Association between gallstones and the risk of biliary tract cancer: a systematic review and meta-analysis

Abstract

Objectives: Biliary tract cancers (BTCs) are rare but highly fatal. Although the etiology of BTC is poorly understood, gallstones are proposed to be a major risk factor. We conducted a systematic review and meta-analysis to examine the associations between gallstone characteristics and BTC risk.

Methods: We searched the MEDLINE, Embase, and Cochrane Central databases and systematically reviewed cohort and case-control studies published before April 9, 2018. All the included studies reported appropriate risk estimates and confidence intervals (CIs) for associations between the presence, size, number, or duration of gallstones and the risk of BTC, including gallbladder cancer (GBC), extrahepatic bile duct cancer (EBDC), and ampulla of Vater cancer (AOVC). Summary odds ratios (ORs) and their 95% CIs were calculated using a random-effects model in the meta-analysis. Subgroup analyses were conducted to inspect sources of potential heterogeneity, and the Egger test was performed to assess publication bias.

Results: Seven cohort studies and 23 case-control studies in Asian, European, and American populations were included. The presence of gallstones was associated with an increased risk of BTC (OR, 4.38; 95% CI, 3.23 to 5.93; I2=91.2%), GBC (OR, 7.26; 95% CI, 4.33 to 12.18), EBDC (OR, 3.17; 95% CI, 2.24 to 4.50), and AOVC (OR, 3.28; 95% CI, 1.33 to 8.11). Gallstone size (>1 vs. <1 cm; OR, 1.88; 95% CI, 1.10 to 3.22) was significantly associated with the risk of GBC.

Conclusions: Gallstone characteristics, such as presence, size, and number, are associated with an increased risk of BTC. However, significantly high heterogeneity in the meta-analyses is a limitation of this study.

Keywords: Ampulla of Vater; Bile duct neoplasms; Biliary tract neoplasms; Cholangiocarcinoma; Gallbladder neoplasms; Gallstones.

Figure 1.

Flow chart of study selection for the meta-analysis.

Figure 2.

Forest plot showing the relationship between presence of gallstone and the risk of BTC. ¹OR (95% CI) refers to the estimate of effects included in a random-effects model. ²Effect size of Lai et al. [27] was calculated by pooling the results of DM group and non-DM group. ³Effect size of Lowenfels et al. [29] was calculated by pooling the results of Indian and non-Indian. ⁴Pooled the results of three types BTC subsites. ⁵Pooled the results of two types BTC subsites. The numbers are arranged in the order of Table 1. OR, odds ratio; CI, confidence interval; GBC, gallbladder cancer; CCA, cholangiocarcinoma; BTC, biliary tract cancer; EBDC, extrahepatic bile duct cancer; AOVC, ampulla of Vater cancer; DM, diabetes mellitus.