Biliary Atresia


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 

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.


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 


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 

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 


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). 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. 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 (


1.  Schwarz KB, Haber BH, Rosenthal P, Mack CL, Moore J, Bove K et al. Extrahepatic anomalies in 
infants with biliary atresia: results of a large prospective North American multicenter study. 
Hepatology 2013;58(5):1724-1731.

2.  Asai A, Miethke A, Bezerra JA. Pathogenesis of biliary atresia: defining biology to understand 
clinical phenotypes. Nature reviews Gastroenterology & hepatology 2015;12(6):342-352.

3.  Mack CL. What Causes Biliary Atresia? Unique Aspects of the Neonatal Immune System Provide 
Clues to Disease Pathogenesis. Cellular and molecular gastroenterology and hepatology 

4.  Saito T, Terui K, Mitsunaga T, Nakata M, Ono S, Mise N et al. Evidence for viral infection as a 
causative factor of human biliary atresia. J Pediatr Surg 2015;50(8):1398-1404.

5.  Clemente MG, Patton JT, Yolken R, Whitington PF, Parashar UD, Jiang B et al. Prevalence of 
groups A and C rotavirus antibodies in infants with biliary atresia and cholestatic controls. J 
Pediatr 2015;166(1):79-84.

6.  Harper P, Plant JW, Unger DB. Congenital biliary atresia and jaundice in lambs and calves. 
Australian veterinary journal 1990;67(1):18-22.

7.  Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X et al. Identification of a plant 
isoflavonoid that causes biliary atresia. Science translational medicine 2015;7(286):286ra267.

8.  Nakamura K, Tanoue A. Etiology of biliary atresia as a developmental anomaly: recent advances. 
Journal of hepato-biliary-pancreatic sciences 2013;20(5):459-464.

9.  Davit-Spraul A, Baussan C, Hermeziu B, Bernard O, Jacquemin E. CFC1 gene involvement in biliary 
atresia with polysplenia syndrome. J Pediatr Gastroenterol Nutr 2008;46(1):111- 112.

10.  Bessho K, Bezerra JA. Biliary atresia: will blocking inflammation tame the disease? Annual 
review of medicine 2011;62:171-185.

11.  Feldman AG, Mack CL. Biliary atresia: cellular dynamics and immune dysregulation. Semin 
Pediatr Surg 2012;21(3):192-200.

12.  Omenetti A, Bass LM, Anders RA, Clemente MG, Francis H, Guy CD et al. Hedgehog activity, 
epithelial-mesenchymal transitions, and biliary dysmorphogenesis in biliary atresia. Hepatology 

13.  Fenner EK, Boguniewicz J, Tucker RM, Sokol RJ, Mack CL. High-dose IgG therapy mitigates bile 
duct-targeted inflammation and obstruction in a mouse model of biliary atresia. Pediatric research 

14.  Franciscovich A, Vaidya D, Doyle J, Bolinger J, Capdevila M, Rice M et al. PoopMD, a Mobile 
Health Application, Accurately Identifies Infant Acholic Stools. PloS one 2015;10(7):e0132270.

15.  Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated 
direct/conjugated bilirubin levels shortly after birth. Pediatrics 2011;128(6):e1428-1433.

16.  Meyers RL, Book LS, O'Gorman MA, Jackson WD, Black RE, Johnson DG et al. High-dose steroids, 
ursodeoxycholic acid, and chronic intravenous antibiotics improve bile flow after Kasai procedure 
in infants with biliary atresia. J Pediatr Surg 2003;38(3):406-411.

17.  Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS et al. Use of corticosteroids 
after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START 
randomized clinical trial. Jama 2014;311(17):1750-1759.

18.  Young S, Kwarta E, Azzam R, Sentongo T. Nutrition assessment and support in children with 
end-stage liver disease. Nutrition in clinical practice : official publication of the American 
Society for Parenteral and Enteral Nutrition 2013;28(3):317-329.

19.  Sullivan JS, Sundaram SS, Pan Z, Sokol RJ. Parenteral nutrition supplementation in biliary 
atresia patients listed for liver transplantation. Liver Transpl 2012;18(1):120-128.

20.  Shneider BL, Magee JC, Bezerra JA, Haber B, Karpen SJ, Raghunathan T et al. Efficacy of 
fat-soluble vitamin supplementation in infants with biliary atresia. Pediatrics 

21.  Decharun K, Leys CM, West KW, Finnell SM. Prophylactic Antibiotics for Prevention of 
Cholangitis in Patients With Biliary Atresia Status Post-Kasai Portoenterostomy: A Systematic 
Review. Clinical pediatrics 2015.

22.  Davenport M, De Ville de Goyet J, Stringer MD, Mieli-Vergani G, Kelly DA, McClean P et al. 
Seamless management of biliary atresia in England and Wales (1999-2002). Lancet 

23.  Serinet MO, Broue P, Jacquemin E, Lachaux A, Sarles J, Gottrand F et al. Management of 
patients with biliary atresia in France: results of a decentralized policy 1986-2002.
Hepatology 2006;44(1):75-84.