Definition
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. Although
the overall incidence is low (about 1:8,000 to 1:18,000 live births), BA is the most common cause
of neonatal jaundice for which surgery is indicated and the most common indication for liver
transplantation in children.
Infants with BA can be grouped into 3 categories (1):
1. BA without major malformations – sometimes referred to as isolated, non-syndromic or perinatal
BA (without major malformations), this pattern occurs in ~80-85% of infants with BA.
2. BA in association with laterality malformations – also known as syndromic biliary atresia,
fetal-embryonal biliary atresia, or Biliary Atresia Splenic Malformation (BASM), this pattern
occurs in about 10% of infants with BA and includes the clinical presence of laterality defects.
3. BA in association with at least one major malformation – this pattern occurs in about 5- 10% of
infants with BA who have associated anomalies most commonly manifested in the cardiovascular (71%),
genitourinary (47%) and gastrointestinal (24%) systems and without laterality defects.
Etiology and Pathogenesis
The underlying cause(s) of BA remain unknown, but it is present at birth strongly suggesting a
developmental or genetic etiology (Harpavat (2011), JPeds) . With the lack of firm etiologies, a
number of mechanisms has been hypothesized over the years (2, 3). These include viral, toxin-
induced, vascular, genetic contributions, abnormal morphogenesis/development, and autoimmune/
immune dysregulation.
Viral Etiologies – Two animal models of BA which utilize virus (the reovirus mouse model and more
recently the rotavirus mouse model) as well as time-space clustering of BA cases in humans support
a possible viral etiology. The livers of afflicted children exhibit many of the inflammatory
responses characteristic of viral infection including activated macrophages, CD4 and CD8 T cells,
interferon gamma, cytokines such as tumor necrosis alpha, and IgM and IgG antibodies (4, 5).
To-date, a specific virus has not been implicated, with studies failing to consistently identify
associations with specific viral infections, including cytomegalovirus,
reovirus, and Group C rotavirus.
Toxic etiologies – The clustering of cases of BA is also consistent with the possibility of a
toxin- mediated inflammatory response (6). Recently, a toxin, biliatresone, a plant isoflavenoid
found in in Australia, has been implicated in the development of BA in sheep, (7) however no human
associations have been described.
Vascular etiology - while studies have described both hyperplasia and hypertrophy of the hepatic
artery supporting a vascular-mediated etiology for BA, these findings could be secondary to the
characteristic hepatic fibrosis and cirrhosis (2).
Genetic etiologies – Recently, the ChiLDReN network performed whole exome sequencing on 67
participants with BASM. These studies identified a ciliary gene, PKD1L1as a strong candidate gene
for BA as it is expressed in cholangiocytes and known to cause heterotaxy (Berauer, Hepatology
(2019), PMID: 30664273). Moreover, validation of this gene as a cause of a developmental
fibroinflammatory cholangiopathy was recently reported consequent to a liver- restricted deletion
of Pkd1l1 in mice (Hellen, Hepatology (2023), PMID: 36645229). These studies indicate the
likelihood of genetic contributions to BA, but it is not in a straightforward Mendelian fashion.
Concerns for genetic causations for all BA is not clear as monozygotic twins usually have a
discordant. Association studies have identified a few genomic loci with increased susceptibility to
BA, in genes involved in ciliary and cytoskeletal formations (Lam PMID 34455394). Epigenetic
factors have also been postulated as important factors impacting biliary development and the
pathogenesis of BA. Both micro RNA and DNA methylation have been studied in animal models and
humans with BA.
Abnormal morphogenesis - is supported by the observation of ductal plate malformations (persistence
of ductal plates postnatally) in the diagnostic liver biopsies from BA infants (8). The presence of
extrahepatic anomalies including situs inversus, cardiac abnormalities, splenic malformation
(including asplenia, polysplenia or double spleen), preduodenal portal vein and annular pancreas
support the concept of defective embryogenesis targeting or causing obstruction of extrahepatic
bile ducts. Mutations in the CFC1 gene, which encodes cryptic protein and is involved in
determining laterality during fetal development, have been linked to BA patients with laterality
defects (9).
