Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role

SIMPLE SUMMARY: The prevalence of intrahepatic cholangiocarcinoma (iCCA) is rising. About 50% of iCCA arise in patients without known risk factors. We hypothesized that nonalcoholic fatty liver disease (NAFLD) and its most aggressive phenotype (NASH) could be risk factors for iCCA, similarly to other liver malignancies. We verified whether the prevalence of NAFLD and NASH was higher in the peritumor samples of iCCA patients compared with matched healthy controls (liver donors). We found the NASH (but not NAFLD) was over-represented in iCCA patients. Moreover, NASH patients had a shorter survival. Our results demonstrated that NASH is a risk factor for iCCA and underline the importance of dissecting the role of NASH from that of NAFLD as a whole. Prevention protocols for NASH patients should consider also the risk for iCCA and not only HCC. Studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information. ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA (n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723–7.626, p < 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156–2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.