Association of Subclinical Hypothyroidism and Dyslipidemia in Children and Adolescents

Background: Correlation of higher levels of TSH and dyslipidemia in children is controversial. This study was designed to assess the relation between lipid profile components and TSH levels in children. Method: This cross-sectional study was performed in a growth assessment clinic in Shiraz. Children aged between 2 to 18 years that came to the clinic from January till April 2018 were considered. TSH levels equal or above 5 and lower than 10 mIU/L with normal FT4 were considered as subclinical hypothyroidism. Results: 666 children were euthyroid while 181 had subclinical hypothyroidism. Mean total cholesterol in euthyroid children was 160.50 ± 29.070 mg/dl and in SH group 161.39 ± 28.694 mg/dl (P=0.713). Mean LDL-C in euthyroid children was 90.96 ± 24.996 mg/dl and in SH group 89.10 ± 23.852 mg/dl (P=0.369). Mean HDL-C in euthyroid children was 47.94 ± 10.560 mg/dl and in SH group 49.04 ± 10.361 mg/dl. (P=0.211). Mean non HDL-C in euthyroid children was 112.56 ± 27.696 mg/dl and in SH group 112.35 ± 28.136 mg/dl. (P=0.929). Mean triglyceride in euthyroid children was 104.98 ± 54.934 mg/dl and in SH group 113.83 ± 91.342 mg/dl (P=0.215). There was no significant difference in mean serum total cholesterol, LDL, HDL, non-HDL and triglyceride levels between euthyroid and subclinical hypothyroid. Adjusted correlation was not significant between TSH levels and any lipid profile component. Conclusion: By comparing the results of this study with other studies, it is evident that lipid disorder in subclinical hypothyroid children does not have specific


Introduction
Subclinical hypothyroidism is defined as elevated TSH levels while T4 or FT4 levels are normal. [1] It is a common disorder with a prevalence of 1 to 10% in Adult Community, [2,3] while in the pediatrics population subclinical hypothyroidism is slightly lower than 2%. [2,4] Elevated TSH levels are linked with obesity [5], and they are found to be reversible after weight loss, whether being attained through bariatric surgery or diet. [6,7] Subclinical hypothyroidism in adults has been linked to higher chances of cardiac disease, [8][9][10][11][12][13][14] insulin resistance and neuromuscular and neurobehavioral alteration.[10, [15][16][17][18] Several studies have correlated subclinical hypothyroidism in adults with higher levels of total cholesterol, LDL, non-HDL, TG and lower levels of HDL. [19][20][21] However in study by Meisinger et al only higher triglyceride was correlated with higher levels of TSH in male participants. Higher levels of total cholesterol and LDL-C was only true for female participants. [22] Correlation of higher levels of TSH and dyslipidemia in children is controversial. Some studies have showed higher levels of TC, LDL and TG with increase in TSH. [23][24][25][26][27] Conversely another study showed higher levels of TG as the only positive correlation with increase in TSH. [28] Studies about the association of dyslipidemia and subclinical hypothyroidism in children show different results. This cross sectional prospective study was designed to compare lipid profiles including TG, Total Cholesterol, LDL-c and HDL-c in euthyroid vs. subclinical hypothyroid children.

