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Liver Transpl. Author manuscript; available in PMC 2018 January 01.
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Published in final edited form as:

Liver Transpl. 2017 January ; 23(1): 96–109. doi:10.1002/lt.24640.

Biliary Atresia: Indications and Timing of Liver Transplantation

and Optimization of Pre-Transplant Care
Shikha S. Sundaram1, Cara L. Mack1, Amy G. Feldman1, and Ronald J. Sokol1
1Digestive Health Institute and Pediatric Liver Center, Children’s Hospital Colorado, Section of
Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of
Colorado School of Medicine, Aurora, CO.
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Abstract
Biliary Atresia is a progressive, fibro-obliterative disorder of the intra and extrahepatic bile ducts
in infancy. The majority of affected children will eventually develop end-stage liver disease and
require liver transplantation. Indications for liver transplant in biliary atresia include failed Kasai
portoenterostomy, significant and recalcitrant malnutrition, recurrent cholangitis, and the
progressive manifestations of portal hypertension. Extra-hepatic complications of this disease,
such as hepatopulmonary syndrome and portopulmonary hypertension, are also indications for
liver transplantation. Optimal pre-transplant management of these potentially life threatening
complications and maximizing nutrition and growth require the expertise of a multi-disciplinary
team with experience caring for biliary atresia. The timing of transplant for biliary atresia requires
careful consideration of the potential risk of transplant versus the survival benefit at any given
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stage of disease. Children with biliary atresia often experience long wait times for transplant
unless exception points are granted to reflect severity of disease. Family preparedness for this
arduous process is therefore critical.

Introduction
Biliary Atresia (BA) is a progressive, fibro-obliterative disorder of the intra and extrahepatic
bile ducts with onset in the first 3 months of life. It occurs worldwide, affecting an estimated
1 in 8,000–18,000 live births(1). At least four phenotypes of BA are recognized: isolated
BA, BA associated with laterality defects (asplenia, polysplenia, abdominal situs inversus
and intestinal malrotation), BA associated with other major congenital malformations, and
BA associated with a bile duct cyst (cystic BA). The etiology and pathogenesis of each type
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of BA is uncertain, however, abnormal bile duct development, perinatal viral infection,

prenatal toxin exposure, and a dysregulated immune response have been proposed(1). Early
diagnosis of BA is critical as a surgical Kasai portoenterostomy (KPE) may restore bile flow
if performed prior to age 3 months and help prevent rapid progression of liver injury and
development of cirrhosis. Unfortunately, the vast majority of affected children will

Corresponding Author: Ronald J. Sokol, MD, Professor and Vice Chair of Pediatrics, Chief, Section of Pediatric GI, Hepatology and
Nutrition, Digestive Health Institute, Children’s Hospital Colorado, 13123 E. 16th Avenue, B290, Aurora, CO 80045, Tel:
720-777-6669, Fax: 720-777-7277, [email protected].
 Sundaram et al. Page 2

eventually develop end-stage liver disease, with BA being the leading indication for pediatric
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liver transplantation.

Indications for Liver Transplant (Table 1)

Early Failed KPE
The natural history of children with BA who do not demonstrate bile flow after KPE is
similar to that of children with unrepaired BA. Very few will survive beyond 24 to 36
months of age without undergoing liver transplantation (2–4). Success of the KPE can best
be judged by restoration of bile flow and clearance of jaundice. At 3 months post KPE, there
is a clear difference in 2 year transplant-free survival between children with total serum
bilirubin <2 mg/dL and those with total bilirubin >6 mg/dL (84% vs. 16%, p<0.001) (5).
Likewise, if jaundice has resolved by 3 months post KPE, the 10-year transplant-free
survival rate ranges from 75% to 90%; conversely, if jaundice persists after KPE, the 3-year
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transplant-free survival rate is only 20%. Thus, children who do not demonstrate good bile
flow and clearance of jaundice by 3 months post KPE should be evaluated early for
transplantation, ideally by 6–9 months of age.

Late Diagnosis of BA
While the benefits of early performance of KPE are well established, the concept of a
threshold age beyond which KPE is futile, thus requiring proceeding directly to liver
transplantation, remains controversial. Patients undergoing a “late KPE”, variably defined as
age >90, 100 or 120 days, have diminished but variable long-term survival with their native
liver. Previous studies have reported 42% two year, 23–45% four to five year, 15–40% ten
year, 29% fifteen year, and 13% twenty year survival with native liver (6–10). Neither
advanced histologic fibrosis nor nodular appearance of the liver at the time of KPE reliably
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predict outcome after surgery (9, 11, 12). However, KPE in infants with cirrhosis and ascites
may precipitate hepatic decompensation. Several studies have suggested that patients with a
previous KPE are at increased risk for bowel perforations and biliary complications from
liver transplant while others showed no increased length of the transplant operation, blood
loss, operative complications, or intensive care unit and hospital length of stay (8, 13–18).
While future research may help identify a reliable early biomarker that predicts which child
should undergo late KPE versus move towards primary liver transplant, current practice
varies by center.

Failure to Thrive
Children with poor bile drainage following KPE will uniformly develop significant
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malabsorption, protein-energy malnutrition, growth failure and developmental delay (19). A

subset of those with normalization of serum bilirubin will also suffer from these
consequences, albeit variably delayed, despite good bile flow. The resultant loss of lean
body mass and subcutaneous adipose tissue are best demonstrated by triceps skinfold and
mid-arm circumference measurements (20). In addition, biochemical and clinical
deficiencies of fat-soluble vitamins, iron and zinc are common and require aggressive
supplementation and frequent monitoring (21). Metabolic bone disease resulting in recurrent
long-bone fractures with minimal trauma may also develop as end-stage liver disease

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progresses, even without vitamin D or calcium deficiency. The presence of failure-to-thrive

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requiring aggressive nutritional support (including nasogastric feedings or parenteral

nutrition) or unremitting bone disease should prompt liver transplant evaluation.

Bacterial Cholangitis
Between 40–80% of patients with KPE experience at least one episode of bacterial
cholangitis before the age of 2 years, and 25% of patients experience multiple episodes (22,
23). Post-operative cholangitis has been associated with decreasing rates of 1, 3, and 5-year
survival with native liver compared to children without cholangitis (92%, 76% and 76% vs.
80%, 51% and 23%, respectively (P<0.01) (24). In addition, repeated cholangitis confers a
3-fold increased risk for early failure after KPE and 2-fold increased risk for failure 3 years
after KPE (25). Liver transplant should be considered when a child develops recurrent
cholangitis despite aggressive antibiotic therapy, multi-resistant bacterial organisms,
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episodes of life-threatening sepsis, or severely impaired quality of life due to recurrent

hospitalizations for cholangitis.

Portal Hypertension
Although 60% of infants with BA will initially have restored bile flow after KPE, hepatic
fibrosis is progressive and portal hypertension (PHT) develops in the majority of children.
Manifestations of PHT, including splenomegaly with hypersplenism, esophageal and
gastrointestinal varices and ascites, are associated with significant morbidity and mortality.
A study from the Childhood Liver Disease Research Network (ChiLDReN; United States
and Canada) characterized PHT in 163 children with BA (mean age 9.2±5.6 years) with their
native liver. Definite PHT (presence of complication of PHT or splenomegaly and
thrombocytopenia) or possible PHT (presence of splenomegaly or thrombocytopenia only)
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was identified in 67% of subjects. The most common complication of PHT was variceal
bleeding, occurring in 20% of subjects, although the majority (62%) of patients had only one
episode of variceal bleeding (46). In addition, PHT in BA patients who survive into
adulthood without liver transplantation is nearly universal. In Canada and Europe, 96% of
adult patients with BA had features of PHT, with 65% having evidence of varices, 91%
splenomegaly and 14% ascites (26). These findings corroborate a previous study from
France, showing that 99% of BA survivors with their native liver in adulthood had evidence
of cirrhosis and 70% had significant PHT (27). Thus, the complications of PHT can generate
major morbidity in both children and adults with BA and requires frequent monitoring.

Pruritus
Although more commonly reported in patients with Alagille syndrome and progressive
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familial intrahepatic cholestasis, cholestasis-induced pruritus may occur in BA. In some

patients, pruritus is significant enough to greatly impair quality of life for both patient and
family. In these instances, one must confirm that the diagnosis of BA is correct, that other
medical causes of pruritus (such as atopy, pediculosis or urticaria) have been excluded and
that maximal medical management (including ursodiol, rifampin or naltrexone, Table 2) has
failed (28). Liver transplant should be considered for patients with intractable pruritus and
interference with sleep or normal activities unresponsive to medical management.

