Graves’ disease (GD), an organ-specific autoimmune disease, is the most common cause of hyperthyroidism. Tumour necrosis factor-alpha (TNF-α) exhibits immunological and metabolic activities involved in the induction and maintenance of immune responses. We attempted to evaluate the relationship between GD and serum TNF-α and its soluble receptors (sTNFRs), soluble TNF receptor 1 and 2 (sTNF-R1 and sTNF-R2). A total of 72 GD patients and 72 matched healthy individuals were recruited for this study. Serum TNF-α and sTNFRs were measured by sandwich ELISA. In our study, no significant difference was observed in TNF-α, but sTNFRs were found to be significantly elevated in GD patients compared to healthy individuals. Serum sTNFR levels were positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), and TNF-α was negatively correlated with thyroid-stimulating hormone (TSH) in the GD group. It was also shown that thyrotropin receptor antibody (TRAb) was positively correlated with TNF-α and sTNFRs. Spearman’s correlation analysis showed that only sTNF-R1 was positively correlated with complement C3. Multiple linear regression analysis suggests that serum levels of sTNF-R1 and FT4 may play an important role in the serum level of FT3. According to the median value of FT3 level, GD patients were further divided into a high FT3 group and a low FT3 group. The serum levels of sTNF-R1 in the high FT3 GD group were significantly higher than those in the low FT3 GD group. In conclusion, sTNFRs may play an important role in anti-inflammatory and immune response in GD.
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Qing Zhu, Jianbin Su, Xueqin Wang, Mengjie Tang, Yingying Gao, and Dongmei Zhang
Brenda Anguiano, Carlos Montes de Oca, Evangelina Delgado-González, and Carmen Aceves
Thyroid hormones are involved in the development and function of the male reproductive system, but their effects on the prostate have been poorly studied. This work reviews studies related to the interrelationship between the thyroid and prostate. The information presented here is based upon bibliographic searches in PubMed using the following search terms: prostate combined with thyroid hormone or triiodothyronine (T3), thyroxine (T4), hypothyroidism, hyperthyroidism, or deiodinase. We identified and searched 49 articles directly related to the issue, and discarded studies related to endocrine disruptors. The number of publications has grown in the last 20 years, considering that one of the first studies was published in 1965. This review provides information based on in vitro studies, murine models, and clinical protocols in patients with thyroid disorders. Studies indicate that thyroid hormones regulate different aspects of growth, metabolism, and prostate pathology, whose global effect depends on total and/or free concentrations of thyroid hormones in serum, local bioavailability and the endocrine androgen/thyronine context.
Jiayang Lin, Peizhen Zhang, Yan Huang, Xueyun Wei, Dan Guo, Jianfang Liu, Deying Liu, Yajuan Deng, Bingyan Xu, Chensihan Huang, Xiaoyu Yang, Yan Lu, Lijing Jia, and Huijie Zhang
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.
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.
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.
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.
Chun-feng Lu, Wang-shu Liu, Xiao-qin Ge, Feng Xu, Jian-bin Su, Xue-qin Wang, and Yan Wang
Adenosine deaminase (ADA) is essential for the differentiation and maturation of lymphocytes, while lymphocytes infiltration in thyroid tissue is a vital pathological feature of Graves’ disease (GD). The aim of the present study was to compare the concentration of ADA between healthy controls (HC) and patients with GD, and evaluate the association between ADA and GD.
A total of 112 GD patients and 77 matched HC were enrolled in this study. Each participant was examined for thyroid hormones and autoantibodies, ADA concentration, and thyroid ultrasonography.
Serum ADA levels in GD patients were significantly higher than that in HC subgroup (P < 0.001). In GD patients, serum ADA levels were positively associated with serum-free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), thyroid-stimulating hormone receptor antibody (TRAb) levels, and total thyroid gland volume (thyroid VolT) and negatively associated with serum thyroid-stimulating hormone receptor (TSH) levels (all P < 0.05). There were no similar correlations in the HC subgroup. Multiple linear regression analysis suggested that serum TSH, FT3, and ADA levels played an important role in serum TRAb levels.
Our results demonstrated that serum ADA levels were closely associated with GD.
