1. Primary Sclerosing Cholangitis and Liver Transplantation Cary A. Caldwell MD Associate Clinical Professor of Medicine

2. Primary Sclerosing Cholangitis and Liver Transplantation Y

3. Primary Sclerosing Cholangitis and Liver Transplantation

4. Primary Sclerosing Cholangitis Review Chronic cholestasis and clinical symptoms Pathophysiology, Natural History Indications for Liver Transplant LTx Special Considerations of PSC for LTx Survival and Outcome Post LTx Post LTx Issues

5. Primary Sclerosing Cholangitis PSC Bile duct strictures

6. PSC Primary Sclerosing Cholangitis PSC features : 50% asymptomatic at 1st presentation Fatigue and Pruritus Pain, Wt loss, Fever, Chills 30% Bacterial Cholangitis.

7. PSC : Reversibility Transition Point Larusso Hepatology pages 746-764, 29 AUG 2006

8. PSC categorization Symptomatic vs Asymptomatic Serum AlkP level. AST/ALT 2-3 x or normal. Bilirubin BR Small vs Large Duct disease “Small duct PSC” too small to be identified by endoscopy (ERCP). 75% both small and large ducts, 15% small ducts only, 10% large ducts only. Small duct PSC typically insidious progression or with end-stage liver disease IBD association or w/o Little to NO correlation b/n severity of PSC and that of associated IBD. Furthermore, Rx of IBD has little effect on the course of PSC, and vice versa PSC can occur after colectomy. But colectomy may reduce recurrent PSC post Liver Transplant Autoimmune association or w/o Serum pANCA, SMA, ANA, IgM, IgG, IgM

9. PSC Complications Cirrhosis manifesting portal hypertension variable Hepatosplenomegaly most frequent finding on clinical exam Osteopenic bone disease is a complication of advanced PSC Fat malabsorption with steatorrhea and malabsorption Vitamins deficiency with prolonged cholestasis.

10. PSC Pathophysiology Hepatology pages 746-764, 29 AUG 2006

11. PSC Progression PSC is often separated into four phases, but not easily demarcated: (1) small duct cholangitis (2) progressive cholestasis (3) cirrhosis (4) decompensation. Large duct lesions developing during the second phase may speed progression. Cholangiocarcinoma CCA can develop at any time. Asymptomatic patients possibly better prognosis, but “lead time bias” Small duct PSC usually less rapidly progressive than large duct PSC.

12. PSC Survival Contingent on stage of disease Hepatology Kim WR. pp 746-764, 29 AUG 2006

13. Survival Rates PSC and other Liver Diseases Hepatology pages 746-764, 29 AUG 2006

14. PSC Treatment UDCA therapy can improve serum AlkP, BR, ALT but.. no benefit on slowing disease or prolonging survival. UDCA rx (12-15 mg/kg daily) in U.S. trial a/w improved LFTs but no effect on liver histology or transplant-free survival. ERCP for diagnosis of suspicious biliary stricture and ERCP stent of dominant stricture. Cholestyramine and other Rx for pruritus Treatment of Fat Soluble Vitamins and Bone disease. Ultimately Liver Transplantation LTx

15. Unique Transplant indications for PSC Chapman et al. HEPATOLOGY, Vol. 51, No. 2, 2010 Intractable pruritus, recurrent bacterial cholangitis, and cholangiocarcinoma. Granting of MELD bonus for PSC is uncommon PSC patients with early CCA may benefit from LTx within protocol Unpredictable course of PSC in time of limited organ supply, justifies consideration of Living Donor Liver LDL Transplantation

16. PSC Outcomes post Liver Transplant LTx Tischendorf 14:735-746, 2008 PSC is the fifth most common indication for OLT in U.S.A. In Scandinavian countries, PSC is even the leading indication for OLT Excellent long-term outcome 5-year patient survival of 85%. However, retransplantation rates higher for patients with PSC than w/o. (9.6% vs 4.9%).

17. Post Liver Transplant LTx Care Lucey 19:3-26, 2013 Discharge home with clinic appointment w/n 1 week usually once or twice weekly visits x 4, then monthly x 3, thereafter variable Medication list: CNI (TACROLIMUS), STEROID (PRED taper), MMF URSO UDCA Prophylactic Antibiotics and Antivirals, URSO Wound care, return to ADLs, return to work Liver function LFT tests are routinely monitored after LTx Depending on LFTs, imaging with U/S, MRI or ERCP Histology ie Liver Biopsy

18. Choice of Immunosuppression IMS Lucey 19:3-26, 2013 Indication for Transplant (choice may impact recurrence; HCV, AIH, PSC) History of Rejection Comorbidities Medication side effects ( CNI - DM or CKD) Anticipation of Pregnancy (mTOR or MMF) History of Infection History or risk for Cancer

