To test the hypothesis that lipid intake is associated with triglycerides to HDL-cholesterol ratio (TG/HDL-cholesterol), a predictor of the development of cardiovascular disease, in obese children and adolescents, independently from the level of overweight, insulin resistance, blood pressure, and non-alcoholic fatty liver disease (NAFLD).
One hundred and eighty non-diabetic obese children/adolescents (age range 6–16 years) were enrolled. Diet (3-day weighed dietary record), physical and biochemical parameters and liver ultrasonography were measured. The impact of lipid intake on TG/HDL-cholesterol ratio >2.2 was measured by regression models, adjusting for covariates (age, gender, height, weight, systolic and diastolic blood pressure, NAFLD positivity, HOMA-IR, and total energy intake).
Independently from covariates, children consuming a diet with a fat content higher than 35% of total energy had a significantly higher chance [OR = 3.333 (95% CI: 1.113–9.979), P = 0.031] to have a TG/HDL-cholesterol >2.2 than children consuming less than 35% of fat. Moreover, if saturated fatty acids (SFA) intake was higher than 13% of total energy, children had a significantly higher chance [OR = 4.804 (95% CI: 1.312–17.593), P = 0.018] to have a TG/HDL-cholesterol >2.2 than children consuming less than 13% of SFA in their diet.
High fat intake, especially SFA intake, is associated with TG/HDL-cholesterol levels of obese children and adolescents, independently from other cardiovascular risk co-factors. Further intervention studies will contribute to clarify the potential role of changes in the composition and amount of fat in the diet of obese children and adolescents, on their cardiovascular risk factors.
The dramatic epidemiological impact of obesity has caused a progressive anticipation of the onset of diabetes, hypertension, and cardiovascular disease also in youth and adolescence [1, 2]. All these obesity-associated morbidities promote cardiovascular disease, leading to a reduction of life expectancy . At the same time, preventive and therapeutic interventions for obesity have not shown encouraging results, especially in the long term . On these bases, early recognition and a prompt intervention to reduce cardiovascular and metabolic risk factors in obese children and adolescents are recommended [5, 6].
Diet has been identified as a crucial component of prevention of cardiovascular disease. In fact, excess of fat mass accumulation is the consequence of a chronic excess of energy intake in respect to energy requirement. In addition to the energy content of the diet, macronutrient composition has been suggested to be involved in the regulation of food intake and its associated metabolic pathways [7, 8]. In particular, in both children and adults, high-fat diets have been associated with obesity and other non-communicable chronic diseases [9, 10]. The risk of developing cardiovascular disease could, in fact, be increased by a high-fat diet, not only for the associated increase of a pro-atherogenic post-prandial lipid profile, but also for the effects of inflammation, insulin sensitivity, and blood pressure [11,12,13]. Most of these effects are associated with the quality of fatty acid intake: in general, trans fatty acid intake was associated with the risk of coronary heart disease (CHD), whereas the role of other fatty acids is still controversial, although a protective effect was primarily associated with unsaturated fatty acids intake, both monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). Moreover, the reduction of SFA intake in children, mostly when they were replaced with PUFA, has been demonstrated to lead to an improvement on LDL-cholesterol and DBP without a negative effect on growth and development [14,15,16].
