ObjectiveRegarding the exact association between hypothyroidism, levothyroxine replacement and kidney dysfunction, there is a lack of study to summarize the previous evidence. The aim of this study is to explore these relationships.MethodsThe PubMed, Cochrane Library, EMBASE, and Google Scholar were searched for observational studies and RCTs. The included studies were conducted in adult nonpregnant participants and analyzed kidney outcomes of interest in serologically confirmed hypothyroidism patients. Additionally, studies that examined kidney outcomes during levothyroxine treatment were retrieved. Standard Mean Difference (SMD), Odds Ratios (ORs) and Risk Ratios (RRs) were estimated as the effect variables.ResultsTotally, 46 studies were included. Both non-distinct hypothyroidism and subclinical hypothyroidism (SHypo) were significantly associated with the prevalence of chronic kidney disease (CKD) (OR 1.94, 95% CI [1.62, 2.32]) (OR 1.87, 95% CI [1.55, 2.27]). Non-distinct hypothyroidism and SHypo were also associated with estimated glomerular filtration rate (eGFR) reduction (SMD -0.68, 95% CI [-0.81, -0.55]) (SMD -0.99, 95% CI [-1.59, -0.38]). No significant association between hypothyroidism and CKD incidence was found, and its association with end-stage renal disease (ESRD) was not significant in patients with underlying kidney dysfunction. No significant improvement in eGFR was observed after levothyroxine treatment, either in non-distinct hypothyroidism or in SHypo patients.ConclusionThis study verifies a cross-sectional association between hypothyroidism and kidney dysfunction. However, no definitive prospective association was found. The bidirectional causal association between hypothyroidism, levothyroxine replacement and kidney outcomes remain controversial based on evidence from extensive observational studies. More large-scale randomized controlled trials are needed to supplement this evidence in practice to avoid overtreatment or undertreatment.ResponseThe registraton information has been mentioned in the Methods section.

Background and Objectives Euthyroid autoimmune thyroiditis (AIT) during early pregnancy has been linked to adverse pregnancy outcomes, yet the underlying mechanisms remain unclear. This study aimed to investigate the differences in gut microbiota (GM) composition and fecal metabolites between patients with euthyroid AIT and healthy women in the first trimester of pregnancy, and to explore potential associations between them.Methods A total of 26 pregnant women with euthyroid AIT and 30 healthy pregnant women in their first trimester were enrolled. Gut microbiota profiles were analyzed using 16S rDNA gene sequencing, while fecal metabolomic profiling was performed via ultrahigh-performance liquid chromatography-mass spectrometry. Correlations between GM and fecal metabolites were further evaluated.Results Significant diferences in GM composition were observed between euthyroid AIT patients and healthy controls. Metabolomic analysis revealed distinct fecal metabolic signatures in euthyroid AIT patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that diferential metabolites were mainly involved in arachidonic acid metabolism, alpha-linolenic acid metabolism, serotonergic synapses, and bile secretion pathways. Furthermore, a relationship between specific gut microbes and altered fecal metabolites was identified in the euthyroid AIT group.Conclusions Pregnant women with euthyroid AIT in the first trimester exhibit distinct alterations in gut microbiota and fecal metabolic profiles, which may contribute to adverse pregnancy outcomes. Elucidating the correlations between GM and fecal metabolites may provide new insights into potential strategies for preventing and managing complications associated with euthyroid AIT in early pregnancy.

Thyroid disorders are common endocrine diseases worldwide, with an increasing incidence in recent years. However, the relationship between long-term carbon monoxide (CO) exposure and various types of thyroid disorders remains unclear. This study aimed to explore the association between long-term CO exposure and the odds of thyroid disorders in a Chinese adult population. Data from the Thyroid Disease, Iodine Nutrition, and Diabetes Epidemiology (TIDE) study were used, including 73,900 adult participants from 31 provinces in mainland China. Individual CO exposure levels were assessed using the Space Time Extra Trees model (1 × 1 km high-resolution data). Thyroid disorders were defined according to standard criteria, incorporating serum antibody levels (for thyroid autoimmunity [TA], thyroglobulin antibody [TgAb], and thyroid peroxidase antibody [TPOAb]) and thyroid function tests (for overt and subclinical hyper- and hypothyroidism). Multivariable generalized linear models were used to compute adjusted odds ratios (ORs). Higher levels of 5-year average CO exposure were associated with an increased prevalence of TA and TgAb positivity. Participants in the highest CO exposure quartile had 1.19 times the odds of TA and 1.33 times the odds of TgAb positivity compared to those in the lowest quartile. The exposure-response curve revealed a linear positive correlation between CO concentrations and the prevalence of TA and TgAb positivity, independent of iodine status and other confounders. No significant associations were observed for other thyroid disorders. In this large cross-sectional study, long-term exposure to higher ambient CO levels was associated with increased odds of TA, particularly TgAb positivity, with evidence of a dose-response relationship. These findings suggest a potential link between ambient CO exposure and TA, though causality cannot be established due to the cross-sectional design. Further longitudinal research is needed to elucidate causal mechanisms and potential interactions with other environmental pollutants.

