Abstract
The severity of hepatic fibrosis is the primary predictor of liver-related morbidity and mortality in patients with nonalcoholic fatty liver disease (NAFLD). Unfortunately, noninvasive serum biomarkers for NAFLD-associated fibrosis are limited. We analyzed baseline serum samples for 24 cytokines of 97 patients with biopsy-proven NAFLD. These patients were prospectively enrolled in a clinical study (ClinicalTrials.gov NCT00794716) to identify cytokines associated with liver fibrosis in patients with nonalcoholic steatohepatitis. Patients were stratified according to severity of hepatic fibrosis (mild, stage 0-1, n = 37; moderate, stage 2, n = 40; and advanced, stage 3-4, n = 20) while controlling for age, race, sex, body mass index, and diabetes mellitus. Interleukin-8 (IL-8), osteopontin (OPN), and monocyte chemoattractant protein 1 (MCP1) were associated with liver fibrosis (P < 0.001, P = 0.005, P = 0.016, respectively). After controlling for steatosis, lobular inflammation, hepatocyte ballooning, age, sex, body mass index, diabetes mellitus, hypertension, and metabolic syndrome status, IL-8 remained strongly associated with fibrosis (P = 0.001). Furthermore, IL-8 was also a strong predictor of increased fibrotic liver injury compared to established markers of hepatic fibrosis. Hepatic gene expression from 72 patients with NAFLD (n = 40 mild fibrosis; n = 32 advanced fibrosis) from the Duke University Health System NAFLD Clinical Database and Biorepository revealed IL-8, MCP1, and OPN gene expression to be increased and differentially expressed in patients with advanced hepatic fibrosis. Thus, serum IL-8, MCP1, and OPN may reflect up-regulated gene expression during liver fibrosis in NAFLD. Conclusion: Serum IL-8, MCP1, and OPN may serve as a test for advanced hepatic fibrosis in NAFLD and thus reveal novel targets for antifibrotic therapies. The increased serum IL-8, MCP1, and OPN that correspond with associated hepatic gene expression lend strength to such analytes as ideal surrogate serum biomarkers for severity of hepatic fibrosis.