Nonalcoholic fatty liver disease is associated with intrahepatic cholangiocarcinoma and not with extrahepatic form: definitive evidence from meta-analysis and trial sequential analysis.

Background: Cholangiocarcinoma is a cancer with poor prognosis. The detection of risk factors is fundamental to identify subjects at higher risk of cholangiocarcinoma. Nonalcoholic fatty liver disease (NAFLD) represents a leading cause of chronic liver disease worldwide. Recent data suggested that NAFLD increases the risk of cholangiocarcinoma development. However, it is necessary to better explain the strength of association between NAFLD and cholangiocarcinoma.

Methods: A systematic research of current case-control, cohort, clinical trial and meta-analysis on the main electronic databases was made. A recent systematic review was recognized. We performed cumulative meta-analyses with sensitivity analysis excluding studies with large sample size and with great clinical heterogeneity, then we checked for further studies. At the final step, three trial sequential analyses were done as well.

Results: NAFLD determines an increased risk of total cholangiocarcinoma and intrahepatic cholangiocarcinoma (iCCA) development: odds ratio (OR) (95% confidence interval [CI]): 1.88 (1.25-2.83), OR (95% CI): 2.19 (1.48-3.25), respectively. On the contrary, NAFLD does not show a significant effect on extrahepatic cholangiocarcinoma (eCCA) (OR (95% CI): 1.48 (0.93-2.36). The trial sequential analyses regarding total cholangiocarcinoma and iCCA showed that z-curve was outside computed alpha boundaries, proving that the positive association was conclusive. The trial sequential analysis about eCCA showed that z-curve was inside computed futile boundaries, proving that negative results were conclusive.

Conclusion: The performance of new sensitive analyses and the respective trial sequential analyses, after withdraw of confounding factors, suggested the existence of definitive association only between NAFLD and iCCA development and not with eCCA.