Giorgina Mieli-Vergani

Paediatric Liver, GI & Nutrition Centre

King’s College London School of Medicine

King’s College Hospital

London, UK

Acute Liver Failure

in Children

< 1960s ? liver disease in children

1970s liver disease in children

1980s tertiary centres

1990s liver transplant

Paediatric Hepatology: a young subspecialty

Acute liver failure in childhood

rare

… but pathology different from adults

… a paediatric hepatologist’s headache

definition

management

borrowed from

adult experience

Acute liver failure

Fulminant liver failure

versus

Definition?

Acute/Fulminant liver failure in childhood

important for treatment decision

important for result comparison

massive liver necrosis with encephalopathy

developing within 8 weeks from the first

signs of illness in a patient without

underlying chronic liver disease

Fulminant hepatic failure in adults

massive liver necrosis with encephalopathy

developing more than 8 weeks from the first

signs of illness in a patient without

underlying chronic liver disease

Late onset (subacute) hepatic failure in adults

Encephalopathy

often late, terminal event

Acute liver failure in childhood

difficult to diagnose,

particularly in infants

the most common presentation is

subacute

Acute liver failure in childhood

if encephalopathy is a major

criterium for definition…

King’s prognostic indicators (non paracetamol patients)

Fulminant hepatic failure

prothrombin time > 100 sec (irrespective of grade of encephalopathy)

or

any 3 of the following variables (irrespective of grade of encephalopathy):

age <10 or >40 years

nonA-nonB, halothane, idiosyncratic drug reactions

jaundice to encephalopathy > 7 days

prothrombin time > 50 sec

bilirubin > 300 mmol/l

O’Grady et al, Gastroenterology 1989;97:439-45

Underlying liver disease

Acute liver failure in childhood

frequent in paediatrics

tyrosinaemia

neonatal haemochromatosis

Wilson

autoimmune

mitochondrial disorders

etc

King’s Definition - 1996

Multisystem disorder in which severe acute

impairment of liver function, with or without

encephalopathy, occurs in association with

hepatocellular necrosis in patients with no

recognised underlying chronic liver disease

Acute liver failure in childhood

Bhaduri & Mieli-Vergani, Sem Liver Dis 1996;16:349-355

no known evidence of chronic liver disease

biochemical evidence of acute liver injury

hepatic-based coagulopathy (not corrected

by vitamin K):

PT > 15s or INR > 1.5 with encephalopathy

or

PT >20s or INR >2.0 with or without

encephalopathy

Acute liver failure in childhood

Acute Liver Failure Study Group, USA -1996

ALF Symposium, London 2005

Acute hepatocellular injury with severe impairment

of liver function

(INR >2, not responsive to vitamin K),

with or without encephalopathy in patients without

known underlying liver disease

Acute liver failure in childhood

Acute liver failure in childhood

without underlying liver disease

with underlying liver disease

different prognosis and management

Acute liver failure in childhood

Liver transplant

what criteria should be used?

Acute liver failure in childhood

adult criteria?

aetiology based criteria

Criteria for liver transplant

Transplant

if cause of ALF treatable by LT

if predicted outcome of LT better

than that of underlying disease

if no severe brain damage

Acute liver failure in childhood

Acute liver failure in childhood

encephalopathy → poor prognosis

young children may die with no obvious

encephalopathy

without underlying liver disease

with underlying liver disease

Acute liver failure

response to medical treatment possible

even in the presence of encephalopathy

(e.g. mitochondrial disorders)

prognosis and management depend

on the cause of underlying liver disease

Acute liver failure in childhood

prognostic criteria

other than

encephalopathy

are needed

When to list for transplant?

15 survived

29 died

Acute liver failure in childhood

King’s: 44 children with ALF not transplanted

…prognostic indicators?

Bhaduri & Mieli-Vergani, Sem Liver Dis 1996;16:349-355

Indicators of poor prognosis

Acute liver failure in childhood

age < 2 years

max INR ≥ 4

max bilirubin ≥ 235 mmol/l

WBC ≥ 9x109/l

Prognostic indicators Acute liver failure in childhood

age, max INR, max bilirubin, WBC

% mortality

any 1 indicator 76

any 2 indicators 93

any 3 indicators 96

all 4 indicators 100

Prognostic indicators King’s: 44 children with ALF not transplanted

aetiology

presence of encephalopathy

Acute liver failure in childhood

no correlation with:

correlation with: max degree of encephalopathy grade I-II = 44% mortality

grade III-IV = 78% mortality

P<0.02

Acute liver failure in childhood

Prognostic indicators - INR

dead

alive

P<0.001

0

5

10

15

20

25

INR < 4 INR ≥ 4

still valid with improved

paediatric intensive care?

impossible to determine in

the era of transplantation

Acute liver failure in childhood

King’s prognostic indicators

potential for the liver to regenerate

lifelong immunosuppression if LT

Acute liver failure in childhood

Ethical dilemma if no underlying liver disease

extra-corporeal assist devices

hepatocyte transplantation

Acute liver failure in childhood

New approaches

auxiliary liver transplantation

Auxiliary liver transplant

Acute liver failure – Auxiliary transplant

Acute liver failure – Auxiliary transplant

time 0

6 months

18 months

Acute liver failure – Auxiliary transplant

1 month

6 months 18 months

24 months

survival 85%

off drugs 29%

weaning 53%

Acute liver failure – Auxiliary transplant

Hepatocyte transplant for

acute liver failure

transient synthetic and detoxifying function

site accessible in coagulopathic patients

no immunosuppression

2.5 x 106 cells/ml

Alginate beads

~400-450µm

Encapsulated hepatocytes

liver

Site of injection

Hepatocyte transplant for

acute liver failure

peritoneum

spleen

before Tx retrieved microbeads

Hepatocyte in alginate beads

for acute liver failure

First human application – King’s

Herpes simplex FHF

hepatocyte transplant

aged 2 weeks – March 2011

“Liver implant gives boy another chance of life” NEWS

8 months

5 patients

Herpes simplex 1

neonatal haemochromatosis 2

indeterminate 2

Hepatocyte in alginate beads

for acute liver failure

King’s, 2011-13

outcome

2 alive without liver transplant

2 bridge to liver transplant

1 care withdrawn

(Down syndrome with cardiac failure, stable INR)

clinical condition improved in all

early referral to specialised centres

transplant when necessary

Acute liver failure in childhood

The message – The future

Rx related to aetiology

development of effective bridges

to recovery