Background: Congenital hypothyroidism (CH) is a common metabolic disorder in children that can impact growth and neurodevelopment, particularly during infancy and early childhood. DUOXA2, a DUOX maturation factor, plays a crucial role in the maturation and activation of dual oxidase DUOX2 (a member of the NADPH oxidase family). DUOX2 can correctly migrate to the plasma membrane from the endoplasmic reticulum (ER) with the help of DUOXA2, and the two proteins together form a stable complex that promotes hydrogen peroxide (H2O2) generation in the synthesis of thyroid hormones. Genetic alterations in DUOXA2 lead to defects function of DUOX2 protein causing inherited CH.

Objectives: This review discusses the relationship between DUOXA2 and CH, including the pathogenic mechanisms of CH in children caused by DUOXA2 mutations and the possibility or promise of DUOXA2 gene screening as a diagnostic marker for CH in the clinic.

Methods: The review synthesizes current research on the biological role of DUOXA2 and DUOX2 in thyroid hormone synthesis, the molecular impact of DUOXA2 mutations, and the clinical implications of genetic screening for CH.

Results: Mutations in DUOXA2 disrupt this process of H2O2 generation in the synthesis of thyroid hormones , leading to inherited CH. Early identification through DUOXA2 gene screening could improve diagnostic accuracy, which facilitates early intervention and personalized treatment.

Conclusions: DUOXA2 gene screening holds promise for enhancing diagnostic accuracy in CH. However, it cannot be used as a sole diagnostic indicator, and to optimize diagnostic sensitivity, it should be combined with the screening of other relevant genetic mutations and diagnostic tools. Further research is needed to refine screening protocols and explore therapeutic options.

There is limited data concerning the effect of untreated subclinical thyroid disorders on mortality in older adults. Therefore, this study aimed to analyze 5-year overall mortality among participants in the PolSenior study with treated and untreated subclinical thyroid dysfunction.

The study group consisted of 407 participants with thyroid disorders (305 with hypothyroidism and 102 with hyperthyroidism) and 2776 euthyroid individuals aged 65 years and older. Overall mortality risk factors were assessed with Cox proportional hazard regression. Additionally, overall survival analyses were performed with Kaplan‒Meier estimates stratified by sex and hypo-/hyperthyroidism status.

In women, there was no difference in survival between the euthyroid and hypothyroid groups. Survival was significantly worse in patients with subclinical hyperthyroidism than in euthyroid and treated hyperthyroidism patients. In men, there were no differences in survival between the hyperthyroidism group and the subclinical hypothyroidism or euthyroid group. Notably, survival was better in the treated hypothyroidism group than in the euthyroid group. According to the multivariate models, subclinical hyperthyroidism appeared to be linked to a 30% reduction in survival among women (hazard ratio [HR] for mortality = 1.43; 95% CI = 0.98-2.07, p = 0.06) but not among men.

Our study showed that women with subclinical hyperthyroidism had a higher mortality rate. At the same time, men with treated hypothyroidism had improved survival compared to those in the euthyroid group among participants aged 65 years and older during a 5-year follow-up period. Subclinical hypothyroidism did not influence the survival rates.

Thyroid hormones influence the function of essentially every system of the body, including the cardiovascular and metabolic system. Thyroid hormone replacement with levothyroxine (LT4) is the mainstay of pharmacological management for people with (especially clinically overt) hypothyroidism, and it is important to ensure the cardiovascular and metabolic safety of this treatment. This is especially so as in hypothyroidism, cardiometabolic risk factors and cardiovascular disease are highly prevalent conditions and will often coexist in an individual patient. Accordingly, we have reviewed the cardiometabolic consequences of hypothyroidism and intervention with thyroid hormone replacement.

Numerous observational studies and meta-analyses have described multiple potentially adverse cardiometabolic consequences of hypothyroidism, including exacerbation of cardiovascular and metabolic risk factors (especially dyslipidaemia), functional impairment of the heart and vasculature (including accelerated atherosclerosis) and increased risk of advanced cardiovascular outcomes. LT4 usually improves cardiometabolic risk factors in people with hypothyroidism and some (but not all) studies have reported improved vascular and cardiac function in LT4-treated populations. Observational data have suggested the possibility of improved cardiometabolic outcomes with LT4 treatment, particularly in younger people with hypothyroidism, although data from randomised, controlled trials are needed here. Importantly, LT4 (with or without additional triiodothyronine) appears to be safe from a cardiovascular perspective, as long as overtreatment and iatrogenic thyrotoxicosis are avoided.

Overall, the current evidence base supports intervention with LT4 to protect the cardiometabolic health of people with hypothyroidism who require thyroid hormone replacement, although more data on long-term clinical outcomes are needed.

Background: Thyroid dysfunction is common in older adults and poses diagnostic and management challenges for clinicians. In this narrative review, we present published data focusing on special considerations in the diagnosis and management of hypothyroidism and hyperthyroidism in older adults. Methods: A comprehensive literature search of the PubMed and Ovid MEDLINE databases was conducted from January 2000 to December 2024 to identify pertinent articles in English for this narrative review. Results: Due to significant cardiovascular risk if untreated, both overt hypothyroidism and hyperthyroidism should be treated in older adults. Findings from observational studies do not support treating older adults with subclinical hypothyroidism with a thyrotropin (TSH) <7 mIU/L. However, observational data have demonstrated an increased risk of cardiovascular mortality and stroke in older adults with subclinical hypothyroidism with TSH 7.0-9.9 mIU/L and of coronary heart disease, cardiovascular mortality, and heart failure in those with TSH ≥10 mIU/L, suggesting levothyroxine treatment in these individuals should be considered. Data from clinical trials failed to show improvement with levothyroxine in hypothyroidism symptoms or fatigue in older adults with subclinical hypothyroidism compared with placebo. Over- and under-replacement with thyroid hormone is common and should be avoided, as population-based studies have shown associations with adverse cardiovascular and skeletal events. Subclinical hyperthyroidism with a TSH <0.1 mIU/L should be treated in older individuals as it has been associated with increased cardiovascular risk and bone density loss based on observational data. Randomized controlled trials have shown that long-term low-dose methimazole is a viable alternative to radioactive iodine in older adults with hyperthyroidism. Conclusions: A personalized approach should be undertaken in the diagnosis and management of thyroid dysfunction in older adults. Multiple factors should be considered, including physiological age-related changes in thyroid function, comorbidities, and polypharmacy. Care should be taken to maintain euthyroidism in order to avoid adverse events.

This multicenter, open-label, randomized controlled trial (RCT) aims to assess the efficacy and safety of levothyroxine monotherapy in lowering the risk of cardiovascular disease (CVD) in untreated older adults with subclinical hypothyroidism (SCH) who are diagnosed according to population-specific TSH reference values.

