The C55A Single Nucleotide Polymorphism in CTLA-4 Gene, a New Possible Biomarker in Thyroid Autoimmune Pathology Such as Hashimoto's Thyroiditis.

Hashimoto's thyroiditis (HT) is a chronic autoimmune disorder characterized by the production of autoantibodies against the thyroid gland. Different studies have shown that several genes may be associated with HT, which explains why patients often have family members with thyroiditis or other autoimmune diseases. The aim of this case-control study was to evaluate the correlation between polymorphisms at the level of exon 1 from the CTLA-4 gene and the susceptibility to developing HT. In this study, we found that there is no statistically significant association between the polymorphism rs231775 (A22G in exon 1) of the CTLA-4 gene and a genetic predisposition to HT. In contrast, a strong association was discovered for the first time between C55A in exon 1 of the CTLA-4 gene and HT. Our findings suggest that there is a genetic relationship between the CTLA-4 (+55A/C) genotype and the seropositivity against thyroid autoantigens, such as anti-thyroid peroxidase (ATPO) and anti-thyroglobulin antibodies (ATG).

Exploratory Longitudinal Analysis of the Circulating CHIT1 Activity in Pediatric Patients with Obesity.

Macrophage activation and cytokine release play a pivotal role in inflammation-mediated metabolic disturbances in obesity. The proinflammatory macrophage secretes human chitotriosidase (CHIT1). The expression of the CHIT1 in visceral adipose tissue is associated with cytokine production. Our study aimed to assess whether the CHIT1 circulating activity, as a macrophage activation indicator, reflects the change of the adiposity level and the insulin resistance (IR) in children with obesity. We longitudinally (median follow-up period of 7 months; IQR [5 to 8.5] and {2 to 13} months) evaluated the CHIT1 circulating activity, the adiposity level (waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WtHR), and body mass index (BMI)-for-age z score), and two surrogate markers of IR (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR and the triglycerides-to-high density lipoprotein cholesterol ratio, TG/HDLc) in 29 pediatric patients (16 girls and 13 boys) with obesity. We found a significant reduction in CHIT1 circulating activity (Wilcoxon test, p = 0.015) and a decrease in TG/HDLc at the follow-up evaluation (Wilcoxon test, p < 0.001). Indicators of adiposity were positively correlated with HOMA-IR at baseline, among which WC was the sole indicator associated with HOMA-IR (Spearman's rank correlation coefficients, p < 0.05) at follow-up. Human chitotriosidase has the potential to be a valuable measure of the progression of subclinical inflammation in children with obesity. Subclinical inflammation, as expressed by the circulating CHIT1 activity, progresses independently of the abdominal adiposity, as measured by the clinical indicators, and is associated with a change in insulin resistance.

Evaluation of Circulating Chitotriosidase Activity in Children with Obesity.

Childhood obesity progresses to metabolic disturbances via low-grade inflammation. Identifying novel molecules that reflect the activity of the immune responses is critical in understanding its underlying pathogenesis. Our exploratory study aimed to evaluate the change of chitotriosidase (CHIT1) plasma activity according to Body Mass Index (BMI)-for-age z score in pediatric patients. The study evaluated 68 children consisting of 47.1% girls with a mean age of 12.47 ± 3.71 years and 52.9% boys with a mean age of 11.93 ± 3.18 years. The effect of the most frequent CHIT1 gene variants, the 24 base pair duplication (dup24) and G102S polymorphism, upon the association between circulating CHIT1 activity and the obesity level, was also investigated. A significantly higher logCHIT1 plasma activity was found in children with extreme obesity than in children with overweight (p = 0.048 for the uncorrected CHIT1 and 0.026 for the corrected CHIT1). The BMI-for-age z score significantly (p = 0.031) predicts increased CHIT1 activity in children with overweight, obesity, and extreme obesity after controlling for the two gene variants, age, gender, and time since weight gain. Dup24 and G102S polymorphism were significant independent predictors (p-values < 0.002) for the change of CHIT1 plasma activity. Circulating CHIT1 might be an accurate indicator of inflammation in children with obesity. Its role and the effect of the dup24 and G102S variants on the CHIT1 activity should be validated in a larger cohort.

Inflammation-Related Markers and Thyroid Function Measures in Pediatric Patients: Is the Grade of Obesity Relevant?

