Biliary atresia

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A 5 week old infant is seen for the first time at the paediatrics outpatient’s clinic with jaundice. The baby boy was being followed up by his GP for jaundice since the age of 6 days. As he was otherwise a well child, his mother was assured that the jaundice was likely related to breastfeeding. His GP grew concerned when his jaundice persisted and performed a formal serum bilirubin when he was 4 weeks old, which showed that he had a predominantly conjugated hyperbilirubinaemia. After his thyroid function tests returned as normal and a urinary tract infection was excluded, he was referred to a tertiary hospital for further evaluation. Radioisotope excretion studies showed good hepatic uptake but absent excretion into the intestine within 24 hours.

Bottom Line:

Any infant with jaundice lasting more than 14 days must have a formal serum bilirubin checked with conjugated/unconjugated differentials

Pale stools may not easily be identifiable and so may provide false reassurance

The most important prognostic factor for a Kasai portoenterostomy is age. The older the patient at the time of surgery, the less successful the outcome

What is biliary atresia?

Extrahepatic biliary atresia is a destructive inflammatory obliterative cholangiopathy which affects both intra and extra hepatic ducts with progressive destruction leading to cholestasis, fibrosis and cirrhosis.

The disease is classified according to the most proximal biliary obstruction:

Type 1 (~ 5%):         Patency to the level of the common bile duct and proximal cystic duct

Type 2 (~ 2%):         Patency to the level of the common hepatic duct

Type 3 (> 90%):      The entire extra hepatic biliary tree is non patent 

How common is it?

In UK and France, the prevalence is 1 in 17000 -19000 livebirths.

In east Asian countries it is much more common, with the frequency in Taiwan being quoted at 1 in 5000.

What else is associated with biliary atresia?

Biliary atresia is associated with other congenital malformations in up to 20% of cases. The most common of these is the biliary atresia splenic malformation

syndrome, (10% in Europe and the US).

CharacteristicsEstimated frequency
Splenic malformation (polysplenia, asplenia)100%
Situs inversus37%
Intestinal malrotation60%
Preduodenal portal vein40%
Absent inferior vena cava70%
Cardiac anomalies (VSD, ASD, HLH)45%
Pancreatic anomalies11%
Clinical features in biliary atresia splenic malformation syndrome - Adapted from Biliary Atresia. Hartley J, Davenport M, Kelly D. Lancet 2009; 374:1704-13

 

Biliary atresia has also been described with other genetic disorders, for example in trisomies 18 and 21.

In 80-90% of neonates, it is an isolated finding. Thus two clinical phenotypes are described: the syndromic or embryonic forms associated with other congenital/genetic abnormalities, and the far more common perinatal or acquired form in which BA is an isolated finding.

The theory is that in the perinatal or acquired form, the obliterative process begins later in the perinatal period than it does in the syndromic form (which may begin in the embryonic phase).

Any theories of pathogenesis?

The cause of BA is unknown but is likely to be multifactorial:

 Genetic: Genes associated with different parts of the inflammatory pathway (e.g. CFC1, ICAM1,CD14 endotoxin receptor gene) have variable polymorphism frequency in children with biliary atresia.

Viral: Studies inoculating mice with rotavirus strains, reovirus and cytomegalovirus have resulted in jaundice and intrahepatic histology similar to biliary atresia. Liver biopsies from human patients showed 90% of infants expressed a protein linked to inflammation secondary to a viral immune response.

Immunological: It is unlikely that a direct viral cause is responsible for the pathogenesis of biliary atresia as viral particles have not been isolated in biopsies. Rather, viral infection may be the trigger to activation of the innate immune response which causes apoptosis and cell death. It is more likely that infection is a second injury to a liver which is already susceptible to damage through genetic or immunological dysregulation. Lymphocyte mediated biliary inflammation seems the most likely mechanism by which bile duct obliteration occurs but the trigger for this response is unknown. 

How do patients present?

Typically biliary atresia presents in early infancy with persistent jaundice, dark urine and pale stools. A 2012 published study however concluded that even experienced professionals often fail to recognize stool colour associated with biliary obstruction. 

How is it diagnosed?

All term infants who remain jaundiced after 14 days should have serum bilirubin levels measured with conjugated/unconjugated differentials.

Physiological and breast milk jaundice manifests as unconjugated hyperbilirubinaemia, whereas most forms of liver disease present with raised conjugated bilirubin.

