Sex-Specific Metabolite Biomarkers of NAFLD in Youth: A Prospective Study in the EPOCH Cohort

Context: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed nations. There are currently no accurate biomarkers of NAFLD risk in youth. Objective: Identify sex-specific metabolomics biomarkers of NAFLD in a healthy cohort of youth. Design/Setting: This prospective study included 395 participants of the EPOCH cohort in Colorado, who were recruited 2006-2009 ("T1 visit") and followed for 5 years ("T2 visit"). We entered 767 metabolites measured at T1 into a reduced rank regression model to identify the strongest determinants of hepatic fat fraction (HFF) at T2, separately for boys and girls. We compared the capacity of metabolites versus conventional risk factors (overweight/obesity, insulin, alanine transaminase, aspartate transaminase) to predict NAFLD (HFF >= 5%) and high HFF (fourth vs first quartile) using area under the receiver operating characteristic curve (AUC). Results: Prevalence of NAFLD was 7.9% (8.5% of boys, 7.1% of girls). Mean +/- SD HFF was 2.5 +/- 3.1%. We identified 13 metabolites in girls and 10 metabolites in boys. Metabolites were in lipid, amino acid, and carbohydrate metabolism pathways. At T1, the metabolites outperformed conventional risk factors in prediction of high HFF but not NAFLD. At T2, the metabolites were superior to conventional risk factors as predictors of high HFF (AUC for metabolites vs conventional risk factors for boys: 0.9565 vs 0.8851, P = 0.02; for girls: 0.9450 vs 0.8469, P = 0.02) with similar trends for NAFLD, although the differences were not significant. Conclusions: The metabolite profiles identified herein are superior predictors of high HFF when assessed 5 years prior and concurrently in a general-risk setting.