Risk Factors for Cholangiocarcinoma, Role of Diabetes Mellitus and Hepatitis B Virus Infection in the Intrahepatic and Extrahepatic Cholangiocarcinoma: A case-control study in China

Background: Diabetes mellitus (DM) and hepatitis B virus infection enhance the incidence of intrahepatic and extrahepatic cholangiocarcinoma, but their significance is unclear. Here, we conducted a population-based case-control study in China to evaluate the effects of DM, HBV infection, and other possible risk factors for cholangiocarcinoma. Methods: A hospital-based, case-control study of 245 CCA patients (168 eCCA and 77 iCCA) diagnosed at The Second Affiliated Hospital of Harbin Medical University in China between January 2019 and June 2024 and 490 healthy controls matched 2:1. Cholangiocarcinoma risk variables and correlations were analyzed using conditional logistic regression and the synergism index. Results: Cholangiocarcinoma (CCA) was significantly and positively correlated with diabetes mellitus, HBV infection, cholecystolithiasis, choledocholithiasis, hepatolithiasis, cholecystectomy history, and thyroid diseases, with adjusted odds ratios AOR= 1.41, 0.35, 1.70, 5.40, 0.30, 0.49, 5.42, respectively. Without complications, diabetes mellitus had an AOR=0.21 and with complications, AOR=0.46, which are substantial risk factors for CCA. eCCA Cholelithiasis (AOR=1.51), CBD stones (AOR=4.51), hepatolithiasis (AOR=0.29), and thyroid disorders (AOR=8.56) were significant in subgroup analyses. Diabetes mellitus without and with complications (AOR=0.43 and AOR=0.70) also increased eCCA risk. Cholelithiasis, cholecystectomy, hepatolithiasis, and HBV infection were risk factors for iCCA (AOR=4.91, 0.39, 0.34, and 0.20), respectively. However, diabetic mellitus (AOR=1.30) is also a significant risk factor for iCCA. Conclusion: In this study, cholelithiasis, hepatolithiasis, CBD stones, HBV infection, and diabetes mellitus (DM) were independent risk factors for cholangiocarcinoma, especially extrahepatic and intrahepatic cholangiocarcinoma. By understanding this synergy, high-risk cholangiocarcinoma prevention methods can be devised.