Biliary atresia

Authors:Jessi Erlichman, MPHKathleen M Loomes, MDSection

Editor:Elizabeth B Rand, MDDeputy Editor:Alison G Hoppin, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Mar 2017. | This topic last
updated: Jan 10, 2017.
INTRODUCTION Biliary atresia (BA) is a progressive, idiopathic,
fibro-obliterative disease of the extrahepatic biliary tree that presents
with biliary obstruction exclusively in the neonatal period [1]. Although
the overall incidence is low (about one in 10,000 to 20,000 live births [2-
5]), BA is the most common cause of neonatal jaundice for which
surgery is indicated and the most common indication for liver
transplantation in children.
TYPES OF BILIARY ATRESIA Infants with biliary atresia (BA) can be
grouped into three categories:

Biliary atresia without any other anomalies or malformations This

pattern is sometimes referred to as perinatal BA, and occurs in 70
to 85 percent of infants with BA [1,6,7]. Typically, these children are
born without jaundice, but within the first two months of life, jaundice
develops and stools become progressively acholic.

Biliary atresia in association with laterality malformations This

pattern is also known as Biliary Atresia Splenic Malformation
(BASM) or "embryonal" biliary atresia, and occurs 10 to 15 percent
of infants with BA [6-9]. The laterality malformations include situs
inversus, asplenia or polysplenia, malrotation, interrupted inferior
vena cava, and cardiac anomalies. Data suggest that children with
BASM have poorer outcomes compared to those with perinatal BA,
possibly due to the associated cardiac abnormalities [8-10].

Biliary atresia in association with other congenital malformations

This occurs in the remaining 5 to 10 percent of BA cases;
associated congenital malformations include intestinal atresia,
imperforate anus, kidney anomalies, and/or heart malformations
[7,11,12].

Regardless of the type of BA, in each case, the histology and

cholangiogram are characteristic: the histology typically shows
inflammation, portal tract fibrosis, cholestasis, and bile duct proliferation;
the cholangiogram demonstrates loss of patency of the extrahepatic bile
ducts.
Because of the cholangiographic findings, BA was previously termed
"extrahepatic biliary atresia," to distinguish it from "intrahepatic biliary
atresia," which was a histopathologic grouping of disorders in which the
intrahepatic bile ducts are primarily affected. However, disorders
primarily affecting the intrahepatic bile ducts are now categorized by the
genetic, metabolic or infectious cause, rather than by the histologic
finding. (See "Causes of cholestasis in neonates and young infants".)
PATHOGENESIS The cause of biliary atresia (BA) is unknown,
although several mechanisms have been implicated, as outlined below.
In some patients, several of these mechanisms may contribute to the
development of BA. Conversely, BA may be the common phenotype that
can be caused by a variety of injuries to the biliary system occurring in
the perinatal period.
Viral etiologies Clustering of cases of BA in time and space suggest
a possible viral etiology. As an example, an analysis of 249 cases of BA
over a 16-year period in New York State demonstrated seasonal patterns
of incidence that varied by region in the state; in New York City, the risk
of BA was highest for infants born during the Spring months, whereas
outside of New York City infants born in the Fall months had a higher risk
[13]. To date, a specific virus has not been implicated; investigations
have failed to identify associations with several specific viral infections
including cytomegalovirus, reovirus, and group C rotavirus [14-17].
Toxic etiologies The clustering of cases of BA is also consistent with
the possibility of a toxin-mediated inflammatory response. The strongest
evidence for this hypothesis comes from three reported outbreaks of BA
in lambs in Australia in 1964, 1988, and 2007 [18]. In each outbreak, in a
time of drought ewes that gave birth to affected lambs had grazed on
lands that had previously been flooded. A significant number of offspring
were thin, jaundiced, had acholic stools, and eventually died, and
autopsy revealed a diagnosis of BA. The hypothesized mechanism is
that the pregnant ewes ingested a toxin when grazing on lands
previously submerged. A novel isoflavonoid toxin was isolated from the
Dysphania plant, which was harvested in Australia at the site of a recent
outbreak. This toxin caused severe damage to the extrahepatic biliary
tree in a zebrafish model, and also loss of cilia in neonatal mouse
cholangiocytes. This evidence suggests that an environmental toxin may
be implicated in some cases of BA [19].
Genetic etiologies Genetic factors may play a causative role in the
small subgroup of patients with BASM malformations, as suggested by
the following observations:

Mutations in the CFC1 gene, which encodes cryptic protein and is
involved in determining laterality during fetal development, have been
associated with BASM syndrome. A heterozygous mutation in CFC1 was
found in five out of ten infants with BASM [20]. The frequency of this
mutation in infants with BASM is twice that found in a population of
healthy individuals. Thus, CFC1 mutations may predispose to BASM but
are not sufficient to cause the disease.

A transgenic mouse with a recessive deletion of the inversin gene

provides an animal model for BASM, displaying situs inversus and
extrahepatic biliary obstruction [21].

