Association between subclinical thyroid dysfunction and cognitive decline: findings from the ELSA-Brasil study.

BACKGROUND: Thyroid dysfunction has been associated with cognitive decline and dementia. However, the role of subtle thyroid hormone alterations in cognitive function is still debatable. METHODS: Participants without overt thyroid dysfunction aged 35-74 years at baseline were evaluated in three study waves (2008-10, 2012-14, and 2017-19). We assessed baseline thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Cognitive performance was evaluated every four years in each wave using 10-word immediate and late recall, word recognition, semantic (animals category) and phonemic (letter f) verbal fluency, and the trail-making B-version tests. A global composite z-score was derived from these tests. The associations of TSH, FT4, and FT3 levels with cognitive decline over time were evaluated using linear mixed-effect models adjusted for sociodemographic, clinical, and lifestyle variables. RESULTS: In 9,524 participants (mean age 51.2±8.9 years old, 51% women, 52% White), there was no association between baseline TSH, FT4, and FT3 levels and cognitive decline during the follow-up. However, increase in FT4 levels over time was associated with faster memory (ß=-0.004, 95%CI=-0.007; -0.001, p=0.014), verbal fluency (ß=-0.003, 95%CI=-0.007; -0.0005, p=0.021), executive function (ß=-0.004, 95%CI=-0.011; -0.003, p<0.001), and global cognition decline (ß=-0.003, 95%CI=-0.006; -0.001, p=0.001). Decrease in FT4 levels over time was associated with faster verbal fluency (ß=-0.003, 95%CI=-0.007; -0.0004, p=0.025) and executive function (ß=-0.004, 95%CI=-0.007; -0.0003, p=0.031) decline. CONCLUSION: An increase or decrease in FT4 levels over time was associated with faster cognitive decline in middle-aged and older adults without overt thyroid dysfunction during 8 years of follow-up.

Serum Vitamin B12 and Holotranscobalamin Levels in Subclinical Hypothyroid Patients in Relation to Thyroid-Stimulating Hormone (TSH) Levels and the Positivity of Anti-thyroid Peroxidase Antibodies: A Case-Control Study.

Background Subclinical hypothyroidism (SCH) is characterized by elevated thyroid-stimulating hormone (TSH) levels, while thyroid hormones (free thyroxine (T4) and free triiodothyronine (T3)) remain within the reference ranges. Vitamin B12 (cobalamin) deficiency is common in patients with autoimmune disorders, including autoimmune hypothyroidism. The study was aimed at evaluating serum vitamin B12 levels and holotranscobalamin (HoloTC) levels in SCH patients and ascertaining their association with a risky level of TSH and the positivity of anti-thyroid peroxidase (anti-TPO) antibodies. Methodology A case-control study was conducted at Azadi Teaching Hospital, Duhok, a city in the Kurdistan region of Iraq, involving 153 participants, including 72 newly diagnosed SCH patients and 81 healthy controls. Serum levels of vitamin B12, HoloTC, TSH, free T4, free T3, and anti-TPO antibodies were measured based on different principles. Results The mean age of patients with SCH was 32.87±8.7 years, with predominantly females comprising 75% and 77.8% being less than 40 years of age. Moreover, the mean levels of serum TSH (6.96±2.68 µIU/L), anti-TPO antibodies (53.31±81.32 IU/ml), and HoloTC (41.93±19.42 pmol/l) were significantly higher in patients with SCH compared to healthy control participants (p < 0.05), whereas there was a non-significantly higher level of vitamin B12(320.72±98.42 pg/ml) among SCH patients compared to healthy control participants (p = 0.220). The mean levels of vitamin B12 (345.33±103.22 pg/ml) and HoloTC (40.14±18.16 pmol/l) were insignificantly lower in SCH patients with TSH levels more than 7 µIU/L (p > 0.05), as well as the mean levels of vitamin B12 (308.82±96.12 pg/ml) and HoloTC (41.14±19.29 pmol/l) insignificantly lower in SCH patients with positive anti-TPO antibodies (p > 0.05).  Conclusions This study highlights the potential association between SCH and altered vitamin B12 status, particularly evident in HoloTC levels. The presence of positive anti-TPO antibodies and the degree of elevation in TSH levels may exacerbate vitamin B12 deficiency in SCH patients.

