INVITED REVIEW
Biliary Atresia: Clinical Lessons Learned
Amy G. Feldman and Cara L. Mack
ABSTRACT
Biliary atresia is a rare disease of unclear etiology, in which obstruction of
the biliary tree causes severe cholestasis leading to cirrhosis and ultimately
death if left untreated. Biliary atresia is the leading cause of neonatal
cholestasis and the most frequent indication for pediatric liver transplan-
tation. Any infant with persistent jaundice beyond 2 weeks of life needs to be
evaluated for biliary atresia with fractionation of the bilirubin into con-
jugated and unconjugated portions. Early performance of a hepatoportoen-
terostomy in the first 45 days of life to restore bile flow and lessen further
damage to the liver is thought to optimize outcome. Despite surgery,
progressive liver scarring occurs, and 80% of patients with biliary atresia
will require liver transplantation during childhood.
Key Words: biliary atresia, liver transplant, neonatal cholestasis
(JPGN 2015;61: 167–175)
B iliary atresia (BA) is the most common cause of cholestasis in
the first 3 months of life and the most frequent pediatric
indication for liver transplantation, accounting for up to 50% of
pediatric liver transplants in the United States. The incidence in the
United States is
1 in 12,000 live births and is the highest in Taiwan
(
1 in 5600) and the lowest in Europe (
1 in 18,000). BA is more
common in female infants, Asians, and African Americans (1);
however, it can be seen in infants from all of the countries and racial
populations. At the time of diagnosis, a Kasai hepatoportoenter-
ostomy (HPE) is performed in an attempt to reestablish biliary flow.
Unfortunately, this procedure fails to prevent the intrahepatic
biliary cirrhosis from progressing, and the majority of children
will need transplant for survival.
PATHOGENESIS
The etiology of BA is unknown, and theories of pathogenesis
include viral infection, autoimmune-mediated bile duct destruction,
and abnormalities in bile duct development because of genetic
mutations. With regard to a gene mutation association, a recent
study from China analyzed single-nucleotide polymorphisms
(SNPs) and susceptibility genes in BA through genome-wide
association studies (2). The results revealed a strong association
of BA with the SNP rs17095355 on chromosome 10q24. Two genes
Received September 17, 2014; accepted January 30, 2015.
From the Section of Pediatric Gastroenterology, Hepatology and Nutrition,
Digestive Health Institute, Children’s Hospital Colorado, University of
Colorado School of Medicine, Aurora.
Address correspondence and reprint requests to Amy G. Feldman, MD,
Section of Pediatric Gastroenterology, Hepatology and Nutrition,
Digestive Health Institute, Children’s Hospital Colorado, University
of Colorado School of Medicine, 13123 East 16th Ave, B290, Aurora,
CO 80045 (e-mail: amy.feldman@childrenscolorado.org).
The authors report no conflicts of interest.
Copyright # 2015 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000000755
JPGN  Volume 61, Number 2, August 2015
Copyright 2015 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
in the region of this SNP include X-prolyl aminopeptidase P1
(XPNPEP1) and adducin 3 (ADD3). XPNPEP1 is expressed in
biliary epithelia and is involved in the metabolism of inflammatory
mediators. ADD3 is expressed in hepatocytes and biliary epithelia
and is involved in the assembly of spectrin-actin membrane protein
networks at sites of cell-to-cell contact. Defective ADD3 could
result in excessive deposition of actin and myosin, contributing to
biliary fibrosis. A recent study from the United States tested the
association of SNPs on chromosome 10q24 and BA and found the
strongest signal to be at rs7099604 within the ADD3 gene (3). We
refer the reader to a complete review of potential etiologies of BA
(4), and will focus herein on recent immunopathogenesis studies.
A plethora of data have been accumulated to support both
an early virus infection and an aberrant immune response in the
pathogenesis of disease. One theory that ties these 2 together is that
the bile duct injury in BA may be initiated by a virus infection
followed by a secondary autoimmune response targeting bile duct
epithelia (5). The damaged bile duct cells may express self-proteins
that are recognized as foreign, and elicit autoreactive T-cell-
mediated inflammation and B-cell production of autoantibodies.
In 1974, Landing (6) first proposed that BA and other
infantile obstructive cholangiopathies were caused by viral infec-
tion of the liver and the hepatobiliary tree. Candidate viruses that
may trigger the bile duct injury include cytomegalovirus (CMV)
(7), rotavirus (8), and reovirus (9). Controversy remains as to the
detection of all of these viruses at the time of diagnosis, and it is
possible that the virus infection of the biliary tree is short-lived.
Rotavirus is an interesting candidate, because the rhesus rotavirus-
induced mouse model of BA recapitulates the early events in the
inflammatory biliary obstruction found in human BA (8,10). A
recent study by Lin et al (10) found a significant decrease in BA
incidence in Taiwan following introduction of the rotavirus vacci-
nation. The authors proposed that although rotavirus vaccination is
initiated at 2 months of age, later than the usual age of onset of BA,
herd immunity may decrease rotavirus infection during pregnancy
or the neonatal period. The authors also, however, showed that the
incidence of BA was negatively correlated with the country’s gross
domestic product, so further studies will be important to determine
whether the rotavirus vaccine or overall improvement in socio-
economic status was truly responsible for the decreased incidence
of BA. The greatest body of research entails investigations of CMV
at the time of diagnosis of BA. A higher prevalence of CMV
antibodies in the mothers of infants with BA, higher serum CMV-
