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Acute liver failure in children

ARTICLE in SEMINARS IN LIVER DISEASE JUNE 2008

Impact Factor: 5.12 DOI: 10.1055/s-2008-1073115 Source: PubMed

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Acute Liver Failure in Children
Robert H. Squires, Jr., M.D.1

ABSTRACT

Acute liver failure (ALF) in children differs from that observed in adults in both
the etiologic spectrum and the clinical picture. Children, particularly very young ones, do
not demonstrate classical features of encephalopathy and the definition of ALF has been
revised to include patients with advanced coagulopathy, regardless of mental status. A
significant number of these children will go on to require transplant or die. Etiologies vary
by age with metabolic and infectious diseases prominent in the first year of life and
acetaminophen overdose and Wilsons disease occurring in adolescents. In almost 50% of
cases, however, the child has an indeterminate cause for ALF. Management requires a
multidisciplinary approach and is directed at establishing the etiology where possible and
monitoring, anticipating, and managing the multisystem complications that occur in
children with ALF. Overall, short-term outcomes are better in children than adults but
are dependent upon the degree of encephalopathy and diagnosis.

KEYWORDS: Acute liver failure, acetaminophen, hepatitis, APAP

A cute liver failure (ALF) is not a diagnosis but a
clinical syndrome. ALF was initially characterized in
adults with biochemical evidence of severe hepatic
dysfunction (e.g., jaundice and coagulopathy) compli-
cated by hepatic encephalopathy that develops within
8 weeks of the onset of the signs and symptoms of liver
disease.13 Initial studies in children utilized the adult
definition of ALF.46 However, recognition of hepatic
encephalopathy in children is difficult and may not be
clinically apparent until the terminal stages of the
disease process.6 Thus, more recent single site reviews
of ALF have included children without clinical ence-
phalopathy.7,8
The Pediatric Acute Liver Failure (PALF) Study
Group was formed in 2000 as a multisite, multinational
consortium to prospectively study ALF in children from
birth up to 18 years of age. A consensus reached by 21
PALF investigators defined entry criteria of the study:
(1) no evidence of a known chronic liver disease; (2)
hepatic-based coagulopathy that is not corrected by
parenteral administration of vitamin K; (3) hepatic
encephalopathy must be present if the uncorrected
prothrombin time (PT) or international normalized ratio
(INR) was between 15 and 19.9 seconds or 1.5 to 1.9,
respectively; and (4) hepatic encephalopathy was not
required if the PT or INR was greater than or equal to
2.0 seconds or 2.0, respectively.9 Other presentations of
liver failure such as subfulminate hepatic failure,10,11
acute-on-chronic liver failure,12,13 and primary non-
function following liver transplantation14 were ex-
cluded from the PALF study and will not be covered
in this discussion.
ETIOLOGY
In North America and the United Kingdom, the etiol-
ogy of ALF differs quite dramatically between adults and
children.9,15 In adults, almost 50% of cases are due to

