Non-alcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic
steatohepatitis (NASH) are common causes of chronic liver disease and
major components of the metabolic syndrome. NASH is characterized by the presence
of steatosis with necro-inflammation and fibrosis, progressing to cirrhosis and
hepatocellular carcinoma. The pathogenesis of NAFLD and NASH originally was
regarded as “two-hit” model, suggesting that the accumulation of fat in the liver cells
(steatosis) as the first sensitizes the liver to a second hit that triggers a cascade of tissue
damages (necro-inflammation and fibrosis). Today, it is widely accepted, that a more
complex process, involving multiple parallel metabolic hits is responsible for tissue
injury, and that other factors promote disease progression. Thus, now, lipotoxicity,
mitochondrial dysfunction, insulin resistance and oxidative stress are considered as the
main mechanisms in the pathogenesis of NASH. Reactive oxygen species (ROS), lipid
peroxidation products and cytokines are involved in the progression, including the
migration of resident hepatic pro-fibrogenic cells, which leads to fibrosis. Hepatocyte
death, inflammation, and cellular senescence also play a role in the pathogenesis of the
disease. The interaction between inflammatory cells including Th17 cells and other cell
types such as hepatocytes, stellate cells, hepatic progenitor cells and ductular
components is of pivotal importance, as well as the reactivation of developmental
morphogenic signaling pathway, the hedgehog.
Keywords: Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis,
Pathogenesis.