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The Frequency of Subclinical Hypothyroidism in Obese Children and Adolescents and Its Relationship with Metabolic Parameters and Atherogenic Index

Objective The effect of subclinical hypothyroidism on glucose and lipid metabolism in obese children is controversial. This study aims to compare cardiovascular risk factors in obese patients with or without subclinical hypothyroidism and determine the frequency of subclinical hypothyroidism in obese children and adolescents. Materials and Methods A total of 1130 obese children and adolescents aged 6–18 years were included in this single-center cross-sectional study. Metabolic parameters such as thyrotropin, free thyroxine, free triiodothyronine, homeostasis model assessment for insulin resistance, atherogenic index, and lipids were evaluated. The patients were divided into two groups—subclinical hypothyroidism group (free thyroxine normal, thyroid-stimulating hormone 5.5–10 mIU/L) (n = 59) and the control group (free thyroxine normal, thyroid-stimulating hormone < 5 mIU/L) (n = 1071). Results Subclinical hypothyroidism was detected in 59 (5.2%) of 1130 patients. The mean body mass index was similar in both groups. The mean serum insulin, homeostasis model assessment for insulin resistance, triglyceride, atherogenic index of plasma, aspartate aminotransferase, and alanine aminotransferase levels were higher in the subclinical hypothyroidism group, and the mean high-density lipoprotein cholesterol level was lower than the control group (P = .005, P < .001, P = .028, P < .001, P = .001, P < .001, and P = .018, respectively). While a positive correlation was observed between the thyroid-stimulating hormone levels and insulin, homeostasis model assessment for insulin resistance, alanine aminotransferase, triglyceride, and basal cortisol levels, a negative correlation was found between thyroid-stimulating hormone and high-density lipoprotein cholesterol. Conclusion Subclinical hypothyroidism can negatively affect the lipid and glucose profile.


INTRODUCTION
The number of overweight or obese children in the world has increased more than tenfold, from 11 million in 1975 to 124 million in 2016. 1 The longer a person is obese, the greater there is morbidity, healthcare costs, and workforce loss in adulthood. 2 The most common abnormality of thyroid function in obese children is isolated hyperthyrotropinemia, also known as subclinical hypothyroidism (SH), followed by minor changes in triiodothyronine (T3) and thyroxine (T4) ratios. 3,4 SH is defined as elevated serum thyroid-stimulating hormone (TSH) in the presence of normal serum total and free thyroxine (fT4) levels. 5 The prevalence of SH is 4-20% in adults and 1.5-3% in children. 6 SH is a common finding in overweight and obese

What this study adds on this topic?
The frequency of subclinical hypothyroidism is 5.2% in obese Turkish children and adolescents. In obese children and adolescents, low high-density lipoprotein cholesterol, hypertriglyceridemia, insulin resistance, basal cortisol, alanine aminotransferase, atherogenic index of plasma, and hypertransaminasemia are associated with thyroid-stimulating hormone concentrations. Increased thyroid-stimulating hormone can negatively affect the lipid and glucose profile.
children with a 7-36% rate. [7][8][9][10][11] There are several factors associated with SH, such as chronic lymphocytic thyroiditis, iodine deficiency, medications, gene defects, genetic syndromes, and obesity. 7 It has been hypothesized that the increase in TSH concentrations in obesity may represent a mechanism aimed at increasing energy expenditure. 12 In this context, the existence of an adipose tissu e-hyp othal amus-pitui tary-thyro id axis has been suggested. This model claims that leptin secreted by adipocytes affects communication between adipocytes and the hypothalamus by increasing the secretion of thyrotropinreleasing hormone (TRH) and TSH and the peripheral conversion of T4 to T3. 13 Some studies have identified SH as an essential risk factor for developing and progressing cardiovascular disease, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) in obese children and adolescents. 5,14 In a study conducted with obese children and adolescents, Aeberli et al 15 showed that TSH levels were significantly correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), insulin, and homeostasis model assessment for insulin ratio (HOMA-IR). Despite uncertainty about the underlying mechanism, the finding that abnormalities in thyroid function mostly normalize after weight loss supports the hypothesis that TSH elevation in obese patients is reversible and is a consequence rather than a cause of obesity. 13,16 The prevalence of SH in Turkish obese children and adolescents was reported in the range of 9.2-36%. 8,9,17 The prevalence of SH is high in obese children, and the necessity of L-thyroxine therapy is still an important debate.
Therefore, the aim of the present study was (1) to determine the frequency of SH in obese children and adolescents, (2) to investigate the relationship between high TSH levels and various anthropometric measurements (body mass index, body mass index standard deviation score, waist/hip ratio), atherogenic index, and metabolic parameters (lipid profile and insulin resistance) in these children.

