Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management

Abstract

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Keywords: Cirrhosis; Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Obesity.

Figure 1

Risk factors and proposed mechanisms for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis-related hepatocellular carcinoma. The development of NAFLD and NASH-related HCC is multifactorial. Proposed pathogenic mechanisms include obesity, peripheral and hepatic insulin resistance from type 2 diabetes, increased hepatic lipid storage and lipotoxicity, EMT, genetic mutations and intestinal mibrobiota dysregulation. HCC: Hepatocellular carcinoma; EMT: Epithelial to mesenchymal transition; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; FFA: Free fatty acid; IGF: Insulin-like growth factor; LPS: Lipopolysaccharide; PNPLA3: Patatin-like phospholipase domain-containing 3; TM6SF2: Transmembrane 6 superfamily member 2.