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Hepatopulmonary Syndrome (HPS) and Portopulmonary Hypertension (POPH)

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HPS and POPH may occur as a consequence of BA and are indications for liver
transplantation because of reversibility after, and high mortality without, transplantation
(29–32). HPS is characterized by arterial hypoxemia caused by intrapulmonary vascular
dilatations in patients with portal hypertension or congenital porto-systemic shunts. Hypoxia
and fatigue are the main clinical symptoms and HPS is present in 3 to 20% of children with
cirrhosis or being evaluated for liver transplantation (31, 33). HPS diagnosis is established
by demonstrating increased right to left intrapulmonary shunting by transthoracic, saline
contrast-enhanced echocardiography or macro-aggregated albumin scanning. POPH is
defined as increased mean pulmonary artery pressure (mPAP) due to increased pulmonary
vascular resistance identified on cardiac catheterization in a patient with normal pulmonary
artery wedge pressure and portal hypertension. Exertional dyspnea, hypoxia and eventual
right-sided heart failure are clinical features. POPH is rarer that HPS, present in <1% of
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children with cirrhosis or awaiting liver transplantation (30, 32, 34). There is no effective
therapy to reverse HPS (although supplemental oxygen may improve PaO2) and although
therapies for pulmonary artery hypertension may be useful to bridge a patient with POPH to
transplantation, they should not substitute for liver replacement (34). BA patients should be
screened at least annually and at the time of transplant evaluation with pulse oximetry and if
hypoxia, dyspnea, a new heart murmur or fatigue is present, consideration should be given
for transthoracic Doppler echocardiography using agitated saline (34). Severe hypoxemia
(PaO2 < 45–50 mm Hg) in HPS has historically posed an increased risk for complications
and mortality following liver transplantation, however more recent reports suggest transplant
can be performed safely (34). POPH should be aggressively treated prior to liver transplant
to reduce mPAP to < 35 mmHg. A mPAP>50 mm Hg remains a contraindication to liver
transplantation at many centers because of high intra- and post-operative mortality. In
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summary, both HPS and POPH are indications for liver transplant in biliary atresia, however,
the severity and pace of progression of these disorders dictates the urgency with which
transplant evaluation should be performed.

Hepatorenal Syndrome
Hepatorenal syndrome (HRS) is a rare complication of end-stage liver disease in which
acute renal dysfunction secondary to diminished renal blood flow occurs in the absence of
intrinsic renal disease(35). HRS generally resolves after liver transplantation(36); therefore,
children who develop HRS should be evaluated and listed for liver transplantation.

Hepatic Malignancy
Malignancy is a well-recognized complication of chronic liver disease. Although rare,
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hepatocellular carcinoma (HCC) may affect ~1% of children with BA and can occur as early
as infancy (37, 38). Cholangiocarcinoma is even rarer. An elevated alpha fetoprotein level or
concerning lesion on ultrasound should immediately lead to more definitive imaging to
confirm HCC and evaluate for metastases. Complete surgical resection is the only curative
option, although chemotherapy may be more effective in children than adults (39). Milan
criteria may not be applicable in children and successful liver transplant outcomes have been
achieved even in children who did not meet the more liberal University of California San

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Francisco criteria (single tumor <6.5 cm or maximum of three tumors with none >4.5 cm
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and cumulative tumor size <8 cm) or the “up to seven” criteria (absence of angioinvasion,
number of nodules plus the maximum size of the largest nodule equal or lower than 7).
Therefore, decision to list for transplant must be individualized for each child (40).
Transplant should be considered in the absence of radiological evidence of extrahepatic
disease or gross vascular invasion, irrespective of size of the lesion or number of lesions
(41). In the most recent UNOS guidelines, children with HCC are listed with their calculated
Pediatric End Stage Liver Disease (PELD) score for 6 months and then are upgraded to a
PELD of 34.

Pre-transplant management
Optimal pre-transplant management requires a multi-disciplinary team with experience in
biliary atresia and chronic liver disease complications. The team includes pediatric
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hepatologists and surgeons, nurses, dieticians, social workers, feeding specialists, child
psychologists or behavioral specialists, pharmacists and other specialists as needed. A
number of critical issues must be addressed in every BA patient on a trajectory towards
transplant (Tables 2 and 3).

Nutritional Management
One of the key predictors of successful liver transplantation in BA patients is nutritional
status at the time of transplant (42) . Thus, maintaining the child’s nutritional homeostasis
while awaiting liver transplantation is critical to transplant outcomes and the normal growth
and development of the child. Nutritional assessment should be part of the standard of care
from the time of BA diagnosis through the post-transplant period. In addition to length,
weight and head circumference, routine measurement of triceps skinfold thickness and mid-
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arm circumference (MAC) every 3 months provides a much better indication of the child’s
nutritional status and will dictate the aggressiveness with which nutritional support is
initiated (Table 3). Weight gain alone can give the false impression of adequate nutrition as
hepatosplenomegaly, ascites, and edema may confound this measurement. Triceps skinfold
thickness (measure of adipose tissue) and MAC (measurement of lean body mass) give a
better representation of the child’s status. Serum markers of nutritional status, such as
visceral proteins, are problematic since liver synthetic failure may alter levels of albumin,
retinol binding protein, and transferrin irrespective of nutritional status.

In the presence of cholestasis and cirrhosis, the goal for energy intake should be between
125–140% of recommended caloric requirements based on ideal body weight. Additional
calories may be needed to provide for catch-up growth if a significant deficit in weight is
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present, as detailed in Table 3. Increasing the caloric density of formula to 24 or 27 kcal/oz

(100.5 or 113 kjoule/30 mL) by mixing with less water, using glucose polymers or MCT
(medium-chain triglyceride) oil can also spur growth. Breast milk can be continued and
supplemented with a breast milk fortifier, however, in our experience it is challenging to
assure adequate weight gain on this regimen in the presence of severe cholestasis. Thus, an
infant formula containing a substantial amount of MCT oil (which is less dependent on bile
acids for absorption), but also containing adequate essential fatty acids as long chain

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triglycerides, is preferred. Protein intake should be preserved (at least 2–4 g/kg/d) and not
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restricted because of the presence of cirrhosis (Table 3).

Whenever possible, oral feeding is preferred, but with increasing anorexia, vomiting because
of ascites and debilitation from progressive liver disease, supplemental nasogastric feedings
may be required to meet caloric and fluid requirements and prevent or reverse inadequate
weight gain in children awaiting liver transplantation. The use of narrow-bore, soft,
weighted Silastic or polyurethane feeding tubes is generally well tolerated, with minimal
risk of aspiration or upper gastrointestinal hemorrhage (43, 44). Compared with bolus
gavage feeding techniques, continuous formula infusions lead to better energy balance (43).
Nutritional rehabilitation using enteral drip feedings (140% of recommended caloric intake,
4 g/kg/d of protein) in children with BA and cirrhosis awaiting liver transplant leads to
improved nutritional status without hyperammonemia or adverse clinical and biochemical
effects (45, 46). Nocturnal or continuous 24 hours per day nasogastric feedings can be safely
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administered in the home. Because of portal hypertensive gastropathy and the risk for
development of gastric varices, gastrostomy tubes are contra-indicated in this setting.

Occasionally, despite adequate energy intake or because of intolerance to enteral feedings,

adequate growth is not achievable using enteral nutrition. Parenteral nutrition through an
indwelling central venous catheter may be required (in addition to ad lib oral feedings) while
a child is bridged to liver transplantation. Delivered energy may need to be increased and
standard intravenous protein and lipid loads are generally well tolerated. Copper and
manganese (both normally excreted in bile) should be reduced in the parenteral nutrition
solution in BA patients and zinc may be increased. In our experience, this can be done safely
at home, with excellent improvement in pre-transplant nutritional status and post-transplant
outcomes (47).
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Intestinal absorption of fat-soluble vitamins is severely impaired in BA patients who fail to

drain bile into the intestinal lumen (21). Frequent assessment of these fat soluble vitamins
(Table 3) is required, particularly in those awaiting liver transplantation. Standard vitamin
supplements designed for children with fat malabsorption have inadequate levels of these
vitamins for BA patients with elevated serum total bilirubin (43). Large doses of individual
vitamins (Table 3) are often required to prevent deficiency in BA patients with a serum
direct bilirubin > 2 mg/dl, thus avoiding potentially fatal consequences such as intracranial
hemorrhage (48, 49). Bile acid binding resins and iron should not be administered
simultaneously with fat-soluble vitamin supplements. Serum levels and ratios (Table 3)
should be closely monitored at a minimum each 3 months while awaiting liver transplant
and sooner if changes in the doses of vitamins are made. Occasional patients in whom the
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enteral route is unsuccessful may require parenteral administration of these vitamins. Status
of iron and zinc should also be monitored periodically given that subclinical gastrointestinal
blood loss may lead to iron deficiency and excessive fecal and urine zinc losses in BA may
lead to deficiency; oral supplementation generally resolves these deficiencies (Table 3) (21).

