Body Mass and Biochemical Indexes in Obese Children: Changes in Metabolic Syndrome Development

Introduction

In early 2000s, a certain ‘rejuvenation’ trend of some somatic diseases became especially apparent. At this, the growing negative roles are played by such factors as sedentary lifestyle, improper diet, and repeated stress resulting in dysfunction of cardiovascular, endocrine, respiratory, and digestive systems accompanied with psychological alterations. One of manifestations of this trend is increasing rate of obesity among children and adolescents [1]. In 2016, WHO estimated the worldwide number of overweight/obese children and adolescents aging 5 to 19 yr by about 340 million, while in 2019, there were about 1

million obese children at the age less than 5 yr [2, 3]. The gold standard to diagnosticate obesity in children is based on BMI and percentile charts [4]. Importantly, the overweight and obesity can be combined with metabolic syndrome (MS). There is a common view that in the pediatric population, MS is diagnosed by abdominal obesity accompanied with two of three other clinical symptoms: 1) hyperinsulinemia and/ or disturbed glucose metabolism and/or insulin resistance, 2) arterial hypertension, and 3) dyslipidemia. A special attention should be focused on obese youngsters with MS symptoms in relation to 1) increased risk of the development of type 2 diabetes mellitus and cardiovascular diseases even at the early age and 2) a high probability of future chronic diseases at mature age. The early MS detection in children employing typical parameters of carbohydrate and lipid metabolism as biochemical markers needs additional criteria to take the timely preventive or therapeutic measures prior to the development of obesity-related diseases [4, 5].

The aim of the study was to study the relationship of individual biochemical parameters with body mass index (BMI) in obese children to assess the possibility of early diagnosis of metabolic syndrome (MS).

Discussion

According to modern pathogenetic views, obesity results from chronic inflammatory process in the adipose tissue, which tends to affect hepatocytes and cardiomyocytes [8, 9]. In the following, such complications can occur as non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease [10]. Most of obese patients demonstrated hepatic abnormalities (85%) and the changes in cardiovascular system (40%). Despite the absence of significant differences between some indices in control and obese groups, the interquartile range revealed elevation of the following indices in the experimental group in comparison with the age-related norm observed in the control group: 1) total cholesterol, 4.4-5.1 mM (vs 4.4 mM); 2) triglycerides, 0.85-1.12 mM in children aging 0-9 yr (vs <0.85 mM) and 1.0-1.47 mM in adolescents aging >9 yr (vs <1.0 mM), and 3) LDL, 2.85-3.34 mM (vs <2.85 mM) [7]. Elevation of these indices resulted from significant rise of LDL and drop of HDL. Correspondingly, in experimental group AI was 1.5-fold higher than the control value (Table 1) attesting to increased intensity of lipid peroxidation in the blood plasma of obese patients. The mean value of НОМА- IR=7,8 in experimental group indicated a moderate degree of insulin resistance, although it was near to the boundary value separating moderate and high degree of this resistance (НОМА-IR>8). At this, both fasting insulin and НОМА-IR, CARO (typical indices used to assess the MS symptoms) positively correlated with BMI (Figure 1).

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Thus, the development of obesity was accompanied with aggravation of insulin resistance, which was also indicated by the flat glucose tolerance curve and hyperinsulinism. Combination of these symptoms with dyslipidemia in experimental group attested to MS (Tables 1 & 2).

Definition of obesity as chronic inflammatory process including oxidative stress as one of its pathologic elements explains acute interest in СоQ10 due to the key role, which this coenzyme plays in the performance of mitochondrial respiratory chain and taking into consideration its antioxidant function [8, 11, 12]. In this study, which predominantly enrolled the children with moderate obesity, no significant differences in plasma levels of СоQ10 relatively to the control value were observed. Literature reports the contradictory data on relations between obesity and СоQ10. Examination of adolescents aging 10-19 yr with predominantly moderate obesity and elevated total cholesterol revealed a drop in total plasma СоQ10 by 51 and 59% in boys and girls, respectively [13]. In similar examination of obese children at the same age with elevated total cholesterol and LDL, the plasma СоQ10 was low irrespective of the presence of MS symptoms [14]. However, another study of 10-13-year children with moderate obesity and elevated plasma cholesterol revealed no abnormal changes in СоQ10 level, which was normalized to cholesterol [15].