Background To investigate the association between urinary iodine concentration (UIC) and metabolic abnormalities in a nationwide adult population in China. Methods Data were obtained from the Thyroid Disorders, Iodine Status and Diabetes Epidemiology study, a cross-sectional survey across 31 provinces in China. Adults were classified into iodine-deficient (< 100 µg/L), iodine-adequate (100–199 µg/L), iodine-more-than-adequate (200–299 µg/L), and iodine-excess (≥ 300 µg/L) groups based on UIC. High metabolic burden (HMB) was defined as the presence of ≥ 2 metabolic abnormalities. Multivariable logistic regression models evaluated associations between iodine status and metabolic abnormalities. Restricted cubic spline (RCS) models explored dose–response relationships. Results After adjustment, compared to the iodine-adequate group, those with iodine-excess had lower odds of metabolic abnormalities, including abdominal obesity (OR = 0.865), elevated blood pressure (OR = 0.821), hyperglycemia (OR = 0.905), hypertriglyceridemia (OR = 0.790), and HMB (OR = 0.846) (all P < 0.05). However, RCS analyses revealed complex, nonlinear dose–response relationships between UIC and metabolic abnormalities (all P for nonlinearity < 0.05), suggesting that increasing iodine levels do not consistently lead to a reduced risk of metabolic abnormalities, but rather exhibit varying patterns across different metabolic components. Conclusion Excess-iodine are associated with a lower risk of metabolic abnormalities, but the RCS analyses suggest a more complex relationship between UIC and metabolic abnormalities. These findings underscore the need for further prospective studies to explore the underlying mechanisms of this complex relationship. Clinical trial number : not applicable

OBJECTIVE:This study aimed to investigate the associations between per- and polyfluoroalkyl substances (PFAS) and distinct obesity-metabolic phenotypes and explore underlying mechanisms. METHODS:A total of 8692 adults from NHANES 2003-2018 were classified into four phenotypes as follows: metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy non-obesity (MHNO), and metabolically unhealthy non-obesity (MUNO). Multiple statistical models were used to evaluate the associations between PFAS exposure and distinct phenotypes. Network toxicology and molecular docking were employed for mechanistic exploration. RESULTS:Logistic regression analyses showed congener-specific associations of PFAS with MHO, MUO, and MUNO. PFUA was inversely associated with all three phenotypes (OR = 0.60, 0.55, and 0.79, respectively; p < 0.05). Weighted quantile sum (WQS), quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR) analyses consistently indicated the negative associations of PFAS mixture exposure with MHO (ORWQS = 0.67, log[OR]Qgcomp = -0.48; p < 0.001) and MUO (ORWQS = 0.81, log[OR]Qgcomp = -0.24; p < 0.001). Stratified BKMR suggested the inverse PFAS-BMI relationship was independent of metabolic status. The peroxisome proliferator-activated receptor signaling pathway was predicted to link PFAS and obesity-metabolic phenotypes. CONCLUSIONS:Although PFAS mixture exposure may not increase the risks of obesity and metabolic abnormalities, congener-specific effects on distinct phenotypes indicate the necessity of analyzing specific compositional profiles of PFAS exposure when evaluating endocrine toxicity.

Abstract Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.

