Thyroid Hormone Research Articles

The thyroid hormone activating enzyme, DIO2, is a potential pan-cancer biomarker and immunotherapy target.

Type 2 deiodinase (D2), encoded by DIO2 gene, catalyzes the activation of the prohormone thyroxine (T4) into the bioactive hormone triiodothyronine (T3) in peripheral tissues, thereby regulating the intracellular Thyroid Hormone (TH) availability. Recently, several studies have demonstrated that a drastic increase in the peripheral activation of TH, via D2, fosters tumor progression, metastasis, and immunity. To further prove the clinical relevance of D2 in human cancer, based on public Database of The Cancer Genome Atlas (TCGA), we conducted a pan-cancer analysis of DIO2 expression in various cancer types and investigated the association of DIO2 expression with the tumor microenvironment (TME) components and immune cell infiltration, along with the DIO2 genetic alteration types. Although with different expression levels between the various cancer types, the pan-cancer analysis showed that DIO2 was highly expressed in most tumors and related to the progression of some tumor types. Furthermore, DIO2 expression was also significantly correlated with TME components, immune cell infiltration, and immunoinhibitory and immunostimulatory gene subsets. The relevance of this study is that it adds a clinical relevance to the recent demonstrations that D2 accelerates tumor invasion in animal models and poses DIO2 gene as a potential prognostic marker in various human cancers.

Thyromimetics and MASLD: Unveiling the Novel Molecules Beyond Resmetirom.

Resmetirom, the first FDA-approved drug for nonalcoholic steatohepatitis (NASH) with fibrosis in obese patients, when combined with lifestyle modifications, improves NASH resolution and reduces fibrosis by at least one stage. Low thyroid hormone (T3) levels are linked to a higher risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Epidemiological studies have confirmed the positive correlation between hypothyroidism and MASLD. Unraveling the molecular mechanisms of T3 signaling pathways in MASLD will enhance the prospects of identifying effective and specific targets. Therefore, this review discusses the significant role of thyroid hormones in the homeostasis of fat metabolism and describes the possible molecular mechanisms of thyromimetics in the treatment of MASLD. A comprehensive search in PubMed and EMBASE was conducted using the keywords "thyromimetics and liver diseases," "thyroid hormone and liver diseases," "hypothyroidism and liver diseases," "T3, T4 and liver disease," and "resmetirom and liver disease." Relevant papers published before October 2024 were included. T3 treatment enhances mitochondrial respiration, biogenesis, β-oxidation, and mitophagy, reducing liver lipid accumulation. However, T3 treatment causes cardiotoxicity through thyroid hormone receptor (THR)α agonistic activity. To address this, molecules with high THRβ agonistic but lower THRα activity have been developed. Besides resmetirom, other THRβ agonists like TG68, CS27109, MB07811, and KB-141 show promising results in experimental studies. These molecules upregulate THRβ target genes, activate genes for fatty acid β-oxidation in mitochondria and fatty acid breakdown in peroxisomes, downregulate the genes involved in de novo lipogenesis, reduce inflammation by downregulating NF-κB/JNK/STAT3 signaling pathways, and accelerate fibrosis resolution by downregulating the expressions of fibrosis marker genes in NASH liver tissue. Future clinical studies should thoroughly investigate THRβ agonists, including TG68, CS27109, MB07811, and KB-141.

