34 Global Journal of Gastroenterology & Hepatology, 2013, 1, 34-45

E-ISSN: 2308-6483/13 2013 Synergy Publishers

Biliary Atresia: A Challenging Diagnosis
Mostafa Mohamed Sira
*
, Tahany Abdel-Hameed Salem and Ahmad Mohamed Sira
Department of Pediatric Hepatology, National Liver Institute, Menofiya University, 32511 Shebin El-koom,
Menofiya, Egypt
Abstract: Biliary atresia (BA) constitutes about one third of all neonatal cholestasis (NC) and the most common
indication (up to 50%) of liver transplantation (LTx) in children. Despite extensive studies, its etiopathogenesis has not
been clearly revealed. Treatment is primarily surgical based on reinstitution of bile flow by Kasai portoenterostomy, the
success of which is largely dependent on the early diagnosis before 60 days of age. If portoenterostomyis not successful
or not performed, LTx is

the only life-saving alternative. Accurate diagnosis of BA, particularly distinguishing it from other
causes of liver injury in the neonatal period, is challenging as there is a high degree of overlap in clinical, biochemical,
imaging, and histological characteristics. There is no single preoperative investigation that enables the diagnosis of BA
to be made with certainty. Liver biochemistry assessment, biliary radionuclide excretion scanning, magnetic resonance
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous needle
liver biopsy, and laparoscopy can all be helpful, but their results are not individually diagnostic. The current review
presents an overview of BA with emphasis on the recent diagnostic modalities.
Keywords: Biliary atresia, diagnosis, Doppler, liver biopsy, neonatal cholestasis, ultrasound.
1. DEFINITION
Biliary atresia (BA) is an idiopathic progressive
inflammatory process of the extrahepatic bile ducts with
obliteration and concomitant ongoing damage of the
intrahepatic bile ducts resulting in chronic cholestasis,
progressive fibrosis, and eventually biliary cirrhosis [1].
2. EPIDEMIOLOGY
Although the incidence of BA is approximately 5 to
32 cases per 100,000 live births, it constitutes nearly
one third of all NC cases [2]. The reported incidence is
highest in Asia and the Pacific region [3]. The
estimates in Taiwan and J apan range from 1.1 to 3.7
cases per 10,000 live births [4, 5], while it occurs in
approximately 1 in 18,000 in Western Europe [3]. In the
United States, BA occurs with an estimated frequency
of 1 in 8000 to 15,000 live births, resulting in 250 to 400
new cases per year [6]. Females are affected slightly
more often than males [3]. Some studies of time- and
space-time distribution of BA have suggested seasonal
variation and clustering of cases [7].
3. CLASSIFICATION
Clinically, BA is classified into two types, perinatal
and embryonic. Perinatal, (acquired, or non-syndromic)
form of BA; accounts for approximately 90% of affected
infants. Patients with this type are asymptomatic,
anicteric at birth, and develop jaundice in the first
postnatal weeks. These infants are otherwise healthy


*Address correspondence to this author at the Department of Pediatric
Hepatology, National Liver Institute, Menofiya University, 32511 Shebin
El-koom, Menofiya, Egypt; Tel: +2-048-222-2740; Fax: +2-048-223-4586;
E-mail: msira@liver-eg.org
and appear to suffer from a perinatal insult that leads to
biliary obstruction [8]. Embryonic (syndromic) form of
BA; patients with this type have no jaundice-free
interval and suffer from one or more congenital
anomalies, such as interruption of the suprarenal
segment of the inferior vena cava with azygous
continuation, preduodenal portal vein, midline
symmetric liver, intestinal malrotation, situs anomalies,
bronchial anomalies, and polysplenia or asplenia. The
embryonic form thus appears to be caused by a
developmental abnormality of the biliary tree and
includes those infants with the biliary atresia splenic
malformation (BASM) syndrome [9].
Surgical (Anatomical) types of BA are classified on
anatomical basis, referring to the level and severity of
the obstruction. The most commonly used J apanese
classification describes 3 main types (Figure 1). Type I,
atresia of the common bile ducts with patent
gallbladder (GB) and hepatic ducts (i.e. distal BA).
Type II, atresia of the common hepatic ducts with
patent right and the left hepatic ducts (i.e., proximal
BA). Type II is subgrouped into two subtypes. Type IIa,
where the GB, cystic duct and common bile ducts are
patent (sometimes with a cyst in the hilum, i.e., cystic
BA). Type IIb; with the cystic, common bile duct and
common hepatic duct are all obliterated. Type III; is
characterized by atresia of the entire extrahepatic
biliary tree (i.e., complete BA) [10]. Most often, BA is
complete (type III, 73%) or subcomplete (type IIb,
18%), with cystic BA and distal BA being infrequent
(types IIa and I, 6% and 3%, respectively) [11].
