Secondary sclerosing cholangitis: contemporary etiologies, diagnostic pathways, and treatment strategies for clinicians: a narrative review

Background and Objective: Secondary sclerosing cholangitis (SSC) comprises a heterogeneous group of identifiable etiologies causing inflammation and fibrosis of the bile ducts. Given that SSC often progresses more rapidly than primary sclerosing cholangitis and treatment is frequently etiology-directed, early recognition is critical. In this narrative review, we summarize contemporary causes of SSC and propose a diagnostic and management approach for clinicians. Methods: We performed a narrative literature review using PubMed search with medical subject headings (MeSH) and free text terms for SSC and key etiologies, including critical illness/ischemic cholangiopathy, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), infectious, coronavirus disease 2019 (COVID-19)-associated cholangiopathy, immunoglobulin G4 (IgG4)-related/eosinophilic cholangitis, drug-induced cholangiopathy, including immune checkpoint inhibitors and ketamine, malignancy-associated, and post-procedural ischemic injury. The search included randomized trials, observation studies, case reports, case series, and practice guidelines. Two reviewers independently screened studies, reviewed full texts, and synthesized findings by etiology. Key Content and Findings: SSC following ischemic injury in critically ill patients (SSC-CIP) accounted for a significant portion of the recent literature, which presents with persistent cholestatic liver injury after intensive care unit (ICU) recovery. Infectious causes include recurrent pyogenic cholangitis, parasitic disease, HIV-related, and, most notably, given the recent pandemic, post-COVID-19 cholangiopathy. Infectious etiologies mirror SSC-CIP and may often progress to liver failure. Immune-related SSC [IgG4-related sclerosing cholangitis (IgG4-SC) and eosinophilic cholangitis] requires targeted serologies, tissue confirmation with biopsy, and typically responds briskly to corticosteroids. Drug-induced SSC is increasingly linked to immune checkpoint inhibitors, given their rise in use, as well as ketamine, and may be steroid refractory. SSC associated with malignancy requires cross-sectional imaging and tissue diagnosis. Endoscopic therapy may palliate obstruction, but liver transplantation is the definitive option for advanced disease. Conclusions: Given its diverse etiologies, SSC requires a structured evaluation that integrates exposure history, laboratory investigations, magnetic resonance cholangiopancreatography (MRCP)/endoscopic retrograde cholangiopancreatography (ERCP) patterns, and histology for diagnosis. Etiology-specific therapy may slow progression, but early transplant referral is critical for rapidly progressive phenotypes.