1
Professor of Pediatrics, University of Pittsburgh; and Clinical Director
of Gastroenterology, Hepatology, and Nutrition, Childrens Hospital
of Pittsburgh, Pittsburgh, Pennsylvania.
Address for correspondence and reprint requests: Robert H.
Squires, Jr., M.D., Clinical Director of Gastroenterology, Hepatology,
and Nutrition, Childrens Hospital of Pittsburgh, 3705 Fifth Avenue,
Pittsburgh, PA 15213 (e-mail: squiresr@upmc.edu).
Liver Failure and Liver Support; Guest Editor, William M. Lee, M.D.,
F.A.C.P.
Semin Liver Dis 2008;28:153166. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1073115. ISSN 0272-8087.
153
154 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 2 2008
acetaminophen overdose, either intended or unintended,
with hepatitis B and non-acetaminophen drug-induced
liver injury occurring playing a prominent role. In
children, acetaminophen overdose accounts for fewer
than 20% of cases, while metabolic disease, autoimmune
disease, and infectious hepatitis, due primarily to herpes
viruses occurring in infants, are the more commonly
diagnosed conditions. Unfortunately, a diagnosis is not
established in up to 50% of children.
Acetaminophen/Paracetamol
Since its introduction into the pediatric pharmacopeia
in the mid-1950s, acetaminophen (N-acetyl-p-amino-
phenol; APAP) has become the first-line analgesic/
antipyretic medication for children.16 The usual pedia-
tric dose ranges from 10 to 15 mg/kg/dose administered
every 4 hours to a maximum of 80 mg/kg/day. Reports
of accidental ingestion first surfaced in the British
literature in the 1970s, but serious consequences were
not initially apparent. Acetaminophen is not hepato-
toxic in standard doses, but is a dose-related toxin if
detoxification is overwhelmed, resulting in cell death.17
Recent studies have identified a potentially useful bio-
marker, APAP-cysteine protein adducts, which are
detected in the plasma of patients with liver injury
due to APAP long after the parent compound has
been metabolized.18
APAP is the most common identifiable cause of
ALF in children living in the United States and United
Kingdom.9 The PALF study has confirmed at least two
clinical presentations; the first is an acute, intentional
ingestion and the second, referred to as a therapeutic
misadventure, relates to the ingestion of multiple doses
taken over a few days time with the intent to treat
clinical symptoms. The clinical presentation for both
conditions includes a profound uncorrectable coagulop-
athy and dramatically elevated serum aminotransferase
levels that can reach over 10,000 IU/mL coupled with a
normal or mildly elevated total bilirubin. Encephalop-
athy is uncommon or, if present, is typically grade 1 to 2.
If a biopsy is performed, typical findings would include
centrilobular (zone 3) necrosis associated with few other
abnormalities.
ALF following ingestion of a single overdose of
APAP is preventable with prompt patient identification
and early intervention with either oral or intravenous N-
acetylcysteine (NAC). The toxic dose of APAP can with ALF in children.35 While ingestion of these
vary among patients.19 However, ingestion of
140 mg/
kg should be considered potentially toxic.20 Two deaths
were registered in our prospective study; both presented
with late stages of encephalopathy, one with a possible
underlying defect in fatty acid metabolism.21 The use of
the serum APAP concentration-versus-time nomogram
developed by Rumack provides the best guide to poten-
tial toxicity but is only applicable when the time of
ingestion is known and occurred at only a single time
point.22
The therapeutic misadventure resulting in ALF
was first described in 1986 and subsequently confirmed
by others.2225 APAP is often used for systemic symp-
toms that precede the recognition of ALF and may
confound the etiologic role of APAP in a particular
case when fever or other symptoms have been present.
However, a careful history often reveals daily dosing
beyond the recommended 80 mg/kg/day. Adult tablets
or suppositories have been used in children with the false
assumption that APAP is safe at any dose. Altered
metabolism of APAP occurs when glutathione stores
are reduced during prolonged fasting associated with an
extended illness.26 Whether APAP toxicity can occur in
children receiving the recommended dose is unclear, but
it has been described in adults with regular alcohol
consumption.27 One might imagine an unfortunate
alignment of circumstances that would include a pro-
longed febrile illness, coupled with poor intake, multiple
around-the-clock doses of APAP, and possibly an
underlying susceptibility (e.g., fatty acid oxidation de-
fect, altered cytochrome P-450 enzymes); all might
contribute in part to the development of ALF. In a
small study of children with indeterminate ALF, we
found 12.5% of children with positive APAP-cys protein
adducts suggesting APAP led to ALF despite a lack of
history of excessive APAP ingestion, further suggesting
that histories can be quite misleading.28
Hepatotoxins, Herbals, and Non-
Acetaminophen Drug-Induced ALF
Drug or toxin-induced liver injury is uncommon in
children and is rarely identified as a cause of ALF.9,29
Children are increasingly exposed to a variety of over-
the-counter, prescription, and herbal medications as well
as environmental toxins and recreational drugs. Assess-
ment of causality, however, must be determined by
circumstantial evidence culled from a detailed history,
degree of clinical suspicion, and clinical presenta-
tion.30,31 Differences in drug metabolism as well as the
absence of comorbidities between children and adults
may also play a role in the frequency, demographics, and
clinical manifestation of hepatotoxic injury.3234
Amatoxin is a known hepatotoxin found in nine
Amanita species of wild mushrooms and is associated
wild mushrooms is more common in Western Europe,
mushroom hepatotoxicity does occur in the United
States.9,36 Therapeutic medications reported to cause
ALF in children include amiodarone,37 isoniazid,38
minocycline,39 and pemoline.40
As herbal medications are increasingly popular, a
proportionate increase in adverse reactions associated
with these products is to be expected.41 Pyrrolizidine