A heterozygous deletion of FOXA2 has been reported in a family with

heterotaxy, panhypopituitarism, and biliary atresia [22].

Other than these subgroups of patients with BASM, genetic factors may
not play a direct causative role in the development of most cases of BA;
this is suggested by the observation that monozygotic twins usually have
a discordant phenotype. Nonetheless, genetics may still play a role in
disease susceptibility. Association studies have identified a few genomic
loci with increased susceptibility to BA [23,24]. In addition, mutations in
the human Jagged1 gene, which are responsible for Alagille syndrome,
have been found in a few cases of biliary atresia [25]. The Jagged1 gene
encodes a ligand in the Notch signaling pathway, which is critical in the
determination of cell fate during development and may also alter
production of inflammatory cytokines. Epigenetic factors have also been
postulated as important factors impacting biliary development and the
pathogenesis of BA. Both microRNA and DNA methylation have been
studied in animal models and humans [26,27]. (See "Causes of
cholestasis in neonates and young infants", section on 'Alagille
syndrome'.)
Immunologic etiologies Immune dysregulation, either as a primary
disorder or as the result of infectious or genetic triggers, has been
implicated in various studies.

A high concentration of maternal chimeric cells have been found in the

portal and sinusoidal areas of patients with biliary atresia, suggesting
that maternal lymphocytes cause bile duct injury through a graft-versus-
host immune response [28].

Coordinated activation of genes involved with lymphocyte differentiation,
particularly those associated with T helper 1 immunity, has been
identified in liver samples from infants with biliary atresia [29].

Polymorphisms that enhance expression of the CD14 gene, which plays

a role in the recognition of bacterial endotoxin, have been associated
with biliary atresia and idiopathic neonatal cholestasis [30].

CLINICAL FEATURES Most infants with biliary atresia (BA) are born
at full term, have a normal birth weight and initially thrive and seem
healthy.
Signs and symptoms

Jaundice is the first sign of BA. Initially, the jaundice may be seen only in
the sclerae. The onset of jaundice occurs any time from birth up to eight
weeks of age, and it is highly unlikely to appear later.

Some infants have acholic stools. Acholic stools often go unrecognized

because the stools are pale but not white and the stool color can vary on
a daily basis. To help parents distinguish between normal and acholic
stools, printed "stool color cards," webpages, and a free smartphone
application (PoopMD for iPhone or Android), have been developed
[31,32]. In a study from Japan that included more than 300,000 newborn
infants, stool color cards completed by the parents had a sensitivity of
76.5 percent and specificity of 99.9 percent, respectively, for identifying
infants with biliary atresia [33].

Most infants have dark urine because of bilirubin excretion into the urine.
This often is not recognized by parents, who may not realize that infant
urine should not stain a diaper yellow.

If the jaundice has gone unnoticed and the child's disease has
progressed, there may be a firm, enlarged liver and splenomegaly.