Effect of a Low-Molecular-Weight Allosteric Agonist of the Thyroid-Stimulating Hormone Receptor on Basal and Thyroliberin-Stimulated Activity of Thyroid System in Diabetic Rats

The approaches to correct thyroid deficiency include replacement therapy with thyroid hormones (THs), but such therapy causes a number of side effects. A possible alternative is thyroid-stimulating hormone (TSH) receptor activators, including allosteric agonists. The aim of this work was to study the effect of ethyl-2-(4-(4-(5-amino-6-(tert-butylcarbamoyl)-2-(methylthio)thieno[2,3-d]pyrimidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl) acetate (TPY3m), a TSH receptor allosteric agonist developed by us, on basal and thyroliberin (TRH)-stimulated TH levels and the hypothalamic-pituitary-thyroid (HPT) axis in male rats with high-fat diet/low-dose streptozotocin-induced type 2 diabetes mellitus (T2DM). Single and three-day administration of TPY3m (i.p., 20 mg/kg) was studied, and the effect of TPY3m on the HPT axis was compared with that of levothyroxine. TPY3m increased TH levels when administered to both healthy and diabetic rats, normalizing thyroxine and triiodothyronine levels in T2DM and, unlike levothyroxine, without negatively affecting TSH levels or the expression of hypothalamic and pituitary genes responsible for TSH production. TPY3m pretreatment preserved the stimulatory effects of TRH on TH levels and thyroid gene expression. This indicates the absence of competition between TPY3m and endogenous TSH for TSH receptor activation and is supported by our in vitro results on TPY3m- and TSH-stimulated adenylate cyclase activity in rat thyroid membranes. Morphological analysis of thyroid glands in diabetic rats after three-day TPY3m administration shows an increase in its functional activity without destructive changes. To summarize, TPY3m, with the activity of a partial allosteric agonist of the TSH receptor, was created as a prototype of drugs to correct thyroid insufficiency in T2DM.

Associations Between Ambient PM2.5 and Thyroid Hormones in Pregnant Persons in Puerto Rico

Introduction: This study investigates associations between fine particulate air pollution (PM2.5) exposure and thyroid hormone levels during pregnancy in Puerto Rican individuals, a vulnerable population facing socioeconomic and environmental disparities. Methods: This research draws on data from the PROTECT cohort study and involves 1040 participants to measure the effect of PM2.5 on developmentally important thyroid hormones (TSH, T3, T4, and FT4). Pollution concentrations were linked to participant locations using EPA air quality data and analyzed across two visits during gestational weeks 16–20 and 24–28. Results: The results suggest that PM2.5 exposure is positively associated with maternal T3, T4, and FT4 levels but not TSH. These effects vary by timing, with T3 showing stronger associations later in pregnancy and T4/FT4 earlier. Nonlinear dose–response relationships were observed, suggesting thresholds for certain hormones. Discussion: These findings support previous studies linking altered thyroid hormones to adverse birth outcomes and highlight the potential role of air pollution in disrupting maternal thyroid function and its implications for fetal development, calling for further research into mechanisms and interventions to mitigate these risks.

Thyroid Hormone Resistance: A Case Report of a Novel Missense Thyroid Hormone Receptor (THR) Mutation

Thyroid Hormone Resistance: A Case Report of a Novel Missense Thyroid Hormone Receptor (THR) Mutation

The effect of cardiac catheterization on thyroid functions in infants with congenital heart diseases: a prospective observational study

