Long-term Outcome of
Biliary Atresia and
Liver Transplantation
Giorgina Mieli-Vergani
Paediatric Liver, GI & Nutrition Cen...
Biliary atresia
Biliary atresia
 non hereditary, unique to infancy
 complete obliteration or
discontinuity of the hepatic
or common bile...
Biliary atresia
 main intra hepatic bile ducts
 inter lobular bile ducts
 extra hepatic bile ducts
Pathology
Sclerosing...
Biliary atresia
 portal hypertension and cirrhosis as early
as 6 weeks of age
 progressive intra hepatic fibrosis
Evolut...
 congenital hepatic embryopathy
Aetiology ?
 viral infection
 anatomical factors
 immunological factors
 toxic
Biliar...
Biliary atresia
1956
Biliary atresia
Portoenterostomy – learning curve
Ohi R et al, J Pediatr Surg 1990;25:442
Davenport M et al, J Pediatr Sur...
Biliary atresia
Survival after portoenterostomy
Ohi R et al, J Pediatr Surg 1990;25:442
Davenport M et al, Lancet 2004;363...
Long-term survivors with native liver
Howard ER et al, J Pediatr Sur 2001;36:892
Tohoku
Japan
period 1951-1992
# pts 311
5...
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...
 85% normal growth
 80% normal bilirubin, albumin, INR
Karrer FM et al, Arch Surg 1996;131:493Laurent J et al, Gastroent...
 cholangitis: 30-40%
 portal hypertension: 40-75%
Long-term survivors with native liver
Complications
 jaundice: 20%
Da...
Pregnancy:
 ? high rate of miscarriages
Long-term survivors with native liver
 successful pregnancies
observed in most c...
Liver transplant
Paediatric Liver Transplantation
European Liver Transplant Registry
Transplant
Indications
 decompensated chronic liver disease
 liver based, life-threatening metabolic
disorders
 acute l...
Transplant
Contraindications
 large tumours unresponsive to chemotherapy
 severe heart disease
 disease not cured by li...
 hepatic artery thrombosis
 portal vein stenosis
 biliary complications
 outflow problems due to remodelling
of the li...
Paediatric Liver Transplant
 renal impairment *
Medical Complications
 PTLD *
 recurrence of disease
 de novo autoimmu...
Transplant
 steroids
Immunosuppression
 calcineurin inhibitors (CyA, Tacrolimus)
 azathioprine (Immuran)
 mycophenolat...
Transplant
Steroids – Mode of action
 inhibition of IL1 and IL6
production by macrophages
and of all stages of T-cell
act...
Transplant
Steroids – Side effects
 Cushing disease
 bone disease
 glucose intolerance
 risk of infection
 cataracts
...
Transplant
CyA and Tacrolimus – Mode of action
 prevention of IL2 production
by T helper cells
Transplant
CyA
Calcineurin inhibitors – Side effects
Tacrolimus
nephrotoxicity + +
physical distortion + -
diabetes - +
ne...
Transplant
Azathioprine and MMF – Mode of action
 purine nucleotide synthesis inhibitors
 arrest of T and B lymphocyte D...
Transplant
Aza
Azathioprine and MMF– Side effects
MMF
myelotoxicity + +
hepatotoxicity + -
GI symptoms + +
hair loss + +
c...
Transplant
Rapamycin – Mode of action
 macrolide antibiotic
 decreased cytokine production by
T cells (e.g. IL2)
 inhib...
Transplant
Rapamycin – Side effects
 thrombocytopaenia
 hyperlipidaemia
 delayed wound healing
 high risk of infection...
Transplant
Simulect – Mode of action
 anti IL2 receptor monoclonal
antibody
responsible for rejection
but also for tolera...
Transplant
 decrease/stop calcineurin inhibitors
Renal impairment – Management at King’s
 MMF
 rapamycin
Transplant
 monitor EBV DNA
EBV related PTLD – Management at King’s
 decrease immunosuppression
in symptomatic infection...
Transplant
De novo AIH
 associated with autoantibodies, high IgG
and interface hepatitis
Following LT, 4-6% of children d...
 34% special education
 20% grade repetition
Gilmour SM et al, Liver Transpl. 2010;16:1041
823 children (5.42 ± 2.79 yea...
 renal impairment *
 PTLD *
 recurrence of disease
 de novo autoimmune hepatitis *
 cancer *
 cardiomyopathy *
* rel...
~20%
of patients
transplanted in
childhood
experience
severe morbidity
or mortality because
of non-adherence
to treatment
growing up with a liver
transplant is different
from being transplanted
in adulthood
Transition Service
 essential
 multidisciplinary approach
 knowledge of paediatric
liver diseases
Paediatric Liver Transplant
…next great revolution…
induction of tolerance
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Long-term Outcome of Biliary Atresia and Liver Transplantation