Laboratory studies When laboratory studies are performed in infants

after they come to attention because of one of the above symptoms,
they reveal elevations in bilirubin (conjugated bilirubin 2 mg/dL), and
mild or moderate elevations in serum aminotransferases, with a
disproportionately increased GGTP. If coagulopathy is present at
diagnosis, it is most likely due to vitamin K deficiency.
If laboratory studies are performed shortly after birth (before the infant
becomes symptomatic), mild elevations of conjugated bilirubin are seen.
As an example, one study reported mild elevations in conjugated
bilirubin (>0.3 mg/dL) or direct bilirubin (>0.5 mg/dL) at 24 to 48 hours of
life in each of 34 infants who were later diagnosed with BA [34]. The
mean serum direct bilirubin level was 1.4 0.43 mg/dL, as compared
with 0.19 0.075 in control infants. The total bilirubin was not elevated at
that time and conjugated bilirubin did not exceed 20 percent of the total
bilirubin level.
These observations suggest that infants with mildly elevated conjugated
or direct bilirubin levels in the perinatal period should be followed closely
and evaluated for the possibility of BA. Furthermore, they raise the
possibility that measurements of conjugated or direct bilirubin during the
first few days of life could be used as a screening tool for BA [35]. In a
pilot study of such an approach, 11,636 infants were screened for
persistent elevations in conjugated or direct bilirubin during the birth
hospitalization, resulting in early identification of two infants with biliary
atresia, and one with alpha-1 antitrypsin deficiency [36]. Further studies
are needed to determine the sensitivity and cost-effectiveness of this
measure and its potential effect on patient outcome.
DIAGNOSIS Infants with suspected biliary atresia (BA) should be
evaluated as rapidly as possible because the success of the surgical
intervention (hepatoportoenterostomy, the Kasai procedure) diminishes
progressively with older age at surgery [37]. (See 'Predictors of the need
for transplantation' below.)
The evaluation process involves a series of serologic, laboratory, urine,
and imaging tests. The order of diagnostic tests is prioritized based on
testing for treatable diseases first, such as biliary obstruction, infections,
and some metabolic diseases. Because the timing of surgery is crucial
for infants with BA, it is often appropriate to proceed with surgical
exploration, even if all of the test results have not returned. In our
practice, we typically proceed with each of the steps below if the infant is
less than six weeks of age. For those patients six weeks and older, we
still try to complete a full evaluation as rapidly as possible (eg, three to
four days). Our rationale is that some diseases, such as Alagille
Syndrome or alpha-1-antitrypsin deficiency, can mimic many of the
findings of BA.
Additional detail about the evaluation of an infant with cholestasis is
given in a separate topic review. (See "Approach to evaluation of
cholestasis in neonates and young infants".)
Abdominal ultrasound Evaluation of biliary anatomy begins with an
ultrasound. The main utility of the ultrasound is to exclude other
anatomic causes of cholestasis (ie, choledochal cyst) (see "Causes of
cholestasis in neonates and young infants", section on 'Biliary cysts'). In
infants with BA, the gallbladder is usually either absent or irregular in
shape. When a detailed ultrasonographic protocol is used, additional
features can be identified to support the diagnosis of biliary atresia,
including abnormal gallbladder size and shape, the "triangular cord"
sign, gallbladder contractility, and absence of the common bile duct [38-
42]. The triangular cord sign is a triangular echogenic density seen just
above the porta hepatis on US scan. Its presence is highly suggestive of
biliary atresia [43].
Hepatobiliary scintigraphy Patency of the extrahepatic biliary tree
can be further assessed by hepatobiliary scintigraphy. Although some
centers may use phenobarbital to enhance radioisotope excretion, we do
not use phenobarbital because it will delay diagnosis and does not
obviate the need for liver biopsy. Failure of tracer excretion suggests BA,
but does not exclude other diseases. Conversely, if scintigraphy
demonstrates definite excretion of the tracer from the liver to the small
bowel, patency is established, and BA is very unlikely. However, if
excretion is noted on a scan that is performed when the infant is very
young (ie, less than six weeks old), and cholestasis persists, the scan
should be repeated one to two weeks later because the disease process
may progress during the neonatal period.
Liver biopsy We perform a liver biopsy in virtually all infants with
suspected biliary atresia for two reasons. One purpose is to identify
histologic changes consistent with obstruction that warrant surgical
exploration. The other is to differentiate BA from other causes of
intrahepatic cholestasis, which would not need surgical exploration.
Biopsy findings that indicate another etiology include bile duct paucity
(Alagille syndrome), PAS positive diastase resistant granules (consistent
with alpha-one antitrypsin deficiency), loss of MDR3 staining (suggestive
of PFIC3), or giant cell hepatitis without proliferation of ducts.
Characteristic histologic features of BA include expanded portal tracts
with bile duct proliferation, portal tract edema, fibrosis and inflammation,
and canalicular and bile duct bile plugs. The earliest histological changes
associated with BA may be relatively nonspecific, and biopsies done too
early may result in a false negative [44]. At times it is necessary to
