Biliary atresia (BA) is a progressive, idiopathic, fibro-obliterative disease of the extrahepatic biliary tree that presents with biliary obstruction exclusive in the neonatal period. Although the overall incidence is low (about 1:10,000 to 1:20,000 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):
- 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.
- 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.
- 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 or trigger of BA remains unknown. A number of mechanisms has been hypothesized and detailed in several recent excellent reviews (2, 3). These include viral, toxin-induced, vascular, genetic predisposition, 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 – Genetic factors may play a causative role in the small subgroup of patients with BASM malformations. A transgenic mouse with a recessive deletion of the inversin (INV) gene provides an animal model for BASM, displaying situs inversus and extrahepatic biliary obstruction. However, genetic factors may not play a direct causative role in the development of most cases of BA – as suggested by the observation that monozygotic twins usually have a discordant phenotype – but rather play a role in disease susceptibility. Association studies have identified a few genomic loci with increased susceptibility to BA. 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 a2ß1 integrin, interferon-?, 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).
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 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 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.
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).
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, with app resources now available (SickKids BA ipad app).
Medical management following HPE must consider the following categories:
- Steroid Therapy
- Nutritional rehabilitation and strategies
- 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
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).
Steroid Therapy – 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.
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 fortification of expressed breast milk or formula with supplements including glucose polymers, medium chain triglyceride oil and others. Supplemental feeding by nasogastric tube may be necessary as identified by poor weight gain and/or poor linear growth (18). Occasional infants require parenteral nutrition (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).
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.
Liver Transplantation – BA is the commonest 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, growth failure/nutritional deficiency and uncorrectable coagulopathy).
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.
Help your patients learn more about biliary atresia
The LearnAboutBA app is now available for both iTunes and Android users. This new app (designed by the team at The Hospital for Sick Children in Toronto) aims to support the teaching of patients, families and healthcare providers about this important liver disease. Download it for free from the iTunes App Store or the Google Play store.
ChiLDReN Network studies that include patients with biliary atresia
The ChiLDReN Network has several studies that include patients with biliary atresia.
The PROBE, BASIC, and FORCE 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
FORCE: A cross-sectional and longitudinal assessment of the utility of liver stiffness measurement (as assessed by elastography) in children with chronic cholestatic liver disease.
Eligibility: Children currently enrolled in BASIC, PROBE, or LOGIC with a diagnosis of biliary atresia, alpha-1 antitrypsin deficiency or Alagille syndrome.
ClinicalTrials.gov Study NCT02922751
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.
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