Portal Hypertension
Complications of PHT that often require medical or procedural intervention include ascites,
hypersplenism and variceal bleeding, by far the most common and potentially devastating

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complication of PHT. (50, 51). Up to 90% of children with BA have varices on endoscopic
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examination and ~30% will have at least one episode of variceal bleeding (52, 53). The
decision to perform surveillance endoscopies looking for varices (primary prophylaxis)
versus performing the first endoscopy at the time of a variceal bleed is quite controversial. A
recent study from France characterized the incidence of esophageal and gastric varices and
portal hypertensive gastropathy in 225 children with BA who had never had a variceal bleed
(median age 16 months; range: 10–33 months) (48). These children underwent ≥2 repeat
surveillance endoscopies within a 2.4 year time frame (range 1.5 months-10 years), of whom
72% had grade 1–2 esophageal varices at baseline and 34% had grade 3 varices or gastric
cardia varices at follow-up. The authors concluded that progression of varices from the “low
risk” group can be very rapid and estimated a 10% risk of emergence of a high risk
endoscopic pattern over time, justifying the need for surveillance endoscopies and primary
prophylaxis. In contrast, recent consensus from the Baveno VI symposia states that
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screening endoscopy is not universally recommended in children with cirrhosis (54). There
are many arguments against performing surveillance endoscopy in BA patients who have
never had a variceal bleed. First, ~50% of children with BA will require liver transplantation
in the first 2 years of life, thus definitively treating the PHT and risk of GI bleeding.
Secondly, in the study from France detailed above, despite primary prophylaxis with
repeated sclerotherapy or band ligation, 25% of varices could not be eradicated and >30%
had recurrence of varices after eradication. Thirdly, repeat endoscopies entail repeat
exposure to general anesthesia. Recurrent anesthestic events have been associated with
neurocognitive deficits in children (55, 56). Finally, the risk of mortality from a variceal
bleed in children is rare, with mortality estimates of 0–5% based on the published
literature(57–59). Despites the multiple arguments for not performing surveillance
endoscopy, one potential exception would be the BA patient who lives in an extremely
remote area and who would not have ready access to medical care in response to a variceal
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bleed.

Treatment of acute variceal bleeding includes the potential use of blood products,
somatostatin analogs (e.g. octreotide) or terlipressin, sclerotherapy or band ligation, and,
rarely, balloon tamponade or portosystemic shunting. Vitamin K deficient coagulopathy
should be treated with intravenous Vitamin K. In addition, one should administer
intravenous antibiotic therapy, in light of the high risk of potentially fatal infectious
complications in cirrhotic patients with concurrent gastrointestinal bleeding (60).

Octreotide, which causes splanchnic vasoconstriction with subsequent decrease in portal

venous pressure, allows for early control of variceal bleeding and hemodynamic stabilization
prior to proceeding with sclerotherapy or band ligation. Esophageal variceal band ligation is
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the procedure of choice in children due to the low rate of re-bleeding with band ligation
(4%) compared to sclerotherapy (25%), though may not be technically feasible in a child
weighing less than 8–10 kilograms (61). Octreotide may be weaned off over the next 2–5
days, with the rate of weaning based on whether there is residual blood loss post-procedure.
Rare complications from sclerotherapy or band ligation include esophageal perforation,
ulceration or stricture formation.

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Balloon tamponade of esophageal varices or portosystemic shunt surgery should be reserved

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for severe, refractory variceal bleeding. Balloon tamponade (Sengstaken-Blakemore tube)

provides temporary hemostasis by direct compression of esophageal varices and is highly
successful in stopping bleeding. However, recurrence of bleeding within 24 hours of
deflating the balloon occurs in ~50% of patients (53). The risk of major complications,
including esophageal rupture, has been reported in up to 20% of cases and therefore this
procedure should only be performed by experienced personnel (62). Balloon tamponade
should be considered a bridge to either liver transplantation or a portosystemic shunt
procedure. Transjugular intrahepatic portosystemic shunt (TIPS) or, rarely, surgical
portosystemic shunts (portocaval or distal splenorenal shunts) may be necessary to treat
refractory variceal bleeding in BA patients (62).

The standard of care to prevent recurrence of esophageal variceal bleeding, secondary

prophylaxis, includes repeat sessions of endoscopic variceal band ligation or sclerotherapy.
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Endoscopic therapy can be repeated every 2–6 weeks, with approximately 3–5 sessions
necessary to eradicate all varices (51). Unfortunately there is a 30% recurrence rate of
varices after eradication over time. Beta blockade therapy is an acceptable treatment for
prevention of variceal bleeding in adults; however a paucity of data exists for any sustainable
benefits in children (51, 63). Concerns regarding the use of beta-blockade in children
include the lack of data to suggest appropriate dosing in order to decrease heart rate by the
recommended 25% and the concern that infants may suffer poor outcomes from
hypovolemic shock in the setting of variceal bleed while on beta-blockers, with the inability
to mount a tachycardic response. Therefore, at present, the routine use of beta-blockade in
children with significant PHT is not recommended.

For significant variceal rebleeding despite frequent endoscopic ligation, options include
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TIPS, portosystemic shunt or liver transplantation. TIPS is usually a bridge to

transplantation in BA, however it can be considered as a long-term alternative in children
with a good overall prognosis of their liver disease (51). Portosystemic shunts are rarely
considered for recurrent variceal bleeding in the setting of compensated cirrhosis. Based on
primarily adult data, patients with decompensated cirrhosis and ligation-refractory variceal
rebleeding should not undergo portosystemic shunt surgery due to the increased risk of
hepatic decompensation (64), but rather proceed to liver transplantation.

Thrombocytopenia
In BA patients, the most common manifestation of hypersplenism is thrombocytopenia.
Neutropenia is usually without consequence as white blood cells can be mobilized if needed.
Platelet transfusions should be reserved for severe variceal bleeding or clinically significant
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bleeding from other sources in the setting of significant thrombocytopenia (<20–60 ×109/L)
(56). For persistent bleeding related to PHT and thrombocytopenia, partial splenic
embolization can be considered in patients with compensated cirrhosis (65).

Ascites and Hyponatremia

Ascites occurs in approximately one-third of patients with PHT. Diuretic therapy and
exclusion of excess sodium intake are the mainstays of treatment in children (Table 2). For

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mild ascites, a potassium sparing agent such as spironolactone is recommended. In cases of

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moderate to severe ascites, spironolactone plus furosemide should be used, along with
avoidance of high sodium containing foods. Ascites associated with low serum albumin
levels may benefit from intravenous infusions of 20% or 25% albumin followed by IV
furosemide. In the setting of diuretic-refractory ascites associated with respiratory
compromise, feeding difficulties or urinary retention, recurrent large-volume paracentesis
may become necessary. It has been recommended that the volume removed be less than 200
ml/kg body weight and that the rate of removal be less than 680 ml/hour without albumin
infusion. Larger or more rapid volumes removed require albumin infusion to prevent post
paracentesis circulatory dysfunction (66). Hyponatremia (serum sodium <130 meq/L) is not
uncommon in BA patients with ascites. Portal hypertension results in systemic and
splanchnic vasodilation, which effectively reduces arterial blood volume (67). This triggers
release of arginine vasopressin and anti-diuretic hormone (ADH), solute-free water renal
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tubular reabsorption and retention and resultant dilutional hyponatremia (67). Management
of hyponatremia can be challenging. Patients with neurologic symptoms or severe
hyponatremia (<115–120 mequ/L) may benefit from significant fluid restriction. Intravenous
albumin may also be helpful for short-term management. However, patients imminently
headed to liver transplant may require more aggressive correction of hyponatremia with
normal saline or hypertonic saline, used with caution so as not to correct serum sodium more
than 9 meq/L in 24 hours to avoid the risk of central pontine myelinolysis (67). While
vaptans, selective arginine vasopressin V2 receptor antagonists in the kidney tubules, hold
promise for pharmacologic therapy of hyponatremia, they are currently not approved by the
Food and Drug Administration for use in liver disease and cirrhosis due to the increased risk
of liver failure and death (68). The recent addition of serum sodium as a factor in the
calculation of the MELD score may improve the prognostic accuracy of this score.
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Spontaneous Bacterial Peritonitis (SBP)

SBP is a serious complication of PHT and usually occurs in the setting of transient
bacteremia. Infants and children may have vague symptoms including poor feeding, fatigue,
fevers, increased abdominal distension, abdominal pain, vomiting or diarrhea. Studies in
children suggest that the most common pathogen associated with SBP is Streptococcus
pneumonia followed by gram negative organisms and rarely anaerobes(69). Prophylactic
antibiotics targeting the above named organisms should be used in the setting of recurrent
SBP. Furthermore, children with chronic liver disease should receive the pneumococcal
vaccine.

