Continuing Education Activity

Biliary atresia is a disease of the intrahepatic or extrahepatic bile ducts with an unknown etiology. It presents in neonates with jaundice, clay-colored stool, and hepatomegaly. This activity illustrates the evaluation and management of biliary atresia and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Review the morphological classification of biliary atresia.

• Describe the radiological, serological, and histopathological tests to diagnose biliary atresia.

• Summarize the use of peri-operative cholangiogram, porto-enterostomy, and liver transplantation in the management of biliary atresia.

• Identify the importance of improving care coordination among the interprofessional team to facilitate early diagnosis and surgical correction which will improve outcomes in patients with biliary atresia.

Introduction

Biliary atresia is an obstructive cholangiopathy of unknown etiology involving both the intrahepatic and extrahepatic bile ducts. It presents in the neonatal period with persistent jaundice, clay-colored stools, and hepatomegaly. It is fatal if left untreated with a reported survival of less than 10% at 3 years of age.

The earliest reported reference of the condition was in 1817 by Dr. John Burns, who described it as an incurable state of the biliary apparatus. Later on, the first surgical success was achieved by Dr. William Ladds in 1920, but biliary atresia continued to have a dismal outcome until the 1950s when Dr. Morio Kasai first described the Kasai porto-enterostomy by dissecting the proximal obstructed biliary tract and creating a Roux-en-Y loop.[1][2][3] It is now considered the standard procedure and is offered to all children undergoing surgical correction. With the progress and advancement of transplantation surgery, liver transplantation is an option available to children who have either failed to restore the bile flow in the initial Kasai surgery or have developed advanced liver cirrhosis.[4]

Etiology

The etiology of biliary atresia is unknown. Theories suggest a multitude of etiological and causative factors that are both genetic and acquired.

Since about 3% to 20% of children with biliary atresia have some associated syndrome or another congenital abnormality, and as biliary atresia is more common in certain geographic regions, it is likely that some genetic component is present in the pathogenesis of the disease although no single etiology has been found so far.[5][6] Only a few familial cases are described and no increase in the incidence has been noted in the case of twins.

The extrahepatic bile ducts first become visible as an out-pouching of the foregut at 20 days of gestation, and the intrahepatic bile ducts become visible at 45 days, which form from the primitive hepatocytes. The porta-hepatis is the place of the interface between the extra and intrahepatic bile ducts, and the successful union is crucial for the development of the patent biliary system. The non-syndromic isolated type of biliary atresia might result from faulty remodeling in fetal life at the hepatic hilum. This is supported by the fact that there are similarities in the cytokeratin staining of the bile ducts in patients with biliary atresia and first-trimester fetal bile ducts strengthening the possibility that biliary atresia could occur due to the failure of the bile duct remodeling at the hepatic hilum with the persistence of fetal bile ducts.[7]

Other theories favor a possible acquired, inflammatory, and infectious cause for the pathogenesis of the disease. Rotavirus and reovirus type 3 are specially mentioned as their perinatal animal models produced biliary atresia; however, these results have not been consistently seen in humans.[8]

There have also been studies that show immune-related damage to the ductules of patients with biliary atresia due to an increase in the expression of intercellular adhesion molecule (ICAM)-1 in the bile ductules.

Other studies favor an acquired etiology with seasonal clustering of the cases especially in the winter months and also because 50% of the children with the disease have pigmented stools earlier in life which then later became clay-colored.

Classifications

Biliary atresia is not a single disease that results from a specific etiology, but rather it is a phenotype that results from different etiologies. It is broadly classified as syndromic and non-syndromic isolated varieties. Davenport et al. grouped specific entities of biliary atresia based on the similarities they share.[9]

Biliary Atresia Splenic Malformation Syndrome (BASM)

Biliary atresia is associated with polysplenia, vascular anomalies including a pre-duodenal portal vein, interrupted vena cava, azygos continuation, cardiac malformation, malrotation, and situs inversus. In this type, the malformation occurs early in embryogenesis and accounts for the other anomalies. Maternal diabetes seems to play a role, and there is a female predominance.