repeat a liver biopsy at an older age (eg, two to three weeks later).
Histologic findings alone cannot help to distinguish BA from other causes
of obstruction, such as choledochal cyst or external compression.
Therefore, any evidence of obstruction mandates imaging exploration
and a definitive cholangiogram. In some cases, imaging cannot be
performed because the biliary tree is atretic; in this case the surgeon
makes the diagnostic decision based on visual inspection of the biliary
tree.
Cholangiogram If the above steps in the evaluation support the
diagnosis of BA, the infant should be taken to the operating room. The
first step is an intraoperative cholangiogram, which is the gold standard
in the diagnosis of BA. It is essential that patency be investigated both
proximally into the liver and distally into the bowel to determine whether
BA is present. If the intraoperative cholangiogram demonstrates biliary
obstruction (ie, if the contrast does not fill the biliary tree or reach the
intestine), the surgeon should perform a hepatoportoenterostomy (Kasai
HPE) at that time.
An alternative yet valid approach used at some centers is to perform a
percutaneous gallbladder cholangiogram or an ERCP [45-47]. These
procedures are less invasive than intraoperative cholangiogram, but
performance of these procedures in infants requires special expertise
and equipment. Moreover, if BA is confirmed, the infant will still need to
undergo an operation for treatment. The percutaneous gallbladder
cholangiogram can only be performed in an infant with an identified
gallbladder; the procedure is performed by an interventional radiologist.
Alternatively, an endoscopic retrograde cholangiopancreatography
(ERCP) can be used to demonstrate biliary patency in an infant. (See
"ERCP for biliary disease in children", section on 'Neonatal cholestasis'.)
KASAI PROCEDURE If biliary atresia (BA) is confirmed by
cholangiogram, a Kasai procedure (hepatoportoenterostomy [HPE])
should be performed promptly. This operation is undertaken in the
attempt to restore bile flow from the liver to the proximal small bowel
(figure 1) [48]. For this procedure, a roux-en-Y loop of bowel is created
by the surgeon and directly anastomosed to the hilum of the liver,
following excision of the biliary remnant and portal fibrous plate.
If successful, the remaining small patent bile ducts will drain into the roux
limb and jaundice will start to resolve in the weeks following surgery. If
unsuccessful, bile drainage is not achieved, and the child remains
jaundiced. If there is persistent jaundice or elevated serum bilirubin three
months after the Kasai, the patient should be referred for liver transplant
evaluation. (See 'Liver transplantation' below and 'Predictors of the need
for transplantation' below.)
Revision of a non-functioning HPE generally is not recommended. This
is because a revisional procedure is unlikely to be effective if the original
HPE did not achieve bile drainage, and because the revisional
procedure is likely to cause adhesions that increase the technical
difficulty of a subsequent transplant procedure [49]. However, in patients
in whom the initial HPE was successful, revisional HPE may be
appropriate if the patient abruptly develops jaundice, or experiences
recurrent episodes of cholangitis but has no other evidence of chronic
liver disease. In one report of 24 patients who underwent revisional HPE
for these indications, 75 percent achieved bile drainage and 46 percent
survived with their native liver (mean follow-up 92 months) [50].
Even if bile flow is established and cholestasis improves, many patients
will have slowly progressive liver disease despite undergoing the Kasai
procedure, and the majority of patients with BA will ultimately require
liver transplantation. At least 50 percent of patients who undergo HPE
will require liver transplantation by two years of age as a result of
primary failure of the Kasai HPE and/or growth failure. The patient's age
at the time of HPE can predict native liver survival at later time points. As
an example, among those patients who undergo HPE 30 days of life,
the chance of native liver survival at four years of age is nearly 50
percent, whereas among those who underwent HPE between 31 and 90
days of life, the chance of native liver survival at four years of age is 36
percent [51]. (See 'Prognosis' below.)
Thus, the vast majority of individuals with BA will eventually require liver
transplantation. Nonetheless, the Kasai HPE obviates the need for liver
transplantation in a substantial minority and significantly delays the liver
transplantation for many others. Pre-emptive transplant is avoided
because of the advantages of transplanting older, larger patients and
because of the potential for improved transplantation therapies in the
future. At one time pre-emptive transplantation was used to avoid the
difficulties of performing surgery on a patient with a prior HPE. With
modern transplantation techniques, there is no surgical advantage to
pre-emptive transplantation. Therefore, HPE is almost always performed
first. If bile drainage is achieved, it is likely that transplantation will not be
needed for years or decades. Historical series from before the Kasai
procedure was introduced in 1968 report a 10 percent survival rate at
age three years of age, as compared with the 35 to 50 percent survival
rates with native liver at age four years of age, as cited above [52,53].
(See 'Liver transplantation' below.)
POSTOPERATIVE MANAGEMENT Medical care following Kasai
hepatoportoenterostomy (HPE) consists of the following interventions, as
detailed below [54]:

Choleretics and possible use of antiinflammatory medications

Nutritional rehabilitation

Fat-soluble vitamin supplementation

Prevention of cholangitis

Management of portal hypertension and its sequelae

Choleretics Administration of choleretics such as ursodeoxycholic

acid (UDCA) is standard practice in biliary atresia (BA), although its
clinical utility has not been definitively established. UDCA is a hydrophilic
bile acid; when given by mouth it shifts the balance of bile acids towards
hydrophilic forms. This is thought to stabilize membranes and the reduce
generation of free radicals, thus protecting mitochondria from damage.
The recommended dose of UDCA in BA ranges from 15 to 30 mg/kg/day,
and should not exceed 30 mg/kg/day. To avoid potential toxicity, UDCA
therapy should be discontinued if the total bilirubin level rises above 15
mg/dL.
The most clear human data regarding benefits of UDCA come from the
group of patients with primary biliary cholangitis (PBC). In several large
randomized double blind placebo-controlled trials in patients with PBC,
UDCA decreased plasma levels of aminotransferases, improved liver
histology and quality of life, and decreased risk of death and need for
liver transplantation (see "Trials of ursodeoxycholic acid for the treatment
of primary biliary cholangitis (primary biliary cirrhosis)"). However, in
patients with primary sclerosing cholangitis (PSC) a randomized trial
suggested negative effects of long-term, high-dose UDCA therapy [55].
In BA, observational studies suggest a number of possible benefits of
UDCA treatment, ranging from enhanced weight gain to reduced
episodes of cholangitis and improved bile flow, but definitive evidence
from randomized trials is lacking [56,57].
Glucocorticoids Clinical evidence does not support routine use of
glucocorticoids in the treatment of BA [58]. This was shown in a
randomized placebo-controlled trial of glucocorticoid treatment in 140
infants with BA [59]. The glucocorticoids were given for 13 weeks
(intravenous methylprednisolone 4 mg/kg/day for 2 weeks, followed by
oral prednisolone 2 mg/kg/day for two weeks, then tapering), and
outcomes were measured at 6 and 24 months post HPE. No statistically
significant benefit in bile drainage at six months post HPE was observed
in the infants treated with glucocorticoids as compared with the placebo
group. In addition, no statistically significant improvement in survival with
native liver at two years of age was observed in the treatment group.
Moreover, the infants treated with glucocorticoids had significantly earlier
onset of serious adverse events as compared with those given placebo.
Nutrition Nutritional problems in BA are common and difficult to
overcome. Poor nutrition is a significant clinical problem and is one of
the most common indications for liver transplantation.
Caloric needs Several factors contribute to malnutrition in patients
with BA, including malabsorption due to cholestasis, chronic liver
inflammation, and lack of gall bladder. Because of malabsorption and
metabolic alterations, the total caloric needs in infants with BA are
approximately 150 percent of the recommended energy intake for
healthy infants and children (see "Failure to thrive (undernutrition) in
children younger than two years: Management", section on 'Energy
requirements for catch-up growth'). To compensate for losses and
catabolism, the expected protein needs are 3 to 4 g/kg/day in infants and
2 to 3 g/kg/day in children [60-62].
In order to meet these nutritional requirements, several strategies are
utilized. These strategies are similar to those used for infants with other
causes of growth failure, except that they should be implemented
proactively because of the high rates of growth failure in patients with
BA. (See "Failure to thrive (undernutrition) in children younger than two
years: Management", section on 'Energy requirements for catch-up
growth'.)

