Non-Alcoholic Fatty Liver Disease as a Risk Factor for Cholangiocarcinoma: A Systematic Review and Meta-Analysis

Liver organoids: from basic research to therapeutic applications

“…The potential of liver organoids as tools to model other key chronic liver diseases, namely NAFLD and liver fibrosis, is a promising but yet unexplored field. NAFLD has taken the lead as the most common chronic liver disease in developed countries,102 encompassing a broad and progressive spectrum of liver histological alterations—from fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH)—which is an established risk factor for both HCC103 104 and CC 105. An additional strong predictor of liver-related mortality risk in NAFLD106 is fibrosis (an abnormal although reversible deposition of ECM proteins).…”

Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease

“…33,44 Hence, NAFLD, one of the most common causes of chronic liver disease, 1 has also become a leading cause of primary hepatobiliary malignancy. [1][2][3] NAFLD-related liver cancers are often attributed to chronic inflammation and consequent insulin resistance/hyperinsulinemia. 3 Pro-inflammatory cytokines also suppress hepatocyte expression of ESRP2 and promote accumulation of fetal NF2 variants.…”

“…Human NASH and liver cancer show ESRP2 suppression, enrichment with fetal NF2 splice variants, and YAP/TAZ activation NASH increases the risk for both HCC and cancers of the biliary tree (CCA). [1][2][3] Similar to mouse models of NASH that increase the odds for liver cancer, humans with NASH exhibit hepatic induction of developmental signaling pathways, 34 activation of YAP/TAZ, 35 accumulation of YAP(+) ductal cells (a.k.a., the ductular reaction), 36 and liver enrichment for pathways associated with cancer. 37,38 To determine if humans with NAFLD also exhibit reduced expression of ESRP2 we analyzed publicly-available liver RNA sequencing data.…”

“…Liver cancers related to non-alcoholic fatty liver disease (NAFLD) are typically incurable and predicted to progressively increase in incidence and prevalence due to the obesity pandemic which is fueling NAFLD pathogenesis. 1 NAFLD increases the odds of all 4 types of primary liver cancer (i.e., hepatocellular carcinoma [HCC], intra-and extra-hepatic cholangiocarcinoma [CCA], and mixed HCC-CCA) [1][2][3] and unlike most chronic liver diseases which mainly increase the risk of HCC via cirrhosis, NAFLD often leads to cancer in non-cirrhotic livers. 4 Because the mechanisms that enhance vulnerability to hepatobiliary carcinogenesis in NAFLD are poorly understood, developing biomarkers and interventions to improve prevention, diagnosis and treatment of NAFLDrelated liver cancers has languished.…”

Nonalcoholic fatty liver disease and alcoholic liver disease: metabolic diseases with systemic manifestations

“…Aside from the overall increased incidence of HCC observed with progression of cirrhosis, two major systematic reviews and meta-analyses have shed light upon increased malignancy risk observed among NAFLD patients. One study analyzed seven case-control studies comparing a total of 9,102 patients with cholangiocarcinoma against 129,111 controls (57). NAFLD was identified as a risk factor for the development of both intrahepatic (OR 2.22, 95% CI: 1.52-3.24) and extrahepatic cholangiocarcinoma (OR 1.55, 95% CI: 1.03-2.33), respectively.…”