Clinics and Research in Hepatology and Gastroenterology (2012) 36, 278283

Available online at

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SUMMER SCHOOL: PEDIATRIC HEPATOLOGY

Acute liver failure in children and adolescents

Anil Dhawan

Paediatric hepatology, Paediatric Liver, GI and Nutrition Centre, Kings College Hospital, Denmark Hill, London, SE5 9RS,
United Kingdom

Available online 21 April 2012

Summary Acute liver failure is a severe and sudden onset of hepatocyte dysfunction, leading
on to synthetic and detoxication failure, which could progress to multi-organ failure and death.
Common causes vary with age and geographical location. Metabolic liver diseases are frequent
in the young child, sometimes amenable to a specic treatment or prenatal diagnosis. In older
children, viruses, toxics, metabolic diseases (especially Wilson), autoimmune hepatitis are the
main causes. Management should be initiated in conjunction with investigations, as soon as
liver failure is diagnosed. The patients should be early transferred to an expert centre, where
complications can be prevented and liver transplantation is possible. Improved intensive care
management and availability of donor organs (split livers or living-related donors) has made it
possible to transplant young children, and improved their survival chances.
2012 Published by Elsevier Masson SAS.

Highlights difcult to establish, Bhaduri and Vergani dened ALF in

The highest incidence of acute liver failure is seen in new-
borns.
Acyclovir should be started in all neonates with liver fail-
ure, as herpes virus infection is the predominant viral
cause.
In adolescents, the main cause is toxic.
Encephalopathy is not easy to recognize in young children.
EEG changes are seen before clinical symptoms.
Denition
Acute liver failure (ALF) is rare in children but carries high
mortality. As the onset of disease might be in utero and
Tel.: +44 2032 994 408; fax: +44 2032 994 228.
E-mail address: anil.dhawan@kcl.ac.uk
children as a rare multisystem disorder in which severe
impairment of liver function, with or without encephalopa-
thy, occurs in association with hepatocellular necrosis in
a patient with no recognized underlying chronic liver dis-
ease. The Paediatric Acute Liver Failure (PALF) study group
used the following criteria:
hepatic-based coagulopathy dened as a prothrombin
time (PT) greater than or equal to 15 seconds or inter-
national normalized ratio (INR) greater than or equal to
1.5 not corrected by vitamin K, in the presence of clini-
cal hepatic encephalopathy (HE), or a PT greater than or
equal to 20 seconds or INR greater than or equal to 2.0
regardless of encephalopathy (HE);
biochemical evidence of acute liver injury;
no known evidence of chronic liver disease.

2210-7401/$ see front matter 2012 Published by Elsevier Masson SAS.

doi:10.1016/j.clinre.2012.03.022
Acute liver failure in children 279

Misc. 5% (1

3)
6% (1
HM
4%

mune
( 8)
Vi

0)
ra

Autoim
l1
1%
(2
3)

Metabolic 7% (1 Indeterminate 31%

5) (68)

(17)
8%
NH
(51)

W
ils
4%

Figure 2 Age distribution of 215 consecutive children pre-

o
ns
gs 2

sented to Kings College Hospital, London (19902003). Highest

4%
Dru

rate of occurrence of acute liver failure (ALF) is during neona-

(10

tal period, and during adolescence predominant cause of ALF is

)

drugs.

