Exercise Training and Spexin Ameliorate Thyroid Changes in Obese Type 2-Diabetic Rats: The Possible Interlaying Mechanisms.

Thyroid dysfunction and diabetes mellitus are prevalent endocrine disorders that often coexist and influence each other. The role of spexin (SPX) in diabetes and obesity is well-documented, but its connection to thyroid function is less understood. This study investigates the influence of exercise (EX) and SPX on thyroid hypofunction in obese type 2 diabetic rats. Rats were divided into normal control, obese diabetic sedentary, obese diabetic EX, and obese diabetic SPX groups, with subdivisions for M871, and HT-2157 treatment in the later 2 groups. High-fat diet together with streptozotocin injection induced obesity and diabetes. The EX-group underwent swimming, while the SPX-group received SPX injections for eight weeks. Results showed significant improvements in thyroid function, metabolic, oxidative, and inflammatory states with EX and SPX-treatment. The study also explored the involvement of galanin receptor isoforms (GALR) 2/3 in SPX effects on thyroid function. Blocking GALR2/3 receptors partially attenuated the beneficial effects, indicating their interaction. These findings underscore the importance of EX and SPX in modulating thyroid function in obesity and diabetes. Comprehending this interplay could enable the development of new treatment approaches for thyroid disorders associated with obese type 2 diabetes. Additional research is necessary to clarify the exact mechanisms connecting SPX, EX activity, and thyroid function.

Systematic review of epidemiological and toxicological evidence on health effects of fluoride in drinking water.

INTRODUCTION: Fluoride is a naturally occurring substance that is also added to drinking water, dental hygiene products, and food supplements for preventing dental caries. Concerns have been raised about several other potential health risks of fluoride. OBJECTIVE: To conduct a robust synthesis of evidence regarding human health risks due to exposure to fluoride in drinking water, and to develop a point of departure (POD) for setting a health-based value (HBV) for fluoride in drinking water. METHODS: A systematic review of evidence published since recent reviews of human, animal, and in vitro data was carried out. Bradford Hill considerations were used to weigh the evidence for causality. Several key studies were considered for deriving PODs. RESULTS: The current review identified 89 human studies, 199 animal studies, and 10 major in vitro reviews. The weight of evidence on 39 health endpoints was presented. In addition to dental fluorosis, evidence was considered strong for reduction in IQ scores in children, moderate for thyroid dysfunction, weak for kidney dysfunction, and limited for sex hormone disruptions. CONCLUSION: The current review identified moderate dental fluorosis and reduction in IQ scores in children as the most relevant endpoints for establishing an HBV for fluoride in drinking water. PODs were derived for these two endpoints, although there is still some uncertainty in the causal weight of evidence for causality for reducing IQ scores in children and considerable uncertainty in the derivation of its POD. Given our evaluation of the overall weight of evidence, moderate dental fluorosis is suggested as the key endpoint until more evidence is accumulated on possible reduction of IQ scores effects. A POD of 1.56 mg fluoride/L for moderate dental fluorosis may be preferred as a starting point for setting an HBV for fluoride in drinking water to protect against moderate and severe dental fluorosis. Although outside the scope of the current review, precautionary concerns for potential neurodevelopmental cognitive effects may warrant special consideration in the derivation of the HBV for fluoride in drinking water.

Evaluation of thyroid dysfunction in childhood-onset systemic lupus erythematosus: Risk factors for Hashimoto's thyroiditis.

