Acute liver failure in neonates Anil Dhawan, Giorgina Mieli-Vergani *

Early Human Development (2005) 81, 1005 — 1010
www.elsevier.com/locate/earlhumdev
Acute liver failure in neonates
Anil Dhawan, Giorgina Mieli-Vergani *
Paediatric Liver Centre, Institute of Liver Studies, Variety Club Children’s Hospital,
King’s College School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK
KEYWORDS
Neonatal acute liver
failure;
Coagulopathy;
Herpes simplex virus;
Metabolic disease;
Neonatal
haemochromatosis;
Liver transplant
Abstract Acute liver failure (ALF) in neonates is a rare but often fatal event.
Though in adults and older children, a main symptom of ALF is hepatic
encephalopathy, this is very difficult to diagnose and prove in infants. Causes of
ALF in neonates encompass metabolic, infectious and haematological disorders,
congenital vascular/heart abnormalities, and drugs. Infants with ALF should only be
treated in specialised paediatric hepatology centres with facilities for liver
transplantation, since for many liver transplant, with a long term survival of over
60%, is the only therapeutic option.
D 2005 Elsevier Ireland Ltd. All rights reserved.
Acute liver failure (ALF) is a rare but mainly fatal
disorder in neonates, the mortality for which is 70%
without liver transplantation. Management
requires a multidisciplinary approach involving
hepatologists, neonatologists and transplant surgeons, to support the child until liver regeneration
or liver transplantation takes place. The most
common aetiologies are liver based metabolic
disorders and perinatally acquired infections. Liver
damage can be reversed in certain metabolic
conditions by altering the diet and in some
infections by appropriate antimicrobial treatment,
but when it is advanced, liver transplantation is the
only life saving option.
* Corresponding author. Paediatric Liver Centre, Variety Club
Children’s Hospital, King’s College Hospital, Denmark Hill, London
SE5 9RS, UK. Tel.: +44 20 7346 4643; fax: +44 20 7346 4224.
E-mail address: giorgina.vergani@kcl.ac.uk
(G. Mieli-Vergani).
1. Definition
The definition of ALF in children and neonates is a
subject of controversy. In adults, in 1970, Trey and
Davidson defined ALF as ba potentially reversible
condition, the consequence of severe liver injury,
in which the onset of hepatic encephalopathy is
within eight weeks of the first symptoms of illness,
in the absence of pre-existing liver diseaseQ [1].
This definition is unsatisfactory for children, especially during infancy, not only because it is very
difficult to identify signs of encephalopathy in this
age group, but also because encephalopathy can be
a very late event in the course of the disease.
Moreover, children presenting with ALF often do
have an underlying unrecognized liver disease.
Bhaduri and Mieli-Vergani have addressed this issue
and proposed the following definition of ALF in
children: ba rare multisystem disorder in which
severe impairment of liver function, with or
0378-3782/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2005.10.003
1006
A. Dhawan, G. Mieli-Vergani
without encephalopathy, occurs in association with
hepatocellular necrosis in a patient with no recognised underlying chronic liver diseaseQ [2].
infection in women of childbearing age and their
sexual partners and to treat the infected baby as
soon as possible.
1.1. Aetiology
1.3. Metabolic diseases
Causes of ALF during the newborn period are listed
in Table 1 [3,4] and include inborn errors of
metabolism, perinatal infections, hypotension/
shock, and haematological conditions like haemophagocytic lymphohistiocytosis. Identifying the
cause of ALF not only provides indication of
prognosis but also dictates specific management
options.