A total of 254 patients with SCH who meet the diagnostic criteria will be recruited, and the baseline clinical data of the patients will be collected. Then, a total of 127 patients will be randomly divided into each of the treatment and control groups, and the treatment group will receive daily levothyroxine doses (Merck Euthyrox® levothyroxine 50 mcg tablet). Specifically, 50 µg of levothyroxine per day will be administered to patients in the treatment group (or 25 µg to patients with a body weight < 50 kg) for at least 48 weeks to maintain thyroid-stimulating hormone (TSH) levels within the normal range. The participants in the control group will be subjected only to thyroid status evaluation, and the results will be recorded. The participants will complete five visits before and after the start of the trial, and differences in the change in carotid intima-media thickness (CIMT), maximum mean change in plaque burden, and changes in lipid profiles, bone mineral densities, and incidences of fatal and nonfatal cardiovascular events between the initial visit and the last follow-up visit will be evaluated via vascular ultrasound.

We will explicitly address whether levothyroxine replacement therapy provides cardiovascular benefits for older adults with subclinical hypothyroidism.

ClinicalTrials.gov, No. ChiCTR2400092634. Registered on 30 November 2024. Recruitment for this study began on December 1, 2024, and continues until at least until November 30, 2025.

Hypothyroidism is one of the most common endocrine disorders in dogs, that is caused by reduction in thyroxine hormone production.

This study aimed to detect the incidence of clinical hypothyroidism among cases suffering from dermatological changes or obesity, investigate the complications in severely affected hypothyroid dogs and evaluate the response to levothyroxine treatment.

Total number of 212 dogs of different ages, breeds and of both sexes were included in this study, where 200 dogs were suffering from alopecia or obesity, the other 12 healthy dogs were used as control group.

After ruling out other causes of alopecia and obesity, hypothyroidism was diagnosed in 28 dogs (14%) depending on the result of thyroid function test. Results of this study showed that the highest incidence of hypothyroidism was reported in Golden retriever (21.42%) followed by Griffon dogs (17.85%). Additionally, hypothyroidism was mostly reported in middle-aged dogs (60.71%) of different breeds. Males (57.14%) revealed higher incidence than females. The hypothyroid dogs showed a wide range of clinical signs including dermatological, metabolic, psychological alterations in addition to cardiovascular, respiratory, neuromuscular, gastrointestinal and gynecological abnormalities. Radiography revealed pulmonary edema in dogs affected with heart problems (N = 2), dilated esophagus in hypothyroid dogs showing vomiting (N = 2). Echocardiographic examination of hypothyroid dogs with heart problems revealed first grade diastolic dysfunction. Treatment with levothyroxine induced clinical improvement within one month of administration.

Hypothyroidism is a relatively common condition in dogs compared to other diseases causing dermatological changes or obesity in dogs. Therefore, it must be considered for early diagnosis and treatment before encountering complications that could be life threatening for dogs.

To investigate the effect of parathormone and thyroid hormones, along with their associated biochemical factors in individuals with and without symptoms indicative of temporomandibular disorder (TMDs) admitted to the internal medicine department.

The study involved 416 participants with symptoms indicative of TMDs and 415 controls. Serum concentrations of anti-thyroid peroxidase antibody (Anti-TPO Ab), free triiodothyronine, free thyroxine, thyroid-stimulating hormone, parathyroid hormone, calcium, sodium, potassium, magnesium, phosphorus, vitamin D, vitamin B12, folate, creatine kinase, haemoglobin, ferritin, C-reactive protein and sedimentation rate were analysed.

The serum level of anti-TPO Ab was found to be elevated in participants with symptoms indicative of TMDs in comparison to controls (p < .001). However, no significant differences were observed in the other parameters assessed between the two groups (p > .05).

Serum concentrations of parathormone and thyroid hormones associated biochemical factors are not affected in participants with symptoms indicative of TMDs except Anti-TPO Ab.

Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food/drug interactions, and patient adherence. XP-8121 (levothyroxine for subcutaneous administration) is a ready-to-use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single-center, 2-part study aimed to characterize the PK and dose proportionality of XP-8121 SC compared to 600 μg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP-8121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open-label, crossover, fixed-sequence study (n = 30). Dose linearity was evaluated by escalating XP-8121 SC doses up to 1200 μg. Part 2 was an open-label, single-period study (n = 30) evaluating PK characteristics of a single dose of XP-8121 SC (1500 μg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline-adjusted levothyroxine concentration increased rapidly in plasma (Tmax median: 3.1 h); absorption for all XP-8121 SC doses was slower compared to 600 μg oral levothyroxine, and levels remained elevated for 4-5 days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP-8121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUCss). Overall, these data for XP-8121 provide adequate predictive performance to inform future phase 2 studies.

Background: Overtreatment with thyroid hormone is common and is associated with multiple adverse health outcomes, especially in older adults. Higher overtreatment rates have been reported among women. Understanding this sex difference could lead to better clinical utilization of therapy in at-risk populations. Methods: We performed a retrospective cohort study to examine the relationship between iatrogenic thyrotoxicosis and patient sex, adjusting for demographics, comorbidities, body composition, and thyroid hormone dosing using electronic health records for adults age 50 and older in a large community health system in the United States. Results: A total of 20,724 patients met all inclusion criteria, of whom 77% were female and 23% non-White. Women were more likely to have a low thyrotropin (TSH) compared to men (36.7% vs. 23.9%; unadjusted hazard ratio [HR] = 1.67 [95% confidence interval {CI} 1.56-1.79]). Many covariates varied by sex, including rates of several comorbidities, and there was a small but statistically significant difference in the median daily levothyroxine dose per actual body mass: 1.1 μg/kg in male patients compared with 1.2 μg/kg in female patients (p < 0.001). Adjusting for covariates other than dose did not significantly change the sex-related risk of iatrogenic thyrotoxicosis. In fully adjusted Cox models including dose per actual body mass, the female versus male HR = 1.50 [CI 1.34-1.69] was also not different from models which did not account for dose (p = 0.422). However, the association between female sex and thyrotoxicosis risk was partially mediated when adjusting for dose per ideal body mass (HR = 1.30 [CI: 1.16-1.46]; p < 0.001) and was fully mediated by dose calculated using lean body mass (HR = 1.06 [CI: 0.95-1.19]; p < 0.001). That is, women had higher risk of iatrogenic thyrotoxicosis compared to men receiving similar actual body mass doses, whereas women and men receiving comparable lean body mass doses had comparable risk. Conclusions: Mediation analysis demonstrates that the increased risk of iatrogenic thyrotoxicosis in older women may be attributable to differences in body composition between men and women. The use of ideal or lean body weight-based dose calculators in place of actual body weight dosing could reduce this potential source of iatrogenic thyrotoxicosis risk in older women.

