VACCINATIONS AND SEROLOGIC TESTS DURING … · Biliary Atresia: Complications Cholangitis (post-Kasai)
Long-term Outcome of Biliary Atresia and Liver Transplantation
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Transcript of Long-term Outcome of Biliary Atresia and Liver Transplantation
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
Biliary atresia
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)
Biliary atresia
main intra hepatic bile ducts
inter lobular bile ducts
extra hepatic bile ducts
Pathology
Sclerosing cholangitis affecting:
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%
congenital hepatic embryopathy
Aetiology ?
viral infection
anatomical factors
immunological factors
toxic
Biliary atresia
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 1997;32:479
% survival:
1980-1990: 60%
1973-1977: 48%
1953-1967: 10%
1968-1972: 27%
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
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
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
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
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
Pregnancy:
? high rate of miscarriages
Long-term survivors with native liver
successful pregnancies
observed in most centres
Biliary atresia
Liver transplant
Paediatric Liver Transplantation
European Liver Transplant Registry
Transplant
Indications
decompensated chronic liver disease
liver based, life-threatening metabolic
disorders
acute liver failure
quality of life
chemotherapy-responsive malignant tumours
Transplant
Contraindications
large tumours unresponsive to chemotherapy
severe heart disease
disease not cured by liver transplantation
sepsis
severe pulmonary disease
hepatic artery thrombosis
portal vein stenosis
biliary complications
outflow problems due to remodelling
of the liver
Paediatric Liver Transplantation
Surgical Complications
Paediatric Liver Transplant
renal impairment *
Medical Complications
PTLD *
recurrence of disease
de novo autoimmune hepatitis *
cancer *
cardiomyopathy *
* related to anti-rejection Rx
non adherence *
Transplant
steroids
Immunosuppression
calcineurin inhibitors (CyA, Tacrolimus)
azathioprine (Immuran)
mycophenolate mofetil (MMF or CellCept)
rapamycin (Sirolimus)
anti IL2 receptor (Simulect)
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
Transplant Steroids – Side effects
Cushing disease
bone disease
glucose intolerance
risk of infection
cataracts
hyperlipidaemia
growth retardation
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 - +
neurotoxicity + +
cardiotoxicity - +
PTLD + +
cancer + +
Transplant
Azathioprine and MMF – Mode of action
purine nucleotide synthesis inhibitors
arrest of T and B lymphocyte DNA
replication
Transplant
Aza
Azathioprine and MMF– Side effects
MMF
myelotoxicity + +
hepatotoxicity + -
GI symptoms + +
hair loss + +
cancer ? ?
vascular problems (NRH) + ?
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)
Transplant
Rapamycin – Side effects
thrombocytopaenia
hyperlipidaemia
delayed wound healing
high risk of infection
cancer ?
Transplant
Simulect – Mode of action
anti IL2 receptor monoclonal
antibody
responsible for rejection
but also for tolerance!
blocks CD25+ T cells:
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
increase steroids
anti-CD20 (Rituximab)
chemotherapy
stop immunosuppression in
suspected or proven PTLD
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% 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
renal impairment *
PTLD *
recurrence of disease
de novo autoimmune hepatitis *
cancer *
cardiomyopathy *
* related to anti-rejection Rx
non adherence *
Paediatric liver transplantation
Medical complications
~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