Chapter

Acute Liver Failure in Children

4 James Squires and Estella Alonso

Introduction Compounding the diagnostic challenge, pinpointing the

Pediatric acute liver failure (PALF) is not a single diagnosis.
Rather, PALF is a complex, rapidly progressive clinical syndrome
that is the final common pathway for many disparate conditions;
some known and others yet to be identified [1, 2]. The estimated
frequency of acute liver failure (ALF) in all age groups in the USA
is about 17 cases per 100,000 population per year, but the fre-
quency in children is unknown. In the USA, ALF accounts for
10–15% of pediatric liver transplants performed annually [3].
Management requires a multidisciplinary team involving the
hepatologist, critical care specialist, and liver transplant surgeon.
Acute liver failure is a rapidly evolving clinical condition. The
absence of adequately powered studies to inform diagnostic algo-
rithms, to assess markers of disease severity and trajectory, and to
guide liver transplant decisions transfers a significant burden to
the clinician. Constructing a diagnostic approach and individua-
lized management strategy that may include the decision to
pursue liver transplantation is challenging. There are a number
of pressing clinical questions faced when children with PALF first
present. Does the patient have a condition that is treatable? What
is the risk of deterioration or improvement on each day the child
is alive with his/her native liver? Is a living related or deceased
liver transplant necessary for patient survival? Is full recovery
possible without a liver transplant? Are associated morbidities
recoverable or irreversible?
Clinical Characterization
Defining PALF is challenging. In adults, the research definition
requires the onset of hepatic encephalopathy (HE) less than
eight weeks after the first signs of hepatic dysfunction. While
HE is a required element for adults with liver failure, it is
acknowledged that it is difficult to assess in children and may
not be reliably identified in a clinical setting [4]. When present,
developmental differences in the clinical manifestations of HE
have been noted between infants and young children.
Recognizing the difficulties inherent to assessing encephalo-
pathy in children, entry criteria for the longitudinal cohort
study by the Pediatric Acute Liver Failure Study Group
(PALFSG) were developed by a consensus of experts whereby
HE was not a requirement to attain a diagnosis of PALF [5]
(Table 4.1).
time at which the “first signs of hepatic dysfunction” occur is
difficult and dependent upon clinical observation by indivi-
duals with variable expertise in assessing liver disease.
Symptoms such as jaundice may go undetected for a period.
The interval between the apparent onset of jaundice and HE
has been used to characterize various “subtypes” of PALF such
as “hyperacute,” “acute,” and “subacute” PALF, and yet the
first day of the illness is all but impossible to determine. There
are currently no validated alternatives to these imperfect sub-
jective measures to distinguish categories of patients with acute
severe liver injury from ALF or to distinguish ALF that is
recoverable without liver transplant from those who would
die without liver transplant.
In the era before liver transplantation, the dynamic natural
history of PALF was for children to either survive or die and
a worsening clinical course did not preclude a favorable out-
come (Figure 4.1). A previously healthy patient typically
experiences a non-specific prodrome of variable duration
with features that might include abdominal discomfort and
malaise with or without fever. Symptoms may persist or wax
and wane for days or weeks before the child is brought to
medical attention. In the absence of jaundice or other clinically
evident sign of liver dysfunction, the child may receive empiric
treatment to relieve symptoms. However, if there are clinical
signs of liver injury or encephalopathy, or if blood work is
obtained that reveals hepatic dysfunction, the clinical syn-
drome of PALF can be recognized.
With the exception of acute ingestions (e.g., mushrooms,
acetaminophen), the precise onset of disease is rarely identi-
fied. Patient outcome is reflected, in part, by the interaction
among etiology, disease severity, supportive management, and
treatment. Yet, outcomes vary among children with seemingly
similar etiology, disease severity, and treatment; therefore,
additional factors are likely involved to explain these varia-
tions. Modifying factors likely include the inflammatory
milieu, end-organ damage, immune activation, potential for
liver regeneration, and management interventions. Medical
and liver transplant decisions require reliable repeated assess-
ments of the probability of survival with native liver from one
time interval to the next. Liver transplant decisions for children
with ALF, which must include the risks associated with living

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organ donation, are made difficult given the uncertainty of
patient outcome. The uncertainty regarding where the patient
resides along the “natural course” of the disease at the time of
initial presentation or at any point thereafter requires
Table 4.1 PALFSG Study Entry Criteria
• No known evidence of chronic liver disease
• Biochemical evidence of acute liver injury
• Coagulopathy not corrected by vitamin K
◦◦ INR ≥ 1.5 (or PT between 15 and 19.9 seconds) with clinical HE
◦◦ INR is ≥ 2.0 (or PT ≥ 20 seconds) with or without HE
PALF: pediatric acute liver failure; INR: international normalized ratio;
PT: prothrombin time; HE: hepatic encephalopathy.
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Chapter 4: Acute Liver Failure in Children
considerable clinical judgment. Liver transplant arbitrarily
interrupts the natural course of PALF and it is accepted that
some patients who receive a liver transplant may have survived
without one. Given the insufficient number of organs to satisfy
patient needs, the field would be well served if there were
a more precise method to identify those patients who will
survive without a liver transplant, as well as those who will
die despite liver transplant.
Etiology
Specific etiologies can be broadly categorized as infectious,
immunologic, metabolic, and toxin/drug related; however, an
identified cause for liver injury is lacking in approximately
30–50% of cases [5, 6]. Figure 4.2 details the causes of ALF in
1,144 children enrolled in the PALFSG from 19 pediatric liver
transplant centers in the USA, Canada, and the UK between
1999 and 2014. In developing countries, the etiologies are
Figure 4.1 The clinical trajectory of a child with
acute liver failure is difficult to predict. Liver
transplantation interrupts the natural history of
acute liver failure. Improved assessment and
estimate of the clinical trajectory will enhance
transplant decisions in the future. SIRS: systemic
inflammatory response syndrome.
Figure 4.2. Etiology of acute liver failure in 1,144
children from the Pediatric Acute Liver Failure Study
Group (PALFSG) 1999–2014.
APAP: acetaminophen; GALD: gestational
alloimmune liver disease; HLH: hemophagocytic
lymphohistiocytosis. Adapted from reference [1].
37
 Section I: Pathophysiology of Pediatric Liver Disease
similar but are dominated by infectious etiologies, with hepa-
titis A virus (HAV) being the most common identified etiology
[7, 8]. This brief summation of processes that can cause PALF
is supplemented by other chapters detailing each specific dis-
ease state.
Indeterminate
Historically, a specific diagnosis was not established in over 50%
of PALF and these children were categorized as indeterminate
(IND-PALF). Likely, the indeterminate group consisted of some
patients who underwent an incomplete diagnostic evaluation,
and within the PALFSG cohort, inadequate assessments for
autoimmune hepatitis (AIH), mitochondrial disorders, and
other metabolic diseases were the most common deficiencies
[9]. Comprehensive viral testing in PALF has also been found to
often be incomplete [10]. Recent efforts have looked to address
this shortcoming. While almost 43% of the overall PALFSG
participants were categorized as indeterminate (Figure 4.2),
the incorporation of standardized diagnostic test recommenda-
tions into electronic medical record (EMR) order sets enabled
a significant reduction in the percentage of IND-PALF, from
48% during the first two phases of the study (1999–2010) to
30.8% when looking at phase three (2011–2014) [1]. In smaller
studies, the utility of next generation sequencing and un-biased
whole exome sequencing has expanded diagnostic capabilities as
well [11, 12]. Still, “indeterminate” remains the most common
categorization of these critically ill children.
The presentation of IND-PALF mirrors that of most other
children with acute liver failure (Figure 4.1). IND-PALF can
occur at any age and cases do not segregate by sex or race.
Temporal clustering of IND-PALF supports a potential role for
a community-acquired viral infection, but a novel or pre-
viously known pathogenic virus has not been identified [6].
Injury secondary to overzealous inflammatory responses and
immune dysregulation have been suspected in many cases of
IND-PALF and the degree of increasing inflammatory network
connectivity in these patients has been shown to be associated
with poorer outcomes [13, 14]. Some patients with IND-PALF
present with a hemophagocytic lymphohistiocytosis (HLH)-
like phenotype including elevated soluble IL-2 receptor levels
[15, 16]. However, the majority of patients with evidence of
immune activation do not meet criteria for HLH but do exhibit
characteristic features that suggest a common pathogenesis
[17]. This sub-set of IND-PALF patients have distinctive liver
histology which includes a dense CD103+CD8+ T-cell infiltrate
further suggesting an immune mediated liver injury [16, 17].
PALF patients with this “activated” CD8 T cell hepatitis are
more likely to receive liver transplantation than patients with
other causes of PALF. Based on these observations, there has
been a growing trend toward treatment of PALF associated
with activated CD8+ T cell hepatitis with immunosuppression.
However, the therapeutic benefit of this practice remains
unknown [18]. The clinical course of IND-PALF can be vari-
able, yet the trajectory of commonly obtained clinical measures
such as international normalized ratio (INR), total bilirubin,
and the presence of HE has been shown to have important
prognostic value [19]. When considering transplant, having an
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indeterminate diagnosis appears to influence decisions
toward listing [20]. Additional co-morbidities, such as tran-
sient bone marrow suppression and aplastic anemia, can be
seen in these children, even after successful liver transplanta-
tion [6].
Acetaminophen
Acetaminophen (N-acetyl-p-aminophenol (paracetamol)) is
widely used in children for management of fever and pain. It
is available without prescription and is commercially available
as a single formulation or can be compounded with deconge-
stants or narcotics. Acetaminophen (APAP) is safe and well
tolerated when dosing instructions are strictly followed.
However, it has a low therapeutic index, and in certain indivi-
duals or clinical scenarios, chronic administration of therapeu-
tic dosages of acetaminophen can result in significant
hepatotoxic effects [21]. Notably, APAP toxicity is the most
commonly identified cause of PALF in over 1,100 children
enrolled in the PALFSG [1]. Two clinical scenarios are asso-
ciated with acetaminophen hepatotoxicity.
The most common scenario follows an intentional single
ingestion of a hepatotoxic dose of 15–25 g in adults (or
>100 mg/kg in children) in an attempt at suicide or attention-
seeking behavior [22]. Plasma acetaminophen at four and 24
hours after a single ingestion will assist in determining the
relative toxicity of the ingestion [23]. Females over ten years
of age represent the most common demographic associated
with intentional overdose in children, but it should be consid-
ered in all age groups outside the newborn period [5].
Immediately following ingestion, patients may experience
non-specific symptoms of nausea and vomiting. While a liver
biopsy is not generally indicated in the setting of known acet-
aminophen overdose, centrilobular hepatic necrosis is the hall-
mark finding and should raise the consideration of
acetaminophen toxicity even without a clear history of expo-
sure. N-acetylcysteine (NAC) given enterally or intravenously
can successfully reverse the toxic injury if given shortly after
the ingestion, ideally within 24 hours. Mechanistically, NAC
has demonstrated hepatoprotective effects in acetaminophen
toxicity by antagonizing the damage-associated molecular pat-
tern (DAMP) molecule high mobility group box 1 (HMGB1)
which drives a pro-inflammatory program in PALF [24] and by
enhancing hepatic and mitochondrial glutathione levels
(scavenging of reactive oxygen and peroxynitrite) [25]. If treat-
ment is delayed beyond 24 hours following ingestion, the
patient is at increased risk of having irreversible liver injury.
Regardless of the interval between ingestion and presentation,
NAC should be administered when a toxic ingestion has
occurred. Serum aminotransferase levels can reach over
10,000 IU/mL and the total bilirubin is generally lower than
might be expected given the degree of liver injury, typically
<10 mg/dL. Early metabolic acidosis and serum lactate eleva-
tions can be seen along with co-morbidities of acute renal
failure (10–50%) and pancreatitis (0.3–5%) [2]. If treatment
is not initiated, jaundice develops within 48 to 72 hours, with
death occurring in the most severe cases by five to seven days
following the ingestion.
 Chapter 4: Acute Liver Failure in Children