The cause–effect relationship between diet and cardiovascular disease has to be analyzed with the disease itself as the endpoint. This is possible in adulthood but not in childhood, when the available surrogate endpoints are some cardiovascular risk factors associated with the future onset of the clinical disease. Nevertheless, children have the advantage over adults of short-term exposure to obesity and associated morbidity and this offers the chance to reduce the impact of potential confounders in the analysis. Dyslipidemia, including hyper-LDL cholesterolemia, hypo-HDL cholesterolemia and hyper-triglyceridemia, is a major risk factor of cardiovascular disease . The triglyceride/HDL-cholesterol ratio (TG/HDL-cholesterol) has been proposed as a good predictor of cardiovascular disease. It has been shown to reflect small dense LDL particles, more atherogenic than larger buoyant LDL particles, and has been reported to be an independent risk factor for coronary heart disease [18,19,20]. High levels of TG/HDL-cholesterol were associated with increased cardiovascular risk, metabolic syndrome, and increased arterial stiffness [21, 22]. Moreover, TG/HDL-cholesterol has been shown to be a better predictor of cardiovascular events rate, and LDL particle size than other commonly used parameter as the non-HDL cholesterol [23, 24]. Furthermore, in a cohort of obese Italian children, a level of TG/HDL-cholesterol >2.2 has been shown to be a better predictor of cardiometabolic risk factors and preclinical signs of organ damage than non-HDL cholesterol . Finally, a trial led on male adults has shown that a high level of TG/HDL-cholesterol could predict mortality, based on cardiovascular and coronary diseases . Other factors than dyslipidemia, such as insulin resistance, high blood pressure, and non-alcoholic fatty liver disease (NAFLD), contribute to cardiovascular risk in obese people [27,28,29]. Therefore, already in childhood, several factors contribute to the cardiovascular disease risk and the specific contribution of lipid intake on this risk is, to the best of our knowledge, unknown in obese children.
Therefore, the aim of this study was to test the hypothesis that lipid intake is associated with TG/HDL-cholesterol in obese children and adolescents, independently from other cardiovascular risk cofactors, i.e., insulin resistance, blood pressure, and NAFLD.
Materials and methods
One hundred and eighty obese children and adolescents were enrolled in the study. They were consecutively recruited at the moment of their first access to the Obesity Clinic of the Regional Center for Pediatric Diabetes in Verona (Italy) from January the 1st 2018 and December the 31st 2019. Inclusion criteria were: age between 6–16 years, European ancestry and body mass index (BMI) greater than the age-specific and sex-specific BMI cutoff for obesity (using the World Health Organization BMI cutoffs as reference) . Exclusion criteria were: secondary obesity, known chronic hepatic diseases, congenital or chronic diseases, malformations, and ongoing drug therapies. The consent of the parents and assent of the child below the age of 10 years was obtained. The protocol was approved by the Institutional Ethics Committee of Verona (Italy).
Anthropometric and clinical data
At recruitment, anthropometric and clinical data were collected. Weight was measured to the nearest 0.5 kg on standard physician’s beam scales, with the child wearing only underwear and no shoes. Height was measured to the nearest 0.5 cm on a stadiometer without shoes, with the child’s heels, buttocks, shoulders, and head against the vertical wall with line of sight aligned horizontally. BMI was calculated as body weight (in kilograms) divided by body height (in meters) squared. BMI values were standardized (BMI z-score) using age-specific and sex-specific median, standard deviation and power of the box-cox transformation (least mean square method) based on World Health Organization norms . Waist circumference was measured as the minimal circumference measurable on the horizontal plane between the lowest portion of the rib cage and the iliac crest. Waist-to-height ratio (WHtR) was calculated and used as an index of body fat distribution, as previously described . Puberty was assessed by Tanner stage, categorizing subjects into: prepubertal (Tanner stage: 1), pubertal (Tanner stage: 2–4), and post-pubertal (Tanner stage: 5). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded three times on the right arm in mmHg using a manual sphygmomanometer and a cuff appropriate for the children’s age; the average of the three blood pressure values was used for analysis .
Venous blood samples were collected in the morning after an overnight fast of at least 8 h. Serum liver enzymes [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and triglycerides (TG), total cholesterol and high-density lipoprotein cholesterol (HDL-cholesterol), were measured using standard laboratory procedures at the central Laboratory of the university hospital. The laboratory is part of the Italian National Health System, is certified according to International Standards ISO 9000 (www.iso9000.it/) and undergo semiannual quality controls and interlab comparisons .
