Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease

Reliable noninvasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving nonalcoholic steatohepatitis (NASH) and to identify potential noninvasive discriminators of NAFLD severity and pattern. Cytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike information criterion was used to determine cytokines retained in multivariable models. Of 235 subjects, 31% had Definite NASH on liver histology, 43% had Borderline NASH, and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL-8) was higher in those with stage 3-4 fibrosis and lobular inflammation. Soluble IL-2 receptor alpha was higher in children with stage 3-4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, Definite NASH, lobular inflammation, and ballooning. IL8 increased with steatosis and fibrosis severity; soluble IL-2 receptor alpha increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity. Conclusion: Plasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. More targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as noninvasive discriminators of disease severity.