Genetic effect of thyroid function-related diseases on acute respiratory distress syndrome: a Mendelian randomization study.

BACKGROUND: Previous studies have shown an association between acute respiratory distress syndrome (ARDS) and thyroid function. However, their causal relationship remains unspecified. Therefore, this study aims to explore the causal relationship between ARDS and thyroid function-related diseases with Mendelian Randomization (MR) analysis. METHODS: ARDS dataset finn-b-J10_ARDS, finn-b-E4_THYROID dataset of disorders of the thyroid gland (DTG) and finn-b-E4_HYTHYNAS of hypothyroidism were acquired from public database. In univariate MR (UVMR), causal effects between DTG, hypothyroidism and ARDS were investigated using 5 types of algorithms, and reliability was validated by sensitivity analysis. Moreover, multivariate MR (MVMR), enrichment and interaction network analyses of genes corresponding to SNPs of DTG and hypothyroidism were carried out. Significant level was chosen as p<0.05. RESULTS: UVMR identified DTG and hypothyroidism (P < 0.05, OR > 1) as risk factors, and were causally related to ARDS. Reliability of UVMR results was confirmed through sensitivity analysis, and results were stable and reliable. However, DTG and hypothyroidism had no effect on ARDS in MVMR, possibly because these factors had independent effects on ARDS. Ultimately, 96 and 113 genes corresponding to SNPs of DTG and hypothyroidism were found closely related to immune-related pathways. CONCLUSIONS: UVMR and MVMR analysis revealed a causal connection between DTG and hypothyroidism as risk factors with ARDS, providing robust evidence for investigation into relationship of hypothyroidism on ARDS and between DTG and ARDS.

Lifestyle Medicine's Role in Common Hormonal Disorders: A Case-Based Discussion.

Hormonal disorders like PCOS (Polycystic Ovary Syndrome), autoimmune thyroid disease (AITD) including Hashimoto's thyroiditis, male hypogonadism are commonly encountered in clinical practice in the US and worldwide, with rising frequency. These typically affect patients during young or middle age, compared with other common chronic illnesses like type 2 diabetes, hypertension, atherosclerotic cardiovascular disease, where onset may usually be in middle or older age. Multiple studies point to the role of disordered lifestyle health behaviors as contributory to these endocrinopathies, and conversely therapeutic lifestyle changes leading to improvement in signs, symptoms, biochemical markers, and sequelae of these conditions. This article presents 3 different real life case studies of the conditions enlisted above and documents the positive impact of lifestyle improvements on their disease condition. Therapeutic lifestyle behaviors are an extremely useful and important component of management of these familiar endocrinologic disorders, and clinicians need to routinely counsel their patients about healthy lifestyle interventions when treating these common syndromes.

Cut-off values of coronary risk factors in women with hypothyroidism.

Women with hypothyroidism are at higher risk of cardiovascular diseases and the consequent mortality. It is not known whether cut-off values of coronary risk factors in women with hypothyroidism are the same as healthy women. This may help to initiate interventions as early to prevent cardiovascular mortality. Therefore, this study was conducted to determine the cut-off values of coronary risk factors in women with hypothyroidism. One hundred women patients with hypothyroidism were compared with 100 healthy controls. Significantly higher mean body mass index (BMI), waist circumference (WC), triglycerides and low-density lipoprotein cholesterol (LDL-C) were observed in women with hypothyroidism than without it. All variables showed an area under curve (AUC) value of >0.6 in receiver operator characteristic curve (ROC) analysis, and similar to healthy women.

Rising Incidence and Comorbidities of Endogenous Hypothyroidism in Republic of Korea from 2004 to 2018: A Nationwide Population Study.