immunoglobulin (Ig) M levels, and greater amounts of Ig deposits
on the canalicular membrane of the hepatocytes in infants with BA
have been reported (11). Strong evidence for a perinatal CMV
infection associated with BA was described by Xu et al (12). Liver
tissue obtained at the time of portoenterostomy on 85 infants with
BA was analyzed by real-time polymerase chain reaction (PCR) for
the presence of multiple viruses, and the majority (60%) was
positive for CMV. Studies confirming the presence of CMV in
PCR-positive liver samples were performed with immunocyto-
chemical detection of CMV-pp65 antigens within liver bile duct
epithelia and hepatocytes. Brindley et al (13) analyzed the liver
memory T-cell response to a variety of viruses from infants with BA
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at the time of diagnosis. The majority (56%) of patients with BA had
significant increase in interferon (IFN)-g-producing liver T cells in
response to CMV homogenate and CMV-pp65 antigen, suggesting
that perinatal CMV infection had occurred. An interesting obser-
vation from the past virus studies is the ability of all of the 2 above-
mentioned viruses to infect and damage bile duct epithelia, lending
support to a primary cholangiotropic viral infection as the initiating
event in the pathogenesis of BA.
In the last decade, scientific investigations have concentrated
on the role of the adaptive immune system in bile duct injury in BA.
A plausible theory that could explain the progression of biliary tract
injury that predominates in BA is that of an autoimmune-mediated
attack on biliary epithelia. After the initial viral insult to the biliary
tree, the damaged bile duct epithelial cells may express previously
sequestered ‘‘self’’ antigens that are recognized as foreign and elicit
autoreactive TH1-cell-mediated inflammation and B-cell pro-
duction of autoantibodies directed at duct epithelia. The predomi-
nant cellular immune response in BA encompasses activated CD4þ
and CD8þ T cells within portal tracts that produce TH1 cytokines
(interleukin-2 and IFN-g) and macrophages secreting tumor necro-
sis factor (TNF)-a (14,15). These lymphocytes have been found
invading between bile duct epithelia, leading to degeneration of
intrahepatic bile ducts. The strongest evidence for the autoimmune
theory has been gained from mouse studies, in which autoreactive T
cells and autoantibodies targeting bile duct epithelia have been
identified (16–18). In humans, only circumstantial evidence exists
for the role of autoimmunity in BA pathogenesis. Human leukocyte
antigen (HLA) associations with BA have been reported with
conflicting results. European and American studies of HLA pre-
dominance in BA found no significant differences compared with
controls (19). In contrast, a Japanese study found significant
association between BA and HLA-DR2 as well as a linkage
disequilibrium with a high frequency of HLA-A24-B52-DR2
(20). The presence of autoantibodies and periductal immune depos-
its, suggesting a humoral autoimmune response, has also been
described (11,17). The potential contribution of adaptive immune
and autoimmune responses to bile duct injury in BA is represented
in Figure 1. Research pertaining to deciphering the etiology of BA is
robust and is focusing on genetic and immunologic links to the
pathogenesis of disease.
Another area of research in BA has focused on the extensive
fibrosis that occurs with this disease. Portal bridging fibrosis and
even cirrhosis are commonly seen at the time of diagnosis of BA,
and the degree of fibrosis correlates with outcome. One mechanism
of fibrogenesis that could explain the severity of fibrosis entails the
Hedgehog (Hh) pathway. The Hh pathway is important in tissue
remodeling and Hh activation, with subsequent epithelial-mesench-
ymal transition (EMT) of cells involved in fibrogenesis related to
hepatobiliary diseases. It has been previously shown in BA that
biliary epithelia undergo EMT, promoting fibrosis. BA patient
livers demonstrated significant upregulation of Hh ligand within
intra- and extrahepatic ductular cells, as well as increased expres-
sion of Hh target genes. In addition, immature ductular cells within
BA livers showed a profibrotic mesenchymal phenotype that was
Hh responsive (21). The authors concluded that excessive Hh
activation impedes ductular morphogenesis and enhances fibrogen-
esis by promoting accumulation of immature ductular cells with a
mesenchymal phenotype. Most searches for defects at the chromo-
somal level have produced negative results; however, recently,
a genetic link to the Hh pathway has been described. Identified
deletions at chromosome 2q37.3 in patients with BA results in
deletion of 1 copy of glypican-1 (GPC1), a heparan sulfate pro-
teoglycan that regulates Hh signaling and inflammation. Liver
tissues of patients with BA had reduced levels of apical GPC1
in cholangiocytes compared with controls. Cui et al (22) used a gpc1
knockdown zebrafish model to show developmental biliary defects
and gallbladder atresia. Exposure of the gpc1 morphants to cyclo-
pamine, an Hh antagonist, rescued the gpc1-knockdown phenotype.
These studies not only identify GPC1 as a risk gene for BA but also
offer mechanistic insight into the potential pathogenic role of GPC1
and Hh in BA.
Another potential mechanism associated with activation of
fibrosis involves the recent novel finding of prominin-1 (PROM-1)
expressing stem cells adjacent to ductular reactions within the portal
tracts of patients with BA and in murine BA (23). The PROM-1þ
cells expressed both markers of epithelial and mesenchymal cells,
produced collagen, and correlated with portal fibrosis and bilirubin
levels. In addition, expansion of PROM-1þ cells was associated
with the activation of fibroblast growth factor and transforming
growth factor-b providing potential mechanisms of action of

