Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormally elevated aminotransferases in the United States. NAFLD encompasses a spectrum of disorders characterized by intrahepatic fat accumulation (simple hepatic steatosis) accompanied by varying degrees of hepatic necroinflammatory activity and hepatic fibrosis (nonalcoholic steatohepatitis or NASH) through to cirrhosis. NAFLD is considered the hepatic manifestation of the metabolic syndrome and is associated with increased mortality, particularly cardiovascular disease (CVD)‐related mortality.

Nonalcoholic fatty liver disease is characterized by fat accumulation in the liver in the absence of excessive alcohol consumption (less than 20 g/day) and exclusion of other secondary causes of hepatic steatosis. Primary NAFLD is closely associated with other features of metabolic syndrome, particularly insulin resistance. Secondary causes of NAFLD can be related to nutrition (i.e., rapid weight loss, malnutrition), drug‐induced (i.e., methotrexate, tamoxifen, chemotherapies, etc.), metabolic (i.e., lipodystrophy, abetaproteinemia) and other causes (i.e., bypass surgery, bacterial overgrowth, celiac disease, etc.).

Nonalcoholic fatty liver disease represents a histopathological spectrum ranging from simple hepatic steatosis to steatohepatitis characterized by necroinflammatory changes which increases the risk for progression to advanced fibrosis and cirrhosis. In 2005, the Pathology Committee of the NASH Clinical Research Network (NASH‐CRN) designed and validated a histological feature scoring system for diagnosing and grading the severity of NAFLD. According to this scoring system, accumulation of greater than 5% hepatic fat is the minimum requirement for the histological diagnosis of NAFLD. Macrovesicular steatosis is usually present in zone 3 or panacinar distribution, while azonal steatosis is most often seen in those with advanced fibrosis.

In contrast to simple steatosis, steatohepatitis (NASH) is characterized by the presence of macrovesicular steatosis and necroinflammatory changes including cytological ballooning and lobular inflammation. Histological distinction between simple steatosis and NASH is important because 25–50% of patients will develop progressive fibrosis and 15–25% will progress to cirrhosis, while only 1–4% of patients with simple steatosis will progress to advanced fibrosis. The presence of cytological ballooning is key to diagnosis of steatohepatitis even when there is a paucity of hepatic steatosis or lobular inflammation. Ballooning injury results in cellular change in which the hepatocytes become enlarged and the cytoplasm becomes irregularly clumped with optically clear, nonvesiculated areas. Ballooned hepatocytes may form Mallory–Denk bodies (MDB), which are eosinophilic, ropey cytoplasmic inclusions consisting of hyperphosphorylated, misfolded cytokeratin filaments.

In steatohepatitis, fibrosis classically begins in zone 3 as delicate strands of collagen that are present in a perisinusoidal distribution. Periportal fibrosis can subsequently develop and extend into the surrounding parenchyma. With progression of fibrosis, there is an overall reduction in hepatic steatosis, inflammation, and ballooning. Unlike viral hepatitis, bridging fibrosis in NASH may result from extension of the perisinusoidal fibrosis with retention of the hepatocytes within the fibrotic network. These complexes of trapped hepatocytes within the fibrotic network are eventually replaced with regenerative nodules with progression to cirrhosis. Other histological features, including nonzonal small patches of hepatoctyes with microvesicular steatosis, megamitochondria, glycogenated nuclei, large lipogranuloma, and hepatocellular glycogenosis, may be seen in biopsies of patients with NAFLD but the clinical significance of these findings is unclear.