Environmental Risk Factors for Gallbladder Cancer: Field-Wide Systematic Review and Meta-Analysis

Background & aims: Cholelithiasis is the most well-recognized risk factor for gallbladder cancer (GBC), the predominant biliary-tract malignancy; however, credibility on other modifiable exposures remains uncertain. We performed a field-wide systematic review and meta-analysis on environmental factors associated with GBC.

Methods: We systematically searched Medline/PubMed and Embase up to May 8, 2023, to identify randomized and nonrandomized studies examining environmental factors for GBC. We conducted random-effects meta-analyses focusing on longitudinal studies. Evidence from case-control studies was considered complementary. Evidence credibility was graded by prespecified criteria including the random-effects estimate, 95% confidence interval (CI), P value, statistical heterogeneity, small-study effects, and robustness to unmeasured confounding.

Results: We identified 215 eligible primary studies and performed 350 meta-analyses across 7 domains: lifestyle, reproductive, metabolic, dietary, infections, interventions, and contaminants and occupational exposures. Based on longitudinal evidence, body mass index (relative risk [RR] _{per 5-unit increase}, 1.27; 95% CI, 1.21‒1.33), hip circumference (RR _{per 5-cm increase}, 1.16; 95% CI, 1.11‒1.22), infection of bile ducts (RR, 31.7; 95% CI, 24.8-40.6), high parity (RR, 1.48; 95% CI, 1.30‒1.68), obesity (RR, 1.70; 95% CI, 1.44‒2.01), overweight (RR, 1.28; 95% CI, 1.14‒1.43), waist circumference (RR _{per 5-cm increase}, 1.14; 95% CI, 1.10‒1.18), and waist-to-height ratio (RR _{per 0.1 increase}, 1.49; 95% CI, 1.36‒1.64) were robustly associated with increased GBC risk, whereas high education (RR, 0.63; 95% CI, 0.49‒0.82) was associated with reduced risk (moderate-to-high credibility). Another 39 significant associations showed lower credibility, including different exposure scenarios of tobacco smoking, alcohol consumption, and insufficient physical activity.

Conclusions: This study offers a detailed appraisal and mapping of the evidence on modifiable factors for GBC. Further high-quality prospective studies are essential to validate emerging associations and inform preventive strategies in high-incidence areas. (Systematic review registration: CRD42023434673.).