19. Post Liver Transplant Abnormal LFTs Lucey 19:3-26, 2013 Allograft parenchymal injury rejection ACR autoimmunity AIH Recurrent disease: HCV, HBV, PBC, PSC, AIH, alcohol Drug injury de novo infection recurrent NAFLD Biliary injury strictures: anastomotic, CMV cholangitis, HAT biliary casts recurrent PSC Vascular Metabolic Non hepatic

20. PSC : Histology Hepatology Thuns, S. p746-764, 29 AUG 2006 Primary injury to medium-large bile ducts, can be missed on liver biopsy. The smaller bile ducts (<100 μm) become obstructed and disappear (“ductopenia”). Concentric periductal fibrosis (“onion-skinning”) Chronic cholestasis: bile stasis, pseudoxanthomatous changes, Mallory bodies, and copper. These changes are not pathognomic of PSC and can include: PBC, atresia, AIH and GVHD.

21. PSC : MR vs ERCP Larusso,N Hepatology746-764, 29 AUG 2006 Fulcher AS, Radiology 200;215:71-80 (1)cholangiographic findings of multifocal strictures and beading (2)compatible biochemical abnormalities (3) exclusion of secondary causes strictures due to surgery, trauma, ischemia, tumors and infections (cryptosporidiosis, CMV, HIV)

22. Diagnostic Criteria for recurrent PSC Charatcharoenwitthaya 14:130–132, 2008 Confirmed diagnosis of PSC before transplantation Cholangiogram : non-anastomotic biliary strictures 3 mos post LTx Exclusion of other conditions associated with biliary strictures; ischemia (H.A.T. or cold preservation), infections (CMV, bacterial) immune mediated ABO incompatibility Liver biopsy showing fibrous cholangitis, fibro-obliterative lesions.

23. PSC Recurrence post Liver Transplant LTx Alabraba 15:330-340, 2009 Dx rPSC made in 61 of 263 grafts (23 %), median time 4.6 yr s

24. Survival in patients with PSC Recurrence Campsen 14:181-185, 2008 130 patients PSC transplanted b/n 1986-2006 1, 5,10 yr Survival 91%, 76%, 61% Disease recurrence 22 /130 patients (16.9%)

25. PSC Recurrence with or w/o colectomy Alabraba 15:330-340, 2009

26. PSC Recurrence with ECD allograft Alabraba 15:330-340, 2009

27. Post LTx Cardiovascular and CKD Lucey 19:3-26, 2013 DiseasePrevalence rate metabolic syndrome`50-60% systemic hypertension 40-85% diabetes10-64% obesity24-64% dyslipidemia40-66% cigarette smoking10-40% chronic kidney disease CKD 30-80% end stage kidney ESLD5-8%

28. Immunosuppression IMS side effects Lucey 19:3-26, 2013 Side EffectSteroidCNImTORMMF kidney-++++ proteinuria- bone disease +++ --- gastrointestinal+/---+ bone marrow---+ cholesterolemia+++++- diabetes +++-- hypertension +++-- pulmonary fibrosis--+

29. Post Transplant De Novo Malignancies Lucey 19:3-26, 2013 MalignancyRelative Risk Skin cancer20-70% Lymphoma 10-30% Oropharyngeal3-14% Lung2.7- 2.5% Colorectal CA *25-30% if UC present Kidney CA5-30% * Although data limited, PSC transplant patients w/CUC have an annual colonoscopy

30. Post Transplant Metabolic Bone Status Lucey 19:3-26, 2013 Dietary Intake: Calcium and Protein Serum Calcium, Phosphate,Parathyroid hormone levels 24 - hydroxyvitamin D level 24 hour urinary Calcium ( 200-300mg / day) Gonadal status: free testosterone (male), menopausal status (estrogen) Thyroid function Assessment of bone pain or fracture BMD Dexa Lumbar Hips Spine Spinal radiographs (thoracolumbar)

31. Precautions for LTx patient on IMS Lucey 19:3-26, 2013 Frequent handwashing reduces the risk of infection Shoes, socks, long-sleeve shirts, and long pants should be worn for activities that will involve soil, tick and unnecessary sun exposure During periods of maximal IMS…avoid crowds to minimize respiratory exposure LT recipients should avoid the consumption of water from lakes and rivers LT recipients should avoid unpasteurized milk products and raw eggs and meats (uncooked pork, poultry, fish, and seafood) LT recipients should avoid high-risk pets (rodents, reptiles, chicks, ducks, birds) LT recipients should take precautions to prevent vector (including mosquito)