Bacterial Cholangitis
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Cholangitis, one of the most common complications of BA, should be considered in any
patient who develops fever, vomiting, right upper quadrant pain, pale stools, worsening
jaundice, or rising aminotransferases with cholestatic laboratory values. A high index of
suspicion is necessary, as fewer than 30% of patients with cholangitis will have a positive
blood culture. Aggressive treatment with IV antibiotics that target gram negative and
anaerobic bacteria should be administered. The use of prophylactic antibiotics such as
Trimethoprim-Sulfamethoxazole (Table 2) to prevent cholangitis after KPE is common
practice, however, studies of the utility of antibiotic prophylaxis have yielded conflicting

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results. In one study of 214 patients with BA in the Netherlands, antibiotic administration
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after KPE was independently associated with 4-year transplant-free survival; however, the
incidence of cholangitis was not lower in the patients receiving antibiotic prophylaxis
suggesting that there may have been other factors that contributed to improved survival (70),
such as suppression of the intestinal microbiome and activation of innate inflammation in the
liver. In a smaller study of 19 patients with BA who experienced an episode of cholangitis,
there was a lower recurrence rate and higher survival rate in patients who received neomycin
or trimethoprim/sulfamethoxazole prophylaxis compared to those children who received no
antibiotics (71). There is a paucity of data regarding use of probiotics to prevent cholangitis.
Multi-centered prospective randomized control studies are needed to better understand the
utility of prophylactic antibiotics in preventing cholangitis and improving transplant-free
survival after KPE (69).

Surgical revision of KPE

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In select non-cirrhotic patients who achieve sufficient bile drainage following the initial
KPE, but then develop sudden onset bile flow cessation, redo/revision-KPE may be an
option. In this procedure, surgical removal of fibrotic tissue is performed in an attempt to
restore bile flow. Although redo KPE may theoretically make future transplantation more
difficult (due to adhesions, increased blood loss, and increased surgical time), in select cases
redo-KPE may offer patients long-term survival with their native liver (72–74).

Immunizations
Vaccine preventable infections are a recognized and potentially serious complication
following pediatric liver transplant that lead to significant morbidity, mortality, and costs.
The Infectious Diseases Society of America (IDSA) recommends that children with chronic
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liver disease receive all age appropriate vaccines based on the Centers for Disease Control
(CDC) annual schedule for immunocompetent people, with a goal of completing the primary
vaccine series and any necessary booster doses prior to transplantation. The CDC’s Minimal
Ages and Intervals Schedule can be utilized to accelerate vaccinations for children in whom
transplant is anticipated to occur in the near future(75). Live vaccines (MMR and Varicella)
should be administered if transplantation is not anticipated within four weeks (76). In
countries where tuberculosis (TB) is endemic, the tuberculin skin test (TST) should be part
of the pre-transplant work-up; however, it should be noted that live vaccines can interfere
with the TST response, therefore the TST must either be placed before/on the same day as
live vaccines are given or the TST must be delayed 4–6 weeks after live vaccines are given.
Despite recommendations, studies have shown as many as 71% of pediatric solid organ
transplant recipients have not received their full set of standard pediatric immunizations at
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the time of transplant (77, 78). Future studies are needed to design and implement strategies
to improve immunization rates in this population of children.

Timing of transplant in Biliary Atresia

While BA is the most common indication for pediatric liver transplant, there is a paucity of
data to guide optimal timing of transplant listing. Analysis of 2001–2004 UNOS data
suggested that only patients with a PELD score of greater than 17 experienced considerable

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 Sundaram et al. Page 11

survival benefit in terms of life years gained from liver transplant (79). BA patients,
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however, are often listed with low PELD scores, primarily due to normal or near normal
albumin and prothrombin time. In addition, weighting mechanisms designed to benefit
infants, such as low weight z-score, are often not achievable because of artificially elevated
weight due to ascites, organomegaly and aggressive nutritional interventions. Moreover,
calculated PELD scores in BA may not accurately reflect true mortality risk reflected by
complications of portal hypertension, variceal bleeding and refractory ascites. As such,
common practice is to list BA patients when sick enough to assume the potential risk of
transplant, while still well enough to both benefit and survive the surgery.

Once listed, BA patients have a median wait time in the United States of 90 days and a
median calculated PELD score of 15 at the time of transplant (UNOS data). Unfortunately,
the U.S. Department of Health and Human Services “Final Rule”, mandating a nationwide
allocation system for deceased donor liver transplant designed to benefit patients based
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primarily on their medical status, has not uniformly benefited pediatric patients (80) . Recent
studies demonstrate that ~15% of children with chronic liver disease have either died on the
waiting list or been removed because they are too ill to transplant (81). The PELD system
may be particularly tenuous for children less than 12 months of age, many of whom have
BA, and in whom wait list mortality is higher (25%) than older pediatric patients (10%) and
adults (82). Transplant centers have therefore increasingly appealed to Regional Review
Boards for exception points on a case-by-case basis, resulting in a five- fold increase in
PELD exception point use between 2002 and 2013 (83). In fact, PELD exception point
utilization now occurs in the majority of pediatric liver transplants, with significant
variability by region (84–86). Children < 12 months of age, including BA, have particularly
high rates of exception score requests, with those listed by exception scores more likely to
be white and privately insured (83). These data draw attention to shortcomings in the current
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allocation system for pediatric patients awaiting liver transplant and potential disadvantages
for underserved populations.

Aggressive use of alternative surgical strategies can increase access to liver transplant for
BA patients. Living donor transplants (LDT) may reduce not only pediatric waitlist time but
also waitlist mortality (87). LDT can be timed to optimize outcomes, transplanting when the
patient is in relatively good nutritional status and hopefully preserving brain and
neurocognitive development. Some believe that LDT as young as 6 months of age, before
patients show signs of significant malnutrition and hepatic decompensation, may avoid
complications of cirrhosis and allow for even better post-transplant outcomes. In addition,
LDT allows for procurement from a healthy donor with elective scheduling of the operation
and shorter cold ischemia times (41, 87). Excellent patient survival, comparable to older
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children, is seen even in very young (< 90 days old) and small (< 10 kilograms) infants
transplanted at experienced pediatric centers (88–90) . A Markov model simulation found an
increase of 17.45 additional expected life years when a LDT was performed in a patient with
a PELD of 15–25 with one or less systemic complication as compared to those with PELD
scores >25 who had more than one systemic complications (91). LDT at experienced centers
have excellent outcomes, for both donor and recipient, with similar surgical complication
rates as cadaveric transplants (92–95). Unfortunately, access to LDT is not uniform as public
insurers are less likely to cover donor surgeries. Increased utilization of split liver

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 Sundaram et al. Page 12

transplants, while more technically difficult, allows one donor to provide grafts for 2
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recipients. Currently, only about 10% of eligible donor livers in the United States are split,
missing an opportunity to expand access to transplant for BA patients (96). High pediatric
waitlist mortalities emphasize the continued need to target novel approaches to increase the
donor pool.

Family preparedness is critical to the long-term success of BA patients through the pre-and
post-transplant periods. It is essential that the family have a clear understanding of their
child’s medical condition, as well as resources available to them for support. Caregivers and
patients are often plagued with feelings of inadequacy, guilt, stress, lack of control, anger
and fear. Establishing a trusting relationship between the family, child, and care team can
ease these burdens. Acknowledging and addressing these emotions can also positively
impact both the long term family structure and disease management (97). Formal assessment
tools, such as the Pediatric Transplant Rating Instrument (PTR-I), can help identify specific
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psychosocial risk factors for poor outcomes, including family motivation, knowledge of the
transplant procedure, treatment adherence, and the quality of the relationship with the
medical team (97). In addition, children with BA may have neurocognitive and expressive
language developmental delays and gross motor weakness, thus benefitting from formal
neurodevelopmental testing and therapeutic interventions (98, 99). Early identification of
psychosocial and developmental vulnerabilities will allow for early interventions to
maximize outcomes (98, 99).

