Advances in Pediatrics 64 (2017) 285–305

ADVANCES IN PEDIATRICS

Biliary Atresia
Epidemiology, Genetics, Clinical Update,
and Public Health Perspective

Amarilis Sanchez-Valle, MDa, Noor Kassira, MDb,

Veronica C. Varela, MPHc, Stephanie C. Radu, BSc,
Charles Paidas, MD, MBAb, Russell S. Kirby, PhD, MSc,*
a
Division of Genetics and Metabolism, College of Medicine, University of South Florida, Tampa,
FL, USA; bDivision of Pediatric Surgery, College of Medicine, University of South Florida, Tampa,
FL, USA; cDepartment of Community and Family Health, College of Public Health, University of
South Florida, Tampa, FL, USA

Keywords
 Biliary atresia  Obstructive jaundice  Portoenterostomy  Liver cirrhosis
Key points
 Biliary atresia is a rare birth defect, with prevalence of 0.5 to 0.8 per 10,000
births in developed nations, and remains a surgical disease with good outcomes
with the Kasai portoenterostomy, although age at operation plays a key deter-
mination in outcome.
 Although some genetic factors and associations have been identified, biliary
atresia appears to have multifactorial etiologies, which remain unclear.
 Timely work-up of obstructive jaundice is of key importance to performing por-
toenterostomy before 90 days of life, should biliary atresia be the diagnosis.
 For those who do not have successful drainage after operation, liver transplant
remains the only option.
 Universal screening, using stool color cards or other methods, may improve age
at diagnosis and treatment, leading to improved outcomes for infants with biliary
atresia.

*Corresponding author. Birth Defects Surveillance Program, University of South Florida,

13201 Bruce B. Downs Boulevard, MDC56, Tampa, FL 33612-3805. E-mail address:
rkirby@health.usf.edu

http://dx.doi.org/10.1016/j.yapd.2017.03.012
0065-3101/17/ª 2017 Elsevier Inc. All rights reserved.
286 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

B
iliary atresia is a rare destructive, inflammatory condition in which pro-
gressive fibrosis of the biliary tree in an infant leads to bile duct obstruc-
tion and consequent liver cirrhosis [1]. If left untreated, progressive liver
cirrhosis leads to death by age 2 [2]. Biliary atresia can be classified into 3 cat-
egories, all of which are dependent on the level most proximal to the biliary
obstruction (Fig. 1). Type I involves obstruction of the common bile duct, char-
acterized with luminal patency down to the common bile duct, and accounts for
approximately 5% of cases. Type II, characterized with patency to the level of
the common hepatic duct, accounts for approximately 2% of cases. In both
types, there is some preservation of the intrahepatic ducts, although they
may morphologically still be abnormal and irregular. Given this abnormality
in structure, they typically do not dilate, despite the presence of an obstruction.
Finally, type III involves obstruction at the level of the porta hepatis [3]. In
most populations, type III accounts for more than 90% of cases and is charac-
terized by most of the proximal part of the extrahepatic biliary tract within the
porta hepatis entirely solid [2]. On abdominal exploration, a dense inflamma-
tory proximal remnant is noted at the porta hepatis. Distal ducts may be well
preserved, atrophic, or even absent. In this type, the intrahepatic ducts are
grossly abnormal. In addition, it is important to distinguish this type of biliary
atresia from a choledochal cyst, because there may be an associated extrahe-
patic cyst formation in type III biliary atresia. The key to distinguishing

Fig. 1. Schematic illustration of classification of biliary atresia. (From Hartley LJ, Davenport
M, Kelly DA. Biliary atresia. Lancet 2009;374(9702):1705.)
BILIARY ATRESIA 287

between the two is the intraoperative cholangiogram that demonstrates a

dilated intrahepatic system in choledochal malformations, whereas biliary
atresia demonstrates nothing intrahepatically or an abnormal, irregular, nondi-
lated biliary tree. The gallbladder is usually abnormally small and may still
have a small lumen. Biliary atresia associated with splenic malformation syn-
drome may reveal slightly different appearance in the structures, with frequent
absence of the common bile duct and minuscule gallbladder with a small prox-
imal remnant. On microscopic analysis, the biliary remnant is composed of
dense fibrous tissue in the distal portion and the proximal portion of the
remnant is composed of tiny ducts and glands surrounded by fibrosis and
inflammation [4–6].
The etiology behind biliary atresia is still not fully understood, although its
symptoms are known. An infant with suspected biliary atresia typically pre-
sents with persistent jaundice lasting longer than 2 weeks after birth and acholic
stools as well as dark urine [2].

DESCRIPTIVE EPIDEMIOLOGY
Population-based epidemiologic research on biliary atresia poses challenges due
to the nature of biliary atresia presentation and diagnosis. This article discusses
screening and diagnosis at length later and refers to issues related to surveillance.
In many developing nations, birth defects surveillance programs do not exist, and
cases are identified only at presentation to hospital facilities. In more developed
countries, surveillance programs typically identify cases diagnosed during the
initial hospital stay, during the first month, or through the first year of life.
Most birth defects surveillance programs focus on the diagnosis of specific condi-
tions and retain diagnosis codes (usually International Classification of Diseases, Ninth
Revision, Clinical Modification; International Classification of Diseases, Tenth Revision; or
Centers for Disease Control and Prevention-British Paediatric Association
(CDC-BPA)). Details concerning the date of diagnosis, treatment, and outcomes
for infants with birth defects are not a primary focus of birth defects surveillance.
Because many infants with biliary atresia are asymptomatic at birth, the diagnosis
often occurs after newborn discharge and could be missed by registries focusing
on birth defects occurring in the neonatal period or by those relying exclusively
on passive ascertainment methods [7]. The most recent national prevalence esti-
mates for major birth defects in the United States did not include an assessment of
the prevalence of biliary atresia due to the unreliable available data [8]. For these
reasons the data on the descriptive epidemiology of biliary atresia are limited to
reports from smaller registries and hospital-based clinical studies.