In the second most common presentation, patients inadver- Table 4.2 Medications and Toxins Associated with Acute Liver Failure
tently partake in a “therapeutic misadventure” whereby they
Type Xenobiotics
unintentionally overdose by taking therapeutic doses of multi-
ple APAP-containing medications [22]. Risk factors for devel- Anti-infective Clavulanic acid/amoxicillin
oping severe hepatotoxicity secondary to a therapeutic Trimethoprim–sulfamethoxazole
misadventure include concomitant use of other medicines that Isoniazid
alter hepatic metabolism, delayed medical care, younger age, Minocycline/doxycycline
and prolonged periods of fasting [26]. In both adults and chil- Quinolone (ciprofloxacin,
dren, polymorphic variants in UDP-glucuronosyltransferase norfloxacin)
(UGT) 1A, a main metabolizing enzyme of APAP, have been Voriconazole
shown to affect the risk of developing APAP toxicity [27, 28]. Macrolide (erythromycin,
The presence of acetaminophen adducts in the serum may clarithromycin, azithromycin)
indicate unsuspected hepatotoxicity or underreported acetami- Others
nophen (ab)use [29]. Additionally, the presence of adducts in Anticonvulsants Phenytoin
indeterminate cases of PALF suggests occult APAP toxicity may Valproic acid
play a role in approximately 10% of children where a distinct Carbamazepine
diagnosis for ALF cannot be established [30]. Although the Others
magnitude of this clinical problem in children is not well Immunomodulators/ Methotrexate
defined, between 16% and 48% of acetaminophen-induced ALF anti-inflammatory Azathioprine
in adults results from unintentional overdosing, reinforcing the Non-steroidal anti-inflammatory
concept that accidental misuse of this medication leading to drugs
serious liver injury is relatively common [22]. Similar to children Acetaminophen
with a single intentional overdose, alanine aminotransferase Biological (i.e., infliximab,
levels can reach into the many thousands with a relatively low basiliximab, etc.)
total bilirubin level. Others
Recreational drugs Ecstasy
Medication (Non-Acetaminophen) or Toxin Cocaine
Liver injury caused by drugs, herbals, or toxins other than Others
acetaminophen was identified in a little more than 3% of Complementary, Pyrrolizidine alkaloids
cases in the PALFSG registry, the vast majority occurring in alternative or herbal Germander
children over ten years of age [1, 5]. Anti-epileptics (valproic medication Ma huang
acid, phenytoin, carbamazepine, felbamate) are the most com- Chaparral
mon offenders in children [5, 31]. Valproic acid, particularly in Black cohosh root
children with unsuspected mitochondrial disease, may preci- Pennyroyal
pitate ALF. The list of xenobiotics associated with liver failure Kava
is extensive and expanding; a partial list is found in Table 4.2. Others
Hepatotoxic agents, such as industrial solvents and mushroom Toxin/industrial Amatoxin (mushrooms from
toxin, are dose dependent and will predictably result in liver solvents Amianita spp.)
injury or failure. The diagnosis of hepatotoxic liver injury is Carbon tetrachloride
often one of exclusion, based on latency, clinical features, Tricholorethylene
laboratory values, histology, and a response to removal of the 2-Nitropropane
offending agent [32]. However, idiosyncratic drug reactions 1,2,3-Trichloropropane
remain a common etiology. Given the complexity of drug-
induced liver injury, the Drug-Induced Liver Injury Network
(DILIN), established by the National Institutes of Health in
2003, has and continues to standardize the nomenclature and patterns, and management of liver injury attributable to med-
causality assessment of drug-induced liver injury (DILI) ications, herbals and dietary supplements.
including those associated with liver failure. In April of 2012 A careful history of exposure to hepatotoxins should be
the website LiverTox® (http://livertox.nlm.nih.gov/index.html) obtained from the family of any child presenting with ALF,
was launched as a joint effort of the Liver Disease Research including prescription and non-prescription drugs in the
Branch of the National Institute of Diabetes and Digestive and home that could have been ingested accidentally. In teenagers,
Kidney Diseases (NIDDK) and the Division of Specialized a history should include evidence of depression, recreational
Information Services of the National Library of Medicine drug use (e.g., cocaine, ecstasy), or solvent sniffing. Any expo-
(NLM), National Institutes of Health. The purpose of sure to hepatotoxic drugs, chemicals, or herbals should be
LiverTox® is to provide up-to-date, accurate, and easily considered possibly related to the liver injury. Ingestion of the
accessed information on the diagnosis, cause, frequency, Amanita mushroom is clearly traced to ALF.

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 Section I: Pathophysiology of Pediatric Liver Disease
Liver biopsy can assist in the diagnosis of drug-induced
idiosyncratic liver injury. The histologic pattern of injury
observed should be that expected from the drug to which the
patient has been exposed. The patterns seen are hepatitis
(hepatocellular necrosis), cholestasis, mixed cholestasis and
hepatitis, and steatosis. Drugs that cause hepatitis (e.g., isonia-
zid, propylthiouracil, and halothane) have the greatest poten-
tial for causing PALF. Drugs associated with steatosis (e.g.,
sodium valproate, amiodarone) may also cause liver failure.
Drugs that cause cholestasis (oxacillin) rarely produce liver
failure, whereas drugs that cause mixed cholestasis and hepa-
titis (sulfa drugs) sometimes do. If histology differs from that
expected by the drug in question, another cause should be
sought. Exposure to a drug or toxin should not preclude
a thorough search for other causes of liver injury.
Immune Mediate Liver Injury
Autoimmune Marker Positive
The classic serological markers associated with autoimmune
liver disease, which include anti-nuclear antibody (ANA),
smooth muscle antibody (SMA), and liver–kidney microsomal
(LKM) antibody, are found to be positive in 28% of children
with ALF [33]. However, the true frequency of positive auto-
immune markers in PALF is not known as all three markers
were obtained in only 55% of patients in the PALFSG, while
21% of children showed no markers [9]. Autoimmune-marker
positive PALF has been reported in children as young as nine
weeks and therefore should be considered in all age groups
outside of early infancy.
The presence of autoantibodies in PALF is more common in
those with a final diagnosis of autoimmune hepatitis (AIH,
93%); however, they can be found in patients with other
known causes of liver failure such as Wilson disease, drug-
induced liver failure, and indeterminate [33]. Elevated serum
globulins may not be present, and the condition appears to be
evenly distributed among males and females. Histologic features
show evidence of immune activation with the presence of
a lymphoplasmocytic-enriched portal tract infiltrate, central
perivenulitis, and lymphoid follicles with evidence of massive
hepatic necrosis [34]. Notably, there should be no evidence of
chronicity on the initial biopsy. While the presence of autoanti-
bodies does not appear to significantly associate with outcomes,
children who are LKM positive were found to be younger and
more likely to undergo liver transplantation compared with
other autoantibody subjects [33]. Corticosteroids can interrupt
the liver injury in many patients and while steroid treatment did
not improve survival overall in autoantibody positive children,
the sub-group of patients with a known diagnosis other than
AIH had a higher risk of death [33]. Some children appear to
tolerate weaning corticosteroids without recurrence of their
disease, while recurrent disease may be more common in adults.
Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is an enigmatic
condition characterized by fever, hepatosplenomegaly, marked
elevation in serum aminotransferase levels, cytopenias,
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hypertriglyceridemia, hyperferritinemia, and hypofibrinogen-
emia and should be conceptualized as a phenotype of critical
illness due to toxic activation of immune cells from different
underlying mechanisms [35, 36]. Additional diagnostic criteria
now include low or absent natural killer (NK) cell activity,
serum ferritin >500 μg/L, and soluble CD25 (soluble interleu-
kin-2 receptor) >2400 U/mL. It can present from infancy
through adolescence, although it is most commonly diagnosed
in the first five years of life.
Indeterminate Pediatric Acute Liver Failure Associated with
Activated CD8+ T Cell Hepatitis
As noted above, a subset of children with IND-PALF is noted
to have evidence of immune dysregulation and inflammatory
overactivation. While specific classification criteria are lacking,
this emerging PALF-associated disease may benefit from
future efforts to better define and categorize these patients,
identifying a unique PALF cohort who would benefit from
targeted immunosuppression therapies.
Other Primary Immune Deficiencies
Primary immune deficiencies (PID) is a rapidly growing group
of >350 conditions characterized by increased susceptibility to
infections, autoimmunity, and auto-inflammation [37]. An
expanding understanding of the reciprocal interactions
between the liver and the immune system has identified PID,
particularly those with inherited defects in T and B cells or
innate immunity, as contributors to children presenting with
ALF [38]. Specific conditions that have been associated with
liver failure include autoimmune regulator (AIRE) deficiency
and SP110 deficiency [38].
Gestational Alloimmune Liver Disease
Gestational alloimmune liver disease (GALD), results from an
intrauterine alloimmune liver injury and is the single most
common cause of neonatal ALF [39]. The phenotype of neo-
natal liver disease in association with siderosis of various
extrahepatic tissues has been termed neonatal hemochroma-
tosis (NH) for over 20 years. Recently, it has been determined
that GALD accounts for 60–90% of NH cases. The remaining
patients with the NH phenotype have been found to have
a variety of disorders including mitochondrial DNA depletion
syndrome, bile acid synthetic defects, Down syndrome with
myelodysplasia, and severe perinatal infection. While HLH
may also present with extra-hepatic iron deposition, iron is
present in the reticuloendothelial system (e.g., spleen and
macrophages) which is spared in the NH phenotype. In GALD-
NH, maternal immunoglobulin G appears to activate fetal
complement, which leads to the formation of the membrane
attack complex and results in liver cell injury. The resultant
pathologic siderosis seen in both the liver and various extra-
hepatic tissue results from severe liver injury causing iron
overload due to poor regulation of maternofetal iron flux.
The degree of liver injury can be so profound that death from
liver failure can occur within the first few weeks of life [39, 40].
Therefore, liver failure associated with GALD-NH is

