Clin Liver Dis 10 (2006) 149 168

Acute Liver Failure in Children

John Bucuvalas, MDa,T, Nada Yazigi, MDa,
Robert H. Squires, Jr, MDa,b
a
Division of Gastroenterology, Hepatology and Nutrition,
Cincinnati Childrens Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
b
Division of Gastroenterology, Hepatology and Nutrition, Childrens Hospital of Pittsburgh,
3705 Fifth Avenue, Pittsburgh, PA 15213, USA

Acute liver failure (ALF) is a rare but devastating illness. Specific therapy to
promote liver recovery is often not available, and the underlying cause of the
liver failure is often unknown. Although liver transplantation has increased the
chance of survival, patients who have ALF still face an increased risk of death,
both while on the waiting list and after liver transplantation [1,2]. This arti-
cle examines the current knowledge of the epidemiology, pathobiology, and
treatment of ALF in children and identifies potential gaps in knowledge for fu-
ture study.

Definition

ALF results when loss of liver function, caused by rapid death or injury to a
large proportion of hepatocytes, leaves insufficient parenchymal mass to sustain
life. In adults, ALF is defined as the development of hepatic encephalopathy
within 8 weeks of jaundice in a patient who has no prior history of liver disease.
This definition is inadequate for children, because the early stages of encepha-
lopathy are difficult to assess, and encephalopathy may not be apparent until
terminal stages of ALF in infants [3]. Furthermore, the duration of illness can
be difficult to assess, particularly in infants who present with ALF in the first
few weeks of life secondary to a condition that may be caused by unrecognized
metabolic diseases (eg, mitochondrial disease or a defect of fatty acid oxidation).

T Corresponding author.
E-mail address: john.bucuvalas@cchmc.org (J. Bucuvalas).

1089-3261/06/$ see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.cld.2005.10.006 liver.theclinics.com
150 bucuvalas et al

Table 1
Coma stage for children younger than 4 years
Stage Clinical signs Reflexes Neurologic signs
Early (I and II) Inconsolable crying, sleep reversal, Hyper-reflexic Untestable
inattention to task
Mid (III) Somnolence, stupor, combativeness Hyper-reflexic Most likely untestable
Late (IV) Comatose, arouses with painful Absent Decerebrate or
stimuli (IVa) or no response (IVb) decorticate

In an effort to address the ambiguity associated with the definition of ALF in

children, the Pediatric Acute Liver Failure Study Group (PALFSG) came to con-
sensus regarding the definition of ALF in children. The PALFSG defined ALF as

 Biochemical evidence of liver injury

 No history of known chronic liver disease
 Coagulopathy not corrected by vitamin K administration
 INR greater than 1.5 if the patient had encephalopathy or greater than 2.0 if
the patient does not have encephalopathy

A scale to assess encephalopathy in children younger than age 4 years was

developed by the PALFSG (Table 1). As the pathophysiology of liver failure
becomes better understood, definitions should reflect disease mechanisms rather
than clinical descriptions. Until then, the consensus definition can be used to
identify children who have ALF.

Etiology

Determination of the cause of ALF in infants and children has relied on case
reports, extrapolation from adult data, retrospective reports from single centers,
and personal experience. Consequently, the understanding of the causes of ALF
has been hampered by center bias and differing definitions of this clinical con-
dition. Nevertheless, the causation of ALF in infants and children can be grouped
into several broad categories that include infections, shock, immune dysregula-
tion, toxins and medications, metabolic disorders, and other less frequent causes
such as neonatal iron storage disease.
The prevalence of specific causes of ALF in children differs from those de-
scribed in adults and also varies as a function of age within the pediatric popu-
lation [2]. Cause varies across geographic regions and countries. For instance,
in regions where hepatitis E or hepatitis A are endemic, these infections will
typically be the most common cause of ALF [4,5]. In a prospective multicenter
study, the most comprehensive report from North America to date, 229 children
who had ALF were identified; 35 had acetaminophen toxicity, and 118 had
ALF of indeterminate cause (Table 2; unpublished data). Autoimmune hepati-
tis, metabolic liver disease including Wilsons disease, ischemic hepatitis, and
Table 2
Causes of acute liver failure and potential outcome as a function of age

Liver transplantation Age

Spontaneous probably required for 6m 3 to
Cause Specific therapy recovery survival b6 mo to 3 y 11 y N11 y
Infection: Herpesvirus Y Y N Y N N N
Hepatitis A N Y Y N Y Y Y
Indeterminate N Unlikely Y Y Y Y Y
Vascular: Budd-Chiari syndrome varies N Y Y Y Y Y
Ischemic hepatitis N Y N Y Y Y Y
Immune dysregulation: NK cell dysfunction (HLH) Y ? ? Y Y Y Y
Autoimmune Y Y varies N Y Y Y
Inherited: Wilsons disease N Rare Y N N N Y
Mitochondrial N Rare N Y Y Y Y
Tyrosinemia Y With therapy varies Y Y N N
Galactosemia Y With therapy Y N N N
Fatty acid oxidation defect Y Y varies Y Y Y ?
acute liver failure in children