Prevalence
Recent prevalence estimates for biliary atresia in Western countries are in the
range of 0.5 to 0.8 per 10,000 live births [2,9]. Several reports from the Pacific
basin suggest higher prevalence rates. Chiu and colleagues [10] report an over-
all prevalence of 1.5 per 10,000 births in Taiwan, whereas Wada and col-
leagues [11] reported a prevalence of 1.1 per 10,000 births in a regional
288 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

study in Japan. Girard and colleagues [12] reported a prevalence of 2.6 per
10,000 births in French Polynesia. Although these reports suggest variability
in biliary atresia prevalence globally, this could be due to differences in diag-
nostic practice or surveillance methods or to race/ethnic or genetic factors, envi-
ronment, or infectious pathogens.
Temporal and spatial trends
Research on temporal and spatial variation in biliary atresia prevalence is
limited. Lin and colleagues [13] found a declining trend in the prevalence of
biliary atresia in Taiwan for the years 2004 to 2009 and speculated that this
might be due to improvements in socioeconomic status or to increased avail-
ability and use of rotavirus vaccine. On the other hand, Wada and colleagues
[11] found no temporal or spatial patterns to biliary atresia prevalence in Hy-
go Prefecture, Japan, during 1985 to 2004, and Yoon and colleagues [14]
o
found no temporal trend in the prevalence of biliary atresia in metropolitan At-
lanta. Although there is some evidence for spatial variation in biliary atresia
prevalence [15], the results are inconclusive; more research with databases of
greater spatial and temporal extent is needed.
Risk factors
Race/ethnic variation in the prevalence of biliary atresia has been identified in
several studies. Yoon and colleagues [14] found higher prevalence among
nonwhite (predominantly black) infants in metropolitan Atlanta, whereas
The and colleagues [16], analyzing data from the National Birth Defects Pre-
vention Study, found an adjusted odds of 2.29 (95% CI, 1.07 to 4.93) for
non-Hispanic black infants compared with non-Hispanic whites. Studies exam-
ining prevalence of biliary atresia among infants of Hispanic and Asian origin,
however, compared with other race/ethnic groups have not been done. The ob-
servations of higher biliary atresia prevalence in Taiwan, Japan, and
Micronesia [17–20], although interesting, may be due to genetic factors, diet
and nutrition, or other cultural practices, or result from differences in clinical
diagnostic practices, surveillance methods, or other factors.
Evidence concerning differences in prevalence by gender of infant is incon-
clusive. Several studies suggest that rates of biliary atresia are higher among
girls [10,14,20]. Wada and colleagues [11] confirmed this association, finding
a relative risk of 1.80 (95% 1.24–2.62) for girls compared to boys. A Swedish
study [21], however, found a higher prevalence among boys compared with
girls, 0.8 and 0.6 per 10,000 live births, respectively, although this was not sta-
tistically significant (P<.06). Additional research is needed to determine
whether there is an association between gender and biliary atresia.
Although several researchers have examined the role of season of birth and
prevalence of biliary atresia, most of these studies have found no association
[21–24]. Yoon and colleagues [14] reported, however, an elevated prevalence
in metropolitan Atlanta during the winter months (December–March) than
the summer months (April–July). Jimenez-Rivera and colleagues [15] reported
on seasonality in a systematic review of international prevalence and outcomes
BILIARY ATRESIA 289

for biliary atresia, concluding that the evidence to date does not support season-
ality as a factor in this birth defect.
More research on the role of maternal characteristics and biliary atresia is
needed. Although biliary atresia has been associated with older maternal age
[21], evidence concerning an association with higher parity is inconclusive
[14]. Smoking does not seem to be a risk factor for biliary atresia [16]. There
is limited research concerning maternal nativity, maternal educational attain-
ment, and socioeconomic status as risk factors for biliary atresia.
The prevalence of biliary atresia is greater among preterm (<37 weeks’ gesta-
tion) infants [10,14,21]. Yoon and colleagues [14] also found that among white
infants, the rate of biliary atresia for full-term, low-birth-weight infants was
significantly greater (relative risk 9.40; 95% CI, 1.38–47.46) than among full-
term, normal-birth-weight infants. Most cases of biliary atresia are isolated or
have related hepatobiliary anomalies and are classed as having sequence
events. Infants with biliary atresia and malformations in other body systems
are rare, and occasional cases of biliary atresia with chromosomal abnormal-
ities have been reported. Yoon and colleagues [14] reported 38 isolated cases
(66.7%), with 11 cases of sequence (18.6%), 6 cases of multiple defects
(10.1%), and 2 cases of syndromes (3.3%). Caton and colleagues [25] studied
extrahepatic biliary atresia in New York State from 1983 to 1998 and found
that 249 of 369 cases (64.7%) were isolated or sequence events.