This study aims to determine the incidence, clinical course, and risk factors of hypothyroidism following cardiac catheter (CC) in infants with congenital heart diseases (CHD). This prospective study involved 115 patients with CHD, all aged 3 years or younger, who underwent CC, as well as 100 healthy age- and sex-matched controls. Baseline thyroid function tests (TFTs) were conducted for both the patients and controls. In the CHD cohort, TFTs were reassessed 4 weeks after the CC, and for those with abnormal TFT values at this time, the tests were repeated after 2 weeks. Levothyroxine was started for patients with persistent abnormal TFTs, at 4 weeks and 6 weeks assessments after CC. Four weeks after CC, 12% of the studied group exhibited hypothyroidism. Univariate analysis identified significant predictors of hypothyroidism following CC: aortic stenosis (RR = 10.0 (1.49–66.99), P = 0.018), duration of fluoroscopy during CC (RR = 2.12 (0.99–4.26), P = 0.05), and total iodinated contrast media (iCM) during CC (RR = 2.5 (1.35–3.55), P = 0.019). Multivariate analysis indicated that iCM dose was the sole significant predictor of developing hypothyroidism (RR = 2.10 (1.01–3.23), P = 0.04). ROC curve analysis showed that the cut-off point of iCM dose for prediction of hypothyroidism evolution is 8.7 gm/kg, (sensitivity: 83%, specificity: 65%), while the cut-off point of fluoroscopy duration which predicts the development of hypothyroidism is 24 min (sensitivity: 83%, specificity: 66%). Acquired hypothyroidism after CC persisted in 4% of this cohort for 6 months.Conclusion: Higher doses of iCM and longer duration of fluoroscope during CC are risk factors for the evolution of hypothyroidism post-CC. We recommend assessing thyroid profile 4 weeks after CC, particularly in patients who received an iCM dose greater than 8.7 gm/kg and/or exposed to fluoroscopy for more than 24 min. What is known:• The use of excess iodine leads to transient inhibition of thyroid hormones biosynthesis via the Wolff-Chaikoff effect.• Infants with congenital heart diseases (CHD) are more prone to hypothyroidism due to higher frequency of abnormal thyroid morphology and routine exposure to supraphysiological doses of iodine.What is new:• Exposure to a total dose of iodinated contrast media more than 8.7 gm/kg and a fluoroscopy duration more than 24 min during cardiac catheter are risk factors for the evolution of thyroid hypofunction following cardiac catheter.

Predictive value of technetium-99m sodium pertechnetate thyroid scintigraphy in determining the permanence of congenital hypothyroidism

Objectives: We aim to investigate the predictive value of [99mTc] pertechnetate thyroid scintigraphy in determining the permanence of congenital hypothyroidism (CH). Material and Methods: A retrospective analysis of [99mTc] pertechnetate thyroid scans performed for evaluation of CH at the Nuclear Medicine Unit of a hospital in Hong Kong between January 1, 2008, and December 31, 2018, was conducted. Scintigraphic findings and parameters at diagnosis, including thyroid stimulating hormone (TSH), free thyroxine (fT4), gender, and gestational age, were reviewed. The need for lifelong thyroxine replacement therapy was reviewed. Results: The study included 85 subjects, with 74 (87.1%) presenting with eutopic thyroid and 11 (12.9%) showing thyroid dysgenesis. Patients with scintigraphic evidence of thyroid dysgenesis required permanent thyroid hormone replacement therapy. Among the patients with eutopic thyroid, a higher TSH level was associated with the need for lifelong thyroid hormone replacement therapy (cutoff TSH value 18.72 mIU/L, sensitivity 77.3% and specificity 53.8%). Gender, gestational age, and fT4 did not show significant differences between the transient and permanent CH groups in patients with eutopic thyroid. Conclusion: Scintigraphic findings of thyroid dysgenesis indicate a high prevalence of permanent CH. In patients with eutopic thyroid, higher TSH levels predict the requirement for lifelong thyroid hormone replacement therapy. These results provide insights into the prediction of CH and aid in individualized treatment decisions for patients with CH.

A comprehensive analysis to reveal the underlying molecular mechanisms of natural killer cell in thyroid carcinoma based on single-cell RNA sequencing data