Background: Hypothyroidism, a prevalent endocrine disorder, results from insufficient thyroid hormone production or release, affecting metabolism. However, disparities in comorbidities and treatment trajectories may exist between endogenous and exogenous hypothyroidism. Methods: Data from the Korean National Health Insurance Service from 2004 to 2018. Endogenous hypothyroidism was defined as cases with two or more diagnostic codes for hypothyroidism coupled with a history of thyroid hormone intake exceeding 60 days. To eliminate iatrogenic hypothyroidism, individuals with diagnosis codes for thyroid cancer, treatment codes for thyroid surgery, or radiotherapy were excluded. Hypothyroidism-related comorbidities were defined as new occurrences of the corresponding diagnosis code after the diagnosis of hypothyroidism during the entire study period. Results: The age-standardized incidence of endogenous hypothyroidism among men was 0.2 per 1,000 person-years in 2004, increasing to 0.8 in 2018. Among women, the incidence increased from 1.6 per 1,000 person-years in 2004 to 3.7 in 2018. When comparing age groups of 20s-50s and 60s-90s, both sexes in the 60s-90s demonstrated a more rapid increase in incidence than those in the 20s-50s age range. Patients with endogenous hypothyroidism demonstrated a higher incidence of mood disorders across all age groups and cerebrovascular disease in individuals ≥60 years old, regardless of sex. Conclusion: In Republic of Korea, endogenous hypothyroidism incidence has been increased in recent years. The incidence of endogenous hypothyroidism is increasing more rapidly in men than in women, especially in the elderly. Patients with endogenous hypothyroidism seem to have a heightened risk for cerebrovascular disease and mood disorders.

Interpretable machine learning model predicting immune checkpoint inhibitor-induced hypothyroidism: A retrospective cohort study.

Hypothyroidism is a known adverse event associated with the use of immune checkpoint inhibitors (ICIs) in cancer treatment. This study aimed to develop an interpretable machine learning (ML) model for individualized prediction of hypothyroidism in patients treated with ICIs. The retrospective cohort of patients treated with ICIs was from the First Affiliated Hospital of Ningbo University. ML methods applied include logistic regression (LR), random forest classifier (RFC), support vector machine (SVM), and extreme gradient boosting (XGBoost). The area under the receiver-operating characteristic curve (AUC) was the main evaluation metric used. Furthermore, the Shapley additive explanation (SHAP) was utilized to interpret the outcomes of the prediction model. A total of 458 patients were included in the study, with 59 patients (12.88%) observed to have developed hypothyroidism. Among the models utilized, XGBoost exhibited the highest predictive capability (AUC = 0.833). The Delong test and calibration curve indicated that XGBoost significantly outperformed the other models in prediction. The SHAP method revealed that thyroid-stimulating hormone (TSH) was the most influential predictor variable. The developed interpretable ML model holds potential for predicting the likelihood of hypothyroidism following ICI treatment in patients. ML technology offers new possibilities for predicting ICI-induced hypothyroidism, potentially providing more precise support for personalized treatment and risk management.

Navigating the thyroid-gynecologic interplay: a systematic review and meta-analysis thyroid-gynecologic interaction.

Thyroid disorders are considered to be linked to various health issues, including gynecologic cancers. Studying this association is crucial in clinical practice. This approach was applied through searches in Scopus, WOS, PubMed, and Google Scholar. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was followed. The quality assessment was checked. The meta-analyses were performed using R-4.3.2 (COMPANY, CITY, STATE, COUNTRY) and SPSS version 28 (COMPANY, CITY, STATE, COUNTRY). The results demonstrated that 19 studies investigated the association between thyroid disorders and gynecologic cancers in adult females. The studies were categorized into two groups: group 1 examined thyroid status in various gynecologic cancers, while group 2 comprised case-control studies examining gynecologic cancer incidence in females with thyroid disorders compared to control. Among females with gynecologic cancers, 13% (95% confidence interval [CI], 10-17%) had hypothyroidism. When comparing hypothyroidism and hyperthyroidism across studies, the overall percentage for hypothyroidism was 14% (95% CI, 9-22%), while for hyperthyroidism, it was 3% (95% CI, 2-5%). The odds ratio for hypothyroidism in females with uterine cancer was 2.65 (P<0.05). Additionally, hypothyroidism showed a significant risk ratio of 1.3 (P<0.05) for different gynecologic cancers. However, hyperthyroidism was significantly associated with increased ovarian cancer mortality (RR, 2.14; P=0.03); conversely, hypothyroidism showed no significant relationship (RR, 1.35; P=0.26). The findings concluded that hypothyroidism is significantly associated with various gynecologic cancers, suggesting a potential role in its pathogenesis. Conversely, hyperthyroidism is linked to an increased risk of ovarian cancer mortality. Further research is needed to clarify whether hyperthyroidism predisposes females to ovarian cancer.

