Acute Liver Failure in Children

Review Article
Acute Liver Failure in Children
Joel B. Cochran, DO and Joseph D. Losek, MD
Objective: To review the incidence, etiologies, pathophysiology,
and treatment of acute liver failure (ALF) in children. Emphasis
will be placed on the initial management of the multiple organ
system involvement of ALF.
Method: MEDLINE search from 1970 to March 2005 was
performed. Search headings were as follows: acute liver failure,
fulminant liver failure, pediatric liver failure, hepatic encephalopathy, and liver transplantation. Studies written in English were
selected. Pediatric studies were emphasized. Adult studies were
referenced if there were no pediatric studies available in regard to a
specific aspect of liver failure.
Conclusions: Pediatric acute liver failure is a rare but lifethreatening disease. The common etiologies differ for given age
groups. Management includes treating specific causes and supporting multiple organ system failure. Commonly associated disorders
that require initial recognition and treatment include energy
production deficiencies (hypoglycemia), coagulation abnormalities,
immune system dysfunctions, encephalopathy, and cerebral edema.
Criteria used to determine the need for liver transplant are reviewed
as well as the difficulties associated with predicting which patients
will meet these criteria and how rapidly liver transplant will become
the only option. Finally, experimental procedures that may provide
additional time for the liver to recover are briefly reported.
Key Words: acute liver failure, multiple organ system
A
cute liver failure (ALF) is classically described as severe
liver injury in a patient without a previous history of liver
disease who develops encephalopathy within 8 weeks of the
initial symptoms.1 This definition can be problematic in
children who may or may not develop encephalopathy in the
course of their ALF. Therefore, a more applicable definition of
ALF in children is a multisystem disease process in a patient
with severe liver dysfunction who had not had a previous
history of liver disease.2
The true incidence of ALF in children is not known.
Approximately 675 pediatric liver transplants are done in the
United States each year, of which 10% to 13% are done
secondary to ALF.3,4 However, these numbers do not account
for most children who recover without liver transplant.
Pediatric Department, Medical University of South Carolina, Charleston, SC.
Address correspondence and reprint requests to Joseph D. Losek, MD,
Division of Emergency/Critical Care, Pediatric Department, Medical
University of South Carolina, 135 Rutledge Ave, PO Box 250566,
Charleston, SC 29425. E-mail: [email protected]
Copyright n 2007 by Lippincott Williams & Wilkins
ISSN: 0749-5161/07/2302-0129
The etiology of ALF varies with age (Table 1). The most
common causes in neonates are metabolic abnormalities,
neonatal hemochromotosis, acute viral hepatitis, and unknown
causes.5 In children older than 1 year viral hepatitis, drugs and
unknown causes are the most common etiologies.6,7
The diagnosis of ALF can be difficult if obvious signs of
jaundice have not developed. There is usually a prodrome of
malaise, nausea, emesis, and anorexia. Progressive jaundice
develops and encephalopathy can occur hours to weeks later.
The classic adult symptoms of asterixis, tremors, and fetor
hepaticus (the peculiar breath odor of patients with severe liver
disease) are often absent in children. Because both ALF and
sepsis are associated with multiple organ system failure,
differentiating between the two can be difficult.
The purpose of this report is to review the management
of the multiple organ system dysfunctions associated with
ALF in children. These will include energy production
deficiencies, coagulation abnormalities, immune deficiencies, encephalopathy and cerebral edema. Emphasis will be
give to the initial medical treatment, and the difficulties
determining when liver transplant becomes the only option.
ENERGY PRODUCTION DEFICIENCIES
The liver is the key organ in the production and the
distribution of nutrients in fasting and fed states.8,9 The liver
uses 20% to 25% of the body’s energy requirements.10 In
ALF, there can be an 80% to 85% loss of hepatocyte mass,
but hepatic energy requirements are not decreased. This is
likely due to the systemic inflammatory response to ALF
even in the absence of sepsis.11 Liver failure often results in
impaired glycogen storage and a diminished ability for
gluconeogenesis.12 Fat and protein stores are used, and this
can lead to breakdown of muscle and adipose tissue. Insulin,
glucagon, and growth hormone levels are increased which
further leads the catabolic drive for gluconeogenesis.8
Hypoglycemia becomes a persistent problem and causes
increased pancreatic glucagon synthesis and subsequent
muscle protein catabolism and release of amino acids.
