Metabolic Syndrome in Obese Children—Clinical Prevalence and Risk Factors

The prevalence of childhood obesity is increasing worldwide. Some obese children can go on to develop metabolic syndrome (MetS), but exactly who among them remains to be determined. The aim of this study was to indicate predisposing factors for metabolic syndrome, especially those that can be modified. The study comprised 591 obese children aged 10–12 years. They were all Caucasian residents of Gdańsk, Poland, with similar demographic backgrounds. Clinical examination, anthropometry, biometric impedance analysis, blood tests (including oral glucose tolerance tests (OGTT) and insulinemia), and dietary and physical activity evaluation were conducted. The results of our study show that the risk factors for MetS or any of its components include male sex, parental (especially paternal) obesity, low body mass at birth, as well as omitting breakfast or dinner. There are few risk factors for metabolic syndrome both in obese adults and children. Some of these predictors can be modified, especially those in relation to lifestyle. Identifying and then influencing these factors may help to reduce the development of metabolic syndrome and consequently improve health and quality of life.


Background
Prevalence of obesity is rapidly increasing. According to World Health Organization (WHO) in 2016 it affected as many as 650 million people and 2 billion adults were overweight. At the same time 41 million children younger than 5yrs were overweight or obese and over 340 million children and adolescents aged 5-19yrs were overweight or obese. 1 Number of children with obesity increases and one should expect that complications of obesity in this age group will increase too.
Obesity, de ned as the excess of fat tissue, is wide spread all over the world and it affects all age groups. 2 Obesity, among other, is well known risk factor of metabolic syndrome (MetS) which comprises cardiovascular diseases (CVD), diabetes mellitus (DM), hypertension, atherosclerosis as well as other complications. 3 Although etiology of obesity is complex, genetic predisposition is permissive and, actually, interacts with environmental agents including physical activity and diet. Heritable factors seem to have 40-85% contribution in obesity's etiology. 4 Apart from genetic predisposition, other recognized constituents such as: metabolom, metabolic programming during both gestational and post gestational period can be modi ed to some extent. 4 Consequently development of obesity and its complications might be reduced. 5 Metabolic syndrome is recognized consequence of obesity and it can occur as early as in adolescence.
Certainly, not all obese children will develop all or any complications of obesity. Which one of children living with obesity are mostly prone to MetS remains to be fully elucidated.
In the systematic review of 85 studies in children, median prevalence of metabolic syndrome in all populations was 3.3% (range 0-19.2%), in overweight children it was 11.9% (range 2.8-29.3%), and in Page 3/18 obese subjects − 29.2% (range 10-66%). For non-obese, non-overweight populations the range was 0-1% [6]. Almost 90% of obese children and adolescents have at least one feature of the metabolic syndrome. 7 . On the basis of NHANES 1999 to 2002 data, the prevalence of metabolic syndrome in adolescents 12 to 19 years old ranged from 0-9.4%; variation in this estimate was the result of different criteria used to de ne metabolic syndrome. 8 In the report from BIOSHARE-EU, prevalence of metabolic syndrome in obese subjects ranged from 24-65% in females and from ≈ 43% to ≈ 78% in males and substantially exceeded the prevalence in metabolically healthy obese ones. 9 The divergences were conditioned by the country.
In the light of child's dynamic growth and maturation population of children is unique. Obesity is diagnosed on the basis of percentile charts, when BMI > = 95th centile. Moreover, according to IDF consensus -commonly used by most of the authors -metabolic syndrome may be recognized in children not younger than 10yrs old. 10 It takes some time before metabolic syndrome complicates obesity. Nevertheless the younger the child becomes obese the earlier in life he or she might suffer from its complications. 11 However one must remember that not all children suffering from obesity will develop MetS.
The aim of our study was to identify factors favoring the presence of one or all compounds of metabolic syndrome in obese children. Secondly, we analyzed the results in order to indicate which of them are modi able.