There is both human and animal data in support of a role of immune dysregulation. These data
include increased expression of intercellular adhesion molecules, increased frequency of the
HLA-B12 allele, oligoclonal expansion of lymphocytes, and prevention of experimental biliary
atresia in mice by loss of α2β1 integrin, interferon-γ, CD8+ cells, and NK cells (10, 11). Recent
work has demonstrated a significant upregulation of the Hedgehog pathway in BA causing epithelial
to mesenchymal transition, and leading to fibrosis (12). It is entirely possible and perhaps most
likely, that BA is of diverse etiology – secondary to dysmorphogenesis in the minority and one or
more viral infections in an immunologically and genetically susceptible host in the majority.
The preliminary mouse and human data that have been generated based on hypotheses of
autoimmune/autoreactive response that results in injury to the bile duct are the basis for the
current trial of IVIg in infants with biliary atresia being conducted by the ChiLDReN consortium
(13).
Clinical Features
Most infants with BA are born at full term, have a normal birth weight and initially thrive and
seem healthy. Jaundice is almost always the first sign of BA, although initial jaundice is possibly
seen only in the sclerae. The onset of jaundice occurs any time from birth up to 8 weeks of age,
and it is highly unlikely to appear later. Physiologic jaundice is dominated by
indirect/unconjugated bilirubin and generally clears by 2-3 weeks. Most infants with BA develop
acholic stools; however, 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” and a free smartphone application (PoopMD for iPhone or
Android) have been developed (14). Most infants have dark urine because of bilirubin excretion into
the urine. However, 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. Clues for infants with the
fetal-embryonal form of BA include asplenia or polysplenia on ultrasound, and evidence of
congenital heart disease.
Diagnosis
Earliest diagnosis of BA is important because the prognosis is closely related to timing of Kasai
portoenterostomy (HPE). The evaluation process involves a series of laboratory and radiographic
imaging studies, followed by cholangiogram. The order of diagnostic investigations may be
prioritized based on testing for treatable conditions first – these include biliary obstruction,
infections, and some metabolic diseases. Some diseases, such as Alagille syndrome or alpha-1-
antirypsin deficiency, can mimic many of the findings seen in BA.
Laboratory studies - Serum direct/conjugated bilirubin levels may be elevated from shortly after
birth (15). Typically, serum gamma glutamyltranspeptidase is markedly elevated. Infants with mildly
elevated conjugated or direct bilirubin levels in the perinatal period should be followed closely
and evaluated for the possibility of BA. The presence of hypoalbuminemia, coagulopathy and
thrombocytopenia may indicate significant progression of disease.
Abdominal ultrasound – Evaluation of biliary anatomy begins with an ultrasound and Doppler study,
which can quickly exclude other anatomic causes of cholestasis, such as a choledochal cyst. In
infants with BA, the gallbladder is usually hypoplastic, irregular in shape, or absent. When a
detailed ultrasonographic protocol is utilized, additional features can be identified to support a
diagnosis of biliary atresia, including the “triangular cord” sign, although this can be operator dependent.
The ultrasonographic findings of polysplenia/asplenia, intestinal malrotation,
interrupted IVC or midline liver should prompt immediate referral for pediatric hepatology
consultation and expedited evaluation for BA.
Cholangiogram - The gold standard for diagnosing BA remains intra-operative cholangiogram by an
experienced pediatric surgeon, with the diagnosis established when contrast injected into the
biliary remnant fails to pass into the intestine, when there is no lumen in the biliary tract
remnant to inject with contrast, or when the biliary tract is not visible at all. More recently,
interventional radiologists have been performing percutaneous transhepatic cholecystograms (PTCCs)
to directly assess the potential patency of the intra and extrahepatic biliary lumen at the same
procedure while obtaining a liver biopsy (Parra, PMID: 36639762). In expert hands, this is a very
useful procedure that can identify biliary atresia, but also those who do not have this disease and
therefore would not need an intra-operative cholangiogram.
