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Pathogenesis of nonalcoholic fatty liver disease

David A Tendler, MD
Section Editor
Keith D Lindor, MD
Deputy Editor
Kristen M Robson, MD, MBA, FACG


Nonalcoholic fatty liver disease (NAFLD) is a clinico-histopathological entity with histological features that resemble alcohol-induced liver injury, but by definition, it occurs in patients with little or no history of alcohol consumption. It encompasses a histological spectrum that ranges from fat accumulation in hepatocytes without concomitant inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) that may or may not have associated fibrosis. The latter condition, referred to as nonalcoholic steatohepatitis (NASH), may progress to cirrhosis in up to 20 percent of patients [1]. NASH is now recognized to be a leading cause of cryptogenic cirrhosis [2].

The pathogenesis of nonalcoholic fatty liver disease has not been fully elucidated. The most widely supported theory implicates insulin resistance as the key mechanism leading to hepatic steatosis, and perhaps also to steatohepatitis. Others have proposed that a "second hit," or additional oxidative injury, is required to manifest the necroinflammatory component of steatohepatitis. Hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria have all been suggested as potential oxidative stressors.

This topic review will focus on the pathogenesis of NAFLD. An approach to such patients is presented separately. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults" and "Natural history and management of nonalcoholic fatty liver disease in adults".)


Hepatic steatosis is a manifestation of excessive triglyceride accumulation in the liver. This can occur from the excessive importation of free fatty acids (FFA) from adipose tissue, from diminished hepatic export of FFA (secondary to reduced synthesis or secretion of very low-density lipoprotein [VLDL]), or from impaired beta-oxidation of FFA. The major sources of triglycerides are from fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis [3].

Excessive importation of FFA can result from either increased delivery of triglycerides to the liver (as seen with obesity and rapid weight loss), or from excessive conversion of carbohydrates and proteins to triglycerides (eg, secondary to overfeeding or use of total parenteral nutrition).

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Literature review current through: Nov 2017. | This topic last updated: Mar 09, 2016.
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