQI, 0.91 (0.57-1.45) for PTFQI, 0.95 (0.70-1.29) for TSHI, 0.98 (0.70-1.01) for TT4RI and 2.12 (0.17-5.78) for FT3/FT4 ratio. Cross-lagged analysis supported the temporal association from fasting glucose to impaired thyroid hormones sensitivity indices. Conclusions: Our findings could not demonstrate that thyroid hormones sensitivity status is a predictor of diabetes onset in the euthyroid population. Elevated fasting glucose (above 7.0 mmol/L) appeared to precede impaired sensitivity indices of thyroid hormones. [ABSTRACT FROM AUTHOR]

The most common hormonal and metabolic disease in early childhood is congenital hypothyroidism (CH). This study aimed to describe CH in large-scale birth cohort data and summarize the results of serum thyroidstimulating hormone (TSH) and free thyroxine (fT4) levels in 2-yr-old children. Data were obtained from the Japan Environment and Children’s Study (JECS), and we identified 171 children with CH detected in newborn screenings or medical records (170.5 per 100,000 population). Infants with CH are at higher risk of developing congenital diseases than those without CH. Of 171 children with CH, 20 (11.7%) were diagnosed with congenital heart defects, 33 (19.3%) had chromosomal or other congenital abnormalities, and 23 (13.5%) had Down syndrome. At the age of 2 yr old, the median and 95% reference range values for TSH and fT4 were 2.13 (0.78–5.52) µIU/mL and 1.2 (1.0–1.5) ng/dL, respectively. Moreover, boys had slightly higher TSH and fT4 levels than did girls. Data on the distribution of TSH and fT4 in 2-yr-old children should be useful for decreasing the misclassification of thyroid disorders in the pediatric population. Trial-off treatment and re-evaluation of thyroid function are needed to classify permanent congenital hypothyroidism and transient congenital hypothyroidism after 3 yr of age. [ABSTRACT FROM AUTHOR]

Introduction: Hypothyroidism, a prevalent endocrine disorder, leads to a generalised metabolic slowdown due to insufficient thyroid hormone production, potentially resulting in elevated levels of serum uric acid and creatinine, thus affecting renal function and purine metabolism. Aim: To assess serum creatinine and serum uric acid levels in hypothyroid patients while establishing correlations with their thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) levels. Materials and Methods: A comparative cross-sectional study was conducted in the Department of Biochemistry, Government Medical College, Kozhikkode, Kerala, India. The study involved 140 participants, including 70 recently diagnosed hypothyroid patients and 70 age- and sex-matched euthyroid individuals. Thyroid hormone levels (FT3, FT4) and TSH were quantified using the Cobas e411 electro-chemiluminescence technique. Serum creatinine levels were measured using the Modified Jaffe's method, and serum uric acid levels were assessed through the Uricase method (Enzokit). Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 21.0, and tables and graphs were generated using Microsoft Word and Excel. Results: The mean age of study participants of control group was 39.02 years and of the hypothyroid group was 36.80 years. The comparative cross-sectional analysis revealed significantly higher levels of serum uric acid and serum creatinine in hypothyroid patients compared to euthyroid controls. Specifically, hypothyroid patients exhibited a mean serum uric acid level of 10.77±2.34 mg/dL, while euthyroid controls had a mean of 4.37±0.94 mg/dL. Mean serum creatinine levels for hypothyroid patients and euthyroid controls were 2.16±0.80 mg/dL and 0.75±0.14 mg/dL, respectively. Notably, a significant positive correlation was observed between serum uric acid and serum creatinine levels with TSH (r=0.42, p-value<0.001 and r=0.45, p=0.00, respectively). Conclusion: The study identified significantly higher levels of serum uric acid and creatinine in hypothyroid patients compared to euthyroid individuals, potentially attributed to haemodynamic changes and disruptions in purine metabolism. Regular monitoring of these parameters is crucial for individuals with hypothyroidism. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic psychiatric disorder with inconsistent behavioral and cognitive abnormalities with profound effects on the individual and the society. Individuals with schizophrenia have altered thyroid function, but results from observational studies are conflicting. To date, it remains unclear whether and in which direction there is a causal relationship between thyroid function and schizophrenia. To investigate causal paths, a bidirectional two-sample Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies including up to 330,132 Europeans. Thyroid function was described by the normal-range thyroid-stimulating hormone (TSH) and free thyroxine levels as well as an increased and decreased TSH status. The iterative radial inverse-variance weighted approach with modified second order weights was used as the main method. Based on a discovery and replication sample for schizophrenia, pooled effect estimates were derived using a fixed-effect meta-analysis. Robustness of results was assessed using both a range of pleiotropy robust methods and a network analysis that clustered genetic instruments potentially responsible for horizontal pleiotropy. Genetic liability for hypothyroidism was inversely associated with schizophrenia ( ; 95% CI: (-0.10; -0.02); ). No notable associations were observed between other thyroid parameters and schizophrenia. Furthermore, no associations could be detected in the reverse direction. Our results suggest that an elevated level of TSH reduce the risk for schizophrenia. The role of thyroid function and the hypothalamic-pituitary-thyroid axis in the development of schizophrenia should be subject of further research. [ABSTRACT FROM AUTHOR]