Therefore, ALF needs to be considered in children who are
found to be hypoglycemic and, likewise, children who are
diagnosed with ALF need to be closely monitored for
hypoglycemia. It has been shown that energy expenditure in
ALF is still increased despite sedation, analgesia, muscle
paralysis, and mechanical ventilation.13
COAGULATION ABNORMALITIES
Coagulation abnormalities can be significant in patients with ALF. The production of multiple clotting factors
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Pediatric Emergency Care Volume 23, Number 2, February 2007
Cochran and Losek
TABLE 1. Etiology of ALF in Children
Younger than 1 yr (80)
Etiology
1 yr and older (146)
Percentage
Metabolic
Type I tyrosinemia
Mitochondrial
Urea cycle disorder
Galactosemia
Fructose intolerance
Neonatal hemochromatosis
Undetermined
Viral hepatitis
Other
42
16
16
15
10
Etiology
Percentage
Unknown
Viral hepatitis
Hepatitis non-A and non-B
Hepatitis A
Hepatitis B
Drug induced
Other
47
27
10
4
10
2
IMMUNE DEFICIENCIES
remaining contraindications to liver transplant.28,29 Levels
and function of complement are reduced in children with
ALF.18,30 Neutrophil adherence and killing function are also
reduced.18,31 Kupffer cells are dysfunctional in ALF.32 These
cells help clear gut derived endotoxins from the portal
circulation and prevent the release of cytokines into the
portal circulation. In a study of children with ALF, 43% had
bacteremia.33 The etiology for most infections is Staphylococcus aureus, but in 1 study,34 nearly one third of the
infections were fungal.
Patients with acute liver failure and serious infections
often do not show the classic signs of fever and laboratory
results of leukocytosis. This is likely secondary to the altered
immune response that increases the risk of infection in acute
liver failure patients. Because ALF and sepsis are associated
with multiple organ system failure and sepsis is a
complication of ALF, it may be difficult to differentiate
one from the other.
Several studies have looked at methods of prophylaxis
against bacterial infections in ALF. In a combined adult and
pediatric study, 58% of the patients who did not receive
prophylactic antibiotics developed bacterial infections compared with 35% who did receive prophylactic antibiotics.34 In a
study of 101 adult patients with ALF, patients were divided into
groups that did or did not receive prophylactic antibiotics at the
time of admission.29 The patients randomized to receive
prophylactic intravenous antibiotics, or a combination of
intravenous and oral antibiotics, had statistically less infections
than those given antibiotics at the time of clinical suspicion.
Those patients who received prophylactic antibiotics had a
significantly better chance of receiving a liver transplant when
they met transplant criteria versus those who did not receive
prophylactic antibiotics. Antibiotics used for prophylaxis in
these studies were either intravenous cefuroxime alone or with
amphotericin B. After blood cultures, the initiation of
cefuroxime should be considered in children with ALF.