technically a terminal event of a chronic intrauterine liver
disease. However, the phenotype of a family’s index case of
NH confronting the clinician is one of ALF and thus deserves
to be included in this section for clinical purposes.
Characteristic clinical features of GALD-NH include an
ALF presentation usually at birth and almost always in the
first days of life. The majority (70–90%) of affected infants
are born premature and a history of maternal sibling death is
common. Medical history often reveals intrauterine growth
restriction and oligohydramnios. Refractory hypoglycemia,
severe coagulopathy, hypoalbuminemia, elevated serum ferri-
tin (>1000 μg/L), and ascites are often noted. Strikingly, serum
aminotransferase levels are normal or near normal and should
alert the clinician to the possibility of GALD-NH [39].
Extrahepatic iron deposition is a hallmark finding.
Hemosiderin deposition in the minor salivary glands obtained
by a buccal mucosal biopsy is often seen. Alternatively, MRI of
the abdomen would suggest the diagnosis with the finding of
reduced T2-weighted intensity of the liver and/or the pancreas
relative to the spleen. Exchange transfusion and high-dose
intravenous immunoglobulin (IVIG) is the preferred treat-
ment to remove offending antibodies and block their action,
including activation of complement [39].
Inherited Metabolic Disease
Metabolic diseases may not fit the definition of ALF precisely
as the condition was certainly present prior to presentation.
However, a number of conditions will present acutely in a child
who is not known to have the condition until the diagnosis is
established and ALF may be the initial presentation. Overall,
metabolic diseases account for just under 10% of PALF [1].
While some conditions, such as mitochondrial disease, may
present at any age, many metabolic conditions presenting as
liver failure segregate within age groups. Metabolic conditions
that should be considered in these age groups are listed in
Table 4.3. Details of the specific conditions can be found in
other sections of this textbook. Highlighting those which have
been associated with a presentation of ALF is the purpose of
this section.
Metabolic conditions affecting infants in the first few
months of life include galactosemia, tyrosinemia, Niemann–
Pick type C, mitochondrial hepatopathies, hereditary fructose
intolerance, urea cycle defects, and the defects associated with
recurrent PALF [41–43]. Galactosemia should be considered in
a child consuming breast milk or other lactose-containing
formula and developing liver failure associated with reducing
substances in the urine. Hepatosplenomegaly is common and
profound coagulopathy can be seen with only modest amino-
transferase elevations [2]. Similarly, tyrosinemia can present
with a profound coagulopathy and normal or near normal
serum aminotransferase levels. Both galactosemia and tyrosi-
nemia can present in association with gram-negative sepsis.
Niemann–Pick type C is a lysosomal storage disease and
marked splenomegaly is often noted. Hereditary fructose intol-
erance more classically presents in an older child after the
introduction of fructose and/or sucrose, however, several
newer infant formulas contain fructose and ALF in the
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Chapter 4: Acute Liver Failure in Children
Table 4.3 Metabolic Disease Presenting as Acute Liver Failure
Age Condition
<6 months Galactosemia
Niemann-Pick type C
Tyrosinemia
Glycosylation defect
Mitochondrial disease*
Infantile liver failure syndrome
type 1 (LARS deficiency)
Hereditary fructose intolerance
NBAS deficiency
7 months to 4 years Mitochondrial disease*
Tyrosinemia
alpha 1-antitrypsin deficiency
Infantile liver failure syndrome
type 1 (LARS deficiency)
Hereditary fructose intolerance
Urea cycle defects
5 years to 18 years Wilson disease
Mitochondrial disease*
Fatty liver of pregnancy
* Fatty acid oxidation defects, respiratory chain defects, mitochondrial DNA
depletion.
neonatal period has been reported [42]. Mitochondrial hepa-
topathies are increasingly recognized as an important cause of
liver failure due to deficiencies in respiratory complexes I, III,
or IV or mitochondrial DNA depletion. With rare exceptions,
mitochondrial hepatopathies have associated systemic mito-
chondrial dysfunction characterized by progressive neurologic
deficiencies, cardiomyopathy, or myopathy. Multisystem
mitochondrial dysfunction has historically served as a relative
contraindication to liver transplant [44]. However, patients
with mitochondrial diseases (excluding POLG-related disease)
have more recently been shown to tolerate solid-organ trans-
plant with post-transplant survival similar to non-
mitochondrial disease patients [45]. Unfortunately, multi-
system involvement may not be apparent at the time of liver
transplant, and progressive extra-hepatic disease can occur.
Lactic acidosis and an elevated molar ratio of lactate to pyr-
uvate (>25 mol/mol) have historically been used to alert the
clinician to the possibility of a mitochondrial hepatopathy;
however, recent analysis of the PALFSG cohort found that
neither an elevated serum lactate ≥ 2.5 mmol/L nor an elevated
lactate:pyruvate (L:P) ratio were specific for mitochondrial
disease in the setting of PALF and elevation did not predict
clinical outcome [46]. Thus it appears that secondary mito-
chondrial dysfunction, independent of the cause of acute liver
failure, may drive lactate and L:P abnormalities in PALF and
that neither diagnosis nor clinical decisions (including con-
siderations for liver transplant) should be based solely on these
findings [46]. Defects in fatty acid oxidation, a primary func-
tion of mitochondria, may become clinically apparent during
a period of fasting, as a consequence of anorexia associated
41
 Section I: Pathophysiology of Pediatric Liver Disease
with an acute illness, or when the infant begins to sleep through
the night. With these defects, hyperammonemia is common as
are extra-hepatic manifestations involving the neurologic, car-
diac, and muscular symptoms [2]. Recurrent PALF episodes
have been associated with the infantile liver failure syndrome
type I (LARS mutations) and NBAS deficiency. Importantly,
ALF in the neonatal period may be the initial presentation of
these rare disorders and a high clinical suspicion is indicated to
make the diagnosis [43, 47].
In older infants and young children up to five years of age,
mitochondrial diseases, tyrosinemia, hereditary fructose intol-
erance, and urea cycle defects can be identified. Mitochondrial
hepatopathies, particularly disorders of fatty acid oxidation,
occur commonly in this age group [48]. Hereditary fructose
intolerance outside the neonatal period presents when fruc-
tose-containing foods, such as fruits, are introduced into the
diet. Urea cycle defects typically present with hyperammone-
mia, mental status changes and seizures, but without liver
synthetic dysfunction. However, PALF has been associated
with arginosuccinate synthetase deficiency (citrullinemia
type 1) and ornithine transcarbamylase deficiency, although
the mechanism of liver injury is uncertain [2, 49, 50].
Wilson disease is the most common metabolic condi-
tion associated with PALF in children over five years of age
[1]. The presence of a Coombs-negative hemolytic anemia,
marked hyperbilirubinemia, low serum ceruloplasmin, and
a low serum alkaline phosphatase should prompt consid-
eration of Wilson disease, but confirming the diagnosis
remains a challenge. Findings in a predominately adult
population suggests that the combination of an alkaline
phosphatase to total bilirubin ratio of <4 and an aspartate
aminotransferase to alanine aminotransferase ratio of >2.2
provided a rapid and accurate method for diagnosis of
Wilson disease presenting as ALF [51]. However, these
findings have not yet been confirmed in a pediatric popu-
lation. Fatty acid oxidation defects can also present with
ALF in older children and adolescents.
Infectious Diseases
A non-specific prodrome consisting of fever, nausea, vomit-
ing, and abdominal discomfort will precede many cases of
ALF in children regardless of etiology. Therefore, it is not
surprising that early accounts of ALF often attributed the
cause to a virus or infection. As the ability to identify specific
infectious agents through serology, culture, and polymerase
chain reaction technology has been applied, the burden of
viral associated-PALF has become clearer. Although
a comprehensive infectious diagnostic work-up is often not
performed [10], acute viral infection as the cause of PALF
was identified in only 8.4% of subjects [1]. The common
hepatitis viruses have not often been found in ALF unless
they were endemic to the region or in association with
a community outbreak. Although a yet unidentified infec-
tious agent may account for some unexplained cases of ALF
in children, efforts to identify rare infectious agents in adults
have not been fruitful. Therefore, a reasonable alternative is
to classify as indeterminate any patient without an
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identifiable cause for the ALF until a more specific diagnosis
can be established.
Hepatitis Viruses
Acute HAV infection accounts for up to 80% of PALF in
developing countries [7, 8, 52]. Since the introduction of the
HAV vaccine in 1995, HAV infection in North American
children has dramatically declined. In the PALFSG study,
only 0.5% of children with ALF had acute HAV infection [1].
In children that do develop acute HAV, less than 1% will
proceed to ALF.
Acute hepatitis B virus (HBV) infection resulting in ALF is
uncommon in pediatric series from Western Europe and
North America, where HBV is not endemic. Among the
PALFSG cohort, 0.3% of children had HBV as a final diagnosis
[1]. However, in areas where it is endemic, the incidence of
HBV-induced PALF is much higher. Death occurs more com-
monly in older patients and in individuals who acquired HBV
following a blood transfusion.
Hepatitis C virus (HCV) infection has rarely been identi-
fied as the cause for ALF, and only a single case of HCV was
noted in the more than 1,100 children in the PALFSG [1].
Hepatitis E virus infection is documented by association
with epidemics of water-borne diseases not caused by HAV or
by the presence of anti-hepatitis E virus antibody in serum.
Most experience with hepatitis E virus comes from the Indian
subcontinent, where 38% of PALF cases were caused by hepa-
titis E virus alone or in combination with HAV [53]. Pregnant
women are also highly vulnerable to HEV-ALF, with one study
demonstrating a case fatality rate of 10.1%, with women in the
third trimester particularly at risk.
Infection with Viruses Other Than Hepatitis Viruses
The viruses in the herpes family are highly cytopathic and can
cause severe hepatic necrosis, often in the absence of signifi-
cant inflammation. Herpes simplex virus, human herpes virus
6 (HHV-6), varicella–zoster virus, cytomegalovirus, and
Epstein–Barr virus have been reported to cause ALF in both
immunocompromised and immunocompetent hosts [1].
Herpes simplex virus most commonly affects infants and new-
borns while Epstein–Barr virus is the virus most frequently
implicated in older children and adolescents. As herpes sim-
plex virus is a sexually transmitted disease, it should also be
considered in sexually active adolescents. HHV-6 was detected
in the explanted livers of patients who underwent liver trans-
plant for ALF of unknown cause. However, this virus is so
prevalent as a latent infection in humans that causality may be
difficult to prove in cases of ALF. Little is known about the
incidence or case fatality rates among children with ALF sec-
ondary to herpes virus infection. However, early detection
utilizing newer diagnostic techniques, such as real-time poly-
merase chain reaction, and early institution of specific therapy
may improve survival.
Parvovirus B19 routinely infects children, causing one of
the common childhood exanthemas. It rarely can cause severe
bone marrow depression and has been associated with mild
hepatitis. Its role as a cause of PALF is controversial as it is