Thyroxine regulates pig Sertoli cell line proliferation and maturation through the IKK/NFκB and p38 MAPK signaling pathways.

The aim of this study was to investigate the signaling pathways involved in the proliferation and differentiation of pig Sertoli cells (SCs) mediated by thyroid hormone (T3) to provide a theoretical and practical basis for enhancing pig semen production. The effects of different concentrations of T3 on the proliferation of pig SCs were evaluated using the CCK8 assay. The impact of T3 on the proliferation and differentiation of pig SCs was further examined using RNA-seq, qPCR, and Western Blotting techniques. Additionally, the involvement of the p38 MAPK and NFκB pathways in mediating the effects of T3 on SCs proliferation and differentiation was investigated. Our findings revealed a strong correlation between the dosage of T3 and the inhibition of pig SCs proliferation and promotion of maturation. T3 regulated the activation state of the NFκB signaling pathway by upregulating IKKα, downregulating IKKß, and promoting IκB phosphorylation. Furthermore, T3 facilitated SCs maturation by upregulating AR and FSHR expression while downregulating KRT-18. In conclusion, T3 inhibits pig SCs proliferation and promote pig SCs maturation through the IKK/NFκB and p38 MAPK pathways. These findings provide valuable insights into the mechanisms by which T3 influences the proliferation and maturation of pig SCs.

Solving the Dilemma: Van Wyk-Grumbach Syndrome.

The Van Wyk-Grumbach syndrome (VWGS) (hypothyroidism, ovarian mass, and precocious puberty) has been extensively documented in the literature as long-term hypothyroidism manifesting as an ovarian mass. The authors of this study describe this entity in a young girl, aged 10, who presented with abdominal pain with a multiloculated ovarian cyst. She was evaluated, and it was discovered that she had delayed bone age, precocious puberty, and a small height. Following her diagnosis of autoimmune thyroiditis and the initiation of thyroxine replacement therapy, the ovarian cysts spontaneously regressed. To avoid needless assessment and surgical mishaps, this entity should be considered in situations of ovarian mass, particularly those with precocious puberty and thyroid disorders.

Hypothyroidism after hemithyroidectomy: a systematic review and meta-analysis.

BACKGROUND: The incidence of hypothyroidism following hemithyroidectomy and risk factors associated with its occurrence are not completely understood. This systematic review investigated the incidence and risk factors for hypothyroidism, thyroxine supplementation following hemithyroidectomy as well as the course of post-operative hypothyroidism, including the time to hypothyroidism and incidence of transient hypothyroidism. METHODS: Searches were conducted in MEDLINE, EMBASE, Scopus, and Cochrane library for studies reporting the incidence of hypothyroidism or thyroxine supplementation following hemithyroidectomy. RESULTS: Sixty-six studies were eligible for inclusion: 36 reported risk factors, and 27 reported post-operative course of hypothyroidism. Median follow-up was 25.2 months. The pooled incidence of hypothyroidism was 29% (95% CI, 25-34%; P<0.001). Transient hypothyroidism occurred in 34% of patients (95% CI, 21-47%; P<0.001). The pooled incidence of thyroxine supplementation was 23% (95% CI, 19-27%; P<0.001), overt hypothyroidism 4% (95% CI, 2-6%, P<0.001). Risk factors for development of hypothyroidism included pre-operative thyroid stimulating hormone (TSH) (WMD, 0.87; 95% CI, 0.75-0.98; P<0.001), TSH ≥ 2 mIU/L (RR, 2.87; 95% CI, 2.43-3.40; P<0.001), female sex (RR, 1.19; 95% CI, 1.08-1.32; P=0.007), age (WMD, 2.29; 95% CI, 1.20-3.38; P<0.001), right sided hemithyroidectomy (RR, 1.35; 95% CI, 1.10-1.65, P=0.003), the presence of autoantibodies anti-TPO (RR, 1.92; 95% CI, 1.49-2.48; P<0.001), anti-Tg (RR, 1.53; 95% CI, 1.40-1.88; P<0.001), and Hashimoto's thyroiditis (RR, 2.05; 95% CI, 1.57-2.68; P=0.001). CONCLUSION: A significant number of patients will develop hypothyroidism or require thyroxine following hemithyroidectomy. An awareness of patient risk factors and postoperative thyroid function course will assist in counselling patients on their risk profile and guiding management.