Context: Observational studies have provided insufficient information on the association between thyroid function and the risk of cerebral small vessel disease (CSVD); moreover, the causality of this link is still unclear. Objective: This study aims to investigate whether genetically predicted variation within thyroid function is causally associated with the risk of CSVD using 2-sample Mendelian randomization (MR) analysis. Methods: In this 2-sample MR study with genome-wide association variants, we estimated the causal effects of genetically predicted thyrotropin (thyroid-stimulating hormone, TSH; n = 54 288), free thyroxine (FT4; n = 49 269), hypothyroidism (n = 51 823), and hyperthyroidism (n = 51 823) on 3 neuroimaging markers of CSVD, including white matter hyperintensity (WMH; n = 42 310), mean diffusivity (MD; n = 17 467), and fractional anisotropy (FA, n = 17 663). The primary analysis was conducted by the inverse variance--weighted MR method, followed by sensitivity analyses using MR-PRESSO, MR-Egger, weighted median, and weighted mode methods. Results: Genetically increased TSH was associated with increased MD (β = .311, 95% CI 0.0763, 0.548, P = .01). Genetically increased FT4 was associated with increased FA (β = .540, 95% CI 0.222, 0.858, P < .001). Sensitivity analyses using different MR methods showed similar directions but lower precision. No significant associations of hypothyroidism or hyperthyroidism with WMH, MD, or FA were found (all P > .05). Conclusion: This study indicated that genetically predicted increased TSH was associated with increased MD, as well as increased FT4 with increased FA, implying the causal effect of thyroid dysfunction on white matter microstructural injury. There were no significant causal relationships of hypothyroidism or hyperthyroidism with CSVD. Further investigations should verify these findings and clarify the underlying pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

As previously demonstrated, serum beta-human chorionic gonadotropin (β-hCG) is linked to identifying early gestational abnormalities. This research was aimed at investigating the correlation between serum β-hCG levels and thyroid metabolic function in pregnant women with hyperemesis gravidarum (HG). Ninety-one pregnant women with HG were selected as the study group and divided into early pregnancy (EP), mid-pregnancy (MP), and late pregnancy (LP) groups according to their gestational weeks, while 84 normal pregnant women were selected as the control group. Venous blood was collected from pregnant women in both groups and serum β-hCG levels were measured by chemiluminescent immunoassay. The levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), thyroid-stimulating hormone receptor antibody (TRAb), and thyroglobulin antibody (TgAb) were tested by chemiluminescent microparticle immunoassay. Visual analog scale (VAS) scores were utilized to assess the degree of HG. Pearson analysis was implemented to measure the correlations between serum β-hCG levels and serum FT3, FT4, TSH, TPOAb, TRAb, TgAb, as well as VAS scores and the correlations between β-hCG, FT3, FT4, TSH, TPOAb, TRAb, TgAb, as well as VAS scores and gestation period. The receiver operating characteristic (ROC) curve was plotted to analyze the diagnostic values of thyroid hormones, thyroid-related antibodies, and β-hCG levels for HG. Versus those in the control group, β-hCG, FT3, FT4, TPOAb, TRAb, TgAb levels, and VAS scores were higher and TSH levels were lower in the study group. Versus those in the EP group, β-hCG, FT3, FT4, TPOAb, TRAb, TgAb levels, and VAS scores of pregnant women in the MP and LP groups were decreased, and TSH levels were increased. Serum β-hCG levels of pregnant women with HG were positively correlated with FT3, FT4, TPOAb, TRAb, TgAb, and VAS scores and negatively correlated with TSH levels. Serum β-hCG, FT3, FT4, TPOAb, TRAb, TgAb levels, and VAS scores of pregnant women with HG had a negative correlation with the gestation period, while TSH levels had a positive correlation with the gestation period. The ROC curve analysis showed that β-hCG and thyroid function-related indicators were of high clinical values in the diagnosis of HG. Collectively, our article suggests that serum β-hCG expression of pregnant women with HG is abnormally elevated and closely related to the degree of HG and hyperthyroidism. In addition, β-hCG and thyroid function-related indicators have certain diagnostic efficacy for HG. [ABSTRACT FROM AUTHOR]