Summary
This review of the descriptive epidemiology of biliary atresia suggests regional
variation in prevalence, with increased prevalence among female infants and
infants of non-Hispanic black mothers. Advanced maternal age may be associ-
ated with increased prevalence of biliary atresia. Prevalence is also higher
among preterm and low birth weight infants. Perhaps due to the limited sur-
veillance data across larger populations, there are few detailed descriptive
epidemiologic studies for biliary atresia.

GENETICS OF BILIARY ATRESIA

Biliary atresia is considered a complex disease model due to the intricate
interactions between environmental factors and genetic predisposition [26].
Although biliary atresia is the most common cause of pediatric liver transplant,
until recently there was limited information regarding the genetics role in the
etiology of this complex disease. Biliary atresia is considered a congenital
anomaly because it represents an abnormal development of an organ system.
In 1985, Hyams and colleagues [27] described 2 sets of identical twins with
discordant biliary atresia, suggesting that it is not inherited in a mendelian
manner. Familial cases that have been reported, however, support the theory
of a higher genetic predisposition.
Genome-wide studies have been used in many complex diseases to try
to identify susceptibility loci. In 2010, Garcia-Barcelo and colleagues [28] car-
ried out a genome-wide association study, successfully identifying a strong
290 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

association between the 10q24 loci and biliary atresia. On the other hand,
Leyva-Vega and colleagues [29] described a potential disease susceptibility re-
gion in 2q37.3. One of the patients described had a deletion of this region that
included 30 genes, but his father had the same deletion and he did not have
liver disease, demonstrating the complexity of this disease.
Another genetics aspect of biliary atresia is the inflammatory reaction that
occurs due to a viral illness or other environmental factors. Research concern-
ing the genetics of inflammatory response causing disease is ongoing, with a
current focus on the function and regulation of microRNAs (miRNAs) in the
biliary atresia disease process. The miRNAs are small molecules that have
been shown to be tissue specific and disease specific. One mechanism by which
miRNAs regulate gene expression is by interacting with the RNA-induced
silencing complex (RISC) [30]. Studies by Xiao and colleagues [31] have shown
up-regulation of the miRNA miR200-b in patients with biliary atresia. The ef-
fects of miRNAs in gene regulation and expression could explain why some of
the identified susceptibility loci or genes do not behave in a mendelian manner.
Biliary atresia can present in combination with other congenital anomalies or
as part of a syndrome. In 1993, Davenport and colleagues [32] proposed the
term, biliary atresia splenic malformation (BASM) syndrome, for a subgroup of pa-
tients who presented with biliary atresia and polysplenia and had a poorer
prognosis with an unclear etiology. Currently, the Online Inheritance in
Man database, https://www.omim.org/, does not recognize the term BASM
as a syndrome. Several other recognized genetic syndromes, however, are asso-
ciated with specific genes that present with biliary atresia. The genetic syn-
dromes that have been associated with biliary atresia include Mitchell-Riley
syndrome, cat-eye syndrome, Zimmermann-Laband syndrome, and Fanconi
anemia complementation group Q. Additionally, although Martinez-Frias syn-
drome, Lambert syndrome, and mental retardation Buenos Aires type are asso-
ciated with biliary atresia, these syndromes have not yet been associated with a
genetic disturbance.
Genetic syndromes and biliary atresia
1. Mitchell-Riley syndrome is an autosomal recessive disorder that is associated with
biliary atresia, intrauterine growth restriction, cholestasis, duodenal atresia, je-
junal atresia, intestinal malrotation, neonatal diabetes, hypoplastic pancreas,
and diarrhea. It is caused by a mutation in the RFX6 gene, the regulatory factor 6.
This rare disorder is frequently associated with fatal prognosis in the first year of
life.
2. Cat-eye syndrome is an autosomal dominant disorder caused by a supernumer-
ary inversion duplication of (22) (q11). The clinical presentation includes low-set
ears with preauricular pits or tags, stenotic ear canals, hypertelorism, coloboma
of the iris and retina, microphthalmos, cleft palate, congenital heart defects,
biliary atresia, intestinal malrotation, anal atresia with fistula, renal agenesis,
and radial aplasia.
3. Zimmermann-Laband syndrome is an autosomal dominant syndrome that is
characterized by birth weight above the 90th centile, coarse facies, prominent
BILIARY ATRESIA 291

mandibule, long lobulated posteriorly rotated ears, hearing loss, thick eyebrows,
synophrys, cataracts, thick lips, gingival hyperplasia, cardiomyopathy, aortic
root dilatation, hepatomegaly, extrahepatic biliary atresia, scoliosis, hypoplastic
nails, hypertrichosis, hypotonia, and seizures. It is caused by a mutation in the
potassium family gene KCNH1.
4. Fanconi anemia complementation group Q is an autosomal recessive disorder
that causes short stature, low-set ears, biliary atresia, esophageal atresia, absent
thumbs and bone marrow failure. It is caused by a mutation in the excision-repair
cross-complementing group 4 gene ERCC4.
Genetic syndromes that are not yet associated with a gene
1. Martinez-Frias syndrome is an autosomal recessive disorder characterized by
intrauterine growth restriction, biliary atresia, hypoplastic pancreas, duodenal
and/or jejunal atresia, intestinal malrotation, and hypospadias.
2. Lambert syndrome is an autosomal recessive disorder that causes clubfoot, in-
tellectual disability, macrostomia, malar hypoplasia, preauricular tags, auricular
meatal agenesis, inguinal hernia, biliary atresia, and hypospadias.
3. Mental retardation Buenos Aires type syndrome is described as causing failure to
thrive, microcephaly, low-set protruding ears, strabismus, myopia, ptosis,
downslanting palpebral fissures, long curly eyelashes, prominent nose, atrial
septal defect, situs abdominalis inversus, intrahepatic biliary atresia, hypospa-
dias, intellectual disability, and spastic gait.