Background: Performance of thyroid function assays can vary significantly. To address this issue, the Centers for Disease Control and Prevention (CDC) Clinical Standardization Programs conducted an interlaboratory comparison of free thyroxine (fT4) immunoassays (IAs) and laboratory-developed tests (LDTs). This assessment aimed to determine the current performance characteristics of these assays as a first step toward measurement standardization. Thyrotropin (TSH) IAs were also evaluated. Methods: Assays measured 41 blinded individual-donor sera, including a sample from a pregnant woman (for fT4 analysis only) and three serum pools, with 11.3-32.1 pmol/L (0.881-2.49 ng/dL) fT4 and 0.337-21.6 mIU/L TSH in duplicate over 2 days. Passing-Bablok regression analysis performed pre-recalibration compared assays performance to the CDC fT4 reference measurement procedure (RMP) or TSH all-lab mean (ALM). Additionally, the impact of linear regression-based recalibration of assays to the CDC fT4 RMP or TSH ALM was estimated. Inter-assay agreement of sample classification according to the assay-specific reference interval (RI) was assessed pre- and post-recalibration. Results: A total of 21 fT4 and 17 TSH assays participated. Pre-recalibration, median biases of TSH measurements to the ALM were -1.2% [confidence interval or CI -1.8% to -0.4%], and good classification agreement among TSH assays was observed. fT4 assays all showed a negative median bias to the RMP, with higher bias among IAs (median: -20.3%, CI [-21.5% to -19.4%]) than LDTs (median: -4.5%, [CI -6.1% to -3.2%]). Of the individual-donor sera, only 21 out of 40 samples were classified uniformly by all fT4 assays, indicating poor inter-assay agreement. Post-recalibration, agreement improved to 33 out of 40 individual-donor sera correctly classified by all tested IAs and LDTs. Similar improvement in post-recalibration median percent bias was observed for fT4 IAs (median: -0.2, [CI -1.2% to 0.6%]) and LDTs (median: -0.3%, [CI -2.5% to 1.4%]). Conclusions: The comparison among fT4 assays emphasizes the need for measurement standardization to improve accuracy and comparability. This and previous studies demonstrate the possibility to develop common fT4 RIs via standardization, enabling the use of evidence-based clinical guidelines universally in patient care. Recalibration can effectively address high variability in fT4 assays, ensuring consistent diagnostic classification.

Central hypothyroidism is a rare disorder resulting from impaired thyroid hormone production due to deficiencies in TSH secretion from the pituitary or TRH secretion from the hypothalamus. This review aims to summarize recent advances in the etiology, diagnosis, and treatment of central hypothyroidism, with an emphasis on diagnostic and therapeutic challenges.

A comprehensive review of the literature was conducted, focusing on genetic and acquired causes, particularly those related to hypothalamic-pituitary tumors and the effects of surgical and radiotherapeutic interventions. Diagnostic approaches and treatment strategies, including levothyroxine therapy and monitoring, are analyzed.

Early diagnosis requires simultaneous measurement of free T4 and TSH to prevent neurological sequelae, especially in congenital cases. Central hypothyroidism is associated with risks such as growth and developmental impairment, as well as metabolic and cardiovascular disturbances. Levothyroxine therapy is crucial for correcting hormonal deficits and improving patient outcomes; however, careful dosing is necessary to avoid potential complications, particularly in vulnerable populations.

Personalized treatment and continuous monitoring are essential to optimize clinical outcomes and enhance the quality of life in affected individuals. A thorough understanding of central hypothyroidism's etiology and management is necessary to improve early detection and therapeutic strategies.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

Liquid ethanol-containing levothyroxine (e-LT4) is known to circumvent malabsorption induced by food, drugs, or pathological conditions. Recently a new ethanol-free formulation of liquid levothyroxine (ef-LT4) has been commercialized. No studies have compared e-LT4 with ef-LT4. The aim of the present study is to compare thyroid hormone profile in patients treated with e-LT4 and ef-LT4.

We retrospectively retrieved thyroid hormonal profile and clinical data of 48 patients diagnosed with hypothyroidism who had been on stable treatment with an e- LT4 formulation at the same dosage for at least one year and who decided to switch to ef-LT4 for tasting issue.

A significant increase in TSH levels was observed after 6 months on ef-LT4 treatment (2.5 ± 0.8 mIU/ml vs. 3.1 ± 1.0 mIU/ml, respectively, p < .001), while fT4 decreased [1.2 ng/dl (IQR 1.1-1.4) vs. 1.1 ng/dl (1.0-1.2), respectively, p = .047], maintaining the same dosage of LT4. In 31 patients, for whom data were available 12 months after the switch, TSH further increased (2.50 ± 0.9 mIU/ml at baseline vs 3.2 ± 0.9 mIU/ml after 6 months vs 3.5 ± 0.9 mIU/ml at 12 months, p < .001) and fT4 decreased [1.2 ng/dl (IQR 1.1-1.4) vs. 1.1 ng/dl (IQR 0.9-1.3) vs 1.0 ng/dl (IQR 0.9-1.1), p = .008].

ef-LT4 formulation seems to be less effective compared to e-LT4 over time. However, further prospective cross-sectional studies, performed in large sets of patients, even on concomitant therapy with interfering drugs, are needed.

Subclinical hypothyroidism is associated with metabolic diseases; however, it remains controversial in older individuals.

This work aimed to investigate the relationship between thyrotropin (TSH) levels and metabolic diseases.

In this cross-sectional study, sampling was conducted from nationally representative general communities from 31 provinces in mainland China. A total of6791 older (aged ≥65 years) and 55 303 young participants (aged 18-64 years) were selected after excluding individuals with overt hyperthyroidism or overt hypothyroidism. According to the kit, TSH reference range (0.27-4.2 mU/L) and the age-specific TSH range previously formulated (an upper limit of 8.86 mU/L for older adults and 6.57 mU/L for young adults), the older adults and young adults were separately divided into 4 groups based on their TSH levels. Main outcome measures included anthropometric assessments, serum concentrations of thyroid functions, and various metabolic parameters.

In contrast to young adults, there was no significant increase in the prevalence of any metabolic disorders assessed in the slightly elevated TSH group (TSH 4.21-8.86 mU/L) compared to the euthyroid group (TSH 0.27-4.2 mU/L) among older adults. After adjusting for interference factors, a TSH level higher than 8.86 mU/L was found to be an independent risk factor for low high-density lipoprotein cholesterol (OR, 1.84; 95% CI, 1.14-2.98) and dyslipidemia (OR, 1.49; 95% CI, 1.09-2.04) when compared to the euthyroid group in older adults.

Slightly elevated TSH levels are not associated with an increased risk of metabolic diseases in older adults. Therefore, we recommend raising the upper limit of the TSH range for individuals aged 65 years and older.

Existing studies have focused on the relationship between vitamin B6 and thyroid disease. However, there is a lack of large cross-sectional studies reporting on the relationship between vitamin B6 and thyroid function. Therefore, the present study aimed to assess the association between vitamin B6 intake and thyroid function in a population of US adults aged 20 years and older, using data from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2012.

Demographic, dietary, thyroid function, and relevant data from NHANES 2007-2012 were collected. The relationship between vitamin B6 intake and thyroid function was analysed using weighted multiple regression and restricted cubic spline analysis, including subgroup and interaction analysis.

