GASTROENTEROLOGY 2008;134:1741–1751
Evaluation and Management of End-Stage Liver Disease in Children
Mike A. Leonis William F. Balistreri
Pediatric Liver Care Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, and Department of
Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
End-stage liver disease in children presents a chal-
lenging array of medical and psychosocial problems
for the health care delivery team. Many of these prob-
lems are similar to those encountered by caregivers of
adults with end-stage liver disease, such as the devel-
opment of complications of cirrhosis, including as-
cites, spontaneous bacterial peritonitis, and esopha-
geal variceal hemorrhage. However, the natural
history of disease progression in children and their
responses to medical therapy can differ significantly
from that of their adult counterparts. Children with
end-stage liver disease are especially vulnerable to
nutritional compromise; if not effectively managed,
this can seriously impact long-term outcomes and
survival both before and after liver transplantation.
Moreover, close attention must be given to vaccina-
tion status and the clinical setting at which health
care is delivered to optimize outcomes and the deliv-
ery of high-quality pediatric health care. In this re-
view, we address important components of the eval-
uation and management of children with chronic
end-stage liver disease.
S pecial consideration must be given to the evaluation
and management of infants and children with end-
stage liver disease, many of which are distinct from con-
siderations applied to the adult population. The mantra
of pediatricians that “children are not little adults” is
especially true for pediatric patients with end-stage liver
disease, for although they can progress to have “adult-
like” complications, such as portal hypertension, ascites,
spontaneous bacterial peritonitis, and variceal bleeding,
there are differences in the natural history of their dis-
ease, responses to medical therapy, and overall nutri-
tional and psychosocial needs that are distinct from
those of their adult counterparts (Figure 1).
The reasons for these differences in clinical features are
numerous. Immature hepatic function in the newborn
and young infant makes this group of patients vulnerable
to in utero insults, such as infectious agents (eg, cyto-
megalovirus, iron overload, and so on), as well as post-
natal insults, such as infectious (eg, bacterial sepsis) or
metabolic (eg, galactosemia, or parenteral nutrition–
induced cholestasis) insults. Additional important con-
tributors to morbidity in infants and children with end-
stage liver disease include compromised nutritional sta-
tus during an especially vulnerable time period for
normal development, as well as significant extrahepatic
organ dysfunction, such as cardiac or renal disease in
patients with Alagille syndrome, or significant cardiac,
muscular, and neuronal involvement in patients with
mitochondrial or storage diseases. The pediatric popula-
tion also is afflicted with a set of diseases with a natural
history that is distinct from that of adults with end-stage
liver disease, such as biliary atresia or one of the syn-
dromes of progressive familial intrahepatic cholestasis,
which can have an especially aggressive course, leading to
cirrhosis in the first several years of life.
Important features of the evaluation and management
of children with end-stage liver disease are addressed in
this review, with the primary emphasis on those whose
end-stage liver disease is due to chronic liver disease.
Comprehensive reviews of end-stage liver disease in chil-
dren due to acute liver failure have recently been pub-
lished.1,2
General Considerations
The etiology of end-stage liver disease in children
varies with age of presentation (Table 1). For example,
infants with biliary atresia who were diagnosed late in the
course of the disease or underwent a Kasai portoenteros-
Abbreviations used in this paper: PELD, Pediatric End-Stage Liver
Disease.
© 2008 by the AGA Institute
0016-5085/08/$34.00
doi:10.1053/j.gastro.2008.02.029
1742 LEONIS AND BALISTRERI
Figure 1. Critical considerations for optimizing the clinical care and
outcomes of children with end-stage liver disease. Critically ill children
with end-stage liver disease have multiple complex medical issues that
must be adequately addressed to achieve optimal healthy outcomes.
tomy that failed to reconstitute adequate biliary drainage
can develop cholestatic cirrhosis within the first year of
life. Complications can include severe synthetic dysfunc-
tion along with complications of portal hypertension
including ascites, spontaneous bacterial peritonitis, and
variceal bleeding. In fact, biliary atresia is the most com-
mon indication for orthotopic liver transplantation in
children, with the mean age of liver transplantation for
patients with biliary atresia being 11 months.3 Improved
survival without liver transplantation occurs when total
serum bilirubin level is ⬍2 mg/dL at 3 months after
portoenterostomy.4 Another factor that impacts survival
includes the surgical experience of the center at which the
portoenterostomy is performed.5 Other conditions, such
as progressive intrahepatic cholestasis syndromes or ag-
gressive presentations of ␣1-antitrypsin deficiency, can
have a similar natural history.
Adolescents with unsuspected chronic autoimmune
hepatitis or Wilson’s disease can present with stigmata of
cirrhosis, such as ascites, jaundice, acute variceal bleed-
ing, or mental status changes. In addition, it is not
uncommon for these disorders to present to a pediatric
hepatologist following an urgent care visit wherein an
incidental observation of elevated serum aminotransfer-
ase levels was noted in a mildly ill patient.