SCREENING
Biliary atresia is the most common cause of death from liver disease in children
and is the most common cause for liver transplant in the pediatric population
[33,34]. A delay in biliary atresia diagnosis is one of the most important factors
in predicting effective bile drainage after surgery and improving future disease
prognosis. The signs and symptoms of biliary atresia typically include pale colored
stool, persistent jaundice, and dark urine in an otherwise healthy infant [35].
Several screening methods are under consideration to aid in earlier diagnosis
of biliary atresia. These proposed methods include serum bile acid, liver bi-
opsy, serum directed bilirubin, urinary sulfated bile acid, fecal bilirubin, stool
color cards, and various radiologic methods [36,37]. Most of these methods
have not been fully evaluated or compared in terms of efficacy, sensitivity,
and specificity nor has their feasibility and cost-effectiveness as screening tools
been explored. The stool color card has received the most attention, especially
internationally.
The stool color card is a simple and effective method that may aid in earlier
diagnosis of biliary atresia and potentially reduce the time to treatment with
the Kasai procedure. Stool color cards have photographs of normal and
abnormal stool colors and appearance and can be used to evaluate stools prior
to newborn discharge or sent home with the mother with information on how
to use the card and how to contact a physician, hospital, or public health pro-
gram in the event of a potentially abnormal infant stool. Taiwan launched
a national stool color card screening program for biliary atresia in 2004,
292 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

integrating the stool color card into the child health booklet given to all women
in the nation during their postpartum care. Several studies have examined the
effectiveness of the implementation of the stool color card in reducing mortal-
ity and morbidity for biliary atresia in Taiwan, and a recent study found that
the average return rate of stool color cards at an infant’s 1-month checkup was
84.3% [38]. The mean age at time of Kasai after implementing the national
screening program was 59.7  19.4 days compared with approximately
70 days prior to implementation [38]. At the 1-month health checkup, sensi-
tivity, specificity, positive predictive value, and negative predictive value of
the card were 76.5% (95% CI, 62.2–90.7), 99.9% (95% CI, 99.9–100.0),
12.7% (95% CI, 8.2–17.3), and 99.9% (95% CI, 99.9–99.9), respectively.
The high sensitivity and specificity of the card are likely to contribute to a
more prompt diagnosis, which then leads to a quicker time to Kasai and sub-
sequently better outcomes, such as improved native liver survival probabilities
[38,39]. The positive predictive value of 12.7% indicates, however, that many
infants identified as at risk using the card ultimately are found to not have
biliary atresia. Use of the stool color card also significantly reduced hospitali-
zation rates, increased native liver survival times, and reduced mortality [39].
The stool color card has also been implemented in Canada, the United
Kingdom, and France; however, Taiwan is currently the only country with a
national screening program. Two studies were recently done in Canada exam-
ining outcomes from home-based, family-centered screening programs for
biliary atresia implementing the stool color cards [34,40]. Because the United
States and Canada have similarly low incidence rates for biliary atresia, the
experience in Canada may provide an indication of how well stool color cards
may work in the United States. Overall, the utilization rate of the cards in both
studies ranged from 60% to 100%, but return rates ranged from 55% to 63%
[34,40]. Although many parents did not return the cards, follow-up showed
that the cards were used to compare their infant’s stool color. Morinville and
colleagues [34] noted that the highest return rates were seen with parents
who received the cards at maternity visits as well as received a reminder about
the cards in the mail or a reminder phone call in the third/fourth week post-
partum. Perhaps due to the low incidence rate of biliary atresia in Canada
(1 in 19,000 live births) no cases were diagnosed in either study. The Canadian
experience shows that implementing a stool color card screening program is
feasible in North America, including the United States.
As technology, specifically smartphones, becomes more widespread, re-
searchers have explored the potential of a smartphone app as a screening
tool for biliary atresia. A team at Johns Hopkins University created a smart-
phone app called PoopMD in 2015 for use in screening infants for biliary
atresia. The app was created with the input of a panel of expert pediatricians
from different backgrounds. A gold standard of stool color pictures was created
for the app to compare with the user’s photographs. The app distinguishes pic-
tures as examples of acholic, normal, or indeterminate stools [41]. Users can
automatically send pictures of their infant’s stool to their pediatrician, removing
BILIARY ATRESIA 293

the need for a pediatrician to make a follow-up call or for the parent to mail
back the traditional stool color cards. A pilot study using this app found it to
have a sensitivity of 100% and a specificity of 89%, with Laplace-smoothed pos-
itive and negative likelihood ratios of 6.44 and 0.13 respectively [41]. In the pi-
lot study, no images were labeled as acholic by the app, whereas 11% of the
images were falsely labeled as indeterminate. Although the app misclassified
11% of the images, no normal stools were misclassified as acholic stools [41].
Although research on the effectiveness of this and other apps is required, their
prospects for use as a possible screening tool in the United States seem
favorable.