BackgroundThyroid carcinoma (THCA) is the most common cancer of the endocrine system. Natural killer (NK) cell play an important role in tumor immune surveillance. The aim of this study was to explore the possible molecular mechanisms involved in NK cell in THCA to help the management and treatment of the disease.MethodsAll data were downloaded from public databases. Candidate hub genes associated with NK cell in THCA were identified by limma, WGCNA and singleR packages. Functional enrichment analysis was performed on the candidate hub genes. Hub genes associated with NK cell were identified by Pearson correlation analysis. The mRNA-miRNA-lncRNA and transcription factors (TF) networks were constructed and the drug was predicted.ResultsThe infiltration level of NK cell in THCA tissues was higher than that in paracancerous tissues. KEGG functional enrichment analysis only obtained two signaling pathways, thyroid hormone synthesis and mineral absorption. CTSC, FN1, SLC34A2 and TMSB4X identified by Pearson correlation analysis were considered as the hub genes. Receiver operating characteristic analysis suggested that hub genes may be potential diagnostic biomarkers. In mRNA-miRNA-lncRNA network, FN1 had the highest correlation with IQCH-AS1, and IQCH-AS1 was also correlated with hsa-miR-543. In addition, FN1 and RUNX1 were also found to have the highest correlation in TF network. Finally, NK cell-related drugs belinostat and vorinostat were identified based on ASGARD.ConclusionThe identification of important signaling pathways, molecules and drugs provides potential research directions for further research in THCA and contributes to the development of diagnostic and therapeutic approaches for this disease.

Rapid changes in plasma corticosterone and medial amygdala transcriptome profiles during social status change reveal molecular pathways associated with a major life history transition in mouse dominance hierarchies.

Social hierarchies are a common form of social organization across species. Although hierarchies are largely stable across time, animals may socially ascend or descend within hierarchies depending on environmental and social challenges. Here, we develop a novel paradigm to study social ascent and descent within male CD-1 mouse social hierarchies. We show that mice of all social ranks rapidly establish new stable social hierarchies when placed in novel social groups with animals of equivalent social status. Seventy minutes following social hierarchy formation, males that were socially dominant prior to being placed into new social hierarchies exhibit higher increases in plasma corticosterone and vastly greater transcriptional changes in the medial amygdala (MeA), which is central to the regulation of social behavior, compared to males who were socially subordinate prior to being placed into a new hierarchy. Specifically, the loss of social status in a new hierarchy (social descent) is associated with reductions in MeA expression of myelination and oligodendrocyte differentiation genes. Maintaining high social status is associated with high expression of genes related to cholinergic signaling in the MeA. Conversely, gaining social status in a new hierarchy (social ascent) is related to relatively few unique rapid changes in the MeA. We also identify novel genes associated with social transition that show common changes in expression when animals undergo either social descent or social ascent compared to maintaining their status. Two genes, Myosin binding protein C1 (Mybpc1) and μ-Crystallin (Crym), associated with vasoactive intestinal polypeptide (VIP) and thyroid hormone pathways respectively, are highly upregulated in socially transitioning individuals. Further, increases in genes associated with synaptic plasticity, excitatory glutamatergic signaling and learning and memory pathways were observed in transitioning animals suggesting that these processes may support rapid social status changes.

The impact of COVID-19 infection on thyroid function.

Extensive research on COVID-19 has revealed a notable link between the disease and thyroid disorders, highlighting complex interactions between thyroid hormones, immunomodulatory signaling molecules within the thyroid gland, and viral infections. This study evaluated the relationship between thyroid function and COVID-19 in Iraqi patients at Adiwaniyah Teaching Hospital. The cohort for this investigation comprised all patients who were admitted to the isolation center at the Teaching Hospital during the timeframe extending from January 2024 to June 2024. Each participant included in this research underwent comprehensive evaluations of their thyroid function, which is composed of the measurement of thyroid-stimulating hormone (TSH), total triiodothyronine (T3), and serum total thyroxine (T4) levels. Results showed that the serum T4 levels in all participants included in the study were observed to range from 20 to 182 (ng/dl), with the average concentration recorded at 87.26 ± 38.29 (ng/dl); no statistically significant disparity was noted in the mean serum T4 levels relative to the severity of the disease (p = 0.291). The serum TSH levels across all enrolled individuals spanned from 0.03 to 82 (mU/L), with a mean concentration of 5.55 ± 12.36 (mU/L); similarly, there was no statistically significant difference in the mean serum TSH levels when assessed against the disease severity (p = 0.926). According to the serum thyroid hormone concentrations, the cohort was stratified into 17 (24.6%) individuals classified as hypothyroid, 34 (49.3%) categorized as euthyroid, and 18 (26.1%) identified as hyperthyroid. Furthermore, no significant correlation was identified between the disease's severity and the participants' thyroid status (p = 0.556). In conclusion, patients with COVID-19 are liable to develop thyroid function abnormalities that may explain several of the long-term symptoms associated with the disease.