OBJECTIVE: Increased frequency of autoimmune thyroid disease, particularly Hashimoto's thyroiditis (HT) was reported several studies in the literature, in individuals with childhood-onset systemic lupus erythematosus (cSLE). Our study aimed to investigate the prevalence and contributing factors of thyroid dysfunction and HT among cSLE patients. METHODS: Thyroid function tests were obtained cross-sectionally from cSLE patients. Demographic, clinical, and laboratory characteristics and activity scores were collected from medical records. Patients diagnosed with cSLE were compared to the healthy control group for the frequency of thyroid dysfunction. The Mann-Whitney U, independent samples t test, and the Chi-square or Fisher's exact test were used to compare study groups. A p-value below 0.05 was considered statistically significant. RESULTS: Out of 73 cSLE patients, 14 (19.1%) had subclinical hypothyroidism, 9 (12.3%) had clinical hypothyroidism, 12 (16.4%) were diagnosed with HT, and 12 (16.4%) had a family history of HT. Thyroid USG was performed in 5 euthyroid patients and 1 borderline subclinical hypothyroid patient with positive thyroid autoantibody and reported as diffuse heterogeneous echogenicity enlargement in the thyroid gland. There were no significant differences in clinical and laboratory data or medication used between the groups with and without HT; however, patients with HT had a higher frequency of clinical hypothyroidism and family history of HT. Cumulative prednisolone dose was significantly lower in patients diagnosed with HT. The frequency of HT was considerably higher in patients with cSLE compared to the healthy control group. CONCLUSION: The results demonstrate an increased incidence of HT in cSLE patients, even if they are euthyroid, and recommend that cSLE patients be screened more frequently.

Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study.

AIM: We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). MATERIALS AND METHODS: In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. RESULTS: After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. CONCLUSIONS: In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

Thyroid function spectrum in Cushing's syndrome.

PURPOSE: Thyroid disorders have been reported in hypercortisolism patients. Endogenous Cushing's syndrome (CS) potentially complicates its metabolic sequelae. We investigated thyroid function in CS patients to determine this relationship. METHODS: In this cross-sectional study, we screened CS patients from 2016 to 2019 at our hospital. Patient demographic, medical history, and laboratory data were collected. Additionally, we performed a meta-analysis to demonstrate the prevalence of thyroid dysfunction in patients with CS. RESULTS: Among 129 CS patients, 48.6% had triiodothyronine (TT3), 27.9% had thyroxine (TT4), 24.6% had free T3 (FT3), 27.7% had free T4 (FT4), and 6.2% had thyroid-stimulating hormone (TSH) levels below the reference values. Those with clinical CS showed more pronounced thyroid suppression than did those with subclinical CS. Cortisol levels were markedly greater in patients with pituitary hypothyroidism (P < 0.001). Serum cortisol levels throughout the day and post low-dose dexamethasone-suppression test (LDDST) results correlated with thyroid hormone levels, particularly in ACTH-independent CS. Correlations varied by thyroid status; FT3 and TSH were linked to cortisol in euthyroid individuals but not in those with low T3 or central hypothyroidism. TSH levels notably halved from the lowest to highest cortisol tertile post-LDDST. Finally, meta-analysis showed 22.7% (95% CI 12.6%-32.9%) central hypothyroidism in 528 CS patients of nine studies. CONCLUSION: Thyroid hormone levels are significantly correlated with cortisol levels and are impaired in patients with CS. However, the physiological adaptation and pathological conditions need further study.

Development and Validation of a Prediction Model for Thyroid Dysfunction in Patients During Immunotherapy.

OBJECTIVE: This study was designed to develop and validate a predictive model for assessing the risk of thyroid toxicity following treatment with immune checkpoint inhibitors. METHODS: A retrospective analysis was conducted on a cohort of 586 patients diagnosed with malignant tumors who received programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. Logistic regression analyses were performed on the training set to identify risk factors of thyroid dysfunction, and a nomogram was developed based on these findings. Internal validation was performed using K-fold cross-validation on the validation set. The performance of the nomogram was assessed in terms of discrimination and calibration. Additionally, decision curve analysis was utilized to demonstrate the decision efficiency of the model. RESULTS: Our clinical prediction model consisted of 4 independent predictors of thyroid immune-related adverse events, namely baseline thyrotropin (TSH, OR = 1.427, 95%CI:1.163-1.876), baseline thyroglobulin antibody (TgAb, OR = 1.105, 95%CI:1.035-1.180), baseline thyroid peroxidase antibody (TPOAb, OR = 1.172, 95%CI:1.110-1.237), and baseline platelet count (platelet, OR = 1.004, 95%CI:1.000-1.007). The developed nomogram achieved excellent discrimination with an area under the curve of 0.863 (95%CI: 0.817-0.909) and 0.885 (95%CI: 0.827-0.944) in the training and internal validation cohorts respectively. Calibration curves exhibited a good fit, and the decision curve indicated favorable clinical benefits. CONCLUSION: The proposed nomogram serves as an effective and intuitive tool for predicting the risk of thyroid immune-related adverse events, facilitating clinicians making individualized decisions based on patient-specific information.