Conclusions
Until the time arrives in which we are able to understand the exact pathophysiology of
biliary atresia and, therefore, develop a primary cure, liver transplantation will remain a
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crucial treatment modality for this rare disease. Children with BA require liver transplant
related to a variety of morbid complications, including severe malnutrition, portal
hypertension and infection. Timing transplant for BA in order to maximize health, both pre
and post-transplant, remains as much an art as science. The current organ allocation schema
does not consistently allow for equitability of liver transplant in children affected by BA,
particularly those who are young. Pediatric waitlist mortality also emphasizes the critical
need for novel approaches to expand the donor pool. In the meantime, optimization of pre-
transplant care as highlighted in this review will allow transplant teams to maximize
transplant outcomes.

Acknowledgments
Supported in part by grants from NIH U01DK062453 and NIH/NCATS Colorado CTSA Grant UL1TR001082. Its
Author Manuscript

contents are the authors’ sole responsibility and do not necessarily represent official views the National Institutes of
Health.

References
1. Sokol RJ, Shepherd RW, Superina R, Bezerra JA, Robuck P, Hoofnagle JH. Screening and outcomes
in biliary atresia: summary of a National Institutes of Health workshop. Hepatology. 2007; 46:566–
581. [PubMed: 17661405]

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 13

2. Hitch DC, Shikes RH, Lilly JR. Determinants of survival after Kasai’s operation for biliary atresia
using actuarial analysis. J Pediatr Surg. 1979; 14:310–314. [PubMed: 480093]
Author Manuscript

3. Lilly JR, Karrer FM, Hall RJ, Stellin GP, Vasquez-Estevez JJ, Greenholz SK, Wanek EA, et al. The
surgery of biliary atresia. Ann Surg. 1989; 210:289–294. discussion 294-286. [PubMed: 2673083]
4. Altman RP, Lilly JR, Greenfeld J, Weinberg A, van Leeuwen K, Flanigan L. A multivariable risk
factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: twenty-five years of
experience from two centers. Ann Surg. 1997; 226:348–353. discussion 353-345. [PubMed:
9339941]
5. Shneider BL, Brown MB, Haber B, Whitington PF, Schwarz K, Squires R, Bezerra J, et al. A
multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr.
2006; 148:467–474. [PubMed: 16647406]
6. Schreiber RA, Barker CC, Roberts EA, Martin SR, Alvarez F, Smith L, Butzner JD, et al. Biliary
atresia: the Canadian experience. J Pediatr. 2007; 151:659–665. 665 e651. [PubMed: 18035148]
7. Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard J, Reding R, Auvert B. Is the
Kasai operation still indicated in children older than 3 months diagnosed with biliary atresia? J
Pediatr. 2001; 138:224–228. [PubMed: 11174620]
Author Manuscript

8. Alexopoulos SP, Merrill M, Kin C, Matsuoka L, Dorey F, Concepcion W, Esquivel C, et al. The
impact of hepatic portoenterostomy on liver transplantation for the treatment of biliary atresia: early
failure adversely affects outcome. Pediatr Transplant. 2012; 16:373–378. [PubMed: 22463739]
9. Davenport M, Puricelli V, Farrant P, Hadzic N, Mieli-Vergani G, Portmann B, Howard ER. The
outcome of the older (> or =100 days) infant with biliary atresia. J Pediatr Surg. 2004; 39:575–581.
[PubMed: 15065031]
10. Serinet MO, Wildhaber BE, Broue P, Lachaux A, Sarles J, Jacquemin E, Gauthier F, et al. Impact
of age at Kasai operation on its results in late childhood and adolescence: a rational basis for
biliary atresia screening. Pediatrics. 2009; 123:1280–1286. [PubMed: 19403492]
11. Superina R, Magee JC, Brandt ML, Healey PJ, Tiao G, Ryckman F, Karrer FM, et al. The anatomic
pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early
postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg.
2011; 254:577–585. [PubMed: 21869674]
12. Salzedas-Netto AA, Chinen E, de Oliveira DF, Pasquetti AF, Azevedo RA, da Silva Patricio FF,
Cury EK, et al. Grade IV fibrosis interferes in biliary drainage after Kasai procedure. Transplant
Author Manuscript

Proc. 2014; 46:1781–1783. [PubMed: 25131036]

13. Neto JS, Feier FH, Bierrenbach AL, Toscano CM, Fonseca EA, Pugliese R, Candido HL, et al.
Impact of Kasai portoenterostomy on liver transplantation outcomes: A retrospective cohort study
of 347 children with biliary atresia. Liver Transpl. 2015; 21:922–927. [PubMed: 25832004]
14. Sandler AD, Azarow KS, Superina RA. The impact of a previous Kasai procedure on liver
transplantation for biliary atresia. J Pediatr Surg. 1997; 32:416–419. [PubMed: 9094006]
15. Urahashi T, Ihara Y, Sanada Y, Wakiya T, Yamada N, Okada N, Mizuta K. Effect of repeat Kasai
hepatic portoenterostomy on pediatric live-donor liver graft for biliary atresia. Exp Clin
Transplant. 2013; 11:259–263. [PubMed: 23530849]
16. Meister RK, Esquivel CO, Cox KL, Concepcion W, Berquist W, Nakazato P, deVries PA. The
influence of portoenterostomy with stoma on morbidity in pediatric patients with biliary atresia
undergoing orthotopic liver transplantation. J Pediatr Surg. 1993; 28:387–390. [PubMed: 8468652]
17. Millis JM, Brems JJ, Hiatt JR, Klein AS, Ashizawa T, Ramming KP, Quinones-Baldrich WJ, et al.
Orthotopic liver transplantation for biliary atresia. Evolution of management. Arch Surg. 1988;
Author Manuscript

123:1237–1239. [PubMed: 3052364]

18. Visser BC, Suh I, Hirose S, Rosenthal P, Lee H, Roberts JP, Hirose R. The influence of
portoenterostomy on transplantation for biliary atresia. Liver Transpl. 2004; 10:1279–1286.
[PubMed: 15376306]
19. DeRusso PA, Ye W, Shepherd R, Haber BA, Shneider BL, Whitington PF, Schwarz KB, et al.
Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia
Research Consortium. Hepatology. 2007; 46:1632–1638. [PubMed: 17929308]
20. Sokol RJ, Stall C. Anthropometric evaluation of children with chronic liver disease. Am J Clin
Nutr. 1990; 52:203–208. [PubMed: 2375285]

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 14

21. Feranchak, ASFJ.; Sokol, RJ. Medical and Nutrtional Management of Cholestasis in the Infant and
Child. In: Suchy FJ, SR.; Balistereri, WF., editors. Liver Disease in Children. 4th. Cambridge
Author Manuscript

University Press; p. 419-434.

22. Rothenberg SS, Schroter GP, Karrer FM, Lilly JR. Cholangitis after the Kasai operation for biliary
atresia. J Pediatr Surg. 1989; 24:729–732.
23. Davenport M, Kerkar N, Mieli-Vergani G, Mowat AP, Howard ER. Biliary atresia: the King’s
College Hospital experience (1974–1995). J Pediatr Surg. 1997; 32:479–485. [PubMed: 9094023]
24. Qiao G, Li L, Cheng W, Zhang Z, Ge J, Wang C. Conditional probability of survival in patients
with biliary atresia after Kasai portoenterostomy: a Chinese population-based study. J Pediatr
Surg. 2015; 50:1310–1315. [PubMed: 25917622]
25. Chung PH, Wong KK, Tam PK. Predictors for failure after Kasai operation. J Pediatr Surg. 2015;
50:293–296. [PubMed: 25638622]
26. Kumagi T, Drenth JP, Guttman O, Ng V, Lilly L, Therapondos G, Hiasa Y, et al. Biliary atresia and
survival into adulthood without transplantation: a collaborative multicentre clinic review. Liver Int.
2012; 32:510–518. [PubMed: 22098694]
27. Lykavieris P, Chardot C, Sokhn M, Gauthier F, Valayer J, Bernard O. Outcome in adulthood of
Author Manuscript

biliary atresia: a study of 63 patients who survived for over 20 years with their native liver.
Hepatology. 2005; 41:366–371. [PubMed: 15660386]
28. Weisshaar E, Diepgen TL, Luger TA, Seeliger S, Witteler R, Stander S. Pruritus in pregnancy and
childhood--do we really consider all relevant differential diagnoses? Eur J Dermatol. 2005;
15:320–331. [PubMed: 16172038]
29. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease.
Hepatology. 2014; 59:1627–1637. [PubMed: 24089295]
30. Condino AA, Ivy DD, O’Connor JA, Narkewicz MR, Mengshol S, Whitworth JR, Claussen L, et
al. Portopulmonary hypertension in pediatric patients. J Pediatr. 2005; 147:20–26. [PubMed:
16027687]
31. Whitworth JR, Ivy DD, Gralla J, Narkewicz MR, Sokol RJ. Pulmonary vascular complications in
asymptomatic children with portal hypertension. J Pediatr Gastroenterol Nutr. 2009; 49:607–612.
[PubMed: 19820411]
32. Ecochard-Dugelay E, Lambert V, Schleich JM, Duche M, Jacquemin E, Bernard O.
Author Manuscript