TNF-α
OPN Clonal iNOS
expansion γ
Key OPN N-
CXCR3 IF
Virus Ag IL-12 Perforin
Bile duct epithelial Ag granzyme
Macrophage CD8+
CD4+ IFN-γ
(•) CD8+
Dendritic cell (TH1)
Apoptotic bile duct CD4+ T-cell activation
epithelia
B cell

FIGURE 1. Contribution of adaptive immunity in the pathogenesis of BA. This figure summarizes human investigations pertaining to the role of
adaptive immunity in bile duct injury and offers a theory on the role of autoimmune responses in the pathogenesis of disease. Bile duct injury is
initiated by virus infection (ie, CMV) with clonal expansion of virus-specific CD4þ T cells. IL-12, osteopontin, and CXCR3 chemokine receptors all
promote TH1 cell differentiation. These TH1 cells activate effector cells including macrophages (via CD4þ IFN-g stimulation) with subsequent
generation of TNF-a and inducible nitric oxide synthase, cytotoxic CD8þ T cells that directly invade epithelia and release cytotoxic molecules, and
B cells that mature into antibody-producing plasma cells with release of IgM and IgG targeting bile duct epithelia. Over time, proteins from
apoptotic bile duct epithelia may be presented and seen as ‘‘foreign,’’ eliciting autoreactive T-cell-mediated inflammation that perpetuates the bile
duct injury. BA ¼ biliary atresia; CMV ¼ cytomegalovirus; IFN ¼ interferon; Ig ¼ immunoglobulin; IL ¼ interleukin; TNF ¼ tumor necrosis factor.

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 JPGN  Volume 61, Number 2, August 2015 Biliary Atresia: Clinical Lessons Learned

fibrogenesis. These exciting studies of fibrogenesis in BA provide
insight into potential future targets of antifibrotic therapy.
CLINICAL FEATURES
There are 3 distinct clinical patterns of BA (24). The majority
of infants with BA (84%) have the perinatal or acquired form of BA
without associated major malformation. These babies are asympto-
matic, often jaundice-free at birth and appear to be thriving until 2 to
6 weeks of life when they have persistent jaundice, acholic stools,
dark urine, and hepatomegaly. On laboratory evaluation, they have
elevated total and direct bilirubin levels, elevated alanine amino-
transferase (ALT) and aspartate aminotransferase (AST) levels, and
elevated g-glutamyl transpeptidase (GGTP) levels >200 IU/L.
Ascites and splenomegaly, results of portal hypertension, are late
findings and not usually seen on initial presentation. In a second
group (6%), infants have at least 1 major malformation but no
laterality defects. Finally, in 10% of patients with BA, the infants
are syndromic and have 1 or more laterality defects. These infants
appear jaundiced from birth and do not have an asymptomatic
period.
EVALUATION OF NEONATAL CHOLESTASIS
Any infant who remains jaundiced at 2 weeks of age needs to
be evaluated for cholestasis, with fractionation of the bilirubin into a
conjugated (direct) and unconjugated (indirect) portion. Conjugated
hyperbilirubinemia associated with cholestasis is defined as a
direct/conjugated bilirubin of >1 to 2 mg/dL and >20% of the
total bilirubin concentration. One must have a high suspicion for
hepatobiliary dysfunction and proceed with further workup in the
setting of cholestasis, acholic stools, hepatomegaly, or splenome-
galy. In an infant with cholestasis, further evaluation should be
conducted with a sense of urgency to identify those causes that are
amenable to medical and surgical correction (Fig. 2). Outcome of
infants with BA is directly correlated to the timing of diagnosis and
HPE. A comprehensive metabolic panel will likely show a total
bilirubin of 5 to 12 mg/dL and an ALT and AST in the 100 to 200 U/
L, findings not unique to BA. It is rare for an infant with BA to have
a GGTP level <200 U/L. If a low GGTP is observed, progressive
familial intrahepatic cholestasis (PFIC) type 1, PFIC type 2, an
inborn error of bile acid synthesis or metabolism, and panhypopi-
tuitarism should be strongly considered. Findings on history and
physical examination can guide evaluation for specific infectious
and metabolic causes. Initial evaluation should include testing for
a1-antitrypsin (A1AT) deficiency (A1AT level and phenotype),
because this disease can mimic BA early on and, if identified,
the workup for BA would not be necessary. In addition to BA, the
differential for neonatal cholestasis includes extrahepatic obstruc-
tion, infection, endocrine abnormality, metabolic and genetic dis-
orders, and drug injury (Table 1). It is important to quickly identify
treatable causes of cholestasis including infection, galactosemia,
tyrosinemia, cystic fibrosis, hypopituitarism, choledochal cyst,
spontaneous perforation of the common bile duct, and inspissated
bile in the common bile duct.
An abdominal ultrasound is an important part of the initial
evaluation of any infant with cholestasis and should be performed as
soon as it is evident that unexplained cholestasis is present. Ultra-
sound will assess liver structure, size, and composition; look for the