Associations between a normal-range free thyroxine concentration and ovarian reserve in infertile women undergoing treatment via assisted reproductive technology.

BACKGROUND: Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. METHODS: This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12-15.33, 15.34-18.67, and 18.68-22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL. RESULTS: The average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007). CONCLUSION: Low-normal fT4 concentrations are associated with lower ovarian reserve in infertile women.

Increased Absorption of Thyroxine in a Murine Model of Hypothyroidism Using Water/CO2 Nanobubbles.

Thyroxine (T4) is a drug extensively utilized for the treatment of hypothyroidism. However, the oral absorption of T4 presents certain limitations. This research investigates the efficacy of CO2 nanobubbles in water as a potential oral carrier for T4 administration to C57BL/6 hypothyroid mice. Following 18 h of fasting, the formulation was administered to the mice, demonstrating that the combination of CO2 nanobubbles and T4 enhanced the drug's absorption in blood serum by approximately 40%. To comprehend this observation at a molecular level, we explored the interaction mechanism through which T4 engages with the CO2 nanobubbles, employing molecular simulations, semi-empirical quantum mechanics, and PMF calculations. Our simulations revealed a high affinity of T4 for the water-gas interface, driven by additive interactions between the hydrophobic region of T4 and the gas phase and electrostatic interactions of the polar groups of T4 with water at the water-gas interface. Concurrently, we observed that at the water-gas interface, the cluster of T4 formed in the water region disassembles, contributing to the drug's bioavailability. Furthermore, we examined how the gas within the nanobubbles aids in facilitating the drug's translocation through cell membranes. This research contributes to a deeper understanding of the role of CO2 nanobubbles in drug absorption and subsequent release into the bloodstream. The findings suggest that utilizing CO2 nanobubbles could enhance T4 bioavailability and cell permeability, leading to more efficient transport into cells. Additional research opens the possibility of employing lower concentrations of this class of drugs, thereby potentially reducing the associated side effects due to poor absorption.

Curcumin-loaded nanoparticles effectively prevent T4-induced oxidative stress in rat heart.

In this study, we report the cardioprotective effect of the glycerol monooleate (GMO) based nanocurcumin in both in vitro and in vivo conditions under a hyperthyroid state. The heart is one of the primary target organs sensitive to the action of thyroid hormone, and slight variations in the thyroid hormone serum concentrations result in measurable changes in cardiac performance. Hyperthyroidism-induced hypermetabolism is associated with oxidative stress and is an important mechanism responsible for the progression of heart failure. Curcumin has been known to play a protective role against oxidative stress-related diseases like Alzheimer's, asthma, and aging due to its antioxidant properties. Nevertheless, its potent biological activity has been hindered due to its poor bioavailability. To overcome this drawback, a GMO-based biodegradable nanoparticle (NP) formulation loaded with curcumin has been developed, and the protective effect of curcumin-loaded NPs was compared against the native drug. Oxidative stress parameters like reactive oxygen species (ROS) release, change in mitochondrial membrane permeability, lipid peroxidation (LPx), lactate dehydrogenase (LDH) release, and the activity and protein expression of the endogenous antioxidant enzymes like superoxide dismutase, catalase (CAT) and glutathione peroxidase were evaluated. The results from in vitro showed that curcumin-loaded NPs showed better DPPH and NO radical scavenging activity than native curcumin in a concentrations range of 2.5-20 µM. It was also observed that the nanoparticulate curcumin was comparatively more effective than native curcumin in protecting against ROS-induced membrane damage by reducing LPx and LDH leakage at low concentrations of 5-10 µM. Further, curcumin NPs performed better in facilitating the activities of antioxidant enzymes under in vitro and in vivo conditions with respect to time and concentrations, resulting in reduced cellular ROS levels. In this scenario, we anticipate that curcumin-loaded NPs can serve as a better antioxidant than its native counterpart in protecting the heart from oxidative stress-related diseases.