Iron storage disease N Y varies Y N N N

Drugs/toxins: Anticonvulsants N N Y Y Y Y Y
Acetaminophen Y With therapy N Y Y Y Y
Other: Cancer/leukemia Y N N Y Y Y Y
151
152 bucuvalas et al

drug-induced liver disease accounted for the remaining 75 patients. Indetermi-

nate ALF occurred more frequently among children younger than 3 years, and
acetaminophen-induced ALF occurred more frequently in those older than
3 years. These observations are distinct from the causes of ALF in the subset of
children listed for transplantation. In patients who had ALF and were listed for
transplantation, the cause was indeterminate in 77% [6], and almost 90% for
those subsequently underwent liver transplantation. The discrepancy between
the two reports may reflect different definitions of ALF but more likely reflects
the likelihood that some subgroups of patients recover spontaneously and do not
require liver transplantation. These findings further emphasize the importance of
prospective patient-based studies to gather clinical data and of precise disease
definitions when assessing the causation of ALF.

Pathobiology

With severe hepatocellular injury, liver metabolic functions are impaired. Pa-
tients have compromised glucose homeostasis, increased lactate production, im-
paired synthesis of coagulation factors, and reduced capacity to eliminate drugs,
toxins, and bilirubin. As a result, patients develop coagulopathy, hypoglyce-
mia, and acidosis, all of which increase the risk of gastrointestinal bleeding,
seizures, and myocardial dysfunction. Bacterial and fungal infections often com-
plicate ALF. Bacteria may enter the systemic circulation from the gut as a result
of impaired liver macrophage cell function or in association with insertion of
catheters and endotracheal tubes [710]. Depressed production of complement
and acute-phase reactants may contribute to decreased response to infection. The
combination of decreased integrity of the immune system, exposure to anti-
biotics, and insertion of catheters increases the risk of fungal infection.
Multiorgan failure frequently develops in the setting of ALF and is attributed,
in part, to microvascular injury (Fig. 1). The initiation and perpetuation of small
vessel injury in the setting of ALF is incompletely understood but may reflect a
complex interaction of a number of factors such as impaired liver clearance of

Fig. 1. Potential mechanism for development of acute liver failure. CNS, central nervous system.
 acute liver failure in children 153

inflammatory mediators or increased polymerization of actin. A potential

mechanism for the role of actin has been proposed. When the liver is injured,
actin monomers are released from hepatocytes and quickly begin to polymerize.
Typically, polymerization is prevented by gelsolin, an actin-binding protein found
in monocytes and platelets [11]. With ALF, actin scavenger function is com-
promised by depleted gelsolin. Consequently, actin polymerization occurs, and
microvascular function is compromised. The clinical effects of this destructive
cascade are manifested by cardiovascular compromise, oxygen exchange ab-
normalities leading to acute respiratory distress syndrome, renal dysfunction, and
disseminated intravascular coagulation.

Pathogenesis of encephalopathy in acute liver failure

Increased intracranial pressure is a major cause of mortality in patients who

have ALF. Although the pathogenesis of encephalopathy is incompletely under-
stood, it seems that hyperammonemia, increased cerebral blood flow, and en-
hanced inflammatory response play central roles [12,13]. Hyperammonemia is
associated with increased levels of glutamine within astrocytes. Accumulation of
glutamine results in cell swelling and brain edema. Nevertheless, hyperammo-
nemia alone does not predict intracranial hypertension. Increased cerebral blood
flow may contribute to the development of cerebral edema by facilitating water
movement down altered osmotic gradients generated by increased concentration
of glutamine within astrocytes [14]. In addition, markers of inflammation such as
tumor necrosis factor alpha (TNF-a) are increased in ALF, perhaps reflecting the
systemic inflammatory response syndrome (SIRS). SIRS seems to result in
worsening encephalopathy, although its direct relationship to brain swelling is not
defined [15]. The interaction of the factors contributing to elevated intracranial
pressure is evident in animal models of hyperammonemia, in which inhibition of
glutamine synthesis decreases cell swelling and results in normalization of ce-
rebral vascular function [14]. The present understanding is incomplete; the
development of intracranial hypertension in patients who have ALF seems to be
multifactorial and to reflect brain edema associated with hyperammonemia, al-
tered glutamine metabolism within astrocytes, and increased cerebral blood flow
as well as the host of factors associated with SIRS.