2-week-old infant
with jaundice

Fractionate bilirubin

Direct bilirubin ≥1 mg/dL (if total bilirubin is <5 mg/dL)

Direct bilirubin ≥20% of total (if total bilirubin is >5 mg/dL)
Hepatosplenomegaly, acholic stools

Yes

Obtain ultrasound and α1-antitrypsin level/phenotype

Proceed with
liver biopsy
Ultrasound with ZZ or SZ Normal ultrasound
obstructing stone, mass, α1 and α1
choledochal cyst phenotype
phenotype.
Bile plugs in portal bile ducts,
Consider urine
bile ductular proliferation,
culture, urine portal fibrosis
Surgical consult α1 reducing
antitrypsin substances, urine
deficiency succinylacetone,
Proceed with intraoperative
specific infectious
cholangiogram. Surgeon
studies as clinically should be prepared to perform
indicated hepatoportoenterostomy

FIGURE 2. Diagnostic algorithm for BA. Infants who remain jaundiced at 2 weeks of age should have their bilirubin fractionated. If the conjugated/
direct bilirubin is 1 to 2 mg/dL or 20% of the total bilirubin, or if the child has pale stools, hepatomegaly, or splenomegaly, further evaluation
needs to be completed including an abdominal ultrasound and a serum A1AT phenotype and level. If the above workup is negative, a liver biopsy
should be performed. A1AT ¼ a1-antitrypsin; BA ¼ biliary atresia.

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 Feldman and Mack JPGN  Volume 61, Number 2, August 2015

TABLE 1. Differential diagnosis of neonatal cholestasis

Infectious Genetic and metabolic

Viral (adenovirus, CMV, coxsackie virus, Epstein-Barr, A1AT deficiency
echovirus,enterovirus, hepatitis A/B/C, herpes simplex, human Alagille syndrome
immunodeficiency virus, parvovirus, reovirus, rubella) Aagenaes syndrome
Bacterial (urinary tract infection, sepsis, listeriosis, tuberculosis) Arthrogryposis, renal dysfunction, and cholestasis syndrome
Spirochete (syphilis, leptospirosis) Bile acid synthetic defects
Parasites (toxoplasmosis, malaria, toxocariasis) Cholestasis of North American Indians
Histoplasmosis Cholesterol synthesis defects
Citrin deficiency
Citrin deficiency
Cystic fibrosis
Dubin-Johnson syndrome
Fatty acid oxidation defects
Galactosemia
Glycogen storage disease type 4
GRACILE syndrome
Hereditary fructose intolerance
Indian childhood cirrhosis
Mitochondrial respiratory chain disorders
Neonatal iron storage disease
Niemann-Pick type C
Peroxisomal disorders
PFIC 1, 2, and 3 (FIC1, BSEP, or MDR3 deficiency)
Rotor syndrome
Lipid storage diseases
Trisomy 13, 18, 21, Turner syndrome
Tyrosinemia
Urea cycle defects
Endocrine Toxins
Hypothyroidism Drugs
Hypopituitarism (septooptic dysplasia) Total parenteral nutrition associated cholestasis
McCune-Albright syndrome Herbal products
Anatomic obstruction Other
BA Cardiovascular abnormalities
Caroli disease Ischemia-reperfusion injury
Choledochal cyst or other congenital bile duct anomaly Perinatal asphyxia
Congenital hepatic fibrosis Extracoporeal membrane oxygenation
Gallstones or biliary sludge Budd-Chiari syndrome
Inspissated bile syndrome Venoocclusive disease
Neonatal sclerosing cholangitis Graft-vs-host disease
Nonsyndromic bile duct paucity Hemophagocytic lymphohistiocytosis
Spontaneous perforation of the bile duct Idiopathic neonatal hepatitis
Tumor/mass Neonatal lupus erythematosus
Malignancy (neonatal leukemia)

A1AT ¼ a1-antitrypsin; BA ¼ biliary atresia; BSEP ¼ bile salt export pump; CMV ¼ cytomegalovirus; PFIC ¼ progressive familial intrahepatic cholestasis.