Inherited disorders of metabolism are an important
cause of ALF in the neonatal period, and must be
promptly investigated because dietary manipulation or disease specific treatment may be life
saving. The most common metabolic diseases to
be considered are galactosaemia, hereditary fructose intolerance, and tyrosinaemia [3—9]. For the
first two, withdrawal of the offending dietary
component is usually life saving. The management
of tyrosinaemia has changed dramatically since the
introduction of 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexenedione (NTBC), which prevents the formation of toxic metabolites and
produces rapid clinical and biochemical improvement [7]. Recently, mitochondrial respiratory chain
defects have been implicated as an etiological
factor for ALF in infants. They usually present with
hypoglycemia, vomiting, coagulopathy, acidosis
and raised lactate with or without neurological
symptoms [10]. Rarely fatty acid oxidation defects
and inborn errors of bile acid synthesis present with
ALF. Neonatal haemochromatosis (NH) is usually
listed under the metabolic disorders associated
with ALF in infancy, though its aetiopathogenesis
is unknown. It is a rare disease, but the most
common cause of ALF in the neonatal period. In NH,
liver injury of fetal onset is associated with massive
intra and extra hepatic iron deposition sparing the
reticulo-endothelial system. It presents with acute
liver failure around birth. It has been suggested
that it may be the ultimate phenotype of different
aetiologies. There is an 80% recurrence rate within
families of affected children. The description of NH
in half siblings born to the same mother has led to
1.2. Viral infections
Perinatal infection with viruses of the herpes
family, adenovirus, parvovirus and hepatitis B can
cause ALF in newborn babies [5,6]. Herpes simplex
virus (HSV) induced ALF is the most common
among viral aetiologies, carries a high mortality
and is rarely accompanied by skin lesions, hence it
should be considered in all sick babies with
coagulopathy and raised transaminases. Infants
with this presentation should be promptly started
on intravenous aciclovir. We have analysed retrospectively the case notes of 11 patients with HSV
induced ALF. A history of possible herpes infection
was elicited in 5 parents, but HSV had not been
suspected clinically. All patients were asymptomatic when discharged from postnatal units, and
presented with non-specific symptoms of poor
feeding and lethargy within 2 weeks from birth.
All had grossly deranged liver function and coagulopathy at presentation. Seven of the 11 patients
had HSV-1 infection, 4 HSV-2. Only two patients,
both of whom received early treatment with
intravenous aciclovir survived. These findings
indicate that it is important to recognise HSV
Table 1
Common causes of acute liver failure in neonates and diagnostic investigations
Disease entity
Diagnostic test
Galactosemia
Tyrosinemia
Neonatal haemochromatosis
Haemophagocytic lymphohistiocytosis and congenital leukaemia
Septicemia and shock
Giant cell hepatitis with hemolytic anemia
HHV-6, Hepatitis B, Adenovirus, Parvovirus
Mitochondrial hepatopathy
Red cell galactose-1-phosphate uridyl transferase
Urine succinyl acetone
Raised ferritin, extrahepatic iron deposition
Bone marrow examination
Positive cultures, clinical scenario
Coombs positive haemolytic anemia
Viral serology and PCR
Mitochondrial DNA, muscle and liver biopsy (open,
if coagulopathy permits) for quantitative respiratory
chain enzyme determination
Echocardiography
History and drug levels
Cortisol levels, short synacthen test
Vascular malformations and congenital heart disease
Maternal overdose (paracetamol) [3]
Hypocortisolism [4]
Acute liver failure in neonates
the suggestion that the disease could be due to
incomplete penetrance or gonadal mosaicism for a
dominant disorder or a mitochondrial defect,
rather than be autosomal recessive, but the precise
pattern of inheritance is unknown. Other proposed
causes of NH are intrauterine infection and maternal alloimmune antibodies. There is often a history
of maternal anaemia, oligohydramnios or megaplacenta. There are no specific diagnostic tests for
NH, but hypersaturation of transferrin with elevated ferritin levels are useful biochemical clues in a
baby with ALF. The diagnosis can only be confirmed
by the demonstration of extra hepatic iron deposits
sparing the reticuloendothelial system, which in
vivo can be sought by performing a biopsy of lip
salivary glands. Intra-hepatic iron deposition on its