SURGICAL CONSIDERATIONS IN BILIARY ATRESIA

Biliary atresia is a disease that, if diagnosed and treated surgically in time, can
have a good outcome. The Kasai portoenterostomy remains the standard of
care. Without surgical intervention, biliary atresia may progress to hepatic
fibrosis, liver cirrhosis, liver failure, or death within 2 years [36]. Biliary atresia
is a lifelong illness although palliative surgery can be done to alleviate the
severity of the illness and to deter mortality. The importance of an early diag-
nosis in achieving successful biliary drainage cannot be overemphasized. As
time progresses, so does the biliary occlusion. If not diagnosed and treated
in a timely manner, sclerosis of the extrahepatic biliary tree progresses
to cirrhosis, liver failure, and then death. As discussed previously, biliary
atresia remains the most common reason for liver transplant in the pediatric
population.
Pathology
The pathogenesis of biliary atresia remains obscure despite many theories
regarding its causes. These include viruses, toxins, failure of recanalization,
genetic factors, defective morphology, and ischemia [42,43]. Regardless of
the culprit, the outcome is the same, with an occlusive panductular cholangiop-
athy of both intrahepatic and extrahepatic bile ducts. Depending on when the
fibrosclerotic injury occurs, the biliary atresia can be classified into 1 of 2 forms.
The early embryonic form, which is rarer, is associated with other anomalies.
The latter, more common form is usually seen without other congenital anom-
alies [44].
Etiology
The exact etiology of biliary atresia remains unknown and is likely multifacto-
rial. Isolated biliary atresia and biliary atresia associated with syndromes are
thought to have different etiologies and onset. Isolated biliary atresia has no
associated defects and may develop later in gestation. Although the cause of
biliary atresia is unknown, it has been suggested that it may be viral mediated
in the perinatal period. In many patients with biliary atresia, at least 1 virus
could be isolated; however, no direct causal relationship has been found. Iso-
lated biliary atresia is more likely acquired rather than congenital, because
affected infants initially had pigmented stool, which then became acholic [45].
294 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

Clinical features
Infants with biliary atresia are usually normal at birth and begin to develop fea-
tures at approximately 3 to 6 weeks of age. When jaundice is present after
2 weeks of life, it is no longer physiologic. Although conjugated hyperbilirubi-
nemia, unpigmented or clay colored stool (Fig. 2), and bilirubinuria are key fea-
tures in biliary atresia, these findings are not specific. Once such findings are
noted, a work-up should be done rapidly to exclude obstructive mechanical
causes of jaundice.
Diagnosis
Conjugated hyperbilirubinemia can have multiple causes, including toxoplas-
mosis, other viruses, rubella, cytomegalovirus, and herpes simplex virus
(TORCH) infections; genetic diseases (Alagille syndrome, a1-antitrypsin defi-
ciency, and cystic fibrosis); metabolic disorders (tyrosinemia, galactosemia, hy-
pothyroidism, and inborn error of bile acid metabolism); parenteral nutrition–
associated cholestasis with neonatal hepatitis; obstructed choledochal cyst;
inspissated bile, and spontaneous bile duct perforation.
In biliary atresia, laboratory findings reveal a conjugated hyperbilirubinemia
and elevated transaminases, alkaline phosphatase, and c-glutamyl transpepti-
dase, but none of these is specific; thus, further investigative studies must be
undertaken.
Ultrasound is a useful adjunct because it is noninvasive. It usually reveals a
shrunken, atrophic gallbladder, although approximately 20% may have what
seems to be a normal gallbladder that at operation is noted to be a gallbladder
mucocele [46]. Choi and colleagues [47] have described the triangular cord sign
on ultrasound, which describes the proximal solid biliary remnant lying ante-
rior to the portal vein bifurcation. This finding is approximately 80% sensitive
and 98% specific in diagnosing biliary atresia. If intrahepatic bile ducts are
dilated, biliary atresia is likely not the diagnosis, because the ducts are fibrotic
and unable to dilate. Other features, such as polysplenia or situs inversus, could
be seen in ultrasound and support the diagnosis of syndromic biliary atresia.

Fig. 2. Gross appearance of acholic stool in an infant with biliary atresia who underwent a
Kasai portoenterostomy
BILIARY ATRESIA 295

