A Circulating Biomarker-based Framework for Diagnosis of Hepatocellular Carcinoma in a Clinically Relevant Model of Non-alcoholic Steatohepatitis; An OAD to NASH

Abstract

Although cirrhosis is a key risk factor for the development of hepatocellular carcinoma (HCC), mounting evidence indicates that in a subset of patients presenting with non-alcoholic steatohepatitis (NASH), HCC manifests in the absence of cirrhosis. Given the sheer size of the non-alcoholic fatty liver disease (NAFLD) epidemic, and the dismal prognosis associated with late-stage primary liver cancer, there is an urgent need for HCC surveillance in the NASH patient. In the present study, adult male mice randomized to control diet or a fast food diet (FFD) were followed for up to 14 mo and serum level of a panel of HCC-relevant biomarkers was compared with liver biopsies at 3 and 14 mo. Both NAFLD Activity Score (NAS) and hepatic hydroxyproline content were elevated at 3 and 14 mo on FFD. Picrosirius red staining of liver sections revealed a filigree pattern of fibrillar collagen deposition with no cirrhosis at 14 mo on FFD. Nevertheless, 46% of animals bore one or more tumors on their livers confirmed as HCC in hematoxylin-eosin-stained liver sections. Receiver operating characteristic (ROC) curves analysis for serum levels of the HCC biomarkers osteopontin (OPN), alpha-fetoprotein (AFP) and Dickkopf-1 (DKK1) returned concordance-statistic/area under ROC curve of > 0.89. These data suggest that serum levels of OPN (threshold, 218 ng/mL; sensitivity, 82%; specificity, 86%), AFP (136 ng/mL; 91%; 97%) and DKK1 (2.4 ng/mL; 82%; 81%) are diagnostic for HCC in a clinically relevant model of NASH