own is not diagnostic, because the neonatal liver is
physiologically iron overloaded and high hepatic
iron content is observed in any form of severe liver
disease in this age group. Magnetic resonance
imaging of the abdomen may demonstrate iron
storage in the pancreas, but iron storage is typically
absent in the spleen. The prognosis of NH has been
universally reported as poor. Chelation treatment
alone is ineffective in altering the course of the
disease. Specific management includes the use of
an antioxidant cocktail [11,12] (Table 2), but its
efficacy has not been tested in controlled trials and
in our own series of 19 patients it has not modified
the outcome [11]. Liver transplantation is the only
therapeutic option for severely affected babies and
is performed successfully even during the first few
days of life, though the waiting period for a suitable
size donor is usually long, given the small size of the
recipient. While waiting for transplantation, single
volume whole blood exchange transfusion may be
helpful to manage symptomatic coagulopathy, and
possibly to remove maternal alloantibodies that
have been recently suggested to play a significant
role in the pathogenesis of this condition. The
survival after liver transplantation for NH in our
center is 50% (median follow up 7.8 years, range 3—
10 years) [11]. Antenatal administration of intravenous immunoglobulins weekly from the 18 week
of gestation until term has been shown to reduce
the severity of the illness in the newborn in a series
Table 2 Anti oxidant cocktail for neonatal haemochromatosis
Vitamin E
N-acetylcysteine
Prostaglandin—E1
Selenium
Desferioxamine
25 IU/kg/day orally
100 mg/kg/day i.v.
0.4 Ag/kg/h i.v. for a maximum
of 2 weeks
3 mg/kg/day i.v.
30 mg/kg/day i.v. until ferritin
b500 ng/ml
1007
of 15 pregnant mothers who previously had an
affected baby [13].
1.4. Ischemic injury
Shock liver can occur after cardiac arrest, a period
of hypotension/hypovolaemia or in the setting of
congestive cardiac failure, even when hypotension
is not clearly documented. Serum transaminase
levels are markedly elevated but they do normalize
rapidly once the circulatory problem is stabilized
[5].
1.5. Vascular causes
Congestive heart failure of any aetiology can
present as liver failure. Conditions that we have
seen in our unit presenting as ALF include hypoplastic left heart, coarctation of the aorta and
right heart failure. Ascites, significant hepatomegaly, coagulopathy and hypoalbuminemia are often
present [5].
1.6. Hematological malignancies
Haemophagocytic lymphohistiocytosis (HLH)
presents with fever, hepatosplenomegaly, pancytopaenia and, in severe cases, with ALF. Biochemically, there are high serum triglycerides and low
fibrinogen. Usually, these patients bleed severely
from venepuncture sites, in contrast to infants
with other forms of ALF. Bone marrow aspiration or
cytospin from body fluids (ascites, cerebrospinal
fluid) usually demonstrate haemophagocytosis.
When HLH presents with ALF, mortality is high
despite aggressive supportive treatment, chemotherapy and bone marrow transplantation [14].
Haematologic malignancies, e.g., congenital leukemia, can present with ALF due to massive
infiltration of the liver. The presence of high fever
with hepatosplenomegaly, high alkaline phosphatase, high lactate dehydrogenase and abnormalities of the peripheral blood film suggest the
diagnosis and bone marrow examination confirms
it [15,16].
2. Management
2.1. General measures
Patients with ALF should be nursed in a quiet
environment with as little stimulation as possible to
minimize acute increases in intra-cranial pressure.
1008
Babies with encephalopathy and those without
encephalopathy, but an international normalized
prothrombin ratio (INR) greater than 4 should be
admitted to the intensive care unit for continuous
monitoring. Patients should be carefully monitored
in respect of haemodynamics and fluid management (blood pressure, urine output), metabolic
parameters (electrolytes, blood sugar) and neurological status (presence of encephalopathy). Sedation should be avoided unless the patient is to be
mechanically ventilated, as it can interfere with
the monitoring of the neurological status. Coagulation and metabolic parameters, full blood count
and arterial blood gases in ventilated patients
should be regularly checked. Controlled trials in
adults have failed to substantiate any beneficial
effect of corticosteroids, interferon, insulin and
glucose, prostaglandin E1, bowel decontamination,
and charcoal hemoperfusion in patients with ALF.