HM - Hematological malignancy
NH - Neonatal haemochromatosis
Figure 1 Aetiology of acute liver failure in 215 consecutive
children who presented to Kings College Hospital, London.
Coagulopathy
The synthesis of coagulation factors are affected at dif-
ferent rates depending on the degree of liver failure, and
measurement of them could act as prognostic markers.
Due to defective synthesis and impaired clearance of pro-
coagulant/anticoagulant factors, a degree of intravascular
coagulation (IC) invariably exists in ALF, and can progresses
to fulminant disseminated intravascular coagulation when
there is associated infection or bleeding.
Aetiology
It varies with age and geographical location: viral hepatitis
is the most common in south East Asia and Latin America, in
Northern America and Europe, the aetiology remains inde-
terminate. Though the exact frequency of ALF in children is
unknown, incidence of ALF in USA is around 5.5/million/year
among all ages (Figs. 1 and 2).
Viral hepatitis
Water-borne viral hepatitis (A and E) is the most common
cause in developing countries. With hepatitis A virus (HAV),
the risk of ALF is 0.1 to 0.4%, with hepatitis E, it is 0.6 to
2.8% in adults, it maybe increased during pregnancy. The
ALF due to hepatitis B virus (HBV) can occur at the time of
acute infection, reactivation of a chronic HBV infection, or
seroconversion from a hepatitis B e antigen positive to a
hepatitis B e antibody (HBeAb)-positive state. Infants born to
HBeAb positive mothers are at special risk between 6 weeks
to 9 months. Super infection or co-infection of HBV-infected
patients with delta virus (HDV) can cause liver failure.
Hepatitis C virus (HCV) infection has not been reported as a
cause of ALF.
Members of the herpes virus family (cytomegalovirus,
Epstein-Barr virus, varicella-zoster, herpes simplex) can
cause ALF. Herpes simplex virus 1 and 2 (HSV) are the pre-
dominant cause of viral-induced ALF during the rst month
of life. Babies present with fever, rash, lethargy, poor feed-
ing, and raised transaminases (in thousands). Treatment
with high-dose acyclovir should be initiated in all neonates
with ALF, until the results for HSV are known. Dengue virus
causing ALF has been reported in tropical countries.
Drugs and toxins
Drug-induced hepatoxicity can be a dose-dependent
response, an idiosyncratic reaction, or a synergistic reac-
tion. Some indigenous or herbal medicines are also
hepatotoxic. Acetaminophen is the most common drug asso-
ciated with ALF. Genetic polymorphism of cytochrome P450
isoenzymes predisposes to acetaminophen toxicity due to
increased toxic intermediates production. Anti-tuberculosis
drugs, particularly isoniazid, are associated with ALF. The
mechanism of toxicity is similar to acetaminophen, oxi-
dation via cytochrome P450 pathway resulting in toxic
metabolites.
The true incidence of idiosyncratic drug-induced
liver injury (DILI) is unknown, maybe up to 14 new
cases/100 000/year. Antibiotics and NSAIDs are the most
common causes. Around 8% of DILI develop ALF. Genetic
susceptibility to certain drugs and underlying mitochondrial
cytopathies are proposed causes. Councils for International
Organizations of Medical Sciences/Roussel-Uclaf Causal-
ity Assessment Method (CIOMS/RUCAM) scales are helpful
in establishing causal relationship between a drug and
liver damage. Using the scoring system, suspected drugs
could be categorized into denite or highly probable,
probable, possible, unlikely and excluded.
Chemotherapy drugs are known to induce veno-occlusive
disease leading on to ALF.
280 A. Dhawan

Table 1 Aetiology and investigations in acute liver failure.

Aetiology Disease specic investigations

Infective Infective
Viral hepatitis A, B, B + D, E Serologic/quantitative tests
Herpes simplex, Adenovirus Hepatitis A: Anti-HAV IgM antibody
Epstein-Barr virus Hepatitis B: HBsAg, HBcAb (IgM), HBcAg
Cytomegalovirus Hepatitis C: Antihep C antibody, hep C PCR
Echovirus, varicella Hepatitis D: antihep D antibody
Measles Hepatitis E: Antihep E antibody (IgM)
Rarely, Lassa, Ebola, Marburg, Dengue, Toga virus Human immunodeciency virus (HIV)
Malaria/Tuberculosis/Septicemia Herpes simplex virus (Neonates)
Leptospirosis, Salmonellosis Cytomegalovirus, Epstein-Barr virus
If indicated:
measles/varicella/adenovirus/echovirus/leptospirosis/
Cultures
Bacterial cultures: blood, urine, stool, throat swab, sputum,
skin lesion if present, ascitic uid if present
Viral culture of urine and skin lesion if present
Metabolic Metabolic
Galactosemia Galactose-1-phosphate uridyltransferase
Tyrosinemia Urinary succinylacetone
Hereditary fructose intolerance Quantitative enzyme assay, q22.3 band mutation in chr 9
Mitochondrial disorders Quantitative mitochondrial DNA assay, mutation analysis
Congenital disorders of glycosylation Transferrin isoelectrophoretic
MCAD deciency Plasma acylcarnitines
Wilsons disease Serum copper and ceruloplasmin
24-h urinary copper pre and post penicillamine
Autoimmune Autoimmune
Type 1 autoimmune hepatitis Immunological tests
Type 2 autoimmune hepatitis Immunoglobulins
Giant cell hepatitis with Coombs- Antinuclear antibodies (ANA)
Positive haemolytic anemia Smooth muscle antibody (SMA)
Liver cytosol antibodies (LCA)
Soluble liver antigen (SLA)
Liver kidney microsomal antibody (LKM)
Antineutrophil cytoplasmic antibodies (ANCA)
Inltrative Inltrative
Leukaemia Bone marrow examination
Lymphoma Ascitic or cerebrospinal uid cytospin
Hemophagocytic Genetics for HLH
Lymphohistiocytosis
Vascular/Ischemic Vascular/Ischemic
Budd-Chiari syndrome Ultrasound, echocardiography
Acute circulatory failure/
Cardiac failure/Cardiomyopathies
Birth asphyxia/shock
Neonatal hemochromatosis Lip biopsy

