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