There is significant variability between different centers on the role, use and timing of other
diagnostic tests such as hepatic scintigraphy (HIDA scan), magnetic resonance
cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP). Such
decisions should never delay timely evaluation of infants still jaundiced after 14 days of life for
direct/conjugated hyperbilirubinemia and referral to a pediatric liver center if cholestasis is
present for earliest decision making on the role and timing of liver biopsy and laparotomy for
intraoperative cholangiogram with potential surgical intervention with hepatoportoenterostomy
(HPE).
Treatment
Surgical Therapy - Earliest diagnosis of BA is important because the prognosis is closely related
to timing of HPE. After the HPE operation, the bilirubin and other laboratory parameters are
monitored over time to determine if bile flow has been achieved. Though the majority of children
with BA undergo liver transplantation, HPE with resultant good bile flow can slow the progression
of injury to the liver. The goal of medical management after HPE is to to maximize growth,
nutrition and development while minimizing the complication of chronic liver disease.
Continued education and counseling of families are paramount.
Medical management following HPE would consider the following categories:
• Choleretics
• Nutritional rehabilitation focused upon cholestasis.
• Fat-soluble vitamin supplementation
• Prevention of cholangitis
• Management of clinical sequelae of portal hypertension
• General pediatric health maintenance strategies (immunization; anticipatory guidance related to
hepatotoxic exposures including medications, infectious hepatitis, alcohol intake in adolescents)
• Attention to need/indications for liver transplant candidacy assessment.
• Other considerations: steroids, long-term intravenous antibiotics, complementary
therapies
Choleretics. Administration of choleretics such as ursodeoxycholic acid (UDCA) is standard practice
in BA, although its clinical utility has not been definitely established. Observational studies
suggest a number of potential benefits, ranging from reduced episodes of cholangitis, optimizing
weight gain, and enhanced bile flow. However, definitive evidence from properly designed randomized
trial is lacking (16). The recommended dose of UDCA in BA ranges from 10-30 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 (255 umol/L).
Nutritional strategies. An important part of the medical management after the Kasai procedure is
meticulous nutritional support. Many factors contribute to malnutrition in BA patients, including
malabsorption due to cholestasis, chronic liver inflammation, and poor oral intake. The total
caloric needs in BA infants are increased above the recommended energy intake for healthy infants
and children. Multiple strategies are needed to meet these increased nutritional requirements, and
may be similar to those used for infants with other causes of growth failure.
Nutritional support should be implemented proactively due to the high rates of growth failure in
infants with BA. These strategies include use of formulas with high medium chain triglyceride (MCT)
content, fortification of expressed breast milk or formula with supplements including glucose
polymers, MCT oil and others. Supplemental feeding by nasogastric tube may be necessary as
identified by poor weight gain and/or poor linear growth (18). Often, infants benefit from early
introduction of parenteral nutrition or IV intralipid to achieve improvement in anthropometric
measurements or consistent weight gain (19). Proactive management is recommended as malnutrition
and growth failure will worsen overall prognosis, with or without liver transplantation.
Fat-soluble vitamin supplementation. All BA patients should receive fat-soluble vitamin
supplementation (vitamins A, D, E, K). Recent data from the ChiLDReN network demonstrated
persistent vitamin deficiency and confirmed the need for ongoing attention to individual vitamin
supplementation and close monitoring of vitamin levels over time (20). Moreover, use of a
supplement that allows for absorption in cholestatic infants is advised (Kamath, PMID: 35868689).
Prevention of cholangitis. Ascending cholangitis is a common complication in BA patients who have
undergone HPE due to the abnormal anatomy and bacterial stasis in the region of the roux- en-Y
limb. Antibiotic prophylaxis to prevent ascending cholangitis is also recommended and
ursodeoxycholic acid is often used in an attempt to promote bile flow. Cholangitis may be life-threatening,
and may impact long- and short-term outcomes. Most clinicians prescribe prophylactic
antibiotics in the first 1-2 years of life, while some recommend longer durations. Few published
studies have measured the effect of prophylactic antibiotics after HPE (21).
Prospective trials are needed to measure the effect of antibiotic prophylaxis after HPE.