Cystic Biliary Atresia

In this type, there is the obliteration of the biliary system with cystic dilatation. The incidence is reported to be around 10%, and it carries a better prognosis.[10]

Cytomegalovirus (CMV) IgM Positive Biliary Atresia

This type represents about 10% of the cases, and most of them are non-Whites. These children present with higher bilirubin and aspartate aminotransferase (AST) levels and more inflammatory infiltrates in the extrahepatic biliary apparatus on histology. This group has the worst prognosis.[11]

Isolated Biliary Atresia

This represents the largest group, but the etiology is unknown.

Morphological Classification

Morphological classification is based on the level at which the biliary lumen is obliterated. The Japanese Association Of Pediatric Surgeons has classified it as:

• Type I: Obliteration of the common bile duct
• Type II a: Obliteration of the common hepatic duct
• Type II b: Obliteration of the common bile duct, hepatic duct, cystic duct with no abnormality of the gallbladder, and cystic dilatation at the porta hepatis
• Type III: Obliteration of the common bile duct, hepatic duct, and cystic duct with no anastomosable ducts at the porta hepatis; this is the most common variety.

Epidemiology

Marked regional variations are reported of biliary atresia with a higher number of cases in Taiwan and Japan of about 1 to 5 in 1000 live births to lower numbers in England and Wales of about 1 to 5 in 20,000.[12][13] Some small series have also shown a seasonal variability.[14][15] Others have shown a slight female predominance.

There is a geographical variance among different varieties of biliary atresia with BASM having a 10% reported incidence in European studies and much less incidence in Asia. Many CMV IgM positive biliary atresia cases are reported from China.

Histopathology

The histological examination of biliary atresia specimens shows variable liver fibrosis, bile duct proliferation, bile duct plugging, cholestasis, inflammatory cell infiltration. Among all the features, bile duct proliferation is a highly sensitive and specific marker for biliary atresia.[16]

History and Physical

Children present in the neonatal period with persisting jaundice, clay-colored stools, and hepatomegaly.[17] Any child with jaundice of over 14 days should no longer be regarded as physiological jaundice and should undergo evaluation. More than half of the children with biliary atresia will have initial pigmented stools that later turn acholic and with the progression of the disease, signs of liver cirrhosis and failure set in with palpable hepatomegaly, splenomegaly, ascites, signs of portal hypertension, and failure to thrive.

Evaluation

There is no single test that can accurately identify biliary atresia from other causes of conjugated hyperbilirubinemia with high specificity. Children undergo both serological and radiological tests along with histopathology to come to a diagnosis.

Laboratory Studies

In biliary atresia, the direct and indirect bilirubin levels are both elevated with the conjugated portion being more elevated. As alkaline phosphatase levels are elevated in children due to bone remodeling, the liver-specific alkaline phosphatase fraction 5' nucleotidase level should be measured. Gamma-glutamyl transpeptidase (GGTP) is present in the canalicular bile membrane and is increased in cases of biliary obstruction. GGTP provides a diagnostic accuracy of 50% to 60% in biliary atresia.[18][19] Serum transaminase levels are mildly elevated.

Imaging Studies

Ultrasound (US)

Ultrasonography is an easily available, non-invasive test and can provide valuable information regarding the liver texture, vasculature patency, and ascites, and can also exclude other causes of obstructive jaundice like a choledochal cyst.[20][21] Ultrasonography shows a hypoplastic or absent gallbladder. It can be done both in the pre and postprandial state, which will show the non-filling of the gallbladder. It can identify the triangular cord sign that was first described by Park et al. as the presence of a solid proximal biliary remnant in front of the bifurcation of the portal vein.[22] However, some authors disagree on the accuracy and specificity of this sign. Antenatally, infants with a congenital variety of biliary atresia can be detected with an abnormal maternal US scan at around 20 weeks gestation, which can facilitate an early postnatal US and timely referral. Despite the ease and availability of ultrasound, the diagnostic accuracy of this modality for diagnosing biliary atresia is only 78%.

Hepatobiliary Scintigraphy

This study uses a technetium labeled compound diisopropyl iminodiacetic acid (DISDIA).[23] The presence of isotope in the intestine excludes biliary atresia. The reliability of this test decreases in the presence of high levels of conjugated bilirubin. It also carries a 10% false-positive or false-negative rate. 