Material And Methods
This study was a part of the "6-10-14 for Health" integrated weight management program for children with overweight and obesity from Gdansk, Poland, previously described. [12][13][14] Analyzed data included children aged 10-12yrs attending the interventional program in 2011-2015. Children were screened in primary schools and if overweight or obesity was diagnosed they were invited to multidisciplinary, 12-month-long program. Patients ow is presented in Fig. 1.
All the children during rst interventional visit were examined by pediatrician (incl. weight, height, waist circumference measurement), and bioelectric impedance analysis (BIA) was performed. All children were referred to blood works within 4 weeks from the rst visit. Body mass, BMI centile, waist circumference centiles, blood pressure centiles were assessed using Polish centile charts, as recommended by WHO. [15][16][17] Medical history was taken and collected data included: body mass at birth (below 2,5 kg was assumed as hypotrophy, more than 4,0 kg -macrosomy), parents' BMI, any metabolic disease in family members, feeding pattern (original questionnaire, speci c questions regarding breakfast and supper time and quality). Lifestyle and diet were evaluated too. Waist circumference (WC) over 90th percentile and waisthip -ratio (WHR) > 0.8 for girls and > 0.9 for boys were interpreted as abnormal.
For children younger than 10 years old waist-hip-ratio (WhtR) seems to be more accurate than WC.
In our study, although all the participants were at least 10 years old, WhtR was also calculated.
Overweight was diagnosed if BMI centile was ≥ 85th and obesity was diagnosed when BMI was ≥ 95th centile on recommended centile charts. 15 Central obesity was recognized when WC was above 90th or WhtR was > = 0.5.
The results of biometric impedance analysis were assessed according to standard values. 18 Blood testes included: aminotransferases, lipid fractions, thyroid stimulating hormone, tyrosine, Hb1c, oral glucose tolerance test (OGTT) along with insulin level at the same time points and the results were compared to standard values for appropriate age and sex.
Physical activity was evaluated by means of Kash Pulse Recovery Tes t. [20][21] and classi ed as excellent, very good, good, moderate, poor and very poor.
Nutritional habits were evaluated by the dietitian on the basis of data given by children and parents.
Special attention was paid on breakfast ( rst course within 2hr after wake up) and dinner (last meal eaten 2 hr before sleep).
Metabolic Syndrome (MetS) was diagnosed according to IDF, 22 in children with WC > 90th centile and at least two out of the following metabolic features: HDL < 40 mg/dl, TG > 150 mg/dl, glycemia > 100 mg/dl and blood pressure > = 130/85 mmHg.

Statistical analysis included:
Normal distribution of continuous variables was veri ed with the Shapiro-Wilk test. Descriptive statistics are presented as the mean or median and standard deviation from the mean. Between-group comparisons were carried out using the Mann-Whitney U test and ANOVA Kruskal-Wallis test. Nonparametric tests were chosen because of the large number of signi cant Shapiro tests, which were used for normality assumption assessment. All statistical tests were 2-tailed and performed at the 5% level of signi cance. Statistical analysis was performed using Statistica 10 software (TIBCO Software Inc., Tulsa, USA 2014).
This study was accepted by the Independent Bioethics Committee for Scienti c Research at Medical University of Gdańsk. The study is registered in clinicaltrials.gov (NCT number): NCT04143074

Results
Page 5/18 591 children aged 10-12ys who entered the program and ful lled questionnaire and had blood works done were assessed in this study. None of the children had any chronic disease which could in uence investigated parameters as well as no infection on the day of examination.
The girls were younger (p = 0,031), shorter (p = 0,028), had lower WC (p < 0,0001), lower WHR (p < 0, 0001), lower WhtR (p = 0,002) and lower DBP (p = 0,044) compared to the boys. Moreover, higher BMI centile (p < 0,001) and higher fat tissue content were characteristic for girls. Elevated systolic blood pressure (SBP) was found in 10% of children, with no difference between girls and boys (Table 1).   Insulin resistance was also more common in children with MetS compared to the remaining.  Children without MetS had normal fasting glucose concentration, whereas children from Group I and IIIpathological in 27.6% cases and 9.9% cases, respectively.
Abnormal HOMA-IR values were signi cantly more common in children with metabolic syndrome (p = 0,005). Although children with MetS had more often elevated aminotransferases activity, the difference was signi cant for ALT only (p = 0.011).