For infants, formulas are concentrated or expressed breast milk is

fortified to provide additional energy. After Kasai HPE, the feed is
typically designed to provide 24 kcal per ounce. If growth is inadequate,
the feed may be increased to 27 kcal per ounce; additional energy
content can be added in solid foods when the infant is old enough.

High-energy supplements, such as glucose polymers (which provide 8

cal/teaspoon) or medium chain triglyceride oil (which provides 7.7
cal/mL), are used to fortify formula or solid foods [58,61]. MCT oil is
useful because it is calorically rich, and it is readily absorbed by patients
with cholestasis because it does not require micellar solubilization.

Despite these measures, many infants and children with BA require

supplemental feeding by nasogastric tube because they are unable to
take enough energy by mouth to meet their increased nutritional needs.
Gastrostomy tubes are not recommended because many patients
develop portal hypertension, leading to gastric varices and the
propensity to develop varices around the gastrostomy tube site.
Candidates for nasogastric feeds are identified by poor weight gain
and/or poor linear growth. Proactive management is recommended
because the malnutrition may worsen the overall prognosis, with or
without liver transplantation [58]. (See "Overview of enteral nutrition in
infants and children".)
Fat-soluble vitamin supplements All jaundiced infants and children
with BA should be given supplements of fat-soluble vitamins. Once
jaundice resolves and vitamins are replete, children can be transitioned
to standard multivitamins. Nevertheless, routine monitoring of vitamin
levels should continue (table 1).
Deficiencies of fat-soluble vitamins are common in patients with BA. In a
series of 29 patients with BA, serologic deficiencies of vitamins A and E
and radiographic evidence of vitamin D deficiency were reported despite
establishment of bile flow by hepatoportoenterostomy [63]. Vitamin
deficiencies occur despite recommended supplementation and are
particularly common among patients with residual cholestasis after Kasai
HPE (serum bilirubin 2 mg/dL) [64,65]. In one study, 81 percent of
infants were found to be Vitamin D deficient before HPE, and vitamin D
deficiency persisted post-HPE despite aggressive supplementation [66].
Therefore, vitamin levels should be monitored frequently (ie, several
times in the first year), starting at the first month after HPE, in order to
adjust supplements appropriately for deficiencies or toxicities (table 1).
Infants with biliary atresia and prolonged jaundice may be deficient in
vitamin K. Patients should receive supplementation with oral vitamin K,
and should be monitored for coagulopathy. Some infants may require
parenteral vitamin K supplementation due to poor absorption of oral
medications in the setting of severe cholestasis.
Complications Children with successful bile drainage following HPE
must be followed closely for complications including ascending
cholangitis and portal hypertension. In addition, all patients should be
routinely monitored for fat-soluble vitamin deficiencies as described
above.
Ascending cholangitis Cholangitis is a common complication in
patients with BA who have undergone a Kasai HPE (excluding post-
surgical complications). The incidence of cholangitis in these patients is
between 40 and 90 percent, with the majority of patients experiencing at
least one episode prior to two years of age [53,67]. These patients are at
risk for cholangitis because of the abnormal anatomy and bacterial stasis
in the region of the roux limb.
Because cholangitis can be life threatening and may impact long- and
short-term outcomes [67,68], most clinicians prescribe prophylactic
antibiotics in the first year of life. Small nonrandomized trials suggest
that the benefits of antibiotic prophylaxis outweigh the risks of antibiotic
resistance [69,70]. As an example, in one series infants treated with
prophylactic antibiotics had half the rate of cholangitis as compared with
infants in a historical control group [69]. Either trimethoprim-
sulfamethoxazole (4 mg/kg/day trimethoprim and 20 mg/kg/day
sulfamethoxazole, divided twice daily) or neomycin (25 mg/kg/day
divided four times daily) appear to be equally effective in decreasing the
incidence of cholangitis [69]. There may be evidence to suggest that
treatment with probiotics can afford a similar prophylactic effect as
antibiotics, but further studies are needed [71].
Recurrent cholangitis may predict the need for liver transplantation as it
can lead to progressive cirrhosis [67]; however, one episode of
cholangitis does not predict early transplantation [6].
Portal hypertension The chronic hepatobiliary inflammation
characteristic of BA leads to progressive biliary cirrhosis. Biliary cirrhosis
causes portal hypertension, which can lead to variceal bleeding and
ascites. In a registry study of 163 children with BA in North America who
had not undergone liver transplantation (average age 9.2 years), half
had definite portal hypertension [72]. Among those with portal
hypertension, 53 percent had a history of variceal bleeding, 17 percent
had ascites, and 34 percent had reduced hepatic synthetic function (PT
>15 seconds or albumin <3 g/dL). Recurrent variceal bleeding and
refractory ascites are indications for liver transplantation [73,74]. (See
'Liver transplantation' below.)
If portal hypertension leads to variceal bleeding, this complication is
often controlled with sclerotherapy or banding. After the first variceal
bleed, sclerotherapy or band ligation is instituted on a repeat basis with
the ultimate goal of complete variceal obliteration. Some centers perform
surveillance endoscopy to gauge the size and status of developing
varices in patients who demonstrate clinical and ultrasonographic signs
of portal hypertension following the Kasai procedure. In a series of 47
children with BA managed with endoscopic surveillance, varices
developed in about half of the children, at a mean of 19 months (range 4
to 165 months) after successful Kasai HPE [75]. Other centers begin
routine surveillance endoscopies only after the patient has experienced
the first variceal bleed. A consensus statement on the management of
portal hypertension in children suggests that primary prophylaxis of
esophageal varices is not indicated except in extenuating circumstances,
such as when the child is not in reasonable proximity to emergency care
[76].
If ascites develops and is severe enough to compromise respiratory
function, it is usually treated with paracentesis followed by chronic
administration of diuretics, beta-blockers, salt and/or water dietary
restriction, or a combination of these interventions.
LIVER TRANSPLANTATION The majority of individuals with biliary
atresia (BA) eventually require liver transplantation; indeed BA is the
most common indication for liver transplantation in infants and children.
In the current era, at least 60 to 80 percent of patients with BA will
require liver transplantation, even with optimal management. (See
'Prognosis' below.)
The indications for liver transplantation for patients with BA include
[58,77-79]:

Primary failure (lack of bile drainage) of the Kasai

hepatoportoenterostomy (HPE)

Prompt referral for liver transplantation evaluation is recommended if

total bilirubin is >6 mg/dL three months or more beyond HPE

Referral for liver transplantation evaluation also should be considered if

total bilirubin is persistently 2 to 6 mg/dL three months or more beyond
HPE

Refractory growth failure This is common in children with cholestasis

Complications of portal hypertension (if these cannot be managed with

other measures)