We aimed to investigate the effect of weight status on inflammation-related markers and thyroid function tests in overweight and obese pediatric patients. Children and adolescents diagnosed between January 2017 and January 2019 with overweight or obesity were included in the study. Neutrophil-to-lymphocyte ratio (NLR), platelet-to lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were calculated for the groups defined according to Body Mass Index (BMI)-for-age z-score: overweight (≥1 BMI-for-age z-score), obese (≥2 BMI-for-age z-score) and severely obese (≥3 BMI-for-age z-score). Severely obese patients had significantly higher value of white blood cells (WBC) counts (median = 7.92) compared with overweight patients (7.37, p = 0.014). Absolute lymphocyte count was significantly associated with obesity degree in children (Spearman's Rho coefficient ρ = 0.228. p = 0.035), whereas absolute polymorphonuclear neutrophils (PMNCs) count was significantly higher in severely obese adolescents than overweight adolescents (overweight: 4.04 vs. severely obese: 5.3 (p = 0.029)). In 8.19% of patients an elevated thyroid-stimulating hormone (TSH) level was found, and 3.36% of patients had a low level of free thyroxine with an elevated level of TSH. Total absolute WBC count may be a reliable inflammation-related marker in obese pediatric patients without metabolic syndrome, but needs to be validated in the context of all possible covariates. Subclinical and overt hypothyroidism may develop from an early age in overweight or obese patients.

Interplay between metabolic and thyroid parameters in obese pubertal children. Does visceral adipose tissue make the first move?

Objectives: The mechanisms of obesity-associated thyroid dysfunction in children are incompletely deciphered. We aimed to evaluate whether visceral adipose tissue (VAT), insulin resistance (IR), inflammation, oxidative stress (OS) are involved in thyroid morpho-functional changes in pubertal obese children. Methods: We recruited 43 obese pubertal children without history of thyroid pathology. Metabolic and thyroid parameters (visceral fat thickness [VFT], waist/hip ratio [WHR], waist/height ratio [WHtR], insulin, glucose, liver parameters, thyroid stimulation hormone [TSH], free thyroxine [FT4], free triiodothyronine [FT3], thyroid and abdominal ultrasonography) were evaluated. Serum monocyte chemoattractant protein-1 (MCP-1) and malondialdehyde (MDA) levels were quantified as markers of inflammation and OS. Results: VFT correlated positively both with WHR (p= 0.034) and the presence of thyroid nodules (p= 0.036). WHR associated with TSH (p= 0.005), FT3/FT4 (p= 0.033) and was independently associated with FT3/FT4 increase (p< 0.001). HOMA-IR increased with visceral obesity (waist circumference, p= 0.001; WHR, p= 0.018; WHtR: p< 0.001), hepatic impairment (alanine aminotransferase, p= 0.019) and hepatic steatosis (HS; p= 0.013) and correlated positively with FT3/FT4 (p= 0.036). TSH was significantly higher in subjects with HS versus those without HS (p= 0.007) and logistic regression analysis identified TSH as a risk factor for HS (p= 0.014). MDA correlated positively with MCP-1 (p= 0.021). Conclusion: VAT and IR may be responsible for changes in thyroid parameters associated with obesity: elevated TSH, FT3/FT4 levels and increased prevalence of thyroid nodules. WHR was predictive of increased FT3/FT4. In obese children, there is an interdependent relationship between HS and thyroid function.

Vitamin D deficiency, insulin resistance and thyroid dysfunction in obese patients: is inflammation the common link?

The aim of this article is to study the possible relation of serum vitamin D concentrations to body mass index (BMI), visceral fat thickness (VFT), insulin resistance (IR), inflammation (serum monocyte chemoattractant protein-1 - MCP-1) and thyroid parameters in obese patients. A total of 158 non-diabetic, obese patients aged 19-68 without a history of thyroid pathology were recruited. Biochemical markers, insulin, 25-OH vitamin D, thyroid parameters (TSH, FT3, FT4, TPO antibodies, TG antibodies) and VFT were measured. Serum MCP-1 evaluated the inflammation. A HOMA-IR cut-off value of 2.5 defined IR. Most patients had severe (70.3%) or moderate (25.3%) vitamin D deficiency. Vitamin D level was negatively associated with BMI (p = .043) and during the cold season with VFT (p = .009). Vitamin D deficiency correlated with Hashimoto's thyroiditis prevalence during the warm season (p = .047) and was a risk factor for its occurrence (p = .021). At 15 ng/mL cut-off value, vitamin D was negatively correlated with MCP-1 (p = .0006). Also, MCP-1 was positive correlated with HOMA- IR (p = .042), TPO-Ab levels (p = .011) and with Hashimoto's thyroiditis (p = .027). MCP-1 was a risk factor for vitamin D deficiency (p < .0001). Our study supports a bidirectional interaction between vitamin D and systemic inflammation in obese patients. Moreover, systemic inflammation is related to the severity and frequency of Hashimoto's thyroiditis. Vitamin D deficiency is the single independent factor associated with Hashimoto's thyroiditis in obese patients.

