A Tale of Two Complications of Obesity: NASH and Hepatocellular Carcinoma.

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in developed countries and its incidence is rapidly increasing. Cirrhosis, and the dreaded complication of hepatocellular carcinoma (HCC), are the major drivers of morbidity and mortality in NASH. Conventional understanding has been that chronic liver damage leads to a cycle of cell death, regeneration and fibrosis during which HCC precursor cells undergo malignant transformation and lead to cancer initiation. This is supported by epidemiologic data which shows that cirrhosis precedes HCC in more than 90% of patients with several forms of chronic liver disease like hepatitis C and alcohol cirrhosis. But the link between fibrosis and carcinogenesis seems less definitive in patients with NASH as a sizeable proportion of NASH patients with HCC do not have significant underlying fibrosis. Several case reports and case series have pointed out this phenomenon of HCC arising in non-cirrhotic NASH (1), and a recent meta-analysis of 19 studies has shown that the prevalence of HCC in non-cirrhotic NASH was up to 38.0% (2). The mechanisms that contribute to the development of HCC in obesity in the absence of NASH and/or overt fibrosis or cirrhosis have remained unexplored. A possible mechanism to explain the role of obesity in the pathogenesis of HCC independent of NASH, was recently reported in a paper in Cell (3) .