Repeated variceal bleeding

Refractory ascites that compromises respiratory, bowel, or renal function

Hepatopulmonary syndrome

Portopulmonary hypertension

Progressive liver dysfunction

Intractable pruritus

Refractory coagulopathy
Among patients transplanted before two years of age, persistent
cholestasis (often complicated by growth failure) and recurrent or
resistant cholangitis are the most common indications for liver
transplantation.
Although it is clear that the vast majority of BA patients will ultimately
require liver transplantation, preemptive transplants should be deferred
as there are advantages to transplanting older and larger patients.
Because the outcomes of liver transplantation improve for infants with
weights >10 kg, as compared to smaller infants, transplantation of
infants with persistent cholestasis may be postponed if growth can be
achieved and the infants are otherwise stable. Supplemental nasogastric
tube feedings are often necessary to attain adequate growth. The
cholestasis may cause chronic pruritus, which often responds to medical
therapy. (See "Pruritus associated with cholestasis".)
For those children who require liver transplantation, prognosis is
generally good. In the United States, the one-year patient- and liver-graft
survival rates for pediatric patients undergoing primary liver transplant
for BA are 92.1 and 83.6 percent, respectively [78]. In international
series, long-term survival is approximately 70 to 80 percent at both 5 and
10 years, and these rates continue to improve in more recent case
series [51,80-83].
BA patients can receive whole or segmental cadaveric grafts, as well as
segments from a living donor. The liver transplant surgery in BA patients
is complicated by presence of intra-abdominal adhesions attributed to
previous HPE. Postoperative outcomes appear to be less favorable in
the subset of BA patients with BASM, due to the enhanced difficulty
associated with liver dissection and vascular reconstruction in these
patients [82]. Poor nutrition is associated with increased mortality either
while awaiting transplantation or after the procedure [84]. Thus, vigorous
nutritional support, including nasogastric feeds, is essential in the pre-
and postoperative care of these patients. (See 'Nutrition' above.)
PROGNOSIS Although long-term prognosis for biliary atresia (BA)
patients is variable, the complementary and sequential approach of
hepatoportoenterostomy (HPE) and liver transplantation affords long-
term survival, with upwards of 90 percent of BA patients surviving into
adulthood [85,86]. Importantly, waitlist and post-transplant mortality is
higher in patients undergoing transplant earlier in life. In a large series,
patients undergoing transplant when they were less than two years of
age had five-year survival of 93.8 percent, compared with 97.1 percent
for those transplanted after two years of age [87]. This observation
underscores the importance of achieving biliary drainage with HPE and
delaying transplantation when possible.
Survival without transplantation Overall survival with native liver
(ie, without transplantation) ranges from 30 to 55 percent at five years,
30 to 40 percent at 10 years, and 20 to 40 percent at 20 years
[37,80,86,88-94]. The long-term outcomes are illustrated by the following
series:

Among 1107 patients diagnosed with BA between 1986 and 2009 in

France, 94 percent underwent the Kasai HPE, leading to initial clearance
of jaundice in 38 percent [86]. Survival with the native liver was 40
percent at 5 years, 36 percent at 10 years, and 30 percent at 20 years of
age. Overall patient survival was 81 percent at 5 years, 80 percent at 10
years, and 77 percent at 20 years of age.

Among 80 patients who underwent the procedure between 1970 and

1986 in Japan, the 5-, 10-, and 20-year survival rates with native livers of
63, 54, and 44 percent, respectively [93]. Half of the 20-year survivors
had cirrhosis, and 20 percent went on to liver transplant or death within a
few years.

Among 104 patients who underwent the procedure between 1977 and
1988 in The Netherlands, 27 percent were alive with native liver 20 years
later [94]. Twenty-one percent of the long-term survivors had normal liver
biochemical tests and no evidence of cirrhosis.

Among 34 patients with BA who underwent Kasai HPE between 1994

and 2011, survival with the native liver was 87.6 percent at 5 years, 76.9
percent at 10 years, and 48.5 percent at 15 years [33]. This represents
substantial improvement in outcomes compared with earlier series,
possibly due to earlier identification of affected infants due to a national
screening program using stool color cards. (See 'Signs and symptoms'
above.)

In addition to complications from portal hypertension and late-onset

cholangitis, the risk of developing cancer in the native liver remains an
important concern. Careful monitoring and treatment of these late
complications is essential. Pregnancy in female survivors of BA is not
without risk, and the pregnancy must be monitored to ensure the health
and safety of the mother and child.
Given the improvements in early identification of infants with BA, and
advances in medical therapy after Kasai HPE, including prophylaxis
against cholangitis and improvements in nutrition and bile flow, it is
reasonable to expect that long-term survival from current cases will
exceed that of these older series. Experimental areas of therapy such as
anti-fibrotic or antiinflammatory agents may improve outcomes in the
future.
Predictors of the need for transplantation Although performance of
the Kasai HPE clearly improves survival overall, the long-term prognosis
is difficult to predict. The three most important prognostic factors for
surgical outcome are younger age at the time of HPE, the expertise of
the surgeon and care center at which the procedure is performed, and
the decrease in serum bilirubin in the first few months after HPE.
Many case series have documented better outcomes when HPE is
performed before 60 days of age and poorer outcomes after 90 days of
age [37,80,88,89]. As an example, in a series of 349 infants diagnosed
and treated for biliary atresia in Canada, older age at time of HPE was
associated with a progressive decrease in patient survival with the native
liver [51]. Among infants who underwent HPE at 30 days, 31 to 90
days, and 90 days, the survival with the native liver at four years of age
was 49, 36, and 23 percent, respectively. In Taiwan, after implementation
of a protocol using universal screening for infant stool color increased
the rate of accomplishing HPE before 60 days of life from 50 to 66
percent, improvements in several clinically important outcomes were
seen: the rate of jaundice-free survival with the native liver at three years
of age improved from 32 to 57 percent, and the rate of overall survival at
five years of age improved from 56 to 89 percent [95]. However, the time
at which early is early enough and late is too late is controversial [96].
Surgical success is dependent on the expertise of the center and
surgeon. Although controversial, it appears that a center that performs at
least five Kasai procedures per year has a better success rate, as
measured by 5- or 10-year long-term survival with the native liver
[81,88,97]. Another surgical factor is anatomic pattern of biliary atresia
identified at time of Kasai hepatoportoenterostomy. Children born without
atresia at the porta hepatis (Ohi classification 1) have the lowest risk of
death or transplantation by two years of age [98].
Among all variables, serum bilirubin post HPE appears to be the most
predictive biomarker of outcome. Data suggest that the serum total
bilirubin level measured three months after Kasai HPE is predictive of
native liver survival [6,99]. In a prospective cohort, among patients with
bilirubin <2 mg/dL three months post-Kasai HPE, two-year survival
without transplantation was 86 percent [99]. Among those with bilirubin
2 mg/dL three months post-Kasai HPE, survival without transplantation
was only 20 percent. Infants with elevated bilirubin were also more likely
to develop poor weight gain, hypoalbuminemia, and coagulopathy.
SUMMARY AND RECOMMENDATIONS Biliary atresia (BA) is a
progressive, idiopathic, fibro-obliterative disease of the extrahepatic
biliary tree that presents with biliary obstruction in the neonatal period,
and is the most common indication for liver transplantation in children.

