From NASH to HCC: current concepts and future challenges

Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), underlies many cases of hepatocellular carcinoma (HCC). In this Review, the authors discuss NAFLD-associated HCC, including its epidemiology, key features that promote hepatocarcinogenesis and the management of HCC in patients with obesity. Key points Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and is strongly associated with metabolic syndrome. NAFLD dramatically increases the prevalence of hepatocellular carcinoma (HCC) development; however, the increased HCC risk of patients with NAFLD is often misdiagnosed. The degree of fibrosis is considered the strongest predictive factor for correlating the progression of NAFLD with life-threating complications. Several factors contribute to the development of NAFLD or NASH and subsequent HCC development; these factors include genetic and environmental modifiers such as diet or lifestyle. The pathogenesis of NAFLD-associated HCC is a complex landscape composed of mechanisms involved in immune