The effect of Metformin treatment in obese insulin-resistant patients with euthyroid goiter.

Objective The study's objective was to evaluate the thyroid parameters in obese insulin-resistant patients with euthyroid diffuse or nodular goiter, following Metformin treatment. Patients and methods The study was experimental, open, and prospective. Fifty-three patients aged 18-68 were enrolled for two years. Obese insulin-resistant patients (cut-off Homeostasis-Model-Assessment of Insulin Resistance-HOMA-IR ≥ 2.5) with euthyroid nodular/diffuse goiter were included. Subjects with diabetes, hypo-/hyper-thyroidism, autoimmune thyroiditis, psychiatric disorders, liver or heart failure were excluded. Patients were randomly assigned to one of the following treatment: Metformin 1000 mg/day + Levothyroxine 25 µg/day (M + LT4 group) and only Levothyroxine 25 µg/day (LT4 group). Thyroid and metabolic parameters' evolution was investigated over six months. Results The two groups were comparable at baseline (p ≥ 0.10). TSH, waist/hip ratio (WHR), visceral fat thickness (VFT), insulin, and HOMA-IR decreased significantly more in M + LT4 group compared to LT4 group. TSH decrease correlated with WHR reduction (p = 0.002) only in M + LT4 group. Moreover, the multivariate regression analysis revealed that insulin's and HOMA-IR levels' decrease was an independent factor associated with FT4's increase (p = 0.031, p = 0.033) just in M + LT4 group. No other independent association between the evolution (Δ) of TSH, thyroid volume (TTV), thyroid nodules-maximum diameter (TN-MD), and metabolic parameters was found. In addition, no significant threshold between groups was reached when ΔFT4, ΔTTV, ΔTN-MD were compared (p > 0.07), although their significant improvement was recorded between the baseline and the follow-up moment in each group (p < 0.003). Conclusion Metformin added to obese insulin-resistant patients treated with Levothyroxine for diffuse/nodular goiter determined a significant decrease in TSH and metabolic parameters, compared to those treated with Levothyroxine alone, but no significant difference regarding thyroid morphology after 6 months.

Thyroid disorders in obese patients. Does insulin resistance make a difference?

OBJECTIVE: The aim of this study was to evaluate the association between insulin resistance and thyroid pathology in obese patients, and compare the results between insulin-resistant and noninsulin-resistant patients. SUBJECTS AND METHODS: Obese/nondiabetic patients, aged 18-70 years, attending the outpatient endocrinology service for 2 years were consecutively included. We evaluated the patients' fasting plasma glucose, insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), thyroid-stimulating hormone (TSH), free thyroxine (FT4), antithyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (Tg-Ab), and thyroid ultrasound. RESULTS: We included 82 patients with a mean age 44.21 ± 12.67 years. The thyroid disorders encountered and their prevalences were: hypothyroidism (14.6%, 95% confidence interval [CI] 8.6-23.8%), hyperthyroidism (1.2%, 95% CI 2.0-6.6%), goiter (28.0%, 95% CI 19.5-3.6%), thyroid nodules (35.4%, 95% CI 25.9-46.2%), and Hashimoto's thyroiditis (32.9%, 95% CI 23.7-43.7%). HOMA-IR correlated positively with TSH levels (r = 0.24, p = 0.028), and this correlation remained after adjustment for body mass index (BMI), waist/hip ratio (WHR), serum cortisol, subcutaneous fat thickness (SFT), visceral fat thickness (VFT), triglycerides, γ-glutamyl transpeptidase (GGT), and alanine aminotransferase (ALT) in multivariate regression analysis (b = 0.207, 95% CI, 0.09-0.385, p = 0.023). TSH levels were significantly higher in patients with HOMA-IR ≥ 2.5 than in those with HOMA-IR < 2.5 (2.03 µIU/mL, interquartile range [IQR] 1.59-2.69 µIU/mL) versus 1.59 µIU/mL, IQR 0.94-2.26 µIU/mL, p = 0.023). CONCLUSIONS: The most prevalent thyroid disorder in patients attending our endocrinology clinic for investigation of obesity was thyroid nodules. One in seven patients had hypothyroidism. Our findings suggest that TSH levels correlate with insulin resistance in obese patients.