The liver can show any of the three types of changes discussed earlier (steatosis, steatohepatitis, and cirrhosis), though on average inflammation is less prominent than in alcoholic liver disease. The term nonalcoholic steatohepatitis (NASH) is used to describe overt clinical features of liver injury, such as elevated transaminases, and the histologic features of hepatitis already discussed. NAFLD is consistently associated with insulin resistance and the metabolic syndrome (Chapter 8). Other commonly associated abnormalities are as follows:
Type 2 diabetes (or family history of the condition)
Obesity, primarily central obesity (body mass index >30 kg/m2 in whites and >25 kg/m2 in Asians)
Dyslipidemia (hypertriglyceridemia, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol)
The key initiating events in NAFLD appear to be the development of obesity and insulin resistance, the latter within both adipose tissue and the liver. These factors combine to increase the mobilization of free fatty acids from adipose tissue, which are taken up by hepatocytes, and to stimulate the synthesis of fatty acids within hepatocytes. It is estimated that over half of the lipid found in hepatocytes in NAFLD is derived from adipose tissue, with most of the remainder coming from de novo synthesis in liver cells. Precisely how the accumulation of lipid in hepatocytes predisposes to the development of NASH is not known and may involve several interrelated mechanisms. Excessive intrahepatic lipids and their metabolic intermediates enhance insulin resistance in the liver and sensitize hepatocytes to the toxic effects of inflammatory cytokines, which are produced in increased amounts in the setting of the metabolic syndrome. In addition, hepatocytes in patients with NASH show evidence of inflammasome activation, possibly due to direct or indirect effects of particular lipids, leading to local release of the pro-inflammatory cytokine IL-1. Other products of lipid metabolism appear to be directly toxic to hepatocytes; proposed mechanisms include increased production of reactive oxygen species, induction of ER stress, and disruption of mitochondrial function. Liver injury resulting from these various insults causes stellate cell activation, collagen deposition, and hepatic fibrosis, which along with ongoing hepatocyte damage lead to full-blown NASH.
NAFLD is the most common cause of incidental elevation of serum transaminases. Most individuals with steatosis are asymptomatic; patients with active steatohepatitis or fibrosis may also be asymptomatic, but some may have fatigue, malaise, right upper-quadrant discomfort, or more severe symptoms of chronic liver disease. Liver biopsy is required to identify NASH and distinguish it from uncomplicated NAFLD. Fortunately, the frequency of progression from steatosis to active steatohepatitis and then from active steatohepatitis to cirrhosis is low (
Fig. 16.19 ). Nevertheless, NAFLD is considered to be a significant contributor to the pathogenesis of “cryptogenic” cirrhosis. Because they share common risk factors, the incidence of coronary artery disease also is increased in patients with NAFLD.
Current therapy is directed toward obesity reduction and reversal of insulin resistance. Lifestyle modifications that lead to weight loss (diet and exercise) appear to be the most effective form of treatment.
Pediatric NAFLD is becoming an increasing problem as obesity and metabolic syndrome approach epidemic proportions. In children, the appearance of the histologic lesions is somewhat different, as inflammation and scarring tend to be more prominent in the portal tracts and periportal regions, and mononuclear infiltrates rather than neutrophilic infiltrates predominate.
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