It is a common knowledge that cholesterol is the main carrier of СоQ10 in the blood plasma, where this coenzyme is the most important element of its antioxidant protection [12]. Here, the experimental patients demonstrated no expected positive correlation be-tween plasma СоQ10 and total cholesterol which was shown in control group (Figure 2).

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Figure 2: Relationship between CoQ10 and total cholesterol in control (a) and experimental (b) groups Insufficient supply of cholesterol with СоQ10 in obese children can result from a drop in СоQ10 level in the liver due to inflammation, which can be one of the causes of dyslipidemia in these patients. Actually, the development of obesity in children is accompanied with progressive rise of plasma cholesterol and drop of plasma СоQ10 [13].

NAFLD is one of the most frequent complications in children and adults resulting from inflammatory process in hepatocytes and manifested by increased levels of liver enzymes. Numerous clinical studies revealed a positive correlation between pronouncedness of NAFLD and MS symptoms [16, 17, 18]. Here, the experimental group demonstrated a significant 2-fold increases of ALT level (within the limits of reference values) and ALT/AST ratio in comparison with the control values. Elevation of this ratio in obese group correlated with manifestation of dyslipidemia reported by increased AI (Figure 3), which reflected association of inflammatory alterations in hepatocytes with up-regulation of oxidative processes; so, this elevation can be viewed as a marker of MS.

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Based on histological alterations in the liver at subcellular level indicated by accumulation of fatty acids in hepatocytes and oxidation of phospholipids in cell membranes (mitochondrial ones included), some researches consider NAFLD as a mitochondrial disease [19]. Remembering the most important role of СоQ10 in performance of mitochondrial respiratory chain and its antioxidant function, one of the aims in this study was analysis of association between the degree of hepatic inflammation assessed by liver enzymes and СоQ10 level. Here, we revealed positive correlation between ALT/AST ratio and plasma СоQ10 in the control group (Figure 4a) in contrast to experimental group, where no such correlation was observed (Figure 4 b).

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Imbalance between ALT/AST ratio and СоQ10 in obese patients can reflect the opposite changes in the levels of plasma ALT and endogenous antioxidant CoQ10 resulting from hepatic inflammation, which elevates the content of liver enzymes in blood plasma and depletes the pool (down- regulates the synthesis) of CoQ10.

The modern literature discusses probable changes in CoQ10 synthesis during NAFLD. Actually, the analysis of numerous clinical and experimental studies of this disease yielded contradictory data about CoQ10 level, which increased in the blood plasma according to some studies and dropped in plasma and hepatic tissue according to other reports, possibly reflecting various stages of pathological process in the liver and depletion of CoQ10 pool [20].

Analysis of all examinees in control and experimental groups established the strong positive correlations between BMI and ALT and between BMI and ALT/AST ratio (Figure 5).

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Our results agree with available data on association between liver enzymes (predominantly, ALT) and MS manifestations. The extensive study of adolescents aging 9-17 yr (n=7271) also established a positive correlation between BMI and ALT, which was especially strong at BMI>20.5 kg/ m2: elevation of BMI by 1 kg/m2 was accompanied by 2.71 U/l increment in ALT [21]. Another study of adolescents aging 10-19 yr (n=808) revealed (in girls, predominantly) the positive correlations between MS manifestations and ALT as well as between such manifestations and low AST/ ALT ratio [22]. Similar results were obtained in other studies, which revealed positive correlations between 1) ALT, on the one hand, and MS severity by Z-Score as well as BMI, on the other hand [23]; 2) ALT, on the one hand, and body weight/ height ratio as well as (to a lesser degree) BMI and waist circumference, on the other [24]; 3) ALT, on the one hand, and BMI, body weight/height ratio, percentage of fat tissue, and waist circumference, on the other hand [25]; and 4) ALT and insulin resistance index HOMA-IR [26, 27].