Infection is a major cause of morbidity and mortality in
patients with ALF.26 Infection has been found to be the
primary cause of death in 11% to 20% of patients with
ALF.26,27 Also extrahepatic sepsis is one of the few
There are multiple potential mechanisms that lead to
the encephalopathy and cerebral edema seen in ALF. A key
important in hemostasis is reduced. There is also the
consumption of clotting factors and platelets secondary to
disseminated intravascular coagulation. Qualitative platelet
abnormalities are also seen in acute liver failure.14,15
Correcting the coagulopathy in ALF has historically
involved the transfusion of fresh frozen plasma (FFP), platelets,
cryoprecipitate, and packed red blood cells. However, the use of
these products often does not correct the coagulopathy.16
Supplemental doses of vitamin K also do not improve the
coagulopathy in acute liver failure.17 Vitamin K is a cofactor,
and the underlying problem in ALF is decreased synthesis of
clotting factors, not vitamin K deficiency. Fresh frozen plasma
is of limited benefit in correcting the coagulopathy in ALF. The
use of FFP should be discouraged unless there is active
hemorrhage, or the patient is hemodynamically unstable.18
Problems associated with the use of FFP include the volume
overload to the patient, risk of transmission of infectious agents,
short duration of action, and the unknown composition of this
pooled product.19
Factor VII is the primary initiator of the hemostatic
process.19 It has the shortest half-life of the vitamin K
dependent factors, therefore is the first factor depleted in
ALF.8,20,21 Recombinant factor VII (rFVIIa) helps form a
stable clot by establishing complexes with exposed tissue
factor, and it also enhances platelet activation.22 The rFVIIa
has several advantages over FFP and other blood products. It
is a recombinant product, therefore it does not pose an
infectious disease transmission risk. It is given in very small
volumes, and its duration is dose dependent. Dosage
recommendations vary from 5 to 110 mg/kg. A dose of 80
mg/kg can normalize the prothrombin time up to 12 hours.20
The rFVIIa should be considered in pediatric ALF patients
with hemorrhagic shock or before invasive procedures such
as liver biopsies.23 – 25
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HEPATIC ENCEPHALOPATHY
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Pediatric Emergency Care Volume 23, Number 2, February 2007
factor is ammonia.35 The liver’s ability to metabolize
ammonia is reduced during acute failure. This results in
hyperammonemia which is associated with the development
of encephalopathy and cerebral edema.
Nearly half the ammonia in the gut is produced by
colonic bacteria.36 Bowel cleansing may be helpful in
decreasing the amount of ammonia in the gut by decreasing
the colonic bacterial counts.35 Agents used for bowel cleansing
include poorly absorbed enteral disaccharides and antibiotics.
Most of the studies have used lactulose and neomycin, but
other disaccharides and antibiotics have been studied as
well.37,38 Virtually, all the studies have looked at these
compounds in the setting of chronic liver failure. The treatment
in ALF should be similar but is only minimally effective.37
The role of naturally occurring benzodiazepines may be
involved in the development of hepatic encephalopathy.39
Endogenous benzodiazepinelike substances and receptors
have been found in patients with ALF.40 However, benzodiazepine antagonists have been shown to only have intermittent
and short-lived benefits in hepatic encephalopathy.36
Two additional measures to decrease the production of
ammonia include dietary protein restriction36 and urea cycle
activation agents.37 In ALF, unlike chronic liver failure,
protein restriction is possible because patients are less likely
to be malnourished, at least initially. Activation of the urea
cycle may also decrease the ammonia load. Ornithine
aspartate provides substrates for ureagenesis and glutamine,
both of which can help remove ammonia from the portal
blood.37
Hepatic encephalopathy of ALF has been classified
into grades 1 to 4B (Table 2). Children with grades 3, 4A,
and 4B are likely candidates for liver transplantation.6
Therefore, prearranged transfer agreements to pediatric liver
transplant centers are recommended for medical centers
which do not provide a liver transplant service. Such
agreements are likely to reduce the risk of treatment delays
during the initial management of the child with ALF.