Portopulmonary Hypertension in Liver Disease Presenting in Childhood. J Pediatr Gastroenterol

Nutr. 2015; 61:346–354. [PubMed: 25885880]
33. Noli K, Solomon M, Golding F, Charron M, Ling SC. Prevalence of hepatopulmonary syndrome in
children. Pediatrics. 2008; 121:e522–e527. [PubMed: 18310172]
34. Krowka MJ, Wiesner RH, Heimbach JK. Pulmonary contraindications, indications and MELD
exceptions for liver transplantation: a contemporary view and look forward. J Hepatol. 2013;
59:367–374. [PubMed: 23557870]
35. Yousef N, Habes D, Ackermann O, Durand P, Bernard O, Jacquemin E. Hepatorenal syndrome:
diagnosis and effect of terlipressin therapy in 4 pediatric patients. J Pediatr Gastroenterol Nutr.
2010; 51:100–102. [PubMed: 20543721]
36. Shusterman B, McHedishvili G, Rosner MH. Outcomes for hepatorenal syndrome and acute
kidney injury in patients undergoing liver transplantation: a single-center experience. Transplant
Proc. 2007; 39:1496–1500. [PubMed: 17580171]
37. Hadzic N, Quaglia A, Portmann B, Paramalingam S, Heaton ND, Rela M, Mieli-Vergani G, et al.
Hepatocellular carcinoma in biliary atresia: King’s College Hospital experience. J Pediatr. 2011;
Author Manuscript

159:617–622. e611. [PubMed: 21489554]

38. Brunati A, Feruzi Z, Sokal E, Smets F, Fervaille C, Gosseye S, Clapuyt P, et al. Early occurrence of
hepatocellular carcinoma in biliary atresia treated by liver transplantation. Pediatr Transplant.
2007; 11:117–119. [PubMed: 17239135]
39. Yu SB, Kim HY, Eo H, Won JK, Jung SE, Park KW, Kim WK. Clinical characteristics and
prognosis of pediatric hepatocellular carcinoma. World J Surg. 2006; 30:43–50. [PubMed:
16369702]

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 15

40. Romano F, Stroppa P, Bravi M, Casotti V, Lucianetti A, Guizzetti M, Sonzogni A, et al. Favorable
outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.
Author Manuscript

Pediatr Transplant. 2011; 15:573–579. [PubMed: 21797955]

41. Squires RH, Ng V, Romero R, Ekong U, Hardikar W, Emre S, Mazariegos GV. Evaluation of the
pediatric patient for liver transplantation: 2014 practice guideline by the American Association for
the Study of Liver Diseases, American Society of Transplantation and the North American Society
for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014; 60:362–398.
[PubMed: 24782219]
42. Utterson EC, Shepherd RW, Sokol RJ, Bucuvalas J, Magee JC, McDiarmid SV, Anand R, et al.
Biliary atresia: clinical profiles, risk factors, and outcomes of 755 patients listed for liver
transplantation. J Pediatr. 2005; 147:180–185. [PubMed: 16126046]
43. Smith J, Horowitz J, Henderson JM, Heymsfield S. Enteral hyperalimentation in undernourished
patients with cirrhosis and ascites. Am J Clin Nutr. 1982; 35:56–72. [PubMed: 6801958]
44. Moreno LA, Gottrand F, Hoden S, Turck D, Loeuille GA, Farriaux JP. Improvement of nutritional
status in cholestatic children with supplemental nocturnal enteral nutrition. J Pediatr Gastroenterol
Nutr. 1991; 12:213–216. [PubMed: 1904935]
Author Manuscript

45. Charlton CP, Buchanan E, Holden CE, Preece MA, Green A, Booth IW, Tarlow MJ. Intensive
enteral feeding in advanced cirrhosis: reversal of malnutrition without precipitation of hepatic
encephalopathy. Arch Dis Child. 1992; 67:603–607. [PubMed: 1599297]
46. Macias-Rosales R, Larrosa-Haro A, Ortiz-Gabriel G, Trujillo-Hernandez B. Effectiveness of
Enteral Versus Oral Nutrition With a Medium-Chain Triglyceride Formula to Prevent Malnutrition
and Growth Impairment in Infants With Biliary Atresia. J Pediatr Gastroenterol Nutr. 2016;
62:101–109. [PubMed: 26196199]
47. Sullivan JS, Sundaram SS, Pan Z, Sokol RJ. Parenteral nutrition supplementation in biliary atresia
patients listed for liver transplantation. Liver Transpl. 2012; 18:120–128. [PubMed: 21987426]
48. Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T, Rosenthal P, et al.
Efficacy of fat-soluble vitamin supplementation in infants with biliary atresia. Pediatrics. 2012;
130:e607–e614. [PubMed: 22891232]
49. Alatas FS, Hayashida M, Matsuura T, Saeki I, Yanagi Y, Taguchi T. Intracranial hemorrhage
associated with vitamin K-deficiency bleeding in patients with biliary atresia: focus on long-term
outcomes. J Pediatr Gastroenterol Nutr. 2012; 54:552–557. [PubMed: 22124309]
Author Manuscript

50. Shneider BL, Abel B, Haber B, Karpen SJ, Magee JC, Romero R, Schwarz K, et al. Portal
hypertension in children and young adults with biliary atresia. J Pediatr Gastroenterol Nutr. 2012;
55:567–573. [PubMed: 22903006]
51. Shneider BL, Bosch J, de Franchis R, Emre SH, Groszmann RJ, Ling SC, Lorenz JM, et al. Portal
hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus
Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant.
2012; 16:426–437. [PubMed: 22409296]
52. Duche M, Ducot B, Ackermann O, Jacquemin E, Bernard O. Progression to high-risk
gastroesophageal varices in children with biliary atresia with low-risk signs at first endoscopy. J
Pediatr Gastroenterol Nutr. 2015; 60:664–668. [PubMed: 25909866]
53. Wanty C, Helleputte T, Smets F, Sokal EM, Stephenne X. Assessment of risk of bleeding from
esophageal varices during management of biliary atresia in children. J Pediatr Gastroenterol Nutr.
2013; 56:537–543. [PubMed: 23263589]
54. Molleston JP, Shneider BL. Preventing variceal bleeding in infants and children: is less more?
Author Manuscript

Gastroenterology. 2013; 145:719–722. [PubMed: 23973849]

55. Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on
neurodevelopment in children: an updated systematic review with meta-regression. PLoS One.
2014; 9:e85760. [PubMed: 24465688]
56. Wagner M, Ryu YK, Smith SC, Patel P, Mintz CD. Review: effects of anesthetics on brain circuit
formation. J Neurosurg Anesthesiol. 2014; 26:358–362. [PubMed: 25144504]
57. Duche M, Ducot B, Ackermann O, Baujard C, Chevret L, Frank-Soltysiak M, Jacquemin E, et al.
Experience with endoscopic management of high-risk gastroesophageal varices, with and without

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 16

bleeding, in children with biliary atresia. Gastroenterology. 2013; 145:801–807. [PubMed:

23792202]
Author Manuscript

58. Eroglu Y, Emerick KM, Whitingon PF, Alonso EM. Octreotide therapy for control of acute
gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr. 2004; 38:41–47. [PubMed:
14676593]
59. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal
varices in 61 children with biliary atresia. J Pediatr Surg. 1989; 24:438–442. [PubMed: 2786958]
60. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the
prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-
analysis. Hepatology. 1999; 29:1655–1661. [PubMed: 10347104]
61. Zargar SA, Javid G, Khan BA, Yattoo GN, Shah AH, Gulzar GM, Singh J, et al. Endoscopic
ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic
portal venous obstruction. Hepatology. 2002; 36:666–672. [PubMed: 12198659]
62. Satapathy SK, Sanyal AJ. Nonendoscopic management strategies for acute esophagogastric
variceal bleeding. Gastroenterol Clin North Am. 2014; 43:819–833. [PubMed: 25440928]
63. Ling SC. Advances in the evaluation and management of children with portal hypertension. Semin
Author Manuscript