Associations between exposure to sodium/iodide symporter inhibitors and markers of thyroid function: A systematic review and meta-analysis.

Perchlorate, nitrate, and thiocyanate are well-known sodium/iodide symporter (NIS) inhibitors that disturb iodide uptake at the thyroid, affecting thyroid function. However, the associations between NIS inhibitor exposure and thyroid function are not well summarized in humans. We aimed to summarize associations between NIS inhibitor exposure and thyroid function markers and to identify key information gaps for future studies. From four databases (Embase, Web of Science, PubMed, CINAHL plus) up to May 31, 2024, we systematically searched studies that examined associations between levels of the three NIS inhibitors and thyroid hormones, including free thyroxine (FT4), total thyroxine (TT4), free triiodothyronine (FT3), and total triiodothyronine (TT3) as well as thyroid-stimulating hormone (TSH). We also conducted a random-effects meta-analysis to estimate the pooled effect size of the associations between NIS inhibitor levels and thyroid function marker levels. Of 2,588 identified studies, we selected 9 studies for full-text review and 4 studies for a meta-analysis. The association between perchlorate and TSH was primarily studied and only three studies considered iodine concentrations. As a result of a meta-analysis, TSH levels were positively associated with levels of combined NIS inhibitors [β: 0.105; 95% confidence interval (CI): 0.046, 0.160] and perchlorate [β=0.133; 95% CI: 0.056, 0.211]. We found negative trends between NIS inhibitors and FT3 and TT4 and positive but nonsignificant trends between FT3 and perchlorate and between TT4 and thiocyanate. Our study provided comprehensive evidence on the association between exposure to NIS inhibitors and thyroid function markers in humans, aligning with the mechanisms observed in in vivo studies.

Thyroid Hormones in the Diversification of Pigment Patterns in Teleosts

Thyroid Hormones in the Diversification of Pigment Patterns in Teleosts

Hypothyroidism Alters Uterine Kisspeptin System and Activity Modulators in Cyclic Rats

Hypothyroidism causes ovarian dysfunction and infertility in women and animals and impairs the hypothalamic expression of kisspeptin (Kp). However, kisspeptin is also expressed in the genital system, and the lack of the Kp receptor (Kiss1r) in the uterus is linked to reduced implantation rates. This study investigated the impact of hypothyroidism on the uterine expression of Kp and Kiss1r in female rats throughout the estrous cycle and the associated changes in uterine activity modulators. Hypothyroidism was induced through daily administration of propylthiouracil (PTU) over a period of 14 days. Plasma levels of LH, E2, and P4, cyclicity, body and uterine weight, uterine histomorphometry, and the gene and/or protein expression of Kiss1, Kiss1r, estrogen receptor α (ERα), progesterone receptor (PR), and thyroid hormone receptor α (TRα) were assessed. Additionally, proliferative activity (CDC-47) and the gene expression of uterine receptivity mediators (SMO, WNT4, BMP2, HAND2, MUC1, and LIF) were evaluated. Hypothyroidism prolonged the diestrus and increased progesterone levels during this phase, while decreasing luteinizing hormone and estradiol on proestrus. In the uterus, hypothyroidism reduced Kp immunostaining on diestrus and KISS1R mRNA levels on proestrus. These changes were accompanied by reduced endometrial glands, reduced uterine proliferative activity, and reduced ERα gene and protein expression. Additionally, hypothyroidism led to reduced uterine gene expression of LIF, BMP2, WNT4, and HAND2. On the other hand, thyroid hypofunction increased uterine PR and TRα immunostaining, while it reduced PGR gene expression on diestrus. These findings demonstrate that hypothyroidism reduces the expression of Kiss1/Kiss1r system in the uterus, which is associated with disrupted uterine estrogen and progesterone signaling and reduced expression of uterine receptivity mediators across the rat estrous cycle.