BACKGROUND:Chronic iodine excess is associated with increased serum thyrotropin (TSH) levels. We assessed the independent and interactive effects of iodine-excess transition outcomes and aging on TSH levels over 20-year follow-up. METHODS:The original prospective cohort study started in 1999 and focused on three communities in North China (n = 1176). Based on the iodine status transition over the 20-year period, the euthyroid participants were categorized into groups according to urinary iodine concentrations (UIC): continuous iodine sufficiency (UIC 100-299 μg/L) (SI-SI, n = 261), from iodine excess (UIC >299 μg/L) to iodine deficiency (UIC <100 μg/L) (EI-DI, n = 145), from iodine excess to iodine sufficiency (EI-SI, n = 530), and continuous iodine excess (EI-EI, n = 240), respectively. RESULTS:During 1999-2004, the baseline median TSH levels were positively associated with the initial UIC levels. After 20 years, for participants with negative thyroid antibodies, the three iodine-excess groups all exhibited elevated median TSH levels (SI-SI 1.81 mU/L vs. EI-DI 2.19 mU/L vs. EI-SI 2.08 mU/L vs. EI-EI 2.01 mU/L), an increased prevalence of mild subclinical hypothyroidism (SCH) with TSH <10.0 mU/L (SI-SI 5.3% vs. EI-DI 11.2% vs. EI-SI 12.3% vs. EI-EI 9.4%) and reduced central thyroid hormone sensitivity compared with the SI-SI group (p < 0.05). However, the EI-EI group had the lowest TSH rising degree (SI-SI 0.32 mU/L [24.57%] vs. EI-DI 0.47 mU/L [24.56%] vs. EI-SI 0.45 mU/L [37.52%] vs. EI-EI 0.21 mU/L [14.18%], p < 0.05). Repeated-measures analysis revealed that aging was primarily related to a stable increase in TSH. Iodine-excess transition outcomes were also associated. Furthermore, a significant interaction effect existed between aging and different iodine-excess transition outcomes, modulating the TSH rising degree. Alleviation of iodine excess promoted aging-related TSH elevation, whereas persistent iodine excess suppressed aging-related TSH elevation. However, among participants with positive thyroid antibodies, no significant interaction effect above was observed. By comparison, there was a greater prevalence of SCH, especially an obvious high prevalence of severe SCH under persistent iodine excess. CONCLUSIONS:Elevated TSH levels induced by chronic iodine excess cannot be downregulated by reducing iodine intake. In nonautoimmune contexts, an interaction effect between iodine status and aging synergistically modulates the TSH rising degree. Iodine excess contributes to mild SCH and is correlated with high baseline TSH levels.

Background:Thyroid nodules (TNs) are common thyroid disorders. Vitamin D (VitD) is linked to thyroid disease risk, but prior studies mainly focused on total serum VitD and TN risk, ignoring different impacts of VitD3 and VitD2 metabolites on TN development. Methods:Between July and December 2021, we conducted a retrospective cohort study in Dalian, China, involving 2,037 euthyroid male petroleum workers (aged 30-60 years) without thyroid autoimmunity (TAI). Serum 25-hydroxy vitamin D [25(OH)VD], 25(OH)VD3 and 25(OH)VD2 levels were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The participants were classified into different groups according to their ultrasound images of TNs based on Chinese-Thyroid Imaging Reporting and Data System (C-TIRADS). C-TIRADS consist of 6 grades, and the upper three indicate TNs with potential malignancy. Results:Analysis of the cohort revealed the prevalence of TNs and VitD levels in this population. No C-TIRADS 5 or 6 nodules were identified. Serum 25(OH)VD levels in the C-TIRADS 4 TN group were significantly lower than those in the C-TIRADS 1, 2, and 3 groups. The overall prevalence of TNs was similar among the VitD-deficient, insufficient, and sufficient groups. However, the prevalence of patients with C-TIRADS 4 TNs was markedly higher in the VitD-deficient group (18.5%) than in the insufficient (5.5%, p < 0.001) and sufficient groups (4.1%, p < 0.001). Identical findings were observed among the groups with low, medium, and high serum 25(OH)VD3 levels, but not among those with different serum 25(OH)VD2 levels. Binary logistic regression analysis revealed that low VitD3 levels [25(OH)VD3 < 19.07 ng/mL] were associated with a significantly increased risk of developing C-TIRADS 4 TNs, with an adjusted odds ratio (OR) of 4.74 (95% confidence interval (CI) [3.13-7.18]; p < 0.001), compared to high VitD3 levels, after adjusting for confounding variables such as age, body mass index (BMI), thyroid function, thyroid autoantibodies, and season of blood draw. Conclusions:VitD3 deficiency, but not VitD2 deficiency, was independently associated with TNs with suspicious malignancy in euthyroid male petroleum workers aged 30-60 years.

