Unraveling the Mechanisms Underlying Primary Sclerosing Cholangitis Through a Multidisciplinary, Integrative Research Approach
Unraveling the Mechanisms Underlying Primary Sclerosing Cholangitis Through a Multidisciplinary, Integrative Research Approach
Background:

 Primary sclerosing cholangitis is a rare chronic liver disease. It affects the bile ducts of
 the

 liver. It can result in bile duct infections, cirrhosis, cancer, and end stage liver disease.
 Researchers want to learn more about this disease.

 Objective:

 To understand the biological causes of primary sclerosing cholangitis.

 Eligibility:

 Adults age 18 and older who have primary sclerosing cholangitis.

 Design:

 Participants will be screened with a medical history, physical exam, and blood tests.

 Participants will give blood, saliva, urine, and stool samples. They will have nasal swabs.
 They will complete surveys.

 Participants will get an intravenous (IV) catheter. A plastic tube is inserted into an arm
 vein.

 Participants will have a colonoscopy. A tube with a video camera at the end is inserted into
 the rectum.

 Participants will have an upper endoscopy. A scope with a light and camera at its tip is used
 to look inside the upper digestive tract.

 Participants will have a liver biopsy, entering through the chest wall or a neck vein. Blood
 is drawn from a blood vessel that carries blood to the liver. A liver tissue sample is taken.

 Participants will have magnetic resonance imaging or spectroscopy. They will get a contrast
 agent through an IV.

 Participants may have an optional bone marrow aspiration. A large needle is inserted into the
 hip to withdraw marrow.

 Participants will have a liver ultrasound.

 Participants will complete a 3-day food diary. They will have a nutrition assessment.

 Participants may give contact details for people who live with them, to also take part in
 this study.

 Participation will last for 12 months....
In this single-site, small-scale prospective natural history study, we intend to recruit up
 to 40 patients with PSC diagnosed by standard clinical, biochemical, or imaging features
 (including up to 30 with a known diagnosis of IBD) and up to 90 controls. Evaluation of
 subjects with PSC and of controls, as well as all study related procedures will take place at
 the National Institutes of Health Clinical Center.

 Participants with PSC:

 We plan to obtain epidemiological as well as bio-samples from multiple body compartments
 presumably involved in development and progression of PSC. These will include the nasal and
 oral cavities, small bowel, colon, portal and systemic venous circulation, bile duct system
 and liver, and optionally bone marrow.

 Control Participants:

 We plan to collect epidemiological data as well as blood samples, nasal swabs, salivary
 samples and stool samples from family members and cohabitants of subjects affected with PSC.

 All or part of samples will be interrogated using cutting edge research methodologies which
 may include quantitative immunophenotyping via mass cytometry, microRNA sequencing of targets
 of interest, metagenomic sequencing, and other high throughput "omics" techniques. The robust
 datasets generated from these multi-omics investigations will be integrated and mined using
 advanced bioinformatics tools by leading experts in the field.
-  PARTICIPANTS:

 INCLUSION CRITERIA:

 In order to be eligible to participate in this study, an individual must meet all of the
 following criteria:

 1. Stated willingness to comply with all study procedures and availability for the
 duration of the study

 2. Male or nonpregnant female, greater than or equal to 18 years of age

 3. Evidence of PSC established by biochemical testing and either MRCP or ERCP.
 Participant must have evidence of large duct disease on imaging.

 4. Agreement to adhere to Lifestyle Considerations throughout study duration.

 EXCLUSION CRITERIA:

 An individual who meets any of the following criteria will be excluded from participation
 in this study:

 1. Pregnant or lactating women or females of child-bearing age not taking measures to
 prevent pregnancy during the period of study.

 2. History of clinical, serologic, or histopathologic evidence supporting etiologies of
 chronic liver disease other than PSC

 3. History of liver transplantation

 4. Diagnosis consistent with secondary sclerosing cholangitis (cholelithiasis, bile duct
 strictures secondary to ischemia, HIV cholangiopathy, etc.).

 5. Current or past clinical evidence of decompensated liver disease (e.g. ascites,
 bleeding esophageal varices, spontaneous bacterial peritonitis, encephalopathy, etc.).

 6. History of liver or bile duct lesions concerning for malignancy.

 7. Ca-19-9 >130 U/microL

 8. Alpha-fetoprotein level greater than 200 ng/microL.

 9. Patients with active bacterial, viral, or fungal, systemic or localized infection.

 10. Unwillingness to refrain from ingesting probiotics during study.

 11. History of systemic disease not related to PSC that is poorly controlled or associated
 with declining functional status. Examples include but are not limited to: poorly
 controlled diabetes mellitus, chronic renal failure with eGFR is <60
 microl/min/1.73m^2, chronic

 symptomatic heart failure or severe COPD.

 12. Patients with history of malignancy other than superficial skin cancer (BCC/SCC) in
 the last 3 years prior to enrolment.

 13. History of portal vein thrombosis

 14. Patients with severe allergic reactions to iodine or other contrast, which cannot be
 controlled by premedication with antihistamines or steroids.

 15. History of gastric and/or proximal small bowel surgery including bariatric surgery
 such as Roux-en-Y gastric bypass

 16. Contraindication to monitored anesthesia care and/or medications that are commonly
 used for conscious sedation during GI Endoscopy

 17. Use of anti-coagulant and anti-platelet agents excluding aspirin and NSAIDs

 18. Contraindications to completing MRCP or MRI

 19. Absolute neutrophil count below 1000/mm^3

 20. Hemoglobin level below 10.0 g/dl

 21. Platelet count lower than 50,000/mm^3.

 22. INR greater than or equal to 1.5, PTT greater thna or equal to 1.3 times control
 and/or any known history of disease associated with

 increased bleeding diathesis.

 23. Inability to provide informed consent

 CONTROLS:

 INCLUSION CRITERIA:

 In order to be eligible to participate in this study, an individual must meet all of the
 following criteria:

 1. Male or female greater than or equal to 18 years of age

 2. Any individual who is either a parent, sibling or child of a PSC patient enrolled to
 the study, or an unrelated person who has been living with the patient for at least 3
 consecutive months before study enrollment

 EXCLUSION CRITERIA:

 An individual who meets any of the following criteria will be excluded from participation
 in this study:

 1. History suggestive of PSC

 2. History of chronic liver disease (except for steatosis)

 3. History of malignancy other than superficial skin cancer (BCC/SCC) in the last 3 years
 prior to enrollment.

 4. History of Inflammatory Bowel Disease

 5. Antibiotic use within the last 6 weeks

 6. Pregnancy

 7. Inability to provide informed consent