The study included 6954 participants with a weighted mean age of 47.39  ± 16.60 years, mean vitamin B6 intake of 2.07 ± 1.15 mg, and mean TT4 level of 7.88 ± 1.61 μg/dL. A statistically significant negative correlation was noted between vitamin B6 intake and TT4 levels (β  =  -0.05, 95% CI  =  -0.10 to 0.00, P  =  0.033). In addition to this, subgroup analyses we found: In the gender subgroup, a significant negative correlation was found between vitamin B6 intake and TT4 levels in the male population (β = -0.06, 95% CI  =  -0.11 to -0.01, P  =  0.028); in the age subgroup, a significant negative correlation was found between vitamin B6 intake and TT4 levels in older people aged 60-80 years (β  =  -0. 13, 95% CI  =  -0.23 to -0.04, P  =  0.008); in the BMI subgroup, we found a significant negative correlation between vitamin B6 intake and TT4 levels in overweight people (BMI: 25-29.9 kg/m2) (β  =  -0.13, 95% CI  =  -0.20 to -0.06, P < 0. 001); in the iodine content subgroup, we found a significant negative correlation between vitamin B6 intake and TT4 levels in people with a normal iodine intake (100-299 ug/L) (β  =  -0.07, 95% CI  =  -0.13 to -0.01, P  =  0.021). Finally, in the subgroups of gender, age, BMI, and iodine content, no interaction was found.

To summarise, we believe that vitamin B6 may reduce serum TT4 levels by inhibiting inflammation.

Hyperlipidemia, a major risk factor for cardiovascular diseases, is associated with limitations in clinical lipid-lowering medications. Drug repurposing strategies expedite the research process and mitigate development costs, offering an innovative approach to drug discovery. This study employed systematic literature and guidelines review to compile a training set comprising 176 lipid-lowering drugs and 3254 non-lipid-lowering drugs. Multiple machine learning models were developed to predict the lipid-lowering potential of drugs. A multi-tiered validation strategy was implemented, encompassing large-scale retrospective clinical data analysis, standardized animal studies, molecular docking simulations and dynamics analyses. Through a comprehensive screening analysis utilizing machine learning, 29 FDA-approved drugs with lipid-lowering potential were identified. Clinical data analysis confirmed that four candidate drugs, with Argatroban as the representative, demonstrated lipid-lowering effects. In animal experiments, the candidate drugs significantly improved multiple blood lipid parameters. Molecular docking and dynamics simulations elucidated the binding patterns and stability of candidate drugs in interaction with related targets. We successfully identified multiple non-lipid-lowering drugs with lipid-lowering potential by integrating state-of-the-art machine learning techniques with multi-level validation methods, thereby providing new insights into lipid-lowering drugs, establishing a paradigm for AI-based drug repositioning research, and expanding the repertoire of lipid-lowering medications available to clinicians.

Hypothyroidism is a relatively common condition, which generally cannot be reversed. Hypothyroid individuals are dependent on provision of exogenous thyroid hormone as a lifetime therapy. Levothyroxine therapy provides satisfactory treatment for most. However, a subset of patients are not restored to their baseline quality of life.

As discussed here, a number of solutions have been tried, including addressing accompanying conditions, rigorous titration of therapy, and combination therapy with levothyroxine and liothyronine. The latter has limited success with improving quality of life, but does appear to be associated with patient preference. The discrepancy between quality of life and patient preference may be important to understanding the nuances of successful hypothyroidism treatment.

Future efforts to improve hypothyroidism therapy could tease out which are the specific subset of patients who benefit from combination therapy, such as those who have unresolved symptoms attributable to hypothyroidism at baseline and those with genetic polymorphisms that might impair thyroid hormone delivery to tissues. Better understanding of the drivers of patient preference for combination therapy should also be revealing. A future goal is to prevent autoimmune hypothyroidism from developing and to treat hypothyroidism completely by generating fully functioning thyroid follicles from stem cells.

Hypothyroidism (HoT) treatment involves lifelong thyroxine replacement therapy and regular monitoring. The objective of this study was to assess the impact of clinical pharmacist (CP) intervention in managing drug-related problems (DRPs) on outcomes among patients with HoT receiving levothyroxine (LT4) therapy.

A randomized controlled trial involved patients with HoT attending a university hospital's endocrinology and metabolism outpatient clinic from March 2022 to September 2022. Participants were randomly assigned to control (CG) and intervention groups (IG). CP identified and classified DRPs based on Pharmaceutical Care Network Europe (PCNE) v9.1 criteria. The validated version of the Morisky-Green-Levine (MGL) 4-question scale was used to measure adherence. All patients included in the study were assessed during their first visit and again two months later at their second visit.

43 patients were assigned to the CG (n = 25) and IG (n = 18). Diabetes (21.6 vs. 20.5%) and hypertension (16.2% vs. 11.7%) were the most prevalent comorbidities in both the CG and IG, respectively. A total of 118 DRPs belonging to both groups were detected. In the IG group, the total number of DRPs significantly decreased from 66 to 24, and the total potential drug-drug interactions (pDDIs) decreased from 21 to 0 between the first and second visits (p < 0.001). CG and IG patients had no difference in adherence levels at the first and second visits (p > 0.05). A statistically significant increase in adherence to the time of taking the medication was observed between the first and second visits in IG (55.5% vs. 94.4%, p = 0.008).

This study highlights the frequent occurrence of DRPs and LT4 therapy adherence problems in patients with HoT. The findings suggest that the intervention of CPs, by increasing adherence to LT4 therapy and decreasing DRPs, could significantly contribute to improving patients' treatment outcomes.

This study protocol has been retrospectively registered at ClinicalTrials.gov (NCT06408909) at 06/05/2024.

The management of hypothyroidism during Ramadan represents a tangible challenge as levothyroxine (L-thyroxine), the first-line treatment for hypothyroidism, must be administered on an empty stomach at least 30 min before a meal in order to enhance its absorption.

The present study aimed to compare the thyroid-stimulating hormone (TSH) levels among patients with hypothyroidism treated with an extra dose of l-thyroxine (25 mcg L-thyroxine, treatment group) versus a standard/regular dose (1.6 mcg/kg) of l-thyroxine (control group) during the month of Ramadan.

This study is a randomized controlled clinical trial that included patients with hypothyroidism. Eligible participants (n = 103) were randomly allocated to the treatment group and the control group. Both groups attended five visits before, during, and after Ramadan. Several tests were conducted, including thyroid function, lipid profile, HbA1c, and vitamin D.

One of the most significant findings of the present study is that the extra dose of 25 mcg of L-thyroxine during Ramadan maintained the TSH levels of patients within the normal reference range, i.e., 0.55-4.78 mIU/L, at each visit during and after Ramadan without the need to wait 30 min before the meal. The mean TSH values were comparable between the treatment group and the control group during the five visits (visit 1, 3.00 ± 2.44 and 3.45 ± 3.02; visit 2, 3.62 ± 3.21 and 3.74 ± 2.74; visit 3, 4.19 ± 3.85 and 4.89 ± 2.92; visit 4, 3.54 ± 2.96 and 5.15 ± 4.26; and visit 5, 3.61 ± 3.05 and 3.32 ± 2.57, respectively).