Associative Learning in Subclinical Hypothyroidism at Different Ranges of Thyroid Stimulating Hormone: A Cambridge Neuropsychological Test Automated Battery (CANTAB) Study of Visual Paired Association Learning Task.

BACKGROUND: Associative learning deficits are constantly found in subclinical hypothyroidism (SCH). Despite achieving normal thyroid stimulating hormone (TSH) levels, a considerable number of patients undergoing levothyroxine (LT-4) treatment frequently complain about memory retrieval. The Paired Association Learning (PAL) task involves computerised testing on the CANTAB- Cambridge Neuropsychological Test Automated Battery, also considered a screening tool for Alzheimer's disease (AD). PURPOSE: This study aimed to investigate the impact of different levels of TSH on visual associative learning in SCH and determine if these impairments were reversed with LT-4. METHODS: A total of 134 participants were included in this cross-sectional study. Group 1: 35 healthy controls; patients with SCH (Group 2: 33 newly identified cases; Group 3: 32 patients on LT-4 with elevated TSH; Group 4: 34 euthyroid but on LT-4). A thyroid profile and a neuropsychological clinical assessment were done. The visual PAL task was performed on CANTAB. RESULTS: PAL was significantly impaired (p = <0.05) in all 3 patient groups as compared to Group 1. The PAL total errors (adjusted) scores were significantly higher in Groups 2 and 3, indicating that associative learning is definitely impaired in SCH, reaching levels previously seen in patients with AD. CONCLUSION: Our findings encourage screening for visual associative learning or memory retrieval in patients with SCH. The study present has established a more reasonable threshold of TSH 2.5mIU/L to encourage examination of associative learning and the initiation of LT-4 in SCH. Poor PAL task performance in patients with SCH may have significant implications in clinical settings for suspecting AD.

Comparison between Liquid and Tablet Formulations in the Treatment of Congenital Hypothyroidism up to 3 Years of Age: The First Italian Study.

Background/Objectives: Levothyroxine (L-T4) is available for use in congenital hypothyroidism (CH) in three formulations: tablets, drops, and oral solution. This study aims to compare the efficacy and safety of all three L-T4 formulations. Methods: We enrolled 63 children born between January 2019 and April 2023 in the Emilia-Romagna Region (Italy) and diagnosed with CH by newborn screening. They were divided according to the L-T4 formulation used: drops (Group D), oral solution (Group S), and tablets (Group T). Clinical and laboratory data were collected up to 3 years after the start of replacement therapy. Results: Serum-free thyroxine (sFT4) and thyroid stimulating hormone (sTSH) normalization occurred within the first month of treatment in most patients of all groups. No negative effects on growth and cognitive development were observed. At 7-15 days we found higher median sTSH levels (p = 0.031) and a greater percentage of patients with sTSH > 5 µU/mL (p = 0.011) in Group S than in Group T, but comparable sFT4 levels. At 12 months, a greater percentage of patients of Group D showed sFT4 values below the normal range than Group S (p = 0.011) and Group T (p = 0.038); Conclusions: Overall, our study reported an equal efficacy of the L-T4 oral solution compared to drops and tablets in CH treatment. A larger series of patients and a long-term follow-up are needed.

Effect of Presence of Uni- or Bilateral Thyroid Adenoma on Recovery of Pituitary-Thyroid Axis and Creatinine Concentration in Radioiodine-Treated Cats.

Radioiodine therapy (RAIT) is the gold standard for treatment of hyperthyroidism in cats. The aim of this study was to evaluate the effect of the presence of uni- or bilateral thyroid adenoma on changes in total thyroxine (TT4), thyroid-stimulating hormone (TSH), and creatinine concentration over a period of 6 to 12 months following RAIT. Fifty-one hyperthyroid cats presented for RAIT between April 2021 and April 2022 were prospectively enrolled. Cats with an increased creatinine concentration (creatinine ≥ 140 µmol/L), renal morphology abnormalities, and suspected thyroid carcinoma were excluded. TT4, TSH, and creatinine were determined before and one week and one, three, six, and twelve months following RAIT. The effects of the re-examination timepoint following RAIT and the presence of uni- or bilateral thyroid adenoma based on technetium-99m scintigraphy on TT4, TSH, and creatinine were analysed by mixed effects modelling. Cats with bilateral adenoma had significantly higher TSH concentrations after RAIT compared to those with unilateral adenoma. TT4 concentration significantly decreased one week (p < 0.001) and again one month following RAIT (p < 0.001). TSH and creatinine concentration significantly increased one month post RAIT (both p < 0.001). As indicated by an increase in TSH concentration, the pituitary-thyroid axis needs a minimum of one month post RAIT to recover from hyperthyroidism-induced suppression, but hypothyroidism necessitating levothyroxine supplementation might not be diagnosed before 6 or even 12 months post RAIT. Although creatinine did not increase significantly after one month post RAIT in this cohort, an increased creatinine concentration was detected at later timepoints in individual cats.