Relationship of thyroid function with genetic subtypes and treatment with growth hormone in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.

Optimizing Thyroxine Dosage After Total Thyroidectomy: Understanding the Factors at Play.

INTRODUCTION: Total thyroidectomy is evolving as the choice of treatment for non-malignant thyroid conditions. Therefore, an ideal method of thyroxine replacement is necessary to avoid the ill effects of under- and over-replacement in such patients. AIM: To assess the correlation between optimal thyroxine dose and potential variables like lean body mass (LBM), body surface area (BSA), body mass index (BMI), body weight, age, and sex in patients who underwent total thyroidectomies for benign multinodular goiters in our institute. MATERIALS AND METHODS: A longitudinal cohort study was undertaken at the Government Medical College Thrissur, a tertiary care provider in India, between October 2018 and September 2019. One hundred adult patients who underwent a total thyroidectomy for various benign thyroid conditions were included. They were initially given thyroxine 75 µg upon discharge and received follow-up doses every two months until they achieved euthyroid status on two consecutive visits. The variables evaluated at this stage included age, sex, actual body weight, lean body weight, BMI, and biochemical data (triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH)). Correlation, multiple step-wise regression, and variance were carried out using EPI INFO version 7.2.2.6. RESULTS: The best predictors for optimum thyroxine dose were BSA (0.923, P < 0.01) and LBM (0.921, P < 0.01), compared with body weight (0.833, P < 0.01) and BMI (0.523, P < 0.01). In our study, the least significant factor was the age of the patient (r = 0.117, P < 0.01). There was no significant association between gender and thyroxine dose. The mean thyroxine dose was 1.87 µg/kg of the patient's body weight. CONCLUSION: The optimum thyroxine replacement based on BSA or LBM is a more ideal method than based on BMI or body weight alone.

Thyroid-related Hormones and Hypertension Incidence in Middle-Aged and Older Hispanic/Latino Adults: The HCHS/SOL Study.

Background: Thyroid-related hormones act to regulate metabolic pathways and blood pressure (BP). However, the relationship of TSH and peripheral thyroid hormones and the role of the hypothalamic-pituitary-thyroid axis on hypertension development is not fully understood. We assessed sex-specific associations of thyroid-related hormones with BP and hypertension in Hispanic/Latino adults followed for 6 years. Methods: We studied 1789 adults, ages 45 to 74, free of diabetes at baseline from a subcohort of the Hispanic Community Health Study/Study of Latinos. We assessed TSH, free T4 (FT4), T3, and various indicators of thyroid axis. Using multivariable linear and Poisson regression adjusted for survey design and confounding variables, we estimated a priori sex-specific associations of thyroid-related hormones with changes in BP and hypertension development. Results: In men and women, TSH and TSH/FT4 ratios were associated with changes in diastolic BP and T3 with changes in pulse pressure and the development of hypertension from prehypertension. In men, a 1-SD increase in TSH [incident rate ratio (IRR) = 1.42; 95% confidence interval (CI): 1.15, 1.75] and TSH/FT4 ratio (IRR = 1.20; 95% CI: 1.07, 1.35) were positively associated with the development of hypertension from prehypertension while the TSH/FT4 ratio (IRR = 0.85; 95% CI: .72, 1.00) was protective in women. We observed sex-specific differences in associations of the T3/FT4 ratio and indices of pituitary sensitivity to thyroid hormones with changes in pulse pressure and hypertension development. Conclusion: Thyroid-related hormones are associated with sex-specific changes in BP and hypertension among Hispanic/Latino adults consistent with selected studies conducted in other populations. Mechanisms underlying associations of pituitary sensitivity to thyroid hormones with BP and hypertension development warrant further study.

Triiodothyronine/Thyroxine Ratio as a Marker of Clinical Response to Levothyroxine Replacement in Patients With Hypothyroidism.