Risk of Incident Thyroid Dysfunction in the Post-Acute Phase of COVID-19: A Population-Based Cohort Study in Hong Kong.

OBJECTIVE: The evidence of thyroid dysfunction in the post-acute phase of SARS-CoV-2 infection is limited. This study aimed to evaluate the risk of incident thyroid dysfunction in the post-acute phase of COVID-19. METHODS: This retrospective, propensity-score matched, population-based study included COVID-19 patients and non-COVID-19 individuals between January 2020 and March 2022, identified from the electronic medical records of the Hong Kong Hospital Authority. The cohort was followed up until the occurrence of outcomes, death, or 31 January 2023, whichever came first. Patients with COVID-19 were 1:1 matched to controls based on various variables. The primary outcome was a composite of thyroid dysfunction (hyperthyroidism, hypothyroidism, initiation of antithyroid drug or levothyroxine, and thyroiditis). Cox regression was employed to evaluate the risk of incident thyroid dysfunction during the post-acute phase. RESULTS: A total of 84 034 COVID-19 survivors and 84 034 matched controls were identified. Upon a median follow-up of 303 days, there was no significant increase in the risk of diagnosed thyroid dysfunction in the post-acute phase of COVID-19 (hazard ratio [HR] 1.058, 95% confidence interval 0.979-1.144, P = .154). Regarding the secondary outcomes, patients with COVID-19 did not have increased risk of hyperthyroidism (HR 1.061, P = .345), hypothyroidism (HR 1.062, P = .255), initiation of antithyroid drug (HR 1.302, P = .070), initiation of levothyroxine (HR 1.086, P = .426), or thyroiditis (P = .252). Subgroup and sensitivity analyses were largely consistent with the main analyses. CONCLUSION: Our population-based cohort study provided important reassuring data that COVID-19 was unlikely to be associated with persistent effects on thyroid function.

No causal relationship between thyroid function and Parkinson's disease: A bidirectional Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is the second most prevalent degenerative disease globally. While observational studies have demonstrated a correlation between thyroid function and PD, the causal relationship between these two factors remains uncertain. METHODS: A bidirectional Mendelian randomization (MR) analysis was performed to explore the causal relationship between thyroid function (free thyroxine [FT4], thyroid-stimulating hormone [TSH], hyperthyroidism, and hypothyroidism) and PD. GWAS summary-level statistics of thyroid function and PD were obtained from publicly available GWAS databases. The inverse variance weighted method was the main MR approach to assess causal associations. In addition, two additional MR methods (MR-Egger regression and weighted median) were performed to supplement the IVW. Furthermore, various sensitivity tests were performed to verify the reliability of the MR findings: (i) Heterogeneity was examined by Cochrane's Q test. (ii) Horizontal pleiotropy was assessed by the MR-Egger intercept test and MR-PRESSO global test. (iii) The robustness of MR results was estimated using the leave-one-out method. RESULTS: Various MR results showed that FT4, TSH, hyperthyroidism, and hypothyroidism did not causally affect PD (P > 0.05). Likewise, PD did not causally affect FT4, TSH, hyperthyroidism, and hypothyroidism (P > 0.05). Cochrane's Q test indicated that MR analysis was not affected by significant heterogeneity (P > 0.05). MR-Egger intercept test and MR-PRESSO global test indicated that MR analysis was not affected by a remarkable horizontal pleiotropy (P > 0.05). The leave-one-out method demonstrated the stability of MR results. CONCLUSION: MR analysis did not support a causal relationship between thyroid function and PD.

Iron Status, Thyroid Dysfunction, and Iron Deficiency Anemia: A Two-Sample Mendelian Randomization Study.