Myxedema ascites? A rare presentation of ascites in severe hypothyroidism: A case report and review.

Ascites represents an infrequent sequela of hypothyroidism, manifesting in fewer than 4% of affected individuals. Herein, we delineate a case characterized by profound hypothyroidism accompanied by substantial ascites, further complicated by cardiac insufficiency. A 29-year-old female, previously diagnosed with postradiation hypothyroidism subsequent to a diagnosis of Grave's disease 11 years prior, presented with exacerbating dyspnoea, abdominal distension, and orthopnea. In January 2024, she was admitted with massive ascites, exhibiting clinical manifestations of both hypothyroidism and cardiac failure. Thyroid function tests were markedly abnormal, with a thyroid-stimulating hormone level of 77.65 mIU/L, triiodothyronine at 2.2 nmol/L, and thyroxine levels below 3.2 pmol/L. Echocardiographic evaluation revealed dilated cardiomyopathy with a significantly reduced systolic (ejection fraction of 25.9%) and diastolic function (E/A ratio of 0.87). Analysis of the ascitic fluid demonstrated a serum-ascites albumin gradient exceeding 1.1 g/L (3 g/L). Ultrasonography of the abdomen ruled out portal hypertension, while computed tomography of the abdomen confirmed extensive ascites without evidence of malignancy. Under the supervision of a specialist, the patient was administered a high dosage of levothyroxine (300 mcg), leading to a significant amelioration in both thyroid function parameters and her ascites. Subsequent thyroid function tests demonstrated a decrease in thyroid-stimulating hormone levels to 11.7 mIU/L and an increase in thyroxine levels to 15.6 pmol/L, indicating a positive response to the thyroid hormone replacement therapy. Subsequent echocardiographic assessment showed improvement in the ejection fraction to 26.9% and diastolic function (E/A ratio of 1.27). Myxedema ascites, though infrequent, is readily amenable to treatment. The serum-ascites albumin gradient exceeding 1.1 g/L may be indicative of hypothyroidism-associated ascites, although the paucity of studies renders it uncertain whether this is a characteristic feature. Further investigation into the etiology, diagnostic criteria, and management strategies for ascites in the context of hypothyroidism is warranted.

A Real-World Pharmacovigilance Study of the FDA Adverse Event Reporting System Events for Trametinib.

OBJECTIVE: This research investigates adverse drug events (ADEs) linked to trametinib, utilizing data from the FDA Adverse Event Reporting System (FAERS) database, covering the period from Q2 2013 to Q4 2023. METHODS: We gathered data on ADEs associated with trametinib from the second quarter of 2013 to the fourth quarter of 2023. After standardizing the data, we applied various analytical methods to quantify signals, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation for Neural Networks (BCPNN), and multi-item gamma Poisson shrinker (MGPS). RESULTS: In our examination of 2200 ADE reports with trametinib cited as the primary suspect, we identified 191 adverse reaction terms across 23 system organ classifications. The most frequently reported classifications were general disorders and administration site conditions, with 1254 cases (ROR 0.83, PRR 0.85, IC -0.23, EBGM 0.85), followed by neoplasms (benign, malignant, and unspecified, including cysts and polyps) with 802 cases (ROR 3.59, PRR 3.32, IC 1.73, EBGM 3.32), and investigations with 794 cases (ROR 1.74, PRR 1.66, IC 0.73, EBGM 1.66). Notably, this study also uncovered previously unlabeled adverse reactions such as cheilitis, lobular panniculitis, ulcerative keratitis, and stridor. CONCLUSION: While trametinib provides therapeutic advantages, it is associated with several potential adverse reactions. It is crucial for healthcare providers to closely monitor patients for symptoms such as cheilitis, lobular panniculitis, ulcerative keratitis, stridor, and other adverse events (AEs) during treatment.

