Non-alcoholic fatty liver disease: more than just ectopic fat accumulation

Obesity and the intimately associated scourge of type 2 diabetes are global pandemics whose prevalence has increased exponentially, particularly in affluent economies. Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of excess adiposity is now the principal cause of chronic liver disease in many countries. Consistent with its pivotal role, the majority of obese patients have concomitant NAFLD. However, while obesity is a risk factor for disease progression, only a minority with NAFLD develop liver-related complications. This reflects the complex interplay of factors that modulate NAFLD progression. Despite the focus on liver-related outcomes in patients with NAFLD, the majority succumb to cardiovascular disease and to cancer. Interestingly, recent epidemiological data suggest that the presence of hepatic steatosis is independently associated with cardiovascular and cancer risk. In this article we describe the pathogenic pathways that link obesity to NAFLD progression and how liver disease evolution can result in pro-atherosclerotic and oncogenic systemic dysfunction.