Other adjuncts to diagnosis include a hepatobiliary technetium Tc 99m imi-

nodiacetic acid (HIDA) scan. Infants should be pretreated with phenobarbital
(5 mg/kg/d) for 5 days before the study [48]. An abnormal HIDA (Fig. 3) re-
veals rapid uptake of nucleotide by the liver with absence of excretion into
the gut, even on 24-hour delayed images. If there is advanced biliary atresia
or hepatic parenchymal disease from another cause, there may be delayed up-
take of isotope and no gut excretion. Excretion into the gut, however, effec-
tively rules out biliary atresia.
Both magnetic resonance cholangiopancreatography (MRCP) and endo-
scopic retrograde cholangiopancreatography (ERCP) have been described in
the work-up of biliary atresia as well. MRCP is not as specific as ultrasound
in the diagnosis of biliary atresia. Sensitivity and specificity have been reported
as 90% and 70%, respectively. Although MRCP may be useful in defining
biliary anatomy, especially with choledochal cysts, it cannot rule out biliary
duct obstruction [49]. ERCP has also been used because it can demonstrate
a patent biliary tree; however, significant technical expertise is needed as
well as a small side-viewing scope, making its use less practical. Neither
ERCP nor MRCP has become routinely used.
Percutaneous liver biopsy in the hands of an experienced pediatric patholo-
gist familiar with biliary atresia has a diagnostic accuracy of 90% to 95%. His-
tology reveals preservation of the hepatic architecture with bile duct
proliferation, bile plugs, and periportal fibrosis [50].
Surgery
Portoenterostomy is typically the first surgical procedure that is, done in cases
of biliary atresia to rectify bile drainage. Surgeon Mario Kasai first described

Fig. 3. Abnormal HIDA imaging in an infant later confirmed to have biliary atresia. After in-
jection of radioisotope, there is uniform distribution of activity within the liver. Even at 24 hours,
on delayed images, there is neither visualization of the gallbladder nor excretion in the gut.
296 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

the Kasai portoenterostomy in the 1950s as a management surgery for biliary

atresia [2]. Typically called Kasai, this procedure is now widely used for the
correction of bile flow in infants diagnosed with biliary atresia. Kasai’s effective-
ness is typically strongest before a patient is 60 days of age [37,51]. Kasai can
achieve complete clearance of jaundice, restore excretory and synthetic liver
function, and enable healthy growth and development [2]. The success of Kasai
is measured by the clearance of jaundice and is defined as the achievement of
normal bilirubin (<2 mg/dL) concentration within 6 months postsurgery [2].
Many centers report high rates of early success with clearance of jaundice rates
as high as 60% to 80% [52]. The clinical status established post-Kasai has been
found to predict future disease outcomes. Wildhaber and colleagues [53] found
that the clinical status established 6 months post-Kasai showed a 96% positive
predictive value for predicting future successful outcome at 2 years after Kasai
and a 76% negative predictive value for future failure at 2 years after Kasai.
If biliary atresia has not been ruled out by the diagnostic maneuvers
described previously, surgery should proceed in a timely manner. Preoperative
antibiotics are administered as well as vitamin K, given the poor absorption of
the fat-soluble vitamins. An intraoperative cholangiogram is the next step
with anticipated portoenterostomy in the same operation if the diagnosis is
confirmed. Surgical therapy is the only hope for a cure in biliary atresia and
the only procedure to have proved long-term success is the Kasai portoenter-
ostomy. The cholangiogram is performed with a limited right upper quadrant
incision and the gallbladder is exposed and a small incision made in the fundus.
A cholangiogram catheter is introduced and contrast material is injected to
obtain a formal cholangiogram (Fig. 4). A normal cholangiogram demonstrates
contrast excretion into the duodenum, common bile duct, common hepatic
ducts, and intrahepatic ducts (Fig. 5). If no gallbladder lumen can be found,
this in of itself confirms a diagnosis of biliary atresia. If biliary atresia is

Fig. 4. Gross photo of intraoperative cholangiogram demonstrating mobilized gallbladder

with cholangiogram catheter in place after demonstration of abnormal ductal system. The in-
fant then underwent a Kasai portoenterostomy.
BILIARY ATRESIA 297

Fig. 5. Normal-appearing intraoperative cholangiogram in a child with obstructive jaundice

and abnormal HIDA in whom biliary atresia was ruled out. Initial images show contrast filling
the gallbladder and extrahepatic ducts, subsequent filling of the duodenum, and then filling of
the intrahepatic ducts.

confirmed, the incision is extended to a subcostal incision and the Kasai por-
toenterostomy is begun.
The liver can be mobilized at this point and everted onto the anterior
abdominal cavity, but care must be taken because this maneuver can kink
venous return via the inferior vena cava to the heart. The gallbladder is mobi-
lized off the liver bed and dissection is carried down to the common bile duct
and duodenum, where it is divided at the upper border of the duodenum. The
gallbladder and fibrous ductal remnant are then used as traction to move prox-
imally. The cystic artery is ligated and the hepatic arteries are identified. As
dissection proceeds proximally, the portal vein and its branches up to the
bridging veins should be identified. At this point, the cone-shaped fibrous plate
is identified on the liver. The fibrous plate is now excised using a fresh blade or
298 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

scissors flush with the liver bed. Care should be taken not to enter the liver pa-
renchyma, but all of the portal plate should be resected [54].
A traditional Roux-en-Y anastomosis is then performed. The Roux limb is
constructed 15 cm distal to the ligament of Treitz and approximately 40 cm
in length. It is brought to the portal plate in a retrocolic fashion. The portoen-
terostomy is then created in an end-to-side fashion with fine absorbable suture
[55]. Care should be taken to ensure it is a wide anastomosis (2 cm). A drain is
then placed in the subhepatic space and the incision closed.

