Abstract
Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and encompasses a large spectrum of clinic-pathological entities including steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis and its complications[1]
A rapid progression to NASH with stage three fibrosis (12 weeks) and hepatocellular carcinoma (HCC) development (24 weeks) has been observed in the mouse model developed by Tsuchida et al.[77] who administered to C57BL/6J mice a Western diet rich in fat, fructose, and cholesterol combined with a weekly dose of intraperitoneal carbon tetrachloride
The prevalence of NAFLD and the low incidence of HCC among patients without cirrhosis makes the surveillance in NAFLD non-cirrhotic patients not cost-effective
Summary
Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of metabolic syndrome and encompasses a large spectrum of clinic-pathological entities including steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis and its complications[1]. NAFLD patients, the rs780094 C>T variant has been associated with the severity of liver fibrosis and with higher serum triglyceride values[41], whereas the role of this SNP in determining the progression of NAFLD to HCC has not yet been clarified.
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