The Serum Biomarkers of Cardiovascular Disease Are Elevated in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) With Advanced Fibrosis and Histologically-Proven Non-alcoholic Steatohepatitis (NASH): 2017 Presidential Poster Award

Abstract

Introduction: NAFLD is associated with increased risk for cardiovascular disease (CVD) and CV mortality. The progressive NAFLD or NASH and especially those with hepatic fibrosis are at risk for mortality. Given that CVD is the top cause of death in NAFLD/NASH, it is possible that these subjects may share the same pathogenic environment as those with CVD. Recently, N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and osteopontin (OPN) have been shown to be associated with CVD. Our aim was to see if these biomarkers are associated with the aggressive form of NAFLD such as NASH or significant hepatic fibrosis. Methods: The study cohort included 170 biopsy-proven NAFLD subjects who were prospectively consented and enrolled. Liver biopsies were assessed by the study hepatopathologists and graded for degree of steatosis (0-3), necroinflammation and fibrosis (0-4). Sera samples were frozen from the time of biopsy were used to measure serum levels of OPN (pg/mL), NT-proBNP (pg/mL) and adiponectin (ng/mL) using MILIPLEX® MAP assays by Luminex®. Results: Histologic NASH was seen in 52% of NAFLD and % had stage 2 or higher fibrosis. The median OPN levels were higher in NASH as compared to steatosis alone (3109 vs. 2251, p < 0.01). Additionally, adiponectin levels were lower in NASH as compared to hepatic steatosis by using quartile 4 as cutoff point (34% vs. 53%, p < 0.05). Furthermore, as compared to fibrosis stage (0-1) (2598), the median OPN levels were higher in patients with advance fibrosis (fibrosis stage ≥2) (3360, p < 0.01) as well as bridging fibrosis (3242 vs 2598, p < 0.05). Also, higher levels of OPN positively correlated with AST (r=0.17; p=0.03) and serum ferritin (r=0.28; p=0.03), while adiponectin only positively correlated with HDL (r=0.33; p < 0.01). Histologically, serum OPN significantly correlated with the presence of polymorphonuclear (r=0.24; p < 0.01), and Mallory-Denk body (r=0.28; p < 0.01) in the liver biopsy. In the multivariate analysis, serum OPN was independently associated with presence of histologic NASH in NAFLD patients (OR 2.9 [95% CI 1.2-6.7]). In contrast NT-proBNP was not detectable in both groups. Conclusion: Increased serum levels of OPN seem to be associated with presence of NASH and advanced hepatic fibrosis in patients with NAFLD. Further studies are needed to validate these findings and to determine if serum OPN can also predict presence of development of CVD in subjects with NAFLD.