Postoperative management
The typical postoperative course involves nasogastric drainage and intravenous
fluids until there is evidence of bowel function. Once feeds are resumed and there
is no evidence of a bile leak, the drain is removed. Corticosteroids and ursodeox-
ycholic acid are used to help with biliary flow. Studies regarding the effect of ste-
roids have shown improvements in early bilirubin clearance early on, but no
improvement in overall outcome [56]. Antibiotics are also typically administered
and continued postoperatively to minimize the risk of cholangitis. Fat-soluble vi-
tamins (vitamins A, D, E, and K) must also be supplemented given that these
vitamins are usually deficient in cholestatic infants.
The most common complications after a Kasai portoenterostomy are cholan-
gitis, fat malabsorption, and portal hypertension. Cholangitis typically occurs
within the first 2 years after operation most commonly and is secondary to
bile stasis and that intestinal contents flow in an ascending manner through
the conduit [57]. Patients typically present with jaundice, fever, pale stools,
and further signs of sepsis. Cholangitis is common; in 1 study the incidence
of cholangitis after the Kasai portoenterostomy was 59% [58]. Patients with
postoperative cholangitis tend to have lower survival rates [59]. Treatment of
cholangitis involves intravenous fluids and rapid institution of intravenous an-
tibiotics. Some surgeons treat with corticosteroids if the cholangitis is severe or
refractory.
To prevent fat malabsorption, medium-chain triglyceride formula is given
until there is evidence of adequate bile drainage in addition to fat-soluble vita-
mins. If fat-soluble vitamins and appropriate formula are not supplemented,
coagulopathy, rickets, ataxia, and keratopathy may develop.
Portal hypertension is present in many of these patients but may improve if
adequate bile drainage is obtained. Sequelae of portal hypertension include
esophageal varices, hypersplenism, and ascites. Endoscopic intervention is
required for those who bleed from the varices, with banding and sclerotherapy
the preferred treatment. Ascites should be treated with dietary restriction and
diuretic use. If portal hypertension is progressing and liver function is pre-
served, medical management may continue. Some patients do not have resto-
ration of liver function and clearance; therefore, these patients need to be
evaluated for a liver transplant.
Minimally invasive surgery has come into increasing use. In the treatment of
biliary atresia, whereas use of laparoscopic portoenterostomy surgery is more
BILIARY ATRESIA 299

common, evidence for improved outcomes with laparoscopic Kasai remains

elusive. Sun and colleagues [58] recently reported that the native liver survival
rate did not differ between cases of undergoing laparoscopic surgery versus
open surgery, and other studies report similar results [60]. Laparoscopic sur-
gery seems to have some benefits compared with open Kasai, including shorter
hospital stay after surgery, quicker time to resume normal diet, and less blood
loss during surgery [58,61]. One of the main disadvantages of laparoscopic sur-
gery is the lengthy operation time, with laparoscopic surgery significantly
longer [58]. Overall, whether laparoscopic Kasai is better than open Kasai is
unclear, and many of the studies comparing these surgical techniques have
small sample sizes. More research must be done to determine whether one
method produces better outcomes than the other.

Outcomes
The Kasai portoenterostomy has undoubtedly influenced the prognosis of
infants with biliary atresia. Successful biliary drainage has been linked to the
timeliness of Kasai portoenterostomy because cirrhosis and fibrosis are time
dependent. Typically liver function tests do not improve until at least 3 weeks
to 4 weeks postoperatively because initial flow may be sluggish. Initially, the stool
color may change within the first 10 days to 14 days from surgery. This is seen in
two-thirds of patients [3,62,63]. In patients with documented bile flow, half
continue to drain bile well and are essentially cured. In the remaining half who
initially had good bile drainage, ongoing inflammation and scarring lead to liver
failure and its sequelae of jaundice, portal hypertension, and failure to thrive.
Liver transplantation then is required. In this group who initially had drainage
post-Kasai, liver transplantation occurs at a mean age of 5.4 years. The remaining
patients (15% to 30%) who have no clinical evidence of drainage post-Kasai
never experience clinically relevant bile drainage, with evidence of liver failure
within months [3]. Evaluation for liver transplantation, either cadaveric or living
related, should be undertaken before the arrival of end-stage liver disease.
Multiple factors affect the success of Kasai procedure. Some of these factors
include age of infant and experience of the center performing the surgery as
well as the extent of liver damage at time of surgery. Varying reports document
better outcomes if portoenterostomy is completed between 60 days to 90 days
of life; however, the specific age at which better outcomes are more likely is
unknown, in part due to the various forms of biliary atresia that exist
[64,65]. Ohi and colleagues’ [66] long-term follow-up study revealed 60 days
as the time before a change in survival was noted. They found that infants
operated before the 60 days had a 70% 10-year survival compared with 30%
if older than 60 days at time of operation. Another series by this group revealed
better outcomes before 90 days with worsened outcomes after [18]. Therefore,
most centers have a goal to operate before 90 days, but the sooner the better. If
diagnosis of biliary atresia occurs after 90 days, portoenterostomy may still be
the goal operation. Davenport and colleagues [67] found an acceptable survival
rate in children who underwent portoenterostomy after 100 days of age.
300 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