Prevalence of abnormal thyroid hormone levels in acute new-onset atrial fibrillation

Prevalence of abnormal thyroid hormone levels in acute new-onset atrial fibrillation

The incidence and influencing factors of recent suicide attempts in major depressive disorder patients comorbid with moderate-to-severe anxiety: a large-scale cross-sectional study

BackgroundMajor depressive disorder (MDD) is a recurrent and persistent mental illness. However, there is a lack of research that distinguishes the severity of comorbid anxiety disorders in MDD, and insufficient evidence exists regarding the prevalence of MDD patients with comorbid moderate-to-severe anxiety in the Chinese population.MethodsThe study included 1718 MDD patients (894 with moderate-to-severe anxiety symptoms and 824 without moderate-to-severe anxiety symptoms). Clinical symptoms and development were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), Hamilton Anxiety Rating Scale-14 (HAMA-14), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI). The blood pressure and thyroid hormone levels were measured.ResultsWe found that the incidence of MDD patients with moderate-to-severe anxiety symptoms was 52.04%. The prevalence of recent suicide attempts in MDD comorbid moderate-to-severe anxiety patients was 31.8%, which was 4.24 times higher than that in patients without moderate-to-severe anxiety. Additionally, suicide attempters had elevated levels of thyroid stimulating hormone (TSH), anti-thyroglobulin (TgAb), thyroid peroxidases antibody (TPOAb), systolic blood pressure (SBP), and diastolic blood pressure (DBP) compared to non-suicide attempters. We further identified CGI score, TSH, TPOAb, and DBP as influential factors for recent suicide attempts in MDD individuals who had moderate-to-severe anxiety symptoms. These indexes could distinguish between suicide attempts and non-suicide attempts in MDD patients with moderate-to-severe anxiety symptoms.ConclusionsOur findings mainly indicated a high prevalence of recent suicide attempts in MDD patients with moderate-to-severe anxiety. Several clinical correlates, thyroid hormones, and blood pressure might contribute to recent suicide attempts in MDD patients with moderate-to-severe anxiety symptoms.

Cardiovascular Findings and Effects of Caffeine on Experimental Hypothyroidism.

Thyroid hormone deficiencies can disrupt organ functions, significantly impacting the cardiovascular system. Recently, the effects of thyroid hormones on the heart have garnered increased attention. However, most studies are conducted on humans using clinical data, while cellular-level and experimental studies remain limited. This study aimed to investigate the cardiovascular implications of hypothyroidism and evaluate the impact of caffeine on cardiac health in rats induced with hypothyroidism using propylthiouracil (PTU). The study involved 60 rats divided into six groups. Group 1 served as the untreated control. Group 2 received PTU for two months to induce hypothyroidism. Group 3 received PTU for one month, followed by caffeine for one month. Group 4 received caffeine for two months. Group 5 received both PTU and caffeine simultaneously for two months. Group 6 received PTU for one month, followed by one month under normal conditions. During necropsy, normal thyroid glands were observed in Groups 1, 4, and 6, enlarged thyroids in Group 2, and smaller thyroids in Groups 3 and 5. Microscopic examination revealed varying thyroid histologies: Group 2 showed significant epithelial cell proliferation and absent colloid, while Groups 3, 5, and 6 had altered yet colloid-containing acini. Macroscopic inspection of hearts appeared normal across all groups. However, histopathological examination revealed significant hyperemia and microhemorrhages in Group 2, contrasting with normal findings in other groups. Immunohistochemical analysis indicated reduced cardiac troponin expression in Group 2, while other groups maintained prominent expression. Additionally, Group 2 displayed increased serum TSH levels and decreased T3 and T4 levels. The findings suggest that administering caffeine alongside or after PTU treatment in rats with experimentally induced hypothyroidism may ameliorate thyroid and cardiac irregularities. This study indicates caffeine's potential in mitigating the adverse effects of hypothyroidism on thyroid and heart health.