presence of ascites; identify other causes of extrahepatic obstruction
such as choledochal cyst, mass, sludge, or stone. If the infant has a
choledochal cyst then no further workup is necessary, and the infant
should be referred directly to a pediatric surgeon. Although there
may be findings on an abdominal ultrasound suggestive of BA
including absence of the gallbladder, a triangular cord sign (a cone-
shaped fibrotic mass cranial to the bifurcation of the portal vein),
situs inversus, or splenic abnormalities; an ultrasound is not sensi-
tive or specific for BA and is highly operator dependent. Approxi-
mately 20% of patients with BA have a normal or small gallbladder.
Hepatobiliary scintigraphy (HIDA) can exclude BA if excretion
from the liver into the intestine is observed; however, its specificity
for differentiating BA from other obstructive causes of cholestasis
is relatively low (33%–80%), and performing a HIDA scan may
delay the diagnosis of BA (25). The use of HIDA scans in
the evaluation of neonatal cholestasis is highly controversial and
center dependent. At this time, endoscopic retrograde cholangio-
pancreatography and magnetic resonance cholangiopancreatogra-
phy are of limited utility in the evaluation of neonatal cholestasis
(26).
Percutaneous liver biopsy remains a crucial part of the
diagnosis of BA. In a recent multicentered study, blinded pathol-
ogists were able to identify BA or other obstructive process that
would necessitate surgical exploration in 96% of infants with BA
when an adequate liver biopsy specimen was obtained (27). Charac-
teristic histologic findings of BA include bile ductular proliferation,
bile plugs in portal bile ducts, and portal tract inflammation and
fibrosis (Fig. 3). Early in the course of BA, liver biopsy findings
may not be clear and repeat biopsy at a later date may be necessary.
In patients in whom histology suggests BA or other obstructive
process, the infant should undergo intraoperative cholangiogram to
define the biliary anatomy and localize the area of obstruction. The

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 JPGN  Volume 61, Number 2, August 2015 Biliary Atresia: Clinical Lessons Learned

FIGURE 3. Histology of the liver and bile duct in BA. A, Bile duct proliferation and bile duct plug (arrow) (hematoxylin and eosin, 200).
B, Expanded portal tracts with increased fibrosis, bile duct proliferation, and bile plug in portal tract bile duct (trichrome, 250). C, Proximal
common hepatic duct in porta hepatis with apoptosis and disruption of biliary epithelium lining a narrowed but patent lumen, lymphocytic
infiltration around duct, and increased concentric sclerosis (hematoxylin and eosin, original magnification100). D, Remnant of common bile
duct with absent lumen and concentric sclerosis (hematoxylin and eosin, original magnification40). BA ¼ biliary atresia.

surgeon should be prepared to perform an HPE if cholangiography
fails to show a patent biliary tree.
Unfortunately, late diagnosis of BA remains a problem in the
United States. The average age at HPE in the United States is
61 days, and 44% of patients still undergo HPE after 60 days of life
(28). There are several obstacles that contribute to this problem.
First, breast-feeding jaundice is a common problem (15% of breast-
fed babies remain jaundiced at 3 weeks), whereas neonatal cho-
lestasis is a rare problem (only 0.04%–0.02% of infants have
cholestasis) (29). Few primary care physicians see >1 or 2 patients
of BA during their careers and as a result may dismiss jaundice at 2
weeks of age to be the result of breast-feeding without considering
BA. Second, in the United States health care system, infants are
routinely seen at 2 weeks of age and not again until 8 weeks of age.
Without a routine 4-week visit, the crucial diagnostic period to
identify and intervene for BA is often missed. Third, there are no
pathognomonic lab findings that distinguish BA from other causes
of neonatal cholestasis. Finally, at this time, there are no universal
screening programs in place in the United States to help identify
infants with BA within the first month of life.
KASAI HEPATOPORTOENTEROSTOMY
In 1959, Kasai developed the HPE procedure in which a
Roux-en-Y loop of jejunum is anastomosed to the hilum of the liver,
thus creating a new conduit for biliary drainage. The HPE has
transformed BA from a universally fatal disease in early childhood
to one in which restoration of bile flow and normalization of
bilirubin may result in long-term survival with the native liver.
HPE reestablishes short-term bile drainage in approximately two-
thirds of patients. Several factors have been reported to affect
outcome after HPE. Nonmodifiable risk factors that predict poor
outcome include obstruction proximal to the common bile duct,
bridging fibrosis at the time of HPE, and polysplenia syndrome.
Prognostic factors related to care include age at Kasai, experience of
the center in managing BA, and accessibility to liver transplant.
Increased age at HPE has a progressive and lasting detrimental
effect on outcome. If the HPE is performed within the first 60 days
of life, 70% to 80% of patients show bile drainage. If performed
between 60 and 90 days, 40% to 50% of patients show drainage;
after 90 days of life only 25% of patients show drainage; if
performed later than 120 days of life <10% to 20% of infants will
show evidence of drainage (30). In a recent French study of 695
patients with BA, survival with native liver was best in children who
underwent the HPE procedure in the first 45 days of life (30).
Outcome is also best if HPE is performed at an experienced center.
In a study from the United Kingdom, overall survival and survival
with native liver were both significantly greater in centers that
performed >5 HPEs per year (61.3% vs 13.7% and 91.2% vs 75%)
(31). This has led to centralization of care in many European
countries. These modifiable prognostic factors offer areas in which
quality initiatives could drastically improve disease outcome.
Success of the HPE can best be judged by restoration of bile
flow and clearance of jaundice. By 3 months after HPE, a clear
difference in the 2-year transplant-free survival can be seen between
those children with total bilirubin <2 mg/dL compared with those
with total bilirubin >6 mg/dL (84% vs 16%; P < 0.0001) (28). If
jaundice clears successfully by 3 months after HPE, the 10-year
transplant-free survival rate ranges from 75% to 90%; conversely, if
jaundice persists after HPE, the 3-year transplant-free survival rate
is only 20%. There is no standard treatment regimen for patients
with BA who are post-HPE. Regimens may include ursodeoxy-
cholic acid, antibiotic prophylaxis against cholangitis, and a fat-
soluble vitamin preparation. Steroids were previously believed to
improve clinical outcomes secondary to their choleretic, anti-
inflammatory, and immunomodulatory properties. In the recent
multicenter trial in which 140 infants with BA from 14 centers
across the United States were, however, randomized to receive

