Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH

Oct 10, 2018Transplantation

Key Biological Processes Behind the Progression from Fatty Liver Disease to Liver Inflammation

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming the most frequent indication for liver transplantation in western countries.

NAFLD includes conditions ranging from simple fat accumulation to severe liver damage like cirrhosis and cancer.
Lipid accumulation in predisposed individuals may lead to liver cell death, inflammation, and scarring.
Free fatty acids and free cholesterol have been identified as toxic agents contributing to liver damage.
Pathological interactions between the liver, adipose tissue, and gut are involved in the progression of NAFLD.
Inflamed adipose tissue may release harmful lipids, while changes in gut health could promote inflammatory responses that worsen liver conditions.

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Nonalcoholic fatty liver disease (NAFLD) represents a growing cause of chronic liver injury, especially in western countries, where it is becoming the most frequent indication for liver transplantation. Nonalcoholic fatty liver disease encompasses a spectrum of diseases that from simple steatosis (pure NAFLD) can progress to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD and the mechanisms behind its progression to NASH have been extensively studied. However, although the processes that determine fat accumulation are mostly clear, the mechanisms associated with the progression of the disease are not fully characterized. In predisposed patients, lipid accumulation can promote lipotoxicity and mitochondrial dysfunction, thus triggering hepatocyte death, inflammation and fibrosis. The specific role of different lipids has been identified and free fatty acids as well as free cholesterol have been identified as toxic species. To make the picture more complex, the pathogenesis of NAFLD involves pathological connections between several organs, including the adipose tissue and the gut, with the liver. The "inflamed" adipose tissue plays a key role in the release of toxic lipids, whereas alterations in the gut-liver axis have been associated with the progression from NAFLD to NASH mediated by dysbiosis, alteration of intestinal barrier, and finally bacterial translocation, which can trigger proinflammatory and profibrogenetic pathways, finally leading to cirrhosis development.

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Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH

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