Alanine aminotransferase cutoffs for the pediatric fatty liver disease: Major impact of the reference population.

OBJECTIVES AND STUDY: The often-recommended alanine aminotransferase (ALT) cutoffs (girls 21 U/l, boys 25 U/l) are based on a NHANES cohort. A novel concept of metabolic dysfunction associated steatotic liver disease (MASLD) emphasizes the role of ALT. We tested the prevalence of increased ALT and MASLD in children with overweight or obesity applying population-based and NHANES-based cut-offs. METHODS: Six- to seventeen-year-old children underwent data collection in a prospective Physical Activity and Nutrition in Children (PANIC) study. ALT 95th percentiles were calculated from 1167 separate measurements considering various confounders. Test cohort comprised 1044 children with overweight/obesity. RESULTS: ALT values increased at puberty onset (p = 0.031) and correlated negatively with age in girls (r = -0.222, p < 0.001). Particularly overall and central obesity increased ALT, whereas underweight or metabolic abnormalities had smaller effect. After applying the tested exclusions, the age-related ALT 95th percentiles were 24-29 U/l for girls and 29-32 U/l for boys. In 6-8-year-old children with overweight/obesity, the prevalence of increased ALT and MASLD were 21.6% and 2.4% with age-specific PANIC cutoffs. In older children, when NHANES-based cutoffs were used, there was a trend for higher prevalence of increased ALT and MASLD in all age groups for both sexes, reaching significance for increased ALT in 12-16-year-old boys (NHANES 63.5%, 95% confidence interval [CI]: 56.4%-70.0% vs. PANIC 47.1%, 95% CI [40.1%-54.2%]) and 9-11-year-old girls (60.0% [49.4%-69.8%] vs. 31.8% [22.8%-42.3%]), respectively. Increased ALT/MASLD were more common in boys than in girls, and in boys these increased with age, whereas in girls these peaked at age 9-12 years. CONCLUSION: A reference population impacts on the prevalence of increased ALT and MASLD. Considering this help optimizing screening while avoiding unnecessary investigations and surveillance. The prospective part of this study is registered in clinicaltrials.gov; identifier NCT01803776.

Cross-sectional associations between cardiorespiratory fitness and NMR-derived metabolic biomarkers in children - the PANIC study.

Objective: Cardiorespiratory fitness has been inversely associated with cardiovascular risk across the lifespan. Some studies in adults suggest that higher cardiorespiratory fitness is associated with cardioprotective metabolite profile, but the evidence in children is lacking. Therefore, we investigated the cross-sectional association of cardiorespiratory fitness with serum nuclear magnetic resonance derived metabolic biomarkers in children. Methods: A population sample of 450 children aged 6-8 years was examined. Cardiorespiratory fitness was assessed by a maximal exercise test on a cycle ergometer and quantified as maximal power output normalised for lean body mass assessed by dual-energy X-ray absorbtiometry. Serum metabolites were assessed using a high throughput nuclear magnetic resonance platform. The data were analysed using linear regression analyses adjusted for age and sex and subsequently for body fat percentage (BF%) assessed by DXA. Results: Cardiorespiratory fitness was directly associated with high density lipoprotein (HDL) cholesterol (ß=0.138, 95% CI=0.042 to 0.135, p=0.005), average HDL particle diameter (ß=0.102, 95% CI=0.004 to 0.199, p=0.041), and the concentrations of extra-large HDL particles (ß=0.103, 95% CI=0.006 to 0.201, p=0.038), large HDL particles (ß=0.122, 95% CI=0.025 to 0.220, p=0.014), and medium HDL particles (ß=0.143, 95% CI=0.047 to 0.239, p=0.004) after adjustment for age and sex. Higher cardiorespiratory fitness was also associated with higher concentrations of ApoA1 (ß=0.145, 95% CI=0.047 to 0.242, p=0.003), glutamine (ß=0.161, 95% CI=0.064 to 0.257, p=0.001), and phenylalanine (ß=0.187, 95% CI=0.091 to 0.283, p<0.001). However, only the direct associations of cardiorespiratory fitness with the concentrations of HDL cholesterol (ß=0.114, 95% CI=0.018 to 0.210, p=0.021), medium HDL particles (ß=0.126, 95% CI=0.030 to 0.223, p=0.010), ApoA1 (ß=0.126, 95% CI=0.030 to 0.223, p=0.011), glutamine (ß=0.147, 95% CI=0.050 to 0.224, p=0.003), and phenylalanine (ß=0.217, 95% CI=0.122 to 0.311, p<0.001) remained statistically significant after further adjustment for BF%. Conclusions: Higher cardiorespiratory fitness was associated with a cardioprotective biomarker profile in children. Most associations were independent of BF% suggesting that the differences in serum metabolites between children are driven by cardiorespiratory fitness and not adiposity.

