Elevated Serum Growth Differentiation Factor 15 Levels in Hyperthyroid Patients.
ABSTRACT: Background: Recent studies have shown that growth differentiation factor 15 (GDF15), a member of the transforming growth factor-? (TGF-?)/bone morphogenetic protein (BMP) superfamily, plays an important role in appetite, type 2 diabetes, and cardiovascular diseases. Since thyroid hormone has pleiotropic effects on whole-body energy metabolism, we aimed to explore the effect of thyroid hormone on circulating GDF15 levels in humans and GDF15 genes expression in C57BL/6 mice.Methods: A total of 134 hyperthyroid patients and 105 healthy subjects were recruited. Of them, 43 hyperthyroid patients received thionamide treatment for 3 months until euthyroidism. Serum GDF15 levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. To determine the source for the increased circulating GDF15, C57BL/6 mice were treated with T3, and GDF15 gene expressions in the liver, skeletal muscle, brown adipose tissue (BAT), inguinal white adipose tissue (iWAT), epididymal white adipose tissue (eWAT) were analyzed by quantitative real-time polymerase chain reaction (PCR).Results: Serum GDF15 levels were significantly elevated in hyperthyroid patients as compared with healthy subjects (326.06 ± 124.13 vs. 169.24 ± 82.96 pg/mL; P < 0.001). After thionamide treatment, GDF15 levels in hyperthyroid patients declined markedly from 293.27 ± 119.49 to 118.10 ± 71.83 pg/mL (P < 0.001). After adjustment for potential confounders, serum GDF15 levels were independently associated with hyperthyroidism. T3 treatment increased GDF15 expression in the brown adipose tissue of C57BL/6 mice.Conclusions: Serum GDF15 levels were elevated in patients with hyperthyroidism and declined after thionamide treatment. Thyroid hormone treatment upregulated GDF15 expression in mice. Therefore, our results present the clinical relevance of GDF15 in humans under the condition of hyperthyroidism.
Project description:Background:Glycoprotein non-metastatic protein B (Gpnmb) has been identified as a new cytokine secreted by hepatocyte that plays an important role in balancing lipid homeostasis and development of obesity and metabolic disorders. However, information is not available regarding the association between circulating Gpnmb and hyperthyroid in humans. Methods:We measured serum Gpnmb in 180 hyperthyroid patients and 82 healthy subjects that were recruited from the clinic. Of them, 46 hyperthyroid patients received thionamide treatment for 3 months. Results:Hyperthyroid subjects had higher levels of circulating Gpnmb than healthy controls (47.8 ± 10.1 ng/mL vs 31.0 ± 4.9 ng/mL, P < 0.001). Subjects with higher levels of serum free triiodothyronine (T3) and free thyroxine (T4) had higher levels of circulating Gpnmb. After thionamide treatment, levels of circulating Gpnmb in hyperthyroid subjects remarkably declined with significant improvement of thyroid function (P < 0.001). Furthermore, the change of circulating Gpnmb levels was significantly associated with basal metabolic rate (BMR) and thyroid hormones, including free T3 and free T4, adjusting for age, gender, smoking and BMI before thionamide treatment. In multivariable logistic regression analyses, circulating Gpnmb was significantly associated with risks of hyperthyroidism (OR (95% CI): 1.44 (1.20-1.74), P < 0.001), adjusted for age, gender, BMI, fasting glucose, HOMA-IR, LDL-cholesterol, ALT and AST. Conclusions:These findings indicate that circulating Gpnmb concentrations are independently associated with hyperthyroid, suggesting that circulating Gpnmb may be a predictor of risk for hyperthyroidism and can be used for therapeutic monitoring.
Project description:Fibroblast growth factor 21 (FGF21) is identified as a potential biomarker for liver diseases. However, information is limited regarding serum FGF21 and impaired liver function in hyperthyroidism. We aim to determine the potential association of serum FGF21 levels with impaired liver enzymes in hyperthyroid patients. In this case-control study, 105 normal subjects and 122 overt hyperthyroid patients were included. Among them, 41 hyperthyroid patients who obtained euthyroid status after thionamide treatment received second visit. Serum FGF21 levels were determined using the ELISA method. Compared to the normal subjects, patients with hyperthyroidism had significantly elevated serum liver enzymes, including alanine transaminase (ALT) (p < 0.001), aspartate aminotransferase (AST) (p < 0.001) levels, as well as FGF21 levels (p < 0.001). Further analysis showed serum FGF21 (p < 0.05), as well as thyroid hormone (TH) free T3 (p < 0.05), free T4 (p < 0.05) levels were higher in hyperthyroid patients with impaired liver enzymes than in those with normal liver enzymes. After reversal of hyperthyroid state, elevated serum FGF21 levels in hyperthyroid patients declined significantly (p < 0.001), with a concomitant decrease in serum ALT (p < 0.001), AST (p < 0.001) levels. Correlation analysis showed close correlation between FGF21 and ALT (p < 0.002), AST (p < 0.012), free T3 (p < 0.001), free T4 (p < 0.001). Further logistic regression analysis revealed FGF21 is significantly associated with elevated ALT [Odds Ratio, OR 1.79, (95% confidence interval, CI), (1.30-2.47), P < 0.001], AST [1.59 (1.07-2.34), p < 0.020]. After adjustment of potential confounders, the association between FGF21 and elevated ALT remained significant [1.42 (1.01-1.99), p < 0.043]. In conclusion, serum FGF21 is independently associated with impaired liver enzymes in hyperthyroid patients.