32. Precautions for LTx patient on IMS Lucey 19:3-26, 2013 Work in high-risk areas; construction, animal care settings, gardening, landscaping, farming should be reviewed with the transplant team. LT recipients should review hobbies to assess potential infectious disease risks, Travel by LT recipients, especially to developing countries, should be reviewed with the transplant team a minimum of 2 months before departure to determine optimal strategies for the reduction of travel-related risks LT recipients should be educated about sun avoidance and sun protection through the use of a sun blocker of at least 15 and protective clothing. Because of the strong association of lung, head, and neck cancers with smoking, the sustained cessation of smoking pre and post LTx is advised. For female LT recipients of a child-bearing age, preconception counseling about contraception and the risks and outcomes of pregnancy should start in the pretransplant period and should be reinforced after transplantation

33. COLONOSCOPY post Transplant Should Antibiotic Prophylaxis be given for COLONOSCOPY? For Endoscopy EGD….. 1. Cirrhosis WITH acute GI bleeding 2. Cystic lesions along the GI tract 3. Bile-duct obstruction WITH cholangitis 4. Sterile pancreatic fluid Collection 5. Percutaneous endoscopic feeding tube placement Other than these five indications, antibiotic prophylaxis is never indicated for EGD TRANSIENT BACTEREMIA: 0% to 25% for EGD, and Colonoscopy – Lowest Risk 7% to 51% for just Chewing Food 20% to 40% for using a Toothpick 20% to 68% for Flossing Your Teeth

34. Dental Antibiotic Prophylaxis post Transplant Should Antibiotic Prophylaxis be given for Dental procedures? 2005 survey of dental protocols at U.S. organ transplant centers, 239 out of 294 centres (83%) reported recommending Atbx prophylaxis Scully et al : Atbx prophylaxis to organ transplant patients before invasive dentistry when w/n 6mos post LTx without citing evidence-based research. Based on current evidence-based research, Atbx prophylaxis not universally advised. Individualized case-by-case basis. If antibiotic prophylaxis is recommended, the patient's physician should prescribe

35. Strategies for Dental and Oral care post LTx Except for emergencies, LTx patients should avoid dental treatment for 3 months post-op. Dosage of immunosuppressive drugs is highest in the early post-transplant period When allograft stable and medically cleared then OK for dental work. Risk of bacterial infections, oral candidiasis, reactivation of herpes simplex virus, uncommon viral and fungal infections, hairy leukoplakia, and aphthous ulcers. Oral ulcers may be caused by herpes simplex virus reactivation or side effects of IMS may become problems for these patients. Cyclosporine: Impaired would healing. Gingival hyperplasia, Ca blockers, Tacrolimus: less gingival overgrowth but oral ulcerations and numbness Azathioprine: Bone marrow suppression,stomatitis and opportunistic infections. Mycophenolate mofetil: Opportunistic infections, and gastrointestinal problems. Corticosteroids: Increase risk of oral infection, and may mask signs of infection. If cushingoid facies (moon face) : oral lesions resulting from cheek and tongue biting Sirolimus: Oral ulcers can result from high levels of sirolimus

36. Quality of Colonoscopy Examination Complete colonic lavage Visualization of ENTIRE colon Difficulty of procedure, Diverticulosis Withdrawal time of scope Adenoma Detection Rate ADR. Higher the ADR… less likely missed colonic lesion. Experience of the Colonoscopist. Choose your Gastroenterologist as you would your Surgeon. Use of Advance Imaging Colonoscopy techniques, Distinction b/w polyp surrounded by normal mucosa, DALM.

37. Quality of Colonoscopy Examination Cecal Intubation Cecal Intubation Rates

38. Quality of Colonoscopy Examination Withdrawal Time ADR Adenoma Detection Rate

39. Use of Advanced Colonoscopy Techniques

40. Therapy of IBD in Transplant Patients Mesalamine, Imuran, Steroids Biologic Agents (Infliximab, etc) Biologic Agents TNF-α antagonist-related liver injury can occur. Mechanism of drug injury : hepatocellular or autoimmune. Dose/Duration independent. Is it safe to use Remicade, Humira, Cimzia in Transplant patients ????

41. Therapy of IBD in Transplant Patients Mohabbat Vol 3. 6 p 569–574, Sept 2012

42. Transplantation for PSC Transplant provides long term survival and improved QOL Recurrence of PSC post transplant variable 5-30% Distinction b/n strictures of PSC vs other post transplant strictures Risk of recurrence possibly a/w intact colon, prednisone, quality of donor liver. Immunosuppression IMS tailored to other medical issues. Monitoring of other medical issues: HTN, Skin exams, Lipids, Vitamins, Bone Disease Surveillance of COLON

43. Primary Sclerosing Cholangitis and Liver Transplantation

44. Transplantation for PSC Transplant can resolve symptoms of ESLD and PSC Excellent long term survival and improved QOL Recurrence of PSC post transplant variable 5-30% Distinction b/n strictures of PSC vs other post transplant strictures Risk of recurrence possibly a/w intact colon, prednisone, quality of donor liver. Immunosuppression IMS tailored to other medical issues. Monitoring of other medical issues: HTN, Skin exams, Lipids, Vitamins, Bone Disease THANK YOU