PEDIATRIC VS ADULT ORGAN TRANSPLANT

1. PEDIATRIC VS ADULT ORGAN TRANSPLANT WALDO CONCEPCION, MD FACS. Professor of Surgery Chief of Clinical Transplantation Stanford University KIEV SYMPOSIUM JULY 3-4, 2017

2. PEDIATRIC LIVER TRANSPLANTATION

3. Overview • Background information • Common etiologies of pediatric liver disease • Listing process for liver transplant • OLT surgery • Post op complications

4. Milestones in Pediatric Liver Transplant • 1963-First attempt at liver transplant in a human by Starzl • 1967-First successful liver transplant by Starzl • 1979-FDA approves Cyclosporine • 1983-NIH Consensus Conference declares liver transplantation a valid therapy for ESLD • 1984-First reduced-size liver transplant • 1987-UW Solution • 1988-First split-liver transplant • 1989-Tacrolimus introduced into clinical trials • 1990-First successful living-related liver transplant

5. 5 Year Actuarial Survival: Ped. Liver Transplants % % Years After Transplant

6. INDICATIONS FOR PEDIATRIC LIVER TRANSPLANTATION

7. Biliary Atresia • Congenital condition, common bile duct blocked or absent • 1 in 10,000 live births, females > males • Etiology is unknown (infectious, immune, abnormal bile, error in dev) • Jaundice at birth • Clay colored stools, cirrhosis often present • Need prompt recognition, persistent elevation of direct bili • Abdominal US, absent gallbladder • HIDA scan • Liver biopsy and intra-operative cholangiogram • Kasai procedure prior to 8 weeks (or 12) of life • Without Kasai, survival is not greater than 2 years old

10. KASAI - PORTO-ENTEROSTOMY

11. Alagille Syndrome • Autosomal dominant • Liver, cardiac, skeletal, eye, renal involvement with characteristic facies • Variable expression • JAG1 mutation or NOTCH2 • 1 in 100,000 • Bile duct paucity, cholestatic liver disease, peripheral pulmonic stenosis, moyamoya disease, renal • Poor growth, small stature • Increased bile acids-->pruritus, xanthomas • Fat soluble vitamin deficiencies • Skeletal abnormalities

12. Alagille Syndrome

13. ALAGILLE SYNDROME

14. Fulminant Hepatic Failure • Hepatic necrosis with acute loss of hepatic function • Includes encephalopathy and coagulopathy • Occurs within 8 weeks of onset of liver disease • Absence of pre-existing liver disease

15. Fulminant Hepatic Failure • In the US: 2000 cases each year across all age groups • Pediatrics: estimated to be 50 cases per year • Males=females • Without OLT, 80-90% mortality • Some centers state survival rates of 50-75%

16. Etiology • Viral hepatitis and drug-induced hepatotoxicity are the two most common causes of FHF in children • Toxins, metabolic diseases, autoimmune hepatitis, ischemic • Often, no specific etiology is found

17. FULMINANT HEPATITIS

18. Hepatitis A-E EBV CMV Varicella-zoster virus Herpesvirus Parvovirus Adenovirus Echovirus Infections50% of cases of FHF

19. Liver Tumors • LPCH major referal center for liver tumors • Hepatoblastomas (HB): most common liver cancer in children • Hepatocellular carcinomas (HCC): underlying liver disease, metabolic disease, hepatitis

20. HEPATOBLASTOMA

21. Multifocal tumor. Response to chemotherapy. Unresectable after chemotherapy. No evidence of active extra-hepatic metastasis. No gross vascular invasion. Adequate cardiac status. Liver Tumors: Indication for liver transplantation

22. Liver Transplantation in Children with HB & HCC at Stanford* *Beaunoyer et al: Pediatr Transpl 11:655, 2007

23. Metabolic Disorders • Urea cycle defects • Wilson’s disease • Hemachromatosis (neonatal iron storage disease) • Alpha-1-antitrypsin deficiency • Crigler-Najjar • Metabolic Acidemias (Methylmalonic acidemia, others)

24. Urea Cycle

25. Listing for Liver Transplantation The Model for End-Stage Liver Disease (MELD) and Pediatric End-Stage Liver Disease (PELD) are numerical scales that are currently used for liver allocation. The MELD and PELD scores are based on a patient's risk of dying while waiting for a liver transplant, and are based on objective and verifiable medical data. UNOS website: www.unos.org/resources

26. Organ Distribution • February 2002 implementation of MELD/PELD • Objective data only • The Model for End-Stage Liver Disease (MELD) and Pediatric End-Stage Liver Disease (PELD) are numerical scales that are currently used for liver allocation. The MELD and PELD scores are based on a patient's risk of dying while waiting for a liver transplant, and are based on objective and verifiable data.