4. ETIOLOGY AND PATHOGENESIS
The basic etiology of BA is still not clear [1]. The
suspected causes generally fall into infection or
Biliary Atresia: A Chall enging Diagnosis Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 35
autoimmune-/immune-mediated categories, with the
possibility of inherited predispositions [12]. It was
proposed that BA was the result of a multihit
pathologic process, in which a viral or toxic insult to
biliary epithelium leads to newly expressed or altered
antigens on the surface of bile duct epithelia. These
antigens are presented by macrophages to T
lymphocytes. Cytotoxic T cells then elicit a T helper-1
cellular response causing bile duct epithelial injury,
eventually, resulting in fibrosis and occlusion of the
extrahepatic bile ducts [13].
4.1. The Infecti ous Causes
It was suggested that BA is caused by an immune
response to an unknown triggering event. As a
potential initiator of this immune process, a viral
infection has been considered. This hypothesis has
been supported by findings of individual viral strains in
BA patients [14]. It was also supported by the
observation that all livers of BA patients stained
positive for Mx protein (a myxovirus resistance protein)
and toll-like receptor, both of which are markers known
to be up-regulated during viral infections [15]. Different
viral agents have been associated with BA; such as
cytomegalovirus (CMV), human papilloma virus,
reovirus, and rotavirus [16, 17]. In contrast, no
association with hepatitis A, B and C viruses has been
found [18].
4.2. Genet ic Causes
Several observations suggest that a genetic
component plays a role in the pathogenesis of BA as
familial cases have been reported [3]. It was reported
that about 20% of patients with BA have non-hepatic
congenital anomalies, including situs anomalies in 8%.
The increased incidence of non-hepatic anomalies in
patients with BA and the genetic mutations reported in
subsets of patients with laterality defects suggest that
multiple genes are involved [9]. Mutations in the
J AGGED1 gene; which are associated with Alagille
syndrome, have been found in about 10% of patients
with BA [12] suggesting that J AGGED1 could be a
modifying factor in patients with BA [13].
By analyzing the phenotype of hepatocyte nuclear
factor 6 (Hnf6)-knocked out mice, the GB was absent,
the extrahepatic bile ducts were abnormal, and the
development of the intrahepatic bile ducts was
perturbed in the prenatal period [19]. Moreover,
mutations in genes coding for alanine-glyoxylate
aminotransferase [20], X-prolyl aminopeptidase P and
adducin 3 genes [21] have also been linked to the
occurrence of BA.
4.3. Defective Morphogenesis
Several lines of evidence suggest that fetal form of
BA is caused by defective morphogenesis of the biliary
tree. Because anomalies of visceral organ symmetry
(polysplenia syndrome) are associated with BA, it is of
interest that a recessive insertional mutation in the
proximal region of mouse chromosome 4 or complete
deletion of the inversion (INV) gene in the mouse leads
to anomalous development of the hepatobiliary system
in this model [13].
4.4. Immunologic Causes
The immune response has received the most
attention in human based studies of BA pathogenesis
[22]. Genes that encode a variety of immune regulatory
proteins, in part, control the susceptibility of immune or
autoimmune injury to biliary epithelia [23, 24].
The infiltration of CD4
+
and CD8
+
T lymphocytes
and macrophages has been consistently observed in
the periductal space or along the duct epithelium in
conjunction with increased expression of cytokines
[25]. Davenport et al., [14] demonstrated that CD4
+
T
lymphocytes and natural killer (CD56
+
) cells
predominated in the liver and extrahepatic bile duct of
patients with BA, and that intercellular adhesion
molecule-1 was expressed in sinusoidal endothelium.
Ghonein et al., [26] demonstrated that hepatic
expression of intercellular adhesion molecule-1 was

Figure 1: Schematic il lustration of bil iary atresia
classification. Illustration by Mostafa Sira, Department of
Pediatric Hepatology, National Liver Institute, Menofiya
University. GB: gallbladder; HD: hepatic duct; CHD: common
hepatic duct; CD: cystic duct; CBD: common bile duct.
36 Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 Sira et al.
significantly higher in BA compared to other cholestatic
disorders in neonates. Moreover, Sira et al., [27]
reported that CD56 expressed on the majority of biliary
epithelial cells but not in other neonatal cholestatic
disorders.
4.5. Autoi mmunity i n BA
BA shares features with several autoimmune
diseases, such as the female predominance, apparent
triggering by viral infection, and aberrant major
histocomptability expression in bile duct epithelium.