INTRODUCTION: Given the clinical association between thyroid dysfunction and iron deficiency anemia (IDA), as well as their shared association with iron status, this study aimed to investigate the causal relationship between iron status and thyroid dysfunction, while also examining the risk of IDA in relation to thyroid dysfunction. METHODS: A two-sample mendelian randomization (MR) study was conducted to identify the causal relationship of iron status on thyroid dysfunction, as well as thyroid dysfunction on IDA. Large-scale European population-based genome-wide association study databases were utilized (Genetics of Iron Status consortium, ThyroidOmics consortium, FinnGen consortium, and UK Biobank). Inverse variance-weighted (IVW) was used as the main analysis. In addition, we used weighted median and MR-Egger to enhance the robustness. Sensitivity analysis was conducted to evaluate the robustness of MR results. RESULTS: The IVW estimates did not reveal any significant causal relationship between serum iron status markers and thyroid dysfunction. However, a significant causal relationship was observed between hypothyroidism and IDA (odds ratio [OR] = 1.101, 95% confidence interval [CI] = 1.048-1.157, p < 0.001). Repeated analyses also demonstrated a similar trend (OR = 1.023, 95% CI = 1.011-1.035, p < 0.001). Sensitivity analysis supported that the MR estimates were robust. CONCLUSION: In our MR study, an upregulation of the hypothyroidism-associated gene was found to be significantly associated with an elevated risk of IDA in the European population. These findings may offer novel therapeutic insights for clinicians managing patients with hypothyroidism, IDA, or their comorbidities.

Burden of Thyroid Dysfunction Among Type 2 Diabetes Mellitus Patients in South East Nigeria with Emphasis on its Prevalence and Pattern of Presentation: A Case-Controlled Study.

BACKGROUND: Studies from different parts of the world on thyroid dysfunction have shown it to be widespread in patients with type 2 diabetes mellitus (T2DM); however, there is insufficient local data to support this observation. AIM: To determine the burden of thyroid dysfunction among patients with T2DM at a Tertiary Hospital in Southeast Nigeria with emphasis on its prevalence and pattern of presentation. METHODS: Four hundred and seventy-two subjects were recruited for the study. All the subjects (100%) were of African descent. Three hundred and fifty-four (354) of them were patients with T2DM, while 118 subjects who did not have T2DM served as the controls. This study is a descriptive cross-sectional study involving patients with type 2 diabetes mellitus attending the Diabetes Clinic or receiving treatment in the Medical Wards. Subjects were recruited using systematic sampling. The first patient was selected by simple random sampling, and subsequently, every consecutive subject was selected. Blood samples were tested for HbA1c, fT3, fT4, thyrotropin, and thyroid stimulating hormone. Socio-demographic information was retrieved from patient medical records. We used the Student's t-test for statistical comparison of quantitative variables such as weight, height, blood pressure, serum TSH, and serum T3; while for comparison of proportions, we used a Chi-squared test. We set a p-value of less than 0.05 to be statistically significant. RESULTS: Females formed the majority of the study population accounting for 56.5% of the type 2 DM patients and 62.7% of the controls. We observed that the mean age of the type 2 DM patients was 57.5 (±9.3) years, which was similar to the mean age of controls: 57.7±8.9 (p=0.17). We also observed that the mean age at diagnosis of DM was 54±7.6 years, while the mean duration of DM for all the type 2 DM patients was 6.5±2.8 years. We observed that in patients with T2DM, the prevalence of thyroid dysfunction was 12.4% and among the controls, a prevalence of 1.7% was observed (P <0.05). Females formed the majority (75%) of T2DM patients with thyroid dysfunction and hypothyroidism was the most common type of thyroid dysfunction (93.2%) observed in this study. CONCLUSION: The prevalence of thyroid dysfunction in T2DM patients in this study was 12.4% which was high compared to 1.7% observed in the controls (P = 0.001). The majority of those who had thyroid dysfunction were females. About 9 in 10 of all subjects with thyroid dysfunction had hypothyroidism.

