What is biliary atresia in infants?

Biliary Atresia: Comprehensive Overview

Definition and Epidemiology

Biliary atresia is an obliterative inflammatory cholangiopathy affecting both extrahepatic and intrahepatic bile ducts that presents in the neonatal period and, if untreated, leads to death within the first 1-2 years of life. 1

• Incidence varies globally from 1 in 10,000 to 1 in 20,000 live births, with highest rates in Asia and the Pacific region (up to 32/100,000 live births) 2, 3
• In Western Europe, the incidence is approximately 1 in 18,000 live births 3
• Females are affected slightly more often than males 3
• BA is the most common cause of chronic childhood cholestasis and the leading pediatric indication for liver transplantation, accounting for 14-46% of pediatric liver transplants (excluding other causes) 1, 4

Pathophysiology and Etiology

• The disease involves inflammatory damage to intra- and extrahepatic bile ducts with progressive sclerosis, narrowing, and eventual obliteration of the biliary tree 3
• The cholestatic injury triggers an intrahepatic fibrotic process beginning at birth that culminates in cirrhosis within months 2
• The etiology remains unknown, but proposed mechanisms include viral infection (acting late in gestation), genetic susceptibility, developmental abnormalities, or environmental toxin exposure 2, 4
• BA is not considered a hereditary condition, though genetic mechanisms likely play a role in susceptibility 3, 4
• The rarity of BA in premature infants supports an agent acting late in gestation 4

Clinical Variants

BA presents as a clinically heterogeneous disease with several distinct variants: 2

• Isolated BA (most common)
• Biliary Atresia Splenic Malformation (BASM) syndrome
• Cat-eye syndrome-associated BA
• Cystic BA
• CMV-associated BA

Clinical Presentation

Affected infants present with the classic triad of conjugated jaundice, pale (acholic) stools, and dark urine, typically manifesting by 3 weeks of life. 2, 5

• Hepatomegaly or hepatosplenomegaly may be present on examination 2
• Later findings include ascites coincident with progressive liver disease 2
• Jaundice persisting beyond 14 days of age warrants prompt evaluation for conjugated hyperbilirubinemia 4
• Without treatment, median survival is 8 months, with death occurring within 2 years 4

Diagnosis

Any infant older than 14 days with jaundice requires prompt evaluation to determine if conjugated hyperbilirubinemia is present. 4

• Once infectious, metabolic, and endocrine disorders are excluded and findings are consistent with BA, exploratory laparotomy with intraoperative cholangiogram should be performed expeditiously 4
• Early diagnosis is critical because success rates of the Kasai procedure decrease significantly with time, particularly after 3 months of age 1, 5
• Stool color card screening programs (as implemented in Taiwan and studied in Canada) can eliminate late diagnosis and improve outcomes by enabling families to monitor stool color for the first 21 days of life 5

Treatment Algorithm

Initial Surgical Management: Kasai Portoenterostomy

The Kasai portoenterostomy is the treatment of choice and must be performed within the first 2 months of life by an experienced surgeon to achieve optimal outcomes. 1, 6

• When performed early by experienced surgeons, the Kasai procedure results in prolonged survival in up to 70% of infants 1, 6
• Success rates significantly decrease when performed after 3 months of age 1, 6
• The procedure requires precision with minimally invasive tissue anastomoses using fine suture needles (5-0 or 6-0) for bile duct reconstruction 6
• Approximately 25-35% of patients who undergo Kasai portoenterostomy survive more than 10 years without liver transplantation 4

Post-Kasai Medical Management

Prophylactic antibiotics are essential post-operatively to reduce recurrent cholangitis rates and improve survival. 6

• Ursodeoxycholic acid is commonly used to promote bile flow, though regimens are not standardized 6
• Close monitoring is required for complications including cholangitis, portal hypertension, variceal bleeding, fat-soluble vitamin deficiencies, and growth failure 6

Prognostic Indicators Post-Kasai

If total serum bilirubin falls below 2 mg/dL within 3 months following Kasai procedure, up to 70% of patients may have prolonged transplant-free survival. 6

