Review article: is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions?

Non-alcoholic fatty liver disease (NAFLD) is currently conceptualised as a clinical spectrum that results from a ‘multiple-hit’ process which begins with simple steatosis and subsequently renders the hepatocytes susceptible to a variety of insults. Ultimately, more serious liver injuries like non-alcoholic steatohepatitis (NASH) and cirrhosis may develop. Although the metabolic syndrome is considered the crucial player in the pathogenesis of NAFLD, recent studies have highlighted novel pathophysiological mechanisms in this clinical entity. To discuss the pathophysiology of NAFLD based on the hypothesis that simple steatosis and NASH are discrete entities rather than two points on a spectrum. A literature search was conducted in August 2012 on PubMed, Ovid Embase, Ovid Medline and Scopus using the following search terms: steatosis, non-alcoholic steatohepatitis, pathophysiology, fatty liver, natural history and genetics. Simple steatosis and NASH appear as two distinct pathophysiological entities and progression from pure fatty liver to NASH appears to be so rare as to warrant publication. The possible pathogenetic pathways specifically related to NASH are highlighted. Although simple steatosis and non-alcoholic steatohepatitis are currently viewed as two histological subtypes of the unique spectrum of non-alcoholic fatty liver disease, the two conditions are likely distinct not only from a histological but also from a pathophysiological standpoint. Efforts to distinguish simple steatosis from non-alcoholic steatohepatitis using non-invasive modalities should be informed by the current pathophysiology of these two clinical entities.