The present study demonstrated that the extra dose of L-thyroxine had a positive effect on keeping the TSH levels of patients in the normal reference range at each visit during and after Ramadan. However, in the control group, the mean TSH levels were higher than the normal range at visits 4 and 5.

In recent years, the incidence of cardiovascular disease (CVD) has risen steadily, significantly impacting public health. Subclinical hypothyroidism (SCH) remains a controversial risk factor for CVD. This review examines the associations between SCH and dyslipidemia, carotid intima-media thickness (C-IMT), cardiac dysfunction, and cardiovascular event risk. Evidence suggests SCH may exacerbate atherosclerosis and cardiac dysfunction through mechanisms such as increased LDL synthesis, oxidative stress, and impaired vascular endothelial function. However, the causal link between SCH and cardiovascular outcomes remains unclear due to study design heterogeneity and overreliance on TSH levels. Elevated TSH may not solely reflect thyroid dysfunction but could also indicate compensatory responses to inflammation, aging, or stress. Large-scale studies like NHANES and IPD meta-analyses show a strong association between SCH and cardiovascular risk in younger populations, which diminishes in older adults due to physiological TSH increases. The cardiovascular benefits of levothyroxine (L-T4) therapy in SCH patients are limited, especially in older individuals, where a narrow therapeutic window increases side effect risks. Studies relying solely on TSH as a diagnostic and therapeutic target have significant limitations, as TSH cannot distinguish adaptive thyroid adjustments from pathological states and overlooks the role of free thyroid hormones (FT3/FT4). Future research should integrate multi-dimensional markers (such as oxidative stress indicators, vascular elasticity measures, and thyroid antibody status) and adopt longitudinal study designs to more accurately assess the clinical significance of SCH.

Evidence regarding the relationship between thyroid hormone levels within the normal range and the incidence of chronic kidney disease (CKD) in adults is scarce. This study aimed to identify the association between thyrotropin (TSH) and free thyroxine (FT4) levels with the incidence of CKD in a large cohort study over long-term follow-up.

This prospective cohort study, with an 18-year follow-up, included 4118 adults without CKD from the Tehran thyroid Study (TTS). Participants were categorized by tertiles of normal TSH levels (low-normal, middle-normal, and high-normal) and abnormal TSH. The study outcome was incident CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) for CKD incidence based on thyroid hormone levels.

The HR for CKD development was 1.08 (95%CI: 1.01-1.15) per 1 SD increase in the TSH levels. Compared with participants with low-normal TSH levels, those with high-normal (HR:1.37; 95%CI: 1.03-1.84) and abnormal TSH (HR:1.24; 95%CI: 1.05-1.46) had a significantly higher risk of developing CKD. In subgroup analyses, the association between TSH level and CKD was significant in participants younger than 60 years, females, non-obese, non-smokers, and those without diabetes and hypertension. No association was observed between FT4 levels and incident CKD (HR: 0.92; 95%CI: 0.79-1.09). However, a significant association was observed between FT4 levels within the normal range and CKD development in those younger than 60 years old (HR: 0.77; 95% CI: 0.61-0.98).

Increased TSH levels, even within the normal range, linearly increased the risk of CKD even after adjustment for important risk factors. As a result, TSH may potentially be an independent risk factor for incident CKD.

Refractory hypothyroidism often poses a clinical problem, as treatment regimens are difficult to individualise to the patient and the feasibility of its delivery is difficult to organise within a healthcare system. We present a patient who became intolerant of intramuscular (IM) levothyroxine (LT4) after 18 years of treatment; thus, subcutaneous (SC) LT4 was initiated.

A 13-year-old female with newly diagnosed hypothyroidism remained hypothyroid despite escalating doses of oral LT4 and LT3. Thyroxine malabsorption was further suggested by nasogastric administration of LT4, whereby high-dose thyroxine administration resulted in only a 2.8 pmol/L increase in free T4 level (normal >5.14 pmol/L). She eventually achieved long-term euthyroid status at the age of 18 with fortnightly IM LT4 alongside oral LT4 and LT3. This was maintained for 18 years. Unfortunately, scar tissue developed around injection sites, resulting in increased pain and difficulty in administration. SC LT4 was trialled with success, and she has remained euthyroid for the last 6 years with self-administration and minimal side effects.

Refractory hypothyroidism often presents a challenge for clinicians, both for diagnosis and management. We discuss a patient with the longest follow-up to date within the published literature for both IM and SC LT4 for patient-administered treatment of refractory hypothyroidism and review the literature on alternative formulations available.

Hypothyroidism is typically treated with levothyroxine monotherapy. However, despite normalized serum thyroid-stimulating hormone levels, 5-10% of patients continue to experience persistent symptoms, raising concerns about the adequacy of thyroxine monotherapy. Combination therapy with levothyroxine and liothyronine has been proposed as an alternative, but it presents practical challenges, including dosing complexity, the short half-life of triiodothyronine, increased monitoring requirements, and potential adverse effects. Moreover, there is no clear consensus within the medical community regarding the superiority of combination therapy over levothyroxine monotherapy, although some studies indicate potential benefits in specific patient populations. Genetic factors, such as polymorphisms in the DIO2 gene, may influence individual responses to therapy, further complicating treatment. To address the limitations of combination therapy, we propose a novel approach: TTCombo. This digital health technology delivers personalized doses of levothyroxine and liothyronine, improving treatment adherence and optimizing outcomes. By providing individualized, physiologically tailored hormone replacement, TTCombo has the potential to revolutionize hypothyroidism management and enhance patient quality of life.

Background Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disorder. While eating disorders have been associated with other autoimmune diseases, no studies have explored this relationship in patients with HT to date. This study aimed to evaluate eating behaviors in euthyroid patients with HT. Materials and methods This case-control, cross-sectional study included a total of 107 patients diagnosed with HT, aged 18-45 years, as well as 54 healthy volunteers. Thyroid function tests, anti-thyroid peroxidase (TPO), and anti-antithyroglobulin (Tg) antibodies were measured in all participants. The Three-Factor Eating Questionnaire (TFEQ), the Night Eating Questionnaire (NEQ), and the International Physical Activity Questionnaire (IPAQ) were used to assess eating disorders and physical activity levels. Results Compared to the healthy control group, patients with HT, especially those receiving levothyroxine (LT4), had significantly higher scores on the TFEQ and NEQ. A positive correlation was detected between TFEQ and NEQ scores and anti-TPO and anti-Tg levels, LT4 treatment duration, and LT4 dose. However, there were no significant differences between the groups in terms of the IPAQ scores. A negative correlation was found between TFEQ scores and serum triiodothyronine (sT3). In patients with HT, thyroid-stimulating hormone (TSH) levels were within the higher-normal range, while sT3 levels were lower-normal compared to controls. Conclusion There is a spectrum of eating disorders among patients with HT. The underlying cause of these disorders remains unclear and may be associated with thyroid antibodies and/or hormonal status. In LT4 replacement therapy, efforts should be made to mimic true physiology as closely as possible. In the follow-up of patients with HT, while TSH is within lower-normal limits, sT3 levels may be observed to be in a higher-normal range. In selected cases, a combination of T4/T3 therapy or T3 extract may be recommended. Close monitoring of patients with HT is essential, particularly for potential eating disorder-related complications, such as obesity.