Free thyroxine (FT4) in serum is routinely measured in clinical practice to diagnose and monitor thyroid disease. Due to its concentration in picomolar range and the delicate equilibrium of free and protein-bound T4, accurate measurement is challenging. As a consequence, large inter-method differences in FT4 results exists. Optimal method design and standardization of the FT4 measurement is therefore necessary. The IFCC Working Group for Standardization of Thyroid Function Tests proposed a reference system with a conventional reference measurement procedure (cRMP) for FT4 in serum. In this study, we describe our FT4 candidate cRMP and its validation in clinical samples. This candidate cRMP is based on equilibrium dialysis (ED) combined with determination of T4 with an isotope-dilution liquid chromatography tandem mass-spectrometry (ID-LC-MS/MS) procedure and was developed according to the endorsed conventions. Its accuracy, reliability, and comparability was investigated using human sera. It was shown that the candidate cRMP adhered to the conventions and its accuracy, precision, and robustness were adequate in serum of healthy volunteers. Our candidate cRMP measures FT4 accurately and performs well in serum matrix. [ABSTRACT FROM AUTHOR]

Introduction: In our hospital, physicians noticed high free thyroxine (fT4) concentrations without complete suppression of thyroid-stimulating hormone (TSH) in blood samplesof patients at the outpatient clinic, which appeared to occur more often following the introduction of a new fT4 immunoassay. This discordance may be explained by incorrect reference intervals, analytical issues, or patient-related factors. We aimed to establish the contribution of the possible factors involved. Methods: Reference intervals of both fT4 immunoassays were re-evaluated using blood samples of healthy volunteers and the new immunoassay’s performance was assessed using internal quality controls and external quality rounds. The frequency of discordant fT4 and TSH pairings obtained from laboratory requests were retrospectively analysed using a Delfia (n = 3174) and Cobas cohort (n = 3408). Last, a literature search assessed whether the time of blood draw and the time of levothyroxine (L-T4) ingestion may contribute to higher fT4 concentrations in L-T4 users. Results: The original reference intervals of both fT4 immunoassays were confirmed and no evidence for analytical problems was found. The Delfia (n = 176, 5.5%) and Cobas cohorts (n = 295, 8.7%) showed comparable frequencies of discordance. Interestingly, 72–81% of the discordant results belonged to L-T4 users. Literature indicated the time of blood withdrawal of L-T4 users and, therefore, the time of L-T4 intake as possible explanations. Conclusions: High fT4 without suppressed TSH concentrations can mainly be explained by L-T4 intake. Physicians and laboratory specialists should be aware of this phenomenon to avoid questioning the assay’s performance or unnecessarily adapting the L-T4 dose in patients.

Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (β = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (β = −0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required.