Consequently, it has been proposed that tissue injury in
patients with BA may represent an autoimmune-
mediated process. Some patients with BA were
positive for serum immunoglobulin G and antineutrophil
cytoplasmic antibodies, with higher levels of the
antineutrophil cytoplasmic antibodies compared with
children and adults with other liver diseases [13].
4.6. Vascul ar Et iology
An ischemic etiology for BA has been proposed
based on direct experimental evidence [28].
Intrahepatic and extrahepatic bile ducts receive their
blood supply exclusively from the hepatic arterial
circulation [13]. Several investigators have
demonstrated an arteriopathy in branches of the
hepatic artery of the extrahepatic biliary tree of patients
with BA. It has been proposed that the vasculopathy
may be the primary lesion in patients with BA [29].
4.7. Ductal Plat e Malformat ion
Ductal plate malformation (DPM) is one of the
etiologic theories for the development of BA. It is a
possible primary factor in the pathogenesis of BA
causing defects in development of the intra hepatic bile
ducts, and this has been clinically observed in some
patients. This maldevelopment is thought to occur by
failure of the remodeling process of ductal plate
structures between 11 and 13 weeks of gestation [12].
Abnormal remodeling leads to DPM that is believed to
be responsible for the liver lesion of congenital hepatic
fibrosis and other bile duct dysplasias. A number of
infants with BA show evidence of DPM on liver biopsy
[30].
4.8. Maternal Microchi merism
Maternal microchimerism occurs when a small
number of maternal cells are transferred to the
offspring during pregnancy. This is known to occur in
up to 40% of normal pregnancies. Maternal-fetal
lymphocytic transfer is known to occur during
pregnancy starting as early as the tenth week of
gestation and continuing up to delivery [31].
Significantly larger numbers of maternal XX
+
cells,
CD8
+
T cells, CD45
+
cells, and cytokeratin-positive cells
were found in the portal area and sinusoids of patients
with BA in comparison with control patients suggesting
that maternal immunologic insults represent the
underlying pathogenesis in BA [32].
4.9. Toxin Exposure
Time and space clustering of cases of BA have led
to the proposal that an environmental toxin could be
involved in its pathogenesis. Currently, other than
infectious agents, no environmental agent has been
clearly associated with BA in humans. Two outbreaks
of BA in lambs and calves in Australia may have been
related to a fungal or other environmental toxin
exposure [13]. Other observations suggested the
presence of a phytotoxin or mycotoxin that could insult
the fetal hepatobiliary tree [33].
5. CLINICAL FEATURES
Infants with cholestasis may present with prolonged
conjugated hyper-bilirubinemia, passage of dark urine
with or without pale (acholic or clay-colored) stools
[34]. Intrahepatic and extrahepatic forms of cholestasis
share numerous clinical and biochemical features and
no clinical symptom is pathognomonic of each [35].
After birth, the clinical features of BA is jaundice
(conjugated hyper-bilirubinemia lasting beyond two
weeks of life), acholic stools, dark urine and
hepatomegaly [3].
The general condition of the child is usually good.
There is no failure to thrive, at least in the first months.
Thereafter, weight loss and irritability develop,
accompanied by increasing levels of jaundice. Later
signs include splenomegaly (suggesting portal
hypertension), ascites and hemorrhage (which can be
intracranial, gastrointestinal or from the umbilical
stump) due to impaired absorption of vitamin K. If
untreated, this condition leads to cirrhosis and death
within the first years of life [3]. In our experience,
intracranial hemorrhage may be the initial presentation
even before the appearance of jaundice.
6. EVALUATION OF BA
There are some obstacles that make an early
diagnosis of BA challenging. First, despite the need for
Biliary Atresia: A Chall enging Diagnosis Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 37
early surgical intervention in this disease, there is a
general lack of understanding of the importance of
early identification among health care providers. Few
primary care physicians see more than 1 or 2 cases of
BA during their careers, whereas unconjugated
hyperbilirubinemia is extremely common, particularly
among breast-fed infants [36]. A second obstacle is the
lack of convenient methods of screening. The efficacy
of stool color cards and conjugated bilirubin testing
were evaluated in Europe and Asia [4, 37-39]. A third
obstacle is that the jaundiced infant may not be seen at
the optimal time for identification of BA. The
unconjugated hyperbilirubinemia, due to breast feeding
in the first 2-3 weeks of life, may obscure the
conjugated hyperbilirubinemia of BA making it appear
that jaundice is actually improving. As the indirect
bilirubin falls during the first month of life in an infant
with BA who is also breast-fed, it may appear that there
is an overall improvement in jaundice [9].