alkaloids found in Jamaican bush tea, Symphytum
(comfrey), Heliotropium, and Senecio are metabolized by
cytochrome P450 to highly reactive species that result in
a dose-dependent direct hepatotoxic injury.42 A history
of ingestion of an herbal cocktail should be sought if a
child presents with clinical and/or histological features of
veno-occlusive disease (VOD). However, there is at least
one report of a newborn infant presenting with VOD
who was exposed to herbal tea throughout the preg-
nancy.43
Antiseizure medications constitute the highest
percentage of medication-induced ALF in children.9
Valproic acid (VA) is metabolized via mitochondrial
b-oxidation and can cause ALF by either direct injury
to liver cell mitochondria44 or by unmasking a more
generalized mitochondrial disorder.45,46 The population
at greatest risk for VA-associated ALF is children less
than 2 years of age with developmental delay and
receiving multiple anticonvulsant medications, although
it can occur in older children and adults.47 Carbamaze-
pine, phenobarbital, and phenytonin can cause an idio-
syncratic reaction or result in multisystem injury that is
recognized as the antiepileptic hypersensitivity syn-
drome.48 The clinical presentation is typically associated
with fever, skin rash, and progressive pulmonary symp-
toms. The underlying mechanism is likely immune
mediated as early recognition with treatment utilizing
intravenous gamma globulin and steroids can result in
significant clinical improvement.
Infection
An infectious etiology is often considered when children
present with nonspecific symptoms such as myalgia,
fever, decreased appetite, and listlessness and ALF.
Interestingly, we identified an infectious etiology in
only 17/331 (5%) of children with ALF presenting in
North America and the United Kingdom.9 Infections
are identified more frequently in the younger population,
particularly those in the first 4 weeks of life. The
infectious agents found in young infants include herpes
simplex, adenovirus, enterovirus, and paramyxovirus,
while Epstein-Barr virus (EBV) occurred more fre-
quently in older patients. Overall, we found only three
children with hepatitis A, one child with hepatitis C, and
no child was identified with hepatitis B. This pattern of
infectious causes of ALF is quite distinct from that seen
with North American adults where hepatitis A and B
account for 3% and 7% of cases, respectively.15 Reasons
for this discrepancy are likely related to routine immu-
nizations in children for hepatitis B and, more recently,
hepatitis A.49,50
Hepatitis A virus is a common cause in areas
where it is endemic or referral centers for endemic
areas,8,51 but not in developed countries in the absence
of an outbreak.52 While hepatitis B is a reported cause of
ACUTE LIVER FAILURE IN CHILDREN/SQUIRES 155
ALF in infants,53 it occurs more commonly in adults and
risk factors include older age and genotype D.54 Hep-
atitis C virus is a very rare primary cause of ALF.
Hepatitis E occurs within endemic areas such as India,
Africa, and Mexico. Pregnant women who become
infected with hepatitis E are at a greater risk of devel-
oping ALF.55,56 Adenovirus should be considered when
patients present with nasopulmonary symptoms in the
setting of an immunocompromised patient,57,58 but can
occur in apparently normal patients.59 The role of
human herpesvirus-6 in ALF is unclear as it has been
found in explanted livers of children with ALF and in
control livers.60 Echo virus is described primarily in
newborns or neonates and is usually associated with
systemic viral sepsis.61,62 Parvovirus B19 has been pro-
posed as a cause for ALF,63 but whether it is a primary
cause or a confounding factor in the setting of other viral
diseases (e.g., hepatitis A, EBV) is not clear.64,65 Parvo-
virus has been implicated in those patients with ALF
who subsequently develop aplastic anemia,66 but suffi-
cient proof of the association has not been gathered.
Epstein-Barr virus is known to be a cause of ALF67,68
and can be associated with hemolytic anemia69 and
hemophagocytic syndrome.70 It is more commonly an
issue in children with immunodeficiencies. Herpes sim-
plex occurs most commonly in the first 2 weeks of life
and is almost always associated with systemic disease.
Immune Dysregulation
Autoimmune hepatitis (AIH) typically presents as a
chronic, inflammatory liver disease. However, 2 to
5% of patients with AIH will present with signs and
symptoms of acute liver failure manifested by progressive
jaundice, encephalopathy, and uncorrectable coagulop-
athy over a period of 1 to 6 weeks without an antecedent
history of an underlying liver disease. Patients will have
at least one positive autoimmune marker (e.g., antinu-
clear antibody, anti-smooth muscle antibody, liver-kid-
ney microsomal antibody, or soluble liver antigen) and
may or may not have an elevated IgG level. Unfortu-
nately, nonspecific elevation of autoimmune antibody
titers can occur in children with ALF, making the
diagnosis difficult.71 Liver histology supporting a diag-
nosis of autoimmune liver disease may be helpful and
should be performed before initiating therapy. However,
histology is not always confirmatory.7274 Approximately
5% of children with ALF were diagnosed with AIH in
the PALF study.9
Hemophagocytic lymphohistiocytosis (HLH)
presents as an overwhelming inflammatory condition
associated with fever, hepatosplenomegaly, and cytope-
nia with some cases associated with liver failure.75,76 It
can be a primary disorder or it can be associated with
other immune deficiencies such as Chediak-Higashi
syndrome and X-linked lymphoproliferative disease.
156 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 2 2008
HLH can also develop following viral or bacterial
infection in both normal and immunocompromised
(e.g., transplant, chemotherapy) patients.77 The under-
lying mechanism for some patients appears to be natural
killer cell (NK-cell) dysfunction that results in an
unbridled inflammatory process.78 Celiac disease, an
immune-mediated enteropathy, has been associated
with ALF.79,80 Sclerosing cholangitis is a rare cause
of ALF.81
Metabolic
Metabolic causes of ALF may be observed in all age
groups, but is more common in children less than 1 year
of age.9,82 Galactosemia and hereditary tyrosinemia type
1 can present with liver failure before the results of the
newborn screen are available and should be strongly
considered in the setting of a profound, uncorrectable
coagulopathy with minimal aminotransferase elevation.
Mitochondrial disorders typically present with multi-
system involvement that includes skeletal and/or cardiac
myopathy, renal tubular dysfunction, seizures, develop-
mental delay, and some degree of hepatic dysfunction.
Liver failure does not occur in all children with mito-
chondrial disorders, but it may be the initial presenting
feature for some,83 due to mitochondrial depletion84 or a
specific mitochondrial DNA (mDNA) or nuclear gene
mutation affecting the respiratory chain complex85 or
mitochondrial fatty acid oxidation.86,87 Fatty acid oxi-
dation disorders associated with ALF include defects in
long-chain fatty acid transport,88 medium-chain acyl-
coenzyme A dehydrogenase deficiency, short-chain 3-
hydroxyacyl-coenzyme A dehydrogenase deficiency,89
and long-chain 3-hydroxyacyl-coenzyme a dehydrogen-
ase deficiency.90 Complex disorders involving both mi-
tochondrial complex and fatty acid oxidation have been
observed.91 More patients with fatty acid oxidation
defects associated with ALF will likely be identified
with advancing technology and increased clinical suspi-
cion.21 Identification of a multisystem mitochondrial
disorder, such as Alpers disease, would be a contra-
indication for a liver transplant.92
Wilsons disease is currently the most common
metabolic disease presenting with ALF in older children
and adolescents.9 Clinical features often include a non-
specific prodrome of fever and listlessness followed by
deepening jaundice. Biochemical features of Wilsons
disease include evidence of hemolysis, markedly elevated
serum bilirubin, and a normal or low serum alkaline
phosphatase.9395
Other Causes
Neonatal hemochromatosis presents in the first few days
to weeks of life with a profound coagulopathy with
normal aminotransferase levels, ascites, and multiorgan
failure associated with the accumulation of iron into
extrahepatic tissues that include the pancreas and heart.
The nomenclature surrounding this condition is confus-
ing as it has no relationship to hemochromatosis diag-
noses in adults. Our understanding of the underlying
pathology of this disorder has advanced over the last few
years.96 Recent studies by Whitington and Malladi
suggest that it is an allo-immune disorder with maternal
antibody generated against an antigen found in the fetal
liver.97 Other causes of ALF include Budd-Chiari syn-
drome,98,99 VOD,100 malignancy,101,102 shock and other
low-output cardiac states,103105 and heat stroke.106
Indeterminate
A specific diagnosis is not identified in 50% of children
with ALF.9 Previously indeterminate cases were classi-
fied as either non-A non-B hepatitis, neonatal hepatitis,
or non-A through non-E hepatitis. Efforts to identify
novel or unexpected hepatotropic viruses have not yet
been undertaken in children, but such searches in adults
were unrevealing.107,108 Identification of APAP-cys ad-
ducts in almost 12% of children with indeterminate ALF
without a clear toxic exposure to APAP suggests that
within the indeterminate group are undiagnosed or
unsuspected etiologies that include infections, metabolic
disease, drug or toxin, and/or immunological disor-
ders.109111
MANAGEMENT
Close collaboration between gastroenterology/hepatol-
ogy, intensive care, neurology, neurosurgery, nephrol-
ogy, metabolic disease specialists, and transplant
surgeons will afford the child the best opportunity to
survive. After the initial characterization of the patient
presentation, proper patient management follows along
multiple parallel paths: (1) monitor and support the
patient and organ systems, (2) identify and treat com-
plications, (3) develop an age-appropriate diagnostic
prioritization strategy, and (4) treat the patient to max-
imize health and survival.112115
Characterize the Presentation
The chaos surrounding the patient with ALF makes the
initial assessment challenging, but a detailed history and
physical examination cannot be overlooked or abbrevi-
ated. If a specific diagnosis can be secured, an effective
treatment could alter the natural history of the disease.
The history should include the onset of symptoms
such as jaundice, change in mental status, easy bruising,
vomiting, and fever. Exposure to contacts with infectious
hepatitis, history of blood transfusions, a list of prescrip-
tion and over-the-counter medications in the home,
intravenous drug use or a family history of Wilsons
 ACUTE LIVER FAILURE IN CHILDREN/SQUIRES 157