Study Population
This study was performed in the Pediatric Endocrinology Department of İnonu University Hospital. A total of 1130 obese children 6-18 years of age who had been brought to the outpatient clinic were consecutively recruited for the study from March 2013 to September 2017. Our study is a single-center and cross-sectional study. Inclusion criteria for the study were: (1) an age range of 6-18, (2) a BMI greater than the 95th percentile for age and gender, based on the standards of the Centers for Disease Control and Prevention (CDC), 18 and (3) absence of a prior major illness. Exclusion criteria were: (1) patients with overt hypothyroidism (excluding SH), patients with chronic lymphocytic thyroiditis, patients with Cushing's syndrome, patients receiving thyroid hormone, and patients receiving topical or systemic glucocorticoid medication; (2) cases with familial dyslipidemia; (3) patients with syndromic, monogenic, and secondary obesity; and (4) patients with TSH levels >10 IU/ mL. Hospital records of the cases were reviewed retrospectively. The patients were divided into two groups according to the thyroid function test results. Subjects with normal fT4 levels and 5.5-10 mIU/L TSH levels were included in the SH group.
The control group consisted of subjects with normal fT4 levels and TSH levels of <5.5 mIU/L. Both groups were compared in fasting plasma glucose, insulin, HOMA-IR, lipid profile, and other metabolic parameters.

Ethical Approval
Ethics Committee Approval: The study proposal was approved by the Ethics Committee of Inonu University Faculty of Medicine (Approval Number: 2020-155). Since the study was performed retrospectively,patient informed consent forms were not needed.

Anthropometric Examination
A complete physical examination, including anthropometric measurements, was performed on each child. Puberty development was assessed according to Tanner staging. A testicular volume of 4 mL or more in males and ≥2 breast development in females according to Tanner's staging were accepted as signs indicating the onset of puberty. 19,20 Anthropometric assessments were performed in the morning, following an overnight fast, without street clothes and shoes. A Harpenden stadiometer (with a sensitivity of 0.1 cm) was used for height measurement. Weight measurement was performed via the BMI SECA scale (with a sensitivity of 0.1 kg). BMI was calculated as weight in kilograms divided by height in meters squared. Waist circumference was measured at the level of the umbilicus while standing and breathing regularly, hip circumference was measured at the level of the iliac crest, and blood pressure was measured by a standard mercury sphygmomanometer after at least 10 minutes of rest.

Laboratory Measurements
Hypertension and systolic blood pressure were accepted as above the 95th percentile for age and gender. 21 Insulin resistance was defined using the HOMA-IR using the following standard formula: [fasting insulin (mIU/mL) × fasting glucose (mmol/L)/22.5]. 22 Insulin resistance was defined as a HOMA-IR >2.5 in prepubertal children and >3.16 in pubertal children. 23,24 Samples were taken for at least 12-14 hours post-fasting, and blood glucose (FBC), lipid profile (HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, TC: total cholesterol, TG: triglyceride), and insulin levels were measured. Serum TC levels >200 mg/dL, triglyceride (TG) levels >150 mg/dL, LDL-C levels >130 mg/dL, or HDL-C levels <40 mg/dL were accepted as dyslipidemia. 25,26 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) normal values were set below 41 U/L and 37 U/L, respectively. With basal cortisol enzyme immunoassay kits, the normal level was taken as 3-21 μg/dL.
Fasting insulin, TSH, and fT4 levels were studied with twochamber two-step enzymatic immunoassay methods using a Beckman Coulter D×I 800 device. According to reference values of Beckmann Coulter TSH and fT4 kits used in our hospital laboratories, TSH low and high limit values were set as 0.35-5.5 mIU/mL, and fT4 low and high limit values were set as 0.61-1.32 ng/dL. The fT3 normal range is given in the range of 1.9-4.2 pg/mL. SH is defined as an elevated serum TSH concentration [≥5.5 lU/mL (97.5th for our assay)] in the presence of normal serum fT4. The glucose oxidase method for blood glucose measurement and Olympus AU 2700 were used for lipid measurement. Insulin levels were measured by electrochemiluminescence method on Roche Modular Analytics E-170 immunoassay analyzer (Roche Diagnostics, USA). The atherogenic index of plasma (AIP) was calculated as the logarithm of the molar ratio of triglyceride to high-density lipoprotein cholesterol (TG/HDL-C). AIP was classified as <0.11 as low risk, 0.11-0.21 as intermediate risk, and >0.21 as increased risk. 27 Upper abdominal ultrasonographic examination was performed to diagnose hepatosteatosis using the GE LOGIC S8, USA, ultrasound device. Liver ultrasound findings were listed as follows: normal liver appearance (no hepatosteatosis), mild (stage 1), moderate (stage 2), and severe hepatosteatosis (stage 3). 28