Metabolic disorders Mitochondrial disorders, especially deciencies of com-

Metabolic disorders, such as galactosemia, tyrosinemia type
I and hereditary fructose intolerance, rarely inborn errors
of bile acid synthesis, can present with ALF, particularly in
the neonate. A lactose-free diet should be started on any
infant presenting with ALF or hepatitis until galactosemia is
excluded.
plex I, III and IV, multiple complex deciencies and
mitochondrial DNA (mtDNA) depletion syndrome are asso-
ciated with liver failure. In deciencies of medium-chain
acyl-coenzyme A dehydrogenases (-oxidation of fatty
acids), children could present with hypoketotic hypogly-
caemia, recurrent liver failure, precipitated by otherwise
minor illness. LTx could be done in isolated liver-based
Acute liver failure in children 281

mitochondrial disorders, hence it is important to perform

Table 2 Drugs and toxins causing acute liver failure.
thorough investigation to rule out neuromuscular involve-
ment. Idiosyncratic reaction
Wilsons disease could present as ALF, with a high Antibiotics (penicillin, erythromycin, sulfonamides,
mortality without LTx. The acute hepatic presentation is quinolones, isoniazid)
characterized by liver failure, Coombs-negative hemolytic Phenytoin/Sodium valproate/Carbamazepine
anaemia, and low serum alkaline phosphatase. A Wilson
Nonsteroidal anti-inammatory drugs
index, based on serum bilirubin, serum albumin, interna-
Ecstasy
tional normalized ratio, aspartate aminotransferase (AST),
Antiretroviral drugs
and white cell count (WCC) at presentation identied a cut-
Ketoconazole
off score of 11 for death, and proved to be 93% sensitive and
Allopurinol
98% specic, with a positive predictive value of 88%.
Propylthiouracil
Amiodarone
Neonatal hemochromatosis (NH) Drugs that can unmask mitochondrial cytopathy
Troglitazone
It is the single most common cause of ALF during the rst Diclofenac/Sulindac/Mefenamic acid
month of life, associated with massive iron deposition in Tolcapone
the liver and extrahepatic tissues, including heart and pan- Valproic acid
creas, but with sparing of the reticulo-endothelial system. Amiodarone
The current hypothesis suggests NH to be an alloimmune pro- Simvastatin
cess, where a maternal antibody is directed towards a foetal Isoniazid
liver antigen, resulting in activation of fetal complement
formation of membrane attack complex (MAC) thus hepa- Synergistic drug interactions
tocyte loss. This is supported by the prevention of severe Amoxycillin + clavulinic acid
disease by ante- and post-natal treatment with intravenous Isoniazid + rifampicin
immunoglobulin. NH presents with jaundice, coagulopathy, Trimethoprim + sulfamethoxazole
moderately elevated alanine aminotransferases, high fer- Dose dependent
ritin and raised iron saturation levels. High ferritin is seen Acetaminophen
in other causes of neonatal liver failure, and the diagnosis Halothane
can only be conrmed by demonstration of extrahepatic iron
deposits sparing the reticulo-endothelial system, by a labial Toxins
salivary gland biopsy or MRI. The disease varies in severity: it Amanita phalloides (mushroom poisoning)
is associated with foetal death, as well as with spontaneous Herbal medicines
recovery. Carbon tetrachloride
Yellow phosphorus
Autoimmune hepatitis (AIH) Industrial solvents

AIH presenting as ALF, is mostly of type 2, with posi-

tive anti-liver-kidney microsomal (LKM) antibodies. Without Investigations
encephalopathy, it could be beneted by immunosuppres-
sion, while urgent LTx is necessary if encephalopathy is Investigations to establish the underlying aetiology are listed
present. in Tables 14.

