Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma

Abstract

Background & aims: Well established risk factors for intrahepatic cholangiocarcinoma such as biliary tract inflammation and liver flukes are not present in most Western countries patients. Although cirrhosis and other causes of chronic liver disease have been implicated, their contribution as risk factors for cholangiocarcinoma is unclear and our aims were to analyze these emerging potential risk factors by systematic examination of case-control series from geographically diverse regions.

Methods: We performed a literature review and meta-analysis of case-control studies on intrahepatic cholangiocarcinoma and cirrhosis and related risk factors. Tests of heterogeneity, publication bias and sensitivity analyses were performed and an overall odds ratio and 95% confidence intervals calculated.

Results: Eleven studies from both high and low prevalence regions were identified. All studies except those evaluating cirrhosis, diabetes, and obesity exhibited significant heterogeneity. Cirrhosis was associated with a combined OR of 22.92 (95% CI=18.24-28.79). Meta-analysis estimated the overall odds ratio (with 95% confidence intervals) for defined risk factors such as hepatitis B: 5.10 (2.91-8.95), hepatitis C: 4.84 (2.41-9.71), obesity: 1.56 (1.26-1.94), diabetes mellitus type II: 1.89 (1.74-2.07), smoking: 1.31 (0.95-1.82), and alcohol use: 2.81 (1.52-5.21). Sensitivity analysis did not alter the odds ratio for any risk factors except smoking and there was no evidence of publication bias.

Conclusions: Cirrhosis, chronic hepatitis B and C, alcohol use, diabetes, and obesity are major risk factors for intrahepatic cholangiocarcinoma. These data suggest a common pathogenesis of primary intrahepatic epithelial cancers.

Fig. 1. Selection of studies for analysis

Flow diagram of identification of studies evaluated in this analysis. 11 case-control studies evaluating risk factors of interest for intrahepatic cholangiocarcinoma were identified.

Fig. 2. Cirrhosis as a risk factor for Intrahepatic Cholangiocarcinoma

A forest plot of case control studies for the association of cirrhosis with intrahepatic cholangiocarcinoma using a fixed effects analysis. The horizontal axis indicates the odds ratio on a log scale. Horizontal lines, 95% CI of point estimates indicated as solid squares, the size of which reflects the percent weight accorded the study in the analysis. The vertical axis indicates individual studies and line of null effect. Vertical solid line indicates the pooled estimate.

Fig. 3. Meta-analyses of case-control studies

A forest plot of case control studies for the association of selected risk factors with intrahepatic cholangiocarcinoma was generated using a random effects analysis for (A) Hepatitis B, (B) Hepatitis C, (C) Alcohol use, (D) Smoking; or using a fixed effects analysis for (E) Diabetes Mellitus type II and (F) Obesity. The horizontal axis indicates the odds ratio (log scale). Horizontal lines, 95% CI of point estimates indicated as solid squares, the size of which reflects the percent weight accorded the study. The vertical axis indicates individual studies and line of null effect.

Fig. 4. Risk factors for Intrahepatic Cholangiocarcinoma

Overall odds ratio (vertical axis) with 95% confidence intervals for intrahepatic cholangiocarcinoma are shown for selected risk factors based on meta-analysis of case-control studies. HBV, Hepatitis B; HCV, Hepatitis C.