A primary goal for the care of children with chronic
diseases is the development of self-management skills
over the course of the patient’s childhood and adoles-
cence to allow for optimal transitioning to an adult
center of care in the early third decade of life. This is a
GASTROENTEROLOGY Vol. 134, No. 6
special challenge for those taking care of pediatric pa-
tients with chronic diseases because the psychosocial
dynamics of delivering clinical care to this patient pop-
ulation are unique from the adult experience. Specifically,
the parent, not the patient, is usually the principal deci-
sion maker partnering with the physician and other
health care providers. Moreover, most children do not
have the maturity or psychosocial resources to adequately
or, in the case of adolescents, independently address the
full complexities of their medical care.6 These deficiencies
may not be easily appreciated in an otherwise “normal-
appearing young adult,” and if not appropriately handled
by the health care delivery team, they can lead to poor
patient compliance with recommended treatment regi-
mens and poor clinical outcomes.7 To satisfactorily ad-
dress these concerns and optimize the child’s long-term
clinical outcome, the care of infants, children, and ado-
lescents with end-stage liver disease should be conducted
at a pediatric facility specifically designed to address the
needs of this distinct patient population with an inte-
grated multidisciplinary approach (Figure 1).8
Several models have been proposed for the gradual
transitioning of patient care responsibilities from the
parent to the child, beginning in early childhood, to
allow for both independent management of care by late
adolescence and a healthier family environment through-
out childhood.6 Factors that positively impact the tran-
sitioning process and health-related quality of life in
patients with chronic conditions include independent
health care visits with pediatric caregivers in the absence
of their parents, self-medication by the patient, gradual
transfers between health care teams, and good commu-
nication between pediatric and adult specialty providers.9
Table 1. Leading Etiologies of End-Stage Liver Disease in
the Pediatric Population
Infants
Biliary atresia
Parenteral nutrition–induced cholestasis
Progressive familial intrahepatic cholestasis syndromes
FIC 1 (ATP8B1) deficiency
BSEP (ABCB11) deficiency
MDR3 (ABCB4) deficiency
Bile acid synthetic defects
Alagille syndrome
Metabolic syndromes
Tyrosinemia
Urea cycle disorders
Glycogen storage disease
Idiopathic neonatal hepatitis
Older children and adolescents
Autoimmune hepatitis
Cryptogenic cirrhosis
Biliary atresia status post-Kasai
␣1-antitrypsin deficiency
Primary sclerosing cholangitis
Wilson’s disease
May 2008
Table 2. Factors Contributing to the PELD Scoring System
Factors, PELD scoring system10
Age (mo, ⬍1 y)
Serum albumin level
Serum total bilirubin level
International normalized ratio
Growth failure (ie, length/height Z score ⬍⫺2)
Clinical situations that allow for consideration of PELD exception
points or elevated status on the transplant waiting list100
Acute liver failure (including acute decompensated Wilson’s
disease)
Urea cycle disorder or other life-threatening metabolic diseases
Hepatic tumor (eg, hepatoblastoma)
Chronic liver disease with
Recurrent gastrointestinal bleeding
Recurrent cholangitis
Recurrent spontaneous bacterial peritonitis
Continued poor growth despite optimal nutritional intake
Renal compromise requiring dialysis
Hepatopulmonary syndrome
NOTE. PELD score ⫽ 0.436 Age (⬍1 y) ⫺ 0.687 Loge Albumin ⫹ 0.48
Loge Bilirubin ⫹ 1.857 Loge International Normalized Ratio ⫹ 0.667
Growth Failure.
Nutritional Assessment and
Management
Children with end-stage liver disease are at risk for
developing nutritional compromise, which can lead to
significant short-term and long-term morbidities and is a
common indication leading to listing of pediatric pa-
tients for orthotopic liver transplantation.3 Severely mal-
nourished infants with end-stage liver disease are at in-
creased risk for death while awaiting orthotopic liver
transplantation, for needing liver transplantation, and
for poor outcome following liver transplantation.10 –12
Failure to gain represents one of the strongest compo-
nents of the Pediatric End-Stage Liver Disease (PELD)
scoring system currently in use for risk-based allocation
of liver donor organs to potential pediatric transplant
recipients.10 Factors comprising the PELD score in addi-
tion to growth failure are included in Table 2.
The etiology of failure to gain weight in children with
end-stage liver disease is multifactorial, due to a combi-
nation of increased energy expenditure, malabsorption of
macronutrients and micronutrients, perturbations in
physiologic anabolic signals, and decreased caloric in-
take. For example, infants and children with biliary atre-
sia have a 29% increase in resting energy expenditure
compared with healthy children, in addition to increased
energy losses in the form of fecal fat loss, and poor
nitrogen balance despite increased protein intake for
age.11,13 Children with chronic liver disease also have
disturbances in the growth hormone axis, in particular
due to diminished production of liver-derived insulin-
like growth factor I.14,15 Insulin-like growth factor I me-
diates the anabolic actions of growth hormone, and end-
stage liver disease in children leads to a growth hormone–
resistant state that negatively impacts growth.
END–STAGE LIVER DISEASE IN CHILDREN 1743
Infants are especially prone to nutritional compromise
due to poor caloric intake, given the high caloric nutri-
tional demands (100 –120 kcal · kg⫺1 · day⫺1) during their
first year of life required for normal growth. Caloric
intake can also be negatively impacted by decreased de-
sire of the infant to feed due to malaise derived from the
disease state, early satiety from delayed gastric emptying,
or debilitating gastroesophageal reflux due to the pres-
ence of large-volume ascites or hepatosplenomegaly, lead-
ing to the clinical picture of functional gastric outlet
obstruction.16
Early life is a critical period for brain growth and
development. Thus, generalized malnutrition in children
with end-stage liver disease can lead to compromised
brain growth and impairment of mental develop-
ment.17,18 Malabsorption of fat-soluble vitamins and
minerals will affect neurologic status, bone homeostasis,
and dental health. Moreover, chronic liver disease can
lead to delayed puberty, and in adolescent girls, primary
or secondary amenorrhea may occur.