Liver function tests typically show raised transaminases, especially serum gamma-glutamyltransferase.

An abdominal ultrasound is an essential basic investigation which may demonstrate an enlarged liver, and an absent or contracted gallbladder after a 4 hour fast. Biliary dilatation is not seen.

Radio isotope excretion studies scan after pretreatment with phenobarbitone 5mg/kg per day for 3-5 days will typically will show good hepatic uptake but absent or reduced excretion into the intestine within 24 hours. This result is not specific for biliary atresia however and is also found in children with Alagille’s syndrome.

Percutaneous liver biopsy is the usual diagnostic method and shows evidence of extrahepatic biliary obstruction such as portal tract fibrosis, oedema, ductular proliferation and cholestasis. Biopsies done before 6 weeks of age might not have typical features.

The gold standard for diagnosis, particularly if there is any doubt prior to a Kasai portoenterostomy, is an operative cholangiography. Other investigations include an endoscopic retrograde cholangiopancreatography or a magnetic resonance retrograde cholangiopancreatography although these are technically difficult and not widely available.

How is it managed?

i. Kasai portoenterostomy:

The entire extrahepatic biliary tree is excised so that the porta hepatis is transected at the level of the liver capsule and anastomosed to the jejunum via a Roux loop. Success is measured by clearance of jaundice and is defined as achievement of normal bilirubin concentration within 6 months of the procedure.

A Kasai is not curative, and the disease will continue to progress in 70% of children who have had a successful surgery.

The most important prognostic factor for the Kasai portoenterostomy is the patient’s age at the time of the procedure. The older the infant, the less successful the outcome.

Age at Kasai4 year survival with native liver10 year survival with native liver
<30 days49%49%
31-90 days36%25%
>90 days23%15%
Biliary Atresia in Canada: Influence of age at Kasai on survival with native liver. Adapted from Biliary Atresia: The timing needs a changin’. Chitsaz E, Schreiber RA, Collet JP, Kaczorowski J. Canadian Journal of Public Health 2009;100(6):475-77

 

Because timing is such a factor in outcome, some countries (Taiwan, Japan) are considering implementing a screening program based on stool colour cards to increase awareness of biliary atresia among parents and physicians. A 2011 study showed that stool colour card screening may be associated with a decline in late referrals.

Complications of Kasai:

Ascending cholangitis presents in the first few months post surgery and manifests as a recurrence of jaundice, acholic stool and abdominal pain. Recurrent or late cholangitis suggests an obstruction of the Roux loop.

A degree of hepatic fibrosis or cirrhosis is apparent even in children with a successful Kasai. Portal hypertension is present in most cases and has its own complications such as ascites or variceal bleeds.

Regular ultrasound scans and annual alpha feto protein levels should be part of a long term review to screen for development of malignancy secondary to cirrhosis.

 

ii. Liver transplantation:

Indications and timing for a liver transplant depends on the success of the Kasai portoenterostomy and the rate of complications. Infants who had failed Kasai surgeries will require transplantation within 6 months to 2 years. Children with BASM syndrome have an increased risk of early mortality and morbidity and thus the need for transplantation is greater. Living related liver transplantation is successful in Taiwan and Japan and allow for planned and timely transplantation with good reported outcomes. 

 

References:

  1. Biliary Atresia. Hartley J, Davenport M, Kelly D. Lancet 2009; 374:1704-13
  2. Current management of biliary atresia. Kelly D, Davenport M. Arch Dis Child 2007; 92:1132-35
  3. Prolonged Neonatal Jaundice and the Diagnosis of Biliary Atresia: A single center analysis of trends in age at diagnosis and outcomes. Wadhwani S, Turmelle Y, Nagy R, Lowell J, Dillon P, Shepherd R. Pediatrics 2008; 121 (5): 1438-40
  4. Biliary Atresia: The timing needs a changin’. Chitsaz E, Schreiber RA, Collet JP, Kaczorowski J. Canadian Journal of Public Health 2009;100(6):475-77
  5. Stool color card screening for Biliary Atresia. Tseng J, Lai M, Lin M, Fu Y. Pediatrics 2011; 128(5) 1209

 

 

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About 

Dr Li-Zsa Tan iss an advanced trainee in paediatric gastroenterology and general paediatrics. Based in Sydney as a Fellow in Gastroenterology, she thinks Jean-Luc Picard is the best Star Trek captain EVER and wonders if someone would like to do a coffee run now, please.