often associated with other viruses known to cause PALF. This
virus has been sought and not found in other studies involving
larger numbers of patients with ALF and aplastic anemia [54].
Syncytial giant cell hepatitis with ALF was associated
with paramyxovirus infection in a series from Toronto
[55]. This infection is more likely to result in chronic
progressive hepatitis or late-onset hepatic failure than ALF
but should be considered in all three circumstances. Other
viruses associated with ALF include adenovirus, dengue
fever, and members of the enterovirus family such as echo-
virus and coxsackie A and B.
Non-Viral Infectious Hepatitis
Infectious agents other than viruses only rarely have been
recorded as producing ALF. Despite the rarity of occurrence,
they should be considered carefully in every case because they
are potentially treatable.
Systemic sepsis occasionally presents in a manner that is
virtually indistinguishable from ALF. Reported infectious
etiologies include Neisseria meningitides infection, septic
shock and intra-abdominal abscesses, and portal sepsis with
enteric organisms. Spirochetal infection can affect liver func-
tion and produce severe hepatitis, even hepatic failure.
Congenital syphilis has rarely been determined as a cause of
ALF but should be excluded carefully in any neonate with
severe hepatitis. Leptospirosis very rarely causes hepatic fail-
ure. Finally, in endemic areas, Brucella spp. (brucellosis),
Coxiella burnetii (Q fever), Plasmodium falciparum, and
Entamoeba histolytica infections have presented as ALF.
Other Rare Causes
Liver failure may be the presenting manifestation of a systemic
condition. For example, leukemia can present as liver failure
[1]. Cardiovascular shock associated with systemic hypoten-
sion, as seen in patients with trauma, sepsis, hemorrhage,
cardiomyopathy or left heart failure (e.g., hypoplastic left
heart) or following cardiac bypass may also develop liver fail-
ure. Budd–Chiari syndrome is a rare cause of PALF as obstruc-
tion of the hepatic venous outflow can lead to hepatomegaly,
ascites, and evidence of hepatocellular injury. Liver failure may
be the presenting feature of celiac disease and, if recognized, is
potentially treatable following institution of a gluten-free diet
[56].
Diagnostic Approach
The diagnostic evaluation of children with ALF can be chal-
lenged by many factors. These include the volume of blood
needed to complete diagnostic tests, a rapid clinical trajectory
ending in death or liver transplantation prior to a complete
evaluation, a differential diagnosis that is incomplete or not
prioritized, or clinical improvement that mitigates diagnostic
curiosity. In PALF, as many as 30% of patients are left with an
indeterminate diagnosis. Given the rarity of PALF, an age-
based diagnostic approach is useful to improve diagnostic
yield [1]. If a specific diagnosis can be secured, an effective
treatment could alter the natural history of the disease.
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Chapter 4: Acute Liver Failure in Children
A detailed history and physical examination cannot be
overlooked or abbreviated. 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
prescription and over-the-counter medications in the home,
intravenous drug use, or a family history of Wilson disease, α1-
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 condi-
tion with an acute presentation.
Physical assessment should include evaluation of growth,
development, and nutrition status; evidence of jaundice,
bruises, or bleeding following venipuncture; and petechiae.
Hepatomegaly alone or with splenomegaly, ascites, and per-
ipheral edema can be present. Kayser–Fleischer rings are pre-
sent in only 50% of patients with Wilson disease who present
with ALF. Fetor hepaticus is a sweet distinctive aroma to the
breath associated with HE but is rarely present. Findings sug-
gestive of chronic liver disease include digital clubbing, palmar
erythema, cutaneous xanthoma, and prominent abdominal
vessels, suggesting long-standing portal hypertension. Altered
mental status should be assessed but may be difficult to assess
in infants and young children.
Laboratory tests for diagnosis will necessarily compete with
other studies required to assess the health of the patient and the
severity of liver injury. Therefore, laboratory studies needed
for management and diagnosis should be prioritized into three
areas: (1) general tests to assess hematological, renal, pancrea-
tic, and electrolyte abnormalities; (2) liver-specific tests to
assess the degree of inflammation, injury, and function; and
(3) diagnostic tests. As almost 50% of children with ALF are
under four years of age, limitations on the volume of blood that
can be drawn demand a knowledgeable prioritization of tests.
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 high priority tests are performed expeditiously.
The distribution of diagnoses varies greatly within the
pediatric age group. While some conditions such as herpes
simplex virus can occur within all age categories, others such
as GALD and Wilson disease are found within a narrower age
range. Therefore, age-based diagnostic prioritization would
serve to enhance the likelihood of establishing a diagnosis as
quickly as possible. Table 4.4 lists minimal diagnostic tests that
have been shown to be most useful for children of different
ages based upon the expected diagnoses. Diagnostic tests
should not be limited to those listed but should take a high
priority when testing is initiated.
Identification of those conditions that are amenable to
specific therapy, relevant to subsequent pregnancies, or
which would be a contraindication to liver transplantation,
should take priority. Acute acetaminophen toxicity, herpes
simplex, and HLH have targeted treatments that can be life-
saving. Autoimmune hepatitis, a potentially treatable cause of
43
 Section I: Pathophysiology of Pediatric Liver Disease

Table 4.4 Recommendations for Minimal Diagnostic Evaluation by Age in Pediatric Acute Liver Failure (adapted from Ref 1)

Recommended age of
Suspected etiology Recommended tests diagnostic testing
<3 mo 3 mo to 18 y
Systemic herpes infection Herpes blood PCR x x
Urea cycle; other metabolic defects Serum amino acid profile x x
GALD screen Ferritin x
Mitochondrial screen Lactate, pyruvate x x
FAO defects Plasma acylcarnitine profile x x
Tyrosinemia Urine succinylacetone x
Systemic enterovirus infection* Enterovirus blood PCR x x
Acetaminophen toxicity Acetaminophen level x
Hepatitis A Hepatitis A virus IgM x
Hepatitis B Hepatitis B surface antigen x
EBV infection EBV VCA IgM or PCR x
Autoimmune Disease Antinuclear antibody x
Anti–smooth muscle ab x
Liver kidney microsomal ab x
IgG x
Wilson disease** Ceruloplasmin x
24-hour urine copper x
DILI/HDS Exposure Drug history x x
Galactosemia and tyrosinemia Confirm newborn screen results x
Hepatitis B in newborn Confirm maternal hepatitis B serology Procedures x
Viral infection Viral testing for adenovirus, enterovirus, HHV-6, parvovirus, x x
influenza
HLH Soluble IL2R, ferritin, triglyceride level x x
Vascular/Anatomical Abnormality Abdominal ultrasound with Doppler x x
Infection Blood culture x x

* unlikely needed > 3 y

** unlikely needed < 1 yAb, antibody; APAP, acetaminophen; EBV, Epstein–Barr virus; FAO, fatty acid oxidation defects; GALD, gestational alloimmune liver
disease; HDS, herbal dietary supplement; HHV-6, human herpes virus-6; HLH, hemophagocytic lymphohistiocytosis; IL2R, interleukin-2 receptor; PCR,
polymerase chain reaction; VCA, viral capsule antigen

ALF in children of all ages, should be considered early in the
evaluation process to enable prompt initiation of treatment.
However, autoimmune markers are found in conditions other
than autoimmune hepatitis, thus necessitating subjective clin-
ical judgment to influence the final diagnosis and treatment
strategy [33]. Acute liver failure may be the initial symptom
associated with metabolic defects related to carbohydrate, fatty
acid, and protein metabolism in which dietary management
serves as treatment. Identifying an index case of GALD will
provide an opportunity to treat the mother during subsequent
pregnancies with intravenous immunoglobulin and prevent
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the condition in subsequent pregnancies. Recovery from the
acute liver injury in tyrosinemia can be accomplished with
nitisinone (2(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexa-
nedione). A patient with a systemic mitochondrial disease
presenting as ALF, either independent of or associated with
valproate intake, will be unlikely to benefit from liver trans-
plant as outcome is uniformly poor. Characterization of under-
lying mechanisms of liver injury associated with immune
dysregulation, metabolic disorders, and unsuspected acetami-
nophen exposure will identify patients who may be amenable
to targeted treatment strategies.
 Chapter 4: Acute Liver Failure in Children