Other considerations: steroids, long-term intravenous antibiotics, complementary therapies.
Clinical evidence does NOT support routine administration of glucocorticosteroids in the management
of BA infants following HPE. This was shown in a randomized placebo-controlled trial of 140 infants
with BA, randomized to either 13 weeks of steroid treatment (intravenous methlprednisolone 4
mg/kg/day for 2 weeks, followed by oral prednisolone 2 mg/kg/day for two weeks, then tapering)
compared to placebo (17). Outcomes were measured at 6 months and 24 months post HPE. There was no
statistically significant benefit in bile drainage at 6 months post HPE in infants in the treatment
group compared with placebo group. In addition, there was no statistically significant improvement
in survival with native liver at 2 years of age in the treatment group. The infants treated with
steroids had significantly earlier onset of serious adverse events as compared with those in the
placebo treated group. Despite the results of this study, post-HPE steroids are used in many
centers worldwide, often in combination with long- term intravenous antibiotics (PMID 36496264,
34584878), neither of which have been proven to be effective. The role of herbal and complementary
therapies has not been systematically studied in biliary atresia.
Liver Transplantation – BA is the most common indication for liver transplantation in infants and
children. The majority of individuals with BA eventually require liver transplantation even with
optimal medical management. The indications for liver transplantation for BA patients include:
• Primary failure (lack of bile drainage) of the HPE
• Refractory growth failure
• Complications of portal hypertension that cannot be managed with maximal medical therapeutic
interventions. These include repeated variceal bleeding refractory to endoscopic management;
refractory ascites compromising nutritional intake, respiratory status, and renal function;
hepatopulmonary syndrome and portopulmonary hypertension; and progressive liver dysfunction
(including intractable pruritus, encephalopathy, nutritional deficiency and uncorrectable
coagulopathy).
Prognosis
Prognosis depends in large part on timely recognition of cholestasis, early diagnosis of BA and the
age at which HPE is performed. For infants with the fetal-embryonal form the outcome is often
heavily influenced by the severity of the cardiac defect. For infants with either form of BA it is
recommended that the HPE procedure be performed at an experienced center before 30-45 days of age
for optimal results (22, 23). Even with timely performance of the HPE, about half of infants who
undergo the procedure need liver transplantation by age 2-3 years and about 25% of infants who initially
do well will eventually need liver transplantation by late adolescence for
slowly progressive cirrhosis and its complications; thus more than 75% of children with biliary
atresia will require liver transplantation some time in their life. The outcome of liver
transplantation for BA is generally excellent, However, in order to improve the prognosis of
children with this very serious liver disease, ongoing investigation of pathogenesis is needed so
that targeted therapy can be applied early in the course of this progressive disease.
ChiLDReN Network studies that include patients with biliary atresia
The ChiLDReN Network has several studies that include patients with biliary atresia.
The PROBE and BASIC studies are natural history studies that include patients with biliary atresia.
A natural history study is aimed at acquiring information and data that will provide a better
understanding of rare conditions. Participants will be asked to allow study personnel to obtain
information from medical records and an interview, and to collect blood, urine, and tissue samples
when clinically indicated, in order to understand the causes of these diseases and to improve the
diagnosis and treatment of children with these diseases. All of the information obtained in these
studies is confidential and no names or identifying information are used in the study.
PROBE: A prospective study of infants and children with cholestasis.
Eligibility: Infants up to 6 months of age that have been diagnosed with cholestasis (direct
hyperbilirubinemia).
ClinicalTrials.gov Study NCT00061828
BASIC: A prospective database study of older children with biliary atresia.
Eligibility: Children and adults age 6 months and older that have been diagnosed with biliary
atresia, both before and after liver transplantation.
ClinicalTrials.gov Study NCT00345553
Organizations or foundations that help families dealing with biliary atresia.
The ChiLDReN Network works with numerous groups that support patients and families who are dealing
with rare liver diseases. Please click here to go to that page on our website (Information for
Families). You will see the list of groups and information about them.
Support Groups (childrennetwork.org)
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