BackgroundHashimoto’s Thyroiditis (HT) is the leading cause of primary hypothyroidism, characterized by progressive thyroid follicular cell (TFC) loss and diffuse lymphocytic infiltration. While apoptosis dominates TFC death in HT, the role of pro-inflammatory necroptosis in TFC destruction, especially its cellular heterogeneity, spatial distribution, and inflammatory microenvironmental regulation, remains incompletely elucidated.MethodsWe integrated spatial transcriptomics and multilevel functional validation to map necroptosis-associated cellular and molecular programs in HT. Thyroid tissues from a local clinical cohort were analyzed using transmission electron microscopy (TEM), immunohistochemistry, and immunoblotting to validate necroptosis-associated signatures. In vitro, Nthy-ori 3-1 cells were stimulated with TNF-α, with or without IFN-γ, to characterize necroptosis-associated signaling in thyrocytes.ResultsWe identified a distinct TFC subpopulation (Cluster 2) with high enrichment of the TNF signaling pathway and TNFRSF1A expression, which exhibited a necroptosis-susceptible phenotype and served as the core receiver of inflammatory signals from the immune microenvironment. Pseudotime trajectory analysis showed synchronous upregulation of transcripts of core necroptotic molecules (RIPK3, MLKL) at a critical threshold during TFC dedifferentiation. The TEM revealed necroptosis-compatible ultrastructural features in HT thyrocytes. Notably, HT tissues showed an RIPK3-MLKL-predominant necroptosis-associated pattern, with no significant changes in total or phosphorylated RIPK1. Clinically, the expression of necroptosis-related markers (ZBP1, RIPK3, MLKL) in thyroid tissues and circulating pro-inflammatory cytokines (IL-6, IL-1β, IL-1α) in serum were significantly correlated with thyroid autoantibody (TPOAb, TgAb) titers and TFC dedifferentiation. In vitro, pharmacological inhibition of RIPK3 or MLKL effectively preserved thyrocyte membrane integrity, reduced cell death, and suppressed the secretion of pro-inflammatory cytokines.ConclusionsOur study provides a multimodal characterization of necroptosis in HT, showing that the inflammatory immune microenvironment is associated with TFC loss and activation of an RIPK3-MLKL-predominant necroptosis-related program, without detectable upregulation of total or phosphorylated RIPK1. Targeting the RIPK3-MLKL axis may represent an experimental therapeutic hypothesis that requires further validation in primary thyrocytes, organoids, and in vivo HT models.

Evidence linking long-term exposure to particulate matter with thyroid dysfunction is increasing, but data on particulate matter 10 micrometers or less (PM10) exposure and thyroid disorders remain limited. 73,900 subjects aged ≥ 18 years from a nationwide population-based study were included. Thyroid disorders were determined using standardized biochemical testing and thyroid ultrasound examination. Individual long-term PM10 exposure was estimated at a 1 × 1 km spatial resolution using a Space-Time Extra Trees model, and the five-year average concentration preceding enrollment was assigned to each participant's residential address. Weighted estimates were calculated to account for the complex sampling design. The average long-term exposure to PM10 at residential addresses was 111.74 µg/m3, ranging from 35.08 µg/m³ to 374.8 µg/m³. Compared with those in the first quartile (35.08 to 75.50 µg/m³), participants in the highest PM10 quartile (130.80 to 374.80 µg/m³) had higher odds of overt hypothyroidism (OR 1.36 [CI 1.03–1.79]), subclinical hypothyroidism (1.14 [1.04–1.25]), autoimmune thyroiditis (1.10 [1.01–1.20]) and thyroglobulin antibody positivity (1.24 [1.12–1.37]). Each 10 µg/m³ increase in the PM10 concentration was associated with higher odds of overt hypothyroidism (OR 1.16 [1.07–1.25]) and subclinical hypothyroidism (1.07 [1.04–1.10]). TgAb positivity showed an increasing exposure-response pattern across PM10 concentrations. No consistent significant associations were observed for overt hyperthyroidism, subclinical hyperthyroidism, Graves’ disease, or thyroid peroxidase antibody positivity. Long-term PM10 exposure was associated with higher odds of overt hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and TgAb positivity among Chinese adults. These findings suggest that coarse particulate pollution may be a modifiable environmental factor related to hypothyroidism and thyroid autoimmunity.

The relationship between maternal thyroid function and intellectual development of offspring is controversial. Iodine may be an important confounding factor. This study investigated whether maternal iodine status could affect the efficacy of levothyroxine (LT4) treatment during early pregnancy on the intellectual growth of progeny.This prospective study divided participants into two groups; the normal iodine group included 53 mother–child pairs and the low iodine group included 60 mother–child pairs (urinary iodine concentration (UIC) ≥ 150 µg/L and UIC < 150 µg/L). Each iodine status group was further subdivided according to specific maternal thyroid disorders. The two groups were categorized as follows: Control(N), hypothyroxinemia (IH) + LT4, subclinical hypothyroidism (SCH) + LT4, positive thyroid peroxidase antibodies (TPOAbs) + LT4. Finally, the study included eight groups. The Bayley Scales of Infant Development-II were employed to evaluate the neurodevelopment of children (age: 12 -30 months). The main results were age-adjusted scores from the Mental Development Index (MDI) and Psychomotor Development Index (PDI).We found that: 1) Under the similar conditions of thyroid function and treatment, iodine deficiency during early pregnancy reduced the MDI value of the offspring (P < 0.001), while, the PDI value was not affected (P = 0.276). Linear regression demonstrated a substantial positive correlation between maternal UIC and MDI of offspring (B = 0.09 [CI 0.06–0.13]; P = 0.01). In the case of iodine deficiency during pregnancy, LT4 treatment on SCH and IH could not improve offspring MDI scores (P < 0.001, P = 0.037, respectively) in contrast to the normal group. However, under normal iodine status during pregnancy, LT4 treatment on SCH and IH could improve offspring MDI scores (P = 0.525, P = 0.650, respectively) compared with the normal group. Concurrently, the PDI of the aforementioned categories did not differ significantly (P > 0.05). 3) In comparison to the normal group, LT4 treatment on TPOAbs during pregnancy could not improve the MDI of the offspring, regardless of whether the iodine nutritional status was normal or not (P < 0.001, P = 0.047, respectively). These findings suggest that concurrent assessment and optimization of both thyroid function and iodine status during early pregnancy may be essential for maximizing offspring intellectual development.

