- 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.
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Acute Liver Failure in Children
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
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
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
35. Hepatocyte transplant for
acute liver failure
transient synthetic and detoxifying function
site accessible in coagulopathic patients
no immunosuppression
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