Giorgina Mieli-Vergani Paediatric Liver, GI & Nutrition Centre King’s College London School of Medicine at King’s College Hospital London, UK

1. Long-term Outcome of
Biliary Atresia and
Liver Transplantation
Giorgina Mieli-Vergani
Paediatric Liver, GI & Nutrition Centre
King’s College London School of Medicine
at King’s College Hospital
London, UK

2. Biliary atresia

3. Biliary atresia
 non hereditary, unique to infancy
 complete obliteration or
discontinuity of the hepatic
or common bile ducts
 incidence: 1/14,000 – 1/21,000 live births (similar in all races)

4. Biliary atresia
 main intra hepatic bile ducts
 inter lobular bile ducts
 extra hepatic bile ducts
Pathology
Sclerosing cholangitis affecting:

5. Biliary atresia
 portal hypertension and cirrhosis as early
as 6 weeks of age
 progressive intra hepatic fibrosis
Evolution
mean age at death: 11 months
 without treatment:
two year survival: 5%

6.  congenital hepatic embryopathy
Aetiology ?
 viral infection
 anatomical factors
 immunological factors
 toxic
Biliary atresia

7. Biliary atresia
1956

8. Biliary atresia
Portoenterostomy – learning curve
Ohi R et al, J Pediatr Surg 1990;25:442
Davenport M et al, J Pediatr Sur 1997;32:479
% survival:
 1980-1990: 60%
 1973-1977: 48%
 1953-1967: 10%
 1968-1972: 27%

9. Biliary atresia
Survival after portoenterostomy
Ohi R et al, J Pediatr Surg 1990;25:442
Davenport M et al, Lancet 2004;363:1354
 1980-1990: 60%
 1953-1967: 10%
 1968-1972: 27%
 1973-1977: 48%
 1990-2000: 90%
OLT

10. Long-term survivors with native liver
Howard ER et al, J Pediatr Sur 2001;36:892
Tohoku
Japan
period 1951-1992
# pts 311
5 years 33%
10 years 26%
French Obs for
Biliary Atresia
1986-1996
421
32%
27%
King’s
UK
1973-1995
338
60%
45%
Chardot C et al, J Pediatr 2001;138:224
Chardot C et al, Hepatology 1999;30:606 Davenport M et al, J Pediatr Sur 1997;32:479
Biliary atresia

11. Davenport M et al, Lancet 2004;363:1354
Probability of survival with native liver by age at Kasai
(n = 136)
0 25 50 75 100
0.00
0.25
0.50
0.75
1.00
months
< 40 days
40 - 60 days
60 -100 days
>100 days

12.  85% normal growth
 80% normal bilirubin, albumin, INR
Karrer FM et al, Arch Surg 1996;131:493Laurent J et al, Gastroenterology 1990;99:1793
Long-term survivors with native liver
 10% completely normal liver function with
no evidence of portal hypertension (fibrotic liver)
Hadžić N et al, JPGN 2003;37:430
Biliary atresia
 excellent quality of life
Howard ER et al, J Pediatr Sur 2001;36:892

13.  cholangitis: 30-40%
 portal hypertension: 40-75%
Long-term survivors with native liver
Complications
 jaundice: 20%
Davenport M et al, J Pediatr Sur 1997;32:479
Karrer FM et al, Arch Surg 1996;131:493
Laurent J et al, Gastroenterology 1990;99:1793
Biliary atresia

14. Pregnancy:
 ? high rate of miscarriages
Long-term survivors with native liver
 successful pregnancies
observed in most centres
Biliary atresia

15. Liver transplant

16. Paediatric Liver Transplantation
European Liver Transplant Registry

17. Transplant
Indications
 decompensated chronic liver disease
 liver based, life-threatening metabolic
disorders
 acute liver failure
 quality of life
 chemotherapy-responsive malignant tumours

18. Transplant
Contraindications
 large tumours unresponsive to chemotherapy
 severe heart disease
 disease not cured by liver transplantation
 sepsis
 severe pulmonary disease