STUDY QUESTION:Does levothyroxine (LT4) treatment reduce adverse pregnancy outcomes in pregnant women with thyroid dysfunction? SUMMARY ANSWER:LT4 treatment significantly reduces the risks of pregnancy loss, preterm delivery, and gestational hypertension, with no significant impacts on rates of live birth, placental abruption, or gestational diabetes. WHAT IS KNOWN ALREADY:Multiple meta-analyses have examined the impact of LT4 on pregnancy outcomes, but quantitative confidence assessments are still lacking. Thus, an umbrella review is needed to systematically synthesize and assess the quality of this evidence. STUDY DESIGN SIZE DURATION:This umbrella review of systematic reviews and meta-analyses used PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Searches included studies published in English or Chinese up to 20 March 2025. PARTICIPANTS/MATERIALS SETTING METHODS:Included studies were systematic reviews or meta-analyses of randomized controlled trials assessing the effects of LT4 on pregnancy outcomes in women with subclinical hypothyroidism (SCH) or thyroid peroxidase antibody (TPOAb) positivity. A set of 24 associations across six pregnancy outcomes were analyzed: pregnancy loss, preterm delivery, live birth, placental abruption, gestational hypertension, and gestational diabetes. Methodological quality was assessed using AMSTAR 1, and evidence quality was graded using GRADE. Sensitivity analyses were conducted to confirm robustness. MAIN RESULTS AND THE ROLE OF CHANCE:Eleven meta-analyses were included. High-quality evidence showed that LT4 treatment reduced the risks of pregnancy loss (RR = 0.43; class III evidence), preterm delivery (RR = 0.56; class III evidence), and gestational hypertension (RR = 0.63; class IV evidence). Moderate-to-low-quality evidence indicated no significant impact on rates of live birth, placental abruption, or gestational diabetes. Of the 24 associations, 22 were rated as high confidence and two as medium confidence based on AMSTAR 1. Sensitivity analyses confirmed the robustness of the findings, but treatment effects varied according to the study population, treatment timing, and method. For pregnancy loss and preterm delivery outcomes, the risk was significantly reduced only when LT4 treatment was initiated in early pregnancy (pregnancy loss: RR = 0.60, P = 0.03; RR = 0.59, P = 0.003; preterm labor: RR = 0.58, P < 0.0001; RR = 0.46, P < 0.00001). Additionally, women with TSH levels greater than 4.0 mU/l derived greater benefits from LT4 treatment compared to those with TSH levels between 2.5 and 4.0 mU/l. LIMITATIONS REASONS FOR CAUTION:Limitations include small sample sizes, potential biases (selection and reporting), and language restrictions to English and Chinese studies, which may affect generalizability. WIDER IMPLICATIONS OF THE FINDINGS:By integrating high-quality evidence, this study confirms that LT4 can reduce the risk of pregnancy loss and preterm delivery in pregnant women with thyroid dysfunction, supports its clinical application in specific populations, such as SCH patients with positive TPOAb or TSH > 4.0 mU/l, and warns against the risk of overtreatment. The results of this study provide an evidence base for clinical precision intervention. Future studies should address the heterogeneity through standardized large studies, clarify the dose threshold, and evaluate the long-term health effects of LT4 on mothers and infants, to further improve the guidelines and optimize risk stratification management. STUDY FUNDING/COMPETING INTERESTS:This work was supported by the National Key R&D Program of China (Grant No. 2023YFC2508300, 2023YFC2508303, and 2023YFC2508305), the National Science and Technology Major Project (Grant No. 2024ZD0533403), and the National Natural Science Foundation of China (Grant No. 82100831, 81570709, and 82470826). All authors declared no competing interests. REGISTRATION NUMBER:CRD42024586105.

