Mechanisms of disease progression in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic pathology, ranging from simple steatosis (also called nonalcoholic fatty liver or NAFL) in its most benign form, to cirrhosis in its most advanced form. Nonalcoholic steatohepatitis (NASH) is an intermediate level of hepatic pathology. Hepatocyte accumulation of triglyceride is a hallmark of NAFL and NASH, but this sometimes subsides once cirrhosis has developed. Triglyceride storage per se is not hepatotoxic. Rather, it is a marker of increased exposure of hepatocytes to potentially toxic fatty acids. NAFL progresses to NASH when adaptive mechanisms that protect hepatocytes from fatty acid-mediated lipotoxicity become overwhelmed and rates of hepatocyte death begin to outstrip mechanisms that normally regenerate dead hepatocytes. This triggers repair responses that involve activation of hepatic stellate cells to myofibroblasts. The myofibroblasts generate excessive matrix and produce factors that stimulate expansion of liver progenitor populations. The progenitor cells produce chemokines to attract various kinds of inflammatory cells to the liver. They also differentiate to replace the dead hepatocytes. The intensity of these repair responses generally parallel the degree of hepatocyte death, resulting in variable distortion of the hepatic architecture with fibrosis, infiltrating immune cells, and regenerating epithelial nodules. As in other types of chronic liver injury, cirrhosis ensues in patients with NAFLD when repair is extreme and sustained, but ultimately unsuccessful, at reconstituting healthy hepatic epithelia.
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Related Subject Headings
- Oxidation-Reduction
- Liver Neoplasms
- Liver Cirrhosis
- Liver
- Insulin Resistance
- Humans
- Hepatocytes
- Gastroenterology & Hepatology
- Fatty Liver
- Fatty Acids, Nonesterified
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Oxidation-Reduction
- Liver Neoplasms
- Liver Cirrhosis
- Liver
- Insulin Resistance
- Humans
- Hepatocytes
- Gastroenterology & Hepatology
- Fatty Liver
- Fatty Acids, Nonesterified