Pathogenesis into separate and distinct components. For example, findings

suggest that NK cells may have features associated with the
The liver is remarkably tolerant and unperturbed despite its
adaptive immune response such as “memory,” with rapid
engagement with “first-pass” exposure to xenobiotics, foreign
secondary expansion upon re-exposure to antigen that is asso-
proteins, endotoxins, and other potential hepatotoxic sub-
ciated with degranulation and cytokine production. Therefore,
stances. The initiation, potentiation, resolution, and recovery
while missteps in the liver’s overall tolerance of real or per-
of liver injury are efficient, complex, enigmatic, and redundant.
ceived pathogens rarely result in liver failure, understanding
How and why patients within the same diagnostic category,
these events will provide opportunities to extend our knowl-
such as autoimmune hepatitis, can have myriad presentations
edge of the interactions between the liver and its environment.
ranging from asymptomatic elevations of serum aminotrans-
ferases to fatal liver failure is yet to be determined. At the heart
of most models of liver injury rests an aberrant or exuberant Drug- and Toxin-Induced Injury
inflammatory or immune response. It will be through this prism Drug-induced liver injury causes approximately 16% of PALF,
that the discussion on pathogenesis will be viewed. with acetaminophen toxicity accounting for 80% of the drug-
induced cases. The mechanisms by which drugs cause liver
Hepatic Immunology injury vary. Early mechanistic studies in mice demonstrated
the formation of a reactive metabolite, which is responsible for
The liver is a central immunological organ with high exposure
hepatic glutathione depletion and initiation of the toxicity.
to circulating antigens and endotoxins [57]. In addition to
This insight led to the rapid introduction of NAC as a clinical
hepatocytes, an estimated 20–40% of the liver cell mass consists
antidote as it is known to promote glutathione restoration.
of endothelial cells, Kupffer cells, or hepatic macrophages,
However, more recently, substantial progress was made in
lymphocytes, biliary cells, and stellate cells. The immunologic
further elucidating the detailed mechanisms of APAP-
milieu that exists within the liver is notably different than that
induced cell death. Mitochondrial protein adducts trigger
of the peripheral blood compartment. The balance between
a mitochondrial oxidant stress, which requires amplification
CD8+ and CD4+ T cells favors CD8+ cells with effector/mem-
through a MAPK cascade that ultimately results in activation
ory cells more frequent in liver parenchyma than peripheral
of c-jun N-terminal kinase (JNK) in the cytosol and transloca-
blood. Natural killer T-cells (NKT cells) as well as NK cells are
tion of phospho-JNK to the mitochondria. The enhanced oxi-
more abundant in the liver where there is also a large source of
dant stress is responsible for the membrane permeability
gamma–delta T cells. Antigen-presenting cells may be conven-
transition pore opening and the membrane potential break-
tional (e.g., Kupffer cells, liver sinusoidal endothelial cells, and
down. The ensuing matrix swelling causes the release of inter-
dendritic cells) or unconventional (e.g., hepatocytes).
membrane proteins such as endonuclease G, which translocate
Both innate and adaptive immune responses are generated
to the nucleus and induce DNA fragmentation. These patho-
within the liver. However, given the hepatic enrichment by NK
physiological signaling mechanisms can be additionally modu-
cells, NKT cells, and Kupffer cells, it is not surprising that the
lated by removing damaged mitochondria by autophagy and
innate immune response predominates. Under normal cir-
replacing them by mitochondrial biogenesis. Although recruit-
cumstances, the lymphocyte-driven innate response provides
ment of inflammatory cells is necessary for removal of cell
a nimble but temperate reaction to pathogens that present to
debris in preparation for regeneration, these cells have the
the liver. Kupffer cells and other immune cells express pattern-
potential to aggravate the injury [58].
recognition receptors that detect and bind pathogen-
Additional aspects of hepatic injury resulting in drug-
associated molecular patterns expressed on the presumptive
induced, herbal-induced, and herbal and dietary supplement-
pathogen, which is then phagocytosed and quietly eliminated.
induced liver injury constitute an important and growing area
Activated CD8+ cells residing in the liver direct the immune
of active research, though much remains to be discovered in
response against bacterial and viral invasion. Priming of intra-
terms of mechanism. Areas that have recently garnered interest
hepatic T cells may occur within the liver without having to
include bile acid homeostasis, oxidative stress, mitochondrial
circulate through draining lymph nodes, thus expediting the
dysfunction, immune and inflammatory dysregulation, and
immune response. Hepatic NK cells serve to modulate the
lipophilicity [59].
inflammatory response by mediating the balance between
proinflammatory (T helper 1) and anti-inflammatory (T
helper 2) cytokines that are generated [57]. Vascular Injury
Adaptive immune responses involve both B and T cells. Acute liver failure can result from reduced or absent arterial
Very few B cells reside in the normal liver and thus little is blood flow to the liver. The insult can occur because of hemor-
known about their role except under pathologic conditions rhagic shock, trauma, sepsis, coarctation of the aorta, conge-
such as HBV and hepatitis C infections. Antigen-specific nital heart defects associated with low cardiac output,
CD8+ T cells generate an effector response that includes congestive heart failure, and liver transplant. Myriad processes
rapid proliferation coupled with the production of proinflam- are initiated following liver ischemia that include the release of
matory cytokines as well as initiation of cytolytic mechanisms pro- and anti-inflammatory cytokines and chemokines, com-
such as perforin and granzyme. Not unexpectedly, the redun- plement activation, along with the activation of both the innate
dancy of the human immune response cannot be easily divided and the adaptive immune response. Mitochondrial injury

45
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 Section I: Pathophysiology of Pediatric Liver Disease
resulting in ATP depletion and surge in toxic reactive oxygen
species contribute to the injury.
Liver failure associated with acute obstruction of hepa-
tic outflow is rare but has been described in patients later
found to have a coagulation disorder leading to
a hypercoagulable state; in patients with Behçet syndrome
or idiopathic Budd–Chiari syndrome; and in women
immediately postpartum [2].
Immune/Inflammatory Injury
The extent to which hepatic immune dysregulation in gen-
eral or immune-mediated liver injury in particular, together
with the systemic inflammatory response syndrome, is
involved in the pathogenesis of PALF is not known. And
yet, given the rich and varied hepatic immunologic environ-
ment, it would be expected that immune and inflammatory
mechanisms are involved in both the initiation and perpe-
tuation of PALF in most, if not all, cases. Liver cell injury
associated with viral hepatitis is not caused by direct injury
from the virus but rather from “collateral damage” asso-
ciated with a vigorous immune response to clear the virus
from the liver. Drug-induced liver injury may result in the
formation of neoantigens, consisting of reactive metabolites
of the offending drug coupled with cellular constituents that
induce an immune response.
The inflammatory response encompasses both injury
and healing through a dynamic duet between pro- and
anti-inflammatory responses [60]. Proinflammatory
responses are generated by immune effector cells, such as
Kupffer cells, B and T lymphocytes, and neutrophils,
releasing a host of proportioned chemokines, adhesins,
and cytokines. Dynamic network analyses on these inflam-
matory mediators have uncovered general “liver signatures”
that are associated with various outcomes in PALF [6, 14,
61]. The compensatory anti-inflammatory response is
initiated almost simultaneously to disengage the inflamma-
tory response through anti-inflammatory cytokines inter-
leukin-4, interleukin-10, transforming growth factor-β and
others to deactivate the cellular immune function and
reduce antigen-presenting capability. Exaggeration or dys-
regulation of either the pro- or anti-inflammatory
responses can result in increased mortality and susceptibil-
ity to sepsis and multi-organ dysfunction.
Liver Cell Regeneration
Following acute liver injury, survival and recovery is depen-
dent at least in part on the remarkable ability of the liver to
regenerate from injury. The evolution of liver injury in ALF
progresses through three phases; initiation, propagation, and
resolution. During initiation, hepatocyte injury stimulates
Kupffer cell activation and proliferation with release of inflam-
matory mediators [62]. These mediators recruit monocytes
and neutrophils to the liver which propagate the inflammatory
cascade at both the hepatic and systemic level.
Proinflammatory cytokines and TLR ligands, such as
HMGB1, stimulate monocytes to progress to the M1
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macrophage phenotype and inflammatory responses are per-
petuated [63]. During this phase, injured hepatocytes are
engulfed and DAMPs are neutralized. Ultimately, macro-
phages shift to a pro-resolution or M2 phenotype supporting
a microenvironment more conducive to hepatic regeneration.
Regulation of this shift is poorly understood, but prolongation
of the propagation phase is believed to be a fundamental aspect
of ALF with immune dysregulation [64]. Systemic inflamma-
tory response is a hallmark of the propagation phase of hepatic
injury and excessive, prolonged systemic inflammation has
been implicated in ALF-induced cerebral edema and ALF-
related multiple systems organ failure (MSOF) [65].
Prolongation or exaggeration of the proinflammatory response
could exceed what is required for stimulation of hepatocyte
and progenitor cell replication and create a tissue microenvir-
onment that causes direct secondary injury that is additive to
the original insult. Therapy that briskly dampens the inflam-
matory milieu to better support regeneration could fundamen-
tally change disease progression. Likewise, therapies that
directly promote regeneration, such as modulation of glycemic
response, could shift the balance in a favorable direction [66].
Finally, recognition of biomarkers, such as alpha-NH-butyric
acid, which accurately indicate the degree of regeneration,
would be of great benefit to clinicians appraising the need for
liver transplantation [67, 68]. Patients with a biomarker profile
predicting little or no regenerative ability may best be served by
transplantation, while those with a vigorous regenerative
response would hold some hope of recovery.
Liver Histology in Acute Liver Failure
Various patterns of histopathologic injury have been linked
to etiology in children with ALF (Table 4.5). Liver cell necro-
sis is a common characteristic of ALF resulting from viral
infections, most toxic and ischemic injuries, indeterminate
PALF, and some metabolic diseases. The degree of hepatocel-
lular necrosis and its histologic pattern (coagulative vs. con-
fluent) vary by cause and by individual case. Establishing
a pathologic diagnosis by liver biopsy has not been considered
critical in-patient management, largely because of the per-
ceived risks and, at times, the disappointing impact histology
has in altering the treatment strategy or establishing the
diagnosis. However, recent reports have looked to re-shape
the role of liver biopsy, demonstrating that they can be per-
formed safely, especially when the transvenous (e.g., transju-
gular) approach is feasible, and results used to guide diagnosis
and therapy [69].
Most liver samples from children with ALF show massive
confluent or multi-lobular necrosis (Figure 4.3). In many
specimens, it is difficult to identify any remaining viable
hepatocytes. The reticulin framework of the lobule is col-
lapsed, and the mass of the liver is small. A moderate inflam-
matory infiltrate, usually consisting mainly of neutrophils,
may be evident. In some patients, no evidence of regeneration
can be found; in others, there is proliferation of duct-like
structures that probably results from attempts at regenera-
tion. Non-icteric fulminant failure, some drug-induced liver
disease (e.g., acetaminophen), and hypoxic–ischemic
 Chapter 4: Acute Liver Failure in Children