Clinical recognition of malnutrition in infants and
children with end-stage liver disease relies on diligent
monitoring for multiple clinical manifestations, includ-
ing growth failure, muscle wasting, and motor develop-
mental delay. Signs of fat-soluble vitamin or essential
fatty acid deficiencies, such as peeling skin rash, periph-
eral neuropathy, rickets/fractures, or bruising, are fre-
quently encountered if appropriate early intervention is
not performed. The presence of fluid retention and or-
ganomegaly in the setting of a malnourished infant
makes body weight an unsatisfactory marker of adequate
nutrition and growth in this patient population. We
prefer to track linear growth for long-term monitoring,
along with assessment of other anthropometric markers
of body fat and protein reserves, such as triceps skinfold
and midarm circumference.19
Aggressive treatment of nutritional failure must be
initiated in patients with end-stage liver disease. All pa-
tients will require increased caloric intake, which is usu-
ally met in part by increasing their caloric intake to
120%–150% of their estimated daily requirements.19 For-
mulas containing medium-chain triglycerides are used to
maximize fat absorption in the setting of severe cholesta-
sis. Daily supplements of fat-soluble vitamins must be
given as well (see Wieman and Balistreri19). For those still
encountering inadequate growth, nasogastric enteral
tube feedings should be initiated, either as a replacement
of or supplement to daytime bolus feeding. Continuous
nasogastric tube feeding may also be necessary for those
patients experiencing regurgitation or volume intoler-
ance due to ascites or organomegaly. The development of
behavioral feeding problems in infants is not uncommon
during this period but usually can be satisfactorily ad-
dressed with the help of intensive speech therapy and a
multidisciplinary approach.11
1744 LEONIS AND BALISTRERI
Orthotopic liver transplantation may be the only op-
tion for correcting malnutrition in this patient popula-
tion, and good catch-up growth may be achieved in the
majority of survivors, although posttransplant growth
failure can still occur in 15% of patients.19,20
Maximizing Childhood Vaccinations
Infants and children have immature immune sys-
tems and limited immunity to most infectious patho-
gens. Those patients with chronic progressive liver dis-
ease are especially vulnerable to infection due to viral and
bacterial infectious agents. Therefore, careful attention
must be given to ensure that all infants and children with
progressive chronic liver disease receive all of the recom-
mended routine childhood vaccinations, including vacci-
nations against hepatitis A and B.21 For those infants and
children approaching consideration for listing for ortho-
topic liver transplantation, an accelerated vaccination
schedule should be used to maximize the development of
immunity before immunosuppression following trans-
plantation.22 In addition, vaccination of liver transplant
candidates using attenuated live viruses, such as the vari-
cella, mumps/measles/rubella, or some influenza vac-
cines, needs to be timed carefully given the limited avail-
ability of safety data when used in the posttransplant
patient population. Indeed, although there are reports of
the safe administration of the varicella and mumps/
measles/rubella vaccinations in small numbers of pediat-
ric liver transplant recipients, current recommendations
are to avoid the administration of live virus vaccines in
immunosuppressed solid organ transplant recipients un-
til further conclusive safety studies in larger number of
patients are performed.23–26 This is the current practice at
our institution as well.
Children with functional asplenia due to portal hyper-
tension are vulnerable to bacterial infections, especially
from encapsulated organisms such as Streptococcus pneu-
moniae or Neisseria meningitides. Vaccination against these
organisms should be performed at their earliest approved
ages, which is 2 years of age for both the quadrivalent
meningococcal conjugate vaccine (MCV4) and meningo-
coccal polysaccharide vaccine (MPSV4) and 6 weeks of
age for pneumococcal conjugate vaccines.27–29
Complete avoidance of exposure to common viral re-
spiratory and gastrointestinal pathogens is not practical.