Efficacy and safety of resmetirom in MASLD and MASH: network meta-analysis of randomized clinical trials.

Metabolic-Associated Steatohepatitis-Related Liver Disease (MASLD) and, its progressive form, Metabolic-Associated Steatohepatitis (MASH) pose significant global health challenges. Current therapeutic strategies targeting metabolic abnormalities have shown promise but lack specificity for the liver. Thyroid hormones, particularly thyroid hormone receptor beta (THR-β) agonists like resmetirom, offer a targeted approach to liver-related pathways. A network meta-analysis (NMA) comparing different doses of resmetirom to placebo for MASLD and MASH was conducted. PubMed, Scopus, Cochrane, and Webof Science were searched for relevant randomized controlled trials (RCTs). Efficacy outcomes included histological, radiological, and biochemical parameters, while safety outcomes comprised adverse events and treatment discontinuation. Resmetirom demonstrated dose-dependent efficacy in histological and radiological assessments, with the 100 mg dose showing superior MASH resolution and hepatic fat reduction. Biochemical markers indicated improved liver function with resmetirom treatment. However, adverse events, particularly diarrhea and nausea, were more prevalent in the resmetirom group, leading to higher treatment discontinuation rates. Resmetirom shows promise as a therapeutic option for MASLD and MASH management, with significant improvements in liver health parameters. However, safety concerns warrant careful monitoring in clinical practice. Further research is needed to optimize its long-term safety and efficacy.

Digenic Inheritance Mode in Congenital Hypothyroidism due to Thyroid Dysgenesis: HYPOTYGEN translational cohort study.

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and is chiefly caused by thyroid dysgenesis (CHTD). The inheritance mode of the disease remains complex. Gain insight into the inheritance mode of CHTD. Prospective multicenter nationwide translational study in France. We prospectively included 514 patients with CH diagnosed through systematic newborn screening (HYPOTYGEN cohort). We focused on CHTD cases and studied their clinical and molecular phenotypes. Targeted next-generation sequencing using a 78-gene panel, including genes involved in thyroid development, function, transport, metabolism and action of thyroid hormones. Statistical analysis, familial segregation and in vitro functional studies focusing on cell migration have been performed. We analyzed the clinical phenotypes of 458 patients with CH. Cardiac and renal malformations were present in 7.7%(14/182) and 3.9%(7/178) of patients, respectively. Genetic analysis was performed on 292 patients of the cohort, based on criteria for ethnicity and availability of DNA samples for index cases and their parents. A disease-causing mutation in one of the 10 known genes for CHTD was identified in 20/292 (6.8%) patients. We found a digenic mode of inheritance in 16 (5.5%) patients, each carrying a variant in a thyroid development gene and a variant in the H2O2 generation complex gene DUOX2/DUOXA2. Familial segregation analysis and in vitro functional studies supported this model. This work expands our understanding of the molecular causes of CHTD by demonstrating that digenic inheritance can be implicated, with deleterious variants in thyroid development and DUOX2/DUOXA2 genes. The complexity of this model implies a revision of the genetic landscape of CHTD and specific clinical care of patients during long-term follow-up. NCT01916018.

Observational Characterization of the Retreatment Course of Patients With Thyroid Eye Disease.