Table 4.5 Patterns of Histopathologic Injury in Pediatric Acute Liver Failure hepatitis is characterized by sublobular necrosis, with orien-
tation of necrosis around central veins (Figure 4.4) [70].
Pattern Description Etiology
Diffuse hepatic steatosis is observed rarely in ALF in
Necrosis children. This lesion is characterized by hepatocellular fat in
a microvesicular pattern and is identical at a light-
Coagulative Minimal inflammation APAP
microscopic level to the hepatic lesion of Reye syndrome. In
Preserved Toxin adults, it is seen most often in fatty liver of pregnancy; in
architecture children, it is seen in association with toxic injury or inborn
Ischemia errors of metabolism (see “Etiology”). The absence of cell
necrosis in association with failure of liver function implies
Confluent Moderate/severe Viral
organelle failure as the cause. Hepatomegaly is often evident.
inflammation
Serum aminotransferase levels usually are elevated, but only
Few viable Drug to a mild to moderate degree (usually <400 IU/L). Jaundice is
hepatocytes minimal (serum bilirubin concentration usually <10 mg/dL),
Parenchymal collapse which suggests that certain organelle functions remain intact
and that bilirubin production probably is not increased. Full
Ductular reactivity Indeterminate histologic recovery is the rule if the patient survives.
with IHC with A third lesion, characterized by diffuse swelling of hepato-
CD103+CD8+ T-cell
cytes with condensation of organelles and cytoplasmic ele-
Steatosis Micro/Macrovesicular IEM ments (Figure 4.5), is seen in association with some inborn
fat errors of metabolism. Hepatocyte necrosis is spotty and usually
Little or no necrosis Mitochondrial not prominent. Macrovesicular fat with displacement of nuclei
is seen in a variable proportion of hepatocytes, sometimes
Swollen hepatocytes Aspirin (Reye a majority. This lesion suggests organelle injury that is
syndrome) severe enough to cause the death of some hepatocytes.
Organelle Valproate Aminotransferase levels and serum bilirubin levels are elevated
condensation moderately. Full histologic recovery is the rule if the metabolic
injury can be controlled.
Acute on Fibrosis AIH
chronic
In patients in whom ALF may be the initial presentation of
a more chronic condition, such as Wilson disease or auto-
Inflammation Wilson immune hepatitis, acute injury may be present on the back-
Cholestasis ground of chronic changes. The histological pattern may
include fibrosis, inflammation, and cholestasis.
PALF: pediatric acute liver failure; APAP: acetaminophen; IEM: inborn Finally, in many cases of indeterminate PALF, the his-
error of metabolism; AIH: autoimmune hepatitis. Adapted from Alonso
tologic picture may be dominated by a mixed inflammatory
et al. [6].
infiltrate consisting primarily of CD103+CD8+ T cells with

(a) (b)

Figure 4.3 Liver histopathology from a patient with indeterminate acute liver failure. (a) Transjugular biopsy at time of presentation shows confluent
necrosis with a little parenchymal inflammation. There were no viable hepatocytes evident in any of the several cores. This section shows some tubular
structures thought to represent attempted regeneration. (Hematoxylin & eosin, original magnification 200×.) (b) This reticulin stain shows focal collapse.
The distance between the central vein and portal area on the left is diminished, and the reticulin framework between is condensed. (Reticulin stain, original
magnification 100×.)

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 Section I: Pathophysiology of Pediatric Liver Disease
Figure 4.4 Hepatactomy specimen from a teenager who overdosed on
acetaminophen. The specimen showed extensive sublobular necrosis
throughout the liver. The central orientation of the necrosis is evident in this
section because of the hemorrhage in and around the central vein on the right.
The periportal zone is relatively spared, with a narrow rim of viable hepatocytes
seen around the portal triad in the upper left. Between the frank necrosis and
the rim of viable hepatocytes is a zone of hepatocyte injury notable by steatosis
and ballooning of marginally viable hepatocytes. (Hematoxylin & eosin, original
magnification 100×.)
a scattering of plasma cells, neutrophils, and eosinophils in
conjunction with hepatic necrosis [17] (Figure 4.6).
Fibrosis, which would suggest chronic disease, is not pre-
sent. The inflammatory infiltrate is not limited to the portal
tracks but can be found within the lobule and around the
central vein. Serum autoimmune markers may be present,
but often are not, and the underlying cause for the liver
injury may be over zealous T cell response that is poorly
checked by compensatory mechanisms.
Complications and Management
General Management Principles
Close collaboration between gastroenterology/hepatology,
intensive care, neurology, neurosurgery, nephrology, meta-
bolic disease specialists as well as transplant surgeons will
afford the child the best opportunity to survive. After the initial
characterization of the patient presentation, proper patient
management needs to be conducted along multiple parallel
paths: (1) monitor and support the patient and organ systems,
(2) identify and treat complications, (3) develop an age-
appropriate diagnostic prioritization strategy, and (4) treat
the patient to maximize health and survival [2].
Admission to a highly skilled nursing environment, which, in
most cases, will be an intensive care unit is essential and allows
frequent monitoring of mental status. A cardiorespiratory and
oxygen saturation monitor should not substitute for careful and
frequent bedside assessment by an experienced nurse or clini-
cian. 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,
increased respiratory effort, changing heart rate or changes in
blood pressure which might be signs of infection, increasing
cerebral edema, or electrolyte imbalance.
48
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Figure 4.5 Liver biopsy specimen from an infant with hereditary fructose
intolerance and hepatic failure. There is both diffuse hepatocyte necrosis and
steatosis, mainly macrovesicular. Other findings include pseudotubule
formation and condensation of organelles and cytoplasmic elements within
hepatocytes. Interlobular bile ducts also are injured, with irregular shape of
cholangiocytes and some vacuolization. The patient recovered normal liver
function within 5 days of eliminating fructose from the diet. (Hematoxylin &
eosin, original magnification 200×.)
Laboratory monitoring should include a complete blood
count, electrolytes, renal function tests, glucose, calcium, phos-
phorus, ammonia, coagulation profile, total and direct biliru-
bin, and blood cultures. Diagnostic laboratory studies should
be prioritized. While arterial ammonia measurement is ideal, it
is not practical in children with stage 0–II HE; venous ammo-
nia obtained from a free-flowing catheter and promptly placed
on ice and transported to the laboratory may be a suitable
substitute. Placement of central venous catheters can ensure
an uninterrupted glucose source reducing the risk of critical
hypoglycemia.
In the absence of the need for volume resuscitation,
total intravenous fluids should initially be restricted to
between 85% and 95% of maintenance fluids to avoid
overhydration yet still provide sufficient glucose and phos-
phorus to achieve normal serum values. Adjustment in
fluid rates are based upon the clinical conditions, but
relative fluid restriction should be an underlying principle.
Nutritional support, including protein, should be provided
if the patient can eat safely or with intravenous nutritional
support. Some protein restriction may be necessary, but it
should not be eliminated.
Central Nervous System
Encephalopathy
Hepatic encephalopathy is a neuropsychiatric syndrome
associated with hepatic dysfunction. Changes in behavior,
cognition, neurological examination, and electroencephalo-
graphy (EEG) are used to characterize the patient as having
one of five clinical stages of HE ranging from stage 0 with
minimal or no evidence of neurological dysfunction to stage
IV coma (Table 4.6) [71]. Clinical staging of HE was origin-
ally developed to assess patients with cirrhosis and not ALF,
but in the absence of a better clinical tool, use of the current
 Chapter 4: Acute Liver Failure in Children

Table 4.6 Stages of Hepatic Encephalopathy

Stage Clinical Reflexes Neurologic signs Electroencephalography

changes
0 None Normal None Normal
I Infant/child: inconsolable crying, Normal or No focal findings but Normal or mild slowing
inattention to task, not acting like hyper-reflexic responses may be
self to parents poor sleep delayed
Adult: confused, mood changes, Normal Tremor, apraxia, impaired Normal or diffuse slowing to
altered sleep habits, forgetful handwriting theta rhythm, triphasic waves
II Infant/child: inconsolable crying, Normal or No focal findings, delayed Mild/moderate background
inattention to task, not acting like hyper-reflexic responses and shortened abnormalites, focal slowing
self to parents attention span, trajectory
of neurologic signs critical
Adult: drowsy, inappropriate Hyper-reflexic Dysarthria, ataxia Abnormal, generalized
behavior, decreased inhibitions slowing, triphasic waves
III Infant/child: somnolence, stupor, Decreased, Progressive decrease in Mild/moderate background
combativeness absent, or response to external stimuli abnormalites, absense of sleep
increased architecture, focal slowing
Adult: stuporous, obeys simple Hyper-reflexic, Rigidity Abnormal, generalized
commands (+) Babinski slowing, triphasic waves
IV Infant/child: comatose, arouses Decreased, No response to voice or Severe attentuation or slowing
with painful stimuli (IVa) or no absent, or noxious stimuli; brainstem
response (IVb) increased reflexes decreased or
absent
Adult: comatose, arouses with Absent Decebrate or decorticate Abnormal, very slow, delta
painful stimuli (IVa) or no response activity

Figure 4.6 Representative images for double staining with CD8 (red) and CD103 (brown) from PALF case at x10 and x60 magnification.