6.1. Antenatal Diagnosi s
Antenatal diagnosis of BA remains exceptional. BA
types 1 and 2, which are rare, can be suspected on
antenatal ultrasonography (US) scans when a cystic
structure is detected in the liver hilum [40]. GB may be
visualised later in pregnancy, suggesting a delay in its
recanalisation process. When the GB remains
undetectable after birth, the possibility that the patient
has BA has to be carefully investigated [3]. Features of
polysplenia syndrome may be detected by antenatal
US [41]
6.2. Cli nical Di agnosis
The first step in diagnosis is the identification of
conjugated hyperbilirubinemia in an infant with
prolonged jaundice (beyond 2 weeks of age), pale
stools, or dark urine. An examination of the color of a
fresh stool specimen may be useful in differentiating
cholestasis (clay stools) from indirect
hyperbilirubinemia (bright yellow stools). The history
and physical examination may guide diagnostic studies
to identify specific causes of intrahepatic cholestasis
[9]. Poddar et al., [42] reported that clay stool has a
high sensitivity (86%) but low specificity (76%) in
predicting BA. A similar finding was reported by El-
Guindi et al., with 92.5% sensitivity and 55.6%
specificity [43].
6.3. Laboratory Diagnosis
As time is an important factor in BA prognosis, a
wide-ranging approach of investigation is
recommended. Ruling out other etiological possibilities,
in particular, congenital infection (TORCH;
Toxoplasmosis, Rubella, CMV, Herpes simplex virus)
serology is indicated [44].
High serum levels of GGT are commonly observed
in infants with BA. It is still unclear if normal values of
GGT may be found in patients with BA [45]. Alkaline
phosphatase is produced by the epithelial cells of the
bile ducts and serum levels are increased in cases of
extra-hepatic obstruction, cholangitis and intrahepatic
cholestasis. Since alkaline phosphatase is also
produced in the bones, associated bone conditions
may cause difficulties in the interpretation of results. In
the case of high alkaline phosphatase levels and GGT
above 600 U/L, BA or another obstructive duct lesion,
or even alpha-1 antitrypsin deficiency would be the
main diagnostic candidates. In cases of normal serum
values for alkaline phosphatase with GGT below 100
U/L, a diagnosis of progressive familial intrahepatic
cholestasis, or of an innate error of bile acid synthesis
is possible. When the results for alkaline phosphatase
and GGT are not very high, it is probable that a primary
hepatocellular disease is present, such as idiopathic
neonatal hepatitis [46]. GGT has been reported as
discriminative tool of BA and at a cutoff value of 250.5
U/L it had a sensitivity of 86.7% and specificity of 65%
[26].
Serum bile acid levels are increased after birth and
remain high for the first month of life, thereafter slowly
declining to normal childhood levels by 1 year of age.
Serum and urinary bile acids are increased further in
children with cholestatic liver disease. Furthermore, the
pattern of bile acid elevations in BA is not different from
that of other neonatal cholestatic liver diseases, except
for progressive familial intrahepatic cholestasis [47].
The cholestasis of BA is not fully evident at birth but
worsens thereafter. So, pathological elevations of
serum and urinary bile acids may not be present until
2-4 weeks of age. Thus, bile acid levels cannot be used
alone for the screening and early detection of BA [48].
Progressive hepatic fibrosis, in spite of successful
Kasai procedure, is a major problem in patients with
BA. Some serum markers have been used to assess
the stage of hepatic fibrosis before and after surgery.
Serum hayaluronic acid and laminin were found to be a
significant markers of liver fibrosis in patients with BA
[49, 50]. Furthermore, serum procollagen III peptide
and type IV collagen were described to be significant
prognostic markers for the outcome of BA after the
corrective surgery. Lower levels of such markers were
38 Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 Sira et al.
associated with better outcome and good liver
functions [51].
6.4. Imaging
a. Plai n X-Ray
While X-ray may reveal situs inversus or
dextrocardia associated with some cases of BA, it may
also reveal different etiologies of cholestasis. Alagille
syndrome may be suspected if a vertebral image
showed butterfly wing. Congenital toxoplasmosis, or
CMV may cause cerebral calcifications. Periostitis and
osteochondritis were found to be highly indicative of
syphilis [44].
b. Ultrasonography
A rapid, non-invasive investigative method, and,
when performed by a well-trained professional, it
provides excellent results. An accurate diagnosis of BA
is possible if multiple US features are carefully
analyzed [52]. It is extremely useful in the diagnosis of
choledochal cysts and also in verifying the absence of
the GB, which may suggest a diagnosis of BA. US play
a role in screening patients with infantile cholestasis,
mainly focusing on the size, shape and contractility of
GB. Nevertheless, if changes in GB volume occur post-
feeding in serial US analysis, BA cannot be ruled out.
