Endotoxin and Plasminogen Activator Inhibitor-1 Serum Levels Associated With Nonalcoholic Steatohepatitis in Children

Objectives: Recent evidence supports a role for endotoxemia in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). We investigated the association between serum levels of endotoxin, proinflammatory molecules, and histology in children with NAFLD. Patients and Methods: A total of 40 children, mean age of 11.9 +/- 2.8 years (27 male and 13 female), with biopsy-proven NAFLD were consecutively enrolled. Anthropometrics, blood pressure, and parameters of the metabolic syndrome were collected. Serum levels of endotoxin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were measured by an enzyme-linked immunosorbent assay and compared with circulating levels of the same soluble factors in 9 age-and sex-matched normal weight controls (age 11.4 +/- 1.7 years; 6 boys and 3 girls). Results: Children with NAFLD had markedly higher serum concentrations of endotoxin (P<0.01), PAI-1 (P<0.001), TNF-alpha, and IL-6 (P<0.05) than control subjects. Endotoxin (P=0.002), PAI-1, (P<0.001), IL-6 (P=0.002), TNF-alpha (P=0.02), and body mass index (P=0.03) were significantly associated with a NAFLD activity score >= 5 at the univariate analysis. At the stepwise regression analysis, endotoxin (P<0.0001) and PAI-1 (P=0.009) were the most significant predictors for NAFLD activity score. Conclusions: Our findings demonstrate that, apart from TNF-a and IL-6, endotoxin and PAI-1 may represent good markers of NASH. They also reinforce the hypothesis that elevated levels of endotoxin may contribute to the progression from NAFLD to NASH.