Background & Aims
Cholangiocarcinoma (CCA) carries a poor prognosis, is increasing in incidence and its causes are poorly understood. Although some risk factors are known, they vary globally and collectively account for a minority of cases. The aim of this study was to perform a comprehensive meta-analysis of risk factors for intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), from Eastern and Western world studies.

Methods
A literature search of case-control studies was performed to identify potential risk factors for iCCA and eCCA. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Funnel plots were used to assess publication bias, and meta-regression was used to select risk factors for comparison between Eastern and Western studies.

Results
A total of 13 risk factors were selected from 25 case-control studies in 7 geographically diverse countries. The strongest risk factors for both iCCA and eCCA were biliary cysts and stones, cirrhosis, hepatitis B and hepatitis C. Choledochal cysts conferred the greatest risk of both iCCA and eCCA with pooled ORs of 26.71 (95% CI 15.80–45.16) and 34.94 (24.36–50.12), respectively. No significant associations were found between hypertension and obesity for either iCCA or eCCA. Comparing Eastern and Western populations, there was a difference for the association of hepatitis B with iCCA (coefficient = −0.15195; 95% CI −0.278 to −0.025; p = 0.022).

Conclusion
This is the most comprehensive meta-analysis of CCA risk factors to date. Some risk factors, such as diabetes, although less strong, are increasing globally and may be contributing to rising rates of this cancer.