Discussion
Prevalence of obesity is high worldwide, some nd it pandemic. This disease is known to be one of the so called "lifestyle diseases" and it was fathered mostly upon adolescence and adults.
However, incidence of obesity in children is growing fast and the burden of its complications must be considered not only from medical but also socioeconomic point of view.
Obesity increases the risk of other diseases of a uence, such as: hypertension, dyslipidemia, glucose intolerance at the same time being a well known risk factor of CVD and MetS. [23][24][25][26] .
Many authors reported that children with BMI over 75th centile have higher morbidity and mortality of DM2 and CVD in adulthood. [27][28][29][30] . Thus, quality and expectancy of life certainly is and will be affected by obesity.
Metabolic syndrome became an epitome of obesity's complications with high impact on human's wellbeing.
Apart from various de nitions of MetS in children, apparently not all teens with obesity develop metabolic syndrome or not even one of its components. Which of the obese children (in fact whole obese population) are especially predisposed to MetS is still not fully understood. Yet, knowing the risk factors of metabolic syndrome would allow to prevent the latter or at least minimise its prevalence and consequences.
In our study 12.9% of obese children 9-12 years old, participating in "6-10-14" for health" had metabolic syndrome diagnosed − 10.9% of girls and 14.6% of boys. These results are similar to other publications. 31 . It seems that prevalence of obesity and metabolic syndrome in children is more or less the same all over the world.
According to Abdullah et al. young age at the onset of obesity as well as time period it lasts are essential factors of MetS in adolescence. 32 Clearly, appropriate prophylaxis should be undertaken as soon as possible to stop his process..
Our main aim was to identify children who were at highest risk of developing MetS. Recognition of predisposing agents, which can be modi ed, may be crucial, since it is our deep believe that undertaking no prevention will lead to MetS eventually.
The results show that obese children with metabolic syndrome characterize with poor physical performance, bad nutrition habits and glucose intolerance with insulin resistance. Similarly to Mazur et.al., we also found that pathological WhtR predisposes to both MetS and syndrome's certain components. 33 In our study, we found that boys with low body mass at birth had more often MetS. Obviously this fact is irreversible, nevertheless it is known that metabolic programming, which begins in fetal life is going on after birth too. There is slight opportunity to in uence this process by means of "healthy" lifestyle of pregnant woman and can be achieved by education of not only doctors and health providers but also mothers. Promoting exclusively breastfeeding with recommended weaning time presents to be easy way to in uence metabolic programming and weight gain in st 2-3 years of life.
Both or either parent's obesity -especially father's -might depict genetic predisposition to excess body mass in a child, but, on the other hand, illustrates family's lifestyle. It is already known, that obese children more often skip breakfast. 34 . Contrary to some authors, we found that omitting dinner is related to metabolic syndrome or to components of metabolic syndrome too. This feeding pattern ts in modern model of life, characterized additionally with little physical activity and much sedentary time (at school, work and home). Similar observations have already been published. 35 Obviously, there is not much we can do about genetics. However, if genetic predisposition runs in the family it stands for a red ag and preventive measurements should be undertaken in order to alleviate unavoidable consequences of obesity and MetS.
Such, sound knowledge and education on energy balance (via proper diet and physical activity) as driving force against obesity should be promoted. Changes implemented for child's prevention will cover bene cially whole family.
To our knowledge this is the rst study on "factors" predisposing to metabolic syndrome" in obese children and teenagers, carried out in such a large, unanimous population (age, residency).
Taking into account genetic predisposition and environmental in uences we tried to indicate modi able risk factors The results of our study could be used as warning signals for subjects who are genetically predisposed to obesity. In these children certain preventive measures should be undertaken.

Conclusions
Among many risk factors of metabolic syndrome, beside those which are irreversible (such as body mass at birth, gender genetic predisposition etc.) there are many which are dependent on lifestyle. The latter, such as proper, increased physical activity, rational nutrition (regular 'healthy" meals) can be modi ed and such the risk of metabolic syndrome in obese children can be diminished in inexpensive way.
The education and preventive companies addressed to health providers and parents are required in order to lessen morbidity of obesity and metabolic syndrome Availability of data and materials The data that support the ndings of this study are available from [third party name] but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of "6-10-14 for Health" integrated weight management program for children with overweight and obesity from Gdansk, Poland Funding the City of Gdansk authorities. The City of Gdansk had no nancial input to the presented manuscript nor they had an impact on design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Figure 1
Patient screening and quali cation to the study -study ow.

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