Endoscopic Retrograde Cholangiopancreatography

This test is not widely done due to the limited availability of neonatal scopes equipped with a side view. With an increase in expertise and availability, this modality will probably be used in situations where other tests have failed to confirm the diagnosis.[24]

Duodenal Intubation

Aspiration of bile-stained fluid from the duodenum will rule out biliary atresia. This test is not widely performed as it is invasive and unreliable.[25]

Magnetic Resonance Imaging (MRI) and Magnetic Resonance Cholangiopancreatography (MRCP)  

These tests provide greater accuracy but are not readily performed due to expense and requirement of sedation and limited resolution at this young age.

Liver Biopsy

Liver biopsy can differentiate biliary atresia from other causes of cholestatic jaundice with a high level of accuracy. Features suggestive of biliary atresia include bile duct proliferation, bile plugging, multinucleated giant cells, focal necrosis of liver parenchyma, extramedullary hemopoiesis, and inflammatory cell infiltrate. Among these features, bile ductular proliferation is considered the most sensitive and specific feature.[26]

Treatment / Management

Surgical exploration is the only method for accurately and reliably diagnosing and treating biliary atresia 

Peri-Operative Cholangiogram

Peri-operative cholangiogram will definitively diagnose biliary atresia by the failure of passage of dye into the intrahepatic and extrahepatic biliary system.[27][28]

Porto-Enterostomy

The standard surgical technique is the creation of a Roux-en-Y hepatic porto-enterostomy (Kasai procedure) in which excision of the fibrotic biliary remnant, transaction of the fibrous portal plate with dissection extending up to the bifurcation of the portal vein is done. The Roux-en-Y loop reestablishes biliary-enteric continuity and allows bile drainage. 

In rare instances where the gallbladder and common bile duct are patent, a surgeon might consider a porto-cholecystostomy.[29] However, the anastomosis is not as flexible as a standard Roux-en loop, and revisions for repeated biliary obstruction have been described with a poorer long-term outcome. It has a lower incidence of cholangitis. In some cases with type I biliary atresia, hepaticojejunostomy has been described, but the results are inferior to the standard Kasai procedure.

Some drugs are used as adjuncts after surgery to promote biliary drainage, among them, steroids and ursodeoxycholic acid have been extensively described.[30][31] Steroids decrease the inflammatory response and promote bile clearance.[32] A single prospective, randomized, placebo-controlled trial used a low dose of prednisolone (2 mg/kg/day) and showed a significantly increased rate of jaundice clearance in the steroid group but did not provide any survival benefit.[33] Another trial, START (Steroids in Biliary Atresia Randomized Trial) showed no benefit of high dose steroid therapy on biliary clearance at six months post-surgery and had an earlier onset of adverse effects related to steroids.[34] Ursodeoxycholic acid is a hydrophilic bile acid and is normally present in about 1% to 4% of the total bile acid pool. It is known to promote bile clearance and is frequently prescribed postoperatively.

Liver Transplantation

Liver transplantation is an option offered if liver cirrhosis is far advanced or if a Kasai porto-enterostomy has failed.

Differential Diagnosis

• Alagille syndrome
• Alpha 1 antitrypsin deficiency
• TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes simplex virus)
• Caroli disease
• Choledochal cyst
• Idiopathic neonatal hepatitis
• Lipid metabolism disorders
• Total parenteral nutrition-associated hepatitis

Prognosis

Major Determinants of a Satisfactory Outcome After Portoenterostomy

Age at Initial Operation

Liver fibrosis is a time-dependent factor. However, the age at porto-enterostomy and surgical outcomes do not have a linear relationship. This was demonstrated in an age cohort analysis which showed that up to about 90 days of age the outcome of porto-enterostomy could not be ascertained by age alone for the cases of an isolated variety of biliary atresia.[35][36]

Syndromic Variety of Biliary Atresia

Infants with syndromic BASM respond less well to Kasai surgery and have a poorer overall outcome with a higher risk of death.[37]

CMV IgM Positive Associated Biliary Atresia

Those with the poorest outcome and highest risk of death are infants with CMV IgM positive associated biliary atresia.