Despite difficulties in identification due to its small
volume, the contractibility of the GB in BA can be
observed in a percentage of cases due to a patent bile
duct [53]. US evaluate congenital anomalies associated
with BA.
Triangular cord (TC)-sign which represents a cone-
shaped fibrotic mass cranial to the bifurcation of the
portal vein is also a useful diagnostic criterion [54]. The
presence of the TC-sign in the US examination has
shown to be correct in 95% of BA diagnoses, with 85%
sensitivity and 100% specificity [55]. False negative
TC-sign results may occur in some BA cases due to
hepatic radicles, such as hypoplasic or aplasic ducts or
fibrous hepatic ducts, even at early stages [56].
However, this sign does not present or cannot be found
in every patient, and it is largely dependent on
operators' techniques and experience. Furthermore, it
would be difficult to visualize TC-sign if the patient is
very young with hepatic maldevelopment or the
resolution of ultrasonic apparatus is poor [57]. A recent
study reported that TC-sign has 59.3% sensitivity and
88.9% specificity in predicting BA [43].
Abnormal GB is also an important positive pointer to
BA, but this is less reliable as an isolated finding in the
absence of other US features of BA. Abnormal GB was
observed in infants with cystic fibrosis. Infants with no
US evidence of BA will still require further investigation
to establish the cause of their conjugated
hyperbilirubinemia. Tiao et al., [58] reported that, GB
lengths < 1.5 cm had 77.4% sensitivity, 69.8%
specificity for the diagnosis of BA. This finding is in
agreement with that of El-Guindi et al., [43] who found
that GB length of less than 20.5 mm is 81.4% sensitive
and 70.3% specific for BA. In addition, non-contractile
GB had a high sensitivity (92.5%), but low specificity
(51.9%) in discriminating BA.
c. Col or Doppler US
The presence of angiographically perivascular
arterial tufts in the periphery of the hepatic arterial
circulation (hepatic subcapsular flow) was reported in
patients with BA and suggested that these findings
might be useful in the diagnosis of BA [59]. Color
Doppler US was used instead of angiography to
evaluate hepatic arterial changes. On color Doppler US
images, an enlarged hepatic artery and hepatic arterial
flow that extended to the hepatic surface were seen in
all patients with BA. It had a sensitivity and specificity
of 100% and 86% respectively in predicting BA [60]. A
similar study reported that hepatic subcapsular flow
was found in 96.3% of BA group compared to 3.7% in
non-BA group with 96.3% of both sensitivity and
specificity in discriminating infants with BA from those
with non-BA [43].
Hepatic artery diameter (HAD) was found to be
significantly larger in patients with BA (2.1 0.7 mm)
than in patients with non-BA (1.5 0.4 mm) (P <0.001)
and control subjects (1.5 0.4 mm) (P <0.001) [43]. In
addition Humphrey and Stringer [52] reported that HAD
was significantly larger in the BA group than in the non-
BA group (2.2 0.59 mm vs. 1.6 mm 0.4 mm,
respectively; P < 0 .001). The increased size of the
hepatic artery may be secondary to increased arterial
resistance from hypertrophy of the media of
intrahepatic arteries, which has been observed
specifically in BA [43]. Kim et al., [61] reported that, the
optimal cutoff value of HAD was defined as 1.5 mm
which had 92% sensitivity, 87% specificity, and 89%
accuracy. This enlargement may be a compensatory
change to improve the blood supply for the biliary tree,
a secondary change of liver cirrhosis, or an essential
vascular malformation. El-Guindi et al., reported that
HAD at a cutoff value of 2.05 mm had 77.8% sensitivity
and 70.4% specificity in discriminating BA [43].
Biliary Atresia: A Chall enging Diagnosis Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 39
d. Hepat obil iary Scint igraphy
These procedures are invasive and time consuming
and do not significantly increase the accuracy of
diagnosis [62]. Normal hepatic uptake of the radiotracer
occurs within the first 10-15 minutes after injection, but
the excreted tracer reaches the duodenum within 1
hour. If there is an excellent accumulation of the
radiotracer in the liver but no bowel activity at 24 hours,
the diagnosis of BA would be possible [57].
DISIDA Tc99m (Tc99m linked to 2.6-diisopropyl
imino diacetic acid) and BRIDA Tc99m isotopes
(Tc99m linked to 2.4.6-trimethyl-3-bromo imino diacetic
acid), are frequently used in radioisotope scan. They
have a very short half-life, low gamma ray emissions,
very good concentration in the liver, non-conjugated
excretion in the bile and a low renal excretion level.
