Livers · Published 2026-08-05 · DOI 10.3390/livers6040075
Anthony Vignone, Simone Di Cola, Flaminia Ferri, Francesco Covotta, Lewis J. Frey, Wing-Kin Syn, Domenico Alvaro, Vincenzo Cardinale
Primary sclerosing cholangitis (PSC) is a rare cholangiopathy strongly associated with inflammatory bowel disease (IBD), particularly ulcerative colitis. PSC-IBD defines a clinically quiescent but biologically aggressive colitis phenotype, characterized by extensive yet often asymptomatic mucosal inflammation and disproportionately elevated risks of colorectal cancer—approximately 3- to 5-fold higher than in IBD alone—and cholangiocarcinoma (CCA), with IBD comorbidity representing an independent risk factor for hepatopancreatobiliary malignancy. The pathogenesis remains incompletely understood but involves genetic susceptibility, immune dysregulation—including aberrant lymphocyte trafficking and an imbalance between T helper 17 (Th17) and regulatory T (Treg) cells—intestinal barrier dysfunction, and gut–liver axis perturbations involving alterations in the microbiota and bile acid homeostasis. Within the biliary tree, chronic inflammation activates peribiliary glands (PBGs), which harbor stem/progenitor cells. PBG hyperplasia may contribute to periductal fibrosis through Hedgehog signaling and epithelial-to-mesenchymal transition and may represent a key step in PSC-associated cholangiocarcinogenesis. The true burden of PSC-IBD is likely underestimated, as PSC may remain clinically silent for years. Bidirectional screening is therefore essential: all patients with PSC should undergo ileocolonoscopy with biopsies regardless of symptoms, whereas patients with IBD and cholestatic liver biochemistry—particularly elevated gamma-glutamyl transferase or alkaline phosphatase—should undergo magnetic resonance cholangiopancreatography. No medical therapy has demonstrated a clear ability to alter the natural history of PSC, and liver transplantation remains the only definitive treatment for advanced disease. This review integrates current evidence on the epidemiology, pathophysiology, and management of PSC-IBD, critically examining unmet needs in timely diagnosis, mechanistic understanding, and therapeutic development, with particular attention to non-invasive biomarkers, microbiota-directed strategies, individualized risk stratification, and disease-modifying endpoints.
Abstract from DOAJ. Public domain (CC0 1.0).
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Vignone, A., Cola, S., Ferri, F., et al. (2026). Unmet Needs in Primary Sclerosing Cholangitis Associated with Inflammatory Bowel Disease: A Comprehensive Review. Livers. https://doi.org/10.3390/livers6040075