Methods
This study was conducted as part of a larger project on serum lipid and thyroid profile in southern Iranian children and adolescents; details of which are available in another research paper. [29] In short, children with an age of 2 to 18 years that came to a growth assessment clinic in the city of Shiraz for routine growth follow up from January till April 2018 were selected for the study. After consent from their parents, they were checked for serum Total cholesterol, LDL-c, HDL-c, Non-HDL-c, TG, TSH and FT4 levels simultaneously in a non-fast state. For this study, inclusion criteria were: respectively. Assay performance was controlled using Elecsys PreciControl Universal for serum thyroid profile and TrueLab N and TruLab P for lipid profile. Auto Analyser was calibrated using Elecsys TSH CalSet and TruCal U. Inter-assay coefficients of variation (CVs) for TSH are 1.56% for 1.37 mIU/L and 0.08% for 8.62 mIU/L respectively while inter and intra assay coefficient of variations were 3.2 and 2.29% for total cholesterol and 1.6 and 1.49% for triglyceride respectively.  (Table 1) TSH levels equal or above 5 were considered abnormal. All participants with high TSH levels were considered for a second remeasurement. For these participants, second TSH levels were considered for the study.
For analysis, the study group was divided into two age groups: 2-9 and 10-18 each representing before start of puberty and after start of puberty respectively. Participants with TSH levels equal or above 5 mIU/L and lower than 10 mIU/L with normal free T4 levels were categorized as Subclinical Hypothyroid children. Relation between serum TSH and each lipid profile component (dependent variable) was evaluated using partial variable correlation, adjusted for age, gender and BMI Z-score. Comparisons were performed by using chi_squared test for categorical variables in table 4 and by Student t-test for continuous variables in table 3. A value of p < 0.05 was considered statistically significant in all comparisons with confidence interval of 95%. All statistical analysis were performed using SPSS software version 25.0 (SPSS, Chicago, IL, USA).

Results
Based on Table 2, of the 847 children in this study, 666 had TSH levels between 0.3-4.9 IU/ml and were considered as euthyroid while 181 who had TSH levels of 5-9.9 mIU/L and were considered as subclinical hypothyroid participants. There was no significant statistical difference in mean age between euthyroid and subclinical hypothyroid participants. (9.96 ± 3.40 years vs. 9.98 ± 3.28, P = 0.945) 42.8% of euthyroid and 44.8% of subclinical hypothyroid were male. (p = 0.637) Overall, subclinical hypothyroid children had higher BMI Z-scores than euthyroid children. (p = 0.012) ( Table 2) Table 3 shows mean levels of lipid profile components in euthyroid and subclinical hypothyroid children and the subgroups of 2-10 and 10-18 years of age participants.
Overall, there was no significant statistical difference in any of the lipid profile components between euthyroid and subclinical hypothyroid children and in the subsequent age related subgroups. (Table 3) Table 4 shows the prevalence of dyslipidemia in each of the lipid profile components in euthyroid and subclinical hypothyroid children and their respective age groups. Overall, there was no significant statistical difference in prevalence of any of the lipid profile dyslipidemias between euthyroid and subclinical hypothyroid children and in the subsequent age related subgroups. (Table 4) Table 5 shows the association of TSH levels and each of the lipid profile components based on partial correlation method adjusted for age, gender and BMI Z-score. No correlation was seen between TSH levels and any of the lipid profile components. Use of logistic regression was forgoed due to the results of this study. (Table 5) Discussion Based on our study, we found no correlation between TSH levels and lipid profile components. We also found no difference in mean levels of serum lipid levels between euthyroid and subclinical hypothyroid patients. According to Berenson GS, et al, in the Bogalusa Heart study, atherosclerosis will start at childhood and the effect of multiple risk factors on the extent of atherosclerosis was quite evident. One of the major risk factors in atherosclerosis is hyperlipidemia. [31] Although L-T4 treatment exerts some beneficial effects, there is no available data regarding the impact of therapy on metabolic outcomes in SH children. [25,30] The mechanism of how thyroid hormones can affect lipid profile is not completely clear, but thyroid hormones reduce apoB lipoproteins via a non-LDLR pathway that leads to decreased liver apoB production. [32] Although it is generally believed that thyroid hormones and their synthetic derivatives known as thyromimetics, can reduce serum cholesterol by their ability to increase LDLRs but recent study showed that TH and thyroid hormone receptor-β selective agonists GC-1 and KB2115 are able to reduce serum cholesterol by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. [33].
The advantage of our study relative to other studies is that a large number of subclinical hypothyroid children are included and also this is a cross sectional prospective study.
Most of the other studies on relation of TSH and serum lipid concentration are case control studies spanning several years.

Conclusion
From this study, it can be concluded that that high TG is the most common lipid disorder in SCH patient, followed by high non HDL-C. In addition, by comparing the results of this study with other studies, it is evident that lipid disorder in SCH children does not have a specific pattern.