The BRIDA is offering the advantage that 98% of the
dose administered is eliminated by the liver, while with
DISIDA hepatic elimination is 85% [63]. The DISIDA
Tc99m test is not recommended when conjugated
bilirubin levels are over 20 mg/dl. In such cases BRIDA
Tc99m should be employed, since, even with high
levels of bilirubin, it maintains hepatic capture levels of
70%. Premature, very low birth weight newborns and
children on total parentral nutrition, even with pervious
presence of bile ducts, may not present excretion of the
radiopharmaceutical to the intestine. In these cases
there is indication to repeat examination two weeks
later [64].
For patients in whom no intestinal tracer excretion is
detected even after 24 h, scintigraphy is repeated after
giving them ursodeoxycholic acid for 4872 hrs before
the second scan and is continued till the second scan
is over. These additional procedures add to the time
and expense of diagnosis; however, the overall
specificity and accuracy in the event of a non draining
scintigraphic picture remain far from being satisfactory
[65].
Although hepatic scintigraphy showing definite
biliary excretion excludes BA, the absence of excretion
has poor predictive value because any form of severe
cholestasis may show similar findings [66]. Thus non-
excretion of radioisotope neither confirms the diagnosis
of BA, nor rules out the diagnosis of causes other than
BA [67]. Yet, hepatobiliary scintigraphy had 80%
sensitivity, 72.9% specificity, and 74.1% accuracy [68].
The diagnostic accuracy of hepatobiliary scintigraphy

has been reported to be inferior to that of liver biopsy
[35].
6.5. Liver Biopsy
In many cases, the clinical and radiographic findings
are not diagnostic and histologic findings are critical in
patient management decisions [35]. Liver biopsy can
correctly predict extrahepatic biliary obstruction in more
than 90% of cases, directing the evaluation toward
cholangiography [69, 70]. Hepatic histology does not
differentiate patients with the embryonic and perinatal
forms of BA [71].
Lee and Looi [72], reported that, the presence of
moderate to severe bile ductular proliferation (91%)
was the most consistent histological feature noted in
BA with the highest sensitivity (91%) and specificity
(88%) for its diagnosis. They reported bile plugs in 70%
of their cases with 68% sensitivity and 86% specificity
for the diagnosis of BA. Rastogi et al., [34] reported
that ductular proliferation, bile plugs and portal fibrosis
emerged as the best indicators of BA. Moreover, Russo
et al., [73] found a great difference between BA and
non-BA cases where bile duct proliferation, bile plugs in
ducts and canaliculi, and the more severe grades of
portal fibrosis were in favor of BA cases. El-Guindi et
al., [43] reported that ductular proliferation had 100%
sensitivity and 88% specificity, while bile plugs had
96.3% sensitivity and 64% specificity in diagnosing BA.
6.6. Duodenal Tube Test (DTT)
A nasogastric tube is put into the distal portion of
the duodenum and the liquid collected for 24 hours. If
no bile fluid is seen, the test is prolonged for a further
24 hours. The enteral administration of magnesium
sulfate at 25%, with a dosage of 1 ml/kg, or I.V
cholecystokinin, can be performed when biliary fluids
are negative 24 hours after the insertion of the
duodenal tube [63].
DTT test showed a sensitivity of 97.3%, and
specificity of 93.7%, a positive predictive value of
92.3% and a negative predictive value of 98.5%. DTT
is not highly invasive, it is inexpensive and it may be
performed by trained personnel with few specialized
resources. Its high sensitivity, specificity and predictive
value make it a useful tool in the differential diagnosis
of infantile cholestatic jaundice, particularly in the
diagnosis of BA [62]. The presence of bile excludes the
possibility of BA; yet, the absence of bile does not
necessarily indicate BA.
40 Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 Sira et al.
6.7. Cholangi ography
a. Endoscopic Retrograde Cholangiopancreato-
graphy (ERCP)
After the application of the radiological contrast into
the papilla of Vater, it is possible to observe whether or
not there is progression through the bile and pancreatic
ducts [63]. ERCP has a sensitivity of 86 %, a specificity
of 94 % in diagnosing BA [74].
b. Magnet ic Resonance Cholangiopancreatography
(MRCP)
MRCP is a reliable non-invasive imaging technique
for the diagnosis of BA and could help in early referrals
from pediatricians who may spend much time seeking
non-surgical causes for jaundice in infants.
Preoperative MRCP is highly recommended to avoid
unnecessary surgery in infants with cholestatic
jaundice [75]. It has been reported that a small GB by
MRCP can be considered highly suggestive of BA [76].