27. Listing for Liver Transplantation The MELD score calculation uses: * Serum Creatinine (mg/dl) * Bilirubin (mg/dl) * INR The PELD score calculation uses: * Albumin (g/dl) * Bilirubin (mg/dl) * INR * Growth failure (based on gender, height and weight) * Age at listing

28. Organ Distribution • PELD does not include symptoms of liver disease • GI bleeds • Ascites • In complete measure of need for liver transplant in children • Disadvantage for Adolescents

29. Muscle wasting Encephalopathy (sleepy, poor appetite) Ascites Coagulopathy (bruising, GI bleeding) Low serum albumin Elevated ammonia Prolonged PT & PTT Rising bilirubin with low transaminases MANIFESTATION OF LIVER FAILURE CLINICAL LABORATORY

30. Listed for OLT • PELD SCORE • BLOOD TYPE • STATUS 1A--FHF, primary non-function • STATUS 1B--after listed by PELD of 30 for 30 days (met, tumors) • REGIONAL LISTING • NATIONAL LISTING

31. OLT Surgery

32. SPECIAL ISSUES IN PEDIATRIC LIVER TRANSPLANTATION • DONOR AVAILABILITY • USE OF ABO INCOMPATIBLE DONORS • SIZE OF LIVER GRAFT • VASCULAR CHALLENGES: - small size hepatic artery • - portal vein atresia • - lower IVC • - situs inversus • SINGLE OR DUAL BILE DUCTS

36. CJ with Internal Stent

37. Living Donation • Adult to Child

38. Post Operative Care • Immunosuppression: antibody induction (thymo, zenapax), steroids, prograf • Anti-coagulation: heparin, dextran, aspirin, persantine • Anti-infection agents: PCP ppl, CMV and EBV ppl (Valcyte)

39. Kim, WR et al AJT 2017;17 pag 174-251

40. PEDIATRIC LIVER TRANSPLANTS

41. PEDIATRIC LIVER TRANSPLANTS

42. PEDIATRIC LIVER TRANSPLANTS

43. PEDIATRIC LIVER TRANSPLANTS

44. Surgical Complications after Pediatric Liver Transplantation • Portal vein thrombosis or stenosis • Hepatic vein-vena cava thrombosis or stenosis • Hepatic artery thrombosis • Biliary strictures • Cosmetic issues from scarring

45. ADULT LIVER TRANSPLANTATION

46. Indication for Primary OLT Adult

47. Liver Transplantation in the U.S.Current Status • 1-year patient survival: 85–90% in most centers • 3-year survival 75-80%; 8-year survival 60-70% • ~7,000 LT/year last 3 years in 110 centers • >17,000 patients on LT waiting list • ~1,800 deaths/year on waiting list last 3 years • Mismatch between qualified candidates and available organs limits application of LT www.unos.org

48. Patient Selection Criteria for LT • Accepted indications for LT • Advanced chronic liver disease • Acute liver failure • Unresectable hepatic malignancy • Inherited metabolic liver disease • No alternative form of therapy • No absolute contraindication to LT • Willingness to comply with follow-up care • Ability to provide for costs of LT .

49. Contraindications to LT: Absolute • Active alcohol or substance abuse • Advanced cardiopulmonary disease • Systemic sepsis, unresponsive to Rx • Multiorgan failure; multiple pressors • Extrahepatic malignancy • Severe pulmonary hypertension • Severe psychiatric disease likely to affect compliance

50. HEPATITIS C • During the last decade, HCV infection accounted for about 30% of the indications for liver transplant in Europe and North America. • Direct antiviral agents (DAA) are highly effective at curing HCV, even in patients with cirrhosis. • The incidence of decompensated cirrhosis and HCC will continue to decrease, but a large cohort of patients with cirrhosis will be at risk for developing HCC event after HCV has been cured. • Patients without viral clearance (SVR) have a 200% higher risk of developing HCC. • Post-transplant recurrence can be effectively treated with DAA’s.