Dyslipidemia, subclinical inflammation, hepatic cholestasis and endothelial dysfunction in schoolchildren with excess fat: A study from the United Arab Emirates

Background The impact of obesity on cardiovascular health of young children is still to be fully illustrated. This study measured biomarkers for glycemic control, lipid metabolism, systemic inflammation, endothelial dysfunction, and hepatic cholestasis in schoolchildren. Its main purpose was to determine whether metabolic derangements could be detected in young children with excess fat. Method This cross-sectional study involved 967 children in the second, sixth, and tenth grades (median age, 7.3, 11.3, and 15.4 years, respectively). Using the International Obesity Task Force interpretation (IOTF) of body-mass-index (BMI), children were stratified as thin (<5th centiles), normal (5th to <85th centiles), overweight (85th to <95th centiles), obese (95th to <98th centiles), or extremely-obese (≥98th centiles). Waist circumference was also measured. Several metabolic determinations were then used as surrogate biomarkers for cardiovascular risks. Results Prevalence of BMI≥85th centile among the second graders was 13.1%, sixth graders 42.2%, and tenth graders 33.8%. BMI≥85th centile was associated with a tendency for higher hemoglobin A1c (p≥0.160) and higher blood glucose (p≥0.197). For the second graders, BMI≥85th centile was associated with higher high-sensitivity C-reactive protein (hs-CRP, p<0.001), higher tumor necrosis factor-α (TNF-alpha, p<0.001), higher interleukin-6 (IL-6, p<0.001), higher soluble intercellular cytoadhesive molecule-1 (sICAM-1), higher triglycerides (p≤0.024), and lower high-density lipoprotein (HDL, p<0.001). Additionally, for the sixth and tenth graders, BMI≥85th centile was associated with higher gamma-glutamyl transferase (GGT, p<0.001). In the sixth graders, BMI≥85th centile was insignificantly changed with sICAM-1 or the soluble vascular cytoadhesive molecule-1 (sVCAM-1). Conclusions The studied children with excess fat had increased risks for developing systemic inflammation, dyslipidemia, endothelial dysfunction, cholestasis, and diabetes. These results suggest that metabolic biomarkers should be included in the routine assessment of children with an overweight problem.

Committee (AAMD-HREC-2015-3236  and Abu Dhabi Education Council (ADEC). Written study consent was obtained for each participant; consent was obtained from parents or guardians for all the minors included in this study.
As described in detail previously [1], students were randomly recruited by a systematic sampling design; even-numbered students on the ADEC school list were selected. A validated and age appropriate study health questionnaire was distributed to about 2,000 selected students and the response rate was 48.4%. All consented students (consent was obtained from parents or guardians for all the minors included in this study) had anthropometric measurements (weight, height, and waist circumference) and physical examination by a trained nurse. The weight and height were measured by a digital scale stadiometer. Children were asked to stand straight with their heads, backs, and buttocks vertically aligned to the height gauge; their heights were then taken and rounded to the nearest 0.5 cm. Waist circumference was measured with upstretched tapes, midpoint between the bottom of the rib cage and the tip of the iliac crest [1]. Gender-specific bodymass index (BMI) growth charts (US Centers for Disease Control and Prevention, CDC) were used to identify overweight (BMI �85th centile and <95th centile), obese (BMI �95th centile and <99th percentile) and extremely obese (BMI �99th percentile) children [12]. BMI was also determined according to the International Obesity Task Force (IOTF) and World Health Organization (WHO) criteria: Thin <5th centiles; normal 5th to <85 th centiles; overweight 85th to <95 th centiles; obese 95th to <98 th centiles; and extremely-obese �98 th centiles [13]. A website was developed to process BMI values according to the IOTF, WHO, and CDC cut-off criteria [14]. As described in detail previously [2], Microsoft Active Server Pages (ASP) were used for data processing and JavaScript was used for data entry checking. Microsoft SQL Server and relational database management system were used for storing and retrieving data pertaining to the website. The ASP program contained the algorithms, and the database contained the tables needed for calculating BMI values and centiles for the three reference methods.
The statistical analysis was performed using SPSS software version 21.0 (SPSS Inc., Chicago, USA). Data are presented as median, mean, and standard deviation. Multiple groups were compared using Kruskal-Wallis test, as measurements were either not normally distributed or heteroscedastic (unequal variances). P<0.05 was considered significant. Effect size (Cohen's d) was calculated on SPSS using z-score of the tested variable followed by independent-samples ttest (mean difference); effect sizes were classified as small (d = 0.2), medium (d = 0.5), or large (d � 0.8). Raw data are submitted as S1 Dataset and S2 Dataset.