In fact, for those children who will ultimately need or-
thotopic liver transplantation, pretransplant exposure to
select viral pathogens may lessen the morbidity associ-
ated with posttransplant exposure and/or reactivation of
virus in a now immunocompromised host. For example,
children exposed to Epstein–Barr virus before orthotopic
liver transplantation are at a reduced risk for developing
complications of posttransplant lymphoproliferative dis-
ease compared with children who were Epstein–Barr virus
naïve at the time of transplantation.30,31 A similar strat-
GASTROENTEROLOGY Vol. 134, No. 6
ification of risk is present for patients who have been
exposed to cytomegalovirus before transplantation.32
Management of Complications of
Cirrhosis and Portal Hypertension
Portal hypertension leads to a wide variety of
complications with significant morbidity and mortality
in infants and children with end-stage liver disease.33
Complications of portal hypertension in children are
similar to those found in adults and include the devel-
opment of gastroesophageal variceal hemorrhage, ascites,
spontaneous bacterial peritonitis, hypersplenism, and he-
patic encephalopathy. Moreover, recent studies have
shown that children with portal hypertension due to
extrahepatic portal vein obstruction can develop cogni-
tive disabilities impacting measures of sustained alert-
ness and focal attention, although most patients func-
tion normally in other neuropsychiatric domains, raising
the question of whether similar disabilities occur in chil-
dren with intrinsic liver disease.34
Forty percent of children with biliary atresia who have
transplant-free survival at 5 years of life have experienced
new-onset esophageal variceal hemorrhage.35 Despite
this, children with biliary atresia and new onset of esoph-
ageal variceal hemorrhage have a 5-year transplant-free
survival rate exceeding 50%, which is significantly better
than the 17% 5-year survival rate of adults with cirrhosis
and the onset of esophageal variceal hemorrhage.35,36
Higher total serum bilirubin levels are also associated
with much poorer survival in patients with biliary atresia
and new-onset esophageal variceal hemorrhage.35 Al-
though this information on risk factors associated with
poor outcome in patients with biliary atresia is certainly
helpful, an evidence-based approach to the management
of the child with complications of portal hypertension,
due either to intrinsic liver disease or extrahepatic portal
vein obstruction, is important to consider despite the
inherent difficulties in performing such studies.37
Management of Gastroesophageal
Varices and Variceal Hemorrhage
Guidelines for the management of gastroesopha-
geal varices and variceal hemorrhage in adults have re-
cently been published, based on a substantial body of
published clinical research.38 A similar body of literature
is not available to guide pediatricians in the management
of complications of portal hypertension in children. Cau-
tion needs to be exercised before directly extrapolating
the results obtained in adults to the clinical management
of children. To illustrate the point, the use of nonselec-
tive ␤-adrenergic blockade (eg, propranolol) in adults
with portal hypertension reduces the frequency of esoph-
ageal variceal bleeding episodes and improves long-term
survival.38–40 Either propranolol or nadolol may be used,
with the goal of a reduction in heart rate by 25% from
May 2008
baseline, or to 55– 60 beats/min.40 Currently, ␤-adrener-
gic blockade is recommended for both primary and sec-
ondary prophylaxis of variceal hemorrhage in adults with
portal hypertension based on randomized, controlled,
prospective clinical trials.38
A small retrospective analysis of the use of propranolol
in the prevention of portal hypertensive hemorrhage in
children showed that ␤-adrenergic blockade was effective
in reducing further variceal bleeding.41 Of the 21 children
included in this study, 13 were older than 10 years and 19
had cirrhosis as the etiology for their portal hyperten-
sion. Only 4 patients had an episode of gastrointestinal
bleeding before therapy with propranolol was initiated;
therefore, propranolol was used for primary prophylaxis
of hemorrhage for the majority of patients. Adverse ef-
fects of propranolol therapy were reported to be minimal,
causing dizziness in 2 patients and bradycardia in 3
patients, and did not lead to discontinuation of therapy,
and all responded to changing to a long-acting prepara-
tion of propranolol or switching to atenolol.
However, the use of propranolol in children for pri-
mary prophylaxis against hemorrhage from gastroesoph-
ageal varices is controversial and may be associated with
an increased risk of deleterious side effects in young
children, given their relative intolerance to the dosage
required to achieve the recommended 25% reduction in
heart rate.37,42 Infants and young children are dependent
on maintaining an adequate heart rate to maintain ade-
quate cardiac output; thus, their relative intolerance to
␤-adrenergic blockade may be due to this dependency.
Moreover, ␤-blockade may inhibit the usual compensa-
tory increase in heart rate should a child experience a
severe acute variceal hemorrhage, thereby exposing them
to a higher risk of developing hemodynamically signifi-
cant hypotension. Based on expert opinion, the use of
nonselective ␤-adrenergic blockade in children for prep-
rimary prophylaxis of esophageal variceal bleeding
should only be undertaken in the context of a clinical
study.37 For primary or secondary prophylaxis, there are
insufficient data to recommend the use of ␤-adrenergic
blockade in children; however, cautious use may be con-
sidered as it relates to risk reduction in bleeding. Again,
intervention should preferably be performed in the con-
text of a structured prospective clinical study.37
Sclerotherapy has been shown in a randomized, con-
trolled, prospective clinical trial to be effective for elimi-
nating esophageal varices in children and reducing the
incidence of subsequent bleeding episodes. This has been
confirmed in other noncontrolled studies.43 No study has
shown a survival benefit in children. Moreover, a high
incidence of major complications of endoscopic sclero-
therapy has been reported in children, including bleeding
before obliteration, esophageal ulceration, perforation,
and stricture formation.44,45
A randomized prospective clinical trial comparing en-
doscopic injection sclerotherapy with endoscopic variceal
END–STAGE LIVER DISEASE IN CHILDREN 1745
ligation for bleeding from esophageal varices in children
with extrahepatic portal venous obstruction showed that
ligation therapy led to significantly less recurrent bleed-
ing and less major and minor complications.46 The op-
timal interval for performing endoscopic variceal ligation
sessions has not been adequately studied in children.
Sclerotherapy is often the only practical method for
variceal obliteration in an infant, given size limitations
with respect to the esophageal banding apparatus and
concern of entrapment of the full thickness of the esoph-
ageal wall by the rubber band in the young child, causing
ischemic necrosis and perforation.
