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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

Published in: Health & Medicine
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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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