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. Infections 50% of cases of FHF
Hepatitis A-E
EBV
CMV
Varicella-zoster virus
Herpesvirus
Parvovirus
Adenovirus
Echovirus

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

22. Liver Transplantation in Children with HB & HCC at Stanford*
Tumor Type
Mean age
Yr + SD
Lesion >
5 cm
Multifocal
Yrs post
Transplant
% recurr.
HCC
(N=10)
10 + 4 5 6
11% HB
(N=15)
3 + 3 10
20%
*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:

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

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

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

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. Deceased Donor Liver Allocation February 2002 Changes
CTP Score
Ascites
Encephalopathy
Bilirubin
Protime INR
Albumin
  MELD Score
Creatinine
Bilirubin
Protime INR
MELD Score = x Loge(creatinine mg/dL) x
Loge(bilirubin mg/dL) x Loge(INR)

51. 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.

52. Hepatitis B
LT considered a contraindications prior to current treatment options secondary to high rates of reinfection, graft loss and patient death
Pretransplant control of replication (lamivudine, adefovir, tenofovir) now possible
Postoperative HBIg plus nucleoside analogues are standard prophylaxis
Recurrence of HBV currently rare, and most cases manageable
Hepatitis E is emerging as an indication for liver transplantation in Europe.
Yu AS, Keeffe EB. Clin Liver Dis 2003;7:551-72

53. Liver Transplantation for HCC
Selection - Stage 2 limit
Survival rates at four years: 85% overall (of whom 92% recurrence-free) (Mazzaferro 1996)
Overall 5 year survival: 70-75% with recurrence rates <15% (Llovet 1999, Yao 2001)
Liver transplantation offers the best outcome for those who make it to transplant

54. NON-ALCOHOLIC FATTY LIVER DISEASE
With the increasing prevalence of obesity, diabetes and metabolic syndrome, NAFLD may affect as many as 40% of the adult population of United States ( about 100 million).
Slowly progressive disease and a significant proportion of patients progress to decompensated cirrhosis and HCC

55. Recurrent Disease after Liver Transplantation

56. Diseases That May Recur after LT
Hepatitis B
Hepatitis C
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune hepatitis
Malignant tumors
Hemochromatosis
Alcoholic liver disease
Nonalcoholic steatohepatitis
Budd-Chiari syndrome

57. Recurrence of Disease after LT
Some recurrent disease inconsequential, while other recurrence a cause of death or re-LT
Increasing problem as patients live longer after LT
Potential requirement for re-LT an added burden to already limited resources for LT
Results of re-LT inferior to initial LT (survival 62% vs. 87% at 1 year, and 54% vs. 77% at 3 year)1
1UNOS Update: UNOS Scientific Registry. 1996; p

58. ADULT LIVER TRANSPLANTS

59. ADULT LIVER TRANPLANTS

60. ADULT LIVER TRANSPLANTS

61. ADULT LIVER TRANSPLANTS

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63. ADULT LIVER TRANSPLANTS

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65. SUMMARY

66. PEDIATRIC VS ADULT LIVER TRANSPLANT
Pediatric transplants are lower volume vs adult.
Pediatric mortality while awaiting is very low vs adult.
Pediatric etiologies for liver disease more congenital vs adult virals.
Pediatric patients more access to donors vs adults.
Technical challenges are more frequent in children vs adults.
Children suffer more rejections vs adults (25 vs 12%).
Children have better long-term graft and patient survival vs adults.
Children have less recurrence of primary disease vs adults.

67. THANK YOU!