In patients who have recurrent variceal bleeding de-
spite pharmacologic and endoscopic therapy, a portosys-
temic shunt, preferably a distal splenorenal shunt, may
be of benefit. The transjugular intrahepatic portosys-
temic shunt procedure has been used to prevent rebleed-
ing in children, and the Meso-Rex bypass procedure has
been successfully performed in those children whose por-
tal hypertension is due to extrahepatic portal vein ob-
struction, although proceeding with this latter procedure
is dependent on favorable vascular anatomy.47 The re-
sults of portosystemic shunt procedures in children are
different depending on the etiology of the patient’s por-
tal hypertension, with a higher risk of rebleeding and
mortality found in patients with intrahepatic disease
compared with those with extrahepatic disease.48,49
Emergency Therapy for Variceal
Bleeding
Emergency management of acute variceal bleed-
ing in children is similar to that of adults, with similar
pharmacologic, endoscopic, and surgical options avail-
able. Initial management involves stabilization of the
patient with the careful administration of crystalloid or
red blood cells to avoid rapidly filling the intravascular
space. If ongoing variceal bleeding is suspected following
initial attempts to stabilize the patient, the next ap-
proach usually involves the use of continuous intrave-
nous octreotide (1–2 ␮g · kg⫺1 · h⫺1) in an attempt to
lower splanchnic vascular tone, thereby decreasing portal
venous pressure.50 Octreotide is generally well tolerated
in sick infants and children, although safety and efficacy
studies are needed.50 –52 Approximately 30% of pediatric
patients will have persistent hemorrhage despite conser-
vative management and the use of octreotide,50 and these
patients, if hemodynamically stable, will often undergo
endoscopic evaluation for a source of bleeding. Com-
pared with sclerotherapy, endoscopic variceal band liga-
tion is the preferred approach in this scenario because it
is easier and safer to perform in a potentially obscured
field. For severe, uncontrollable variceal bleeding, place-
ment of a Sengstaken–Blakemore tube, designed to bal-
loon tamponade gastroesophageal variceal bleeding, may
be helpful. Use of the Sengstaken–Blakemore tube, while
effective in controlling bleeding, is associated with a high
1746 LEONIS AND BALISTRERI
rate of rebleeding when the tube is removed, a risk of
aspiration pneumonia when the tube is in place, and the
need for sedation when used in children. Rather, use of
the Sengstaken–Blakemore tube is more often reserved
for bridging the patient to a more definitive surgical or
interventional radiologic procedure to address their por-
tal hypertension, such as an emergent portosystemic
shunt surgery or the transjugular intrahepatic portosys-
temic shunt procedure. The transjugular intrahepatic
portosystemic shunt procedure has been successfully per-
formed in children as small as 14 kg, although special
technical modifications must be used. The risk of shunt
occlusion relegates its application to those expected to
soon undergo orthotopic liver transplantation.53
Management of Ascites
Children, and especially infants, are vulnerable to
the complications of ascites. Firstly, the development of
tense ascites, which is fairly common in infants with
end-stage liver disease, may lead to clinically significant
extrahepatic organ dysfunction, including compromise
of gastrointestinal, renal, and pulmonary function. This
alone can lead to severe morbidity and even mortality in
the fragile infant, specifically the development of debili-
tating nutritional compromise in the setting of ascites-
induced gastric outlet obstruction or compromised pul-
monary function exacerbated by an acute viral respiratory
illness. In situations where medically nonresponsive tense
ascites leads to severe extrahepatic organ dysfunction,
therapeutic abdominal paracentesis may lead to improve-
ment in the patient’s overall clinical status, although
unfortunately it is often of short-term benefit. It is our
opinion that therapeutic abdominal paracentesis should
be used cautiously given the significant risk of procedure-
related complications such as hypotension secondary to
large shifts of intravascular volume following the proce-
dure or bacterial peritonitis.
On the other hand, it is often difficult to completely
resolve all ascites with diuretic management without gen-
erating unacceptable levels of hyponatremia or other elec-
trolyte imbalances or compromising intravascular hydra-
tion status; therefore, a mild to moderate amount of ascites
is often tolerated. In addition, tolerating a modest amount
of ascites, as long as extrahepatic organ function is not
compromised, is somewhat desired if the patient is to be
considered for orthotopic liver transplantation to allow for
room for donor transplant organs and subsequent ease of
fascial and skin closure with minimal intra-abdominal com-
pression and compromise of donor organ vascular flow.
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis is a common
occurrence in children with cirrhosis and ascites; how-
ever, data regarding the incidence of spontaneous bacte-
rial peritonitis in children have not been reported. In one
GASTROENTEROLOGY Vol. 134, No. 6
small retrospective study of 12 episodes of spontaneous
bacterial peritonitis in 11 children, symptoms encoun-
tered were similar to those found in adults, including
increased abdominal distention, fever, abdominal pain,
vomiting, diarrhea, and encephalopathy. Most had re-
bound tenderness, and all had reduced bowel sounds.54
Infants with spontaneous bacterial peritonitis can
present with poor feeding behavior and lethargy. As in
adults, however, infants and children with ascites can be
asymptomatic at presentation or present with subtle
findings such as a sudden increase in abdominal disten-
tion or elevated peripheral white blood cell count. Given
the lack of reliable signs or symptoms for the presence of
spontaneous bacterial peritonitis, the policy at our insti-
tution is to perform a diagnostic paracentesis whenever a
patient presents with new-onset ascites.