Josi Vidart, Paula Jaskulski, Ana Laura Kunzler, Rafael Aguiar Marschner, André Ferreira de Azeredo da Silva, and Simone Magagnin Wajner
We performed a systematic review and meta-analysis to comprehensively determine the prevalence and the prognostic role of nonthyroidal illness syndrome (NTIS) in critically ill patients. We included studies that assessed thyroid function by measuring the serum thyroid hormone level and in-hospital mortality in adult septic patients. Reviews, case reports, editorials, letters, animal studies, duplicate studies, and studies with irrelevant populations and inappropriate controls were excluded. A total of 6869 patients in 25 studies were included. The median prevalence rate of NTIS was 58% (IQR 33.2-63.7). In univariate analysis, triiodothyronine (T3) and free T3 (FT3) levels in non-survivors were relatively lower than that of survivors (8 studies for T3; standardized mean difference (SMD) 1.16; 95% confidence interval (CI), 0.41–1.92; I2 = 97%; P < 0.01). Free thyroxine (FT4) levels in non-survivors were also lower than that of survivors (12 studies; SMD 0.54; 95% CI, 0.31–0.78; I2 = 83%; P < 0.01). There were no statistically significant differences in TSH levels between non-survivors and survivors. NTIS was independently associated with increased risk of mortality in critically ill patients (OR = 2.21, 95% CI 1.64.- 2.97, I2 = 65% p < 0.01) The results favor the concept that decreased thyroid function might be associated with a worse outcome in critically ill patients. Hence, the measurement of TH could provide prognostic information on mortality in adult patients admitted to ICU.
Flavia Letícia Martins Peçanha, Reinaldo Sousa dos Santos, and Wagner Seixas da-Silva
The thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), are very important in organism metabolism and regulate glucose utilization. Hexokinase (HK) is responsible for the first step of glycolysis, catalyzing the conversion of glucose to glucose 6-phosphate. HK has been found in different cellular compartments, and new functions have been attributed to this enzyme. The effects of hyperthyroidism on subcellular glucose phosphorylation in mouse tissues were examined. Tissues were removed, subcellular fractions were isolated from eu- and hyperthyroid (T3, 0.25 µg/g, i.p. during 21 days) mice and HK activity was assayed. Glucose phosphorylation was increased in the particulate fraction in soleus (312.4% ± 67.1, n = 10), gastrocnemius (369.2% ± 112.4, n = 10) and heart (142.2% ± 13.6, n = 10) muscle in the hyperthyroid group compared to the control group. Hexokinase activity was not affected in brain or liver. No relevant changes were observed in HK activity in the soluble fraction for all tissues investigated. Acute T3 administration (single dose of T3, 1.25 µg/g, i.p.) did not modulate HK activity. Interestingly, HK mRNA levels remained unchanged and HK bound to mitochondria was increased by T3 treatment, suggesting a posttranscriptional mechanism. Analysis of the AKT pathway showed a 2.5-fold increase in AKT and GSK3B phosphorylation in the gastrocnemius muscle in the hyperthyroid group compared to the euthyroid group. Taken together, we show for the first time that THs modulate HK activity specifically in particulate fractions and that this action seems to be under the control of the AKT and GSK3B pathways.
Till Ittermann, Rehman Mehmood Khattak, Marcello RP Markus, Jens-Peter Kühn, Marie-Luise Kromrey, Giovanni Targher, Antje Steveling, Matthias Nauck, and Henry Volzke
The associations of thyroid function parameters with non-alcoholic fatty liver disease (NAFLD) and hepatic iron overload are not entirely clear. We have cross-sectionally investigated these associations among 2,734 participants of two population-based cross-sectional studies of the Study of Health in Pomerania. Serum levels of thyroid-stimulating hormone (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4) levels were measured. Liver fat content (by proton-density fat fraction; PDFF) as well as hepatic iron content (by transverse relaxation rate; R2*) were assessed by quantitative magnetic resonance imaging. Thyroid function parameters were associated with hepatic fat and iron contents by median and logistic regression models adjusted for confounding. There were no associations between serum TSH levels and liver fat content, NAFLD or hepatic iron overload. Serum fT4 levels were inversely associated with liver fat content, NAFLD, hepatic iron contents and hepatic iron overload. Serum fT3 levels as well as the fT3 to fT4 ratio were positively associated with hepatic fat, NAFLD, hepatic iron contents, but not with hepatic iron overload. Associations between fT3 levels and liver fat content were strongest in obese individuals, in which we also observed an inverse association between TSH levels and NAFLD. These findings might be the result of a higher conversion of fT4 to the biologically active form fT3. Our results suggest that a subclinical hyperthyroid state may be associated with NAFLD, particularly in obese individuals. Furthermore, thyroid hormone levels seem to be more strongly associated with increased liver fat content compared to hepatic iron content.
Stine Linding Andersen, Louise Knøsgaard, Aase Handberg, Peter Vestergaard, and Stig Andersen
A high activity of the deiodinase type 2 has been proposed in overweight, obese, and smoking pregnant women as reflected by a high triiodothyronine (T3)/thyroxine (T4) ratio. We speculated how maternal adiposity and smoking would associate with different thyroid function tests in the early pregnancy.
Cross-sectional study within the North Denmark Region Pregnancy Cohort.