Statistical Analysis
Statistical analysis was performed using the statistical Package for the Social Sciences Statistics 15.0 (SPSS Inc.; Chicago, IL, USA) package program. Categorical variables were analyzed using the chi-square test. The normal distribution of the data was evaluated with the Kolmogorov-Smirnov test. The Student's t-test and the Mann-Whitney U-test were used for comparison of groups according to the parametric values. For correlation analyses, the Pearson test was used for the parametric variables and the Spearman test was used for the nonparametric variables. A P value <.05 was accepted as statistically significant.

Clinical Characteristics of the Subjects
A total of 1130 obese cases (526 girls (46.4%) and 604 boys (53.6%)) were included in the study. The mean age of the patients was 10.9 ± 3.6 years, and 638 (56.5%) cases were pubertal. Demographic characteristics and laboratory data of the patients are shown in Table 1. Demographic and laboratory values of the patients according to puberty status are shown in Table 2.

Comparison of Anthropometric and Laboratory Parameters Between SH (+) and SH (−) Groups
SH was determined in a total of 59 patients (5.2%). There were 1071 patients (94.8%) in the control group whose thyroid function test results were normal. No difference was found between the groups concerning sex distribution (P = .053). The puberty status was similar in both groups (P = .224). While the mean BMI SDS was 2.2 ± 0.3 in the SH group, it was 2.2 ± 0.4 in the control group. Both groups were similar concerning BMI SDS (P = .290). When groups were compared on glucose metabolism, the fasting insulin, IR, and the HOMA-IR levels were higher in the SH group (P = .005, P < .001, and P < .001, respectively). When the groups were compared concerning lipid metabolism, while the HDL-C level was lower, the TG level was higher in the SH group than the control group (P = .018, P = .028, respectively). Anthropometric and laboratory measurements of both groups are summarized in Table 3.