Pathogenesis of acute liver failure by specific mechanisms

The clinical presentation of liver failure, characterized by coagulopathy, jaun-

dice, and encephalopathy, reflects a common path for a myriad of mechanisms
injuring the liver, which, in the end, leave insufficient functioning liver paren-
chymal mass to sustain life (Table 3). The pathogenesis of ALF is likely to reflect
the host reaction determined by genetic susceptibility to a potentially hepato-
toxic stimulus. Description of specific pathobiologic mechanisms for each known
154 bucuvalas et al

Table 3
Causes of acute liver failure
Cause Age less than 3 y (%) Age greater than 3 y (%) Total (%)
Acetaminophen 2 (2) 33 (24) 35 (15)
Indeterminate 55 (60) 63 (46) 118 (52)]
Metabolic 15 (27) 8 (6) 23 (10)
Autoimmune 5 (5) 9 (7) 14 (6)
Drug and toxin 1 (1) 10 (7) 11 (5)
Infectious 4 (4) 3 (2) 7 (3)
Shock 2 (2) 5 (4) 7 (3)
Other 8 (9) 6 (4) 14 (16)

cause of ALF is beyond the scope of this article. Consequently, this discussion
focuses on distinct processes that occur as a result of exposure to toxins, an
altered immune response, vascular insufficiency, and specific inherited defects
with increased risk for ALF.

Drug-induced acute liver failure

Drug-induced ALF, the most common cause of ALF in adults, may occur as a
consequence of either a dose-dependent toxic injury or, more commonly, as an
idiosyncratic reaction at therapeutic doses [16]. In the hepatocyte, lipophilic
drugs and xenobiotics undergo biotransformation to water-soluble products that
are excreted in urine or bile. Genetic polymorphisms of proteins that biotransform
and excrete xenobiotics may increase production of potentially hepatotoxic me-
tabolites. The mechanism of action of drug-induced liver injury includes disrup-
tion of the cell membrane or altered canalicular function, production of reactive
intermediates, immune-mediated injury, Kupffers cell activation, stellate cell
activation, mitochondrial dysfunction, or endothelial cell injury [16]. Synergistic
injury resulting from multiple drug exposures is emerging as a frequent cause of
ALF. In this situation, the single drug exposure is nontoxic, but the combination
compromises the ability of the liver to clear potentially toxic metabolites. Two
distinct mechanisms of drug-induced liver injury are described here.

Acetaminophen

Acetaminophen injures hepatocytes in a dose-dependent fashion, so that the

administered dose is a stronger determinant of the likelihood of a reaction than
the hosts drug-clearance system. Acetaminophen-induced ALF accounts for
more than 50% of the cases in adults and usually occurs within 48 hours of an
intentional overdose. ALF from acetaminophen occurs as a result of conversion
of acetaminophen to the highly reactive metabolite, N-acetyl-p-benzoquinone
imine (NAPQI) through the cytochrome P-450 system [16]. NAPQI is detoxified
by conjugation with glutathione. With depletion of hepatic glutathione stores,
NAPQI binds to cysteine groups on protein, forming hepatotoxic protein adducts.
 acute liver failure in children 155

Although reported cases of acetaminophen-related ALF reflect single, acute

ingestions, others have suggested that liver failure may result from chronic use of
acetaminophen with therapeutic intent [1719]. In either case, serum amino-
transferase levels are typically high, exceeding 3500 IU/L. In a patient who has
sudden marked elevation of serum aminotransferase levels out of proportion to
jaundice, acetaminophen toxicity should be considered as a cause even when
historic evidence is lacking. Measurement of plasma acetaminophen levels pre-
dicts the risk of hepatotoxicity only after a single, acute overdose where the time
of the ingestion is known. In contrast, plasma levels do not reliably foretell risk in
the setting of therapeutic misadventures or with ingestions in the presence of
other risk factors such as fasting or concurrent therapy with CYP 2E1-inducing
drugs (eg, ethanol, isoniazid). In the latter situations, the diagnosis and treatment
are dependent on historical and clinical laboratory findings.
Liver injury occurring as a result of idiosyncratic reactions to drugs is char-
acterized by a latency period ranging from 5 to 90 days from the initial ingestion
of the drug. If liver failure occurs, the outcome is grim: liver transplantation or
death in 75% of cases [16].

Anticonvulsants

Drug-induced ALF may occur as a result of exposure to the anticonvulsants

phenytoin, carbamazepine, and phenobarbital [20,21]. Liver injury occurs within
6 weeks of exposure and is almost always accompanied by severe rash and
eosinophilia indicating an immune-mediated injury. Familial risk and increased
risk in African-Americans for anticonvulsant hypersensitivity has been recog-
nized, suggesting that the clinical condition occurs in genetically susceptible
patients [22]. Although the specific gene associated with risk has not been iden-
tified, in vitro studies suggest that abnormal metabolite detoxification is the basis
for inherited susceptibility [23]. Phenytoin is metabolized by the cytochrome
P-450 system with the production of a highly reactive intermediate. Neoantigens
develop if the reactive metabolite binds covalently to tissue macromolecules, and
the antigens precipitate immune-mediated injury [23]. Autoantibodies recogniz-
ing liver microsomes have been detected in the sera from patients who have hyper-
sensitivity reactions to anticonvulsants, whereas no autoantibodies have been
detected in sera from healthy control subjects or patients taking chronic phe-
nytoin therapy without toxicity [23].