CEREBRAL EDEMA
Increased intracranial pressure (ICP) is common in
ALF and is the major cause of death.41,42 Cerebral edema has
been found in up to 80% of patients dying from ALF.43 The
mechanism of cerebral edema in ALF is unknown. Cerebral
edema is not the direct result of hepatic encephalopathy.44
Two basic theories have been proposed to help understand
the development of cerebral edema: the glutamine hypothesis and the cerebral vasodilatation hypothesis.41
TABLE 2. Classification of Hepatic Encephalopathy Adapted to
Infants/Children
Grade 1: confused, mood changes
Grade 2: drowsy, inappropriate behavior
Grade 3: stuporous but obeys simple commands or sleepy but
arousable
Grade 4A: comatose but arousable with painful stimuli
Grade 4B: deep coma, not arousable with any stimuli
Acute Liver Failure in Children
In ALF, the liver is unable to metabolize ammonia, and
it enters the brain circulation. In the brain, ammonia is
detoxified by the conversion of glutamate to glutamine by
glutamine synthetase. This conversion is located near the
astrocyte cells.45 If significant amounts of glutamine are
produced, it can act as an idiogenic osmol and lead to
swelling of the astrocyte and resultant cerebral edema.46 This
cytotoxic edema, rather then vasogenic edema, has been
demonstrated in histological samples to be a mechanism of
cerebral edema in patients with ALF.47
A second mechanism of cerebral edema is changes that
occur in the cerebral vasculature. Cerebral arterioles are
dilated in patients with ALF. Patients with acute liver failure
and cerebral edema have higher cerebral blood flow than
patients who have not developed cerebral edema.41 The
autoregulation of cerebral blood flow is absent in acute liver
failure.47,48 Both systemically mediated factors and local
(brain) factors have been postulated, but the causes of these
changes in the cerebral vasculature are unknown.
Monitoring ICP in patients with ALF is important
because clinical signs and computed tomography scans are
insensitive diagnostic methods of determining significant
ICP in these patients.49,50 The placement of ICP monitors in
patients with acute liver failure can be risky secondary to
their severe coagulopathy. Plasmapheresis has been used to
correct the coagulopathy before ICP monitor placement.
Neurosurgery consultation is indicated for all children with
ALF. Children who present with signs of pending cerebral
herniation obviously require treatment to lower the ICP and
maintain cerebral perfusion.
TREATMENT OF ACUTE LIVER FAILURE
The treatment of the failing liver itself can be
simplified to 2 arms: medical treatment and surgical
treatment (ie, transplantation). The medical treatments
attempt to improve the physiological functions of the liver,
giving the liver time to recover. The surgical options, for the
most part, are taken once it is clear that the liver has failed.
The medical treatments include plasmapheresis,51 prostaglandin E1,52 and N-acetylcysteine (NAC). Of these, only
NAC is likely to be initially indicated in the patient who
presents with ALF.
The use of NAC in the treatment of acute acetaminophen hepatotoxicity is well documented.53 – 55 The NAC
administered within 8 hours of an acute ingestion of
acetaminophen is totally effective in preventing hepatotoxicity. The mechanism of action is the replenishment of
depleted glutathione stores in the liver. Initial medical
evaluation (as opposed to home management) is recommended for prior healthy children who have ingested 200
mg/kg or greater of a single dose immediate-release
acetaminophen preparation.56 Initiating NAC treatment is
determined by plotting serum acetaminophen levels measured between 4 to 24 hours after an acute ingestion on the
Rumack-Matthews nomogram.53 The duration (20 to 72
hours), the total dose and the route (oral versus intravenous)
of NAC are dependent on the risk of hepatotoxicity.57 Oral
NAC is 140 mg/kg loading dose followed by 17 maintenance
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Cochran and Losek
Pediatric Emergency Care Volume 23, Number 2, February 2007
doses of 70 mg/kg every 4 hours. Intravenous NAC is
150 mg/kg in 200 mL of D5W over 15 minutes, 50 mg/kg in
500 mL of D5W over 4 hours, and then 100 mg/kg in 1000
mL of D5W over 15 hours.58 Intravenous NAC is approved
for children 20 kg or greater in weight. If intravenous NAC is
used in children less than 20 kg, a more concentrated
solution (3%) is recommended to prevent hyponatremia from
excess delivery of free water.59 The efficacy and adverse
events of oral versus intravenous NAC are not significantly
different in children.60,61 Recent evidence has shown that
NAC may be beneficial even when initiated at greater than
24 hours after acetaminophen ingestion.62 The NAC has also
shown to be beneficial in non– acetaminophen-induced liver
failure.63 In non– acetaminophen-induced acute liver failure
NAC increases hepatic oxygen delivery, consumption, and
extraction; improves coagulation parameters; and decreases
the progression of encephalopathy.63,64 There has only been
1 pediatric study examining the effects of NAC in non –
acetaminophen-induced acute liver failure.65 This study was
done in combination with prostaglandin E1 at the time of
reperfusion of the grafted liver and included 25 children. It
was a pilot, open-labeled study to examine the safety of this
combination in pediatrics. No significant adverse effects
occurred. Secondary results showed a significant decrease in
severity of rejection in the treated group. The results further
demonstrated a trend toward decreasing liver enzymes and
the length of hospital stay in the treated group.