Is low cardiorespiratory fitness a feature of metabolic syndrome in children and adults?

OBJECTIVES: Cardiorespiratory fitness has been inversely associated with risk of cardiometabolic diseases. However, there are no studies comparing the independent associations of cardiorespiratory fitness scaled by body size and composition using different approaches with cardiometabolic risk factors between children and adults. We therefore investigated these associations in children and adults using same measures for cardiorespiratory fitness and cardiometabolic risk factors. DESIGN: Cross-sectional. METHODS: A total of 352 children (47.2 % girls) and 572 men were included in the study. Peak oxygen uptake (V̇O2peak) was measured during a maximal exercise test on a cycle ergometer and was scaled by total body mass, total fat free mass, and allometrically modelled body mass, fat free mass, and stature. Insulin, glucose, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were assessed from fasting blood samples and systolic blood pressure and diastolic blood pressure were measured. Homeostatic model assessment for insulin resistance and continuous metabolic risk score were computed. RESULTS: V̇O2peak scaled by body mass was inversely associated with insulin, homeostatic model assessment for insulin resistance, triglycerides, diastolic blood pressure, the cardiometabolic risk score and the number of cardiometabolic risk factors in children and adults. However, these associations attenuated remarkably when V̇O2peak was scaled by total fat free mass or allometrically modelled body mass, fat free mass, or stature. V̇O2peak was consistently and positively associated with high-density lipoprotein cholesterol in children and adults irrespective of the scaling approach. CONCLUSIONS: The inverse associations of cardiorespiratory fitness with cardiometabolic risk factors among children and adults attenuated remarkably when body size and composition were appropriately controlled for. However, the positive association between cardiorespiratory fitness and high-density lipoprotein cholesterol was consistent irrespective of the scaling approach.

The effects of an 8-year individualised lifestyle intervention on food consumption and nutrient intake from childhood to adolescence: the PANIC Study.

We aimed to investigate the effects of a long-term, individualised, family-based lifestyle intervention on food consumption and nutrient intake from childhood to adolescence. We conducted an 8-year diet and physical activity intervention study in a population sample of children aged 7-9 years at baseline in 2007-2009. We allocated the participants to the intervention group (n 306) and the control group (n 198). We assessed diet by 4-d food records at baseline, 2-year follow-up and 8-year follow-up. We analysed the data using linear mixed-effects models adjusted for age at baseline and sex. The consumption of vegetables and vegetable oil-based spreads (fat ≥60 %) increased in the intervention group but did not change in the control group (P < 0⋅001 for time×group interaction). The consumption of fruits and berries increased in the intervention group but decreased in the control group (P = 0⋅036). The consumption of high-fat cheese (P = 0⋅029), butter-based spreads (P = 0⋅001) and salty snacks (P = 0⋅028) increased less, and the consumption of low-fat cheese (P = 0⋅004) increased more in the intervention group than in the control group. Saturated fat intake (P = 0⋅001) increased less, and the intakes of dietary fibre (P = 0⋅003), vitamin D (P = 0⋅042) and vitamin E (P = 0⋅027) increased more in the intervention group than in the control group. The intakes of vitamin C (P < 0⋅001) and folate (P = 0⋅001) increased in the intervention group but decreased in the control group. To conclude, individualised, family-based lifestyle intervention altered food choices towards more recommended diet and resulted in enhanced diet quality from childhood to adolescence.

