The recent occurrence of excessive food availability and lack of exercise combine to cause an epidemic of obesity. Weight excess has been shown to induce insulin resistance that is probably an adaptive mechanism to prevent further fat accumulation, but may eventually become deleterious. In fact, insulin resistance has been demonstrated as the central factor associated with the metabolic syndrome that is defined as a constellation of metabolic abnormalities that are linked to an increased cardiovascular risk. The association of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) with the metabolic syndrome was simultaneously recognized by several authors, by finding that most patients with NAFLD presented some of the features of the metabolic syndrome and that insulin resistance was present. Recently, an almost universal association between insulin resistance and primary NASH was found. However, it has been difficult to include NAFLD as one of the manifestations of the metabolic syndrome, and there is still some scepticism among non-hepatologists concerning the importance of the liver disease in this setting. Nonetheless, there is increasing evidence that NAFLD, although a usually silent and asymptomatic liver disease, has a significant risk of progressing to end-stage liver disease and death. In fact, comparing a group of type 2 diabetes patients with the general population from the same geographical area, the increase in liverdisease related mortality was superior to the increase in cardiovascular-related mortality; other long-term follow-up studies from cohorts of diabetic patients showed increased incidence of non-alcoholic chronic liver disease and of hepatocellular carcinoma. A long-term follow-up study from obese patients showed increased cirrhosis-related mortality. A more recent study, comparing two sequential liver biopsies in 103 patients with NASH, demonstrated that in more than a third of the patients, fibrosis increased between the two biopsies, with some patients even progressing from no fibrosis to cirrhosis; besides worsening of fibrosis occurred even in patients with declining levels of aminotransferases. The interplay between insulin resistance and steatosis seems to be quite obvious with insulin resistance inducing increased flux of free fatty acids from the adipose tissue and increased de novo synthesis of fatty acids in the liver, resulting in an accumulation of triglycerides in the hepatocytes. Yet, it is not clear why some patients develop only steatosis while others develop necroinflammation and eventually fibrosis and cirrhosis. The two-hit theory proposed by Day and James suggests that a second hit, namely oxidative stress or cytokine-related mechanisms, is needed. However, one hit (insulin resistance) is enough to explain all the spectrum of NAFLD. Instead of considering several hits, we should probably consider that the disease has several stages or steps. In fact, Wanless and Shiota suggested that in NASH a four-step model should be considered, the first step being again steatosis facilitated by insulin, the second being necrosis induced by intracellular lipid toxicity or lipid peroxidation, the third would be the release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins and the fourth would be venous obstruction with secondary collapse and ultimately fibrous septation and fibrosis. Although the latter is a very interesting concept that includes the factors associated with the progression to cirrhosis, it still does not explain why only a minority of patients are subjected to intracellular lipid toxicity and progressive fibrosis. Correspondence to: Dr H. Cortez-Pinto, Centro de Gastrenterologia, Hospital de Santa Maria, Av. Prof. Egas Moniz, 1649-035, Lisboa, Portugal. E-mail: hlcortezpinto@netcabo.pt Aliment Pharmacol Ther 2005; 22 (Suppl. 2): 83–85.