Non-Alcoholic Fatty Liver Disease and Risk for Intrahepatic and Extrahepatic Cholangiocarcinoma: Meta-Analysis of Case Control Studies: 12

INTRODUCTION: The incidence of cholangiocarcinoma is increasing worldwide. Over 8000 cases of both intrahepatic (ICC) and extrahepatic cholangiocarcinoma (ECC) are diagnosed every year in the US. Several recent studies have evaluated the role of non-fatty alcoholic liver disease (NAFLD) as a risk factor for cholangiocarcinoma. We performed a meta-analysis of case-control studies to evaluate the role of NAFLD as a risk factor for intrahepatic and extrahepatic cholangiocarcinoma. METHODS: We performed a systematic search of Medline, EMBASE and the Cochrane Library for studies without language restriction for case-control studies evaluating the risk of intra-hepatic and extra-hepatic cholangiocarcinoma in adult patients with NAFLD. We also hand searched grey literature from major gastrointestinal meetings. Standardized forms were used to extract data regarding number of cases of NAFLD and cholangiocarcinoma. Data was extracted by two reviewers independently. Summary odds ratio was calculated using Comprehensive Meta-analysis software. Heterogeneity, quality of studies and publication bias were also assessed. Random effects model was used for calculating the effect size. RESULTS: Ten studies met the inclusion criteria. 9 studies reported data on ICC and 5 studies reported data on ECC. Studies were performed in China, Taiwan, Japan, US, Europe and Korea. The period of patient enrollment ranged from 1992 to 2017. The majority of the studies used hospital based controls. The quality of the studies was assessed using Newcastle-Ottawa Scale. NAFLD was associated with a higher risk of ICC (OR 1.78: 95% CI 1.3–2.5, P = 0.001, I 2 = 81). On subgroup analysis based on region of study, the increased risk was seen only in the studies reported from the Asian countries (5 studies, OR 1.93; 95% CI, 1.22–3.05, P = 0.005) but not from the Western countries (4 studies, OR 1.58; 95% CI 0.83–3.0, P = 0.17). On pooling all studies, risk of ECC was not increased in patients with NAFLD (OR 1.38; 95% CI 0.67–2.83, P = 0.55, I 2 = 95%). However on subgroup analysis, increased risk of ECC was seen in the Western countries (2.42; 95% CI 2.01–2.91, P = 0.0001), but not the Asian countries. No significant publication bias was present. CONCLUSION: NAFLD is a risk factor for cholangiocarcinoma. Increased risk of ICC with NAFLD was seen in the Asian countries and ECC in the Western countries. Further studies are needed to confirm these findings.