Low-density-lipoprotein cholesterol (LDL-cholesterol) was computed using the Friedewald equation [LDL-cholesterol = total cholesterol – (HDL-cholesterol + TG/5)]. Non-HDL cholesterol was calculated as total cholesterol − HDL-cholesterol. Triglycerides and HDL-cholesterol ratio was calculated. Plasma glucose was measured with glucose oxidase method. Insulin and levels were analyzed by enzyme-immunoassay (Mercodia AB, Sweden). Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated as [insulin (mU/L) · glucose (mg/dL)]/405 and used as a fasting biomarker of insulin resistance .
A 3-day weighed dietary record of food and fluid and the amounts consumed was kept by the children/adolescents and their parents . Food was weighed on an electronic scale by the parents. Parents reported the total food intake of their children at meals, and the children/adolescents were encouraged to report all the foods, including snacks, consumed outside home. Kitchen supervisory staff recorded the food consumed at school. Each family recorded the foods and beverages consumed in a logbook provided during the hospital visit. A complete description of how the food was prepared and recipes for composite dishes were also requested. Written instructions with examples of completed forms were also provided. A dietician checked logbooks for completeness and accuracy with each family on the day after the recording. Pictures of different items were shown along with cups, glasses, spoons, and food shapes of different portion sizes, as an aid in determining the amount of food and drinks consumed outside home. Food and drink energy values were calculated from tables of food comparison set out by the National Institute of Nutrition with the use of a computerized database and analysis program (Metadieta, Meteda, S. Benedetto del Tronto, Italy) .
Hepatic steatosis was diagnosed at recruitment, according to ultrasonographic characteristics, including diffuse hyper-echogenicity of the liver relative to the kidneys, ultrasonography beam attenuation, or poor visualization of the intrahepatic vessel borders and diaphragm . Liver ultrasonography has a good sensitivity and specificity for detecting moderate and severe hepatic steatosis, and traditionally its sensitivity is thought to be poor when >20–30% of hepatocytes are steatotic. In this study, a semi-quantitative ultrasonographic scoring of the degree of hepatic steatosis was not available.
Patients baseline characteristics are reported as mean and standard deviation (SD) or median [IQR], according to their Gaussian or non-Gaussian distribution, respectively. Student’s t-test or Mann–Whitney test, as appropriate, were used to compare physical characteristics, biochemical measurements, and dietary variables between patients stratified by gender and TG/HDL-cholesterol ratio. Quartiles of lipid, SFA, MUFA, and carbohydrate intake distribution were also calculated. The cut-off value between the third and the fourth quartile of total lipid (35% of total energy), SFA (13% of total energy), and MUFA (17.5% of total energy) intake were chosen as indicator of high lipid intake, respectively.
The potential role of high lipid intake (fourth quartiles; independent variables) in predicting TG/HDL-cholesterol (TG/HDL-cholesterol >2.2 = 1; dependent variable) was tested by logistic regression analyses (block models); covariates included in the regression models [age, gender, height, BMI z-score, blood pressure, total energy intake, HOMA-IR, NAFLD (yes = 1)] were selected on the basis of the univariate comparisons between TG/HDL-cholesterol categories. Due to collinearity between lipid and carbohydrate intake (r = −0.73, P < 0.001), the latter was not included in the model. Data were analyzed using SPSS version 20.0 software (SPSS, Chicago, IL, USA). A P value of <0.05 was considered to be statistically significant.
Our sample of 180 children had an 80% power to detect, with an alpha-error of 0.05, a positive OR of association of at least 2.44 between a fat intake >35% and TG/HDL > 2.2, adjusting for age, gender, BMI z-score, height, SBP, DBP, HOMA-IR, NAFLD status, and EI. The sensitivity calculation was performed by G-Power 126.96.36.199 software (www.gpowe.hhu.de).