Biologic determinants predisposing to the develop-
ment of spontaneous bacterial peritonitis in children
have not been established. In adults with advanced liver
disease and ascites who developed spontaneous bacterial
peritonitis, there are conflicting data as to whether low
serum complement factors C3 and C4 correlate with the
development of spontaneous bacterial peritonitis.55 How-
ever, in children, low serum levels of complement factors
C3 and C4 were found in the majority (⬎89%) of patients
at the time of diagnosis of spontaneous bacterial perito-
nitis, compared with only 8 of 59 children (14%) with
cirrhosis without spontaneous bacterial peritonitis.54
This observation raises the question of whether the de-
velopment of complement deficiency in children with
cirrhosis predisposes them to the development of spon-
taneous bacterial peritonitis.
Several pediatric studies have been performed evaluat-
ing the organisms isolated from ascitic fluid of children
with spontaneous bacterial peritonitis and liver disease.
In 2 studies, the most frequent organisms isolated in-
clude Streptococcus pneumoniae and other gram-positive
cocci from the majority of cultures, followed by gram-
negative enteric flora.54,56 In a third study, the spectrum
of isolated bacterial organisms is more similar to that
found in ascites from adults with spontaneous bacterial
peritonitis, with the most common organisms isolated
being gram-negative enteric bacteria and less commonly
streptococcal and staphylococcal species.57,58
Treatment of spontaneous bacterial peritonitis should
be with broad-spectrum antibiotics until specific culture
and sensitivity results are available. Cefotaxime (180
mg · kg⫺1 · day⫺1 divided 3 times daily) is the antibiotic
of choice in most pediatric patients, because it effectively
covers the most common organisms. In addition, given
the high rate of recurrence of spontaneous bacterial peri-
tonitis, it is important to verify that children have been
immunized with the pneumococcal antigen vaccine and
that they receive prophylactic antibiotics. In adults, se-
lective decontamination of the gut with the fluoroquin-
olone norfloxacin leads to a substantial reduction of
May 2008
recurrence of spontaneous bacterial peritonitis over a
6-month period following their first episode, as well as a
reduction in all infections upon hospitalization for man-
agement of ascites, including spontaneous bacterial peri-
tonitis.59,60 Given the concern of long-term fluoroquino-
lone use in infants and young children due to safety
concerns regarding possible quinolone-induced arthral-
gia or cartilage toxicity, trimethoprim-sulfamethoxazole
has been advocated for use in children because it has
similar efficacy as fluoroquinolones in the prevention of
spontaneous bacterial peritonitis in adults.61,62
Hepatic Encephalopathy
Although less common than that reported in
adult studies, hepatic encephalopathy can develop in
pediatric patients with either acute liver failure or
chronic end-stage liver disease. Two thirds of infants and
children presenting with acute liver failure develop he-
patic encephalopathy during their first week following
initial presentation.1 The incidence of hepatic encepha-
lopathy in infants and children with chronic end-stage
liver disease has not been studied.
In children, the development of early grades of acute
and chronic hepatic encephalopathy can be difficult to
assess, given the relative psychological immaturity of
infants and young children compared with adults. Many
of the symptoms of early grades of hepatic encephalop-
athy, such as irritability, inconsolable crying, and inat-
tention to task, are relatively nonspecific findings for
moderate to severely ill infants and children in general,
and thus it is often difficult to determine if a newly
presenting patient is in the early stages of hepatic en-
cephalopathy. In addition, children with chronic end-
stage liver disease with portal hypertension may develop
minimal hepatic encephalopathy, leading to subtle im-
pairment of cognitive function, specifically in areas af-
fecting memory and attention span.34,63 These impair-
ments may affect learning capacity but otherwise allow
them to maintain a high level of daily functioning.