Objective Dysthyroid optic neuropathy (DON) is a severe complication of thyroid eye disease (TED) with limited early detection methods. This study aimed to investigate the clinical characteristics of patients with TED who developed DON and to establish a predictive model for early identification of high-risk cases. Methods Herein, 257 TED patients were prospectively included, of whom 68 (26.5%) developed DON. All patients were divided into derivation and validation cohorts, and Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression analyses were applied to identify clinical factors and construct a prediction model. Results In the derivation cohort (185 TED patients), 49 (26.5%) developed DON. DON patients showed significantly higher prevalence of pretibial myxedema (PTM) (22.4 vs 5.9%, P = 0.001), diabetes mellitus (18.4 vs 7.4%, P = 0.029), older age (58.04 ± 11.30 years vs 47.99 ± 10.65 years, P < 0.001), higher CAS (5 vs 4, P < 0.001), elevated triglyceride (TG) levels (1.44 mmol/L vs 1.15 mmol/L, P = 0.042), and lower visual functioning (VF) (43.75 vs 62.50, P < 0.001). LASSO regression analysis identified age, PTM, TG, VF, and CAS as independent predictors of DON. The developed nomogram presented AUCs of 0.853 (95% CI: 0.792–0.914) and 0.856 (95% CI: 0.762–0.950) in the derivation and validation cohorts, respectively. Conclusions Altogether, the findings of this study identify advanced age, elevated CAS, increased TG, lower VF, and PTM as significant predictors of DON in patients with TED. The proposed nomogram offers a practical clinical tool for risk stratification, providing clinicians with an approach for individualized risk assessment and timely therapeutic intervention.

Background:Observational studies have reported associations between thyroid function, encompassing free thyroxine, thyroid-stimulating hormone, hyperthyroidism, and hypothyroidism, and female-specific cancers such as endometrial, breast, ovarian, and cervical cancers. However, the causal relationship remains unclear. Objective:The researchers aimed to explore the causal relationship between thyroid function and female-specific cancers, while also investigating the role of sex hormones (total testosterone and estradiol) as potential mediators in this association. Methods:Initially, the researchers preformed bidirectional two-sample (T-S) Mendelian randomization (MR) analysis using summary-level Genome-wide association studies to investigate the causal relationship between thyroid function and female-specific cancers. Subsequently, the researchers employed mediation MR analysis to assess the potential role of sex hormones as intermediaries in this relationship. The robustness of the findings of this study was further validated through a series of sensitivity analyses. Lastly, the researchers conducted bioinformatics analyses to explore underlying mechanisms, leveraging potentially relevant genes. Results:Bidirectional T-S MR analyses indicated that hypothyroidism reduces the risk of endometrial cancer (OR: 0.33, P = 0.002) and breast cancer (OR: 0.48, P < 0.001). Mediation MR analyses further suggested that hypothyroidism may lower the risk of both endometrial and breast cancers by decreasing levels of total testosterone. Conclusion:The researchers established the causal relationship between thyroid function and female-specific cancers, offering novel perspectives for the early prevention and intervention of endometrial and breast cancer. Furthermore, the researchers investigated the mediating role of sex hormones in the association between hypothyroidism and these cancers, providing valuable insights for future mechanistic research.

ObjectivesInflammasomes are associated with various autoimmune diseases. Herein, we aimed to study the occurrence of inflammasomes in peripheral blood mononuclear cells (PBMCs) from patients with autoimmune thyroiditis (AIT), and the relationship between their abundance and the inflammatory response index of AIT. Furthermore, we examined the effect of iodine on inflammasomes containing NLR family pyrin domain-containing 3 (NLRP3) and inflammasome activation of helper T (Th) cell differentiation regulation in cultured PBMCs.MethodsWe collected PBMCs and serum samples from 50 patients with AIT with normal thyroid function and 50 controls matched for age and sex. In PBMCs, the mRNA and protein expressions of certain inflammasome constituents (e.g., NLRP1, NLRP3, absent in melanoma 2 (AIM2) and caspase-1), interleukin (IL)-1β and IL-18 were assessed using qRT-PCR and western blotting. Enzyme-linked immunosorbent assays (ELISAs) assessed the serum levels of IL-1β and IL-18. Flow cytometry was employed to examine NLRP3 expression on CD14+ monocytes and Th1 and Th17 cell percentages in the groups. AIT- or healthy control-derived PBMCs were stimulated using sodium iodide, with or without lipopolysaccharide (LPS) for 72 h.ResultsPBMCs from patients with AIT had significantly higher levels of pro-IL-18, pro-IL-1β and NLRP3 than did the PBMCs from the healthy controls (P < 0.05). Compared with those from the controls, AIT-derived PBMCs had enhanced levels of active IL-18 and active caspase-1 p20 (P < 0.05), whereas their abundance of active IL-1β was similar (P > 0.05). In serum, the AIT group had enhanced levels of IL-18 compared with the healthy controls (P < 0.05) but had similar levels of IL-1β (P > 0.05). NLRP3 expression on CD14+ monocytes from AIT patients was significantly augmented compared with the healthy controls (P< 0.01). Significantly increased percentages of Th1 and Th17 cells were detected in AIT patients compared with those in the healthy participants (P < 0.001). Sodium iodide treatment upregulated NLRP3 expression in PBMCs during 72 h of culture (P < 0.001). The percentage of Th1 and Th17 cells in AIT patients increased in an iodine-dependent manner (P < 0.01). Iodine had no significant effect on the number of these cells in the healthy control group (P > 0.05).ConclusionAIT-derived PBMC NLRP3 activity and expression increased. Iodine might regulate the immune and inflammatory response of patients with AIT by activating NLRP3 and promoting Th1 and Th17 cell differentiation.