Project description:BACKGROUND:Endothelin-1 (ET-1) is a potent vasoconstrictor, mitogen and inflammatory factor that may contribute to development of atrial fibrillation (AF). Plasma ET-1 levels are increased in hyperthyroid patients, but studies evaluating its relation to AF development in hyperthyroid patients are lacking. OBJECTIVE:The present study seeks to evaluate the relation of plasma ET-1 to AF development as a function of thyroid status. METHODS:Blood samples from euthyroid patients (n = 41), hypothyroid (n = 61), hyperthyroid (n = 41), AF with hyperthyroidism (n = 9), and euthyroid AF (n = 10) patients were collected. Plasma ET-1, CRP, and thyroid hormone levels were measured and compared between groups. RESULTS:Plasma ET-1 levels were higher in hyperthyroid and euthyroid AF patients> hyperthyroid-non-AF > hypo and euthyroid non-AF patients. Plasma ET-1 levels positively correlated with free T3 and T4 levels, and negatively with TSH levels. By multivariate analysis, plasma ET-1 was positively associated with AF, hyperthyroidism, and age. Plasma CRP did not vary by study group in either univariate or multivariate analyses. CONCLUSION:Plasma ET-1 is associated with AF, elevated in hyperthyroid patients and positively correlated with thyroid hormone levels, suggesting that hyperthyroidism may increase ET-1 expression and release. This study may guide development of novel predictors of AF associated with hyperthyroidism, and may help to personalize therapy in hyperthyroid patients.
Project description:Graves' is disease an autoimmune disorder of the thyroid gland caused by circulating anti-thyroid receptor antibodies (TRAb) in the serum. TRAb mimics the action of thyroid stimulating hormone (TSH) and stimulates the thyroid hormone receptor (TSHR), which results in hyperthyroidism (overactive thyroid gland) and goiter. Methimazole (MMI) is used for hyperthyroidism treatment for patients with Graves' disease.We have developed a model using a system of ordinary differential equations for hyperthyroidism treatment with MMI. The model has four state variables, namely concentration of MMI (in mg/L), concentration of free thyroxine - FT4 (in pg/mL), and concentration of TRAb (in U/mL) and the functional size of the thyroid gland (in mL) with thirteen parameters. With a treatment parameter, we simulate the time-course of patients' progression from hyperthyroidism to euthyroidism (normal condition). We validated the model predictions with data from four patients.When there is no MMI treatment, there is a unique asymptotically stable hyperthyroid state. After the initiation of MMI treatment, the hyperthyroid state moves towards subclinical hyperthyroidism and then euthyroidism.We can use the model to describe or test and predict patient treatment schedules. More specifically, we can fit the model to individual patients' data including loading and maintenance doses and describe the mechanism, hyperthyroidism?euthyroidism. The model can be used to predict when to discontinue the treatment based on FT4 levels within the physiological range, which in turn help maintain the remittance of euthyroidism and avoid relapses of hyperthyroidism. Basically, the model can guide with decision-making on oral intake of MMI based on FT4 levels.
Project description:Evidence indicates that cardiac hypothyroidism may contribute to heart failure progression. It is also known that heart failure is associated with an increased risk of atrial fibrillation (AF). Although it is established that hyperthyroidism increases AF incidence, the effect of hypothyroidism on AF is unclear. This study investigated the effects of different thyroid hormone levels, ranging from hypothyroidism to hyperthyroidism on AF inducibility in thyroidectomized rats.Thyroidectomized rats with serum-confirmed hypothyroidism 1 month after surgery were randomized into hypothyroid (N=9), euthyroid (N=9), and hyperthyroid (N=9) groups. Rats received placebo, 3.3-mg l-thyroxine (T4), or 20-mg T4 pellets (60-day release form) for 2 months, respectively. At the end of treatment, hypothyroid, euthyroid, and hyperthyroid status was confirmed. Hypothyroid animals showed cardiac atrophy and reduced cardiac systolic and diastolic functions, whereas hyperthyroid rats exhibited cardiac hypertrophy and increased cardiac function. Hypothyroidism and hyperthyroidism produced opposite electrophysiological changes in heart rates and atrial effective refractory period, but both significantly increased AF susceptibility. AF incidence was 78% in hypothyroid, 67% in hyperthyroid, and the duration of induced AF was also longer, compared with 11% in the euthyroid group (all P<0.05). Hypothyroidism increased atrial interstitial fibrosis, but connexin 43 was not affected.Both hypothyroidism and hyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. Our results stress that normal thyroid hormone levels are required to maintain normal cardiac electrophysiology and to prevent cardiac arrhythmias and AF.