19.  hepatic artery thrombosis
 portal vein stenosis
 biliary complications
 outflow problems due to remodelling
of the liver
Paediatric Liver Transplantation
Surgical Complications

20. Paediatric Liver Transplant
 renal impairment *
Medical Complications
 PTLD *
 recurrence of disease
 de novo autoimmune hepatitis *
 cancer *
 cardiomyopathy *
* related to anti-rejection Rx
 non adherence *

21. Transplant
 steroids
Immunosuppression
 calcineurin inhibitors (CyA, Tacrolimus)
 azathioprine (Immuran)
 mycophenolate mofetil (MMF or CellCept)
 rapamycin (Sirolimus)
 anti IL2 receptor (Simulect)

22. Transplant
Steroids – Mode of action
 inhibition of IL1 and IL6
production by macrophages
and of all stages of T-cell
activation
 induction, maintenance, acute
rejection

23. Transplant
Steroids – Side effects
 Cushing disease
 bone disease
 glucose intolerance
 risk of infection
 cataracts
 hyperlipidaemia
 growth retardation

24. Transplant
CyA and Tacrolimus – Mode of action
 prevention of IL2 production
by T helper cells

25. Transplant
CyA
Calcineurin inhibitors – Side effects
Tacrolimus
nephrotoxicity + +
physical distortion + -
diabetes - +
neurotoxicity + +
cardiotoxicity - +
PTLD + +
cancer + +

26. Transplant
Azathioprine and MMF – Mode of action
 purine nucleotide synthesis inhibitors
 arrest of T and B lymphocyte DNA
replication

27. Transplant
Aza
Azathioprine and MMF– Side effects
MMF
myelotoxicity + +
hepatotoxicity + -
GI symptoms + +
hair loss + +
cancer ? ?
vascular problems (NRH) + ?

28. Transplant
Rapamycin – Mode of action
 macrolide antibiotic
 decreased cytokine production by
T cells (e.g. IL2)
 inhibition of protein kinase
phosphorylation
(affecting B and non immune cells)

29. Transplant
Rapamycin – Side effects
 thrombocytopaenia
 hyperlipidaemia
 delayed wound healing
 high risk of infection
 cancer ?

30. Transplant
Simulect – Mode of action
 anti IL2 receptor monoclonal
antibody
responsible for rejection
but also for tolerance!
 blocks CD25+ T cells:

31. Transplant
 decrease/stop calcineurin inhibitors
Renal impairment – Management at King’s
 MMF
 rapamycin

32. Transplant
 monitor EBV DNA
EBV related PTLD – Management at King’s
 decrease immunosuppression
in symptomatic infection
 increase steroids
 anti-CD20 (Rituximab)
 chemotherapy
 stop immunosuppression in
suspected or proven PTLD

33. Transplant
De novo AIH
 associated with autoantibodies, high IgG
and interface hepatitis
Following LT, 4-6% of children develop
graft dysfunction
 responsive to the addition of classical
treatment for autoimmune hepatitis

34.  34% special education
 20% grade repetition
Gilmour SM et al, Liver Transpl. 2010;16:1041
823 children (5.42 ± 2.79 years post LT)
despite excellent medical outcomes:
Paediatric Liver Transplant
Learning difficulties

35.  renal impairment *
 PTLD *
 recurrence of disease
 de novo autoimmune hepatitis *
 cancer *
 cardiomyopathy *
* related to anti-rejection Rx
 non adherence *
Paediatric liver transplantation
Medical complications

36. ~20%
of patients
transplanted in
childhood
experience
severe morbidity
or mortality because
of non-adherence
to treatment

37. growing up with a liver
transplant is different
from being transplanted
in adulthood

38. Transition Service
 essential
 multidisciplinary approach
 knowledge of paediatric
liver diseases

39. Paediatric Liver Transplant
…next great revolution…
induction of tolerance