atty liver disease (FLD), which is emerging as the most common liver disease in clinical practice, is F etiologically diverse and encompasses a morphological spectrum consisting of hepatic steatosis (fatty liver) and steatohepatitis that progresses to cirrhosis and hepatocellular carcinoma.'J FLD is divided into two broad categories, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD), in an attempt to bring the emerging nonalcoholic causes into focus and to distinguish this form from the long-known alcoholic liver disease. l v 2 However, the remarkably similar pathological spectrum of alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) makes it generally difficult to distinguish AFLD from NAFLD on morphological parameters alone, despite the distinction implied by these etiological designation^.^-* The indistinguishable spectrum of histological features and the progression of both AFLD and NAFLD toward cirrhosis and liver cancer suggest a common, albeit complex, pathogenetic mechanism. We consider FLD in its unity with multiple etiologies and believe that separation of this entity into AFLD and NAFLD may not always serve an etiological distinction because it would be difficult, if not impossible, to carve out the synergistic effects of consumption of even small quantities of alcohol in individuals prone to NAFLD.
Irrespective of the etiological underpinnings, the early phase of FLD usually presents as hepatic steatosis, characterized by accumulation of large (macrovesicular) or small (microvesicular) intracytoplasmic fat droplets in hepatocytes (Fig. 1A). Hepatic steatosis is generally considered innocuous, reversible, and, to a large extent, nonprogressive. Progression of hepatic steatosis to steatohepatitis, ASH or NASH, is influenced by the severity and persistence of the underlying cause of steatosis Abbreviations: FLD, f . q liver disease; AFLD, alcoholic f.tp liver disease; NAFLD, nonalcoholic fatty liver disease; ASH, alcoholic steatohepatitis; NASH, nonalcoholic steatohepatitis; PPARs, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; PPREs, peroxisome proliferator response elements.