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 Feldman and Mack JPGN  Volume 61, Number 2, August 2015

either high-dose steroids following HPE or placebo; there was no
difference between groups in bile drainage at 6 months or 2 years
post-HPE and no difference in transplant-free survival at 2 years
(32).
COMPLICATIONS OF BA
Failure to Thrive and Fat-Soluble Vitamin
Deficiencies
Failure to thrive is a significant problem in patients with BA.
In the Studies of Pediatric Liver Transplant registry, 755 patients
with BA who underwent liver transplantation were analyzed, and
40% had growth failure (33). This growth failure was found to be an
independent risk factor for pretransplant mortality, posttransplant
mortality, longer hospital stays, and graft failure (33). The patho-
genesis of growth failure and malnutrition in infants with BA is
multifactorial. Infants with BA have poor bile flow resulting in
reduced delivery of bile acids to the small intestine, decreased
mixed micelle formation, and subsequent fat and fat-soluble vita-
min malabsorption. In addition, infants with BA often have poor
appetite and increased energy expenditure with a resting energy
expenditure 29% greater than age-matched controls (34). One must
be careful not to be reassured by a normal weight and height in an
infant with BA. Weight can be falsely elevated secondary to ascites
and organomegaly, and diminished height can be a late finding of
poor nutrition. To get an accurate assessment of true nutritional
status, one must check anthropometrics including triceps skin fold
thickness and midarm circumference. Growth failure after HPE is
associated with increased risk of transplantation or death by 24
months of age (35). To that end, the importance of growth is
acknowledged in the present pediatric end-stage liver disease
allocation system in the United States in which children receive
higher scores when they have growth failure (36).
Optimization of nutrition is a crucial part of the care of
infants with BA. Infants should be started on a formula containing
medium-chain triglycerides, which can be absorbed independently
of bile salts. Caloric intake should be approximately 125% of the
recommended dietary allowance based on ideal body weight. If
patients are unable to ingest the needed calories orally, they should
be started on nasogastric tube feeds. Fat-soluble vitamin levels need
to be carefully monitored and treated because deficiencies can result
in rickets, bone fractures, coagulopathy, cerebellar ataxia, and
impaired vision. All of the infants with cholestasis should be on
a fat-soluble vitamin supplement that takes advantage of the ability
of tocopherol polyethylene glycol succinate (TPGS) to be absorbed
independently of bile salts. A recent study showed that fat-soluble
vitamin deficiencies often persist despite initiation of a TPGS
containing liquid multiple fat-soluble vitamin preparation; there-
fore, additional individual vitamin supplementation with vitamin A,
D, E, and/or K should be administered as needed (37) (Table 2).
Nutrition remains a modifiable risk for outcome in BA. Prospective
multicenter trials are needed to better understand the specific effects
of different nutritional interventions on improving outcomes.
Cholangitis
Forty percent to 60% of infants with BA develop cholangitis
in the first 2 years following HPE (28). Because cholangitis is
presumed to be an ascending infection, it only occurs in those
children who have some degree of bile flow. Symptoms may be
nonspecific, and cholangitis should be considered whenever a child
who is post-HPE presents with fever, vomiting, decreased oral
intake, pale stools, worsening jaundice, right upper quadrant
abdominal or shoulder pain, or worsening laboratory values (rising
ALT, AST, GGTP, bilirubin, or white blood cell count). A blood
culture may be positive and common infectious agents include
Escherichia coli, Enterobacter, or Klebsiella; however, <50% of
patients will have a positive blood culture (38). Treatment usually
involves 2 weeks of a broad-spectrum intravenous antibiotic that
covers gram-negative bacteria and anaerobes. Approximately 25%
of patients will have multiple episodes of cholangitis. A study of
141 infants with BA showed that multiple episodes of cholangitis
negatively affect 2-, 5-, and 10-year transplant-free survival (58%,
40%, and 35% in children with 0 to 1 episodes of cholangitis
compared with 36%, 14%, and 14% in children with 2 or more
episodes) (39). Attempts have been made to prevent cholangitis
with prophylactic antibiotics or antireflux surgeries; however, the
efficacy of these interventions remains unclear.
Portal Hypertension and Gastrointestinal
Bleeding
Portal hypertension and associated variceal hemorrhage is a
common and fatal complication in infants with BA. At the time of
HPE, 50% of infants already have evidence of bridging fibrosis and
elevated portal pressures (40). Because BA is a progressive disease,
even with good bile flow the majority of patients will develop
cirrhosis and portal hypertension. In a study of 163 children with
BA surviving with their native liver 1 to 25 years post-HPE, 49% to
63% had clinical evidence of portal hypertension as demonstrated
by ascites, variceal bleeding, hepatopulmonary syndrome (HPS),
splenomegaly, and/or thrombocytopenia (37). In adults, new onset
of esophageal variceal hemorrhage predicts a poor outcome and
shortened survival. Nevertheless, in a study of children surviving
2 years post-HPE, there was no difference in survival between those
with and those without variceal hemorrhage. What was predictive of
outcome was the bilirubin at the time of hemorrhage. Patients with a