Other causes Prognosis

In spite of extensive investigation, the diagnosis could not be
found in the majority of children. Indeterminate ALF is prob-
ably due to an unidentied infectious agent, as suggested
by presentation with severe hepatitis, liver failure and bone
marrow failure mimicking viral-induced disease, or presen-
tation with minimal jaundice and centrilobular necrosis on
histology suggesting drug-induced.
ALF might be the presenting feature of leukaemia or
lymphoma, or. hemophagocytic lymphohistiocytosis (HLH),
an inherited or acquired condition of paradoxical inef-
cient overactivation of natural killer cells and of CD8+
lymphocytes, and defective apoptosis and reduced cytotoxic
activity. Hypoxia, bacterial infections, underlying cardiac
problem, venous outow obstruction are rare other causes
of ALF.
Drawing a categorical line between chances of spontaneous
liver recovery and irreversible ALF is difcult. Several prog-
nostic markers have been proposed to predict outcomes, of
which INR and factor V concentration remains the best ones.
In children with ALF, INR greater than or equal to 4, bilirubin
greater than or equal to 235 mol/L, age less than 2 years
and WBC above 9109 /L are associated with a poor outcome
without LTx. Bhaduri and Mieli-Vergani have shown that the
maximum INR reached during the course of illness was the
most sensitive predictor of the outcome, with 73% of chil-
dren with an INR less than four surviving, and only four of 24
(17%) if greater than 4. A factor V concentration of less than
25% suggests a poor outcome. A prognostic score is avail-
able for decompensated Wilson disease. In acetaminophen
overdose, metabolic acidosis with arterial pH less than 7.3,
282 A. Dhawan

Table 3 Pathophysiology of complications in acute liver failure (ALF).

Encephalopathy
Inhibitory effect of ammonia, Gamma-aminobutyric acid on neuronal cell membranes and synapses
Intracranial hypertension and cerebral oedema
The direct toxicity of toxins on neuronal cells and vasogenic imbalance leading onto uid shifts resulting in cerebral oedema
Renal failure
Direct toxic effect of drugs and toxins on kidneys
Acute tubular necrosis secondary to complications of ALF such as sepsis, bleeding, and/or hypotension
Hepato-renal syndrome: Probably due to vasoactive mediators causing vasoconstriction leading on to a rise in renal vascular
resistance and also a decrease in glomerular capillary ultraltration coefcient
Hypotension
Vasodilatation, probably mediated by increased prostaglandin or nitric oxide, causes hypovolemia. As the disease
progresses, circulatory failure sets in either due to falling cardiac output or depression of brainstem function as a result of
cerebral oedema
Metabolic derangement
Hypoglycemia due to increased plasma insulin levels owing to reduced hepatic uptake and reduced gluconeogenesis
Lactic acidosis is related to inadequate tissue perfusion due to hypotension and hypoxemia resulting from microvascular
shunting of blood from actively respiring tissue
Infection
Impaired Kupffer cell and polymorphonuclear function along with reduced levels of factors such as bronectin, opsonins,
chemo-attractants and components of the complement system.
Hepato-adrenal syndrome
Decreased liver synthesis of Apolipoprotein (apo)A-1, the major protein component of HDL leading on to decreased HDL and
thereby decreased cortisol production

Table 4 Outcome (one-year) of 215 consecutive children with acute liver failure admitted to Kings college hospital, London.

Listed for transplant Not listed Total

Transplanted Not transplanted

Alive Died Alive Died Alive Died

Neonate (< 28 days) 7 4 2 4 12 13 42

Infant (29 days to 1 yr) 3 3 3 0 9 5 23
Child (1.1 to 12 yrs) 36 7 5 5 32 10 95
Adolescent(12.1 to 18 yrs) 18 4 0 1 28 4 55
Total 64 18 10 10 82 31 215