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

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Long-term Outcome of Biliary Atresia and Liver Transplantation

  1. 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. 2. Biliary atresia
  3. 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. 4. Biliary atresia  main intra hepatic bile ducts  inter lobular bile ducts  extra hepatic bile ducts Pathology Sclerosing cholangitis affecting:
  5. 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. 6.  congenital hepatic embryopathy Aetiology ?  viral infection  anatomical factors  immunological factors  toxic Biliary atresia
  7. 7. Biliary atresia 1956
  8. 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. 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. 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. 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. 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. 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. 14. Pregnancy:  ? high rate of miscarriages Long-term survivors with native liver  successful pregnancies observed in most centres Biliary atresia
  15. 15. Liver transplant
  16. 16. Paediatric Liver Transplantation European Liver Transplant Registry
  17. 17. Transplant Indications  decompensated chronic liver disease  liver based, life-threatening metabolic disorders  acute liver failure  quality of life  chemotherapy-responsive malignant tumours
  18. 18. Transplant Contraindications  large tumours unresponsive to chemotherapy  severe heart disease  disease not cured by liver transplantation  sepsis  severe pulmonary disease
  19. 19.  hepatic artery thrombosis  portal vein stenosis  biliary complications  outflow problems due to remodelling of the liver Paediatric Liver Transplantation Surgical Complications
  20. 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. 21. Transplant  steroids Immunosuppression  calcineurin inhibitors (CyA, Tacrolimus)  azathioprine (Immuran)  mycophenolate mofetil (MMF or CellCept)  rapamycin (Sirolimus)  anti IL2 receptor (Simulect)
  22. 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. 23. Transplant Steroids – Side effects  Cushing disease  bone disease  glucose intolerance  risk of infection  cataracts  hyperlipidaemia  growth retardation
  24. 24. Transplant CyA and Tacrolimus – Mode of action  prevention of IL2 production by T helper cells
  25. 25. Transplant CyA Calcineurin inhibitors – Side effects Tacrolimus nephrotoxicity + + physical distortion + - diabetes - + neurotoxicity + + cardiotoxicity - + PTLD + + cancer + +
  26. 26. Transplant Azathioprine and MMF – Mode of action  purine nucleotide synthesis inhibitors  arrest of T and B lymphocyte DNA replication
  27. 27. Transplant Aza Azathioprine and MMF– Side effects MMF myelotoxicity + + hepatotoxicity + - GI symptoms + + hair loss + + cancer ? ? vascular problems (NRH) + ?
  28. 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. 29. Transplant Rapamycin – Side effects  thrombocytopaenia  hyperlipidaemia  delayed wound healing  high risk of infection  cancer ?
  30. 30. Transplant Simulect – Mode of action  anti IL2 receptor monoclonal antibody responsible for rejection but also for tolerance!  blocks CD25+ T cells:
  31. 31. Transplant  decrease/stop calcineurin inhibitors Renal impairment – Management at King’s  MMF  rapamycin
  32. 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. 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.  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. 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. 36. ~20% of patients transplanted in childhood experience severe morbidity or mortality because of non-adherence to treatment
  37. 37. growing up with a liver transplant is different from being transplanted in adulthood
  38. 38. Transition Service  essential  multidisciplinary approach  knowledge of paediatric liver diseases
  39. 39. Paediatric Liver Transplant …next great revolution… induction of tolerance

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