The total sample included 90 males and 90 females. Their median [IQR] age were 11.8 (10.4–13.2) and 12.0 (9.7–13.3) years, respectively (range: 6–16 years). Physical characteristics (age, height, weight, BMI, BMI z-score, WC, WHtR, SBP, DBP, and pubertal stage), prevalence of NAFLD and biochemical variables (fasting blood glucose and fasting insulin, total, HDL-cholesterol, LDL-cholesterol, non-HDL-cholesterol, TG, TG/HDL-cholesterol, ALT, and AST) of the studied sample are shown in Table 1, stratified by gender. Males had significantly (all P < 0.02) higher waist circumference, BMI z-score, systolic blood pressure, ALT, AST, and NAFLD positivity than females. Puberty distribution was statistically different between genders, with females having a more advanced pubertal development then males.
Energy and nutrient intake were not statistically different between genders, but males had significantly (P < 0.04) higher intake of protein expressed as g/day (Table 2).
Percent of total lipid intake and TG/HDL-cholesterol were significantly correlated (Rho 0.21, P = 0.007).
Comparison between groups with low and high TG/HDL-cholesterol
Weight, height, BMI, SBP and DBP, NAFLD positivity, TG, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, fasting plasma insulin and HOMA-IR were significantly (all P < 0.03) higher in children with a TG/HDL-cholesterol >2.2 than in those with TG/HDL-cholesterol ≤2.2. HDL-cholesterol was significantly (P < 0.001) lower in the former than in the latter group (Table 1).
Children with TG/HDL-cholesterol >2.2 had (all P < 0.02) higher protein (g/day), lipid (both as percentage of total energy and g/day), SFA, and MUFA (both as percentage of total energy and g/day) and cholesterol but lower total carbohydrate (percentage of total energy) than those with TG/HDL-cholesterol ≤2.2. All the other variables were not significantly different between the two groups (Table 2).
The main contributors of SFA and MUFA in the children’s diet were dairy products, processed meats, high-fat snacks and fast-food meals.
Regression analysis showed that, independently from covariates (age, gender, BMI z-score, height, SBP, DBP, NAFLD positivity, HOMA-IR, and total energy intake), children consuming a diet with more than 35% of total energy covered by fat had a significantly higher chance [OR = 3.333 (95% CI 1.113–9.979), P = 0.031] to have a TG/HDL-cholesterol >2.2 than children consuming less than 35% of fat in their diet (Table 3).
A second model including also MUFA and total cholesterol among independent variables, showed that children consuming a diet with more than 13% of total energy covered by SFA had a significantly higher chance [OR = 4.804 (95% CI: 1.312–17.593), P = 0.018] to have a TG/HDL-cholesterol >2.2 than children consuming less than 13% of saturated fatty acids in their diet (Table 4).
The main result of this study is that, in obese children/adolescents, a high intake of total lipid or saturated fatty acids are associated with TG/HDL-cholesterol, i.e., a cardiovascular risk factor index, independently from other cardiovascular risk co-factors.
Several studies, conducted in adults, showed that a high fat intake was associated with insulin resistance, glucose intolerance and type 2 diabetes, independently from the level of adiposity [12, 38]. Moreover, a high lipid intake contributes to NAFLD, which further increases insulin resistance . Insulin-resistance is an atherogenic co-factor: reduces capture of glucose by skeletal muscle, increases lipogenesis with increased release of glycerol and free fatty acids into the circulation, which in turn contributes to a greater oxidation of LDL-cholesterol, increases circulating triglycerides and decreases HDL-cholesterol . All these are factors that, associated with the acceleration of the processes, take to the formation of the atherosclerotic plaque and a greater cardiovascular disease risk.
Nevertheless, the results of our study showed that, independently from the level of overweight, insulin resistance and NAFLD, high fat intake contributes to explain TG/HDL-cholesterol inter-individual variability, suggesting that other factors may be involved in the process. One of these factors may be the low-grade inflammation, previously reported in obese children . In fact, available evidence suggests that a high fat intake promotes a proinflammatory state, by increasing gut permeability .