Periportal thickening in the MRCP image seems to
represent periportal fibrosis on histologic examination
and increased sonographic echo in the periportal area
[77]. MRCP is more expensive than hepatobiliary
scintigraphy and not available in all hospitals. One of
the vulnerable points of MRCP is that it does not show
the bile flow itself as does hepatobiliary scintigraphy or
ERCP [75].
c. Intra-Operative Cholangi ograpy (IOC)
IOC is performed when other methods do not permit
a definitive diagnosis. As patients with intrahepatic
cholestasis may have their condition aggravated by
anesthetic products, hemodynamic alterations and
infections, the investigation which precedes IOC should
be as thorough as possible, in an attempt to achieve a
non-invasive diagnosis. IOC should be performed at a
medical center which is capable of performing the
hepatoportoenterostomy immediately if necessary [44].
IOC is the gold-standard for the diagnosis of BA.
However, the rate of negative laparotomy findings
without preoperative liver biopsy is much higher than
that with a preoperative liver biopsy (28% vs. 11%).
Biopsy and IOC, both invasive procedures, become
essential in such cases to confirm the diagnosis.
Among the 3 commonly used tests in NC (US,
hepatobiliary scintigraphy, and liver biopsy), liver
biopsy is the most accurate but most invasive test [65].
6.8. Diagnost ic Laparoscopy
A coarse, irregular, greenish-brown liver with some
degree of fine angiomatous development and an atretic
GB were found laparoscopically in some infants with
BA. However, in case of neonatal hepatitis, the liver
was smooth, sharp-edged, and chocolate brown in
color and simultaneous cholangiography showed the
passage of the contrast material into the proximal
biliary tract and the intestinal system. Laparoscopic
guided puncturing with a needle was used to wash the
bile duct from the GB to decrease jaundice in patients
with inspissated bile syndrome, thus unnecessary
laparotomy was avoided in 25% of the patients [57].
7. DIFFERENTIAL DIAGNOSIS
A major challenge in NC is to differentiate BA from
other non-atretic causes. In developing countries there
are considerable problems of late referral of NC cases
and performing surgery without prelaparotomy liver
biopsy that contributes to a high proportion of negative
laparotomy and increased morbidity [34].
Medical causes of NC must be excluded [3]. The
main differential diagnosis of a biliary obstructive
pattern in a liver biopsy of a cholestatic infant includes
choledochal cysts, bile duct strictures, alpha-1
antitrypsin deficiency, total parentral nutrition-
associated cholestasis, cystic fibrosis, progressive
familial intrahepatic cholestasis type 3, North American
Indian childhood cirrhosis (cirhin deficiency), Alagille
syndrome [78], CMV hepatitis and inspissated bile
syndrome.
8. MANAGEMENT
8.1. Surgical Management
The current surgical management of BA patients
involves two steps: Kasai operation (in the neonatal
period), which aims to restore bile flow and LTx in
children for whom the Kasai operation has failed in its
primary aim or for whom complications of biliary
cirrhosis have supervened [3].
a. Kasai Operat ion (Hepatoporto-Enterostomy)
There is an increased need for early and correct
diagnosis of BA because timely surgical
portoenterostomy is necessary for improved biliary
drainage. Kasai procedures appear to have the best
outcome in children younger than 60 to 80 days [79].
The Kasai operation is an accepted method of
achieving bile drainage in BA [80]. Reports from
several institutions in J apan show that more than 80%
of BA patients become jaundice-free after the Kasai
operation. A favorable course depends essentially on
early surgical intervention [81]. However, progressive
Biliary Atresia: A Chall enging Diagnosis Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 41
liver disease develops in a few patients with successful
Kasai operations and LTx is needed for patients with
frequent postoperative cholangitis and for those with
liver cirrhosis [82].
Clinical outcomes after the Kasai operation can be
divided into three categories; patients who continue in
a jaundice-free state and reach adulthood with few
manifestations of liver disease and portal hypertension;
patients who continue in a jaundice-free state but
whose quality of life is impaired because of some
manifestations of liver disease owing to ongoing
cirrhosis, and who thus need follow-up in planning LTx,
and finally patients whose disease process continues,
leading to death from cholestatic liver failure within the
first two years of life unless successful LTx is achieved
[80]. If the Kasai operation succeeds in restoring bile
flow, the stools become colored and jaundice fades.
The evolution of the biliary cirrhosis is prevented or at
least delayed. Survival with the native liver has been
reported up to adulthood [3].