CONTEXTE: Des études menées dans différentes régions du monde sur la dysfonction thyroïdienne ont montré qu'elle est répandue chez les patients atteints de diabète sucré de type 2 (T2DM) ; cependant, il existe des données locales insuffisantes pour étayer cette observation. OBJECTIF: Déterminer la charge de la dysfonction thyroïdienne chez les patients atteints de T2DM dans un hôpital tertiaire du sud-est du Nigeria, en mettant l'accent sur sa prévalence et son modèle de présentation. MÉTHODES: Quatre cent soixante-douze sujets ont été recrutés pour l'étude. Tous les sujets (100 %) étaient d'origine africaine. Trois cent cinquante-quatre (354) d'entre eux étaient des patients atteints de T2DM, tandis que 118 sujets ne présentaient pas de T2DM et servaient de témoins. Cette étude est une étude transversale descriptive impliquant des patients atteints de diabète sucré de type 2 fréquentant la clinique du diabète ou recevant un traitement dans les services de médecine. Les sujets ont été recrutés par échantillonnage systématique. Le premier patient a été sélectionné par échantillonnage aléatoire simple, et par la suite, chaque sujet consécutif a été sélectionné. Des échantillons de sang ont été testés pour l'HbA1c, le fT3, le fT4 et la thyrotropine, hormone stimulant la thyroïde. Les informations sociodémographiques ont été récupérées à partir des dossiers médicaux des patients. Nous avons utilisé le test t de Student pour la comparaison statistique des variables quantitatives telles que le poids, la taille, la pression artérielle, la TSH sérique et la T3 sérique ; tandis que pour la comparaison des proportions, nous avons utilisé un test du Chi-carré. Nous avons fixé une valeur de p inférieure à 0,05 pour être statistiquement significative. RÉSULTATS: Les femmes formaient la majorité de la population étudiée, représentant 56,5 % des patients atteints de DM de type 2 et 62,7 % des témoins. Nous avons observé que l'âge moyen des patients atteints de DM de type 2 était de 57,5 (±9,3) ans, ce qui était similaire à l'âge moyen des témoins: 57,7±8,9 (p=0,17). Nous avons également observé que l'âge moyen au diagnostic du DM était de 54±7,6 ans, tandis que la durée moyenne du DM pour l'ensemble des patients atteints de DM de type 2 était de 6,5±2,8 ans. Nous avons observé que chez les patients atteints de T2DM, la prévalence de la dysfonction thyroïdienne était de 12,4 % et parmi les témoins, une prévalence de 1,7 % a été observée (P <0,05). Les femmes formaient la majorité (75 %) des patients atteints de T2DM avec une dysfonction thyroïdienne et l'hypothyroïdie était le type le plus courant de dysfonction thyroïdienne (93,2 %) observé dans cette étude. CONCLUSION: La prévalence de la dysfonction thyroïdienne chez les patients atteints de T2DM dans cette étude était de 12,4 %, ce qui était élevé par rapport à 1,7 % observé chez les témoins (P = 0,001). La majorité de ceux qui avaient une dysfonction thyroïdienne étaient des femmes. Environ 9 sujets sur 10 présentant une dysfonction thyroïdienne avaient une hypothyroïdie. MOTS-CLÉS: Dysfonction thyroïdienne; Diabète sucré de type 2; Hypothyroïdie; Sud-est du Nigeria; Prévalence.

Effects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism.

The increasing knowledge of the molecular mechanisms in the cell signaling pathways of malignant cells, has recently led to the discovery of several tyrosine kinases (TKs), mainly TK receptors (TKR), which play a major role in the pathogenesis of many types of cancer. These receptors, physiologically involved in cell growth and angiogenesis, may harbor mutations or be overexpressed in malignant cells, and represent a target for anticancer therapy. Indeed, several therapeutic agents targeting specific altered pathways such as RET, BRAF, RAS, EGFR and VEGFR, have been identified. Tyrosine kinase inhibitors (TKIs) affect TK dependent oncogenic pathways by competing with ATP binding sites of the TK domain, thus blocking the activity of the enzyme, and thereby inhibiting the growth and spread of several cancers. Although the therapeutic action may be very effective, these molecules, due to their mechanism of multitargeted inhibition, may produce adverse events involving several biological systems. Both hypothyroidism and thyrotoxicosis have been reported during treatment with TKI, as well as an effect on the activity of enzymes involved in thyroid hormone metabolism. The pathogenic mechanisms leading to thyroid dysfunction and changes in serum thyroid function tests occurring in patients on TKI are reviewed and discussed in this manuscript.

Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (CPIs) reverse immune suppression that is thought to allow malignant growth. Despite remarkable efficacy in a subset of cancers, their use is accompanied by immune-related adverse events, including endocrinopathies such as hypophysitis, thyroid dysfunction, diabetes, and adrenalitis. These conditions are heterogenous, with differing incidence across CPI types, but are unified by the acuity and extremity of tissue-specific organ failure. Their occurrence may be associated with beneficial tumor control. Further understanding of the risk factors and mechanisms of these endocrine immunotoxicities can help optimize CPI use as well as improve understanding of spontaneous autoimmune diseases.

Thyroid dysfunction in Chinese nasopharyngeal carcinoma after anti-PD-1 therapy and its association with treatment response.

BACKGROUND: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy. METHODS: From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle. RESULTS: The spectrum of thyroid dysfunction was different between the immunotherapy and control groups (P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days (P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042). CONCLUSIONS: For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.

Shared genetics and causal relationships between migraine and thyroid function traits.

BACKGROUND: Epidemiological studies have reported a comorbid relationship between migraine and thyroid dysfunction. METHODS: We investigated the genetic relationship between migraine and thyroid function traits using genome-wide association study (GWAS) data. RESULTS: We found a significant genetic correlation (rg) with migraine for hypothyroidism (rg = 0.0608), secondary hypothyroidism (rg = 0.195), free thyroxine (fT4) (rg = 0.0772), and hyperthyroidism (rg = -0.1046), but not thyroid stimulating hormone (TSH). Pairwise GWAS analysis revealed two shared loci with TSH and 11 shared loci with fT4. Cross-trait GWAS meta-analysis of migraine identified novel genome-wide significant loci: 17 with hypothyroidism, one with hyperthyroidism, five with secondary hypothyroidism, eight with TSH, and 15 with fT4. Of the genes at these loci, six (RERE, TGFB2, APLF, SLC9B1, SGTB, BTBD16; migraine + hypothyroidism), three (GADD45A, PFDN1, RSPH6A; migraine + TSH), and three (SSBP3, BRD3, TEF; migraine + fT4) were significant in our gene-based analysis (pFisher's combined P-value < 2.04 × 10-6). In addition, causal analyses suggested a negative causal relationship between migraine and hyperthyroidism (p = 8.90 × 10-3) and a positive causal relationship between migraine and secondary hypothyroidism (p = 1.30 × 10-3). CONCLUSION: These findings provide strong evidence for genetic correlation and suggest complex causal relationships between migraine and thyroid traits.

Migraine and thyroid dysfunction: Co-occurrence, shared genes and biological mechanisms.

BACKGROUND AND PURPOSE: Migraine and thyroid dysfunction, particularly hypothyroidism, are common medical conditions and are known to have high heritability. Thyroid function measures, thyroid stimulating hormone (TSH) and free thyroxine (fT4), are also known to be genetically influenced. Although observational epidemiological studies report an increased co-occurrence of migraine and thyroid dysfunction, a clear and combined interpretation of the findings is currently lacking. A narrative review is provided of the epidemiological and genetic association evidence linking migraine, hypothyroidism, hyperthyroidism and thyroid hormones TSH and fT4. METHODS: An extensive literature search was conducted in the PubMed database for epidemiological, candidate gene and genome-wide association studies using the terms migraine, headache, thyroid hormones, TSH, fT4, thyroid function, hypothyroidism and hyperthyroidism. RESULTS: Epidemiological studies suggest a bidirectional relationship between migraine and thyroid dysfunction. However, the nature of the relationship remains unclear, with some studies suggesting migraine increases the risk for thyroid dysfunction whilst other studies suggest the reverse. Early candidate gene studies have provided nominal evidence for MTHFR and APOE, whilst more recently genome-wide association studies have provided robust evidence for THADA and ITPK1 being associated with both migraine and thyroid dysfunction. CONCLUSIONS: These genetic associations improve our understanding of the genetic relationship between migraine and thyroid dysfunction, provide an opportunity to develop biomarkers to identify migraine patients most likely to benefit from thyroid hormone therapy, and indicate that further cross-trait genetic studies have excellent potential to provide biological insight into their relationship and inform clinical interventions.