Autoimmune thyroid diseases (ATD) are the most prevalent autoimmune disorders associated with celiac disease (CD). Both conditions can often be detected through serological screening in asymptomatic patients over several years. Various guidelines for screening thyroid disease (TD) are available in children with CD and vice versa.

We conducted a systematic review to identify the most recent and relevant guidelines, comparing their recommendations to analyze key differences and suggesting a practical clinical approach.

Out of 1,294 articles reviewed, we identified 20 guidelines published between January 2013 and January 2024. These guidelines, primarily from gastroenterological organizations in Europe and North America, recommend different timings and methods for screening the co-occurrence of these diseases, both at diagnosis and during follow up. Some guidelines recommend only clinical follow-up without routine serological screening. There is limited consensus on screening for TD [using thyroid-stimulating hormone test (TSH)] in asymptomatic children newly diagnosed with CD, and even less agreement on screening for CD [using anti-transglutaminase antibodies (tTG) immunoglobulin A (IgA) test and total IgA] in children newly diagnosed with TD. No standardized procedures exist for managing patients with isolated low tTG and human leukocyte antigen (HLA) genotyping is rarely recommended as a first- line screening method.

Over the past decade, there has been a growing recognition of the importance of identifying children with co-occurrence of CD and TD who could benefit from early treatment, even in the absence of symptoms. However, international guidelines still show a lack of consensus regarding screening for these frequently associated autoimmune diseases, with notable differences in the use of HLA testing and follow-up protocols.

Medullary thyroid carcinoma is a rare neuroendocrine tumor originating from calcitonin-secreting parafollicular C cells of the thyroid gland. Approximately 25% of cases in adults are hereditary medullary thyroid carcinoma (hMTC), arising from activating, germline pathogenic variants in the REarranged during Transfection (RET) proto-oncogene and causing the syndromes multiple endocrine neoplasia (MEN) types 2A and 2B. A paradigmatic feature of MEN2 is its robust genotype-phenotype correlations, which predict the disease spectrum and age of onset of hMTC and other clinical manifestations. Advances in genetic testing and systemic therapies and an improved understanding of the natural course of MEN2 have transformed the clinical presentation of hMTC from advanced-stage disease to early detection in asymptomatic RET pathogenic variant carriers. The management of hMTC has similarly evolved from aggressive, one-size-fits-all surgical approaches to personalized strategies informed by genotype, biochemical markers, and imaging findings. Risk-reducing early thyroidectomy remains the cornerstone of metastatic hMTC prevention, with the timing of surgery tailored to the specific pathogenic variant and clinical context. Additionally, recent advances in targeted systemic therapies offer promising options for patients with recurrent and/or metastatic disease. This "Approach to the Patient" article explores the diagnostic evaluation, surgical decision-making, systemic treatment options, and follow-up of patients with hMTC, emphasizing the critical role of multidisciplinary care in optimizing outcomes for patients and their families.

Although recent studies indicate a high prevalence of subclinical hypothyroidism (SCH) in women with polycystic ovary syndrome (PCOS), the reported prevalence rates vary widely. Therefore, we conducted this study to estimate the pooled prevalence of SCH among women with PCOS. Additionally, emerging evidence suggests that SCH may negatively impact insulin resistance in PCOS. Thus, we examined its effect on insulin resistance indices as our secondary objective.

We searched PubMed, Web of Science, Scopus, and Embase from their inception to February 25, 2024. Observational studies reporting the prevalence of SCH among women with PCOS were included. Joanna Briggs Institute's (JBI) critical appraisal checklist for prevalence studies was adopted for the risk of bias assessment. The random-effects model was employed to estimate the pooled prevalence with its 95% confidence intervals (CI). The weighted mean difference (WMD) was used to compare the insulin resistance indices between PCOS patients with and without SCH.

Twenty-nine studies comprising 5765 women with PCOS were included. The meta-analysis demonstrated that 19.7% (95% CI: 16.1%; 23.5%) of women with PCOS have SCH. PCOS patients with SCH had significantly higher HOMA-IR (WMD = 0.78, 95% CI: 0.34; 1.22) and fasting insulin (WMD = 2.38, 95% CI: 0.34; 4.42) levels than those without SCH. Differences in fasting plasma glucose and 2-hour postprandial glucose did not reach statistical significance.

This systematic review and meta-analysis found that approximately 20% of women with PCOS have SCH. This underscores the need for regular thyroid function testing in these patients. The prevalence of SCH is influenced by the TSH cut-off used for diagnosis, highlighting the need for establishing a standardized TSH cut-off value. Furthermore, SCH significantly elevates the HOMA-IR index and fasting insulin levels, highlighting its potential impact on insulin resistance. Whether these metabolic changes are clinically important and put these individuals at higher risk of developing type 2 diabetes mellitus and cardiovascular disease requires further investigation.

CRD42024510798.

Not applicable.

Hypothyroidism, a common endocrine disorder, has a high incidence in women and increases with age. Levothyroxine (LT4) is the standard therapy; however, achieving clinical and biochemical euthyroidism is challenging. Therefore, developing an accurate model for predicting LT4 dosage is crucial. This retrospective study aimed to identify factors affecting the daily dose of LT4 and develop a model to estimate the dose of LT4 in hypothyroidism from a cohort of 1,864 patients through a comprehensive analysis of electronic medical records. Univariate analysis was conducted to explore the relationships between clinical and non-clinical variables, including weight, sex, age, body mass index, diastolic blood pressure, comorbidities, food effects, drug-drug interactions, liver function, serum albumin and TSH levels. Among the models tested, the Extra Trees Regressor (ETR) demonstrated the highest predictive accuracy, achieving an R² of 87.37% and the lowest mean absolute error of 9.4 mcg (95% CI: 7.7-11.2) in the test set. Other ensemble models, including Random Forest and Gradient Boosting, also showed strong performance (R² > 80%). Feature importance analysis highlighted BMI (0.516 ± 0.015) as the most influential predictor, followed by comorbidities (0.120 ± 0.010) and age (0.080 ± 0.005). The findings underscore the potential of machine learning in refining LT4 dose estimation by incorporating diverse clinical factors beyond traditional weight-based approaches. The model provides a solid foundation for personalized LT4 dosing, which can enhance treatment precision and reduce the risk of under- or over-medication. Further validation in external cohorts is essential to confirm its clinical applicability.