disease, a-1 antitrypsin deficiency, infectious hepatitis,
infant deaths, or autoimmune conditions might lead to
a specific diagnosis. Evidence of developmental delay
and/or seizures should prompt an early assessment for
metabolic disease. Pruritus, ascites, or growth failure
might suggest a chronic liver condition.
Physical assessment should include a review of
growth, development, and nutrition status and evidence
of jaundice, bruises, and petechiae. Hepatomegaly alone
or with splenomegaly, ascites, and peripheral edema are
often present. Kayser-Fleischer rings are usually not
present in patients with Wilsons disease who present
with ALF. Fetor hepaticus, a sweet unique aroma to the
breath associated with hepatic encephalopathy, is present
only rarely. Findings suggestive of chronic liver disease
include digital clubbing, palmar erythema, cutaneous
xanthoma, and prominent abdominal vessels suggesting
long-standing portal hypertension.
Hepatic encephalopathy (HE) is a neuropsychi-
atric syndrome associated with hepatic dysfunction.116
Changes in behavior, cognition, neurological examina-
tion, and electroencephalogram (EEG) are assessed to
characterize the patient as having one of five clinical
stages of encephalopathy, ranging from stage 0 with
minimal or no evidence of neurological dysfunction to
stage 4 coma (Table 1). Clinical staging of HE was
originally developed to assess patients with cirrhosis and
not ALF, but in the absence of a better clinical tool, it
has been found to have important clinical and prognostic
implications. The patient should be clinically assessed
initially and then multiple times during the day for each
component of the HE score, as clinical progression can
be devastatingly rapid. The clinical utility of the EEG
and other neurophysiological studies should be clarified
in future investigations.117
Initial laboratory tests should be prioritized in
three areas: (1) general laboratories to assess hemato-
logical, renal, pancreatic, and electrolyte abnormalities;
(2) liver-specific tests to assess the degree of inflamma-
tion, injury, and function; and (3) diagnostic tests. As
over 30% of children with ALF are younger than 3 years
of age, limitations on the volume of blood that can be
drawn can be problematic. In addition, required blood
work in preparation for a liver transplant also competes
for this limited resource. Proactive coordination of
laboratory and diagnostic tests is helpful to ensure that
high-priority tests are performed expeditiously.
Monitor and Support the Patient and Organ
Systems
Admission to a highly skilled nursing environment
which, in most cases, will be an intensive care unit,
should also ensure a quiet environment to avoid un-
necessary stimulation from visitors, television, or hospi-
tal personnel that can aggravate encephalopathy and
increase intracranial pressure. Patients with HE can
become combative. To ensure patient and provider
safety, padding should be placed on the side rails of
the bed and more than one provider should be at the
bedside for any intervention. Patient restraint is required
under some circumstances. A cardiorespiratory and
oxygen saturation monitor should not serve as a sub-
stitute for careful and frequent bedside assessment by an