Interestingly, the cut-off of total lipid intake used in this study was occasionally coincident with the highest value of the range of fat intake suggested for children older than 4 years, and adolescents in the Italian Recommended dietary intakes .
A second result of this study is the association between the fat composition of the diet and TG/HDL-cholesterol, independently from potential confounding factors. In particular, a high SFA intake was associated with high TG/HDL-cholesterol values. Even though the debate on the role of SFA in the development of cardiovascular disease is still controversial, what emerges from a wide number of studies is that having a diet with high consumption of SFA can lead to a change in the lipid profile and an increase of cardiovascular risk [44,45,46]. The importance of replacing them with unsaturated fatty acids, both MUFA and PUFA, has likewise been shown. Consumption of these unsaturated fatty acids, together with a reduction of SFA seems to take towards improvement of lipid profile, and consequently towards reduction of the risk of beginning or mortality for cardiovascular disease [47, 48]. In addition, it has been noted that reducing the consumption of SFA in children improves the lipid profile with reduction of the total cholesterol and LDL-cholesterol as well as diastolic arterial blood pressure, without having though negative effects on growth and development . Replacing SFA with MUFA and PUFA has besides shown improvement in cardiovascular risk also as a consequence of the reduction of the number of microparticles in circulation, and thus to a probable improvement of endothelial repair and to increase of endothelial progenitor cells, all elements that take to the reduction of cardiovascular risk . However, in this study the association between TG/HDL-cholesterol with SFA was not affected by high MUFA intake, suggesting that a reduction of SFA might be more effective than increasing MUFA in reducing the cardiovascular risk factors. Therefore, on the basis of the evidence reported above, keeping the quantity of SFA in a diet within the recommended dietary intake suggested rates, i.e., less than 10% of total energy, seems to be reasonable in order to limit cardiovascular risk in obese children and adolescents .
Potential limitations of this study are: (i) ethnicity: only children with European ancestry have been recruited, therefore, it is not possible to generalize these results to children of other ethnic groups; (ii) study design: the cross-sectional design of the study allows to point out just associations between variables and not cause–effect relationships, that could be assessed by future longitudinal studies; (iii) physical activity: physical activity affects energy balance and nutrient metabolism as well as cardiovascular risk factors. Unfortunately, no data on the level of physical activity were available in this population; (iv) assessment of liver content: unfortunately, in this study, a semiquantitative ultrasonographic scoring of the degree of hepatic steatosis was not available and a convenient sampling was used.
This study has also some strengths: (i) the sample set, including obese children and adolescents who have much lower obesity associated comorbidities than obese adults. This allows to explore relationships between variables avoiding potential confounders due to comorbidity; (ii) the measurement of nutritional, anthropometric, biochemical data, and NAFLD positivity in a relatively high number of children and adolescents, by the same operators in the same clinical center; (iii) the inclusion of the main cardiovascular risk cofactors in the analysis of the association between TG/HDL-cholesterol and lipid intake.
In conclusion, the results of this study suggest that a high fat diet and especially a high SFA diet is associated with a high TG/HDL-cholesterol, i.e., a predictor of cardiovascular disease, independently from other cardiovascular risk cofactors. Further intervention studies, using diet with low SFA and adequate fat intake, conducted in obese children and adolescents will contribute to clarify the potential role of changes in the composition and amount of fat in the diet, on their cardiovascular risk factors.
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We are sincerely indebted to the children and adolescents who participated in the study and to their families. We thank the dedicated staff of the Pediatric Diabetes and Metabolic Disorders Unit of the University Hospital in Verona for their support during the clinical study.
This research was funded by grants (FURMAF2019) from the University of Verona to CM.
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The authors declare that they have no conflict of interest.
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Maffeis, C., Cendon, M., Tomasselli, F. et al. Lipid and saturated fatty acids intake and cardiovascular risk factors of obese children and adolescents. Eur J Clin Nutr 75, 1109–1117 (2021). https://doi.org/10.1038/s41430-020-00822-0