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

PURPOSE: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects. METHODS: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models. RESULTS: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (ß) = - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (ß = - 0.0203, + 47% change in ß) and butter-based spreads (ß = - 0.0294, + 30% change in ß), moderate-to-vigorous physical activity (ß = - 0.0268, + 30% change in ß), light physical activity (ß = - 0.0274, + 29% change in ß) and sedentary time (ß = - 0.0270, + 30% change in ß). The intervention had no effect on other plasma lipids. CONCLUSION: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity. CLINICAL TRIAL REGISTRY NUMBER: NCT01803776, ClinicalTrials.gov.

A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.

AIMS/HYPOTHESIS: We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children. METHODS: We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects. RESULTS: Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient ß for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (ß for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR. CONCLUSIONS/INTERPRETATION: The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition. TRIAL REGISTRATION: ClinicalTrials.gov NCT01803776 Graphical abstract.

Child-related and parental predictors for thelarche in a general population of girls: the PANIC study.

BACKGROUND: Obesity has been associated with earlier thelarche, whereas other predictors for it remain unclear. METHODS: We studied child-related and parental predictors for earlier thelarche in 195 girls aged 6-8 years followed up for 2 years. A physician evaluated breast development by inspection and palpation. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry, diet by food records, and physical activity and sedentary time by body movement and heart rate monitors. Parental education, smoking, and alcohol consumption and household income were assessed by questionnaires. Gestational age, birth weight, and maternal prepregnancy BMI were obtained from hospital registers. Predictors for thelarche were examined using logistic regression analysis adjusted for age and follow-up time. RESULTS: The incidence of thelarche during 2 years increased by 11% (OR 1.11, CI 1.06-1.17, p < 0.001) for 1 unit increase in baseline BF%. Girls with a smoking parent had a 2.64 (95% CI 1.21-5.77, p = 0.015) times higher incidence of thelarche than other girls. The associations of lower parental education and higher maternal prepregnancy BMI with the higher incidence of thelarche were largely explained by BF%. Other possible predictors were not associated with thelarche. CONCLUSIONS: Higher BF% and exposure to tobacco smoke are independent predictors for earlier thelarche.

Abdominal adiposity and cardiometabolic risk factors in children and adolescents: a Mendelian randomization analysis.

BACKGROUND: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear. OBJECTIVE: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization. METHODS: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y. RESULTS: WHRadjBMI GRS was associated with higher WHRadjBMI (ß = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: ß = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: ß = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: ß = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (ß = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (ß = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal. CONCLUSIONS: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Adiposity Criteria in Assessing Increased Cardiometabolic Risk in Prepubertal Children.

Objective: Adiposity induces the clustering of cardiometabolic risk factors, and pediatric adiposity is a better indicator for adulthood cardiometabolic diseases than pediatric metabolic syndrome. However, the observed prevalence of pediatric adiposity depends on the methods and cut-points used. Therefore, we aimed to define diagnostic criteria for adiposity which enable more valid identification of prepubertal children at increased cardiometabolic risk. Methods: The participants were 470 prepubertal children (249 boys) aged 6-8 years. The measures of adiposity included body mass index-standard deviation score (BMI-SDS), waist-to-height ratio (WHtR) and body fat percentage (BF%) assessed by bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA). Criteria for adiposity were determined by increased cardiometabolic risk. Cardiometabolic risk factors which correlated with BF% assessed by DXA in the upper but not lower half of BF% (serum insulin and plasma high-density lipoprotein cholesterol, triglycerides, gamma-glutamyl transferase, high-sensitivity C-reactive protein and uric acid) were included in the cardiometabolic risk score (CMS). We computed receiver operating characteristics curves for the measures of adiposity using the ≥90th percentile of CMS as a measure of increased cardiometabolic risk, and local regression curves were graphed to demonstrate the associations of the measures of adiposity with CMS. Results: In girls, WHtR of 0.445 (area under curve 0.778, its 95% confidence interval 0.65-0.91, sensitivity and specificity 0.73) and BF% of 19.5% assessed by BIA (0.801, 0.70-0.90, 0.73) were the best overall criteria for increased cardiometabolic risk. In boys, BMI-SDS of 0.48 (0.833, 0.75-0.92, 0.76) was the best overall criterion for increased cardiometabolic risk. While local regression curves in girls showed that WHtR of 0.445 corresponds well to a point where CMS began to increase, in boys local regression curves suggest that CMS began to increase even at a lower level of BMI-SDS than 0.48. Moreover, the diagnostic ability of the measures of adiposity to exclude increased cardiometabolic risk was poorer than the ability to detect it. Conclusions: In general, the measures of adiposity have sufficient diagnostic accuracy to be utilized as the screening tool for increased cardiometabolic risk. The observed cut-points for adiposity were lower than the traditional cut-points for adiposity.