scoring system has been found to have important clinical and
prognostic implications as mortality has been shown to be
highest in those children who develop grade III and IV HE [4,
19]. The clinical assessment of HE is particularly difficult in
infants and children. Recognition of the subtle impairments
of memory, concentration and mood that are characteristic of
stage I and II HE in infants and children depends on the
experience and skill of the examiner. Multiple modalities
have been used to enhance assessment of neurological func-
tion, such as visual evoked potentials, trans-cranial Doppler,
cerebral near-infrared spectroscopy, and serum biomarkers.
Electroencephalogram (EEG) background abnormalities can
help predict risk of death or need for LT in children with ALF
[72], but this requires a trained neurologist or neurophysiol-
ogist to interpret the EEG. Spectral or quantitative EEG
(sEEG) uses computational analysis to generate

49
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 Section I: Pathophysiology of Pediatric Liver Disease
a quantitative analysis of brain function with minimal inter-
operator variability and can be implemented at the bedside.
A recent single center study in children suggested that sEEG
may be a quantitative tool to allow improved detection and
tracking of encephalopathy in pediatric patients, but future
multi-center validation of these findings is required [73].
Further studies are needed to improve early detection of
neurologic injury, standardize management of seizures and
HE, and to determine whether such interventions improve
outcomes.
Some degree of encephalopathy was present on admission
in 50% of children with ALF entering the PALFSG study, and
64% developed HE within the first seven days following entry
into the study [4]. Children with liver failure should be
assessed frequently as neurological deterioration can be
devastatingly rapid. Distinguishing hepatic-based encephalo-
pathy from other causes of an altered mental status such as
sepsis, hypotension, electrolyte disturbances, anxiety or
“intensive care unit psychosis” is difficult for all age groups.
Hyperammonemia plays a central role in the development of
HE in most cases. However, a specific level of ammonia does
not result in a predictable degree of encephalopathy. Initial
treatment would include minimizing excess stimulation,
reducing protein intake, treating suspected sepsis, and
removing sedative medications that would affect mental sta-
tus. Medical therapy with lactulose is used empirically but
lacks evidence of efficacy. Bowel “decontamination” with
rifaximin or neomycin can be used as a second-tier treatment,
but ototoxicity and nephrotoxicity are potential risks when
neomycin is used. Additional ammonia removal with phar-
macological treatment and, in the most severe cases, extra-
corporeal therapies have been trialed, but efficacy studies are
limited.
Not all patients with HE develop a clinically important
increase in intracranial pressure. However, those that do can
experience devastating consequences. Direct intracranial pres-
sure monitoring is the most sensitive and specific test com-
pared with less invasive neuroradiographic procedures, such as
cranial CT. Monitoring of intracranial pressure remains con-
troversial because of the associated complications of the pro-
cedure and of the difficulty demonstrating improved survival
for those who were monitored within small single center
experiences [74].
Both generalized and focal seizures may occur in children
with ALF. The frequency of non-convulsive (electrographic)
seizures in this population has not been studied in detail and
their impact on neurologic outcome is not known. However,
convulsive and non-convulsive seizures are known to occur
during a critical illness. Treatment typically begins with
a benzodiazepine as the first line agent followed by phenytoin
with increasing adoption of levetiracetam. Practices are vari-
able and there is no definitive standard of care. For seizures
that are refractory to the initial second-line agent, therapeutic
options may include midazolam infusion, phenobarbital,
levetiracetam, or topiramate. The selection of drug will
depend on the patient’s mental status, physiologic stability,
availability of EEG monitoring to titrate drug infusions, and
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institutional experience. Given the association of valproate
with mitochondrial toxicity, this drug should be avoided,
particularly when the etiology of ALF is not known and
POLG-1 mitochondrial disease has not been excluded as
a potential cause.
Cerebral Edema
Cerebral edema is a life-threatening complication of ALF. It
occurs most commonly in those with advanced encephalopa-
thy (grade III or IV) and can be rapidly progressive. Detection
of cerebral edema in the early stages is difficult as non-invasive
assessment with clinical assessment or radiographic studies
may not be sufficiently sensitive. The most sensitive test
requires surgical placement of an intracranial pressure (ICP)
monitor which carries its own risk for the patient with an
uncorrectable coagulopathy and carries a risk of bleeding
between 10% and 20%, although it is often minimal. Use of
activated factor VII in recent years has made placement of ICP
monitors somewhat safer. However, once in place and properly
functioning, intracranial pressure monitoring is useful to
assess response to treatment of increased cerebral pressure
and during surgical procedures, including liver transplanta-
tion, to gauge fluid and medical management of the uncon-
scious patient.
The pathogenesis of cerebral edema is complex, involving
the interaction among ammonia, cerebral blood flow, gluta-
mine production, and inflammation [75]. Elevated levels of
ammonia are generated because of the failing liver which
leads to increased intracerebral concentrations. Ammonia
enters the astrocyte which is rich in glutamine synthetase.
Conversion of ammonia and glutamate to glutamine,
a potent intracellular osmolyte, results in an osmotic gradient
that favors astrocyte swelling that contributes to cerebral
edema and intracranial hypertension. The tight regulation
of cerebral blood flow is tested in the setting of ALF.
Alterations in systemic and intracranial vascular resistance,
coupled with restrictions to blood flow due to edema, make
estimates of an “ideal” cerebral perfusion pressure (mean
arterial pressure minus intracranial pressure) difficult.
Changes in the inflammatory milieu, sepsis, fluid or blood
product administration and other factors can result in
a sudden and often unanticipated increase in intracranial
pressure and its consequences.
Management of cerebral edema involves meticulous sup-
portive management to maintain oxygen saturation above
95%, fluid restriction between 85% and 90% of maintenance,
diastolic pressure >40 mmHg, adequate sedation, head eleva-
tion of 20–30° and neutral head position, and consideration
of empiric broad spectrum antibiotics to minimize the devel-
opment of bacterial infection [76]. Therapies targeted speci-
fically to improve cerebral edema have not met scientific
rigor, but they include hypertonic saline to maintain serum
sodium between 145 meq/L and 150 meq/L, and mannitol
keeping serum osmolarity <320 mOsm/L to create a more
favorable osmotic gradient to extract water from the brain.
Hypothermia has been used in adults with ALF with some
success.