BACKGROUND:  Hypothyroidism is one of the most common endocrine disorders with a simple therapy, that is levothyroxine (LT4). A normal thyroid-stimulating hormone (TSH) measurement is used as a marker of optimal replacement. But, many patients still have symptoms. Triiodothyronine (T3), thyroxine (T4), and their ratio may correlate with clinical improvement. The study aims to assess the T3/T4 ratio as a marker of clinical response in patients with hypothyroidism.  Method: A cross-sectional study was conducted from June to November 2022 at Faiha Specialized Diabetes, Endocrine, and Metabolism Center, in Basrah, southern Iraq. We included 48 adult patients with primary hypothyroidism on LT4 treatment only and TSH within the target reference range for at least within the last six months. Each patient was subjected to a questionnaire that was designed to capture hypothyroidism-related complaints in the form of a five-point Likert scale. Biochemical assessments were done with the measurement of TSH, T3, and T4. RESULTS: Despite having a normal TSH level, nearly all the patients had persistent and varying severity of clinical complaints of hypothyroidism. Tiredness, hair problems, weight gain, and cold intolerance were the most severely persistent symptoms. Patients with scores of two and more for weight gain, cold intolerance, and skin problems had significantly lower T3/T4 ratios (P = 0.04, 0.002, and 0.02, respectively), while in the remaining clinical symptoms, the T3/T4 ratio did not differ significantly. CONCLUSION: A low T3/T4 ratio was significantly associated with resistant symptoms of hypothyroidism and may be used as a marker for treatment efficacy with TSH rather than TSH value alone.

Thyroid ultrasound pattern in primary hypothyroidism is similar to Graves' disease: a report of three cases.

Ultrasound can identify important characteristics in primary hypothyroidism and diffuse hyperthyroidism (Graves' disease). Therefore, sonologists are actively investigating ultrasound criteria to differentiate between these two conditions. Nevertheless, practice shows the absence of such ultrasonic landmarks. For the first time in the literature, three cases of primary hypothyroidism have demonstrated an ultrasound pattern identical to that of Graves' disease. This pattern includes the presence of goiter, marked total hypoechogenicity of the parenchyma, significantly or moderately increased blood flow intensity ('thyroid inferno'), and elevated peak systolic velocity of the superior thyroid arteries. These signs are less common in hypothyroidism compared to hyperthyroidism. Diagnostic data suggest that the pathogeneses of primary hypothyroidism and Graves' disease share the same mechanisms, leading to similar thyroid ultrasound patterns. One of these shared mechanisms is presumably thyroid overstimulation by the autonomic nervous system, which is adequate to the body's hormonal requirements in hypothyroidism but excessive in hyperthyroidism.

Cardiovascular mechanisms of thyroid hormones and heart failure: Current knowledge and perspectives.

A multiple hormonal imbalance that accompanies heart failure (HF) may have a significant impact on the clinical course in such patients. The non-thyroidal illness syndrome (NTIS), also referred to as euthyroid sick syndrome or low triiodothyronine syndrome, can be found in about 30% of patients with HF. NTIS represents a systemic adaptation to chronic illness that is associated with increased cardiac and overall mortality in patients with HF. While conclusions on thyroid-stimulating hormone, free triiodothyronine, total and free thyroxine are currently unresolved, serum total triiodothyronine levels and the ratio of free triiodothyronine to free thyroxine seem to provide the best correlates to the echocardiographic, laboratory and clinical parameters of disease severity. HF patients with either hyper- or hypothyroidism should be treated according to the appropriate guidelines, but the therapeutic approach to NTIS, with or without HF, is still a matter of debate. Possible treatment options include better individual titration of levothyroxine therapy, combined triiodothyronine plus thyroxine therapy and natural measures to increase triiodothyronine. Future research should further examine the cellular and tissue mechanisms of NTIS as well as new therapeutic avenues in patients with HF.

Thyroid disorders and gastrointestinal dysmotility: an old association.