Genetic predisposition to higher body fat yet lower cardiometabolic risk in children and adolescents.

BACKGROUND: Most obese children show cardiometabolic impairments, such as insulin resistance, dyslipidemia, and hypertension. Yet some obese children retain a normal cardiometabolic profile. The mechanisms underlying this variability remain largely unknown. We examined whether genetic loci associated with increased insulin sensitivity and relatively higher fat storage on the hip than on the waist in adults are associated with a normal cardiometabolic profile despite higher adiposity in children. METHODS: We constructed a genetic score using variants previously linked to increased insulin sensitivity and/or decreased waist-hip ratio adjusted for body mass index (BMI), and examined the associations of this genetic score with adiposity and cardiometabolic impairments in a meta-analysis of six cohorts, including 7391 European children aged 3-18 years. RESULTS: The genetic score was significantly associated with increased degree of obesity (higher BMI-SDS beta = 0.009 SD/allele, SE = 0.003, P = 0.003; higher body fat mass beta = 0.009, SE = 0.004, P = 0.031), yet improved body fat distribution (lower WHRadjBMI beta = -0.014 SD/allele, SE = 0.006, P = 0.016), and favorable concentrations of blood lipids (higher HDL cholesterol: beta = 0.010 SD/allele, SE = 0.003, P = 0.002; lower triglycerides: beta = -0.011 SD/allele, SE = 0.003, P = 0.001) adjusted for age, sex, and puberty. No differences were detected between prepubertal and pubertal/postpubertal children. The genetic score predicted a normal cardiometabolic profile, defined by the presence of normal glucose and lipid concentrations, among obese children (OR = 1.07 CI 95% 1.01-1.13, P = 0.012, n = 536). CONCLUSIONS: Genetic predisposition to higher body fat yet lower cardiometabolic risk exerts its influence before puberty.

Associations of Cardiorespiratory Fitness and Adiposity With Arterial Stiffness and Arterial Dilatation Capacity in Response to a Bout of Exercise in Children.

Purpose: To investigate the associations of directly measured peak oxygen uptake ( V˙O2peak ) and body fat percentage (BF%) with arterial stiffness and arterial dilatation capacity in children. Methods: Findings are based on 329 children (177 boys and 152 girls) aged 8-11 years. V˙O2peak was assessed by a maximal cardiopulmonary exercise test on a cycle ergometer and scaled by lean body mass (LM). BF% and LM were measured by bioelectrical impedance. Stiffness index (measure of arterial stiffness) and change in reflection index (ΔRI, measure of arterial dilatation capacity) were assessed by pulse contour analysis. Data were analyzed by linear regression models. Results:V˙O2peak/LM was positively associated with ΔRI in boys adjusted for age and BF% (ß = 0.169, P = .03). Further adjustments for systolic blood pressure, heart rate, and the study group had no effect on this association, but additional adjustment for clinical puberty attenuated it (ß = 0.171, P = .07). BF% was inversely related to ΔRI in boys adjusted for age and V˙O2peak/LM (ß = -0.171, P = .03). V˙O2peak or BF% was not associated with ΔRI in girls or with stiffness index in either boys or girls. Conclusion: Increasing cardiorespiratory fitness and decreasing adiposity may improve arterial health in childhood, especially among boys.