Although jaundice clearance rates and age at Kasai are inversely correlated,
there is no set cutoff point where Kasai should be forfeited and liver transplant
surgery should be the first step taken for disease management [68]. Older in-
fants also have increased risk for morbidity and possibly mortality [67].
With age at treatment such a strong indicator for future disease prognosis,
time to Kasai is important. A delayed time to Kasai is still a prevalent issue
in the literature. Numerous reasons for a lengthy time of Kasai have been iden-
tified, including failure of parents to attend health checkups for the infants, fail-
ure of parents to seek medical advice about persisting jaundice, general delay of
referral for Kasai from physicians, misdiagnosis by the referral hospital,
difficulty of diagnosis by physicians, and misinterpretation of the initial liver
biopsy [37,52].
As with other diseases, experience of the surgeon and facility improves Kasai
outcomes. Surgical centers treating more than 5 cases per year have better out-
comes compared with low-volume centers that treat fewer than 5 cases annu-
ally [69]. In 1999, care for the management of biliary atresia in the United
Kingdom was centralized at 3 surgical centers solely responsible for the man-
agement areas for biliary atresia. Subsequently, shorter times to Kasai and
improved native liver survival rates and lower morbidity/mortality rates
have been reported from the United Kingdom [52].
The extent of liver damage before Kasai is another indicator of surgical out-
comes. The extent of liver damage at the time of surgery is typically dependent
on the age of the patient. There is an association between the progression of liver
damage and increasing age. A lower proportion of cases with advanced liver
damage will benefit from Kasai and have a minimal chance for success [67].
Outcomes have also been influenced by intraoperative and pathologic findings
of the portal plate. Patients with a patent gallbladder had better outcomes when
compared with those with complete fibrosis or complete absence of the fibrous
cone of the portal plate [70]. Bile drainage was universal in patients with ductules
greater than 150 lm and occurred in 86% of those with ductules less than 150 lm
but was only seen in 12% of those with no identifiable ductules [3].

Liver transplant
Biliary atresia remains the most common indication for liver transplant in the
pediatric population. Liver transplant should be undertaken for failures after
portoenterostomy.
Children who obtain a complete jaundice clearance rate and remain clear for
the first 3 years of life have an approximately 80% chance of reaching adult-
hood with their native livers [71]. Infants, however, who do not reach a com-
plete jaundice clearance rate after Kasai or who, despite an initial successful
Kasai, develop liver complications require liver transplantation [71]. Although
a timely Kasai typically does improve native liver survival rates long term,
native liver survival of biliary atresia patients is less than 50% at 20 years
[1]. Therefore, liver transplantation remains the ultimate treatment of more
than 70% of patients [72]. Overall, patient survival after liver transplantation
BILIARY ATRESIA 301

is high, with an actuarial survival rate of 90% at 6 months and 88% at 3 years in
1 study of 567 patients who received a liver transplant [72]. Similar to Kasai,
myriad factors can affect the surgical outcomes of liver transplant. These
include recipient age, growth failure, preexisting transplantation, and retrans-
plantation [33,72]. An important concern in performing liver transplantation
in a patient with biliary atresia is the need for a surgery in a timely manner.
Utterson and colleagues [72] found that 40% of the biliary atresia cases studied
died within 3 months after being on a waiting list for a liver transplant. Scarcity
of suitable donors is also a major concern for liver transplantation in this pop-
ulation [73]. Having a previous Kasai procedure has not been found to signif-
icantly influence the successfulness of a liver transplant although it may
increase the risk of postoperative infection [74]. Repeated cholangitic episodes
may increase the presence of bacteria in the blood and sepsis as well as portal
vein thrombosis, which can increase the risk of infection after liver transplan-
tation [74]. One of the main advantages of a patient initially receiving the Kasai
procedure is the high probability of bile flow restored through Kasai and sub-
sequently deterring patients from undergoing the high-risk surgical procedure
of liver transplant [74]. Previously some investigators believed that a Kasai
adversely affected the outcomes of transplant, but research has not corrobo-
rated this assertion. Therefore, the general consensus remains that despite
age at diagnosis, Kasai portoenterostomy should be performed before liver
transplant is considered.
Although liver transplantation has a postoperative mortality of 6% to 15%, it
may be the only chance for survival in children who fail to drain bile
adequately after portoenterostomy [75–77]. In addition, morbidity exists sec-
ondary to prolonged immunosuppression with increased risk of infection as
well as malignancy. Despite livers available for donation, deaths occur among
children who are on the waiting list because the demand is greater than organ
availability. To better stratify who receives donations first, the United Network
for Organ Sharing uses the pediatric end-stage liver disease (PELD) score in
addition to other variables. Among candidates listed in the United States
with an initial PELD score between 19 and 24, half receive a liver transplant
within approximately 15 weeks of being listed. The 5-year survival rates for
children receiving transplant after portoenterostomy is expected to exceed
90% [75].

SUMMARY
Biliary atresia is a rare birth defect, found in approximately 0.5 to 0.8 per
10,000 births in most populations reported from developed nations. It remains
a surgical disease with good outcomes with the Kasai portoenterostomy,
although age at operation plays a key determination in outcome. Although
some genetic factors and associations have been identified, biliary atresia seems
to have multifactorial etiologies, which remain unclear. Timely work-up of
obstructive jaundice is of key importance to perform portoenterostomy before
90 days of life, should biliary atresia be the diagnosis. Of those who do not
302 SANCHEZ-VALLE, KASSIRA, VARELA, ET AL

have successful drainage after operation, liver transplant remains the only op-
tion. Universal screening, using stool color cards or other methods, may
improve age at diagnosis and treatment, leading to improved outcomes for in-
fants with biliary atresia.

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