Genetic and Functional Studies of Patients with Thyroid Dyshormonogenesis and Defects in the TSH Receptor (TSHR).

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype-phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4-100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP-response-element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient's genotype for a correct diagnostic confirmation.

LT4/LT3 Combination Therapy vs. Monotherapy with LT4 for Persistent Symptoms of Hypothyroidism: A Systematic Review.

Regardless of the cause, hypothyroidism should be treated with levothyroxine. The objectives of management are the normalization of TSH levels and the relief of symptoms. In general, the vast majority of patients who achieve normalization of TSH levels show a resolution of symptoms; however, for a small number of individuals, symptoms persist (despite adequate control of TSH). This scenario generates a dilemma in the therapeutic approach to these patients, because even when excluding other causes or concomitant diseases that can explain the persistence of symptoms, pharmacological management strategies are scarce. Consequently, the efficacy of some less conventional approaches to therapy, such as the use of LT3 monotherapy, desiccated thyroid extracts, and LT4/LT3 combinations, in addressing persistent hypothyroid symptoms have been evaluated in multiple studies. The majority of these studies did not observe a significant benefit from these "nonconventional" therapies in comparison to results with LT4 monotherapy alone. Nevertheless, some studies report that a significant proportion of patients prefer an alternative to monotherapy with LT4. The most common approach has been to prescribe a combination of LT4 and LT3, and this review describes and analyzes the current evidence of the efficacy of LT4/LT3 combination therapy vs. LT4 monotherapy in addressing persistent hypothyroidism symptoms to provide suggested guidelines for clinicians in the management of these patients.

Thyroid Hormone Regulates Postnatal Development of the Rete Testis in Mice.

Thyroid hormone regulates the rate of testis maturation in mammals. Manipulations of thyroid hormone levels in neonatal animals affect various aspects of testis biology. However, there have been no studies examining the effects of thyroid hormone on the rete testis (RT). Here, we used animal models of neonatal hyperthyroidism (injections of triiodothyronine, or T3) and hypothyroidism (goitrogen 6-propyl-2-thiouracil [PTU] treatment) and found that higher levels of thyroid hormone accelerate RT development, while lower levels of thyroid hormone delay it. T3 and PTU treatments influence RT size, proliferation of RT cells, and expression of DMRT1 and androgen receptor in the RT. T3 supplementation accelerates RT development in an organ testicular culture, which indicates the local action of thyroid hormone. Additionally, it was found that follicle-stimulating hormone could be involved in the regulation both of RT proliferation and RT size. The fact that RT cells in a cell culture do not respond to T3 suggests indirect action of thyroid hormone on the RT in vivo or the loss of the responsiveness to the hormone in vitro.

Combined Levothyroxine and Propylthiouracil Treatment in Children with Monocarboxylate Transporter 8 Deficiency: A Multicenter Case Series of 12 Patients.

Objective: To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages. Methods: This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon signed ranks tests and generalized estimated equations to assess effects on thyroid and metabolic markers, and receiver operating characteristics curves to predict optimal dose. Results: Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day. Thyrotropin concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight (z-score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Conclusion: Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

Outcome and incidence of hypothyroidism in low-dose radioactive iodine treatment for hyperthyroidism.

