Nonalcoholic Fatty Liver Disease and Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease in the United States and globally and is estimated to affect approximately 25% of the world population. The increasing prevalence of NAFLD is attributed to the concurrent rise of obesity, diabetes mellitus, hyperlipidemia, cardiovascular disease, and other manifestations of the metabolic syndrome.

The spectrum of nonalcoholic liver disease ranges from simple fatty liver, or NAFLD, to nonalcoholic steatohepatitis (NASH), characterized by cytolytic changes in hepatocytes, such as ballooning degeneration, Mallory (hyaline) bodies, and lobular inflammation ( Fig. 160.1 ). It is this subset of patients with NASH who are at risk for progressive liver fibrosis, ranging from pericellular and perivenular or perisinusoidal fibrosis in zone 3 of the liver lobule to bridging fibrosis and cirrhosis. In the late stages, the fatty infiltration may disappear, leaving a picture of cirrhosis of unclear etiology, often described as cryptogenic cirrhosis.

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Nonalcoholic Steatohepatitis.

Most patients with NAFLD or NASH have features of insulin resistance and may also have syndrome X, characterized by central or visceral obesity, type 2 diabetes, and dyslipidemia. The prevalence of NAFLD appears to be increasing rapidly, in parallel with the epidemic of obesity in Western countries. Multiple environmental factors likely play roles, including high-calorie and high-carbohydrate intake, sedentary lifestyle, and greater consumption of highly refined or processed sugars. In fact, NASH is increasingly observed in children, the population with the fastest-growing incidence of type 2 diabetes. Population-based studies suggest that the prevalence of NAFLD and NASH may be as high as 25% and 2% to 3%, respectively, in the general population. Prospective liver biopsy data from living donors in living-related liver transplantation have shown NASH in up to 25%.

The primary insult in NASH is thought to be insulin resistance, which may lead to increased circulating concentrations of free fatty acids. These may accumulate in the liver, leading to steatosis. A second insult, or second “hit,” may lead to oxidative stress in the liver, resulting in progression to NASH. Many such possible second hits have been proposed, such as altered mitochondrial uncoupling proteins (UCP-2), cytochrome P450 2E1, excess iron, and activation of proinflammatory cytokines, such as tumor necrosis factor-α, nuclear factor kappa B, and interleukin-1, as well as other cascade pathways.