A. Epidemiology

1. Occurs in 1 in 10,000-13,000 births
2. In US, 400-600 new cases annually
3. Females slightly more commonly affected than males
4. Higher incidence in China, but not Chinese born Americans
5. Other congenital abnormalities in 20-30%
6. Associated Conditions
   1. Situs inversus
   2. Polysplenia
   3. Portal vein anomalies

B. Proposed Etiologies (multifactorial)

1. Immune mediated damage
2. Genetic predisposition
3. Antecedent viral infection
   1. Reovirus type 3
   2. Rotavirus
   3. Papillovirus
4. Toxic or metabolic insult
5. Abnormality in bile duct morphogenesis

C. Classification of Extra-Hepatic Biliary Atresia

1. Type I: partial or complete obstruction of the common bile duct
2. Type IIa: obliteration of the common hepatic duct
3. Type IIb
   1. Obliteration of common bile duct, hepatic duct, cystic duct
   2. No gallbladder involvement
4. Type III
   1. Obliteration of common bile, hepatic and cystic ducts
   2. Associated with a fibrous cone that extends to the hilum

D. Pathogenesis of Extra-Hepatic Biliary Atresia

1. Obliterative cholangiopathy
2. Affects all parts of the biliary tree including intra-hepatic ducts
3. Blockage of bile flow causes back-up of bile
4. Results in liver damage which will lead to cirrhosis
5. Causes malabsorption of fat and fat-soluble vitamins
6. Progressive loss of intra-hepatic biliary ducts often continues after surgical correction

E. Liver Biopsy Pathology

1. Early Stages
   1. Portal tract edema
   2. Marginal proliferation of bile ductules shown by immuno-staining for biliary cytokeratins
   3. Infiltrates of neutrophils and lymphocytes
   4. Lymphocytes are activated to Th1 function by interferon gamma and osteopontin [3]
   5. Cholestasis panacinar with inspissated concretions of bile within ductules
2. Later Stages
   1. Portal and periportal fibrosis develops
   2. Nodular regeneration of liver parenchyma seen
   3. Without therapy, progresses to secondary biliary cirrhosis
3. Lymphocyte activation and inflammation likely contributes to fibrotic process

F. Clinical Signs and Symptoms

1. Jaundice persisting after 6 weeks
2. Pale stools but meconium passage normal
3. Darkly pigmented urine
4. Enlarged and firm liver on examination
5. Growth initially normal
6. Decline in nutritional status and activity if untreated

G. Laboratory Evaluation

1. Serum bilirubin: conjugated fraction > 20% of total
2. Liver function tests
3. Coagulation times
4. Blood culture
5. TORCH titers and VDRL
6. Urine for reducing substances (galactosemia, fructosemia)
7. Urine amino acid chromotography (tyrosinemia)
8. Serum alpha1-antitrypsin
9. Liver ultrasound
   1. Looks for presence of biliary ducts and gall bladder
   2. Fibrosis of hepatitis
   3. Excludes cholodochal cyst
10. Liver biopsy gold standard

H. Differential Diagnosis

1. Intra-hepatic bile duct paucity syndrome
   1. Algille's Syndrome
   2. Zellweger's Syndrome
2. Viral hepatitis
3. Metabolic disease
   1. Galactosemia or fructosemia
   2. Tyrosinemia
   3. Alpha-1-Antitrypsin
4. Cystic fibrosis
5. Cholodochal cyst
6. Hypopituitarism
7. Congenital rubella

I. Treatment

1. Kasai Procedure: Portojejunostomy
   1. Resection of entire extra-hepatic biliary tree
   2. Attachment of portus to the jejenum to allow biliary drainage
2. Liver Transplantation
   1. Initial therapy for Type III since no ducts are available for anastomosis at the porta hepatis
   2. Failure of Kasai procedure
   3. Complications: cholangitis, hepatic failure, portal hypertension, and esophageal varices

J. Prognosis

1. Causes of Death
   1. Hepatic failure
   2. Bleeding (vitamin K deficiency or esophageal varices)
   3. Intercurrent infection
2. Without surgery
   1. Mean survival 8 months
   2. <10% 3 year survival
   3. Causes of Death
3. With Kasai procedure
   1. 30-60% 5 year survival b Age >10 weeks at diagnosis bad prognostic indicator

References

1. Carcekkar A, et. al. 2000. J Pediatric Surg. 35(5); 717
2. Lefkowitch JH. 1998. Mayo Clin Proc. 73(1): 90
3. Bezerra JA, Tiao G, Ryckman FC, et al. 2002. Lancet. 360(9346):1653