DISCUSSION
In this study, the relationship between SH and metabolic parameters in obese children and adolescents was evaluated. SH was found in 5.2% of 1130 obese children and adolescents. Fasting insulin, HOMA-IR, basal cortisol, ALT, and TG levels were higher in the SH group, while HDL-C was lower. In addition, there was a positive correlation between TSH levels and fasting insulin, HOMA-IR, fasting glucose, basal cortisol, ALT, and TG levels, while a negative correlation was found with HDL-C levels.
The most common thyroid disorder in obese children and adolescents is increased serum TSH and fT3 levels. 3,4,7,8 This increase in TSH (and therefore T3) can be interpreted as a defense mechanism of the body against weight gain. Conversion of T4 to T3 is increased in obese individuals as a result of increased deiodinase activity due to fat deposition. 7,13 In our study, no significant difference was found between SH (+) and SH (−) subjects in terms of fT3 or fT4 levels. However, while fT4 levels were within the normal range in both groups, fT3 levels were above the normal range. In the light of this information, the fact that fT4 is within normal limits and fT3 levels are increased in obese patients can be explained by this mechanism.
The prevalence of SH in obese children and adolescents has been reported in the range of 7%-36%. [7][8][9][10][11]29 These can be explained by differences in ethnicity, geographical region,   and cut-off values for TSH. Thyroid hormones play a role in basal metabolism and energy expenditure. Therefore, interest in the relationship between thyroid functions and obesity has increased. 13,30 There are studies in the literature showing a positive correlation between TSH and BMI. 11,17 In our study, however, we did not find a correlation between TSH levels and BMI.
No relationship was observed between TSH levels and gender or puberty status. 8,17 Dahl et al 31 found higher TSH levels in boys than girls in a study conducted with 1796 obese/overweight subjects during childhood and adolescence. In our study, no difference was found between the groups with and without SH regarding age, gender, and pubertal status.
Thyroid hormones play an important role in glucose metabolism. Significant hypothyroidism is associated with obesity, insulin resistance, hyperglycemia, dyslipidemia, and increased cardiovascular events. 32 The effect of thyroid functions on metabolic parameters is discussed because of the higher prevalence of SH in obese patients than non-obese patients. Many studies investigate the relationship between thyroid hormones and glucose and lipid metabolism in obese children and adolescences. 8,17,30,32 While some studies reported an association between TSH and insulin and HOMA-IR, some studies have not reported such an association. 8,11,15 In our study, insulin and HOMA-IR values were higher in the SH group. In addition, a positive correlation was found between TSH levels and insulin and the HOMA-IR index.
Thyroid hormones regulate the synthesis, metabolism, and mobilization of lipids. While studies found a significant correlation between TSH levels and TG or TC, some studies did not find a correlation between TSH and lipid concentrations. 8,15,17,33 A positive correlation was found in our research between TSH and triglyceride levels in the SH group, while a negative correlation was found with HDL-C levels. We found a higher frequency of hyperlipidemia in cases with SH. As insulin resistance progresses, triglyceride levels increase, and HDL decreases. The potential mechanism is that HDL particles can be more easily catabolized due to higher TG levels. Also, reduced lipoprotein lipase (LPL) activity and increased neutral lipid transfer contribute to lower plasma HDL-C. 34 Elevated TG and low HDL-C levels in SH patients in our study may be explained by this mechanism. Significant differences in AIP rates was described in patients with SH compared to control groups. 35,36 Rumińska et al 37 reported no association between TSH levels and AIP in obese children. In our study, on the other hand, we found a moderate risk for AIP in obese children with SH, while there was a low risk in patients without SH.
Association with NAFLD and SH has recently been demonstrated in children. 38,39 In a retrospective study of 332 overweight or obese children and adolescents, Kaltenbach et al 38 showed that higher TSH levels were associated with a higher degree of fat infiltration on ultrasound imaging. In some studies, ALT elevation was higher in obese children with SH than in obese children without SH. 9,39 In our study, we found higher AST and ALT levels in obese patients with SH. We also found a positive correlation between ALT levels and TSH levels in obese people with SH. It was also concluded that SH is associated with hypertransaminasemia.
In our study, basal cortisol levels were within normal limits in both groups, and cortisol levels were higher in the SH group than in the group without SH. In our study, we found a significant positive correlation between TSH and basal cortisol levels. Walter et al 40 reported a positive correlation between TSH and cortisol in their study. The increase in cortisol in parallel with the increase in TSH can be explained by decreased cortisol clearance and negative feedback in the blunted hypothalamic-pituitary-adrenal axis. Nevertheless, important questions such as whether this relationship is pathological or physiological and other mechanisms involved in this relationship still remain. Some limitations of the study are that (1) it was designed retrospectively; (2) there was no control group including children and adolescents with normal weight; (3) the iodine status of obese children and genetic causes of SH were not investigated.

CONCLUSIONS
Despite its limitations, risk factors for cardiovascular disease (CVD) (high atherogenic index, insulin resistance, HOMA-IR, TG level, and low HDL-C level) were significantly higher in patients with SH in this study, which compared obese children and adolescents with similar BMI, without including patients with autoimmune thyroid disease in the study. Increased TSH can negatively affect the lipid and glucose profile. As a result, larger prospective studies with an increasing number of cases in each group are needed to investigate the relationship between SH and metabolic changes in obese children and adolescents with SH.