  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