Thyroid Dysfunction Induced by Fungicide Famoxadone Exposure Contributes to Nonalcoholic Fatty Liver Disease in Male Mice: In Vivo, In Vitro, and In Silico Studies.

Thyroid dysfunction has become a serious public health problem, which is considered a trigger of nonalcoholic fatty liver disease (NAFLD). Pesticide exposure could contribute to thyroid dysfunction and NAFLD, but the relationship between these factors remains unclear. In this study, the effects of subchronic famoxadone exposure on thyroid and liver at no observed adverse effect level (NOEL) related concentrations were investigated using in vivo, in vitro, and in silico models. Famoxadone caused hepatic steatosis, lipid metabolism disorder, and liver oxidative stress and induced NAFLD in male mice. The suppression of hepatic fatty acid ß-oxidation was the key factor of NAFLD, which was highly associated with hypothalamic-pituitary-thyroid (HPT) axis hormones disorder. Famoxadone disrupted thyroid hormone biosynthesis by causing thyroid follicle aberrations and abnormal HPT axis-related gene expression. In vitro studies confirmed that famoxadone inhibited the transport of thyroxine (T4) into hepatocytes and the conversion of T4 to triiodothyronine (T3). In silico studies verified that famoxadone interfered with the binding of thyroid hormones to proteins mediating thyroid hormone transport, conversion, and activation. This study comprehensively reported the association between NAFLD and thyroid dysfunction caused by famoxadone, providing new perspectives for the health risk evaluation of pesticides with a similar structure in mammals.

Folate deficiency may increase the risk for elevated TSH in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and thyroid dysfunction (TD) are two common chronic endocrine disorders that often coexist. Folate deficiency has been reported to be related with the onset and development of T2DM. However, the relationship between folate deficiency and TD remains unclear. This study aims to investigate the association of serum folate with TD in patients with T2DM. METHODS: The study used data on 268 inpatients with T2DM in the Beijing Chao-yang Hospital, Capital Medical University from October 2020 to February 2021. Thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and serum folate were measured with chemiluminescence immunoassay (CLIA), and folate deficiency was defined as a serum folate concentration < 4.4 ng/mL. Ordinary least squares regression models were used to assess the association of serum folate with TSH concentration. Multivariable logistic regression models were performed to explore the correlation of folate deficiency and the risk for elevated TSH. RESULTS: 15.3% of T2DM patients had TD. Among those patients with TD, 80.5% had elevated TSH. Compared with the normal-TSH and low-TSH groups, the prevalence of folate deficiency was significantly higher in the elevated-TSH group (P < 0.001). Serum folate level was negatively associated with TSH (ß=-0.062, 95%CI: -0.112, -0.012). Folate deficiency was associated with the higher risk for elevated TSH in patients with T2DM (OR = 8.562, 95%CI: 3.108, 23.588). CONCLUSIONS: A low serum folate concentration was significantly associated with a higher risk for elevated TSH among T2DM patients.

The association between thyroid dysfunction, autoimmune thyroid disease, and rheumatoid arthritis disease severity.

