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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.
COAGULATION ABNORMALITIES
Coagulation abnormalities can be significant in patients with ALF. The production of multiple clotting factors
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129
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
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HEPATIC ENCEPHALOPATHY
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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
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131
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 OGrady 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
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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
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 patients 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
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