Maternal thyroid-stimulating hormone (TSH), total T4 (TT4), total T3 (TT3), free T4 (fT4), and free T3 (fT3) were measured in stored blood samples (median gestational week 10) by an automatic immunoassay. Results were linked to nationwide registers, and live-birth pregnancies were included. The associations between maternal adiposity (overweight or obese), smoking, and log-transformed TSH, fT3/fT4 ratio, and TT3/TT4 ratio were assessed using multivariate linear regression and reported as adjusted exponentiated β coefficient (aβ) with 95% CI. The adjusted model included maternal age, parity, origin, week of blood sampling, and diabetes.
Altogether 5529 pregnant women were included, and 40% were classified with adiposity, whereas 10% were smoking. Maternal adiposity was associated with higher TSH (aβ 1.13 (95% CI 1.08–1.20)), whereas maternal smoking was associated with lower TSH in the early pregnancy (0.875 (0.806–0.950)). Considering the T3/T4 ratio, both maternal adiposity (fT3/fT4 ratio: 1.06 (1.05–1.07); TT3/TT4 ratio: 1.07 (1.06–1.08)) and smoking (fT3/fT4 ratio: 1.07 (1.06–1.09); TT3/TT4 ratio: 1.10 (1.09–1.12)) were associated with a higher ratio.
In a large cohort of Danish pregnant women, adiposity and smoking showed opposite associations with maternal TSH. On the other hand, both conditions were associated with a higher T3/T4 ratio in early pregnancy, which may reflect altered deiodinase activity.
David P Sonne, Asger Lund, Jens Faber, Jens J Holst, Tina Vilsbøll, and Filip K Knop
Bile acids are possible candidate agents in newly identified pathways through which energy expenditure may be regulated. Preclinical studies suggest that bile acids activate the enzyme type 2 iodothyronine deiodinase, which deiodinates thyroxine (T4) to the biologically active triiodothyronine (T3). We aimed to evaluate the influence of bile acid exposure and incretin hormones on thyroid function parameters in patients with type 2 diabetes. Thyroid-stimulating hormone (TSH) and thyroid hormones (total T3 and free T4) were measured in plasma from two human studies: i) 75 g-oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals with increasing fat content with concomitant ultrasonographic evaluation of gallbladder emptying in 15 patients with type 2 diabetes and 15 healthy age, gender and BMI-matched controls (meal-study) and ii) 50 g-OGTT and isoglycaemic intravenous glucose infusions (IIGI) alone or in combination with glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP1) and/or GLP2, in ten patients with type 2 diabetes (IIGI-study). In both studies, TSH levels declined (P<0.01) similarly following all meal and infusion stimuli. T3 and T4 concentrations did not change in response to any of the applied stimuli. TSH levels declined independently of the degree of gallbladder emptying (meal-study), route of nutrient administration and infusion of gut hormones. In conclusion, intestinal bile flow and i.v. infusions of the gut hormones, GIP, GLP1 and/or GLP2, do not seem to affect thyroid function parameters. Thus, the presence of a ‘gut–thyroid–pituitary’ axis seems questionable.
Nannan Bian, Xiaomeng Sun, Biao Zhou, Lin Zhang, Qiu Wang, Yu An, Xiaohui Li, Yinhui Li, Jia Liu, Hua Meng, and Guang Wang
Bariatric surgery has become the most effective treatment for morbid obesity. Increasing evidence showed that bariatric surgery can alleviate insulin resistance and influence thyroid function. This study aimed to investigate the relationship between changes in thyroid function and adipose tissue insulin resistance (adipo-IR) after bariatric surgery.
A total of 287 non-diabetic participants with regular thyroid function were recruited and divided into the lean, overweight and obese groups. Among them, 50 morbidly obese patients submitted to bariatric surgery.
The obese group had a higher level of adipo-IR, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), FT3/free thyroxine (FT4) and metabolism disorders than the lean and overweight groups. BMI was correlated with TSH, FT3, FT3/FT4 and adipo-IR (r = 0.309, 0.315, 0.322 and 0.651, respectively, all P < 0.001). Adipo-IR was significantly correlated with TSH (r = 0.402, P < 0.001), FT3 (r = 0.309, P < 0.001), and FT3/FT4 (r = 0.228, P < 0.05). Bariatric surgery resulted in a sharp decline in BMI, adipo-IR, TSH, FT3 and FT3/FT4 levels, meanwhile, metabolic disorders improved. The decrease in BMI after bariatric surgery was significantly correlated with reductions in adipo-IR (r = 0.577, P < 0.001) and TSH (r = 0.401, P = 0.005). Interestingly, the fasting blood glucose, fasting insulin, adipo-IR and TSH in the higher TSH group decreased more remarkably than in the lower TSH group.
Obese individuals with higher TSH levels had an obvious metabolic improvement after bariatric surgery.