Gastrointestinal motility symptoms may be closely related to thyroid diseases. Sometimes, such symptoms are the only thyroid disease-related clue although the degree of the symptoms may vary. The exact mechanism of action of thyroid hormones on gastrointestinal motility is not completely understood, however, a clue lies in the fact that muscle cell receptors can be directly acted upon by thyroxines. Both hypo- and hyperthyroidism can cause impairment of gastrointestinal motility, modifying structure and function of pharynx and esophagus, and regulating esophageal peristalsis through neuro-humoral interaction. In hyperthyroid patients, alterations of postprandial and basic electric rhythms have been observed at gastro-duodenal level, often resulting in slower gastric emptying. Gastric emptying may also be delayed in hypothyroidism, but an unrelated gastric mucosa-affecting chronic modification may also cause such pattern. Hyperthyroidism commonly show malabsorption and diarrhoea, while hypothyroidism frequently show constipation. In summary, it can be stated that symptoms of gastrointestinal motility dysfunction can be related to thyroid diseases, affecting any of the gastrointestinal segment. Clinically, the typical thyroid disease manifestations may be missing, borderline, or concealed because of intercurrent sicknesses. Motility-linked gastrointestinal problems may easily conceal a misdetected, underlying dysthyroidism that should be carefully analyzed. Here, we aim to elaborate on the associations between thyroid disorders and GI dysmotility and the common clinical manifestations associated with GI dysmotility.

The predictive value of free thyroxine combined with tubular atrophy/interstitial fibrosis for poor prognosis in patients with IgA nephropathy.

Background: IgA nephropathy (IgAN), the most common type of glomerulonephritis, has great individual differences in prognosis. Many studies showed the relationship between thyroid hormones and chronic kidney disease. However, the relationship between free thyroxine (FT4), as a thyroid hormone, and IgAN is still unclear. This study aimed to evaluate the impact of FT4 on IgAN prognosis. Methods: This retrospective study involved 223 patients with biopsy-proven IgAN. The renal composite outcomes were defined as: (1) ESRD, defined as eGFR < 15 ml/(min·1.73 m2) or initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, renal transplantation); (2) serum creatinine doubled from baseline; (3) eGFR decreased by more than 50% from baseline. The predictive value was determined by the area under the curve (AUC). Kaplan-Meier and Cox proportional hazards analyses assessed renal progression and prognosis. Results: After 38 (26-54) months of follow-up, 23 patients (10.3%) experienced renal composite outcomes. Kaplan-Meier survival curve analysis showed that the renal survival rate of the IgAN patients with FT4<15.18pmol/L was lower than that with FT4≥15.18pmol/L (P < 0. 001). Multivariate Cox regression model analysis showed that FT4 was a protective factor for poor prognosis of IgAN patients, whether as a continuous variable or a categorical variable (HR 0.68, 95%CI 0.51-0.90, P =0.007; HR 0.04, 95%CI 0.01-0.20, P <0.001). ROC curve analysis showed that FT4 combined with t score had a high predictive value for poor prognosis of IgAN patients (AUC=0.881, P<0.001). Conclusion: FT4 was a protective factor for IgAN. In addition, FT4 combined with tubular atrophy/interstitial fibrosis had a high predictive value for poor prognosis of IgAN.

Associations between low muscle mass and clinical characteristics of health population in China.

Objectives: The primary aim of this study is to discern the association between specific clinical parameters and low muscle mass (LMM). We endeavor to elucidate the determinants of LMM and the predictive potency of individual factors. Methods: In this retrospective cross-sectional study, we encompassed 450 older adult Chinese participants (252 males and 198 females). Muscle mass quantifications were performed using bioelectrical impedance analysis. Comprehensive data encompassing demographic details (age, sex, height, and weight) and laboratory results (complete blood count, thyroid function, liver function, and renal function) were systematically recorded. Logistic regression models, coupled with receiver operating characteristic curve analytics, were employed to ascertain the variables influencing LMM and to evaluate the predictive validity of each parameter on LMM. Results: Upon confounding adjustment for age, gender, body mass index (BMI), and free thyroxine (FT4) persisted as a determinant of LMM. Specifically, individuals with an FT4 exceeding 1.105 ng/dL exhibited a 1.803-fold increased propensity for LMM relative to those with FT4 values below the specified threshold. Incorporating age, gender, BMI, and FT4 in the diagnostic algorithm enhanced the precision of LMM. The results differ between men and women. In the male population, we can still observe that FT4 has a certain value in the diagnosis of LMM, but this phenomenon is not found in the female population. Conclusions: Elevated FT4 concentrations, albeit within clinically accepted limits, are inversely associated with muscle mass. As such, FT4 could be postulated as a potential biomarker for LMM in geriatric individuals, especially in the male group.