Peak oxygen uptake cut-points to identify children at increased cardiometabolic risk - The PANIC Study.

We aimed to develop cut-points for directly measured peak oxygen uptake ( V ˙ O 2 peak ) to identify boys and girls at increased cardiometabolic risk using different scaling methods to control for body size and composition. Altogether 352 children (186 boys, 166 girls) aged 9-11 years were included in the analyses. We measured V̇O2peak directly during a maximal cycle ergometer exercise test and lean body mass (LM) by bioelectrical impedance. We computed a sex- and age-specific cardiometabolic risk score (CRS) by summing important cardiometabolic risk factors and defined increased cardiometabolic risk as >1 standard deviation above the mean of CRS. Receiver operating characteristics curves were used to detect V̇O2peak cut-points for increased cardiometabolic risk. Boys with V̇O2peak <45.8 mL kg body mass (BM)-1  min-1 (95% confidence interval [CI] = 45.1 to 54.6, area under the curve [AUC] = 0.86, P < 0.001) and <63.2 mL kg LM-1  min-1 (95% CI =52.4 to 67.5, AUC = 0.65, P = 0.006) had an increased CRS. Girls with V̇O2peak <44.1 mL kg BM-1  min-1 (95% CI = 44.0 to 58.6, AUC = 0.67, P = 0.013) had an increased CRS. V̇O2peak scaled by BM-0.49 and LM-0.77 derived from log-linear allometric modeling poorly predicted increased cardiometabolic risk in boys and girls. In conclusion, directly measured V ˙ O 2 peak <45.8 mL kg BM-1  min-1 among boys and <44.1 mL kg BM-1  min-1 among girls were cut-points to identify those at increased cardiometabolic risk. Appropriately controlling for body size and composition reduced the ability of cardiorespiratory fitness to identify children at increased cardiometabolic risk.

Longitudinal associations of physical activity and sedentary time with cardiometabolic risk factors in children.

BACKGROUND: There are few prospective studies on the associations of changes in objectively measured vigorous physical activity (VPA∆ ), moderate-to-vigorous physical activity (MVPA∆ ), light physical activity (LPA∆ ), and sedentary time (ST∆ ) with changes in cardiometabolic risk factors (∆ ) in children. We therefore investigated these relationships among children. METHODS: The participants were a population sample of 258 children aged 6-8 years followed for 2 years. We assessed PA and ST by a combined heart rate and movement sensor; computed continuous age- and sex-adjusted z-scores for waist circumference, blood pressure, and fasting insulin, glucose, triglycerides, and high-density lipoprotein (HDL) cholesterol; and constructed a cardiometabolic risk score (CRS) of these risk factors. Data were analyzed using linear regression models adjusted for age, sex, the explanatory and outcome variables at baseline, and puberty. RESULTS: VPA∆ associated inversely with CRS∆ (ß = -0.209, P = 0.001), body fat percentage (BF%)∆ (ß = -0.244, P = 0.001), insulin∆ (ß = -0.220, P = 0.001), and triglycerides∆ (ß = -0.164, P = 0.012) and directly with HDL cholesterol∆ (ß = 0.159, P = 0.023). MVPA∆ associated inversely with CRS∆ (ß = -0.178, P = 0.012), BF%∆ (ß = -0.298, P = <0.001), and insulin∆ (ß = -0.213, P = 0.006) and directly with HDL cholesterol∆ (ß = 0.184, P = 0.022). LPA∆ only associated negatively with CRS∆ (ß = -0.163, P = 0.032). ST∆ associated directly with CRS∆ (ß = 0.218, P = 0.003), BF%∆ (ß = 0.212, P = 0.016), and insulin∆ (ß = 0.159, P = 0.049). CONCLUSIONS: Increased VPA and MVPA and decreased ST were associated with reduced overall cardiometabolic risk and major individual risk factors. Change in LPA had weaker associations with changes in these cardiometabolic risk factors. Our findings suggest that increasing at least moderate-intensity PA and decreasing ST decrease cardiometabolic risk in children.

Longitudinal Associations of Fitness, Motor Competence, and Adiposity with Cognition.