Project description:The osteoporosis associated with human hyperthyroidism has traditionally been attributed to elevated thyroid hormone levels. There is evidence, however, that thyroid-stimulating hormone (TSH), which is low in most hyperthyroid states, directly affects the skeleton. Importantly, Tshr-knockout mice are osteopenic. In order to determine whether low TSH levels contribute to bone loss in hyperthyroidism, we compared the skeletal phenotypes of wild-type and Tshr-knockout mice that were rendered hyperthyroid. We found that hyperthyroid mice lacking TSHR had greater bone loss and resorption than hyperthyroid wild-type mice, thereby demonstrating that the absence of TSH signaling contributes to bone loss. Further, we identified a TSH-like factor that may confer osteoprotection. These studies suggest that therapeutic suppression of TSH to very low levels may contribute to bone loss in people.
Project description:In humans, measurement of serum thyroid-stimulating hormone (TSH) concentration is commonly used as a first-line discriminatory test of thyroid function. Recent reports indicate that canine TSH (cTSH) assays can be used to measure feline TSH and results can help diagnose or exclude hyperthyroidism.To investigate the usefulness of cTSH measurements as a diagnostic test for cats with hyperthyroidism.Nine hundred and seventeen cats with untreated hyperthyroidism, 32 euthyroid cats suspected of having hyperthyroidism, and 131 clinically normal cats.Prospective study. Cats referred to the Animal Endocrine Clinic for suspected hyperthyroidism were evaluated with serum T4, T3, free T4 (fT4), and TSH concentrations. Thyroid scintigraphy was used as the gold standard to confirm or exclude hyperthyroidism.Median serum TSH concentration in the hyperthyroid cats (<0.03 ng/mL) was significantly (P < .001) lower than concentrations in clinically normal cats (0.05 ng/mL) or euthyroid cats with suspected thyroid disease (0.06 ng/mL). Only 18 (2.0%) hyperthyroid cats had measurable TSH concentrations (?0.03 ng/mL), whereas 114 (69.9%) of the 163 euthyroid cats had detectable concentrations. Combining serum TSH with T4 or fT4 concentrations lowered the test sensitivity of TSH from 98.0 to 97.0%, but markedly increased overall test specificity (from 69.9 to 98.8%).Serum TSH concentrations are suppressed in 98% of hyperthyroid cats, but concentrations are measurable in a few cats with mild-to-moderate hyperthyroidism. Measurement of serum TSH represents a highly sensitive but poorly specific test for diagnosis of hyperthyroidism and is best measured in combination with T4 and fT4.
Project description:Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over- and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole. Design: Retrospective cohort study. Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD. Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4*0.97-11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity. Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.
Project description:Graves' disease is an autoimmune disorder that causes hyperthyroidism because of autoantibodies that bind to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, triggering thyroid hormone release. The physiological control of thyroid hormone homeostasis by the feedback loops involving the hypothalamus-pituitary-thyroid axis is disrupted by these stimulating autoantibodies. To reset the endogenous thyrotrophic feedback control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis by monitoring thyroid hormone levels and coordinating the expression of a thyroid-stimulating hormone receptor antagonist (TSHAntag), which competitively inhibits the binding of thyroid-stimulating hormone or the human autoantibody to TSHR. This synthetic control device consists of a synthetic thyroid-sensing receptor (TSR), a yeast Gal4 protein/human thyroid receptor-α fusion, which reversibly triggers expression of the TSHAntag gene from TSR-dependent promoters. In hyperthyroid mice, this synthetic circuit sensed pathological thyroid hormone levels and restored the thyrotrophic feedback control of the hypothalamus-pituitary-thyroid axis to euthyroid hormone levels. Therapeutic plug and play gene circuits that restore physiological feedback control in metabolic disorders foster advanced gene- and cell-based therapies.
Project description:Introduction:Affective symptoms and attention impairments are found in patients with hyperthyroidism. Our previous data have revealed that the patients with hyperthyroidism experience impairments of the attention networks, but it remains unclear whether these disorders persist after the treatment of hyperthyroidism. Methods:Twenty healthy controls and 25 hyperthyroid patients were recruited and performed the attention network test (ANT) which can simultaneously examine the alertness, orientation and execution control components of the participants. The effect of treatment on affective symptom and attention networks impairments were examined in the patient group after 1-year anti-thyroid medication and reaching euthyroidism for at least 3 months. Results:Anxiety and depression scores of patients with hyperthyroidism were significantly higher than those of the healthy control group. The patients with hyperthyroidism had impairments of the alerting and executive control networks. Meanwhile, the score of HAMA correlated significantly with thyroid hormone and TSH levels, and there was a negative significant correlation between the score of HAMD and TSH level in all subjects. There was a positive correlation between the value of the executive control network and thyroid hormones' levels in all subjects and in the hyperthyroidism group. Anxiety and depression symptoms were improved with methimazole treatment after euthyroidism was reached. The value of the executive control network no longer differed from that of healthy controls, but deficits in the alerting network of hyperthyroidism still persisted after treatment. Conclusion:The patients with hyperthyroidism existed affective symptoms and attention networks impairments. Affective symptoms and attention executive control network impairment were improved following thyroid function normalization in hyperthyroidism.