Table 1 Stages of Hepatic Encephalopathy

Stage Clinical Reflexes Neurological Signs EEG Changes

0 None Normal None Normal

1 Infant/child: Inconsolable crying, Normal or Difficult or impossible to Difficult or impossible to
inattention to task; child is not hyper-reflexic test adequately test adequately
acting like self to parents
Adult: Confused, mood changes, Normal Tremor, apraxia, impaired Normal or diffuse slowing to
altered sleep habits, forgetful handwriting theta rhythm, triphasic waves
2 Infant/child: Inconsolable crying, Normal or Difficult or impossible to Difficult or impossible to
inattention to task; child is not hyper-reflexic test adequately test adequately
acting like self to parents
Adult: Drowsy, inappropriate Hyper-reflexic Dysarthria, ataxia Abnormal, generalized slowing,
behavior, decreased inhibitions triphasic waves
3 Infant/child: Somnolence, stupor, Hyper-reflexic Difficult or impossible to Difficult or impossible to test
combativeness test adequately adequately
Adult: Stuporous, obeys simple Hyper-reflexic, Rigidity Abnormal, generalized slowing,
commands ( ) Babinski triphasic waves
4 Infant/child: Comatose, arouses Absent Decerebrate or decorticate Abnormal
with painful stimuli (4a) or
no response (4b)
Adult: Comatose, arouses with painful Absent Decerebrate or decorticate Abnormal, very slow,
stimuli (4a) or no response (4b) delta activity
158 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 2 2008
experienced nurse or clinician. Input and output should
be strictly monitored. Caregivers must carefully examine
the child multiple times during the day and night to
assess evidence of changing mental status or HE, in-
creased respiratory effort, changing heart rate or changes
in blood pressure which might be signs of infection,
increasing cerebral edema, or electrolyte imbalance.
Laboratory monitoring should include a complete
blood count, electrolytes, renal function tests, glucose,
calcium, phosphorous, ammonia, coagulation profile,
total and direct bilirubin, and blood cultures. Diagnostic
laboratory studies should be prioritized. While obtaining
an arterial ammonia level is ideal, it is not practical in
children with stages 0 to 2 HE; a venous ammonia
obtained from a free-flowing catheter and promptly
placed on ice and transported to the laboratory may be
a suitable substitute. Placement of arterial and central
catheters should be reserved for patients who show signs
of clinical deterioration to late grade 2 or grade 3 HE.
Intravenous fluids should be restricted to between
85% and 90% of maintenance fluids to avoid over-
hydration yet still provide sufficient glucose and phos-
phorus to achieve normal values. Adjustment in fluid
rates are based upon the clinical conditions, but relative
fluid restriction should be an underlying principal. Nu-
tritional support, including protein, should be provided
if the patient can eat safely, or with intravenous nutri-
tional support. Some protein restriction may be neces-
sary, but protein should not be eliminated.
Identify and Treat Complications66,118127
NEUROLOGICAL
Hepatic encephalopathy is not always clinically apparent
in infants and young children. Distinguishing a hepatic-
based encephalopathy from other causes of an altered
mental status such as sepsis, hypotension, electrolyte
disturbances, anxiety, or ICU psychosis is difficult for
all age groups. Hyperammonemia plays a central role in
the development of HE in most cases.128 However, a
specific level of ammonia does not result in a predictable
degree of encephalopathy. Clinical characteristics of HE
are outlined in Table 1. The role of other modalities,
such as visual-evoked potentials,129 continuous EEG
monitoring, and monitoring S-100b and neuron-specific
enolase,130 in the assessment of HE are unclear at the
present time. Initial treatment would include minimiz-
ing excess stimulation, reduction of protein intake,
treating suspected sepsis, and removing sedative medi-
cations that would affect mental status. Medical therapy
with lactulose should be initiated with clinical evidence
of HE. Bowel decontamination with neomycin can be
used as a second-tier treatment, but ototoxicity and
nephrotoxicity are potential risks. Sodium benzoate
was reported to be beneficial in adults with cirrhosis,131
but concerns about increasing blood ammonia with this
treatment have been raised.132
Not all patients with HE develop a clinically
important increase in intracranial pressure. However,
those who do can experience devastating consequences.
Direct intracranial pressure monitoring is the most
sensitive and specific test when compared with less-
invasive neuroradiographic procedures, such as cranial
CT.133 Monitoring of intracranial pressure remains
controversial due to associated complications of the
procedure and no evidence of improved survival for those
who were monitored.134
HEMATOLOGICAL
The PT and INR are used in virtually all prognostic
schemes to assess the severity of liver injury in the setting
of ALF and are assumed to be markers for the risk of
bleeding in ALF patients as well. In patients with ALF,
both procoagulant proteins (e.g., factors V, VII, X, and
fibrinogen) and anticoagulant proteins (e.g., antithrom-
bin, protein C, and protein S) are reduced.135 This
balanced reduction in the pro- and anticoagulant proteins
may account for the relative infrequency of clinically
important bleeding in the ALF patient in the absence
of a provocative event such as infection or increased portal
hypertension. Therefore, the PT/INR may reasonably
reflect the reduction of some of the liver-based coagu-
lation proteins, but not the relative risk of bleeding.
Efforts to correct the PT/INR with plasma or other
procoagulation products such as recombinant factor VII
should occur primarily in the setting of active bleeding or
in anticipation of an invasive surgical procedure.
Bone marrow failure, characterized by a spectrum
of features ranging from mild pancytopenia to aplastic
anemia, occurs in a significant minority of children with
ALF.136 It is identified most commonly in the setting of
indeterminate ALF and may not be clinically evident
until after emergent liver transplantation.137 Treatment
includes immunomodulatory medications that include
steroids, cyclosporine A, antilymphocyte or antithymo-
cyte globulin as well as hematopoietic stem cell
transplant.
GASTROINTESTINAL
Ascites develops in some but not all patients. Precipitat-
ing factors include hypoalbuminemia, excessive fluid
administration, and infection. Treatment includes fluid
restriction and diuretics, but should be reserved for those
patients who experience respiratory compromise or dis-
comfort due to the fluid accumulation. Spironolactone is
the drug of choice to initiate therapy, but furosemide
may also be required. Overly aggressive diuresis may
precipitate hepatorenal syndrome.
Gastrointestinal bleeding occurs surprisingly
infrequently, given the degree of coagulopathy. Pro-
phylactic use of acid-reducing agents is often initiated