Autoimmune thyroiditis is among the most prevalent autoimmune endocrine illnesses. However, the pathophysiology has not been determined, and efficacious treatments are still lacking. The current study used network pharmacology analysis and an experimental autoimmune thyroiditis (EAT) mouse model to explore whether dihydroartemisinin (DHA) has therapeutic effects on autoimmune thyroiditis and to investigate the potentially related mechanisms concerning oxidative stress (OS) responses and T-cell immune imbalance. The therapeutic effects of DHA on autoimmune thyroiditis and potentially related processes were first anticipated using network pharmacology analysis and then verified using the EAT model. DHA may influence the onset of autoimmune thyroiditis by regulating immune imbalance and OS responses, according to network pharmacology analysis. ELISA, immunofluorescence staining, and histopathological examination were used to detect changes in serum thyroid autoantibody levels and intrathyroidal inflammatory infiltration following DHA intervention. RT-PCR was used to determine the spleen's mRNA expression of typical T-cell cytokines, whereas an OS kit and immunohistochemical staining were used to assess the thyroid's glutathione (GSH) content, superoxide dismutase (SOD) activity, and Nrf2 protein expression. Furthermore, serum TgAb levels and intrathyroidal inflammatory infiltrates were considerably lower in EAT mice given high-dose DHA than in vehicle-treated controls. In the spleen, IFN-γ, IL-17A, and IL-6 mRNA expressions were dramatically downregulated, while IL-4 and IL-10 were significantly raised. Following high-dose DHA treatment, GSH content, SOD activity, and Nrf2 protein expression levels were markedly increased in thyroid tissue. These findings imply that DHA administration may suppress TgAb formation and reduce intrathyroidal inflammatory cell infiltration by restoring T-cell immune imbalance and increasing antioxidant capacity via the Nrf2 pathway. This study provides important experimental data for DHA's therapeutic use in patients with autoimmune thyroiditis.

Objective Thyroid parameters undergo significant dynamic changes during pregnancy. This study aimed to comprehensively analyze the impact of abnormal thyroid parameters in each trimester on the incidence of common adverse obstetric outcomes.Methods Blood samples drawn for thyroid parameters in each trimester during the antenatal period were determined after the participants gave birth. Serum thyrotropin, free thyroxine, free triiodothyronine, anti-thyroid peroxidase antibody (TPOAb), and anti-thyroglobulin antibody (TgAb) levels were tested using electrochemiluminescence immunoassays.Results Among all the participants, TAI and hypothyroxinemia in the first trimester (T1) were significantly related to an increased risk of gestational hypertension (OR=5.136, 95% CI 1.537-17.158 and OR=7.683, 95% CI: 1.890-31.229, respectively). Additionally, subclinical hypothyroidism in T1 was independently associated with a higher risk of postpartum hemorrhage (OR = 38.063, 95% CI 2.091-692.834). Besides, subclinical thyrotoxicosis in T1 showed a significant correlation with a raised risk of small for gestational age (OR=14.650, 95% CI 1.221-175.760). Among euthyroid women during the whole pregnancy, either TPOAb+ or TgAb+ in the third trimester was an independent risk factor of premature birth (OR=5.092, 95% CI 1.059-24.481) and low birth weight (OR=8.165, 95% CI 1.717-38.824), respectively.Conclusion Our findings indicate the importance of screening thyroid parameters in early pregnancy and the need to dynamically monitor these parameters throughout the entire pregnancy.

