Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications

Abstract

The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is increasingly recognised. Thus, non-alcoholic fatty liver disease (NAFLD) is now considered the most common cause of liver enzyme elevation in Western countries.1 It is regarded as the hepatic manifestation of the metabolic syndrome (MS), characterised by central obesity and insulin resistance (IR), and resulting diabetes type 2, dyslipidaemia and hypertension.2 NAFLD encompasses mild hepatic steatosis to steatohepatitis (non-alcoholic steatohepatitis (NASH)) with significant necroinflammation and progressive fibrosis. NAFLD is believed to account for a large fraction, if not entirely for what was previously termed ‘cryptogenic cirrhosis’.3 Since cirrhosis is the main risk factor for hepatocellular carcinoma (HCC), liver cancer could be simply a complication of end-stage NAFLD, similar to the situation encountered in other chronic fibrosing liver diseases. However, accumulating evidence suggests that hepatocarcinogenesis may also be related to earlier stages of NAFLD. Case series of patients with HCC and NAFLD as the only identified risk factor strongly suggest that hepatocarcinogenesis is part of the natural history of NAFLD. Based on the known association of NAFLD with IR and MS, approximately two-thirds of the patients were obese and/or diabetic,4 and a remarkable 25% of these patients had no cirrhosis. Considering the rapidly increasing prevalence of both conditions in affluent societies, and their significance in the pathophysiology of NAFLD, a rising incidence of NAFLD and its complications—including HCC—can be expected in the mid-term future. Therefore, it is particularly worrying that the most persuasive evidence for an association between NAFLD and HCC derives from studies on the risk of HCC in patients with MS. In a large prospective cohort study HCC mortality was significantly higher in obese subjects than in those with normal body mass index.5 The most comprehensive data underlining the significance …