when the patient is admitted, but their usefulness
is difficult to assess. Causes for bleeding include
gastric erosions or ulcers due to nonsteroidal anti-
inflammatory medications, varices or gastropathy due
to portal hypertension, or idiopathic gastroduodenal
ulceration. Infection can precipitate bleeding in this
vulnerable population, so blood cultures and initiation
of antibiotics should also be considered when bleeding
develops. Administration of platelets, blood, and
plasma is necessary if bleeding is hemodynamically
significant.
RENAL CONSIDERATIONS
Evidence of renal insufficiency and ALF on admission
should be assessed for evidence of a medication or toxin
as the precipitating cause. Prerenal azotemia can develop
if fluid restriction is too excessive for the patients needs.
Acute deterioration of renal function after presentation
with ALF may result from systemic hypotension due to
sepsis or hemorrhage. Hepatorenal syndrome (HRS) is a
feared renal complication associated with ALF, although
it occurs more commonly in the setting of chronic liver
disease with established cirrhosis.138 HRS can progress
rapidly over the course of 2 weeks (type 1 HRS) or more
slowly (type 2 HRS).139 The diagnosis is suspected
when there is evidence of deteriorating renal function
in the absence of bleeding, hypotension, sepsis, or
nephrotoxic medications and in association with failure
to improve with volume expansion. The urine sodium is
typically low. Renal replacement therapy with contin-
uous venovenous hemofiltration or dialysis may be
necessary in some cases, but only liver transplantation
can reverse HRS.
METABOLIC
Hypoglycemia results from impaired gluconeogenesis
and depleted glycogen stores. Glucose infusion rates of
10 to 15 mg/kg/minute may be required to achieve stable
serum glucose levels and will require a central venous
catheter for hypertonic glucose solutions. Hypokalemia
may occur secondary to dilution from volume overload,
ascites, or renal wasting. Serum phosphorus should be
monitored frequently as hypophosphatemia can be
profound and patient outcome is enhanced if the phos-
phorous can be maintained in the normal range.140
Acid-base disturbances can be complicated with respi-
ratory alkalosis from hyperventilation, respiratory
acidosis from respiratory failure, metabolic alkalosis
from hypokalemia, and metabolic acidosis from hepatic
necrosis, shock, or increased anaerobic metabolism.
INFECTIOUS
Patients with ALF have an enhanced susceptibility to
bacterial infection and sepsis from immune system
dysfunction.141,142 Evidence of infection may be subtle,
such as tachycardia, intestinal bleeding, reduced renal
ACUTE LIVER FAILURE IN CHILDREN/SQUIRES 159
output, or changes in mental status. Fever may not be
present. Blood cultures should be obtained daily or with
any evidence of clinical deterioration and antibiotics
initiated with a clinical concern for sepsis.
Diagnostic Priorities
The etiology of ALF in children differs between age
groups (Table 2). A specific diagnosis is more likely to be
established if diagnostic tests are prioritized based upon
age.
Treatment and Management Tools
PLASMAPHERESIS/PLASMA EXCHANGE
Plasmapheresis facilitates the removal of suspected tox-
ins in the blood to promote a milieu in which the liver
might recover or regenerate. Evidence of its usefulness in
children with ALF is sparse; however, in a study from
the Childrens Hospital of Philadelphia, 243 therapeutic
plasma exchanges in 49 children with ALF resulted in
improvement of coagulation profiles, but had no impact
on neurological outcome or ability of the liver to recover
spontaneously.143 One potential disadvantage of this
procedure is the nonselective removal of potentially
helpful substances such as hepatocyte growth factor.
The use of selective filters to facilitate retention of this
potentially beneficial substance would make this therapy
more attractive.144
STEROIDS
Supraphysiological doses of corticosteroid medications
may reduce inotrope requirements in septic shock. In
addition, adrenal dysfunction may occur in patients with
acute hepatic necrosis and steroids are thought to be
beneficial for that reason. However, a double-blind,
randomized control trial of hydrocortisone or placebo
in 64 adult patients showed no therapeutic effect.145 A
retrospective review of 20 patients with ALF and nor-
epinephrine dependence did show a reduction in nor-
epinephrine requirement, but unfortunately revealed a
significant increase in the frequency of bacteremia due to
resistant organisms and no improvement in outcome.146
Steroids may benefit patients with ALF due to auto-
immune hepatitis. Selective use of corticosteroids in
patients with ALF may be warranted, but cannot be
recommended for most ALF patients.72
MOLECULAR ABSORBENTS RECYCLING SYSTEM
In the elaborate detoxification molecular absorbents
recycling system (MARS), a membrane with albumin-
related binding sites separates the patients blood from
an albumin dialysate. Albumin-bound substances, such
as bilirubin, aromatic amino acids, and endogenous
benzodiazepine-like substances can be transferred to
160 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 2 2008