Hypothyroidism, a condition characterized by an underactive thyroid gland, affects millions worldwide, leading to cognitive and metabolic slowdowns. It is most prevalent in women and older adults, with causes including autoimmune thyroiditis, surgical thyroidectomy, and certain medications.

The standard treatment involves synthetic levothyroxine (LT4) monotherapy, which alleviates symptoms by converting to the active hormone, T3. However, some patients continue to experience symptoms such as fatigue, mood disturbances, and poor quality of life despite normalized TSH levels. This persistence of symptoms may stem from misdiagnosis, inadequate dosing, or incomplete normalization of thyroid hormone signaling.

Research suggests that LT4 monotherapy may not fully restore T3 levels, leading to suboptimal symptom control. Consequently, combination therapy with LT4 and liothyronine (LT3) has been proposed as an alternative, aiming to balance T4 and T3 levels more effectively. Although randomized controlled trials have not identified significant differences in patient-reported outcomes between LT4 monotherapy and combination therapy, they indicate that patients may prefer the latter.

Guidelines from leading endocrinology organizations now recommend considering combination therapy for patients with persistent symptoms despite adequate LT4 dosing. A patient-centered approach, emphasizing shared decision-making and individualized treatment plans, is essential for optimizing outcomes in hypothyroidism management. Further research is needed to refine dosing strategies and identify the patients who would benefit most from combination therapy.

Thyroid hormones, particularly L-thyroxine, are integral to cognitive processes like learning and memory. However, electrophysiological and morphological evidence connecting thyroid hormone activity to hippocampal function remains limited. This study aims to investigate the electrophysiological, morphological, and behavioral effects of L-thyroxine treatment in thyroidectomized (TX) rats, addressing the complex interplay between thyroid hormone regulation and hippocampal function. Adult male and female Wistar rats were assigned to three groups: TX, TX + L-thyroxine (10 µg/100 g/day, i.p., administered one week post-surgery for 4 weeks), and vehicle-control. Behavioral assessments were conducted prior to electrophysiological and morphological recordings. Under urethane anesthesia, hippocampal electrical activity was recorded following entorhinal cortex stimulation, while morphological changes were assessed in the capillary networks of both the hippocampus and the paraventricular nucleus. Results revealed significant changes in hippocampal electrophysiological responses in the L-thyroxine-treated group, including enhanced synaptic plasticity, increased excitatory activity, and more frequent, synchronized neuronal firing in the CA1 and CA3 regions. Additionally, L-thyroxine treatment led to changes in capillary morphology. This integrative study bridges electrophysiological, morphological, and behavioral approaches, enhancing our understanding of thyroid hormone influence on hippocampal function. The findings suggest that the observed electrophysiological and morphological changes could contribute to the cognitive and memory-related symptoms reported by individuals with thyroid dysfunction.

Despite normalization of Thyrotropin (TSH), some patients with hypothyroidism treated with Levothyroxine (LT4) report residual symptoms which may be attributable to loss of endogenous triiodothyronine (T3).

Feasibility trial LT4/liothyronine (LT3) combination vs. LT4/placebo in post-surgical hypothyroidism.

Double-blind, placebo-controlled, 24-week study.

Academic medical center.

Individuals with indications for total thyroidectomy and replacement therapy.

LT4/LT3 5 mcg (twice daily) vs. LT4/placebo (twice daily). LT4 was adjusted at 6- and 12-weeks with the goal of baseline TSH ± 0.5 mcIU/ml.

Changes in body weight, cholesterol, TSH, total T3, free tetraiodothyronine (T4). Cardiovascular function, energy expenditure, and quality of life (ThyPRO-39) were assessed in patients who completed at least the 3-month visit, last measure carried-forward.

Twelve patients (10 women and 2 men), age 51 ± 13.8 years (7 LT4/placebo, 5 LT4/LT3), were analyzed. No significant differences were observed in TSH. Following thyroidectomy, LT4/placebo resulted in higher free T4 + 0.26 ± 0.15 p<0.005 and lower total T3 -18 ± 9.6 ng/dl p<0.003, respectively, not observed in the LT4/LT3 group. The LT4/placebo group had a non-significant increase in body weight, +1.7 ± 3.8 Kg, total- and LDL-cholesterol +43.1 ± 72.8 and +32.0 ± 64.4 mg/dl. Conversely the LT4/LT3 group changes were -0.6 ± 1.9 Kg, -28.8 ± 49.0 and -19.0 ± 28.3 mg/dl, respectively, all non-significant. Non-significant improvement were observed in ThyPRO-39 measures in both groups, while energy expenditure, and diastolic function increased in the LT4/LT3 group.

In this group of patients with post-surgical hypothyroidism LT4 replacement alone does not normalize free T4 and total T3 levels and is associated with non-significant increase in weight and cholesterol. LT4/LT3 combination therapy appears to prevent these changes.

Clinicatrials.gov, identifier NCT05682482.

Our objective was to utilize the National Inpatient Sample (NIS) database for analyzing the outcomes of myxedema coma based on the day of admission and explore five-year mortality trends. This retrospective cohort study examined in-patient mortality and secondary outcomes of patients with myxedema coma from 2016 to 2020 using the NIS database. Patients were selected using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes and divided into weekday and weekend admission groups. From 174,776,205 discharges, 5095 patients were included. Mean age of admitted patients was higher on weekdays (67.1 year) than weekends (66.5), with females constituting 69.4% and 67.4% of admissions, respectively. Weekend admissions had higher odds of inpatient mortality compared to weekdays [adjusted odds ratio (aOR): 1.9, p = 0.01]. The overall mortality rate for myxedema coma rose from 6.8% in 2016 to 13.4% in 2020 (p-value = 0.01). No significant difference in the length of stay, hospitalization cost, and charges, blood transfusion, acute kidney injury requiring dialysis, acute respiratory failure requiring intubation and parenteral nutrition was noted between weekday and weekend admissions. Further studies are needed to identify factors contributing to this disparity and to confirm the findings of increasing mortality related to myxedema.

Hypothalamic-pituitary thyrotropic activity (HPta) is crucial since TSH is the mainstay for evaluating primary hypothyroidism (hT) and replacement therapy in clinical practice. Despite TSH values, some patients experience symptoms and metabolic alterations, raising several issues about hT. The aim of the study was to investigate factors influencing the TSH values achieved after a period of hT induced in a standardized and controlled manner (TSH_time1).

Our institutional database was searched to extract records of differentiated thyroid cancer (DTC) patients undergoing a LT4 withdrawal protocol prior to radioiodine (RAI) administration. We collected clinical and biochemical parameters before LT4 discontinuation and after one month of induced hT. We performed Mann-Whitney U-test and linear regression analyses.

We included 102 patients, with a median age of 44 years. In univariate analyses, TSH_time1 was correlated with age (p 0.005) and the dose pro Kg/die of LT4 assumed until the discontinuation of LT4 (LT4_dose) (p 0.023). The higher the age, the lower the TSH_time1 level. The higher the LT4_dose, the higher the TSH_time1 level. After multivariate analysis, the fittest model included age, BMI, LT4_dose, and systemic inflammation response index with an adjusted R2 of 0.4.