Evidence of the effectiveness of zinc (Zn) and selenium (Se) on resting metabolic rate (RMR) and physical function parameters in people with overweight and obesity is scarce, while the effects of zinc and selenium on thyroid function and body composition are still a topic of debate and controversy. The aim of this randomized, double-blind, and placebo-controlled trial was to examine the effects of a hypocaloric diet and Se–Zn co-supplementation on RMR, thyroid function, body composition, physical fitness, and functional capacity in overweight or obese individuals. Twenty-eight overweight–obese participants (mean BMI: 29.4 ± 4.7) were randomly allocated (1:1) to the supplementation group (n = 14, 31.1 ± 5.5 yrs, 9 females) and the placebo group (n = 14, 32.1 ± 4.8 yrs, 6 females). The participants received Zn (25 mg of zinc gluconate/day) and Se (200 mcg of L-selenomethionine/day) or placebo tablets containing starch for eight weeks. The participants of both groups followed a hypocaloric diet during the intervention. RMR, thyroid function, body composition, cardiorespiratory fitness (VO2max), and functional capacity (sit-to-stand tests, timed up-and-go test, and handgrip strength) were assessed before and after the intervention. A significant interaction was found between supplementation and time on RMR (p = 0.045), with the intervention group's RMR increasing from 1923 ± 440 to 2364 ± 410 kcal/day. On the other hand, no interaction between supplementation and time on the thyroid function was found (p > 0.05). Regarding the effects of Zn/Se co-administration on Se levels, a significant interaction between supplementation and time on Se levels was detected (p = 0.004). Specifically, the intervention group's Se serum levels were increased from 83.04 ± 13.59 to 119.40 ± 23.93 μg/L. However, Zn serum levels did not change over time (90.61 ± 23.23 to 89.58 ± 10.61 umol/L). Even though all body composition outcomes improved in the intervention group more than placebo at the second measurement, no supplement × time interaction was detected on body composition (p > 0.05). Cardiorespiratory fitness did not change over the intervention. Yet, a main effect of time was found for some functional capacity tests, with both groups improving similarly over the eight-week intervention period (p < 0.05). In contrast, a supplement x group interaction was found in the performance of the timed up-and-go test (TUG) (p = 0.010), with the supplementation group improving more. In conclusion, an eight-week intervention with Zn/Se co-supplementation combined with a hypocaloric diet increased the RMR, TUG performance, and Se levels in overweight and obese people. However, thyroid function, Zn levels, body composition, and the remaining outcomes of exercise performance remained unchanged. [ABSTRACT FROM AUTHOR]

Background and Aim: Dyslipidemia is thought to confer risk of cardiovascular disease development. Overt hypothyroidism is associated with lipid abnormalities. As SCH is being diagnosed more frequently in young and middle-aged people, there is a need to know the effect of SCH on cardiovascular risk factors in young in tertiary centre in Gujarat, India. Therefore, the objective of this study is to analyze the relation between SCH and serum lipid parameters in this subgroup. Material and Methods: This observational study was conducted at Department of Medicine at Tertiary Care Institute of Gujarat, India in subjects diagnosed with Sub Clinical Hypothyroidism. Blood samples were drawn at early morning after an overnight fast in a sterile bottle. Serum was separated for the estimation of serum TSH, T3, T4, and total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), which were derived from TC and TG, using Friedwald's Formula [LDL = TC - (HDL + TG/5)], Very low-density lipoprotein (VLDL) derived from TG. Lipid profile was compared with matched controls. Results: The levels of TSH are significantly higher in group II compared to group I, which is statistically significant. (p=0.05) There is a significant increase in the serum TC level in group II individuals when compared to group I, which is statistically significant. (p=0.05). There is also a significant increase in serum LDL Cholesterol in group II individuals when compared to group I individuals, which is statistically significant. Conclusion: Subclinical hypothyroidism (SCH) is associated with increased serum TC and LDL-C levels. Therefore, there is a potential association between subclinical hypothyroidism and atherosclerosis. Larger studies are needed to prove this association in Patients. [ABSTRACT FROM AUTHOR]