Table 2 Diagnostic Priorities by Age

Infectious Disease Drugs/Toxins Cardiovascular Metabolic/Immune

Infant  1y Herpes simplex* APAP misadventure* Hypoplastic left heart Galactosemia

Echovirus Asphyxia Tyrosinemia
Adenovirus Myocarditis Neonatal hemachromatosis
EBV Fructose intolerance
Hepatitis B Fatty acid defects*
Parvovirus Mitochondrial defects*
Measles Hemophagocytic syndrome
HHV-6 Neimann-Pick type C
Enterovirus* NK cell dysfunction*
Child Hepatitis A,B,C,D,E Valproic acid Heart surgery Fatty acid oxidation defects
Leptospirosis INH Cardiomyopathy Leukemia
EBV* Halothane Budd-Chiari syndrome Autoimmune disease*
Acetaminophen* Myocarditis Hemophagocytic syndrome
Phosphorus NK cell dysfunction
Acetylsalicylic acid Wilsons disease
Vitamin A toxicity Mitochondrial defects
Adolescent Hepatitis A*,B,C,D,E Mushroom poisoning Budd-Chiari syndrome Wilsons disease*
Yellow fever Acetaminophen* Congestive heart failure Fatty liver of pregnancy
Dengue fever MAO inhibitor Heat stroke Autoimmune disease*
Lassa fever Bacillus cereus toxin Shock Protoporphyria
Tetracycline Fatty acid oxidation defects
Ecstasy
*More common.
EBV, Epstein-Barr virus; APAP, N-acetyl-p-aminophenol; NK, natural-killer; INH, isoniazid; Hep, hepatisit; MAO, monoamine oxydase.

the membrane binding sites and then to the albumin
within the dialysate for removal. Unbound, free low-
molecular-weight molecules, such as ammonia, can pass
freely down a concentration gradient into the dialy-
sate.147 The MARS system has been used to treat
children with mushroom poisoning and as a bridge for
retransplantation.148,149 However, in the absence of
randomized trials, its relevance in the overall treatment
of ALF is uncertain.150
TRANSPLANT
Hepatocyte transplantation may serve as a bridge to
transplant or, perhaps, a cure for some children with
metabolic diseases. It has been used in a small number of
children with ALF.151,152 However, technical challenges
as well as lack of a readily available source for hepatocytes
have limited the opportunity for this procedure at most
centers.153
Liver transplantation has improved overall sur-
vival for children with ALF. A cadaveric whole, split, or
cut-down liver transplant was used in nearly 86% of all
transplants for ALF in children in a recent report from
the Studies of Pediatric Liver Transplant consortium.154
Living donor liver transplant for children with ALF and
concurrent multiorgan failure is associated with im-
proved 30-day and 6-month survival compared with
recipients of a cadaveric liver allograft.155 Improved
outcome for patients receiving a living donor liver trans-
plant is likely related to decreased cold ischemia time and
wait time, resulting in a more expeditious time to trans-
plant for these seriously ill children. Auxiliary liver
transplantation has been used as a bridge to provide
needed time for the native liver to regenerate.156 The
challenge rests with the determination of the likelihood
that the liver will sufficiently regenerate to allow for
withdrawal of immunosuppression and involution of the
transplanted graft.157
THERAPY FOR SPECIFIC DISORDERS
Identification of a condition amenable to therapy will
allow for early therapeutic intervention in hope that liver
failure can be reversed and transplant or death can be
avoided. Specific conditions and therapies are listed in
Table 3.
OUTCOME
Short-term (21-day) outcome for children with ALF
varies by diagnosis, age, and degree of encephalopathy.9
Survival without liver transplant was highest in the
APAP group (94%), while children with non-APAP
drug-induced ALF (41%), metabolic disease (44%), or
indeterminate ALF (43%) fared less well. The risk
of death increases with the degree of encephalopathy.

