Bile Biochemistry as a Therapeutic Target in Biliary Surgery: Disease-Specific Evidence and Clinical Limits

Background/Objectives: Bile acid therapies have expanded treatment options for cholestatic disease, but their relevance to biliary surgery depends on the diagnosis and endpoint. This critical narrative review examines where molecular evidence changes care and where surgical applications remain untested. Methods: The existing synthesis was supplemented by targeted literature searches and regulatory checks completed on 20 September 2026. Studies were assessed by design, population, outcome, and applicability to surgical decisions. Results: Genetic assessment can identify inherited cholestasis or selected recurrent lithogenic disorders that persist after anatomical treatment. Evidence for ileal bile acid transporter inhibitors supports indication-specific relief of cholestatic pruritus. Recent trials of receptor agonists show that biochemical, symptomatic, and disease-progression outcomes can diverge. Observational studies support biliary diversion in selected patients with inherited cholestasis, although comparisons among procedures and with drug treatment remain uncertain. The expanding genetic spectrum of progressive familial intrahepatic cholestasis and real-world treatment reports refine patient selection but provide limited evidence for long-term surgical outcomes. Bile metabolomics and synthesis markers remain unvalidated for timing cholecystectomy. Conclusions: Molecular findings are useful when they answer a defined diagnostic or therapeutic question. They can guide specialist treatment and surveillance alongside anatomical assessment. Prospective studies must establish whether molecular stratification improves outcomes in biliary surgical populations.