Biliary Atresia and Biliary Hypoplasia

Diagnosis

Jaundice is common in newborns and is secondary to immature hepatic enzyme activity resulting in indirect hyperbilirubinemia. Jaundice persisting beyond the age of 2 weeks should be evaluated by fractionated bilirubin determination. Diagnostic evaluation should be initiated promptly if the direct bilirubin fraction is greater than 20% of the total. Infection, especially when caused by gram-negative bacteria, may cause jaundice. Serologic testing for congenital infection, Pi typing for α ₁ -antitrypsin deficiency, sweat testing or genetic studies for cystic fibrosis, tests to exclude galactosemia, and tests for defects of oxidative enzyme and amino acid metabolism are included in this evaluation. Ultrasound examination of the abdomen should be obtained early in the evaluation. In biliary atresia, the gallbladder is normally shrunken, and no common bile duct is visible. A “triangle cord sign” found on ultrasound has a predictive accuracy of 95%. Hepatobiliary scintigraphy with technetium-99m disofenin (hepatic iminodiacetic acid [HIDA]) with 3 to 5 days of preimaging phenobarbital administration demonstrates no intestinal excretion initially or at 24 hours. Percutaneous liver biopsy is helpful and can yield approximately 90% accuracy in experienced hands. Typical histology demonstrates intracanalicular cholestasis with proliferation of bile ducts. Findings compatible with neonatal hepatitis, periportal fibrosis, and giant cell formation also may be present. Biopsy cannot differentiate biliary atresia from other diseases including α ₁ -antitrypsin deficiency or parenteral nutrition associated liver disease. The most common findings in biliary atresia published in the recent Biliary Atresia Research Consortium experience were bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis.

In the absence of a definitive diagnosis excluding biliary atresia, operative cholangiography must be performed and, if possible, before the age of 60 days. The patient must be prepared for definitive hepatoportoenterostomy at the time of operative cholangiography.

Biliary hypoplasia is diagnosed by the findings on liver biopsy and operative cholangiography. A diminished number of interlobular bile ducts and the cholangiography findings of small intrahepatic and extrahepatic biliary structures with the presence of bile in the gallbladder at exploration are typical. The syndromic form of this disease described by Alagille includes several other important findings. These include characteristic facies, butterfly-like vertebral arch defects, the ophthalmologic finding of posterior embryotoxon, and cardiac anomalies, of which the most common is branch pulmonary artery stenosis. Renal tubular abnormalities may also be present on ultrasound. Recent work has identified the abnormal gene JAG1. Testing for this gene is available.

Etiology

The cause of biliary atresia remains enigmatic. Although approximately 15% of cases occur in the context of other associated anomalies suggesting a genetic basis, most occur randomly or sporadically, which is consistent with a toxic or infectious cause. Animal models of biliary injury have been developed with reovirus and rotavirus as the infectious agent. These agents have not been definitively implicated in biliary atresia in humans. It is suggested that exposure of antigen on biliary epithelium secondary to the consequences of infection leads to an autoimmune-type process. This hypothesis is speculative but is supported by the investigations of the inflammatory process found in biliary atresia. Of particular interest in the sporadic cases is the not-uncommon history that an affected newborn had pigmented stools initially. This history suggests the progressive nature of the biliary injury and is one of the intriguing aspects of this disease.

The most common presentation of the syndromic variety of biliary atresia is in association with splenic and vascular malformations. This grouping of biliary atresia, biliary atresia splenic malformation syndrome, is frequently abbreviated BASM syndrome. In these cases, the associated anomalies may include polysplenia; malrotation; situs inversus; interrupted inferior vena cava with azygous continuation; and preduodenal portal vein, hepatic arterial anomalies and cardiac anomalies, including heterotaxia or more severe lesions.

The genetic abnormality underlying Alagille syndrome has been discovered during the past decade. Studies of JAG1 expression patterns have shown that the associated abnormalities of Alagille syndrome are not coincidental but related to abnormalities of this gene, which codes for a ligand of NOTCH 1.

Classification

Ohi et al. created an effective classification scheme for the biliary abnormalities found in biliary atresia ( Fig. 115.1 ). This scheme allows each case to be designated by the operative findings. One of the important findings of the Childhood Liver Disease Research and Education Network study of 244 infants undergoing the Kasai procedure is that Ohi types II and III including subtypes b, c, and d have a worse prognosis than type I and subtype a. In addition, the BASM category had a worse prognosis than type I. This is important for outcome comparison between centers as well as for individual patient prognosis.

The most common findings at operation are atresia at the porta hepatis (type III) with a fibrous common bile duct (subtype b) and a fibrous mass at the hepatic radicles (subgroup ν). When biliary atresia was first classified, terms such as correctable and noncorrectable were used. These terms are misleading, as Kasai and Suzuki described their surgical procedure for the noncorrectable form of the disease. Most patients have the uncorrectable form of the disease and are still excellent candidates for surgical therapy with a high expectation of benefit if surgery is performed before 60 to 75 days of age. Nevertheless, as many as 10% of all patients never achieve bile drainage because of damage incurred to the intrahepatic biliary tree, and these cases are correctly identified as uncorrectable. At present, we have no way to identify these cases for whom hepatoportoenterostomy will have no merit. However, the biopsy finding of increased periportal fibrosis is highly correlated with poor response to hepatoportoenterostomy.

The work of Bezerra et al. has identified mechanistic explanations for the progression of the atretic process. This appears to be immune in nature and highly correlated with the age of onset of the inflammatory process. Pathologic findings document both from histology and heat maps of genetic markers a progression from inflammation to fibrosis. This progression suggests possibilities for intervention based on the inflammatory process at the time of the Kasai. However, current data are not yet available that would confirm the benefit of this approach.

Operative Management