Hormone measurements using automated immunoassays (IAs) can be affected by the sample matrix. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) is less affected by these matrix effects. In clinical laboratories, testosterone, cortisol and, free thyroxine (FT4) are often measured using IAs. Renal failure alters serum composition in blood samples from people undergoing hemodialysis (HDp) and have, therefore, a complex serum constitution compared to healthy controls (HC). The goal of this study was to investigate the accuracy of testosterone, cortisol, and FT4 measurements in samples of HDp and to get more insight in the interfering factors. Thirty serum samples from HDp and HC were collected to measure testosterone, cortisol, and FT4 using a well standardized isotope dilution (ID)-LC-MS/MS method and 5 commercially available automated IAs (Alinity, Atellica, Cobas, Lumipulse, UniCel DXI). Method comparisons between LC-MS/MS and IAs were performed using both HDp and HC samples. Average bias from the LC-MS/MS was for testosterone, cortisol, and FT4 immunoassays respectively up to 92, 7–47 and 16–27% more in HDp than in HC samples and was IA dependent. FT4 IA results were falsely decreased in HDp samples, whereas cortisol and testosterone concentrations in females were predominantly falsely increased. Correlation coefficients between LC-MS/MS and IA results were lower in HDp compared to HC samples. Several IAs for testosterone (in women), cortisol, and FT4 are less reliable in the altered serum matrix of samples of HDp than in HC. Medical and laboratory specialists should be aware of these pitfalls in this specific population. [ABSTRACT FROM AUTHOR]

BACKGROUND: Up to now, there is no unified conclusion on the selection of animals and drug doses and the criteria for successful modeling in the modeling process of hypothyroid animal models. OBJECTIVE: To explore the feasibility and optimal dose of radioactive 131I in the establishment of hypothyroidism model in rats METHODS: Forty healthy male Sprague-Dawley rats were randomly divided into five groups (n=8 per group). Four groups were injected intraperitoneally with 4.625, 9.25, 12.95, and 18.5 MBq 131I solution to construct hypothyroidism models and the control group was injected with the same amount of normal saline. The body mass of rats was measured before 131I injection, 4, 8, 12, and 16 weeks after injection of 131I. The serum levels of thyroid-stimulating hormone, free triiodothyronine, free thyroxine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, and uric acid were determined by an ELISA kit. Thyroid function was evaluated by 131I static imaging and morphological changes of thyroid tissue were observed by hematoxylin-eosin staining. RESULTS AND CONCLUSION: Compared with the control group, the body mass of the rats in the 9.25, 12.95, and 18.5 MBq groups were significantly decreased at 8, 12, and 16 weeks (P < 0.05). The serum thyroid-stimulating hormone concentration gradually increased in the 9.25, 12.95, and 18.5 MBq groups at 4, 8, 12, and 16 weeks, while the levels of free triiodothyronine and free thyroxine gradually decreased (P < 0.05). The levels of alanine aminotransferase and alkaline phosphatase in the 12.95 and 18.5 MBq groups were significantly higher than those in the control group, while the blood urea nitrogen and creatinine levels in the 18.5 MBq group were significantly higher than those in the control group (P < 0.05). The thyroid glands in each group were clearly visualized before 131I injection, and the target-to-nontarget ratio was not significantly different among groups (P > 0.05). Compared with the control group, the thyroid glands of the 9.25, 12.95, and 18.5 MBq groups were not visualized in the 4th week and the target-to-nontarget ratio was significantly decreased (P < 0.05). The thyroid glands were undeveloped at the 8-, 12-, and 16-week follow-up visits, but there was no statistical difference in the target-to-nontarget ratio among groups (P > 0.05). After injection of 131I, the thyroid follicles of rats became smaller and shrunken, and some of them were irregular. All these findings indicate that intraperitoneal injection of 131I at a dose of 9.25 MBq could successfully establish a stable hypothyroid model in rats within 4 weeks, which provide a reference for the establishment of animal models in the field of nuclear medicine 131I therapy. [ABSTRACT FROM AUTHOR]

