Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort

Abstract

We conducted a prospective study in a large, multiethnic cohort of obese adolescents to characterize clinical and genetic features associated with pediatric nonalcoholic fatty liver (NAFL), the most common cause of chronic liver disease in youth. A total of 503 obese adolescents were enrolled, including 191 (38.0%) whites, 134 (26.6%) blacks, and 178 (35.4%) Hispanics. Participants underwent abdominal magnetic resonance imaging (MRI) to quantify hepatic fat fraction (HFF), an oral glucose tolerance test (OGTT) to assess glucose tolerance and insulin sensitivity, and the genotyping of three single-nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) (patatin-like phospholipase domain-containing protein 3 [PNPLA3] rs738409, glucokinase regulatory protein [GCKR] rs1260326, and transmembrane 6 superfamily member 2 [TM6SF2] rs58542926). Assessments were repeated in 133 subjects after a 2-year follow-up. Prevalence of nonalcoholic fatty liver (NAFL) was 41.6% (209 patients) and ranged widely among ethnicities, being 42.9% in whites, 15.7% in blacks, and 59.6% in Hispanics (P < 0.0001). Among adolescents with NAFL, blacks showed the highest prevalence of altered glucose homeostasis (66%; P = 0.0003). Risk factors for NAFL incidence were white or Hispanic ethnicity (P = 0.021), high fasting C-peptide levels (P = 0.0006), and weight gain (P = 0.0006), whereas baseline HFF (P = 0.004) and weight loss (P = 0.032) predicted resolution of NAFL at follow-up. Adding either gene variant to these variables improved significantly the model predictive performance.

Conclusion: Black obese adolescents are relatively protected from liver steatosis, but are more susceptible to the deleterious effects of NAFL on glucose metabolism. The combination of ethnicity/race with markers of insulin resistance and genetic factors might help identify obese youth at risk for developing NAFL.

Trial registration: ClinicalTrials.gov NCT01966627.

Figure 1

Study flowchart. Study participants are stratified according to ethnicity, presence of NAFL at presentation (HFF >5.5%), and stability or progression/regression of NAFL at follow‐up.

Figure 2

(A) HFF, (B) visceral fat, (C) WBISI, and (D) glucose tolerance of white, black, and Hispanic obese youth with NAFL. Statistical comparisons among continuous variables were made using one‐way ANOVA followed by post‐hoc pair‐wise comparisons by Tukey HSD tests. Differences in prevalence of impaired glucose control were assessed using Fisher’s test. Abbreviations: ANOVA, analysis of variance; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

Figure 3

Associations between (A) PNPLA3 rs738409, (B) GCKR rs1260326, and (C) TM6SF2 rs58542926 SNPs and HFF % in obese/overweight adolescents. Statistical comparisons between groups were made using one‐way analysis of variance (ANOVA). Data are shown as mean ± SEM.

Figure 4

ROC curves for predicting (A) NAFL progression (n = 76) or (B) regression (n = 57) at follow‐up in obese/overweight adolescents. In (A), the AUC was 0.887 when using ethnicity, z‐score BMI change (ΔBMIz), and fasting C peptide (CPEP₀) at baseline as predictors and increased to 0.959, 0.978, and 0.976 when adding either the PNPLA3 rs738409, GCKR rs1260326, or TM6SF2 rs58542926 variant to the model, respectively. In (B), the AUC was 0.827 when using ΔBMIz and HFF% at baseline as predictors and did not improve by adding either the PNPLA3 rs738409, GCKR rs1260326, or TM6SF2 rs58542926 variant (0.763, 0.828, and 0.814, respectively).