TABLE 2. Fat-soluble vitamin supplementation

Vitamin Laboratory sign of deficiency Clinical sign of deficiency Treatment/prevention

Vitamin A Retinol: retinol-binding protein <0.8
Vitamin D 25-OH vitamin D <14 ng/mL ¼ deficiency
<30 ng/mL ¼ insufficiency
Vitamin K Prolonged prothrombin time, elevated protein
in vitamin K absence
Vitamin E Vitamin E: total serum lipid ratio <0.6 mg/g
in <1 y olds or <0.8 mg/g in >1 y olds
Xerophthalmia, keratomalacia
Rickets, osteomalacia
Coagulopathy
Neurologic changes, hemolysis
Liquid vitamin A: 5000 IU by mouth with ADEK daily
or 50,000 IU IM once monthly
Cholecalciferol: 1200–8000 IU/day
1,25 OH2 cholecalciferol: 0.05–0.2 mg  kg1  day1
Phytonadione: 2.5–5 mg twice per week to every day,
if oral therapy is not effective, patients may
require 2–5 mg vitamin K IM
TPGS: 15–25 IU  kg1  day1; D-a tocopherol:
up to 100 IU  kg1  day1

IM ¼ intramuscular; TPGS ¼ tocopherol polyethylene glycol succinate.