BACKGROUND: Rheumatoid Arthritis (RA) and autoimmune thyroid disease (AITD) are the two most prevalent coexisting autoimmune diseases due to their similar pathogenesis. Considering the potential effect of AITD on the severity of RA disease, this study aimed to determine the association between thyroid dysfunction, anti-thyroid peroxidase (anti-TPO) positivity, AITD, and RA disease severity in the Iranian population. METHODS: Three hundred and fifty RA patients who presented to Shahid Beheshti tertiary care center, Qom, Iran, were included in this cross-sectional study. The data were collected through the patient's medical records, interviews, physical examinations, and laboratory tests. The RA disease activity score in 28 joints for RA with erythrocyte sedimentation rate (DAS-28-ESR) was used to divide patients into three subgroups, remission (DAS-28-ESR ⩽ 2.6), mild-to-moderate (2.6 < DAS-28-ESR ⩽ 5.1), and severe disease activity (DAS-28-ESR > 5.1). RESULTS: Using the aforementioned method, 111, 96, and 138 patients were put into remission, mild-to-moderate, and severe disease activity groups, respectively. Anti-TPO antibody positivity rate was 2.93 times more prevalent among patients with severe disease compared to the remission subgroup (OR: 2.93; P-value < 0.001). Patients suffering from a more severe disease were almost 2.7 times more probable to have AITD (OR = 2.71; P-value < 0.001) and they were 82% more likely to have thyroid dysfunction compared to patients in remission (OR = 1.82; P-value = 0.006). CONCLUSIONS: It was demonstrated that thyroid dysfunction, anti-TPO antibody positivity, and AITD were significantly more common among RA patients with more severe disease activity.

Prevalence and clinical correlates of psychotic symptoms in first-episode untreated female chinese patients with major depressive disorder.

BACKGROUND: Recent studies have reported that psychotic symptoms are common in patients with major depressive disorder (MDD). However, few studies have reported the relationship between thyroid function, lipid metabolism and clinical profiles in female MDD patients. Thus, this study aimed to investigate the prevalence of psychotic depression (PD) and its risk factors in first-episode and drug naive (FEDN) depression among the female population in China. METHODS: This was a cross-sectional study involving a representative probability sample of 1,130 FEDN female outpatients with MDD (aged 18 years or older) in China. We collected information relating to socio-demographic characteristics, clinical data and blood samples. The Hamilton Depression Rating Scale 17-item version (HAMD-17), Hamilton Anxiety Rating Scale 14-item version (HAMA-14), and Positive and Negative Syndrome Scale (PANSS) were used to evaluate depressive, anxiety, and psychotic symptoms. RESULTS: The prevalence of psychotic symptoms in female MDD patients was 10.97%. The findings revealed significant differences between MDD female patients with psychotic symptoms and non-PD female patients in the following areas: higher HAMD scores, higher HAMA scores, more severe anxiety and an increased risk of suicide attempts. Further logistic regression analysis showed that psychotic symptoms were associated with higher thyroid-stimulating hormone (TSH) levels and an odds ratio of 1.168. CONCLUSIONS: Our findings supported the hypothesis that higher TSH levels were correlated with psychotic symptoms in female MDD patients. Therefore, serum TSH levels may be a potential biomarker of PD in female MDD patients. In addition, we found that PD was closely associated with suicide attempts and lipid levels, but did not reach statistical significance.

Thyroid hormone profile in preeclampsia patients: a case control study.

Objective: Preeclamptic women are reported to have a higher incidence of thyroid dysfunction that correlates with the severity of preeclampsia. The aim of this study was to assess thyroid hormone profiles in in pregnant women with preeclampsia and gestational hypertension and the risk for thyroid dysfunction.Methods: In this study, age-matched pregnant females in the second trimester of pregnancy, diagnosed with preeclampsia (PE), gestational hypertension (GH), as cases, and apparently healthy normotensive (NT) pregnant woman as controls were recruited. Blood samples were drawn for the assessment of thyroid hormone (TSH, FT3 and FT4) levels and thyroid dysfunction.Results: Out of the total of 133 pregnant women recruited for this study, sub-clinical hypothyroidism was the only thyroid dysfunction common to all study groups, with a prevalence of 3.3% in both PE and NT groups, and 4.3% in the GH group. 1% of women in the PE group had sub-clinical hyperthyroidism, compared to 3.3% in the NT group. Although TSH and FT3 were elevated in normotensives, mean differences between the three groups were not statistically significant. However, mean FT4 levels in the GH group (12.99 ± 1.24) and PE group (12.33 ± 2.26), when compared to the control group (11.55 ± 1.94), were significantly higher (p < 0.05).Conclusion: Undiagnosed subclinical hypothyroidism was found in all the categories of pregnant women studied, which if uncontrolled, could increase the risk of pregnancy-related complications, especially in pregnant women with preeclampsia and gestational hypertension.