In the last decade, investigators focused on diagnostic significance of ALT/AST ratio as an index of insulin resistance in obesity [28, 29]. In a study conducted in Japan on a population of adults with normal weight and obesity, diagnostic criteria for the ALT / AST ratio were established for assessing insulin resistance: in non-obese individuals above 0.82 and above 1.02 for obese patients. In a population based Chinese study in patients with different types of obesity, there was a direct correlation between the ratio of ALT / AST and HOMA-IR. At the same time, the ALT / AST values (0.78-0.8) were slightly lower than in the Japanese study. A comprehensive study of MS patients (n=2585) established the positive correlation between ALT/AST ratio (at the values ≥1) and MS manifestations irrespectively of sex [30]. Another study analyzed the reverse ratio AST/ALT, which also correlated with MS [22].

It should be noted that at the moment there have been no similar attempts to determine the reference values of the ALT/AST ratio as a criterion of insulin resistance for children and adolescents in the literature. Our study on a small sample revealed for obese children with signs of MS the ALT/ AST ratio equal to 1.0 (0.5-1.6), in contrast to children with normal weight, in whom this ratio is 0.6 (0,3-1,1); to clarify the ALT/AST reference values, an analysis of data from a larger number of patients is required.

Thus, the main signs of MS were found in obese children, and the progression of obesity is associated with an increase in MS signs. Association between obesity and hepatic pathology is reflected by correlations between BMI and ALT and between BMI and ALT/AST ratio established here for all examinees in the combined group of control and obese examinees. Importantly, one of MS manifestations (dyslipidemia assessed by AI) increased in parallel with ALT/AST ratio. Consequently, the parameter of liver enzymes ALT/AST ratio, which are associated both with BMI and AI (Figure 6), surely can play the role of early marker indicating the development of MS in obesity.

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The correlations between endogenous antioxidant CoQ10 and total cholesterol, as well as between CoQ10 and the liver enzymes in children with normal body weight attest to balanced control of antioxidant protection of lipoproteins and normal function of the liver. The progress of obesity and the development of inflammation in hepatocytes are accompanied by elevation of plasma levels of liver enzymes and insufficient antioxidant protection reflecting implication of oxidative stress in obesity pathogenesis (Fig. 6). The disturbances in relations between CoQ10 and ALT/AST as well as between CoQ10 and total cholesterol, which are considered as possible reasons of dyslipidemia in obese children and adolescents, can be advanced as indications for treatment with membrane-stabilizing and antioxidant agents.

Author Contributions

Conceptualization, O.V.P, E.A.G. and E.I.K.; Methodology, E.I.K., I.L.A.; Software, O.V.P.; Validation, E.I.K., E.A.G..; Formal Analysis, O.V.P.; Investigation, A.V.D., O.J.K.; Resources, E.I.K. and I.L.A.; Data Curation, E.A.G.; Writing – Original Draft Preparation, O.V.P., E.A.G. and E.I.K.; Writing – Review & Editing, E.A.G. and E.I.K.; Visualization, O.V.P. and E.I.K.; Supervision, E.I.K., I.L.A. and O.S.M.; Project Administration, E.I.K., O.S.M. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Smolensk State Medical University (protocol No 17, November 25, 2017).

Informed Consent Statement: All the parents of the participating infants signed a written in-formed consent.

Acknowledgments: We express our gratitude to the participating children and their families for their consent. We appreciate the statistic aid of Dr. Alexander Berdalin (Federal State Budgetary Institution Federal Center of Brain Research and neurotechnologies of the Federal Medical Biological Agency, Russia). We appreciate the scientific advice from Dr. Sergey V. Revenko (Department of Institute of Experimental Cardiology, Russian Cardiology Research and Production Complex, Russia).

Conflicts of Interest

The authors declare no conflict of interest.