PURPOSE: The purpose of this study was to investigate the longitudinal associations of cardiorespiratory fitness (CRF), motor competence (MC), and body fat percentage (BF%) with cognition in children. METHODS: Altogether, 371 children (188 boys and 183 girls) 6-9 yr of age at baseline participated in this 2-yr follow-up study. We assessed CRF by maximal cycle ergometer test, computed the MC score from the z-scores of the 50-m shuttle run, static balance, and box and block test results, measured BF% by dual-energy x-ray absorptiometry, and assessed cognition using the Raven's Coloured Progressive Matrices (RCPM) score. The associations were studied by linear regression analysis and repeated-measures ANCOVA. RESULTS: In boys, a higher MC score (ß = -0.161, 95% confidence interval [CI] = -0.314 to -0.009), a shorter 50-m shuttle run test duration (ß = 0.152, 95% CI = 0.007-0.296), and a higher number of cubes moved in the Box and block test (ß = -0.161, 95% CI = -0.309 to -0.013) at baseline were associated with a smaller increase in the RCPM score during follow-up. These associations were largely explained by the RCPM score at baseline. However, boys in the highest third (mean difference = 2.5, 95% CI for difference = 0.66-4.33) and the middle third (mean difference = 2.1, 95% CI for difference = 0.39-3.82) of the MC score at baseline had a higher RCPM score over the 2-yr follow-up than boys in the lowest third. CRF, MC, or adiposity was not associated with the RCPM score in girls. Changes in CRF, MC, or BF% were not associated with changes in cognition. CONCLUSIONS: Higher MC at baseline predicted better cognition during the first two school years in boys but not in girls. CRF or adiposity was not associated with cognition in boys or girls.

Associations of Dehydroepiandrosterone Sulfate With Cardiometabolic Risk Factors in Prepubertal Children.

Context: Premature adrenarche (PA) has been associated with overweight and insulin resistance, but the associations of serum dehydroepiandrosterone sulfate (DHEAS) concentration with other cardiometabolic risk factors are uncertain. Objective: To examine the associations of serum DHEAS concentration with several cardiometabolic risk factors in children. Design: Cross-sectional data from the Physical Activity and Nutrition in Children Study. Participants: Population sample of 207 girls and 225 boys aged 7.6 ± 0.4 years. Main Outcome Measures: Cardiometabolic risk factors by serum DHEAS concentration. Results: DHEAS correlated positively with body mass index standard deviation score, body fat percentage, lean body mass, high-sensitivity C-reactive protein (hs-CRP), and alanine aminotransferase (ALT) when adjusted for age and sex. The associations of DHEAS with hs-CRP and ALT disappeared when adjusted also for body fat percentage. When further adjusted for birth weight SD score, DHEAS correlated negatively with low-density lipoprotein (LDL) cholesterol and LDL/high-density lipoprotein (HDL) cholesterol ratio. LDL cholesterol was lower in children with DHEAS ≥40 µg/dL than in those with DHEAS <40 µg/dL, adjusted for age, sex, and body fat percentage (86.5 vs 92.3 mg/dL, P = 0.029). This association strengthened after further adjustment for birth weight SD score (85.3 vs 92.3 mg/dL, P = 0.012). Conclusion: Higher DHEAS is not associated with an increased cardiometabolic risk in prepubertal children. Instead, it may be protective, evidenced by an association with lower LDL cholesterol and LDL/HDL cholesterol ratio. The increased cardiometabolic risk in PA shown in many studies may be due to low birth weight and childhood overweight associated with PA.

Serum 25-Hydroxyvitamin D, Plasma Lipids, and Associated Gene Variants in Prepubertal Children.

