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Nonalcoholic fatty liver disease (NAFLD) is caused by an excessive accumulation of fat within the liver in the absence of other drivers of hepatic steatosis such as alcohol consumption, infection with genotype 3 HCV, or monogenic hereditary disorders. In lieu of these risk factors, NAFLD is closely linked with components of metabolic syndrome such as obesity, diabetes and insulin resistance, dyslipidemia, and hypertension. As such, NAFLD is often viewed as the hepatic manifestation of metabolic syndrome. The worldwide rise in obesity, which has been paralleled by an increase in the prevalence of NAFLD, is attributed to societal changes promoting a sedentary lifestyle and broadening access to high-caloric food and beverages, creating an increasingly obesogenic environment. Indeed, NAFLD now represents the most common cause of abnormal liver blood tests and chronic liver disease in the Western world. Nonalcoholic steatohepatitis (NASH) is currently the second leading cause of liver disease among those awaiting liver transplantation in the United States. Due to the combination of increasing obesity prevalence worldwide, the lack of an established noninvasive diagnostic, and the absence of therapies proven to impede progression, NASH is anticipated to soon become the primary indication for liver transplantation.
The term NAFLD refers to a spectrum of progressive liver damage caused by fat accumulation, ranging from a more indolent steatosis to decompensated liver cirrhosis. The initial stages—termed nonalcoholic fatty liver—are limited to fat accumulation only, with no evidence of inflammation or hepatocyte injury. Later stages are characterized by lobular inflammation and hepatocyte ballooning, which reflect the immune response to liver injury and cellular damage, and can be accompanied by activation of hepatic stellate cells and ultimately fibrogenesis. The presence of inflammation and ballooning is termed NASH. Individuals with NASH can experience either regression to indolent steatosis, smoldering in a steady state of disease activity, or progression to fibrosis and even cirrhosis. In the United States, approximately 25% of adults with NAFLD will progress to inflammatory NASH, which increases the risk of progressive fibrosis, hepatocellular carcinoma, and liver-related mortality.[6,7]