Published online Sep 28, 2014. doi: 10.3748/wjg.v20.i36.12945
Revised: April 28, 2014
Accepted: May 25, 2014
Published online: September 28, 2014
Processing time: 226 Days and 18.5 Hours
Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
Core tip: Nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger of hepatocellular carcinoma (HCC), even in non-cirrhotic livers. The role of inherited factors seems magnified in fatty liver. The common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism has been associated with HCC. Rare loss-of-function mutations in apolipoprotein B resulting in very low density lipoproteins hepatic retention and in telomerase reverse transcriptase influencing senescence have been linked to HCC in NAFLD. Hepatic stellate cells senescence has also been suggested to bridge tissue aging with microbiota alterations in the pathogenesis of obesity-related HCC.