A Restricted Biliary and Cholesterol-Related Biomarker Pattern Associated with Cholecystectomy: Population-Level and Mouse Transcriptomic Evidence

Abstract Background Cholecystectomy may influence hepatobiliary physiology and lipid metabolism, but population-level biomarker patterns and their distinction from associations with underlying gallstone disease remain unclear. We examined liver and lipid biomarkers in relation to self-reported gallbladder surgery and explored potentially relevant hepatic molecular pathways. Methods We conducted a cross-sectional analysis of adults aged ≥ 20 years in the nationally representative NHANES 2017–March 2020 pre-pandemic cycle. Survey-weighted linear regression models evaluated associations of gallbladder surgery with seven liver and four lipid biomarkers after adjustment for demographic, socioeconomic, metabolic, lifestyle, and medication-related factors. Secondary analyses examined joint gallstone–surgery categories, time since surgery, effect modification, and multiple sensitivity analyses. Public mouse liver transcriptomic data were re-analyzed using Hallmark gene-set enrichment analysis. Results Among 9,232 adults, 1,025 reported previous gallbladder surgery. In fully adjusted models, surgery history was associated with 12.4% higher total bilirubin (95% CI, 6.6%–18.6%), 2.7% higher alkaline phosphatase (95% CI, 0.6%–4.8%), and 5.87 mg/dL lower total cholesterol (95% CI, − 10.04 to − 1.69) after false-discovery-rate correction. Bilirubin elevation was concentrated among participants reporting both gallstones and surgery, whereas lower total cholesterol was observed in both surgery groups irrespective of gallstone history. Cholesterol-homeostasis and bile-acid-metabolism pathways were negatively enriched 30 days after cholecystectomy. Conclusion Gallbladder surgery history was associated with a restricted biliary and cholesterol-related biochemical pattern rather than generalized hepatic dysfunction. Longitudinal studies are needed to distinguish effects of surgery from those of underlying gallstone disease.