In infants and children, protein intake should not be
restricted to the point of causing growth failure or com-
promising overall nutritional status, and a target range of
2–3 g · kg⫺1 · day⫺1 is often required to minimize exces-
sive ammonia production.19,64 Of note, intense supple-
mental enteral feeding with branched-chain amino acids
in children with advanced cirrhosis and malnutrition
leads to improvement of anthropometric indices without
generating clinically obvious encephalopathy.64
Oral antibiotics and synthetic disaccharides have been
shown to be effective in minimizing ammonia produc-
tion in adult patients with hepatic encephalopathy.65– 67
Neomycin has been used in children to suppress ammo-
nia-forming bacteria in the gut; however, it must be used
cautiously, because long-term use of this agent has been
associated with deafness and renal toxicity.68,69 Lactulose
and lactitol are synthetic disaccharides that are metabo-
END–STAGE LIVER DISEASE IN CHILDREN 1747
lized by colonizing bacteria in the colon to produce a
variety of small molecular organic acids that lower the
colonic stool pH, thereby trapping diffusible ammonia as
ammonium ion in the fecal stream.70 Lactulose is used as
the mainstay therapy for pediatric patients with hepatic
encephalopathy and elevated serum ammonia levels. This
strategy is based on results from clinical trials in adults,
given that there are no studies evaluating the effective-
ness of lactulose (or neomycin) for the prevention of
hepatic encephalopathy in infants or children with cir-
rhosis or portal hypertension.37,71
Hepatopulmonary Syndrome and
Portopulmonary Hypertension
Pediatric patients with end-stage liver disease can
develop secondary complications of hepatopulmonary
syndrome or portopulmonary hypertension. Although
standard criteria for diagnosing these syndromes in chil-
dren have not been defined, recent reports suggest that
both syndromes can negatively impact pretransplant and
peritransplant morbidity and mortality in children (re-
viewed by Whitworth and Sokol72). Hepatopulmonary
syndrome is defined by the clinical triad of a chronic liver
disorder, intrapulmonary vascular dilatation, and altered
gas exchange resulting in hypoxemia on room air. Hepa-
topulmonary syndrome is associated with a poor prog-
nosis in adult patients with end-stage liver disease.73–75
With respect to the reported experience in children, 9%
of 48 children undergoing orthotopic liver transplanta-
tion at a single pediatric liver transplant center were
diagnosed with hepatopulmonary syndrome.76 At a sec-
ond pediatric liver transplant center, hepatopulmonary
syndrome was diagnosed in 6% of 114 patients who had
undergone transplantation and was more commonly ob-
served in patients with polysplenia and an interrupted
inferior vena cava (4 out of 7 patients had hepatopulmo-
nary syndrome) compared with age-matched controls (0
out of 38 patients).77 Of the 7 children with hepatopul-
monary syndrome in this second study, all had correction
of their oxygen saturation by 6 months posttransplanta-
tion and 1-year posttransplant survival was 100%.77 In
addition, hepatopulmonary syndrome can occur at an
early age and has been reported in a 4-year-old boy with
a type I Abernethy malformation (ie, anomalous diver-
sion of the portal vein into the inferior vena cava, bypass-
ing the liver) and a 2-year-old boy with biliary atresia.78,79
Children with hepatopulmonary syndrome have lower
total bilirubin levels compared with age-matched con-
trols, and cirrhosis may or may not be present.77
Portopulmonary syndrome is defined as pulmonary
arterial hypertension (pulmonary artery pressure ⬎25
mm Hg) associated with severe liver disease or portal
hypertension. When left untreated, portopulmonary hy-
pertension leads to high mortality in adults and chil-
dren.80 – 82 Symptoms of portopulmonary hypertension,
including dyspnea and syncope, should prompt an eval-
1748 LEONIS AND BALISTRERI
uation for portopulmonary hypertension; however, these
findings can be subtle and overlooked. Thus, any patient
with end-stage liver disease or portal hypertension should
be evaluated by echocardiography and cardiology evalu-
ation, especially those who are being evaluated for liver
transplantation.82
Early liver transplantation is crucial in children with
portopulmonary hypertension caused by end-stage liver
disease due to its high morbidity and mortality; however,
successful liver transplantation has been performed in
children with severe portopulmonary hypertension.83,84
Given the high morbidity and mortality associated with
these syndromes, patients on the liver transplant waiting
list in the United States who have developed hepatopul-
monary syndrome are eligible for increased PELD/Model
for End-Stage Liver Disease (MELD) scoring on this basis
alone. Additional clinical indications for petitioning for
PELD exception points are noted in Table 2.
Assessing Additional Extrahepatic
Organ Function
With the option of orthotopic liver transplanta-
tion, pediatric patients with end-stage liver disease can
enjoy a good, long-term quality of life. Thus, it would
behoove caregivers to focus special attention on all ex-
trahepatic organ functions, including cognitive and psy-
chosocial function, that may be secondarily impacted by
the liver disease affecting the child. Moreover, given the
high representation of metabolic and syndromic etiolo-
gies in pediatric patients with end-stage liver disease, it
would not be surprising to find a high incidence of
extrahepatic organ involvement, outside of those systems
affected by the complications of portal hypertension pre-
viously described.85
Carefully assessing renal function in pediatric patients
with end-stage liver disease is important for 2 main reasons.
Firstly, 30%–50% of pediatric liver transplant recipients de-
velop renal dysfunction within 7–10 years posttransplanta-
tion, likely secondary to long-term exposure to calcineurin
inhibitors, which are nephrotoxic.86,87 Thus, if significant
renal insufficiency is encountered in those patients being
considered as candidates for orthotopic liver transplanta-
tion, appropriate planning for the use of renal-sparing im-
munosuppression protocols should be done during the
peritransplant and posttransplant periods. Moreover, in the
pretransplant period, therapeutic maneuvers to preserve re-
nal functional capacity should be used, such as avoiding
aminoglycosides and other nephrotoxic agents whenever
possible. Secondly, hepatorenal syndrome has been ob-
served in children and adolescents with end-stage liver dis-
ease.88,89 Primary screening tests for assessing renal function
in patients with end-stage liver disease include routine uri-
nalysis, a measured glomerular filtration rate, and urine
electrolyte and blood pressure measurements. Finally, in-
trinsic renal disease can develop in some groups of pediatric
GASTROENTEROLOGY Vol. 134, No. 6
patients with end-stage liver disease, such as patients with
Alagille syndrome or hereditary tyrosinemia.