Viral infection

In regions where hepatotropic viruses such as hepatitis E and hepatitis A are

endemic, they are the most common cause of ALF [4,5], but viral infections
were infrequently identified as a cause of ALF in North America and the United
Kingdom. A preliminary multicenter report identified only one patient who had
acute hepatitis A and no patients who had hepatitis B or C (see Table 3, un-
156 bucuvalas et al

published data). Nevertheless, viral causes should be considered in a child

presenting with ALF, because specific therapy is available for viruses such as
herpes simplex [24]. Moreover, ALF associated with common viruses such as
Epstein-Barr virus may be a marker of immune dysfunction [25].

Immune dysregulation

Autoimmune hepatitis (AIH) can present as ALF in children and is an example

of immune dysregulation [2628]. AIH should be considered early in the
presentation because treatment with corticosteroids may permit survival without
liver transplantation. AIH occurs as a result of an immune reaction to liver cell
antigens, possibly triggered by a mechanism of molecular mimicry or loss of self-
tolerance. With the acute presentation, autoantibodies may be absent, and liver
histology shows severe hepatic necrosis accompanied by interface hepatitis and
plasma cell infiltration.
Evidence suggests that ALF, in some patients, may reflect a disproportional
immune response to a common stimulus characterized by impaired cell-mediated
and humoral immunity, increased risk for infectious complications, and aplastic
anemia [15,29,30]. Patients may present with findings consistent with SIRS.
Hematophagocytic lymphohistiocytosis (HLH) may be a prototype for ALF
caused by a disproportional immune response [31]. HLH is a disorder of immune
regulation characterized by decreased natural killer (NK) cell function, uncon-
trolled macrophage activation, and increased proinflammatory cytokines (inter-
feron gamma, TNF-a, interleukin-1, interleukin-2 receptor) [25,3235]. NK cells
comprise a central component of the innate immune system. They mediate cell
cell killing by the perforin and granzyme pathways and are responsible for main-
taining self-tolerance. NK cells constitute a high proportion of innate resident
immune cells in the liver and play a pivotal role in maintaining inflammatory
homeostasis at the port of entry of gut-originating antigens.
It remains to be learned if disturbed NK cell function comprises a fraction of
patients who have ALF of indeterminate cause. Nevertheless, it is tempting to
speculate that such an immune disturbance may play a role in situations other
than systemic HLH. Targeted anti-inflammatory therapy in early stages of disease
might promote recovery and mitigate the need for transplantation. Further studies
will be necessary to characterize the complex immune responses associated with
various causes of ALF, particularly those of indeterminate cause.

Metabolic causes

Liver failure caused by mitochondrial injury or dysfunction is characterized by

lactic acidosis, conjugated hyperbilirubinemia, variably elevated serum amino-
transferase levels, coagulopathy, ketotic hypoglycemia, hyperammonemia, and an
 acute liver failure in children 157

elevated molar ratio of plasma lactate to pyruvate (N20 mol/mol) [3638].

