Risk Factors for Intrahepatic and Extrahepatic Cholangiocarcinoma: a systematic review and meta-analysis

Abstract Background and 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. This study aimed 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 (OR) with 95% confidence intervals and heterogeneity were calculated. Funnel plots were used to assess for publication bias, and meta-regression for select risk factors to compare East versus West studies. Results 13 risk factors were selected from 25 case-control studies in seven 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 inferred the greatest risk of both iCCA and eCCA with pooled OR 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. Lay summary Cholangiocarcinoma (CCA) is a cancer arising in the bile ducts inside (intrahepatic CCA, iCCA) and connected to the liver (extrahepatic, eCCA). It is a very aggressive cancer: 95% of patients die within five years. CCA rates are increasing globally, but the causes of CCA are poorly understood. Those few risk factors that are known account for only a minority of cases. This study aimed to combine and analyse data from previous studies to clarify and quantify the risk factors for CCA and compare them in Eastern and Western countries. The strongest risk factors for both iCCA and eCCA are cysts and stones in the bile ducts, cirrhosis and viruses hepatitis B and C. Some risk factors for CCA, such as diabetes, although relatively less strong, are increasing globally and may be contributing to rising rates of this cancer.