Results
Nine hundred sixty-seven participants were enrolled in this study. Their characteristics are summarized in Table 1. Cardiovascular risk factors were more prevalent in the fathers than in the mothers. In this study culture, intratribal marriages were common (35.8%), Table 1.

Discussion
This study reports on the status of glycemic control, lipid metabolism, systemic inflammation, endothelial dysfunction, and hepatic cholestasis in schoolchildren with excess fat. The results show that significant metabolic derangements are evident in elementary school children with overweight problems. Thus, excess fat negatively impacts the cardiovascular health of young children and prompt interventions are necessary.
Waist-to-height ratio, waist circumference (measured at the midpoint between the bottom of the rib cage and the tip of the iliac crest), and waist-to-hip ratio are simple indicators of cardiovascular risk in persons with obesity. While BMI is the traditional measure of overweight or obese, it is not a good indicator of health risk assessment.
Prevention of childhood obesity requires multidisciplinary efforts, which include regular monitoring during all healthcare visits. Management of obesity necessitates prompt enrolment in a structured program that endorses slow weight loss (good diet and regular exercise) through a family-based behavioral treatment. Psychological problems should be well managed Adverse events of childhood obesity   before children begin a weight loss program. Five percent reduction in BMI can significantly improve the biochemical derangement associated with obesity. Estimated caloric need for 4 to 6 year-old children is 80 to 90 kcal/kg/day and for 7 to 10 year-old children is 70 to 80 kcal/kg/ day (weight gain, 3-5 g/day). Very-low-calorie diets (e.g., 1,000 calories/day) can lead to nutritional deficiencies and should be avoided. The studied biomarkers detected significant metabolic derangements in children with overweight problems, which were evident in early childhood. Therefore, the excess fat in these young children increased their risks for systemic inflammation, dyslipidemia, endothelial dysfunction, hepatic cholestasis, and dysglycemia. Thus, routine workup for childhood obesity Children were stratified as thin (<5th percentile), normal (5th to <85th), overweight (85th to <95th), obese (95th to <98th), or extremely-obese (�98th), using the International Obesity Task Force (IOTF) interpretation of body-mass-index (BMI). Analysis of the five IOTF groups of BMI (underweight, normal, overweight, obese, and extremely-obese) was performed on combined grades using Kruskal-Wallis test; all the laboratory biomarkers were significantly different among the groups (p<0.038), except the VCAM-1 (p<0.742).
https://doi.org/10.1371/journal.pone.0210316.t002 Table 3. Waist circumference and waist-to-height ratio as functions of IOTF-BMI and age.  should include screening for dyslipidemia, diabetes (including insulin resistance), subclinical inflammation, fatty liver, hypertension, obstructive sleep apnea, metabolic syndrome, and polycystic ovarian syndrome. In addition, genetic testing should be offered for children who have extreme obesity [15]. We show here that the biochemical profile that uses hs-CRP, IL-6, TNF-alpha, Hb A 1c , adiponectin, sICAM-1, sVCAM-1, and GGT is helpful. The lack of correlations between the inflammatory biomarkers and the biomarkers of dyslipidemia and hepatic cholestasis (GGT) may suggest that these obesity-associated derangements are independent. The development of obesity needs to be carefully monitored and promptly treated in children and adolescents. The use of biomarkers may help the child and parents to appreciate the seriousness of obesity and encourage them to enroll in a proper weight reduction program. Children with obesity usually consume high calories from nutrient-poor and calorie-dense foods and drinks. They usually have long screen-time and participate less in vigorous exercises. Reversing these habits requires effective counseling and motivations at home and at school. The impact of prescribing drugs that promote weight loss (e.g., orlistat) is still to be illustrated. Bariatric surgery is considered only for adolescents with a sexual maturity rating of 4 to 5, and BMI of 40 kg/m 2 or BMI of 35 kg/m 2 plus obesity-associated complications.