Multiorgan involvement is typically seen and includes neuromuscular abnormali-
ties, kidney dysfunction, cardiomyopathy, and global disturbances of linear
growth, weight gain, and development. Liver histology shows microvesicular
steatosis, with occasional large fat droplets identified along with variable degrees
of fibrosis and, at times, cirrhosis. A primary defect of respiratory chain enzyme
function may present in infancy or be unmasked at a later age with exposure to
the anticonvulsant valproic acid, an 8-carbon branched fatty acid that is metabo-
lized into a possible mitochondrial toxin [39]. Patients who encounter mitochon-
drial toxins, such as the experimental antiviral nucleoside analogue fialuridine,
present with similar clinical, biochemical, and histologic features [40].
Wilsons disease occurs when the ATP7B protein, a P-type ATPase protein
that is involved in transmembrane transport of copper, is absent or nonfunctional
[2,4143]. Patients who have Wilsons disease and ALF have distinctive clin-
ical and biochemical features including Coombs-negative hemolytic anemia,
coagulopathy, modest rises in serum aminotransferase levels, and normal or low
serum alkaline phosphatase levels. Serum copper and 24-hour urinary excretion
of copper are increased.
Disorders of fatty acid oxidation may present with a Reyes-like syndrome
characterized by hepatomegaly, abnormal aminotransferase levels, coagulopathy,
encephalopathy, and microvesicular steatosis. Recently, investigators examined
whether defects in fatty acid oxidation play a broader role in ALF by a ret-
rospective analysis of bile acylcarnitine profiles of 27 children who had ALF, 17
of whom had indeterminate hepatitis [44]. Of particular interest was the obser-
vation that the relative risk of death was 2.86 in the 10 children who had elevated
concentrations of medium- or long-chain acylcarnitines. The authors suggested
that the findings reflected a disorder of fatty acid oxidation unmasked by liver
injury, a genetic modifier for patients who have ALF, or a marker of severe liver
injury. Whatever the underlying mechanism might be, this observation suggests
that use of modern molecular diagnostic techniques may enable identification of
factors that contribute to indeterminate ALF.
Hereditary tyrosinemia results from a genetic defect in tyrosine degradation
and may present as ALF in infancy. The underlying defect is a mutation in the
gene for fumarylacetate hydrolase, the last enzyme in the tyrosine catabolic
pathway. As a result of the defect, there is accumulation of hepatotoxic metabo-
lites (succinylacetone) that mediate the liver damage. The clinical presentation
ranges from ALF to poor weight gain and renal tubular acidosis. Those who
present with ALF often have a profound coagulopathy that is out of propor-
tion to the degree of aminotransferase elevation. A subgroup may present with
Escherichia coli sepsis and multisystem organ failure. A novel treatment with a
medication recently approved by the Food and Drug Administration, 2-(2-nitro-
4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC), brings about clinical
and biochemical improvement [45,46]. NTBC inhibits 4-hydroxyphenylpyruvate
dioxygenase, which interrupts tyrosine degradation before fumarylacetate hydro-
lase; thus the toxic effects of succinylacetone are eliminated.
158 bucuvalas et al

Acute ischemic injury

Ischemic hepatitis may meet criteria for ALF [4749]. Liver histology is
characterized by centrilobular necrosis with preservation of the periportal zone.
Serum aminotransferase levels may reach 5000 to 10,000 IU/L, and coagulopathy
is found in 25% to 50% of patients. Aminotransferase levels decrease rapidly
in response to stabilization of the circulation. The rapid decrease in amino-
transferase levels in the absence of increasing serum bilirubin or worsening
coagulopathy may distinguish ischemic hepatitis from viral or toxic hepatitis.
Prognosis depends on correction of the underlying cause of hypotension.

Care of a child who has acute liver failure

The health care provider faced with a child who has evidence of acute liver
disease must be prepared to address four critical decision points. First, does the
child have ALF? Second, is there specific therapy to treat the underlying cause of
ALF and promote recovery? Third, should the child be listed for liver trans-
plantation? Fourth, does the child require placement of a device to monitor
intracranial pressure?

Does the patient have acute liver failure?

All patients who do not have known liver disease and who present with
elevated aminotransferase levels or conjugated hyperbilirubinemia should be eval-
uated for coagulopathy and evidence of encephalopathy. If there is biochemical
evidence of liver injury, no history of known chronic liver disease, and coagu-
lopathy or change in mental status, the child should be admitted to the hospital,
preferably to a center that has expertise in the care of ALF and the capability to
perform liver transplantation.

Is there specific therapy to treat the underlying cause of acute liver failure
and promote recovery?

To determine whether there is a specific therapy to treat the underlying cause

of liver failure, a comprehensive evaluation must be done in an efficient and
timely fashion (Table 4). A careful medication history should include the patients
use of prescription, over-the counter, herbal, and alternative medications. All
patients must be assessed for symptoms and signs of infection, chronic illness,
and liver disease. The liver size should be documented carefully, because the liver
 acute liver failure in children 159

Table 4
Evaluation of patients who have acute liver failure
Evaluation Population Data
Clinical All patients to assess Neurologic status including level of coma
severity of illness Signs of chronic liver disease (portal
hypertension) or other chronic illness
Signs of infection
Liver size
Biochemical All patients to assess Renal group, calcium, phosphorus, magnesium,
severity of illness capillary blood gas, blood glucose
CBC with manual smear, reticulocyte count
Liver profile, INR, NH3, PT, PTT, Factors V,
VII, VIII and fibrinogen
Imaging studies All patients to identify Abdominal ultrasound with Doppler flows
findings of chronic Head CT scan without contrast to exclude
liver disease and altered hemorrhage, edema; chest radiograph
liver perfusion
As clinically indicated to
identify cerebral edema,
heart failure
Toxins All patients to define Urine toxin screen
causation Serum acetaminophen level
Viral studies As clinically indicated to Serologies for HAV IgM, HBV Hbs Ag,
define causation anti-Hbc, anti-Hbs, HCV, EBV IgM and IgG,
CMV IgM and IgG
PCR for HHV6, EBV, CMV, HSV, enterovirus,
adenovirus, parvovirus
Immune function As clinically indicated to Autoantibody profile
define causation Specific immune studies if available including
NK cell function, perforin, granzyme B, IL-2
Metabolic studies As clinically indicated to Serum triglycerides
define causation Serum ferritin
Serum copper
Urine for organic acids, succinylacetone
Lactate, pyruvate
Tissue studies As clinically indicated to Liver biopsy
define causation Bone marrow biopsy
Muscle biopsy
Abbreviations: anti-HBc, anti-HB core; anti-HBs, anti-HB surface; CBC, complete blood cell count;
CVM, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBs Ag, hepatitis B surface
antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV6, human herpes virus 6; HSV, herpes
simplex virus; IL-2, interleukin 2; INR, international normalization ratio; NK, natural killer; PCR,
polymerase chain reaction; PT, prothrombin time; PTT, partial thromboplastin time.