Maintenance of nutrition is crucial and hypoglycemia should be avoided by use of intravenous
glucose infusion or by ensuring adequate enteral
intake. Total fluid intake is restricted to two-thirds
of the maintenance if the patient is not dehydrated. The concept of protein intake aggravating
or precipitating hepatic encephalopathy has now
been discarded, and adequate calories should be
provided using oral or nasogastric feeding. Investigations to elucidate the cause of ALF should be
performed urgently to start appropriate treatment.
Liver biopsy is only rarely useful and usually
contraindicated because of severe coagulopathy
[5].
A. Dhawan, G. Mieli-Vergani
often used in babies, for whom we prefer using
exchange transfusions.
3.2. Infection
Patients with ALF have impaired immune function.
About 60% of deaths in ALF have been attributed to
sepsis. An active uncontrolled infection is also a
relative contraindication for liver transplantation.
The risk factors for infections include coexisting
renal failure, cholestasis and treatment with thiopental. In adults, the presence of encephalopathy
(grade II or above) has been shown to be associated
with bacterial infection in about 80% of cases and
fungal infections in about 32% of cases. The most
common bacterial infection is due to Staphylococcus aureus, but streptococci or gram negative
organisms such as coliforms are also isolated.
Prophylactic intravenous antibiotics have been
shown to reduce the incidence of culture-positive
bacterial infection from 61.3% to 32.1% in adult
patients. Candida species are the most common
fungal isolates which are often unrecognized and
may be ominous. Deterioration of encephalopathy
after an initial improvement, a markedly raised
leukocyte count, pyrexia unresponsive to antibiotics, and established renal failure are strong
indicators of fungal infection [17,18]. In our unit,
neonates with ALF are treated from admission with
broad spectrum antibiotics (usually third generation cephalosporin and an aminoglycoside), acyclovir and fluconazole.
3.3. Coagulopathy
3. Complications
3.1. Encephalopathy
The most serious complications of ALF are cerebral
oedema with resultant intracranial hypertension
and hepatic encephalopathy. Encephalopathy usually presents late in the course of the illness, and
when present carries a bad prognosis. The conventional grading system for encephalopathy (grade I—
IV) used for adults and older children is not
applicable to babies. Signs of early encephalopathy
in babies are inconsolable crying and sleep disturbance, which can progress to somnolence or
irritability and later to frank coma more or less
responsive to painful stimuli. The infant should be
electively ventilated and sedated at the first signs
of encephalopathy. Mannitol, an osmotic diuretic
that remains the mainstay of treatment for increased ICP in adults and older children, is not
The prothrombin time, expressed as INR, is used as
an indicator of the severity of liver damage and to
decide when to list for transplantation. An INR z 4
is associated with more than 90% mortality and is
the main parameter used in our centre for
transplant listing. Thus, correction of coagulopathy is indicated only if the patient is already
listed for transplant or prior to invasive procedures. Significant disseminated intravascular coagulation is unusual in ALF. The risk of hemorrhage
does not correlate with INR but with thrombocytopenia which can develop rapidly. A platelet
count of less than 100 109/L has been reported
in about two-thirds of adults with ALF. Common
sites of internal haemorrhage include the gastrointestinal tract, nasopharynx, lungs, and retroperitoneum. Intracranial hemorrhage is uncommon.
The presence of significant disseminated intravascular coagulation usually indicates sepsis or secondary HLH. Prophylactic ranitidine or proton
Acute liver failure in neonates
pump inhibitors have been shown to decrease the
incidence of gastric bleeding [19].
3.4. Haemodynamic complication
The early haemodynamic changes in ALF patients
are similar to those seen in the systemic inflammatory response syndrome and reflect a state of
hyperdynamic circulation with decreased systemic
peripheral vascular resistance and increased cardiac output. Circulatory failure is a common mode of
death in patients with ALF, often complicating
sepsis or multiorgan failure. Invasive haemodynamic monitoring like arterial blood pressure,
central venous pressure or lately use of PICCO and
oesophageal echocardiography in adults may provide early evidence of circulatory failure and is
helpful in deciding fluid management, but may be
difficult in small infants. In the presence of
persistent hypotension despite normal filling, noradrenaline is the inotropic agent of choice. Nacetylcysteine has been shown to improve parameters of oxygen metabolism. A combination of
prostacycline and N-acetylcysteine has been found
to be more beneficial for oxygen metabolism than
either drug alone [20,21].