172 www.jpgn.org

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 JPGN  Volume 61, Number 2, August 2015
serum bilirubin concentration 4 mg/dL at the first episode of
esophageal variceal hemorrhage had a transplant-free survival of
>80% for 4 years after the episode compared with 50% survival at
1 year for those with bilirubin levels between 4 and 10 mg/dL and
50% 4-month survival for those with bilirubin levels >10 mg/dL
(41). Management of variceal hemorrhage is derived from adult
studies and includes sclerotherapy, esophageal band ligation,
octreotide, and consideration of b-blockers (42). Furthermore,
studies in a pediatric population are necessary to determine the
utility of primary prophylaxis and the safety of b-blockers in
preventing variceal hemorrhage in at-risk children. Children with
refractory hemorrhage should be referred to a center with expertise
in portosystemic shunting and/or liver transplantation.
Ascites
Twenty-four percent of children post-HPE will develop
ascites related to portal hypertension (28). The presence of ascites
is a risk factor for poor outcome. In 1 study of 104 children who
underwent HPE, good outcome (survival at 2 years with native liver
and bilirubin <6 mg/dL) was only seen in 8% of children who
developed ascites compared with 67% of children without ascites
(28). Ascites can usually be managed with sodium restriction,
diuretics (furosemide and spironolactone), and occasionally para-
centesis. If ascites is refractory to medical management, one should
consider the possibility of a portal vein thrombosis. In addition,
pediatric patients with medically intractable ascites should be
considered for liver transplant.
HPS and Portopulmonary Hypertension
Pulmonary complications are not uncommon in children with
BA and include HPS and portopulmonary hypertension (PPHTN).
HPS is a form of arteriovenous shunting in which intrapulmonary
blood is abnormally shunted from right to left resulting in hypoxia.
HPS can be diagnosed on echocardiography using intravenous
injection of agitated saline. In 1 study, >50% of children with
BA had findings on echocardiogram suggestive of HPS (43). In
clinic, children will present with orthodeoxia, a fall in arterial blood
oxygen when going from the sitting to standing position. HPS can
be treated with liver transplant; however, the optimal timing of
transplant in relation to degree of desaturations remains unclear. It
is important to check a pulse oximetry on children with BA at each
office visit to screen for HPS. Less commonly, children with BA
can develop PPHTN in which vasoconstriction and remodeling in
vessels increases pulmonary artery pressures. Cardiac catheteriza-
tion is required to confirm PPHTN. Liver transplant can reverse
PPHTN if the pulmonary pressure is <50 mmHg. There is a
significant operative risk with high pulmonary artery pressures.
Malignancy
Cirrhosis can predispose a patient to the development of
hepatocellular carcinoma (HCC). HCC has been reported in chil-
dren with BA as early as 8 months of age (44). In almost all of the
patients of HCC in children with BA, serum a-fetoprotein levels
have been elevated. Because early identification of any malignancy
is crucial to outcome, screening children with BA and cirrhosis with
ultrasounds and a-fetoprotein levels is recommended. At this point,
there is no standard of care for timing of surveillance. At our center,
we obtain yearly a-fetoprotein levels and perform an ultrasound
every 2 years for those patients who have cirrhosis. Cholangio-
carcinoma should also be considered because it has been reported in
patients with BA (45).
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Biliary Atresia: Clinical Lessons Learned
LIVER TRANSPLANT
Despite initial success of the HPE in restoring bile flow, 80%
of patients with BA ultimately require liver transplant (46). BA is
the leading indication for liver transplantation during childhood,
accounting for 40% to 50% of all of the pediatric liver transplants
(47). Liver transplant is indicated if there is no initial restoration of
bile flow with HPE, or when complications of end-stage liver
disease develop including failure to thrive, portal hypertensive
gastrointestinal bleeding refractory to medical and endoscopic
management, intractable ascites, HPS, PPHTN, hepatorenal syn-
drome, or significantly impaired quality of life (38). Approximately
50% of liver transplants for BA occur before a child’s second
birthday (48). The question of primary liver transplant (instead of
HPE) for BA sometimes arises when a patient presents with BA at a
late age. It is important to remember, however, that 10% to 20% of
children who undergo HPE after 100 to 120 days of life still have
success in restoring bile flow; liver transplant is technically more
difficult in young small infants, and there is a shortage of available
organs for children <1 year of age owing to size constraints. Some
centers consider primary transplant when a patient has advanced
cirrhosis and evidence of portal hypertension, ascites, or variceal
hemorrhage at the time of diagnosis (38).
OUTCOMES
Before the development of the HPE, BA was a uniformly
fatal disease by 3 years of age. With HPE, up to two-thirds of
patients with BA have short-term clearance of jaundice. Although
the development of the HPE changed the short-term prognosis of
the disease, it was development of liver transplantation in the 1980s
that most significantly affected long-term outcome. One-, 5-, and
10-year survival rates after liver transplant for BA are excellent and
approach 90%, 87%, and 86%, respectively (48); however, all of the
children with BA may face ongoing medical and quality-of-life
challenges. For the group of children who undergo liver transplant,
there is always a risk of posttransplant lymphoproliferative disease,
graft loss, and complications of lifelong immunosuppression
including hypertension, renal abnormalities, and diabetes. For
the 20% of patients who survive into adulthood with their native
liver, ongoing intrahepatic biliary damage continues and results in
liver damage. In a study of 63 adults with BA living with their native
liver 20 years after HPE, 66% had high bilirubin levels, 70% had
signs of portal hypertension, and 97% had evidence of cirrhosis
(49). Both groups of patients score significantly lower on health-
related quality-of-life assessments compared with healthy age-
matched controls, especially in areas of emotional and psychosocial
functioning (50). Ten percent to 15% of children with BA have
significant neurocognitive deficits (intelligent quotient <70), 26%
have learning disabilities, and up to 40% require special educational
services (51).
SCREENING
In order to improve the outcome of BA, we must develop
ways to identify the disease as early as possible. Although we know
that infants do best if they undergo HPE in the first 30 to 45 days of
life, the average age at HPE in the United States is still 61 days (28).
The most promising screening method for BA to date has been the
use of stool color cards to identify infants with acholic stools
(identifiable in 95.2% of children with BA in early infancy)
(52). In Taiwan, a universal screening program was instituted in
2004 through which a stool color card was integrated into the child
health booklet given to every neonate. At 1 month of age, parents
and physicians compared the child’s stool with those printed on the
card. The program has increased the rate of the Kasai operation
173
 Feldman and Mack
before 60 days of life from 49.4% to 65.7%, the jaundice-free rate at
3 months after HPE from 34.8% to 60.8%, and the 5-year survival
with native liver rate from 27.3% to 64.3% (53). It is important to
note that in Taiwan a physician routinely sees all of the infants at
1 month of age, at which time the stool card is reviewed. In the
United States there would need to be a different process in place for
review of the stool cards at 1 month of age. Laboratory abnorm-
alities may be another opportunity to screen for BA. In a recent
retrospective study of 34 infants with BA, all had elevated direct or
conjugated bilirubin levels within the first 72 hours of life, and at 24
to 48 hours of life subjects with BA had mean direct bilirubin levels
significantly higher than infants with other forms of neonatal liver
disease (54). The study needs to be repeated prospectively in a
larger group of patients; however, it may suggest that it would be
possible to do screening for BA by obtaining a direct bilirubin level
on all of the neonates, not just in those with obvious jaundice.
Although all of the screening programs have associated costs, it is
estimated that $18 million would be saved if every patient with BA
underwent HPE before 46 days of life, far more than any screening
program would cost (30). In addition, a pediatric liver transplant
saving policy would reduce the need for pediatric grafts by 50%,
thus shortening the transplant waiting list and decreasing the need
for living-related transplants, all of which have associated donor
morbidity costs.
CONCLUSIONS
Although vast progress has been made in the care for patients
with BA, and it is no longer a lethal childhood illness, the overall
20-year survival remains approximately 77% (55). There are
multiple areas in which progress can still be made to improve
outcome. First, a better understanding of the etiology and patho-
genesis of this fibroobliterative process may allow for development
of new medications that could halt disease progression before
transplantation becomes necessary. Second, universal screening
programs and consolidation of care to experienced centers would
allow for earlier diagnosis and increased long-term success of the
HPE. Third, better choleretic and anticholangitis medications after
HPE may prevent inflammation and infection that results in damage
to the intrahepatic bile ducts. Finally, focus on nutrition and
neurocognitive development at all of the ages would improve
medical and health-related quality-of-life outcomes.
Acknowledgment: The authors thank Dr Melin-Aldana for
histology pictures.
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