Cytosolic sulfotransferases in endocrine disruption.

The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of endocrine hormones as well as a broad array of drugs, environmental chemicals, and other xenobiotics. Many endocrine-disrupting chemicals (EDCs) interact with these SULTs as substrates and inhibitors, and thereby alter sulfation reactions responsible for metabolism and regulation of endocrine hormones such as estrogens and thyroid hormones. EDCs or their metabolites may also regulate expression of SULTs through direct interaction with nuclear receptors and other transcription factors. Moreover, some sulfate esters derived from EDCs (EDC-sulfates) may serve as ligands for endocrine hormone receptors. While the sulfation of an EDC can lead to its excretion in the urine or bile, it may also result in retention of the EDC-sulfate through its reversible binding to serum proteins and thereby enable transport to other tissues for intracellular hydrolysis and subsequent endocrine disruption. This mini-review outlines the potential roles of SULTs and sulfation in the effects of EDCs and our evolving understanding of these processes.

Effects of pethoxamid treatment on the disposition of thyroxine in rats.

Pethoxamid (PXA) is a chloroacetamide herbicide that works by inhibiting the germination of target weeds in crops. PXA is not a genotoxic agent, however, in a two-year chronic toxicity study, incidence of thyroid follicular cell hyperplasia was observed in male rats treated at a high dose. Many non-mutagenic chemicals, including agrochemicals are known to produce thyroid hyperplasia in rodents through a hepatic metabolizing enzyme induction mode of action (MoA). In this study, the effects of oral gavage PXA treatment at 300 mg/kg for 7 days on the disposition of intravenously (iv) administered radio-labeled thyroxine ([125I]-T4) was assessed in bile-duct cannulated (BDC) rats. Another group of animals were treated with phenobarbital (PB, 100 mg/kg), a known enzyme inducer, serving as a positive control. The results showed significant increase (p < 0.01) in the mean liver weights in the PB and PXA-treated groups relative to the control group. The serum total T4 radioactivity Cmax and AUC0-4 values for PB and PXA-treated groups were lower than for the control group, suggesting increased clearance from serum. The mean percentages of administered radioactivity excreted in bile were 7.96 ± 0.38%, 16.13 ± 5.46%, and 11.99 ± 2.80% for the control, PB and PXA groups, respectively, indicating increased clearance via the bile in the treated animals. These data indicate that PXA can perturb the thyroid hormone homeostasis in rats by increasing T4 elimination in bile, possibly through enzyme induction mechanism similar to PB. In contrast to humans, the lack of high affinity thyroid binding globulin (TBG) in rats perhaps results in enhanced metabolism of T4 by uridine diphosphate glucuronosyl transferase (UGT). Since this liver enzyme induction MoA for thyroid hyperplasia by PB is known to be rodent specific, PXA effects on thyroid can also be considered not relevant to humans. The data from this study also suggest that incorporating a BDC rat model to determine thyroid hormone disposition using [125I]-T4 is valuable in a thyroid mode of action analysis.

Thyroid hormones and stroke, the gap between clinical and experimental studies.

Despite plenty of human studies on changes in thyroid hormones after stroke and some animal studies that assessed the effects of thyroid hormone administration on stroke, conclusive evidence for clinical application is lacking. This review aimed to determine the consistency of the results between clinical and preclinical studies. This article reviewed the PubMed, Embase, web of Knowledge, and Google Scholar databases up to June 2023 using the MeSH terms "stroke, cerebral ischemia, cerebral infarction, brain ischemia, brain infarction, triiodothyronine (T3), tetraiodothyronine (T4), thyroxine (T4), and thyroid hormone". The results of clinical and preclinical studies related to T3 substantially confirm each other. That is, in most human studies lower T3 was associated with poor outcomes, and in experimental studies, T3 administration also had therapeutic effects. However, the results of experimental studies related to T4 could not support those of clinical studies. There seem to be some conflicts between experimental and human studies, especially regarding changes and effects of T4 after stroke. The gap between experimental and clinical studies may lead to non-applicable results, wasting time and money, and unnecessary killing of animals.