may shrink rapidly during the course of the illness. A decrease in liver size at a
time when the serum bilirubin is rising and serum aminotransferase levels are
falling reflects generalized hepatocellular necrosis and parenchymal collapse. A
careful neurologic assessment to assess the level of encephalopathy must be done
initially and at regular, frequent intervals during the hospital course, because
changes in neurologic status may reflect worsening cerebral edema, cerebral
hemorrhage, sepsis, or metabolic disturbance. Blood should be collected and pro-
160 bucuvalas et al

cessed promptly to measure serum electrolytes, serum creatinine, urea nitrogen,

calcium, phosphorus, magnesium, creatine phosphokinase, glucose, and pH. Hypo-
glycemia and hypophosphatemia should be treated with appropriate infusions.
A complete blood cell count, blood smear, and reticulocyte count may identify
evidence of an associated bone marrow dysfunction. Liver status can be assessed
by serial measurement of serum aminotransferase levels, total and direct
bilirubin, ammonia, prothrombin time, partial thromboplastin time, and ammonia.
To determine if there is evidence of significant liver synthetic dysfunction, factors
V, VII, VIII, and fibrinogen should be measured, recognizing that factor VIII
levels will be normal even in the face of ALF. To exclude toxin exposure, a toxin
screen and serum acetaminophen level should be measured. The health care
provider must remain aware that a negative study or a nontoxic level of acet-
aminophen does not exclude the possibility of drug-associated liver injury.
Imaging studies are performed to exclude heart failure, anatomic liver ab-
normalities, or altered liver perfusion. An abdominal ultrasound with Doppler
flows and chest radiograph may be done on all patients, and a head CT scan
without contrast to exclude hemorrhage or cerebral edema should done as
clinically indicated.
Although ALF caused by documented viral infection rarely occurs in children
in the United States, identification of a viral cause has significant prognostic and
therapeutic implications. Serologies may be done for hepatitis A virus (IgM), hepa-
titis B virus (hepatitis B antigen, anti-hepatitis B core, anti-hepatitis B surface),
Epstein-Barr virus (IgM, IgG), cytomegalovirus (IgM, IgG), and polymerase
chain reactions for human herpes virus 6, Epstein-Barr virus, cytomegalovirus,
herpes simplex virus, enterovirus, adenovirus, and parvovirus. Immune dys-
regulation can be assessed by measuring an autoantibody profile, cytotoxic T-cell
function, and markers of immune activation, including interleukin-2, gamma-
interferon, and NK cell function. The possibility of metabolic liver disease or
mitochondrial disease can be addressed by measurement of serum copper, lactate,
and pyruvate levels and calculation of the lactate:pyruvate ratio. Collection of
urine for organic acids and succinylacetone measurement should be done as
clinically indicated. If the causation remains uncertain, liver biopsy may be
needed to determine if a specific treatment strategy is indicated. Bone marrow
biopsy or muscle biopsy may be valuable depending on the clinical findings in
the patient and results of the initial biochemical assessment. In summary, the
symptoms, signs, laboratory findings, imaging studies, and assessment of his-
tology permit the clinician to determine if there a specific causation at which
therapy can be directed.

Should the child be listed for liver transplantation?