Liver Dis. 2012; 32:288–297. [PubMed: 23397529]

64. Boyer TD, Haskal ZJ. American Association for the Study of Liver D. The Role of Transjugular
Intrahepatic Portosystemic Shunt (TIPS) in the Management of Portal Hypertension: update 2009.
Hepatology. 2010; 51:306. [PubMed: 19902484]
65. Wolff M, Hirner A. Current state of portosystemic shunt surgery. Langenbecks Arch Surg. 2003;
388:141–149. [PubMed: 12942328]
66. Sen Sarma M, Yachha SK, Bhatia V, Srivastava A, Poddar U. Safety, complications and outcome of
large volume paracentesis with or without albumin therapy in children with severe ascites due to
liver disease. J Hepatol. 2015; 63:1126–1132. [PubMed: 26134185]
67. John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J
Gastroenterol. 2015; 21:3197–3205. [PubMed: 25805925]
68. Wong F, Watson H, Gerbes A, Vilstrup H, Badalamenti S, Bernardi M, Gines P, et al. Satavaptan
for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites
severity. Gut. 2012; 61:108–116. [PubMed: 21836029]
Author Manuscript

69. Larcher VF, Manolaki N, Vegnente A, Vergani D, Mowat AP. Spontaneous bacterial peritonitis in
children with chronic liver disease: clinical features and etiologic factors. J Pediatr. 1985;
106:907–912. [PubMed: 3998946]
70. de Vries W, de Langen ZJ, Groen H, Scheenstra R, Peeters PM, Hulscher JB, Verkade HJ, et al.
Biliary atresia in the Netherlands: outcome of patients diagnosed between 1987 and 2008. J
Pediatr. 2012; 160:638–644. e632. [PubMed: 22082947]
71. Bu LN, Chen HL, Chang CJ, Ni YH, Hsu HY, Lai HS, Hsu WM, et al. Prophylactic oral antibiotics
in prevention of recurrent cholangitis after the Kasai portoenterostomy. J Pediatr Surg. 2003;
38:590–593. [PubMed: 12677572]
72. Mendoza MM, Chiang JH, Lee SY, Kao CY, Chuang JH, Tiao MM, Hsieh CS. Reappraise the
effect of redo-Kasai for recurrent jaundice following Kasai operation for biliary atresia in the era
of liver transplantation. Pediatr Surg Int. 2012; 28:861–864. [PubMed: 22872304]
73. Nio M, Sasaki H, Tanaka H, Okamura A. Redo surgery for biliary atresia. Pediatr Surg Int. 2013;
29:989–993. [PubMed: 23982391]
74. Bondoc AJ, Taylor JA, Alonso MH, Nathan JD, Wang Y, Balistreri WF, Bezerra JA, et al. The
Author Manuscript

beneficial impact of revision of Kasai portoenterostomy for biliary atresia: an institutional study.
Ann Surg. 2012; 255:570–576. [PubMed: 22258066]
75. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK. Advisory Committee on Immunization
Practices Centers for Disease C, Prevention General recommendations on immunization:
recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2006; 55:1–48.
76. Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, Bousvaros A, et al. 2013
IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis.
2014; 58:e44–e100. [PubMed: 24311479]

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 17

77. Feldman AGSS, Beaty B, Kempe A. Hospitalizations for Respiratory Syncitial Virus, Influenza,
and other Vaccine Preventable Illnesses in Liver Transplant Recipients at Freestanding Childrens
Author Manuscript

Hospitals. Hepatology. 2015; 62:279A. [PubMed: 25810240]

78. Feldman AGSS, Beaty B, Kempe A. Immunization Practices Amongst Pediatric Transplant
HEpatologists at SPLIT centers. Hepatology. 2015; 62:177A.
79. Barshes NR, Lee TC, Udell IW, O’Mahoney CA, Karpen SJ, Carter BA, Goss JA. The pediatric
end-stage liver disease (PELD) model as a predictor of survival benefit and posttransplant survival
in pediatric liver transplant recipients. Liver Transpl. 2006; 12:475–480. [PubMed: 16498644]
80. OPTN-RHSA Final Rule with comment period. Fed Regist. 1998:16296–16338. [PubMed:
10177763]
81. Tessier ME, Harpavat S, Shepherd RW, Hiremath GS, Brandt ML, Fisher A, Goss JA. Beyond the
Pediatric end-stage liver disease system: solutions for infants with biliary atresia requiring liver
transplant. World J Gastroenterol. 2014; 20:11062–11068. [PubMed: 25170195]
82. Kim WR, Smith JM, Skeans MA, Schladt DP, Schnitzler MA, Edwards EB, Harper AM, et al.
OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant. 2014; (14 Suppl 1):69–96.
[PubMed: 24373168]
Author Manuscript

83. Hsu EK, Shaffer M, Bradford M, Mayer-Hamblett N, Horslen S. Heterogeneity and disparities in
the use of exception scores in pediatric liver allocation. Am J Transplant. 2015; 15:436–444.
[PubMed: 25612496]
84. Shneider BL, Neimark E, Frankenberg T, Arnott L, Suchy FJ, Emre S. Critical analysis of the
pediatric end-stage liver disease scoring system: a single center experience. Liver Transpl. 2005;
11:788–795. [PubMed: 15973720]
85. Shneider BL, Suchy FJ, Emre S. National and regional analysis of exceptions to the Pediatric End-
Stage Liver Disease scoring system (2003–2004). Liver Transpl. 2006; 12:40–45. [PubMed:
16382460]
86. Salvalaggio PR, Neighbors K, Kelly S, Emerick KM, Iyer K, Superina RA, Whitington PF, et al.
Regional variation and use of exception letters for cadaveric liver allocation in children with
chronic liver disease. Am J Transplant. 2005; 5:1868–1874. [PubMed: 15996233]
87. Lacaille F, Sokal E. Living-related liver transplantation. J Pediatr Gastroenterol Nutr. 2001;
33:431–438. [PubMed: 11698758]
Author Manuscript

88. Yang SC, Huang CJ, Chen CL, Wang CH, Wu SC, Shih TH, Juang SE, et al. Living donor liver
transplantation with body-weight more or less than 10 kilograms. World J Gastroenterol. 2015;
21:7248–7253. [PubMed: 26109812]
89. Sokal EM, Veyckemans F, de Ville de Goyet J, Moulin D, Van Hoorebeeck N, Alberti D, Buts JP,
et al. Liver transplantation in children less than 1 year of age. J Pediatr. 1990; 117:205–210.
[PubMed: 2380818]
90. Sundaram SS, Alonso EM, Anand R. Study of Pediatric Liver Transplantation Research G.
Outcomes after liver transplantation in young infants. J Pediatr Gastroenterol Nutr. 2008; 47:486–
492. [PubMed: 18852642]
91. Arnon R, Leshno M, Annunziato R, Florman S, Iyer K. What is the optimal timing of liver
transplantation for children with biliary atresia? A Markov model simulation analysis. J Pediatr
Gastroenterol Nutr. 2014; 59:398–402. [PubMed: 24821536]
92. Mizuta K, Urahashi T, Ihara Y, Sanada Y, Wakiya T, Yamada N, Okada N, et al. Living donor liver
transplantation in children with cholestatic liver disease: a single-center experience. Transplant
Proc. 2012; 44:469–472. [PubMed: 22410047]
Author Manuscript

93. Barshes NR, Lee TC, Balkrishnan R, Karpen SJ, Carter BA, Goss JA. Orthotopic liver
transplantation for biliary atresia: the U.S. experience. Liver Transpl. 2005; 11:1193–1200.
[PubMed: 16184564]
94. Bourdeaux C, Darwish A, Jamart J, Tri TT, Janssen M, Lerut J, Otte JB, et al. Living-related versus
deceased donor pediatric liver transplantation: a multivariate analysis of technical and
immunological complications in 235 recipients. Am J Transplant. 2007; 7:440–447. [PubMed:
17173657]

Liver Transpl. Author manuscript; available in PMC 2018 January 01.