OBJECTIVE: The study aimed to analyze the outcome of low-dose radioactive iodine (RAI) treatment for hyperthyroidism, disclose whether age and gender influence the outcome and determine the incidence and onset time of hypothyroidism following low-dose RAI. MATERIAL AND METHODS: A total of 158 patients who received doses less than 370 Mbq RAI were enrolled in the study. Treatment outcome and incidence of hypothyroidism were compared between different gender (45 male vs.113 female), age (77 patients ≥45 years old vs. 81 patients <45 years old) and dose (39 patients receiving higher doses RAI vs. 119 receiving lower dose with a cutoff of 222 MBq) groups. Treatment outcomes were categorized into post-treatment hypothyroidism, treatment failure (persistent hyperthyroidism), and euthyroidism. In those becoming hypothyroid, time to develop hypothyroidism was calculated for cumulative incidences over time. RESULTS: Out of 158 patients, 47 (29.7%) developed hypothyroidism, 101 (63.9%) had treatment failure, and 10 (6.3%) remained euthyroid after treatment. Response rates (33.6% vs. 43.5%, p = 0.260) and hypothyroidism incidences (26.9% vs. 38.5%, p = 0.170) did not differ significantly between lower and higher dose groups, neither between lower and higher age groups (p = 0.69 in response rates and p = 0.75 in hypothyroidism incidence). Females exhibited higher response rates (42.5% vs. 20.0%, p = 0.008) and hypothyroidism incidence (46.3% vs. 13.3%, p = 0.004) compared to males. Hypothyroidism onset occurred at a mean of 24.0 ±â€¯29.2 months, and the cumulative incidences over time were 47% and 60% in six and twelve months, respectively. CONCLUSIONS: Low-dose RAI has a low response rate for treating hyperthyroidism. Although there may be a lower incidence of hypothyroidism following low-dose RAI compared to high-dose RAI, hypothyroidism may occur early after treatment. Besides, females have higher response rates but more incidence of hypothyroidism. The balance between the risks and benefits of using low-dose RAI should be taken into deliberate consideration.

The Multifunctional Role of KCNE2: From Cardiac Arrhythmia to Multisystem Disorders.

The KCNE2 protein is encoded by the kcne2 gene and is a member of the KCNE protein family, also known as the MinK-related protein 1 (MiRP1). It is mostly present in the epicardium of the heart and gastric mucosa, and it is also found in the thyroid, pancreatic islets, liver and lung, among other locations, to a lesser extent. It is involved in numerous physiological processes because of its ubiquitous expression and partnering promiscuity, including the modulation of voltage-dependent potassium and calcium channels involved in cardiac action potential repolarization, and regulation of secretory processes in multiple epithelia, such as gastric acid secretion, thyroid hormone synthesis, generation and secretion of cerebrospinal fluid. Mutations in the KCNE2 gene or aberrant expression of the protein may play a critical role in cardiovascular, neurological, metabolic and multisystem disorders. This article provides an overview of the advancements made in understanding the physiological functions in organismal homeostasis and the pathophysiological consequences of KCNE2 in multisystem diseases.

Hypothyroidism alters the rhythmicity of the central clock, body temperature and metabolism: evidence of Bmal1 transcriptional regulation by T3.

In mammals, the central circadian oscillator is located in the suprachiasmatic nucleus (SCN). Hypothalamus-pituitary-thyroid axis components exhibit circadian oscillation, regulated by both central clock innervation and intrinsic circadian clocks in the anterior pituitary and thyroid glands. Thyroid disorders alter the rhythmicity of peripheral clocks in a tissue-dependent response; however, whether these effects are influenced by alterations in the master clock remains unknown. This study aimed to characterize the effects of hypothyroidism on the rhythmicity of SCN, body temperature (BT) and metabolism, and the possible mechanisms involved in this signalling. C57BL/6J adult male mice were divided into Control and Hypothyroid groups. Profiles of spontaneous locomotor activity (SLA), BT, oxygen consumption ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ) and respiratory quotient (RQ) were determined under free-running conditions. Clock gene expression, and neuronal activity of the SCN and medial preoptic nucleus (MPOM) area were investigated in light-dark (LD) conditions. Triiodothyronine (T3) transcriptional regulation of Bmal1 promoter activity was evaluated in GH3-transfected cells. Hypothyroidism delayed the rhythmicity of SLA and BT, and altered the expression of core clock components in the SCN. The activity of SCN neurons and their outputs were also affected, as evidenced by the loss of circadian rhythmicity in V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ and RQ and alterations in the neuronal activity pattern of MPOM. In GH3 cells, T3 increased Bmal1 promoter activity in a time-dependent manner. Thyroid hormone may act as a temporal cue for the central circadian clock, and the uncoupling of central and peripheral clocks might contribute to a wide range of metabolic and thermoregulatory impairments observed in hypothyroidism. KEY POINTS: Hypothyroidism alters clock gene expression in the suprachiasmatic nucleus (SCN). Thyroid hypofunction alters the phase of spontaneous locomotor activity and body temperature rhythms. Thyroid hormone deficiency alters the daily pattern of SCN and medial preoptic nucleus neuronal activities. Hypothyroidism alterations are extended to daily oscillations of oxygen consumption and metabolism, which might contribute to the development of metabolic syndrome. Triiodothyronine increases Bmal1 promoter activity acting as temporal cue for the central circadian clock.