Successful Achievement of Postoperative Bile Flow

patients with satisfactory bile flow with good bile clearance after porto-enterostomy (PE) have a better survival outcome with the native liver. Nio et al. reported that most patients who had survived more than 20 years post-PE had normal to moderately elevated liver function test results post-PE.[38] Similarly, Uchida et al. reported that serum AST measured 1-year post-PE is a strong predictive factor for liver dysfunction.[39] Gupta et al. reported that there was a statistically significant decrease in post-PE GGT compared with preoperative levels in patients who had become jaundice-free.[40]

Size of Microscopic Ductal Structures at the Hilum

The size of the microscopic bile ducts in the transected bile duct remnant has been shown to have prognostic significance in some studies.[41] Others have refuted this claim.

Complications

Post-operative complications include cholangitis, anastomotic leak, intestinal obstruction, portal hypertension, and hepatopulmonary syndrome.

Cholangitis

The exact mechanism for the development of cholangitis is not known. However, the formation of a Roux-en-Y loop with the restoration of a bilio-intestinal flow results in colonization of the loop with bacteria and predisposes to ascending cholangitis. Cholangitis is reported in up to 50% of cases.

Surgeons have tried some surgical maneuvers in the past in an attempt to reduce the risk of cholangitis, but none of the maneuvers have proved useful. These include intussuscepted ileocecal conduit, anti-refluxing jejunal loop valve, use of an appendiceal conduit, stomas of the proximal limb of the Roux-en loop, and omental wrap to the porta hepatis.[35][37]

Children with cholangitis present with fever, worsening of jaundice, and elevation of liver enzymes. Treatment should be prompt and aggressive with broad-spectrum intravenous antibiotics with good coverage against gram-negative bacteria.

Portal Hypertension

Portal venous pressure is high in the majority of infants with biliary atresia due to liver fibrosis. As liver fibrosis is a time-dependent feature, it correlates with age at porto-enterostomy and bilirubin level.[40] It is a bad prognostic sign with the majority of the children progressing on to develop portal hypertension, variceal bleed, and end-stage liver failure.

Variceal Bleeding

Esophageal varices develop at an average of about 2 to 3 years after Kasai porto-enterostomy in 60% of the children and out of these about 30% will bleed. It is recommended that every child with biliary atresia undergo endoscopic surveillance. Those with an active bleed require sclerotherapy or banding

Ascites

Ascites can be caused by portal hypertension, hypoalbuminemia, and hyponatremia. Spironolactone therapy is usually advised. 

Intrahepatic Cysts

Biliary cysts or “lakes” can develop within the livers of patients with biliary atresia and cause recurring attacks of cholangitis. Prolonged use of broad-spectrum antibiotics is recommended. Cases that fail to respond require liver transplantation.

Hepato-Pulmonary Syndrome

This syndrome is characterized by cyanosis, dyspnea, hypoxia, and finger clubbing. The diffuse intrapulmonary shunting is thought to occur due to gut-derived vasoactive compounds that have bypassed the sinusoidal inactivation. Liver transplantation is usually required to reverse the process.

Malignancy

Rare cases of malignant changes have been reported in cirrhotic livers post-PE (hepatocellular carcinoma or cholangiocarcinoma).

Deterrence and Patient Education

Parents should be educated that the initial success rate of a Kasai porto-enterostomy for achieving bile flow is around 60%. Patients are less likely to require liver transplantation if the surgery is performed within 10 weeks of life. Early diagnosis increases the chances of survival with the native liver. Any child with jaundice, clay-colored stools, and dark urine should be investigated for biliary atresia, and proper referral to a specialty center given. Stool color charts and a stool color mobile app have been introduced in an attempt to increase awareness and generate an early referral.

Enhancing Healthcare Team Outcomes

The management of patients with biliary atresia is best done with an interprofessional team approach. The 10-year survival after hepatic porto-enterostomy has improved over time.[42][43] This reflects an improvement in the technique of porto-enterostomy, advancements in liver transplantation, immunosuppressive strategies, and medications. The centralization of specialty centers and the utilization of an interprofessional team have also contributed to the overall improved effect of standardized patient care.[44] Some countries with a high incidence of biliary atresia have introduced a screening method.[45][46] They issue the parents color-coded stool charts and ask them to compare it with their infant’s stool.[47][48] Recognition of pale stool prompts further investigation and early referral.

A recent multicenter study in the United States reported a 2-year overall survival rate of 86% with a 56% native liver survival.[49] In England and Wales, the expected 10-year survival is 90% and a 10-year survival with native liver of 40%.