BA may occur in isolation (70 percent), in association with lateralization

anomalies such as situs inversus or asplenia (10 to 15 percent), or with
other congenital malformations (10 to 15 percent). Those with
lateralization anomalies have a somewhat worse prognosis. (See
'Introduction' above.)

The causes of BA are not well established and are probably

multifactorial; genetic factors may play a permissive role in some cases,
but infectious, toxic, or immunologic mechanisms are probably involved.
(See 'Pathogenesis' above.)

Most infants with BA are born at full term, have a normal birth weight,
and initially thrive and seem healthy. Scleral icterus and/or generalized
jaundice typically develop by eight weeks of age. Infants may also have
acholic (very pale colored) stools (see "stool color card" for examples),
dark urine, and/or a firm liver and splenomegaly. Laboratory testing
reveals elevation in serum conjugated bilirubin (>2 mg/dL) and mild or
moderate elevations in serum aminotransferases with a
disproportionately increased GGTP. (See 'Clinical features' above.)

The diagnosis of BA is made with a series of imaging and laboratory

tests and liver biopsy to exclude other causes of cholestasis. Infants
should be evaluated as rapidly as possible because the success of the
surgical intervention diminishes progressively with older age at surgery.
Because timing is crucial, some infants (eg, those who are eight weeks
or older or with a high clinical suspicion of BA) may not require each
diagnostic step. (See 'Diagnosis' above.)

The definitive diagnosis of BA is made by a cholangiogram. This is

typically performed intraoperatively; if the diagnosis of BA is confirmed,
the surgeon performs a hepatoportoenterostomy (HPE, Kasai
procedure) (figure 1). (See 'Cholangiogram' above.)

We recommend that all infants with BA undergo a Kasai HPE (Grade

1B). This surgery should be performed as soon as the diagnosis of BA
can be made and preferably before 60 days of age. This is because
younger age at the time of the Kasai HPE is associated with better
outcomes (ie, higher likelihood of resolution of cholestasis and longer
survival with the native liver). (See 'Kasai procedure' above and
'Predictors of the need for transplantation' above.)

We suggest that infants and children be treated with ursodeoxycholic

acid (UDCA) after Kasai HPE (Grade 2C). To avoid potential toxicity,
UDCA therapy should be discontinued if the total bilirubin level rises
above 15 mg/dL. We do not recommend treatment with glucocorticoids
(Grade 1A). (See 'Choleretics' above and 'Glucocorticoids' above.)

Infants with BA who are jaundiced are at risk for fat-soluble vitamin
deficiencies and should be treated with supplements of fat-soluble
vitamins and monitored for fat-soluble vitamin deficiencies (table 1). In
addition, they should be given high calorie formula or other nutritional
supplements as required to sustain normal rates of growth. If weight gain
is below normal despite these measures, nasogastric feeds should be
administered to optimize growth. Vigorous nutritional support is also
indicated for non-cholestatic infants with BA. (See 'Nutrition' above.)

After Kasai HPE infants and children are at risk for ascending
cholangitis. Some data has shown that repeated episodes of cholangitis
can hasten the progression of liver disease. To reduce this risk, we
suggest treating all patients with prophylactic antibiotics in the first year
of life (Grade 2B). (See 'Ascending cholangitis' above.)

After Kasai HPE, if there is persistent jaundice three months later then
the patient should be referred for liver transplant evaluation. Other
indications for early liver transplantation include failure to thrive despite
vigorous nutritional rehabilitation. (See 'Liver transplantation' above.)

In the current era, at least 60 to 80 percent of patients with BA will

eventually require liver transplantation. Indications for liver
transplantation include complications of portal hypertension (recurrent
variceal bleeding or intractable ascites), growth failure, and progressive
 liver dysfunction. (See 'Liver transplantation' above.)

A minority of patients with BA treated with Kasai HPE survive to 20 years
or more without liver transplantation. However, many of these patients
have chronic liver disease with cirrhosis and portal hypertension. (See
'Survival without transplantation' above.)

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