Association between Subclinical Hypothyroidism and Adverse Pregnancy Outcomes in Assisted Reproduction Technology Singleton Pregnancies: A Retrospective Study.

Background/Objectives: Women with subclinical hypothyroidism (SCH) were reported to be at an increased perinatal risk. We aimed to investigate the relationship between SCH and perinatal outcomes in singleton pregnancies resulting from assisted reproduction technology (ART). Methods: We retrospectively examined the perinatal outcomes of ART singleton pregnancies in women who underwent thyroid function screening before conception and delivered at our hospital from January 2020 to July 2023. We defined SCH as thyroid-stimulating hormone (TSH) levels > 2.5 mU/L and normal free T4 levels. The patients were categorized into three groups: normal thyroid function (group A), SCH without levothyroxine therapy (group B), and SCH with levothyroxine therapy (group C). The risks of preterm birth, preeclampsia, fetal growth restriction, manual placental removal, and blood loss at delivery were compared among the three groups. Results: Out of the 650 ART singleton deliveries, 581 were assigned to group A, 34 to group B, and 35 to group C. The preterm birth rate at <34 weeks was significantly higher in group B and significantly lower in group C than in group A. The rate of preterm delivery at <34 weeks increased in correlation with TSH levels. Levothyroxine therapy was the significant preventive factor for preterm birth at <34 weeks. Conclusions: The preterm birth rate before 34 weeks was significantly higher in the SCH group. Levothyroxine therapy is a significant protective factor against preterm birth before 34 weeks. Universal screening for thyroid function and appropriate hormone therapy in pregnant women may help reduce perinatal risks, including preterm birth.

A Cross-Sectional Study on the Prevalence of Subclinical Hypothyroidism in Metabolic Syndrome Patients at a Tertiary Care Hospital.

BACKGROUND AND OBJECTIVE: Metabolic syndrome (MetS) is defined as a "constellation" of cardiometabolic risk factors, characterized by hypertension, atherogenic dyslipidemia, hyperglycemia, prothrombotic and proinflammatory conditions which, jointly, increase the risk of suffering cardiovascular diseases (CVD) and type 2 diabetes mellitus. Thyroid dysfunction is also believed to affect parameters such as high-density lipoprotein (HDL) cholesterol, triglycerides, plasma glucose, and blood pressure, in turn increasing the risk of CVD. Subclinical hypothyroidism (SCH), which independently raises the risk of CVDs and their associated complications, is more frequently detected in patients with MetS compared to the general population. When both conditions coexist, the risk of CVD and its complications is significantly heightened. The objective of the study was to find out the prevalence of SCH in patients with MetS. METHODS: A prospective cross-sectional study was conducted in the Department of General Medicine, New Civil Hospital, Surat, Gujarat, India. Eighty patients who fulfilled the criteria for MetS by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), were taken into the study. A detailed history, anthropometric measurements, blood pressure, fasting blood glucose, lipid profile, and thyroid profile (Free T3, Free T4, and serum thyroid-stimulating hormone (TSH)) were undertaken. The thyroid profile was done by chemiluminescence immunoassay (CLIA) method. RESULTS: Out of 80 patients with MetS, 48 were female and 32 were male, with the overall mean age of the study population being 46.5±9.5 years. Among them, 23.7% of the population was found to be having thyroid dysfunction. Among the thyroid dysfunction, SCH was highly prevalent (18.8%), 3.8% patients had overt hypothyroidism and 1.3% patients had subclinical hyperthyroidism. There were no overt hyperthyroid patients in our study. HDL (mg/dl) and TSH (mIU/L) were significantly higher in the SCH group as compared to other types of hypothyroidism group (p-value < 0.05). DISCUSSION: There is a statistically significant prevalence of SCH (18.8%) in MetS patients. It is clear from the study that one-fifth of MetS patients or every fifth patient with MetS had SCH. Thus, looking proactively for SCH in MetS and treating it would prevent conversion to overt hypothyroidism and complications of MetS.