Develop an appropriate real-world data comparator cohort to support the design, execution, and serve as an external control for interventional clinical trials in PSC.

Global, multi-center longitudinal observational cohort study. Collection of prospective clinical data to include liver-related clinical outcomes and safety events, hepatobiliary malignancies, relevant key biomarkers, imaging assessments, PSC-related clinical symptoms, patient-reported outcomes, and medication use in adult patients with PSC.

Inclusion Criteria:

1. Adult patients between 18 and 75 years of age (inclusive) who can comprehend instructions, follow the study procedures and are willing to sign an Informed Consent Form (ICF).
2. Confirmed clinical diagnosis of large duct PSC.

Exclusion Criteria:

1. Clinically significant acute or chronic liver disease of an etiology other than PSC (including but not limited to metabolic-dysfunction associated steatohepatitis (MASH), PBC, HCV, HBV, or alcoholic hepatitis, Wilson's disease, alpha-1 antitryp-sin deficiency, acute or chronic drug-induced liver injury)

   • Patients with PSC and elements of AIH overlap are allowed to enroll
   • Patients with metabolic dysfunction associated steatotic liver disease (MASLD) or benign steatosis are allowed to enroll

2. Small-Duct PSC.

3. Clinically diagnosed secondary or IgG4-related sclerosing cholangitis.

4. Clinically diagnosed infections (including acute cholangitis) and receiving treatment within the past 7 days; patients on chronic suppressive antibiotics for acute cholangitis will be allowed to enroll

5. Hospitalization in the past 7 days

6. UDCA dose >28 mg/kg

7. Evidence of current or historical decompensated cirrhosis based on the following clinical events:

   • Ascites > Grade 2 and requiring treatment
   • Esophageal or gastric variceal bleeding requiring hospitalization
   • Hepatic encephalopathy (as defined by a West Haven score ≥ 2)
   • Spontaneous bacterial peritonitis defined as ascites absolute neutrophil count >250/mm3 in the absence of an intra-abdominal source of infection
   • AKI-HRS according to AASLD Guidelines (Flamm 2021)
   • Portal hypertension based on a platelet count < 150 × 109/L and LSM > 15 kPa with clinical, laboratory, imaging and/or other relevant parameters

8. Prior liver transplantation

9. MELD 3.0 Score >15. For subjects on anticoagulation medication, baseline INR determination for MELD score calculation should take this use into account.

10. History, evidence, or high suspicion of hepatobiliary malignancies or active colon cancer based on imaging, screening laboratory values, and/or clinical symptoms. Patients with a history of colon cancer who have undergone a colectomy and have no current evidence of colon cancer will be allowed to enroll in the study.

11. Participants with current clinical or laboratory evidence of any severe, progressive, or uncontrolled disease, related or unrelated to PSC and which, in the opinion of the investigator, has an expected survival of less than 52 weeks.

12. Participants who are impaired, incapacitated, or incapable of completing study-related assessments or giving informed consent.

13. Prisoners or participants who are involuntarily incarcerated.

14. Participants who are currently participating in an investigational PSC therapy clinical study or who have participated in such a study within the past 12 weeks

15. Absence of data in medical records to assess inclusion and exclusion criteria.

2000 adult participants with confirmed diagnosis of large duct PSC