The study highlights new mechanisms that influence HPta. HPta progressively reduces with age, and this must be considered when evaluating TSH values in the elderly. Furthermore, we report for the first time a rebound effect of HPta, determined by the dose pro Kg/die of LT4 taken prior to its discontinuation. Inflammation and metabolic status also affect these phenomena.

Introduction: Thyroid dysfunction and mood disorders are chronic health conditions with a significant impact on quality of life. This study aimed to investigate the association between thyrotropin (TSH) and clinically relevant depression (CRD) in patients with and without mood disorders, in a population-based sample. Methods: This retrospective cross-sectional study included all consecutive adults (≥18 years) who had TSH and completed the Patient Health Questionnaire (PHQ-9) within 6 months of the index visit, between October 2016 and May 2021, at the University of Utah Health. Data on demographics, hypothyroidism diagnoses, TSH, thyroid hormone replacement (THR), PHQ-9, antidepressant (AD) medications, and mood disorder diagnoses (using the International Classification of Diseases, 10th Revision, Clinical Modification codes; Major depressive disorder single episode-F32, recurrent-F33, persistent mood disorder-F34, bipolar disorder-F30+F31, and mood disorder not otherwise specified-F39) were extracted electronically. CRD was defined as PHQ-9 ≥ 10. t-Test and chi-square test were used to compare continuous and categorical variables, respectively. Logistic regression models were formulated to evaluate the association between TSH and CRD, after adjusting for covariates. Results: The cohort included 33,138 patients, mean age 42.41 ± 16.10 years, 80.67% Caucasian, 69.10% females, and mean PHQ-9 score 10.11 ± 6.94. A total of 45.23% (n = 14,989) patients had a diagnosis of mood disorders, and 49.70% had CRD. Patients with mood disorders were more likely to be female, Caucasian, non-Hispanic/Latino, on AD, had hypothyroidism diagnoses, on thyroid medications, had higher mean PHQ-9 scores, and had CRD. TSH level was associated with an increased odds of CRD (odds ratio [OR] = 1.01, confidence interval [CI], 1.01-1.02, p < 0.009) after adjusting for age, sex, body mass index, Charlson Comorbidity Index, and use of THR and AD. Both the low TSH and high TSH groups showed increased odds of CRD, with respective ORs of 1.19 (CI: 1.04-1.37) and 1.26 (CI: 1.13-1.40). Conclusions: Thyroid dysfunction is associated with an increase in the odds of depression. Future longitudinal cohort studies are recommended to investigate the association between thyroid function and incident depression.

Dialysis/renal insufficiency patients are often accompanied by hypothyroidism due to renal damage, the mechanisms of which are complex. The use of thyroid hormone replacement therapy in such patients has become an important clinical issue. This article reviews the mechanism of hypothyroidism in dialysis/renal insufficiency patients and describes the importance and precautions of thyroid hormone replacement therapy to provide a reference for clinical diagnosis and treatment.

Pericardial effusion is a relatively common complication associated with inflammatory and non-inflammatory diseases. The primary etiology of this condition could be considered when choosing therapeutic options and factors such as effusion size and its hemodynamic consequence. In most cases, small to moderate pericardial effusions can be managed with observation and anti-inflammatory medications unless the effusion develops rapidly. However, in a small proportion of patients, large effusions lead to impaired cardiac filling with hemodynamic compromise and cardiovascular collapse due to cardiac tamponade. The rate at which fluid accumulates is the primary determinant of hemodynamic impact and thus guides the choice of treatment, irrespective of the effusion's size. Severe cases are typically treated with pericardiocentesis with echocardiographic guidance. More aggressive treatments may be necessary for cases due to purulent or malignant etiologies. These cases may require a pericardial window to allow for long-term drainage of the pericardial fluid. This comprehensive review focuses on the epidemiology of pericardial effusion and discusses pathophysiology, diagnostic approaches, and therapeutic options for different causes of secondary pericardial effusions.

Levothyroxine (L-T4) monotherapy is the standard of care for the treatment of hypothyroidism. A minority of L-T4-treated patients remain symptomatic and report better outcomes with combination therapy that contains liothyronine (L-T3) or with desiccated thyroid extract (DTE).

This work aimed to assess patient preferences in the treatment of hypothyroidism.

A systematic review, meta-analysis, meta-regression, and network meta-analysis of randomized controlled trials (RCTs) comparing treatments for adults with hypothyroidism (L-T4 vs L-T4 + L-T3 or DTE). Searches were conducted in PubMed, Embase, and Cochrane databases up to April 10, 2024. Data extraction and quality assessment were independently performed by 4 researchers.

Eleven RCTs (8 cross-over studies) with a total of 1135 patients were considered. Overall, 24% of patients preferred L-T4 vs 52% who preferred L-T4 + L-T3 or DTE; 24% had no preference. The meta-analysis confirmed the preference for combination therapy over L-T4 monotherapy (relative risk [RR]: 2.20; 95% CI, 1.38-3.52; P = .0009). Excluding 4 studies reduced the high heterogeneity (I2 = 81%) without affecting the results (RR: 1.97; 95% CI, 1.52-2.54; P < .00001; I2 = 24%). This preference profile remained when only crossover studies were considered (RR: 2.84; 95% CI, 1.50-5.39; P < .00001). Network meta-analysis confirmed the preference for DTE and L-T3 + L-T4 vs L-T4 alone.

Patients with hypothyroidism prefer combination therapy (L-T3 + L-T4 or DTE) over L-T4 monotherapy. The strength of these findings justifies considering patient preferences in the setting of shared decision-making in the treatment of hypothyroidism.

Hypothyroidism, a prevalent thyroid hormone abnormality identified by biochemical indicators, is prone to serious consequences because of its insidious clinical manifestations and easy underdiagnosis. This research aimed to elucidate the relationships between indicators of lipid and glucose metabolism and hypothyroidism and to assess the value of metabolic indicators for hypothyroidism.

Prevalence surveys were conducted utilizing information from 3254 NHANES individuals who passed screening between 2007 and 2012. Comparisons of baseline characteristics, assessment of logistic regression and subgroup analyses, visualization of restricted cubic splines curves, and validation of causal mediation analyses were performed to obtain a comprehensive view of the relationships between indicators of lipid and glucose metabolism and hypothyroidism.

Lipid and glucose metabolism indicators, especially the unconventional parameters triglyceride‒glucose index (TyG) and remnant cholesterol (RC) and the conventional parameter triglyceride (TG), exhibited robust positive relationships with hypothyroidism and served as crucial mediators in the pathways by which hypothyroidism affects health outcomes. Indicators were varying suggestive for hypothyroidism in distinct populations, with TyG being relatively more valuable.

Indicators of lipid and glucose metabolism (TyG, TG, and RC) were intimately associated with hypothyroidism, with potential applications in the assessment and management of hypothyroidism.

L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain's response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.

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