- Acute liver failure in children is rare but has a different pathology than in adults. It can be difficult to diagnose, especially in infants, and definitions and management strategies have historically been borrowed from adult experiences. - There are different types of acute liver failure including those with and without underlying liver diseases. Prognostic indicators beyond just encephalopathy are needed to determine transplant listing. - New approaches such as auxiliary liver transplants, hepatocyte transplants, and extracorporeal assist devices show promise as bridges to recovery in acute liver failure in children. Early referral to specialized centers is important.

1. 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

2.  < 1960s ? liver disease in children
 1970s liver disease in children
 1980s tertiary centres
 1990s liver transplant
Paediatric Hepatology: a young subspecialty

3. Acute liver failure in childhood
 rare
 … but pathology different from adults
… a paediatric hepatologist’s headache
 definition
 management
borrowed from
adult experience

4. Acute liver failure
Fulminant liver failure
versus

5. Definition?
Acute/Fulminant liver failure in childhood
 important for treatment decision
 important for result comparison

6. 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

7. 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

8. Encephalopathy
 often late, terminal event
Acute liver failure in childhood
 difficult to diagnose,
particularly in infants

9. the most common presentation is
subacute
Acute liver failure in childhood
if encephalopathy is a major
criterium for definition…

10. 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

11. Underlying liver disease
Acute liver failure in childhood
 frequent in paediatrics
tyrosinaemia
neonatal haemochromatosis
Wilson
autoimmune
mitochondrial disorders
etc

12. 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

13.  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

14. 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

15. Acute liver failure in childhood
 without underlying liver disease
 with underlying liver disease
different prognosis and management

16. Acute liver failure in childhood
Liver transplant
 what criteria should be used?

17. Acute liver failure in childhood
 adult criteria?
 aetiology based criteria
Criteria for liver transplant

18. 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

19. Acute liver failure in childhood
 encephalopathy → poor prognosis
 young children may die with no obvious
encephalopathy
without underlying liver disease

20. 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

21. Acute liver failure in childhood
prognostic criteria
other than
encephalopathy
are needed

22. 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

23. Indicators of poor prognosis
Acute liver failure in childhood
 age < 2 years
 max INR ≥4
 max bilirubin ≥ 235 mmol/l
 WBC ≥ 9x109/l

24. 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

25. 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

26. Acute liver failure in childhood
Prognostic indicators - INR
 dead
 alive
P<0.001
0
5
10
15
20
25
INR < 4 INR ≥ 4

27.  still valid with improved
paediatric intensive care?
 impossible to determine in
the era of transplantation
Acute liver failure in childhood
King’s prognostic indicators

28.  potential for the liver to regenerate
 lifelong immunosuppression if LT
Acute liver failure in childhood
Ethical dilemma if no underlying liver disease

29.  extra-corporeal assist devices
 hepatocyte transplantation
Acute liver failure in childhood
New approaches
 auxiliary liver transplantation

30. Auxiliary liver transplant

31. Acute liver failure – Auxiliary transplant

32. Acute liver failure – Auxiliary transplant
time 0
6 months
18 months

33. Acute liver failure – Auxiliary transplant
1 month
6 months 18 months
24 months

34.  survival 85%
 off drugs 29%
 weaning 53%
Acute liver failure – Auxiliary transplant

35. Hepatocyte transplant for
acute liver failure
 transient synthetic and detoxifying function
 site accessible in coagulopathic patients
 no immunosuppression

36. 2.5 x 106 cells/ml
Alginate beads

37. ~400-450µm 
Encapsulated hepatocytes

38.  liver
Site of injection
Hepatocyte transplant for
acute liver failure
 peritoneum
 spleen

39. before Tx retrieved microbeads

40. 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

41.  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

42.  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