long-term outcome of biliary atresia and liver transplantation
DESCRIPTION
Giorgina Mieli-Vergani Paediatric Liver, GI & Nutrition Centre King’s College London School of Medicine at King’s College Hospital London, UKTRANSCRIPT
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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
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Biliary atresia
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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)
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Biliary atresia
main intra hepatic bile ducts
inter lobular bile ducts
extra hepatic bile ducts
Pathology
Sclerosing cholangitis affecting:
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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%
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congenital hepatic embryopathy
Aetiology ?
viral infection
anatomical factors
immunological factors
toxic
Biliary atresia
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Biliary atresia
1956
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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%
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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
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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
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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
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85% normal growth
80% normal bilirubin, albumin, INR
Karrer FM et al, Arch Surg 1996;131:493 Laurent 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
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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
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Pregnancy:
? high rate of miscarriages
Long-term survivors with native liver
successful pregnancies
observed in most centres
Biliary atresia
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Liver transplant
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Paediatric Liver Transplantation
European Liver Transplant Registry
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Transplant
Indications
decompensated chronic liver disease
liver based, life-threatening metabolic
disorders
acute liver failure
quality of life
chemotherapy-responsive malignant tumours
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Transplant
Contraindications
large tumours unresponsive to chemotherapy
severe heart disease
disease not cured by liver transplantation
sepsis
severe pulmonary disease
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hepatic artery thrombosis
portal vein stenosis
biliary complications
outflow problems due to remodelling
of the liver
Paediatric Liver Transplantation
Surgical Complications
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Paediatric Liver Transplant
renal impairment *
Medical Complications
PTLD *
recurrence of disease
de novo autoimmune hepatitis *
cancer *
cardiomyopathy *
* related to anti-rejection Rx
non adherence *
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Transplant
steroids
Immunosuppression
calcineurin inhibitors (CyA, Tacrolimus)
azathioprine (Immuran)
mycophenolate mofetil (MMF or CellCept)
rapamycin (Sirolimus)
anti IL2 receptor (Simulect)
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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
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Transplant Steroids – Side effects
Cushing disease
bone disease
glucose intolerance
risk of infection
cataracts
hyperlipidaemia
growth retardation
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Transplant
CyA and Tacrolimus – Mode of action
prevention of IL2 production
by T helper cells
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Transplant
CyA
Calcineurin inhibitors – Side effects
Tacrolimus
nephrotoxicity + +
physical distortion + -
diabetes - +
neurotoxicity + +
cardiotoxicity - +
PTLD + +
cancer + +
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Transplant
Azathioprine and MMF – Mode of action
purine nucleotide synthesis inhibitors
arrest of T and B lymphocyte DNA
replication
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Transplant
Aza
Azathioprine and MMF– Side effects
MMF
myelotoxicity + +
hepatotoxicity + -
GI symptoms + +
hair loss + +
cancer ? ?
vascular problems (NRH) + ?
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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)
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Transplant
Rapamycin – Side effects
thrombocytopaenia
hyperlipidaemia
delayed wound healing
high risk of infection
cancer ?
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Transplant
Simulect – Mode of action
anti IL2 receptor monoclonal
antibody
responsible for rejection
but also for tolerance!
blocks CD25+ T cells:
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Transplant
decrease/stop calcineurin inhibitors
Renal impairment – Management at King’s
MMF
rapamycin
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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
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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
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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
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renal impairment *
PTLD *
recurrence of disease
de novo autoimmune hepatitis *
cancer *
cardiomyopathy *
* related to anti-rejection Rx
non adherence *
Paediatric liver transplantation
Medical complications
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~20%
of patients
transplanted in
childhood
experience
severe morbidity
or mortality because
of non-adherence
to treatment
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growing up with a liver
transplant is different
from being transplanted
in adulthood
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Transition Service
essential
multidisciplinary approach
knowledge of paediatric
liver diseases
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Paediatric Liver Transplant
…next great revolution…
induction of tolerance