Context: The associations of serum 25-hydroxyvitamin D [25(OH)D] with plasma lipids remain controversial in children. Objective: To examine the associations and interactions of 25(OH)D and related gene variants with lipids in children. Design: Cross-sectional. Setting: Kuopio, Finland. Participants: Population sample of 419 prepubertal white children aged 6 to 8 years. Main Outcome Measures: 25(OH)D, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: Serum 25(OH)D was negatively associated with total cholesterol (ß = -0.141, P = 0.004), LDL cholesterol (ß = -0.112, P = 0.023), HDL cholesterol (ß = -0.150, P = 0.002), and triglycerides (ß = -0.104, P = 0.035) adjusted for age and sex. Associations of 25(OH)D with total cholesterol, LDL cholesterol, and HDL cholesterol remained after adjustment for adiposity, physical activity, sedentary behavior, diet, daylight time, and parental education. Children in the highest quartile of 25(OH)D had the lowest total cholesterol (P = 0.022) and LDL cholesterol (P = 0.026) adjusted for age and sex. Cytochrome P450 family 2 subfamily R member 1 (CYP2R1) rs12794714, CYP2R1 rs10741657, and vitamin D binding protein (DBP) rs2282679 were associated with 25(OH)D adjusted for age and sex. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and C10orf88 rs6599638 with HDL cholesterol adjusted for age, sex, and 25(OH)D. The gene variants did not explain or modify the associations of 25(OH)D with lipids. Conclusions: 25(OH)D was independently and inversely associated with total cholesterol, LDL cholesterol, and HDL cholesterol. CYP2R1 rs12794714, CYP2R1 rs10741657, and DBP rs2282679 were associated with 25(OH)D. CYP2R1 rs12794714 was associated with total cholesterol and LDL cholesterol and chromosome 10 open reading frame 88 (C10orf88) rs6599638 with HDL cholesterol independent of 25(OH)D. None of the gene variants modified the associations of 25(OH)D with lipids. Further studies are needed to detect the mechanisms for the associations of 25(OH)D with lipids.

Effect of a 2-y dietary and physical activity intervention on plasma fatty acid composition and estimated desaturase and elongase activities in children: the Physical Activity and Nutrition in Children Study.

BACKGROUND: Evidence on the effects of lifestyle interventions on plasma fatty acid composition in children is limited. OBJECTIVE: We investigated the effects of a dietary and physical activity intervention on plasma fatty acid composition of cholesteryl esters (CEs) and phospholipids and estimated desaturase and elongase activities in children. DESIGN: We conducted a 2-y controlled dietary and physical activity intervention based on Finnish nutrition and physical activity recommendations in a population sample of 506 children aged 6-8 y. We assessed plasma fatty acid composition by gas chromatography and estimated desaturase and elongase activities as the ratio of product fatty acids to precursor fatty acids. We analyzed data by using linear mixed models adjusted for age and sex. RESULTS: The proportion of total polyunsaturated fatty acids (PUFAs) in CEs tended to increase in the intervention group compared with the control group (P = 0.007 for group × time interaction). The proportion of total PUFAs in phospholipids (P = 0.019 for group × time interaction) and the proportion of linoleic acid in CEs (P = 0.038 for group × time interaction) decreased in the control group. The proportion of α-linolenic acid in CEs (P < 0.001 for group × time interaction) increased and in phospholipids (P = 0.015 for group × time interaction) tended to increase in the intervention group. The proportion of stearic acid in CEs decreased in the intervention group (P = 0.001 for group × time interaction). The proportion of oleic acid in CEs (P = 0.002 for group × time interaction) increased and in phospholipids (P = 0.023 for group × time interaction) tended to increase in the control group. Estimated elongase activity in CEs decreased in the control group (P = 0.050 for group × time interaction). Intervention had no effect on estimated desaturase activities. CONCLUSIONS: Dietary and physical activity intervention had a beneficial effect on plasma fatty acid composition in children by preventing the decrease in the proportion of total PUFAs and linoleic acid and by increasing the proportion of α-linolenic acid. This study was registered at clinicaltrials.gov as NCT01803776.

Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study.