TRANSPLANTATION
A compelling question in pediatric patients with ALF
is which child will get better and which child will have
irreversible liver failure and be a candidate for liver
transplantation.66 Acute liver failure in children can progress
rapidly. The progression from grade 0 encephalopathy to
grade 3 or 4 (Table 2) may be as short as 3 days.6 Rapid
referral to a pediatric liver transplant center is recommended
because nearly half the children who have grade 3 or 4
encephalopathy may die if transplant is not performed.67 In
addition, more than half of patients with grade 4 encephalopathy at the time of transplant do not recover neurologically.6,68
The largest study attempting to predict recovery from
ALF was done by O’Grady et al69 on 588 adult and pediatric
patients. Important variables were the etiology, the age of the
patient, and the grade of encephalopathy. Survival rates were
variable depending on the etiology of the liver failure.
Hepatitis A and acetaminophen toxicity had improved
survival rates (45% and 34%) compared with hepatitis B
and drug reactions (24% and 14%). Second, the age of the
patient was predictive. Patients younger than 11 or older than
40 years had worse survival rates. Lastly, the higher grades of
encephalopathy were associated with poorer survival rates.
Other predictive variables were found for acetaminophenand non – acetaminophen-related liver failure. In acetaminophen toxicity, predictors of poor survival rates were pH less
than 7.3 or a prothrombin time (PT) greater than 100 seconds
combined with a creatinine greater than 3.5 mg/dL and grade
3 or 4 encephalopathy. In non –acetaminophen-related ALF,
poor survival rates were seen if the PT was greater than 100
132
seconds or if any three of the following were found: PT
greater than 50 seconds, bilirubin greater than 17.5 mg%,
younger than 11 years or older than 40 years, cryptogenic or
drug-induced, or jaundice appearing longer than 7 days
before encephalopathy.
Most liver transplant centers still use the O’Grady
criteria.70 Although the study by O’Grady et al69 did include
pediatric patients, the specific number and age of these
patients were not made available. The question of whether
these criteria are applicable to pediatric patients was recently
raised.71 Four other studies that have looked at prognostic
factors of ALF in pediatrics were all retrospective. The first
study looked at pediatric patients with hepatitis A.72 Patients
at risk for mortality without liver transplantation were those
with a PT less than 21% of normal combined with a serum
bilirubin greater than 400 mmol/L independent of the grade
of encephalopathy. The second study is from the Pediatric
Acute Liver Study Group and included 82 patients who
presented with ALF.73 Using logistic regression analysis,
encephalopathy was the only factor which predicted death, or
a need for transplant in these patients. The third study looked
at pediatric risk of mortality scores.74 There were significantly lower pediatric risk of mortality scores (8.8 ± 5.0) in
patients with ALF who recovered versus those who required
emergency liver transplantation (14.9 ± 7.7). The fourth
study of 36 children with ALF concluded that elevated
international normalized ratio, bilirubin, and white blood cell
counts were predictors of poor outcome in ALF without
transplantation.75
Currently, pediatric liver transplants have the highest
graft survival rate of a solid organ at any age.76 Approximately 10% to 15% of pediatric liver transplants are done
secondary to ALF. The largest published series of pediatric
liver transplants included 569 transplants over a 13-year
period.4 Approximately 10% were done secondary to ALF.