Background: Low thyroxine (T4) levels have been observed in critically ill patients; however, controversial results regarding T4 supplemental therapy are reported. The association between serum free T4 (FT4) levels and mortality in critically ill patients has not been fully established and needs to be clarified. Methods: Data from the Medical Information Mart for Intensive Care (MIMIC)-IV were collected and analyzed. The association between FT4 level and 30-day mortality after ICU admission was analyzed using Kaplan-Meier curves, spline smoothing fitting, martingale residuals of the null Cox model, and restricted cubic spline (RCS). Logistic regression, Cox regression, and receiver operating characteristic curve (ROC) were used to uncover the relationship and predictive value of serum FT4 and 30-day mortality in critically ill patients. Results: In the final analysis, 888 patients were enrolled, and the serum FT4 levels were divided into four groups. A significant difference in 30-day mortality was observed between the four groups. Kaplan-Meier curves also presented significantly higher 30-day mortality in groups 1 and 2 (p < 0.0001). Further multivariance logistic regression showed that group 1 with FT4 levels lower than 0.7 mg/dl can predict 30-day mortality (odds ratio (OR) = 3.30, 95% confidence interval (CI) = 1.04-11.31). Spline smoothing fitting analysis showed a "V"-shaped line between 30-daymortality and FT4 level within 0-3 mg/dl. Further RCS analysis showed that the risk of death decreased rapidly as FT4 levels increased when serum FT4 levels were lower than 1.2 mg/dl and started to become flat afterward. The area under the ROC of the lower FT4 level to predict 30-day mortality was 0.833 (95% CI = 0.788-0.878). Both multivariant Cox regression and logistic regression showed that FT4 levels lower than 1.2 mg/dl can independently predict 30-day mortality when adjusted for other potential confounders (HR = 0.34, 95% CI = 0.14-0.82; OR = 0.21, 95% CI = 0.06-0.79, respectively), but its predictive power disappeared when adjusted for T3 or total T4. Conclusion: Serum FT4 levels were significantly negatively associated with 30-day mortality when they were lower than 1.2 mg/dl and could predict the risk of 30-day mortality. A higher FT4 level is potentially related to increased 30-day mortality. [ABSTRACT FROM AUTHOR]

• A highly accurate and precise candidate Reference Measurement Procedure (cRMP) was developed for CDC Clinical Standardization Programs (CDC CSP) free thyroxine (FT4) measurements. • The FT4 cRMP was based on equilibrium dialysis (ED) and isotope dilution liquid chromatography – tandem mass spectrometry (ID-LC-MS/MS) procedures. • The accuracy and precision of the cRMP were validated via an interlaboratory comparison study with excellent agreement between four independent laboratories. • The low limit of detection of cRMP provided sufficient sensitivity to determine FT4 for patients with hypothyroidism. Accurate and reliable measurement of human serum free thyroxine (FT4) is critical for the diagnosis and treatment of thyroid diseases. However, concerns have been raised regarding the performance of FT4 measurements in patient care. Centers for Disease Control and Prevention Clinical Standardization Programs (CDC-CSP) address these concerns by creating a FT4 standardization program to standardize FT4 measurements. The study aims to develop a highly accurate and precise candidate Reference Measurement Procedure (cRMP), as one key component of CDC-CSP, for standardization of FT4 measurements. Serum FT4 was separated from protein-bound thyroxine with equilibrium dialysis (ED) following the recommended conditions in the Clinical and Laboratory Standards Institute C45-A guideline and the published RMP [20,21,23]. FT4 in dialysate was directly quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization. Gravimetric measurements of specimens and calibrator solutions, calibrator bracketing, isotope dilution, enhanced chromatographic resolution, and T4 specific mass transitions were used to ensure the accuracy, precision, and specificity of the cRMP. The described cRMP agreed well with the established RMP and two other cRMPs in an interlaboratory comparison study. The mean biases of each method to the overall laboratory mean were within ±2.5%. The intra-day, inter-day, and total imprecision for the cRMP were within 4.4%. The limit of detection was 0.90 pmol/L, which was sufficiently sensitive to determine FT4 for patients with hypothyroidism. The structural analogs of T4 and endogenous components in dialysate did not interfere with the measurements. Our ED-LC-MS/MS cRMP provides high accuracy, precision, specificity, and sensitivity for FT4 measurement. The cRMP can serve as a higher-order standard for establishing measurement traceability and provide an accuracy base for the standardization of FT4 assays. [ABSTRACT FROM AUTHOR]