• If total bilirubin remains above 6 mg/dL at 3 months post-Kasai, only 16% will survive long-term without transplantation 6
• Total bilirubin between 2-6 mg/dL at 3 months post-Kasai warrants transplant evaluation 6
• Immediate contact with a pediatric liver transplant center should be initiated for total bilirubin greater than 6 mg/dL beyond 3 months post-Kasai 6

Indications for Liver Transplantation

Liver transplantation is indicated when the Kasai procedure fails, when intractable portal hypertension develops, when progressive liver failure occurs, or when diagnosis is delayed. 1, 6

Additional transplant indications include: 6

• Poor weight gain and growth failure despite aggressive nutritional support
• Intractable pruritus severely impacting quality of life
• Recurrent cholangitis unresponsive to medical management
• Treatment-resistant varices or ascites 2
• Hepatopulmonary syndrome 2

Transplantation Options and Outcomes

Children with biliary atresia have the best post-transplant outcomes of any patient group, with 1-year survival of 93% and 5-year survival exceeding 85%. 1, 6

• Transplantation options include reduced-size deceased donor organ, living-related liver transplantation, and split liver transplantation 6
• At least 80% of BA patients are transplanted by 20 years of age, with the majority transplanted under 4 years of age 6
• The overall 10-year actuarial graft survival is 73%, and overall 10-year patient survival is 86% 6
• Delaying transplantation until at least 6 years of age is associated with better graft and patient survival, highlighting the importance of a successful initial Kasai procedure 6
• Small children can be successfully transplanted using reduced-size deceased donor organs or portions of liver from living related donors 1

Management of Specific Complications

Pruritus Management

For cholestatic pruritus post-Kasai, cholestyramine is first-line therapy, starting at 4 g/day and titrating to a maximum of 16 g/day. 7

• Cholestyramine should be administered 2-4 hours before or after ursodeoxycholic acid to avoid binding interactions 7
• Most patients do not benefit from doses exceeding 8-12 g/day, and constipation is the primary side effect 7
• Rifampicin is second-line therapy, starting at 150 mg once to twice daily and titrating to a maximum of 600 mg/day, with liver function monitoring every 2-4 weeks due to hepatotoxicity risk 7
• Third-line options include naltrexone (starting at 12.5 mg/day, titrating to 50 mg/day) or selective serotonin reuptake inhibitors 7
• Antihistamines have limited efficacy and work primarily through sedative properties rather than addressing the underlying mechanism 7
• Corticosteroids are used post-Kasai to reduce inflammatory bile duct changes and improve bile flow, NOT to treat pruritus 7

Portal Hypertension and Variceal Bleeding

• Portal hypertension and variceal bleeding may develop and can be sentinel events prompting transplant evaluation 6
• These complications can occur even after successful Kasai procedures as children develop cirrhosis and progressive portal hypertension over years 1

Nutritional Management

Aggressive nutritional support prior to transplantation is critical, as it improves both patient and graft survival. 6

• Fat-soluble vitamin deficiencies require monitoring and supplementation 6
• Growth failure despite aggressive nutritional support is an indication for liver transplantation 6
• Failing to provide aggressive nutritional support pre-transplant compromises outcomes 6

Long-Term Outcomes and Prognosis

With sequential treatment using Kasai operation ± liver transplantation, BA patient survival is now close to 90%, with the majority having normal quality of life. 3, 8

• Approximately one-third of patients drain bile after Kasai but develop complications of cirrhosis requiring liver transplantation before age 10 4
• One-third have inadequate bile flow following portoenterostomy and develop progressive fibrosis and cirrhosis 4
• Hepatocellular carcinoma risk exists but is low, with anecdotal cases reported even in patients less than 1 year of age 6
• Children with successful Kasai procedures can develop cirrhosis and progressive portal hypertension over years and may require liver transplantation for long-term survival 1

Critical Pitfalls to Avoid

• Delayed diagnosis beyond 3 months of age significantly reduces Kasai success rates and may necessitate primary liver transplantation 1, 5
• Failure to perform Kasai portoenterostomy by an experienced surgeon reduces success rates 1
• Inadequate nutritional support pre-transplant compromises both patient and graft survival 6
• Failure to initiate prophylactic antibiotics post-Kasai increases cholangitis rates and worsens survival 6
• Delaying transplant evaluation when total bilirubin remains elevated at 3 months post-Kasai reduces long-term survival 6