Dietary free-sugar reduction and genetic susceptibility in pediatric non-alcoholic fatty liver disease: a multi-study investigation

The long-term effects of dietary free-sugar reduction and the potential influence of genetic susceptibility on pediatric non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. Three complementary studies involved two independent pediatric cohorts aged 5–14 years. A 48-week randomized controlled trial (RCT; n = 146) evaluated a multicomponent dietary and lifestyle intervention emphasizing free-sugar reduction. An independent cross-sectional study ( n = 242) examined associations of free-sugar intake and PNPLA3 rs738409, TM6SF2 rs58542926, and UGT1A1 rs10929303 with NAFLD. A nested 15-week crossover trial ( n = 14) assessed metabolic responses to low-free-sugar and habitual dietary conditions. In the RCT, free-sugar intake decreased significantly, and NAFLD resolution was more frequent in the intervention group at week 48 (27.4% vs. 11.0%; RR = 2.50, 95% CI 1.18–5.31). NAFLD severity showed a significant treatment-by-time interaction ( P = 0.0016). In the cross-sectional study, PNPLA3 GG (OR = 5.33, 95% CI 1.93–14.70) and TM6SF2 CT (OR = 3.33, 95% CI 1.04–10.70) were associated with NAFLD. Significant genotype–free-sugar interactions were observed for all three variants. In the crossover trial, the low-free-sugar condition was associated with lower fasting glucose, triglycerides, and uric acid; genotype-specific findings remained exploratory. A multicomponent intervention emphasizing free-sugar reduction improved NAFLD outcomes in children. Genetic associations and preliminary intervention findings suggest potential heterogeneity in dietary responses, warranting confirmation in larger studies. The study was retrospectively registered at https://ClinicalTrials.gov (Study ID: NCT06579729, available online at https://clinicaltrials.gov ) on 28 August 2024.