Osteoporosis is frequent in adult patients with cirrho-
sis, leading to spinal fractures that contribute to signifi-
cant patient morbidity. For example, in primary biliary
cirrhosis, the bone mineral density of women patients is
lower than that in age-matched controls before liver
transplantation.90 Moreover, adults who have undergone
orthotopic liver transplantation have abnormally low
bone mineral density that is difficult to rectify posttrans-
plantation.91 Infants and children with chronic choles-
tatic liver disease also can develop significant osteoporo-
sis and long-bone or vertebral body fractures.92,93 The
pathogenesis of osteoporosis in this setting is unclear but
may relate to altered vitamin D metabolism, osteoclast
and osteoblast function, or vitamin K–mediated carbox-
ylation of bone proteins such as osteocalcin.94,95
Also noted earlier, subtle deficiencies in cognitive func-
tion can occur in pediatric patients with cirrhosis and long-
standing portosystemic shunting, although many patients
have normal cognitive function. Given the long-term impli-
cations of even subtly compromised cognitive function, this
topic must remain an active area of future research.
Psychosocial and Ethical
Considerations
The complexity and burden of medical manage-
ment of infants and children with end-stage liver disease
present an enormous emotional, psychosocial, and finan-
cial stress on patients and their family unit. Parents often
are overwhelmed with the fear that their child may die or
that they “caused” their child’s disease (eg, if the child’s
end-stage liver disease is due to a genetically determined
metabolic syndrome, or autoimmune hepatitis within a
family with a predisposition for autoimmune disorders).
Most families struggle with the demands of frequent
doctor’s visits, the pain and prospects of unexpected
complications associated with multiple medical proce-
dures, including frequent intravenous line starts and
blood draws, and the disruption that all of this entails
with respect to the parents’ capacity to maintain their
employment, health insurance (if present), and a satisfac-
tory home environment for the rest of their family mem-
bers.96 Even with early involvement of social and financial
services, the quality of life for these families all too
commonly deteriorates significantly, which further exac-
erbates the prospects for delivering quality care to this
vulnerable patient population.
Unfortunately, the demands of providing adequate
health care to children with end-stage liver disease often
outstrip the capacity of the immediate family resources.
When this happens, social services must be involved to
optimize provision of unmet psychosocial and financial
needs to minimize further negative repercussions for the
child. Transportation, housing, and financial arrange-
ments can often be made to meet the family’s immediate
May 2008
care-related needs. Sometimes even this is not sufficient,
and in select cases, the child may need to be placed in
court-supervised foster care due to the inability of family
members to provide for the medical and psychosocial
needs of the patient.
In addition to clear cases of inadequate family psychos-
ocial resources that may necessitate court involvement, oc-
casionally the courts must be included in the medical deci-
sion-making process when a disagreement arises between
the family and health care providers on deeper ethical di-
lemmas, such as whether it is appropriate for otherwise
well-meaning and loving parents to refuse standard life-
saving medical therapy for the child based on religious
grounds or concerns about side effects or complications of
the proposed medical therapy.97,98 Children are not able to
independently make their own health care decisions, and
although the initial presumption is always that a parent or
guardian speaks and will act for the child’s best interest, this
may not always be considered to be the case by health care
providers. In these examples of tense disagreement between
parents and physicians, the courts must be brought in to
mediate these complex ethical dilemmas, although they
may not necessarily side with the medical team and order
that the child be treated.98,99
Concluding Remarks
Infants and children with end-stage liver disease
have unique characteristics requiring special attention by
health care providers. The primary diseases leading to
end-stage liver disease in this age group often do not
present in adults, and their clinical management can
differ significantly from that of adults as well. A more
complete understanding of the pathogenesis of the dis-
eases leading to end-stage liver disease in infants and
children is absolutely necessary to provide a basis for
establishing a means to halt disease progression and
improve patient outcomes in the future. Moreover, re-
search studies to bolster our management of pretrans-
plant nutrition, ascites, and other complications of por-
tal hypertension must be initiated. To address these
needs, full support of and participation in multicenter
clinical research studies aimed at defining the natural
history and treatment of diseases involved in pediatric
end-stage liver disease is strongly encouraged. Several
such studies are currently ongoing, such as the Studies of
Pediatric Liver Transplantation (SPLIT) and studies of
the Biliary Atresia Research Consortium (BARC), Chole-
static Liver Disease Consortium (CLIC), and Pediatric
Acute Liver Failure (PALF) Study Group. These National
Institutes of Health–funded multicenter pediatric re-
search efforts have already significantly contributed to
our understanding of the natural history and treatment
of children with end-stage liver disease. Continued sup-
port of these research efforts is critical to furthering our
efforts to learn more about risk factors leading to liver
END–STAGE LIVER DISEASE IN CHILDREN 1749
disease progression and effective treatment strategies to
help this vulnerable patient population.
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END–STAGE LIVER DISEASE IN CHILDREN 1751
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Received December 14, 2007. Accepted February 11, 2008.
Address requests for reprints to: William F. Balistreri, MD, Division of
Pediatric Gastroenterology and Nutrition, Cincinnati Children’s Hospital
Medical Center, University of Cincinnati College of Medicine, 3333 Burnet
Avenue, MLC 2010, Cincinnati, Ohio 45229. e-mail: william.balistreri@
cchmc.org; fax: (513) 636-7805.
Supported by Public Health Services grant CA-111819 (to M.A.L.)
and Digestive Diseases Research Development Center grant
DK-064403 (to M.A.L.) from the National Institutes of Health.