1. The ABCs of PSC Jacqueline O’Leary, MD MPH Medical Director of Research, Baylor Simmons Transplant Institute

2. Bias

3. Primary Sclerosing Cholangitis Primary = no known cause Sclerosing = Fibrosis and narrowing Affects the large bile ducts of the liver = plumbing Cholangitis = infection that occurs in the bile ducts.

4. Primary Sclerosing Cholangitis Affects Biliary System

5. Primary Sclerosing Cholangitis What is the biliary system? Bile is made by the liver cells Allows you to absorb your food Bile is toxic to the liver Bile is made – it is secreted into the plumbing of the liver (biliary system): Stored in the gallbladder Exits into the small intestine to help absorb food

6. Primary Sclerosing Cholangitis Affects Biliary System

7. Secondary Sclerosing Cholangitis Secondary = known cause Some of the causes include: Blockage of the bile ducts: Tumor – cancer or non-cancerous Stones / Sludge Abnormal anatomy Parasites Inherited Disorder Toxin Lack of blood flow to bile ducts (ischemia) AIDS Surgery gone wrong

8. Primary Sclerosing Cholangitis Diagnosis Abnormal Liver Tests: Cholestatic profile (alk phos) 60% Men Mean age 30 - 40 years Diagnosis is made by cholangiography Operative Cholangiography ERCP (Endoscopic Retrograde CholangioPancreatography) Scope Magnetic Resonance CholangioPancreatography MRI Diagnosis is not made on liver biopsy

9. Cholangiography in Normal and PSC Normal PSC

10. PSC

11. Cholangiography in PSC

12. Primary Sclerosing Cholangitis

13. Liver Biopsy in PSC Liver biopsy is used in PSC 1) Cholangiogram is normal Small Duct PSC 2) Staging 3) Rule out “over-lap” syndrome PSC with autoimmune hepatitis

14. Liver Biopsy in PSC Early Classic “onion skinning”

15. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Stages Fibrosis or scar is the final common pathway of all liver disease Stage of fibrosis is how much scar or permanent damage has been done. Several scoring systems METAVIR 0-4 Ishak 0-6 Higher score = more scar

16. Stages of Fibrosis Stage 1 Stage 2 Stage 3 Stage 4

17. Regenerating nodules = Cirrhosis

18. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Measure Fibrosis Gold standard is liver biopsy Paired liver biopsy studies: 1/3 are different by 1 stage (scale of 0-4) 2.4% are different by 2 stages Variability is more in diseases like PSC Risks are: bleeding, bile leak, and pain Non – invasive measures have increased: Fibrotest – blood test, in general inaccurate Not validated in PSC

19. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Measure Fibrosis Elastography: Ultrasound No radiation Reimbursed Measures a small area of the liver but much bigger than a biopsy Generally a good test when good images can be obtained. Magnetic resonance: No radiation Not reimbursed Picture of the entire liver Best of diseases (like PSC) with more variability

20. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Measure Fibrosis Standard imaging studies do not evaluate fibrosis: Ultrasound CT scan MRI

21. PSC

22. Primary Sclerosing Cholangitis After Cirrhosis After cirrhosis is diagnosed we no longer discuss stage: Symptoms: Fluid in abdomen = ascites Fluid in legs = edema Mental confusion caused by liver disease = encephalopathy Internal Bleeding from big veins Skin manifestations: Spider angioma

23. Primary Sclerosing Cholangitis After Cirrhosis

24. Liver sickness score = MELD Model for End-Stage Liver Disease 3 lab tests: Bilirubin INR (clotting test) Creatinine (kidney function test)

25. Primary Sclerosing Cholangitis IBD Inflammatory Bowel Disease (IBD) – 75% Autoimmune condition of the intestines Ulcerative Colitis (75%): Colon Crohn’s Disease (25%): Any part of the gastrointestinal track All patients with PSC need to have a colonoscopy: At diagnosis If there are significant changes in bowel habits Progression of PSC is not related to symptoms of/problems with IBD

26. Primary Sclerosing Cholangitis IBD

27. Primary Sclerosing Cholangitis Etiology Unknown Associated with other autoimmune conditions Genetic predisposition Permeability of the bowel The Lancet, Volume 382, Issue 9904, 2013, 1587 - 1599

28. Primary Sclerosing Cholangitis Etiology Unknown Alterations in the way immune cells arrive at their destination: Adhesion molecules increases The Lancet, Volume 382, Issue 9904, 2013, 1587 - 1599

29. Primary Sclerosing Cholangitis Etiology Unknown Intestinal Bacteria The Lancet, Volume 382, Issue 9904, 2013, 1587 - 1599

30. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Course of Disease Slowly Progressive There is no currently approved therapy. Infection in Bile ducts - Cholangitis Routine ERCP does not decrease this risk Bile Duct Cancer - Cholangiocarcinoma 1% risk per year

31. Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis Therapy No FDA approved therapy Ursodiol is sometimes used: Low dose ursodiol (13-15 mg/kg divided 2x/day) improve the liver tests. –Not been shown to improve survival High dose ursodiol (>20 mg/kg divided 2x/day) is not recommended.

32. Pruritis (Itching) Common Cause is unknown Better in the summer—UV light Treatment Cholestyramine 4 g po qd - qid Take 1 hour before or 2 hours after other medications Ursodiol Rifampin Liver injury 10% Antihistamines—only benefit is sedation

33. Sertraline (Zoloft) for Pruritis Randomized placebo controlled trial with wash out and cross over. Highly effective Takes 6 weeks to work Higher dose works better

34. Bone Disease Osteoporosis (thining of the bones) is common Vit D deficiency Postmenopausal status Treatment Ca Vit D Weight bearing exercise Prescription medications

35. Fat Soluble Vitamins Vitamin D—check 25OH Most common Bone problems Vitamin A Vision problems Replete—carefully Vitamin K deficiency Easy Bruising Vitamin E deficiency Dementia

36. Overlap Syndromes Autoimmune liver disease can be diagnosed alone or in combination: Primary Sclerosing Cholangitis (PSC) Autoimmune Hepatitis (AIH) Primary Biliary Cirrhosis (PBC) When more than one is present it is called an “overlap syndrome”. Both diseases require therapy

37. Autoimmune Hepatitis (AIH) AIH can occur alone or with PSC. Previously called Lupoid Hepatitis Strong Female predominance 3.6 : 1 Diagnosis is made with: Requires a liver biopsy Liver tests look different from PSC AST and ALT are elevated Alkaline phosphatase is not elevated

39. Treatments in Development Intercept: FXR agonist Ombetacholic acid Takeda: Humanized monoclonal antibody Alpha 4 -beta 7 Vedolizumab

40. Summary PSC – liver disease of unknown cause that affects the large bile ducts. Alone or as part of an overlap syndrome. IBD is common in patients with PSC Fibrosis is the scar in the liver that results from inflammation. Final common pathway of all liver disease. No known effective treatment at this time, but an active area of research.