The impact of liver transplantation on survival of patients who have ALF has
been dramatic [5052]: 1-year survival may approach 70% to 80%. At the same
 acute liver failure in children 161

time, rapid deterioration in the childs clinical condition may decrease the chance
of survival and normal neurologic outcome even with liver transplantation.
Therefore, the decision to list the patient must be made when the likelihood of
spontaneous recovery is low and the child has not suffered irreversible cerebral
injury or respiratory failure. Because the childs condition is dynamic, the need
and appropriateness of a liver transplant must be frequently reassessed. Prognosis
is based on causation, clinical findings, biochemical indicators, and the presence
of contraindications to liver transplantation [53].
Children who have indeterminate ALF, idiosyncratic reaction to medications
(phenytoin hypersensitivity reaction), or ALF caused by Wilsons disease are un-
likely to survive without transplantation. Patients who present acutely with auto-
immune hepatitis with coagulopathy or acetaminophen-induced liver failure
without acidosis and infants who have metabolic liver disease (tyrosinemia, iron
storage) or shock-induced ALF are more likely to survive without liver transplan-
tation [2]. Patients who have immune-activation syndrome (HLH) or mitochondrial
disease are unlikely to improve despite liver transplantation (Fig. 2) [31,36].
Outcome is worse if the duration of jaundice before the onset of encepha-
lopathy exceeds 7 days [54]. Patients who have cerebral perfusion pressure
greater than 40 mm Hg for more than 2 hours are unlikely to survive without
neurological sequelae. Patients who have stage 3 or 4 coma, regardless of cause,
are unlikely to survive without transplantation [1]. In contrast, children older than
10 years and adolescents with grade 1 or 2 encephalopathy who do not have
Wilsons disease or indeterminate ALF are more likely to survive without
transplantation. Patients who have factor V levels below 10% or prothrombin
time greater than 50 seconds are unlikely to survive without transplantation [54].
The same can be said for patients who have acetaminophen hepatotoxicity that
has elevated serum lactate levels or arterial pH below 7.3 in patients.
Relative and absolute contraindications to transplantation include uncontrolled
infection or sepsis, active or recent malignancy, uncontrolled intracranial hyper-
tension or severe intracranial hemorrhage, and progressive or end-stage extra-

Fig. 2. Spectrum of outcome in relation to cause for children who had acute liver failure.
162 bucuvalas et al

hepatic disease or systemic disease that will not corrected by liver transplantation
[1,36,39,55].

Does the child require placement of a device to monitor intracranial

pressure?

In a retrospective survey of multiple liver centers, investigators sought to

determine the risk of complications associated with monitoring of intracranial
pressure [56]. Epidural transducers had the lowest rates of complication (3.8%)
and fatal hemorrhage (1%). The risk of complication and death was fivefold
greater when subdural and subarachnoid monitors were used. Measurement using
epidural transducers was more variable and less precise, however. From the data
presented, it is not certain if correction of coagulopathy might have prevented
complications. Single-center studies suggest that correction of coagulation is
critical [57,58]. In a single-center study, the risk reported with subdural monitors
was less than 2% when coagulopathy was corrected by administration of fresh-
frozen plasma or recombinant factor VIIa [59]. Insertion of a monitoring device
requires sedation and usually occurs when the patient develops grade 3 or grade 4
hepatic encephalopathy. The decision to place a device to monitor intracra-
nial pressure depends on careful assessment of the patient, effective control
of coagulopathy to permit safe insertion, and close collaboration with neurosur-
geons and intensive care specialists. The best candidates for intracranial moni-
toring are patients who have progressive encephalopathy who have an opportunity
for full recovery based on the cause of ALF.

Clinical care recommendations

General care

ALF is a multisystem disease with a dynamic and often unpredictable course.

The rate of progression of encephalopathy can be very rapid. Efforts are directed
toward management of intracranial pressure and multiorgan failure while
awaiting recovery of liver function or liver transplantation. A coordinated, inter-
disciplinary approach to care is required. Establishment of best practice has been
limited by the paucity of controlled trials in adults and even more so in pediatric
populations. For the most part, care recommendations have been based on obser-
vations from single-center, uncontrolled trials or from case series. A structured
review outlining the position of the American Association for the Study of Liver
Disease on the care of ALF has been published [60]. The recommendations
presented in that comprehensive review were based on a formal review and
analysis of the medical literature. The approach to care of a child who has ALF is
summarized here.
 acute liver failure in children 163