To characterize the retreatment course of patients with thyroid eye disease (TED), who had reactivation after initial therapy with teprotumumab. This was a single-center longitudinal cohort study of patients who received an initial course of teprotumumab for active TED and were followed for at least 6 months. Reactivation was defined as the increase of proptosis of 2 mm or more or an increase in Clinical Activity Score (CAS) of two points or more, as adapted from the Optic-X study. Data collection included patient age, sex, smoking status, history of thyroidectomy or radioactive iodine, proptosis measurements, clinical activity score (CAS) before initial infusion of teprotumumab, time interval to reactivation, diplopia assessment by the Bahn-Gorman scale, CAS at the time of reactivation, and CAS and proptosis measurements after completion of retreatment and retreatment modalities, including clinical monitoring, corticosteroids, teprotumumab, and/or surgery. Among the reactivated cohort, the treatment response of patients who received a second course of teprotumumab was compared with patients who were treated with intravenous (IV) steroids. Twenty-six percent (11/42) of patients experienced reactivation of TED with an average time to reactivation of 9 (SD:5) months (range: 2-20 months), average CAS at reactivation of 4 (SD:1) (range: 3-7), and average increase in proptosis of 3 (SD:1) mm (range: 2-6 mm). Of the 11 patients who reactivated, 4 received a second course of teprotumumab, while 6 received IV steroids. One patient elected to monitor. The patients who received a second course of teprotumumab had a mean (SD) posttreatment CAS score of 0 reduction in proptosis of 4 (2) mm (range: 3-6). The patients who received IV steroids had a mean (SD) posttreatment CAS of 2 (1) (range: 1-4) and a reduction in proptosis of 0 (1) mm (range: [-1] to [2]). Univariate analyses to look at predictors of reactivation found no correlation between factors such as age, sex, duration of TED, smoking status, presence of diplopia, previous treatment with radioactive iodine, history of periorbital surgery, and/or thyroidectomy after initial completion of teprotumumab between the 2 cohorts. We found a significant correlation between the CAS scores before initial treatment (P = 0.036) and thyroid hormone dysregulation (P = 0.006) in those who experienced reactivation. Patients with TED may experience reactivation of the disease after initial therapy with teprotumumab. Reactivated disease responds to repeat therapy with teprotumumab with higher previous CAS and thyroid hormonal dysregulation being the variables that were significantly associated with reactivation. These data underscore the importance of long-term monitoring and exploring underlying triggers for disease reactivation. Understanding these factors could help predict which patients may require retreatment or chronic dosing with teprotumumab. Further studies are essential to advance our understanding of the immunomodulatory effects of teprotumumab, duration of its therapeutic benefit, and potential retreatment strategies to improve long-term patient outcomes.

Sex differences in the prevalence and correlates of suicide attempts in patients with first-episode and drug-naïve psychotic major depression.

Sex differences play an important role in depression prevalence, symptom profile, treatment response, and disease course. However, sex differences in factors associated with suicide attempts (SAs) in first-episode and drug-naïve (FEDN) patients with psychotic major depression (PMD) remain unclear. In this study, 171 patients with FEDN PMD were recruited. Patients' symptoms were assessed using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) positive subscale. In addition, metabolic parameters and thyroid hormone levels were measured. The prevalence of SA was remarkably high in both male and female PMD patients (53.19% vs. 50.81%), without significant differences between the two groups. In male PMD patients, the combination of marital status and TSH levels was found to effectively distinguish between SA and non-SA cases, with an AUC value of 0.87. In addition, the HAMD score and diastolic blood pressure (BP) were significantly associated with the frequency of SAs in this subgroup. For female PMD patients, the combination of positive score, diastolic BP, TSH, and TgAb was found to be a very effective discriminator between SA and non-SA cases, with an AUC of 0.91. Furthermore, duration of illness, positive score, systolic BP, and TPOAb were found to be significantly associated with the frequency of SAs in this subgroup. Our results indicate a high incidence of suicide attempts in both men and women with PMD. Several clinically relevant factors, metabolic parameters, and thyroid hormone function contribute to sex differences in suicide attempts in FEDN PMD patients.