Table 3 Causes of ALF in Children That May Respond
to Specific Therapy
Infection Intervention
Herpes family Acyclovir168
Enterovirus Pleconaril77 (?)
Parvovirus Immune globulin169 (?)
Drug and Toxin
Medication induced Remove offending drug
Acetaminophen N-acetylcysteine170
Amanita phalloides Silibinin, penicillin171
Metabolic Disease
Tyrosinemia type 1 NTBC172
Wilsons disease Liver transplant173
Galactosemia Remove dietary lactose
Fatty acid oxidation IV glucose, avoid fasting174
Immune Dysregulation
Hemophagocytic syndrome VP-16, corticosteroids75
Neonatal hemochromatosis Antioxidant cocktail175
Autoimmune hepatitis Corticosteroids176
ALF, acute liver failure; NTBC, 2-(2-nitro-4-fluoromethylbenzoyl)-1,
3-cyclohexanedione; IV, intravenous.
(?), possibe benefit.
However, 20% of children in the PALF study who
never developed encephalopathy either died or under-
went liver transplant and those who presented with
grade 4 encephalopathy fared better than those who
progressed to grade4 during the course of the study.
The ideal model to predict outcome would ensure
that all patients who need a transplant receive one
(positive predictive value), and all patients who would
survive would not (negative predictive value), but pres-
ently none exists.158 Virtually all of the prognostic
models to date are based upon data and experiences
with adult patients. Kings College criteria were the first
and are the standard upon which others are judged.
Kings criteria take into account patient demographics
that include diagnosis and age, degree of clinical ence-
phalopathy, as well as biochemical determination of
coagulopathy, arterial pH, serum bilirubin, and creati-
nine.159 Several other models have been developed and
include the use of serum lactate160; albumin, lactate,
valine, and pyruvate161; a-fetoprotein162; phosphate163;
APACHE III measurements164; and most recently ac-
tin-free Gc-globulin.165 Most have not been tested
independently in children.
In a retrospective analysis of 97 children admitted
to the Liver Unit of Birmingham Childrens Hospital in
the United Kingdom, multivariate analysis identified the
significant independent predictors for death or liver
transplant were time to onset of hepatic encephalopathy
> 7 days, PT > 55 seconds, and alanine aminotransferase
 2384 IU/L on admission.8 Another single-site study
from the University of California/Los Angeles with 66
patients identified cerebral edema, a rising bilirubin
associated with falling serum aminotransferases, pro-
ACUTE LIVER FAILURE IN CHILDREN/SQUIRES 161
longed PT not responding to fresh-frozen plasma in-
fusions, and a delay in the onset of encephalopathy
to be poor prognostic factors.6 A recent study from
Denver, CO, expanding the reseachers experience with
a Liver Injury Unit score based upon total bilirubin,
INR, and ammonia at presentation and with peak
values, appears to effectively predict survival without
liver transplant; further prospective analyses will be
necessary to confirm these findings.166
Post-transplant survival in pediatric ALF has
improved with time, but remains lower than that ob-
served for children who receive transplants for other
reasons. One- and four-year survival rates are 74% and
69% for children with ALF, compared with 88.2% and
85.6% for children transplanted for reasons other than
ALF, respectively.154 In addition to survival, one must
also consider quality of life following transplant. Con-
ditions that will not be improved by transplant, such as
systemic mitochondrial disorders, should be identi-
fied.167 In the absence of sound markers for patient
outcome, we are left with clinical judgment in concert
with laboratory and clinical parameters to make the best
decision to proceed with liver transplantation, to delay
with the hope of recovery, or to remove the child from
the list because transplant would be futile.
CONCLUSIONS
Children presenting with ALF require a prompt multi-
disciplinary approach to maximize outcomes. Diagnostic
studies must be prioritized based upon age and clinical
presentation and potential for a medical cure. The
indeterminate group offers a real opportunity for study.
Multicenter consortia such as the National Institutes of
Health-sponsored PALF study that collects prospective
clinical data and important biosamples will enhance our
understanding of ALF in children, refine prognostic
indicators, and provide an opportunity to improve diag-
nosis and management in these critically ill children.
ACKNOWLEDGMENTS
The site principal investigators, coordinators, the
Data Coordinating Center of the Pediatric Acute
Liver Failure Study Group (www.palfstudy.org), and
Dr. Patricia Robuck with the NIDDK. The PALF
Study Group is supported by NIH-NIDDK 1 U01
DK07214601.
ABBREVIATIONS
AIH autoimmune hepatitis
ALF acute liver failure
APAP n-acetyl-p-aminophenol, acetaminophen
EBV Epstein-Barr virus
EEG electroencephalogram
162 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 2 2008
HE hepatic encephalopathy
HLH hemophagocytic lymphohistiocytosis
HRS hepatorenal syndrome
INR international normalized ratio
MARS molecular absorbents recycling system
mDNA mitochondrial DNA
NAC N-acetylcysteine
NK-cell natural killer cell
PALF Pediatric Acute Liver Failure [Study Group]
PT prothrombin time
VA valproic acid
VOD veno-occlusive disease
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