Bile Acid Sequestrants in Primary Sclerosing Cholangitis and the Risk of Acute Cholangitis: Cause for Concern?

Kulkarni et al present a multicenter retrospective analysis examining the association between statin therapy and the risk of acute cholangitis in patients with primary sclerosing cholangitis (PSC) (1). Although patients receiving statins were older and at higher baseline risk, the observed association with reduced acute cholangitis events remained consistent after multiple adjustment strategies, suggesting that confounding by age alone is unlikely to fully explain the findings. The proposed mechanistic link between statin therapy and delayed stricture progression is biologically plausible. Given the uncertainty regarding the optimal latency time window, the authors performed secondary analyses using a 1-year exposure lag and assessed the impact of duration of statin use, age subgroups, and cirrhosis or hepatic decompensation. This approach provides robust methodological support for their conclusion of a potential protective effect of statins. An important finding that warrants more detailed consideration relates to cholestyramine, a bile acid sequestrants (BAS). Given the magnitude of the association and the widespread use of BAS in PSC, this result deserves a more nuanced discussion. The association between BAS use and acute cholangitis was strong (hazard ratio 2.98), yet this result was discussed only briefly and largely attributed to indication bias. Unlike statins, BAS exposure was not analyzed as a time-dependent variable, and there was no assessment of duration or cumulative dose. Sensitivity analyses were not performed, and confounding by indication—such as the underlying severity of cholestatic pruritus—was largely unaddressed. Interpretation of the finding was limited, attributing the increased risk primarily to differences in patient characteristics rather than considering BAS as a potential contributor to adverse outcomes. BAS such as cholestyramine bind bile acids in the intestinal lumen and interrupt enterohepatic recirculation, increasing fecal bile acid loss and inducing compensatory changes in hepatic bile acid metabolism (2,3). Alterations in bile acid homeostasis are a hallmark of chronic cholestatic liver diseases such as PSC (4). Although there is no direct evidence that BAS use impairs biliary antimicrobial defenses or reduces bile clearance in vivo, these observations raise a plausible hypothesis for the association with increased cholangitis risk, which merits cautious interpretation. Exploring BAS exposure not solely as a marker of more severe pruritus, but also as a potential contributor to adverse outcomes, would strengthen the clinical relevance of the study. Current evidence for the efficacy of BAS in PSC-associated pruritus is limited. As stated in the 2022 European Association for the Study of the Liver PSC Clinical Practice Guidelines (4), cholestyramine is not formally recommended because of lack of efficacy, and colesevelam failed to demonstrate benefit in a randomized, placebo-controlled trial (5). Moreover, BAS can impair intestinal absorption of several medications, including ursodeoxycholic acid, complicating the risk-benefit profile in PSC (3). In light of these considerations, the strong association observed between BAS use and acute cholangitis in PSC subjects warrants careful reassessment of their role in routine clinical practice. Beyond ethical considerations related to patient safety, uncontrolled BAS exposure may introduce substantial confounding and compromise interpretability of extremely complex randomized clinical trials in PSC. CONFLICTS OF INTEREST Guarantor of the article: Vincenzo Cardinale, MD, PhD. Specific author contributions: Writing of the manuscript: V.C., L.R. Critical revision of the manuscript for important intellectual content: D.A. Final approval: V.C., L.R., D.A. Financial support: V.C. and D.O. were funded by the European Union—Next Generation EU, Mission 4, Component 2, CUP B93D21010860004, Spoke 1, by Project PNC 0000001 D3 4 Health—CUP B53C22006120001, The National Plan for Complementary Investments to the NRRP, Funded by the European Union—NextGenerationEU, and by PRIN 2022 (project n. 20222J7W2K). V.C. and D.A. were funded by Next Generation Europe Grant PE 6 FONDAZIONE HEAL ITALIA “Health Extended Alliance for Innovative Therapies, Advanced Lab-research and Integrated Approaches of Precision Medicine” PE_00000019—CUP B53C22004000006, and by Next Generation Europe Grant: Rome Technopole Flagship 4 (FP 4)—Development, innovation and certification of medical and non-medical devices for health (Decreto MUR del 23 giugno 2022 prot. n. 105; codice ECS 00000024). Potential competing interests: None to report. IRB approval statement: Ethical considerations guided this letter to the Editor.