Age
Obesity and its related disorders are associated with a reduction in the lifespan of about 12 years. In 2008, The Obesity Society recognized obesity as a "disease" [16]. In 2013, the American Medical Association recognized obesity as a chronic complex condition requiring intervention [17]. The 2011 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents recommends lipid screening (nonfasting LDL or fasting lipid panel) between 9 and 11 years and a second screening between 18 and 21 years [18]. Other recommendations include breast-feeding, low intake of saturated fat beginning at 1 year of age, stopping exposure to tobacco, and regular physical activity. Nearly 1 in 3 children screened for high cholesterol at 9 to 11 years have borderline or high levels, thereby increasing their risk for cardiovascular disease. Statin is recommended for LDL >4.9 mmol/L, LDL >4.1 mmol/L with positive family history, or LDL >3.4 mmol/L with positive diabetes. Children with total cholesterol >5.18 mmol/L, HDL <1.17 mmol/L, and LDL >3.37 mmol/L are at risk of early coronary artery disease. More recently, the US Preventive Services Task Force statement issued the following statement: "The current evidence is insufficient to assess the balance of benefits and harms of screening for lipid disorders in children and adolescents younger than 20 years. If the lipid screening is offered as a service by practitioners, patients (and families) should understand the uncertainty about the balance of benefits and harms." [19] Obesity imposes a cluster of subclinical inflammation and endothelial dysfunction. Reduced levels of adiponectin in obesity have been shown to promote inflammatory cytokineinduced expression of cytoadhesive molecules [7]. These results are consistent with our findings of excess fat is associated with decreased adiponectin. In one study, sICAM-1 and sVCAM-1 were measured in children (mean age, 15 y) with obesity [20]. Both adhesive molecules were significantly higher in children with obesity compared to healthy children (sICAM-1: 314 ± 61 ng/mL versus. 265 ± 55 ng/mL; sVCAM-1: 514 ± 187 versus 408 ± 76 ng/mL). sICAM-1 was dependent on BMI and sVCAM-1 was dependent on total cholesterol [20]. The authors concluded "endothelial activation appears in these children" [20]. This current study supports the use of metabolic biomarkers in children with overweight problems. As previously noted, programs that endorse regular exercise and diet modifications, especially in the genetically most susceptible children are highly warranted [21][22][23][24].
Significant childhood metabolic derangements are evident in the presence of overweight problems. This finding is consistent with previous regional [1,2] and international [25,26] studies, and support current understanding of the 'childhood origin of adult diseases'. The clinical use of biomarkers of systemic inflammation, dyslipidemia, dysglycemia, liver disease, endothelial dysfunction, and fat metabolism to monitor progress of the adverse events of access body fat is highly encouraged.
In conclusion, in this study, cardiovascular risks were investigated in school children using a set of biomarkers for systemic inflammation, glycemic control, dyslipidemia, endothelial function, and hepatic cholestasis. Significant biomarkers of inflammation (hsCRP, IL-6, and TNF-alpha) and endothelial dysfunction (sICAM-1 and sVCAM-1) are present in young children with obesity. Prospective studies are necessary to investigate the usefulness of these biochemical markers for the proper clinical care of these patients.