Primary Sclerosing Cholangitis: Evolving Risk Stratification and Emerging Therapies: Clinics in Liver Disease | June 2026

• Primary sclerosing cholangitis (PSC) remains one of the leading indications for liver transplantation despite being a relatively rare disease.

• The incidence and prevalence of PSC continue to rise in Europe and North America, suggesting factors beyond inflammatory bowel disease alone contribute to disease development.

• Approximately 60%–80% of patients with PSC develop inflammatory bowel disease, most commonly ulcerative colitis, while 5%–21% of IBD patients develop biliary abnormalities.

• PSC-associated IBD differs from classical ulcerative colitis, often demonstrating extensive pancolitis with prominent right-sided involvement and a higher colorectal cancer risk.

• Most patients are asymptomatic at diagnosis, with PSC often detected incidentally through abnormal cholestatic liver biochemistry during IBD surveillance.

• Young patients frequently present with elevated transaminases and may initially resemble autoimmune hepatitis before evolving into classical PSC.

• The natural history of PSC is highly variable, ranging from stable disease over decades to rapid progression requiring transplantation.

• Women generally experience a more favorable clinical course, while younger age at diagnosis is associated with a greater burden of PSC-related complications over time.

• Hepatopancreatobiliary malignancies remain a major cause of mortality in PSC.

• PSC substantially increases the risk of:

• Cholangiocarcinoma

• Hepatocellular carcinoma

• Gallbladder cancer

• Pancreatic cancer

• PSC-associated IBD also carries a markedly increased risk of colorectal neoplasia, necessitating intensive colonoscopic surveillance.

• Risk stratification is rapidly evolving with advances in:

• MRI and MRCP imaging

• Liver stiffness measurement

• Serum biomarkers

• Fibrosis assessment tools

• Emerging molecular markers

• No single risk model currently captures the full complexity of PSC, and multimodal approaches are increasingly favored.

• There remains no approved disease-modifying therapy proven to improve transplant-free survival.

• Management currently focuses on:

• Monitoring disease progression

• Managing dominant strictures

• Cancer surveillance

• Optimizing IBD control

• Timely transplant referral

• Ursodeoxycholic acid remains widely used in selected patients, although its role continues to be debated.

• Several promising therapeutic strategies are under investigation, including:

• Norursodeoxycholic acid (norUDCA)

• Bile acid receptor modulators

• Antifibrotic therapies

• Microbiome-targeted approaches

• Immune-modulating therapies

• Increasing evidence suggests that intestinal inflammation may directly influence PSC progression, reinforcing the importance of achieving deep IBD control.

• Future PSC management is expected to move toward precision medicine with individualized risk prediction and targeted therapeutic approaches.

Bottom line: PSC remains a challenging cholestatic liver disease with high risks of transplantation and hepatopancreatobiliary malignancy. Advances in imaging, biomarkers, and emerging therapies are improving risk stratification, but effective disease-modifying treatment remains the major unmet need.