BACKGROUND: We studied for the first time among children differences in plasma alanine aminotransferase (ALT) among genotypes of the rs641738 polymorphism in the MBOAT7 gene that has been associated with increased risk of nonalcoholic fatty liver disease among adults. We also investigated the associations of a genetic risk score combining information from the MBOAT7, PNPLA3, and TM6SF2 polymorphisms with plasma ALT. METHODS: We performed a 2-y follow-up study in 467 Caucasian children aged 6-9 y, genotyped the MBOAT7, PNPLA3, and TM6SF2 polymorphisms, calculated a genetic risk score from these polymorphisms (scored 0-3) and assessed plasma ALT. RESULTS: Children carrying the T allele of the MBOAT7 polymorphism had 7% higher plasma ALT at baseline (17.8 vs. 19.1 U/l, P = 0.022) and 10% higher plasma ALT at 2-y follow-up (18.0 vs. 19.7 U/l, P = 0.022) than the noncarriers. A higher genetic risk score was associated with higher plasma ALT at baseline (17.5, 18.5, 19.2, and 22.8 U/l, P = 0.008 for linear trend) and 2-y follow-up (18.2, 18.9, 18.9, and 32.8 U/l, P = 0.017 for linear trend). CONCLUSION: Children carrying the T allele of the MBOAT7 polymorphism had higher plasma ALT than the noncarriers. Children with the MBOAT7, PNPLA3, and TM6SF2 variants had the highest plasma ALT.

Determinants of Cardiorespiratory Fitness in a Population Sample of Girls and Boys Aged 6 to 8 Years.

BACKGROUND: There are few studies on determinants of cardiorespiratory fitness (CRF) among girls and boys separately in population samples of children. METHODS: We therefore investigated the determinants of CRF, assessed by maximal workload per height using allometric scaling, in a population sample of 162 girls and 177 boys aged 6 to 8 years. We used automated bootstrap feature selection and linear regression models. RESULTS: The strongest determinants of CRF among girls were maximal heart rate (HR; standardized regression coefficient [ß] = 0.31, P < .001), unsupervised physical activity (ß = 0.29, P < .001), lean body mass (ß = 0.23, P = .001), and errors in static balance test (ß = -0.16, P = .02), accounting altogether for 25.7% of variation in CRF. In boys, unsupervised physical activity (ß = 0.24, P < .001), resting HR (ß = -0.25, P < .001), hand grip strength (ß = 0.21, P = .001), errors in static balance test (ß = -0.16, P = .01), organized football (ß = 0.16, P = .01), and unsupervised trampoline jumping (ß = 0.14, P = .04) were the strongest determinants of CRF, accounting altogether for 29.7% of variation in CRF. CONCLUSIONS: These findings suggest that unsupervised physical activity is sufficient in improving CRF in both sexes. Furthermore, larger muscle mass and better balance are associated with higher CRF that has to be taken into account when assessing CRF using maximal cycle ergometer exercise test among children.

Prevalence and associated factors of abnormal liver values in children with celiac disease.

BACKGROUND: The prevalence and factors associated with transaminasemia in celiac disease are poorly known. AIMS: To investigate these issues in paediatric celiac patients and controls. METHODS: Alanine aminotransferase (ALT) was studied in 150 children with untreated celiac disease, 161 disease controls and 500 population-based controls. The association between ALT and clinical and histological variables and the effect of a gluten-free diet were investigated in celiac patients. RESULTS: ALT was >30U/l: celiac disease 14.7%, ulcerative colitis 37.2%, Crohn's disease 16.7%, reflux disease 16.2%, functional gastrointestinal symptoms 8.9%, and controls 3.6%. Factors associated with increased ALT were poor growth (45.5% vs 24.2%, P=0.039) and severe villous atrophy (median 23.0U/l vs partial atrophy 19.0U/l, P=0.008), but not age, sex, body-mass index, type or severity of symptoms and co-morbidities. ALT had a moderate correlation with endomysial (r=0.334, P<0.001) and transglutaminase antibodies (r=0.264, P=0.002) and ferritin (r=-0.225, P=0.03), but not with other laboratory values. On gluten-free diet median ALT decreased from 22.0U/l to 18.0U/l (P=0.002) and 80% of the high values normalized. CONCLUSION: Increased ALT is associated with more advanced serological and histological celiac disease. Adherence to a gluten-free diet appears to result in normalization or reduction of ALT levels.