Circulating blood volume may be altered by depressed cardiac function, sys-

temic inflammatory response, and volume depletion. A central venous catheter
is placed to permit measurement of central venous pressure, to administer
fluids, medications, and blood products, and to collect blood samples. Glucose-
containing maintenance fluids are administered to maintain a glucose infusion
rate of at least 6 to 8 mg/kg/minute. Colloid and crystalloid are administered to
maintain adequate organ perfusion, and vasopressors are used if clinically in-
dicated. Close monitoring of neurologic status, input and urine output, and signs
of infection is necessary, and biochemical analysis of blood samples listed in
Table 4 should be evaluated frequently until the patient becomes stable. Intuba-
tion of patients in grade 3 or grade 4 hepatic coma is performed in most units. For
painful or invasive procedures, a short-acting sedative and short-acting narcotic
may be given. Otherwise, medications that affect level of consciousness should
be avoided so as not to complicate accurate assessment of encephalopathy.
Correction of coagulopathy is required only with hemorrhage or in prepara-
tion for invasive procedures. Vitamin K is given to correct any reversible
coagulopathy. Administration of recombinant factor VIIa produces temporary
correction of coagulopathy and might be useful in the setting of renal insuffi-
ciency in which volume overload is a concern [6163]. Plasmapheresis has not
been shown to improve survival but may serve as a bridge to liver transplantation
[64,65]. Hepatocyte transplantation and artificial liver-assist devices should be
used only in the context of clinical trials [6668]. The relative benefit of treat-
ment with N-acetylcysteine, prostaglandin E, antioxidant therapy, or plasma-
pheresis or infusion has not been determined, although trials examining the
effectiveness of N-acetylcysteine are in progress.
Effective management of encephalopathy is critical for best outcome [13,14].
Close monitoring in an intensive care setting is recommended because the grade
of encephalopathy may change rapidly. With any sudden change in mental sta-
tus, the patient should be evaluated for hypoglycemia, development of infection,
and intracranial hemorrhage. In patients who have grade 1 or grade 2 encepha-
lopathy, sedatives should be avoided, and the patient should be observed closely
in a quiet intensive care setting. In patients who have grade 3 or grade 4 encepha-
lopathy, the head should be elevated to 30 degrees, and endotracheal intubation
should be performed. Cerebral autoregulation of blood flow is lost in patients
who have grade 4 encephalopathy, making the brain susceptible to changes
in systemic blood flow. As noted previously, intracranial pressure monitoring
should be considered for patients who are listed for transplantation. Mannitol
may be given in the event of acute rise of intracranial pressure. The role of
hyperventilation remains uncertain. Short-acting barbiturates may be considered
for refractory intracranial hypertension. Controlled, moderate hypothermia
may be an option in the future but will require rigorous clinical studies in chil-
dren before implementation of this therapy for cerebral edema. Corticosteroids
should be considered only if the underlying cause of ALF is an exaggerated im-
mune response (HLH) or autoimmune hepatitis, not for treatment of intracra-
nial hypertension.
164 bucuvalas et al

Specific therapy should be administered if the underlying cause of ALF has

been determined (see Table 2). Specific therapy increases the chance for survival
with the patients native organ and decreases the demand for organ transplantation.

Outcome

The understanding of the outcome of ALF in children remains uncertain,

limited by the absence of long-term, longitudinal follow-up of patients who have
survived with their native liver and of those who have undergone liver
transplantation. The risk of recurrent disease caused by an autoimmune process
or bone marrow failure is uncertain. Short-term outcome is better understood.
The underlying causation, biochemical measures of liver function, and stage
of encephalopathy predict short-term outcome [54]. Patients who have liver
failure caused by mitochondrial disease are not likely to survive, with or with-
out transplantation. Spontaneous recovery, defined as survival at 3 weeks with-
out liver transplantation, is more frequent in patients who have ischemic or
acetaminophen-induced ALF than in those who have indeterminate or idio-
syncratic drug-induced ALF [2]. Patients who have Wilsons disease and ALF
require liver transplantation for survival. Patients who never developed en-
cephalopathy are more likely to experience spontaneous recovery than those who
develop encephalopathy. In a retrospective study from a single center, indepen-
dent predictors for death or liver transplantation were a period of more than
7 days from initial symptoms to onset of hepatic encephalopathy, prothrombin
time greater than 55 seconds, and aminotransferase levels less than 2384 IU/L on
admission. Grade 3 or grade 4 encephalopathy decreased the chance of survival
without transplantation [69].

Summary

ALF is a devastating disease requiring coordinated care in a specialized cen-

ter for best outcome. In both prospective and retrospective studies, the cause
of most cases of ALF in children is indeterminate. Liver transplantation has
improved short-term outcome, but there is little knowledge regarding the func-
tional health of spontaneous survivors or of liver transplant recipients. Moreover,
for patients who have indeterminate ALF, who comprise the majority of this
population, there are no biochemical markers that specifically identify those who
will have spontaneous recovery and will not require liver transplantation. There
are no proven therapies to promote liver regeneration. It is important to un-
derstand the outcome of ALF, not only in terms of survival but also the functional
status of those who recover with or without liver transplantation [70] (Fig. 3).
Efforts to prevent ALF, to standardize care, and to understand the biology of
the disease so as to develop specific therapy will improve outcome and decrease
the demand for liver transplantation. If it is determined that a proportion of
 acute liver failure in children 165

Fig. 3. Outcome of children with acute liver failure.

patients who have indeterminate ALF have defects in fatty acid oxidation, im-
mune dysregulation, or unrecognized acetaminophen toxicity, specific ther-
apy might be instituted that could improve outcome and avoid the need for
liver transplantation.

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