after the second day of overdose in adequately hydrated
patients, is associated with 90% mortality; other poor prog-
nostic markers are INR greater than 6.5, creatinine greater
than 300 mol/L and hyperphosphatemia.
Management
Once ALF is suspected, contact with a specialist centre
should be made to organize the management and an early
transfer. Prophylactic broad-spectrum antibiotics and anti-
fungals should be started, and acyclovir should be added in
infants and neonates. Children with encephalopathy or an
INR greater than 4 (regardless of encephalopathy) should be
admitted to an intensive care unit. Hypoglycaemia should be
avoided. Protein restriction to limit the possibility of HE has
now been disregarded, and adequate calories should be pro-
vided. Oral or nasogastric feeding is usually well tolerated.
Prophylactic H2 blockers or proton pump inhibitors should
be started to all patients requiring mechanical ventilation.
N-acetylcysteine (NAC) is being increasingly used in non-
acetaminophen induced ALF, as it enhances circulation and
improves oxygen delivery.
Elective intubation and mechanical ventilation should be
considered for patients with grade 3-4 encephalopathy, or
for patients in grade 1 or 2 encephalopathy requiring seda-
tion.
Intravenous uids should be restricted to two-thirds
maintenance, to decrease the possibility of development of
cerebral oedema. If hypotension persists despite adequate
intravascular lling, noradrenaline is the agent of choice.
Acute liver failure in children
In refractory hypotension, hydrocortisone should be con-
sidered. Renal-replacement therapy should be considered
when the urine output is less than 1 mL/kg/h.
Encephalopathy is not always recognisable in chil-
dren, and usually is a late feature. The most serious
complications of ALF are cerebral oedema with resultant
intracranial hypertension and hepatic encephalopathy. Elec-
troencephalographic (EEG) changes occur very early in HE,
even before the onset of psychological or biochemical dis-
turbances.
Coagulopathy is corrected only if the patient is already
listed for LTx, or prior to an invasive procedure, as it is a
dynamic indicator of disease activity.
Disease specic management
In neonatal haemochromatosis, use of antioxidant cock-
tail (N-Acetylcysteine, Selenium, Desferrioxamine,
Prostaglandin E1, Vitamin E) is debated, as there are
no control trials. Intravenous immunoglobulin (IVIG) when
given as prophylaxis to mothers whose previous pregnancy
or child was affected with NH (1 g/kg, weekly from the
18th week until the end of gestation) has been associated
with milder phenotypic expression of the disease and 100%
survival of babies. Evidence is accumulating towards the
usefulness of high-dose IVIG (1 g/kg), in combination with
exchange transfusion resulting in signicant decrease in
the need for LTx. The management of HLH consists of
liver supportive therapy, chemotherapy and discussion of
haematopoietic stem cell transplantation.
Liver assist devices
Liver support devices should provide an extracorporeal sup-
port for short periods, while the native liver regenerates
or a liver transplant becomes available. They are cell-free
cleansing devices, with only the detoxifying function, and
bioarticial liver support systems, which contain human
or animal liver cells and have the theoretic advantage of
providing the synthetic and detoxifying properties. They
decrease the toxins (ammonia, bilirubin, cytokines, etc.) but
have no effect on mortality. Their use is not recommended
outside research setting.
Liver transplantation
LTx is the only treatment that has improved the outcome
of ALF. Careful patient selection is essential to minimize
patients from being listed for LTx and removed due to
spontaneous recovery. Absolute contraindications are xed
and dilated pupils, uncontrolled sepsis, systemic mito-
chondrial or metabolic disorders and severe respiratory
283
failure. Relative contraindications are increasing inotropic
requirements, infection under treatment, cerebral perfu-
sion pressure of less than 40 mm Hg for more than 2 hours,
and a history of progressive or severe neurologic problems.
Auxiliary liver transplantation
It could be orthotopic (part of the native liver is resected
and replaced with a reduced-size graft) or heterotopic (the
donor graft is placed alongside the native liver in the right
upper quadrant). The allograft provides liver function while
the native liver regenerates, and then immunosuppression
can be weaned and eventually stopped. In our series, of 20
children among the 17 survivors, 14 (82%) have successfully
regenerated their native liver and 65% have been withdrawn
from immunosuppression.
Hepatocyte transplantation
Hepatocyte transplantation, where hepatocytes are infused
intraportally into the patients liver, where a proportion of
cells will engraft, has been tried with variable success in
certain liver-based metabolic disorders. Its use in ALF still
remains experimental.
Disclosure of interest
The author declares that he has no conicts of interest con-
cerning this article.
Further reading
Bhaduri BR, Mieli-Vergani G. Fulminant hepatic failure: pediatric
aspects. Semin Liver Dis 1996;16:34955.
Squires RH, Jr., Shneider BL, Bucuvalas J, Alonso E, Sokol RJ,
Narkewicz MR, et al. Acute liver failure in children: the rst 348
patients in the pediatric acute liver failure study group. J Pediatr
2006;148:6528.
Andrade RJ, Robles M, Fernandez-Castaner A, Lopez-Ortega S,
Lopez-Vega MC, Lucena MI. Assessment of drug-induced hepatotox-
icity in clinical practice: a challenge for gastroenterologists. World
J Gastroenterol 2007;13:32940.
Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis
L, Mieli-Vergani G. Wilsons disease in children: 37-year experi-
ence and revised Kings score for liver transplantation. Liver Transpl
2005;11:4418.
Whitington PF, Malladi P. Neonatal hemochromatosis: is it
an alloimmune disease? J Pediatr Gastroenterol Nutr 2005;40:
5449.
Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-
Vergani G, Dhawan A. Safety and efcacy of n-acetylcysteine in
children with non-acetaminophen-induced acute liver failure. Liver
Transpl 2008;14:2530.