Hematologic System
Coagulopathy
Both prothrombin time (PT) and INR are used in virtually all
prognostic schemes to assess the severity of liver injury in the
setting of ALF; however, a prolonged INR is not a measure of
bleeding risk in patients with PALF [77]. In patients with ALF,
both procoagulant proteins (e.g., factors V, VII, and X and
fibrinogen) and anticoagulant proteins (e.g., antithrombin,
protein C, and protein S) are reduced [77, 78]. This balanced
reduction in the pro- and anticoagulant proteins may account
for the relative infrequency of clinically important bleeding in
the patient with ALF in the absence of a provocative event such
as infection or increased portal hypertension. Indeed, some
patients may have manifestations of a hypercoagulable state
such as portal vein thrombosis [79]. Therefore, the PT/INR
may reasonably reflect the reduction of some of the liver-based
coagulation proteins but not the relative risk of bleeding.
Newer assays of coagulation such as thromboelastography
(TEG), rotational thromboelastometry, and thrombin genera-
tion assays provide additional insight into coagulation pro-
cesses but their role in the setting of PALF remain unclear
[77, 80]. Efforts to “correct” the PT/ INR with fresh frozen
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.
Assurance of adequate vitamin K can be accomplished by
intravenous infusion.
Aplastic Anemia
Hepatitis-associated aplastic (HAA) anemia is a bone marrow
failure, characterized by a spectrum of features ranging from
mild pancytopenia to aplastic anemia, that occurs in approxi-
mately 8% of children with ALF. It is identified most com-
monly in the setting of indeterminate ALF and may not be
clinically evident until after emergency liver transplantation.
The clinical phenotype of hepatitis preceding HAA is indis-
tinguishable from that of patients without bone marrow sup-
pression, but patients who ultimately develop HAA have lower
absolute lymphocyte counts at presentation [82]. A recent
histopathology study identified central vein luminal oblitera-
tion reminiscent of sinusoidal obstruction morphology, in
combination with CD8+ dominant lobular infiltrates [81].
Treatment of HAA includes immunomodulatory medications
such as corticosteroids, cyclosporine A, tacrolimus, anti-
lymphocyte or anti-thymocyte globulin as well as hematopoie-
tic stem cell transplant [17].
Gastrointestinal System
Ascites
Ascites develops in some but not all patients. Precipitating
factors include hypoalbuminemia, excessive fluid administra-
tion, and infection. The primary treatment is fluid restriction.
Diuretics should be reserved for patients with respiratory
compromise or generalized fluid overload. Overly aggressive
diuresis may precipitate hepatorenal syndrome.
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Chapter 4: Acute Liver Failure in Children
Bleeding
Gastrointestinal bleeding occurs surprisingly infrequently given
the degree of coagulopathy. Prophylactic 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 use of non-steroidal anti-
inflammatory medications, or idiopathic gastroduodenal ulcera-
tion. Infection can precipitate bleeding in this vulnerable popu-
lation, so blood cultures and initiation of antibiotics should also
be considered when bleeding develops. Administration of plate-
lets, blood, and plasma is necessary if bleeding is hemodynami-
cally significant.
Pancreatitis
Biochemical and clinical pancreatitis is increasingly recognized
as a condition associated with multisystem failure in critically
ill children. In patients who develop pancreatitis in the setting
of ALF, glucose and fluid management may become even more
challenging.
Renal System
Evidence of renal insufficiency and ALF on admission should
be assessed for evidence of a medication or toxin as the pre-
cipitating cause. Prerenal azotemia can develop if fluid restric-
tion is too excessive for the patient’s needs. Acute deterioration
of renal function after presentation with ALF may result from
systemic hypotension in sepsis or hemorrhage. Hepatorenal
syndrome is a feared renal complication associated with ALF,
although it occurs more commonly in the setting of chronic
liver disease with established cirrhosis. Hepatorenal syndrome
can progress rapidly over the course of two weeks (type I) or
more slowly (type II) [83]. 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 expan-
sion. Urine sodium is typically low. Renal replacement therapy
with continuous venovenous hemofiltration or dialysis may be
necessary in some patients, but only liver transplantation can
reverse hepatorenal syndrome. Patients who present simulta-
neously with both ALF and renal dysfunction may have sus-
tained a toxic injury (e.g., acetaminophen, solvent, drugs) or
have Wilson disease.
Metabolic Disorders
Hypoglycemia results from impaired gluconeogenesis and
depleted glycogen stores. Glucose infusion rates as high as
10–15 mg/min per kg body weight may be required to achieve
stable serum glucose levels (between 90 and 120 mg/dL) 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 phos-
phorus should be monitored frequently as hypophosphate-
mia can be profound. When present, phosphorus repletion
may be needed to keep levels above 3 mg/dL [2]. Acid-base
disturbances can be complicated with respiratory alkalosis
from hyperventilation, respiratory acidosis from respiratory
51
 Section I: Pathophysiology of Pediatric Liver Disease
failure, metabolic alkalosis from hypokalemia, and metabolic
acidosis from hepatic necrosis, shock, and increased anaero-
bic metabolism.
Infections
Patients with ALF have an enhanced susceptibility to bacterial
infection and sepsis from immune system dysfunction [2].
Evidence of infection may be subtle, such as tachycardia,
intestinal bleeding, reduced renal output, or changes in mental
status. Fever may not be present. Blood cultures should be
obtained with any evidence of clinical deterioration and anti-
biotics initiated with a clinical concern for sepsis due to gram-
positive or gram-negative organisms.
Cardiopulmonary System
Excessive fluid administration contributes to pulmonary
edema and should be avoided. Careful fluid restriction and
discrete use of diuretics may be needed in some instances but
should be used with caution. Central venous pressure monitor-
ing may assist in assessing volume needs for the child.
Ionotropic support may be needed to maintain perfusion of
vital organs.
Nutrition
Nutrition support should be maintained to avoid a catabolic
state. If it is not safe for the child to receive oral or enteral
feeding, intravenous alimentation should be initiated to pro-
vide at least 1 g/kg protein daily. Adjustment in the protein
allotment may be needed based on the serum ammonia.
Micronutrients such as copper and manganese should be
reduced or eliminated in patients with liver disease while
chromium, molybdenum, and selenium should be reduced or
eliminated if renal disease is also present.
Liver Support
Various iterations of extracorporeal liver support systems have
been investigated in children with ALF to determine if they
might have a measurable impact on clinical outcome.
Unfortunately, virtually all of them have fallen short of the
mark or have been underpowered to assess benefit. Therefore,
they cannot be routinely recommended [84].
Plasmapheresis/Plasma Exchange
Plasmapheresis facilitates the removal of suspected toxins in
the blood to facilitate a milieu in which the liver might
recover or regenerate. Evidence of its usefulness in children
with ALF is sparse, and while coagulation profiles may
improve, the procedure has not been shown to improve neu-
rologic outcome or ability of the liver to recover sponta-
neously. Case reports and case series have suggested these
strategies can serve as a bridge to transplant by improving
coagulation and other biochemical parameters, if only tem-
porarily [84–86]. However, in adults, a recent multicenter,
randomized controlled trial compared 90 participants who
received standard medical therapy with 90 who received
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standard medical therapy plus three days of plasma exchange.
Those who received plasma exchange experienced improved
transplant-free survival. Systemic inflammatory response
syndrome (SIRS) and sequential organ failure assessment
(SOFA) scores fell in the treated group compared to control
group [87]. Similar studies should be performed in children.
One potential disadvantage of this procedure is the non-
selective removal of potentially helpful substances such as
hepatocyte growth factor. The use of selective filters to facil-
itate retention of this potentially beneficial substance would
make this therapy more attractive.
Molecular Absorbent Recirculating System
The molecular adsorbent recirculating system is an elaborate
detoxification system in which a membrane with albumin-
related binding sites separates the patient’s blood from an
albumin dialysate. Albumin-bound substances, such as bilir-
ubin, aromatic amino acids, and endogenous benzodiaze-
pine-like substances, can be transferred to 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 dialysate. The system has been used to
bridge patients with severe liver injury from trauma to
spontaneous recovery [88]. Recent experience in the setting
of PALF demonstrated safety and feasibility as well as
improvements in biochemical parameters such as ammonia,
bilirubin, and creatinine; however, small sample size and
patient heterogeneity precluded a statistical analysis for ben-
efit [89].
Disease Severity Assessment
Once PALF is identified, there are currently no reliable tools to
predict survival or death. Biochemical tests (lactate, total bilir-
ubin, phosphorus, INR, PT, ammonia, vitamin D-binding
protein (Gc-globulin)), clinical features (encephalopathy, cer-
ebral edema), diagnosis (acetaminophen), or combinations of
the three have been tried without reliable success. Existing liver
failure scoring systems, including the King’s College Hospital
Criteria, the Clichy Score, the Model for End-Stage Liver
Disease Score, the Pediatric End-Stage Liver Disease Score,
and the Liver Injury Unit Score, fall well short of the ideal
prognostic tool [2, 71]. Major shortcomings include the com-
mon practice of combining death and liver transplant into
a single outcome, when there is broad agreement that some
patients who received a liver transplant would have survived
had their clinical course not been interrupted by surgery.
Models such as the King’s College Hospital Criteria and the
Liver Injury Unit Score were unable to be validated when the
outcomes of death and liver transplant were separated [90, 91].
Examination of dynamic inflammatory networks measured
serially during the first week does appear to segregate out-
comes of death and survival without transplantation. In that
analysis, those who received a liver transplant had an inflam-
matory network that appeared to have features common to
both those who died and those who survived [13, 61]. Using
a growth mixture model that included clinical data (INR,

encephalopathy, total bilirubin) collected over seven days, five
different trajectories were generated with differing likelihoods
for death or survival [19]. Other models using the trajectory of
data collected over time suggest dynamic models hold some
promise [92, 93].
Liver Transplant
Liver Transplant Decisions
Liver transplantation is often lifesaving when a condition
without specific therapy is irreversible or fails to respond
to treatment. At the same time, liver transplant is also
irreversible and has profound consequences both on
organ allocation as well as the recipient and family. The
high frequency of liver transplant when the diagnosis is
uncertain, coupled with children removed from the liver
transplant list through clinical improvement before an
organ became available, raises the possibility that liver
transplant may proceed in situations in which spontaneous
recovery may have occurred. Long-term outcomes follow-
ing liver transplant for PALF are less favorable than when
liver transplant is performed for chronic liver diseases such
as biliary atresia. This is likely because of multiple factors
including the severity of illness at the time of transplant
and the possibility that the transplant was performed in
circumstances in which death was inevitable regardless of
the intervention. Listing children with ALF for liver trans-
plant has decreased steadily over time [20]. There are likely
multiple contributing factors associated with this finding.
Improvements in the directed therapies and supportive
care [94, 95], improved health care provider experience in
managing the complexity of PALF, recommendations for
age-appropriate evaluations in PALF [6], and published
diagnostic strategies and practice guidelines [44] collec-
tively have enhanced the care afforded to these critically
ill patients. While difficult to quantitate, these factors have
assuredly impacted the multifaceted decisions surrounding
the pursuit of liver transplantation as a therapeutic option.
Still, a more reliable modeling scheme is needed to readily
and effectively distinguish the patient who would die from
the one who would survive without liver transplant and to
recognize when it would be futile to proceed with liver
transplant.
Liver Transplantation
Liver transplantation has undoubtedly improved overall survi-
val for children with ALF. The frequency of transplant in the
setting of PALF has decreased since 2000, and currently is
performed in approximately 38% of patients [2]. Outcome
following liver transplant for both patient and graft survival
has improved, but remains lower than patients receiving trans-
plant for chronic cholestatic diseases [2]. Living donor liver
transplant for children with ALF and concurrent multi-organ
failure is associated with improved 30-day and six-month
survival compared with recipients of a deceased donor liver
allograft [96]. Improved outcome for patients receiving a living
donor liver transplant is likely related to a reduced cold
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Chapter 4: Acute Liver Failure in Children
ischemia time and wait time, resulting in a more expeditious
time to transplant for these seriously ill children. Auxiliary
liver transplant has been used as a “bridge” to provide needed
time for the native liver to regenerate, but challenges remain as
to the timing for withdrawal of immunosuppression and invo-
lution of the transplanted graft [97]. For those patients who
received a liver transplant, neurocognitive testing has identi-
fied deficits in executive functions, fatigue, motor skills, atten-
tion, and health-related quality of life [98].
Hepatocyte Transplant
Pediatric acute liver failure represents a unique opportunity for
liver cell therapy. Here, hepatocyte transplant aims to tem-
porarily improve liver function by supplementing approxi-
mately 5–10% of the native liver volume with donor
hepatocytes and allow the natural regenerative capacity of the
liver to proceed or to stabilize and bridge affected patients to
more traditional liver transplant. Indeed, published experi-
ences of hepatocyte transplant in the treatment of ALF have
shown promising results; however, hepatocyte transplant has
yet to reliably circumvent the need for traditional organ trans-
plant in ALF [99].
Outcomes
In the pre-transplant era, PALF was a devastating condition
with mortality rates ranging from 70% to 95% [100, 101]. More
recently, advances in diagnostic approaches, management stra-
tegies, and surgical techniques have led to improved outcomes
for these critically ill children [1, 20].
Findings from the PALFSG study reveal that outcomes
vary by diagnosis, age, and degree of encephalopathy [1, 5,
20, 41]. Spontaneous survival or survival with their native
liver was highest amongst those with ALF caused by acet-
aminophen. Spontaneous survival occurred less frequently
for those with ALF caused by metabolic disease or drugs
other than acetaminophen, and in indeterminate ALF. As
might be expected, those with higher coma scores had
lower spontaneous survival. Unexpectedly, patients within
the PALFSG without detectable HE were also at risk of
death, presumably due to associated multi-organ system
failure or complications related to secondary bacterial
infection. This observation emphasizes the need for meti-
culous supportive care, even in patients with minimal HE.
For children with an established diagnosis, a lower percen-
tage underwent liver transplant compared to those with an
indeterminate diagnosis. Therefore, children who do not
have a specific diagnosis are more likely to be listed for
and receive a liver transplant. The major causes of death
for all who do not receive a liver transplant include multi-
organ system failure, cerebral edema and herniation, and
sepsis.
Both early and late graft loss and death are higher among
children who undergo liver transplantation for ALF than for
those with chronic liver disease. Reasons for these findings are
uncertain, but one possibility is the immune dysregulation that
may be associated with PALF, which could lead to increased
susceptibility to infection or graft rejection.
53
 Section I: Pathophysiology of Pediatric Liver Disease
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