The survival rate for all the patients was dependent on 3
factors: the age of the patient, the era of the transplant, and
the number of transplants required. Patients younger than 1
year of age had a survival rate of 65% compared with 79%
for older children at 10 years posttransplant. Patients
transplanted after 1993 had increased survival rates versus
those transplanted before 1993. Survival rates were inversely
proportional to the number of transplants needed per patient.
The pretransplant diagnosis did not change the postoperative
survival rate. The introduction of split liver transplants
improved survival rates versus caderveric transplants, but the
difference was not significant.
The success of split liver transplants is important in
pediatrics because it has increased the availability of donors
for the pediatric population.77,78 This allows transplantation
to occur before multiple organ dysfunction and irreversible
hepatic encephalopathy develop. The use of split liver grafts
and living related donors has made a favorable impact in
decreasing pretransplant mortality in pediatric patients.
Another key in the treatment of ALF is supporting the
functions of the damaged liver until it is clear whether the
damage will be irreversible. Auxiliary liver transplants
involve the transplantation of a small piece of a living
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Pediatric Emergency Care Volume 23, Number 2, February 2007
Acute Liver Failure in Children
TABLE 3. Treatment Options in ALF
Dysfunction
Treatment
Hypermetabolic status
Coagulation abnormalities
Immune deficiency
Encephalopathy
(hyperammonemia)
Cerebral edema
Hepatic failure
Comments
IV glucose
Hyperalimentation
FFP
Platelet transfusion
Cryoprecipitate
rFVIIa
Plasmapheresis
Cefuroxime and consider amphotericin B
Bowel cleansing, lactulose/neomycin
Benzodiazepine
antagonist (flumazenil)
Urea cycle activation
agent ornithine aspartate
Intraventricular monitoring
Medical
Plasmapheresis
N-acetylcysteine
Prostaglandins
Surgical
Transplantation
Extracorporeal systems
Close monitoring of serum glucose
Low-protein diet
Active bleeding with shock
Active bleeding with platelet count < 20,000 mm3
Bleeding risk per PT and INR
Invasive procedure
Bleeding risk per PT and INR
Prophylactic antimicrobials
Short-lived benefit
Maintain intracranial perfusion pressure
> 40 mm Hg
Coagulopathy/encephalopathy
Acetaminophen and non– acetaminophen-induced
acute liver failure
Coagulopathy/encephalopathy improve transplant outcome
IV indicates intravenous; INR, international normalized ratio.
related donor liver.79 The native liver can be removed or left
intact mostly depending on the disease process. In ALF, the
hope is to transplant adequate liver mass to allow the
patient’s native liver enough time to recover.
EXTRACORPOREAL SYSTEMS
Extracorporeal systems, which temporarily take over the
function of the liver, include 2 main categories, bioartificial and
artificial. Bioartificial devices include the extracorporeal liver
assist device (ELAD) and the bioartificial liver (BAL). The
artificial device most thoroughly studied is the molecular
adsorbent recycling system (MARS).
The ELAD and BAL systems use a dialysislike cartridge
which house hepatocytes from a porcine (BAL) or a human
hepatoblastoma cell line (ELAD). The patient’s plasma
traverses through the cartridge for a variable period. The
MARS dialyzes blood against an albumin-coated membrane
and then a charcoal column and an ion-exchange resin. Of these
extracorporeal systems, both the BAL and ELAD have
improved the level of encephalopathy and survival of children
with ALF.80 – 82 MARS has had similar effectiveness in adult
patients, but its use in children has not been reported.83
CONCLUSIONS
Acute liver failure in children is a rare but potentially
devastating process. Metabolic disorders are the most common
cause in children younger than 1 year, whereas viral hepatitis is
the most common cause in children 1 year of age and older.
Acute liver failure is associated with the dysfunction of multiple
organ systems. Options for treating these organ dysfunctions as
well as treating liver failure itself are summarized in Table 3.
Because of the difficulties in predicting the children who will
require liver transplant, consultation with or transfer to a
pediatric liver transplant service is strongly recommended early
in the management of children with acute liver failure. Liver
transplantation is a viable option in these patients with 1-year
survival rates now approaching 90%.
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