 Sundaram et al. Page 18

95. Gurevich M, Guy-Viterbo V, Janssen M, Stephenne X, Smets F, Sokal E, Lefebvre C, et al. Living
Donor Liver Transplantation in Children: Surgical and Immunological Results in 250 Recipients at
Author Manuscript

Universite Catholique de Louvain. Ann Surg. 2015; 262:1141–1149. [PubMed: 25563870]

96. Cauley RP, Vakili K, Fullington N, Potanos K, Graham DA, Finkelstein JA, Kim HB. Deceased-
donor split-liver transplantation in adult recipients: is the learning curve over? J Am Coll Surg.
2013; 217:672–684. e671. [PubMed: 23978530]
97. Fung E, Shaw RJ. Pediatric Transplant Rating Instrument - a scale for the pretransplant psychiatric
evaluation of pediatric organ transplant recipients. Pediatr Transplant. 2008; 12:57–66. [PubMed:
18186890]
98. Caudle SE, Katzenstein JM, Karpen S, McLin V. Developmental assessment of infants with biliary
atresia: differences between boys and girls. J Pediatr Gastroenterol Nutr. 2012; 55:384–389.
[PubMed: 22516863]
99. Caudle SE, Katzenstein JM, Karpen SJ, McLin VA. Language and motor skills are impaired in
infants with biliary atresia before transplantation. J Pediatr. 2010; 156:936–940. 940 e931.
[PubMed: 20223479]
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Table 1

Indications for Liver Transplant in Biliary Atresia

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Indications for Liver Transplant in Biliary Atresia

Failed Kasai portoenterostomy
Early absence of bile flow
Late development of cirrhosis despite good bile flow
Late Diagnosis - primary liver transplant
Severe nutritional compromise
Failure to thrive requiring aggressive nutritional support
Metabolic bone disease resulting in fractures
Bacterial Cholangitis
Recurrent despite appropriate antibiotic therapy
Multi-drug resistant organisms
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Life threatening sepsis

Recurrent hospitalizations impairing quality of life
Complications of Portal Hypertension
Refractory variceal bleeding
Significant ascites and episodes of spontaneous bacterial peritonitis
Symptomatic thrombocytopenia
Severe pruritus
Pulmonary Vascular Disorders
Hepatopulmonary Syndrome
Portopulmonary Hypertension
Hepatorenal Syndrome
Hepatic malignancy
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Hepatocellular carcinoma
Cholangiocarcinoma
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Table 2

Medical Treatment Options for Biliary Atresia Pre-transplant (21)

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Treatment Indications Dosage Side Effects

Ursodeoxycholic acid Cholestasis 15–20 mg/kg/d Diarrhea

Pruritus Increased pruritus
Hypercholesterolemia

Bile Acid binding resins Xanthoma 250–500 mg/kg/d Constipation

(cholestyramine, colestipol Pruritus (cholestyramine Hyperchloremic acidosis
colesevelam) Hypercholesterolemia and colestipol) Binding of drugs
Increased steatorrhea
Intestinal obstruction

Naltrexone Pruritus 1–2 mg/kg/d Nausea

Headache
Opioid withdrawal reactions
Hepatotoxicity (?)

Phenobarbital Pruritus 3–10 mg/kg/d Drowsiness

Hypercholesterolemia Behavioral changes
Interference with vitamin D
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metabolism
Risk for suicide and suicidal
behavior

Rifampicin Pruritus 10 mg/kg/d Hepatotoxicity

Drug interactions
Hemolytic anemia
Renal failure

Antihistamines Pruritus Diphenhydramine, Drowsiness

5 mg/kg/d or
Hydroxyzine 2
mg/kg/d

Ultraviolet B light Pruritus Skin burn

Trimethoprim(TMP)/ Cholangitis 2–5 mg/kg/day Hypersensitivity reactions

sulfamethoxasole prophylaxis TMP Displacing unconjugated
bilirubin from albumin
Bone marrow suppression
Hepatotoxicity
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Furosemide Ascites or edema 1 mg/kg/dose (IV) Hyponatremia

1–2 mg/kg/d (Oral) Hypokalemia
Dehydration
Hypersensitivity reactions
Hearing impairment
Bone marrow suppression

Spironolactone Ascites 2–6 mg/kg/day Hyperkalemia

Hyponatremia
Dehydration
Gynecomastia
Hypersensitivity reactions

Octreotide Variceal bleeding 1–5 µg/kg/hr Hypotension

Bowel ischemia

Albumin Refractory ascites 1 gm/kg; 20–25% Fluid overload

albumin (IV)
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Table 3

Nutritional Management of Biliary Atresia Pre-transplant (21)

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Nutritional Index of Assessment Treatment Options Side Effect/

Factor Toxicity

Macronutrients

Energy Anthropometrics, Caloric goal: 125–140% of RDA based on

triceps and subscapular weight for height at 50th percentile
skinfold thickness,
serial measurements of Fortified breast milk or MCT oil-containing infant
weight/height, indirect formulas (e.g., Pregestimil, Alimentum)
calorimetry, fat
malabsorption Concentrate infant formula or add glucose Financial burden,
polymers (polycose powder or solution) or MCT essential fatty
oil products to achieve 24–27 kcal/oz (or 100.5- acid deficiency
113 kjoule/30 mL) formula
Supplemental nighttime or continuous daily
nasogastric drip feedings, consider parenteral Aspiration
nutrition if unresponsive to NG feedings pneumonia
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MCT oil supplements: 1–2 mL/kg/d in 2–4 doses

Essential EFA deficiency: triene: Corn oil or oral lipid emulsions

Fatty Acids tetraene ratio >0.2, IV lipid emulsions
(EFA) ↓linoleic acid level

Protein Mid-arm muscle Protein intake 2–4 g/kg/d in infants

circumference, serum
albumin, prealbumin, Consider protein intake 2 g/kg/d for overt
RBP, transferrin (may hepatic encephalopathy
be reduced due to liver
Branched-chain amino acid containing formula Unknown
failure)
or supplements

Fat-soluble vitamins

Vitamin A Vitamin A deficiency: 5,000–25,0000 U/d orally of water-miscible Hepatotoxicity,

retinol: RBP molar ratio preparation of vitamin A, IM vitamin A injections pseudotumor
<0.8 or serum retinol cerebri,
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<20 µg/dL; relative bone lesions,

dose response; hypercalcemia
conjunctival impression
cytology; xerosis, Bitot
spots

Vitamin D Vitamin D deficiency: Vitamin D3, up to 500–1000 IU/kg/d or Hypercalcemia,

25-OH-D <14 ng/mL, 25-OHD, 3–5 µg/kg/d or nephrocalcinosis
(insufficiency<30 1,25-OH2-D, 0.05–0.2 µg/kg/d
ng/ml), Rickets,
Osteomalacia

Vitamin E Vitamin E deficiency: α-Tocopherol (acetate), 25–200 IU/kg/d Potentiation of

vit. E: total lipid ratio vit. K deficiency-
<0.6 mg/g (age <1 yr) induced
and <0.8 mg/g (age >1 coagulopathy.
yr)
TPGS (tocophersolen), 15–25 IU/kg/d Diarrhea,
hypersomolarity
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Vitamin K Vitamin K deficiency: Oral phytonadione, 2.5 mg twice/wk to 10 mg/d

prolonged prothrombin IM phytonadione 2–5 mg every 4 wk
time/INR, elevated
PIVKA-II

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 Sundaram et al. Page 22

Nutritional Index of Assessment Treatment Options Side Effect/

Factor Toxicity
Prevent deficiency of water-soluble vitamins Fats soluble
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Water
soluble Dose: 1–2 x RDA vitamin toxicity
vitamins

Mineral and trace elements

Calcium Calcium deficiency due 25–100 mg/kg/d up to 800–1200 mg/d Hypercalcemia,

to steatorrhea despite hypercalciuria
corrected vit. D status

Phosphorus Low serum phosphorus 25–50 mg/kg/d up to 500 mg/d Gastrointestinal

despite corrected vit D intolerance
and calcium status

Magnesium Magnesium deficiency: Magnesium oxide, 1–2 mEq/kg/d orally or 50% Respiratory
serum Mg<1.4 mEq/L solution MgSO4 0.3–0.5 mEq/kg IV over 3 hr depression,
(max. 3–6 mEq) lethargy, coma

↓Intestinal
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Zinc Zinc deficiency: plasma ZincSO4 solution (10 mg elemental zinc/mL)

zinc <60 µg/dL 1 mg/kg/d orally for 2–3 months absorption of
copper and iron

Selenium Selenium deficiency: 1–2 µg/kg/d of oral sodium selenite or 1–2 Dermatologic
plasma Se <40 µg/dL µg/kg/d selenium in parenteral nutrition solution changes (skin
eruptions,
pathologic nails,
hair loss),
dyspepsia,
diarrhea,
anorexia

Iron Iron deficiency: ↓serum 5–6 mg/kg/d of elemental iron Teeth staining,
iron, ↑TIBC, iron hemorrhagic
saturation index <16% gastroenteritis
Overdose:
Metabolic
acidosis, coma,
liver failure
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