The most common complications following the
Kasai procedure include ascending cholangitis which
occurs in the first weeks or months after the Kasai
procedure in 30%-60% of cases [3]. Portal
hypertension occurs in at least two-thirds of the
children after porto-enterostomy, even in those with
complete restoration of bile flow [83]. Hepatopulmonary
syndrome and pulmonary hypertension may occur
leading to hypoxia, cyanosis, dyspnea and digital
clubbing [3]. Hepatocarcinomas, hepatoblastomas [84]
and cholangiocarcinoma [85] have been described in
the cirrhotic livers of patients with BA. Screening for
malignancy has to be performed regularly in the follow-
up of patients who underwent a successful Kasai
operation [3].
b. Liver Transplantati on
Indications for LTx depend on the success of Kasai
portoenterostomy and the rate of development of
complications. In infants in whom bile drainage is not
achieved, LTx is usually indicated within 6 months to 2
years of age. However, in those who have had a
successful procedure, LTx should be considered in the
presence of cirrhosis with hepatic dysfunction, or
development of portal hypertension with ascites and
variceal bleeding unresponsive to endoscopic
management [86].
Investigation of factors that predict the need for LTx
help with planning and counseling of families. Such
factors are the concentration of bilirubin at 30 days
after surgery and a pediatric end-stage liver disease
score approach [87]. In children with the syndromic
variants of BA, associated anomalies, especially
congenital cardiac malformations, increase the risk of
both early mortality and morbidity [88].
With advances in surgical techniques and
management, children with BA after LTx can achieve
satisfactory survival, although there remains a high risk
of complications in the early postoperative period [89].
8.2. Adj uvant Therapy
Effective postsurgical management includes
prevention and treatment of complications such as
cholangitis and provision of effective nutritional and
family support [88]. Prophylactic antibiotics (to prevent
cholangitis) and choleretic agents are commonly
prescribed, although definitive evidence supporting
their use is lacking [90]. All infants should have
supplementation of nutrition and fat-soluble vitamins
(A, D, E, and K) to prevent malnutrition, overcome fat
malabsorption and reduce the effects of excess
catabolism. In refractory cases, parenteral vitamins
might be needed. Steatorrhoea from fat malabsorption
can be managed by provision of between 40% and
60% of fat in the feed as medium-chain triglycerides
[91]. Supplementation should contain high-energy,
high-protein feed that provides between 110160% of
the recommended daily amount [88].
9. PROGNOSIS OF BA
Several prognostic factors have been identified in
BA patients. Some of them are related to
characteristics of the disease. The prognosis of the
Kasai operation is worse when BA is associated with a
polysplenia syndrome [92], when macroscopic
obstructive lesions of extra-hepatic biliary remnant are
diffuse (prognosis worsens from type 1 to type 3) [3],
when histological obliteration of the bile ducts
(especially at porta hepatis) is more severe and when
liver fibrosis is more extensive at the time of the Kasai
operation [93]. Other prognostic factors are related to
the management of BA patients and can be improved
[3]. The four year survival with native liver after Kasai
operation is 43%-51% and the four year survival after
LTx is 89%-90% [94].
10. CONCLUSION
In spite of the rare incidence of BA, it represents
about one third of all NC. Effective treatment largely
depends on early diagnosis and discrimination from
42 Global Journal of Gastroenterology & Hepatology, 2013 Vol. 1, No. 1 Sira et al.
other causes of cholestasis. Clinical, laboratory,
radiological and histopathological parameters are all
helpful in diagnosis, yet, no single parameter is 100%
diagnostic. So they are all helpful but not conclusive
leaving IOC as the gold-standard for diagnosis.
Combining different parameters may improve
predictability and early diagnosis of BA and decrease
the need for the invasive IOC.
CONFLICT OF INTERESTS
The authors declare that they have no competing
interests.
ABBREVIATIONS
BA = Biliary atresia
BRIDA Tc99m = Tc99m linked to 2.4.6-trimethyl-3-
bromo imino diacetic acid
CMV = Cytomegalovirus
DISIDA Tc99m = Tc99m linked to 2.6-diisopropyl
imino diacetic acid
DPM = Ductal plate malformation
DTT = Duodenal tube test
ERCP = Endoscopic retrograde cholangio-
pancreatography
GB = Gallbladder
GGT = Gamma glutamyl transpeptidase
HAD = Hepatic artery diameter
Hnf6 = Hepatocyte nuclear factor 6
IOC = Intraoperative cholangiography
MRCP = Magnetic resonance cholangiopan-
creatography
NC = Neonatal cholestasis
TC = Triangular cord
US = Ultrasonography
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Received on 16-04-2013 Accepted on 13-05-2013 Published on 25-06-2013

http://dx.doi.org/10.12970/2308-6483.2013.01.01.6
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