1009
neurologic deterioration. Acid—base imbalance is
common. Metabolic acidosis is present in about 5%
of patients with ALF and is associated with poor
outcome. Lactic acidosis is related to inadequate
tissue perfusion. Sometimes respiratory alkalosis or
acidosis may complicate the clinical picture.
3.7. Liver transplantation
Advances in surgical techniques have made it
possible to perform liver transplantation in newborn babies. The availability of liver transplantation for this age group has significantly improved
survival, but the procedure is contraindicated in
patients with advanced complications of ALF, such
as fixed and dilated pupils, uncontrolled sepsis, and
severe respiratory failure (adult respiratory distress
syndrome) or conditions not treatable by liver
replacement, such as mitochondrial cytopathies
with neurological involvement, HLH, giant cell
hepatitis with Coombs positive haemolytic anaemia
(which recurs after transplant) and malignancies.
Though worse than for older children, the outcome
of neonatal liver transplantation is acceptable,
with a patient survival of about 65% in our centre,
the downside being a life long need for immunosuppressive medications [22,23].
3.5. Renal failure
Renal failure with severe oliguria often develops in
ALF, especially in later stages. In the pediatric
population, the incidence of renal failure is lower
(10—15%) than in the adult population (30%) but
there are no studies in neonates [21]. Renal failure
could be due either to a direct toxic effect on the
kidneys, as in paracetamol overdose, or to a
complex mechanism such as hepatorenal syndrome
or acute tubular necrosis secondary to complications of ALF (sepsis, bleeding, and/or hypotension). Although the mechanism of renal failure is
not clear, it is essential to correct intravascular
hypovolemia. Continuous filtration or dialysis systems are associated with less haemodynamic
instability and consequently less risk of aggravating
latent or established encephalopathy than intermittent haemodialysis.
3.6. Metabolic derangement
Hypoglycaemia is present in some 40% of patients
with ALF. The classic signs and symptoms of
hypoglycemia are often masked, especially in the
presence of encephalopathy, hence regular blood
glucose monitoring is mandatory as hypoglycemia
can worsen the encephalopathy and cause rapid
4. Hepatocyte transplantation
Liver cells isolated from unused donor livers can be
infused in to the failing liver to provide a functioning hepatic mass while the native liver regenerates.
The procedure has shown some encouraging results
as a bridge to transplant, however, the technique
remains experimental [24].
5. Liver support systems
In ALF, there is impairment of synthetic, detoxifying, and biotransformatory activity resulting from
the loss of functioning hepatocytes and Kupffer
cells. Theoretically a support device, which provides all these functions would be ideal, either as a
bridge to liver transplant or, better, to obviate the
need for it, by supporting liver function while the
native liver regenerates. Liver support devices
could be either cleansing devices or bioartificial
liver support systems. Cleansing devices perform
only the detoxifying function of the liver, whereas
bioartificial liver support systems have the theoretical advantage of having synthetic and detoxi-
1010
fying properties. None of these devices have been
tried systematically in children or neonates hence
their use outside research protocols is not recommended [25—27].
A. Dhawan, G. Mieli-Vergani
[12]
[13]
6. Conclusions
[14]
ALF is a multisystem disorder with a high mortality
rate, which should be managed in a specialized
paediatric liver centre with facilities for liver
transplantation, since this procedure, despite improvement in intensive care support, remains the
only effective mode of treatment for most infants.
Liver assist devices and hepatocyte transplant hold
a great potential of providing a bridge to transplant
or avoiding it while the native liver regenerates,
but are still at the experimental stage.
[15]
[16]
[17]
[18]
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