It is estimated that by the year 2050, 16% of the world’s population will be 65 years old and above. As the global aging population continues to grow, there is an increasing focus on thyroid disorders among older individuals. Thyrotropin is widely used in diagnosing subclinical thyroid diseases due to its high sensitivity as an indicator of changes in thyroid function. However, thyrotropin levels change with age, and different reference intervals have been proposed in various studies. The variation in thyrotropin ranges among older adults is probably caused by the heterogeneity of the studied population. This review aims to provide an overview of the existing literature on thyrotropin reference intervals in older adults and their distinction as adaptive or pathologic. Recent research indicates that older individuals may have slightly elevated levels of thyrotropin and higher upper limits of reference intervals. Therefore, a higher thyrotropin threshold for diagnosing and treating subclinical hypothyroidism in the elderly seems reasonable.

BACKGROUND:Studies on the impact of blood glucose indicators on metabolism remain relatively scarce. The aim of this study was to investigate the associations between blood glucose indicators and metabolic disorders in China. METHODS:Data were from the Thyroid disorders, Iodine status and Diabetes Epidemiological survey (TIDE survey), which randomly selected 31 cities from 31 provinces in the Chinese mainland. A total of 68,383 participants without preexisting diabetes and have complete data on blood glucose, lipids, and blood pressure were included in the analysis. The diabetic population was divided into seven groups based on different types of elevated blood glucose levels, including fasting plasma glucose (FPG), postprandial glucose (PPG), and hemoglobin A1c (HbA1c): FPG ≥7 mmol/L; PPG ≥11.1 mmol/L; HbA1c ≥6.5%; FPG ≥7 mmol/L and PPG ≥11.1 mmol/L; FPG ≥7 mmol/L and HbA1c ≥6.5%; PPG ≥11.1 mmol/L and HbA1c ≥6.5%; FPG ≥7 mmol/L, PPG ≥11.1 mmol/L, and HbA1c ≥6.5%. The effects of each blood glucose indicator on metabolism were investigated separately. Weighted calculation was applied during the analysis, with the weighting coefficient based on the number of people corresponding to the population characteristics of each sample in the 2010 Chinese Census. A logistic regression model with restricted cubic splines (RCS) was employed to characterize the nonlinear associations of age and body mass index (BMI) with the risk of diabetes subtypes defined by distinct blood glucose indicators elevations, as well as the relationships between different blood glucose indicators (FPG, PPG, HbA1c) and the risk of metabolic disorders such as hypertension, hypertriglyceridemia, hypercholesterolemia, high low-density lipoprotein cholesterol (high LDL-C) and low high-density lipoprotein cholesterol (low HDL-C). RESULTS:Among individuals with diabetes, elevated PPG alone was the most common abnormality, affecting 26.96% (1382/5127) of the population. Among the seven groups with only one elevated blood glucose indicator, individuals with elevated PPG alone exhibited the highest mean levels of triglycerides (TG) at 2.11 mmol/L (95% confidence interval [CI]: 1.97-2.25 mmol/L, P = 0.004), total cholesterol (TC) at 5.26 mmol/L (95% CI: 5.18-5.33 mmol/L, P <0.001), and low-density lipoprotein cholesterol (LDL-C) at 3.12 mmol/L, (95% CI: 3.06-3.19 mmol/L, P = 0.001). Individuals with elevated PPG alone showed a high prevalence of hypertension (806/1382, 58.32%), hypertriglyceridemia (676/1382, 48.91%), hypercholesterolemia (694/1382, 50.22%), High LDL-C (525/1382, 37.94%), and Low HDL-C (364/1382, 26.34%). The association of age and BMI with the risk of diabetes revealed that the older the patient, the steeper the RCS curve for the odds ratio (OR) of diabetes with elevated PPG alone (age = 60, OR = 2.79, 95% CI [2.49-3.12], P <0.01). Similarly, as BMI increased, the RCS curve for the OR of diabetes with elevated HbA1c alone also steepened (BMI = 35, OR = 3.75, 95% CI [3.23-4.35], P <0.001). Additionally, the RCS yielded a positive association between blood glucose indicators and metabolic diseases risk. In individuals with diabetes, RCS for both the ORs of metabolic diseases (hypertension, hypertriglyceridemia, hypercholesterolemia, high LDL-C, low HDL-C) and the levels of metabolic indicators (TG, TC, LDL-C, HDL-C) revealed some inflection points within the ranges of FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%. CONCLUSIONS:PPG is more closely related to metabolic disorders than FPG and HbA1c in people with diabetes. For patients with diabetes and metabolic disorders, it may be necessary to monitor blood glucose fluctuations within specific ranges (FPG 5-6 mmol/L, PPG 6-8 mmol/L, and HbA1c 5.5-6.0%).