Screening and outcomes in biliary atresia: summary of a National Institutes of Health workshop

Abstract

Biliary atresia is the most common cause of end-stage liver disease in the infant and is the leading pediatric indication for liver transplantation in the United States. Earlier diagnosis (<30-45 days of life) is associated with improved outcomes following the Kasai portoenterostomy and longer survival with the native liver. However, establishing this diagnosis is problematic because of its rarity, the much more common indirect hyperbilirubinemia that occurs in the newborn period, and the schedule for routine infant health care visits in the United States. The pathogenesis of biliary atresia appears to involve immune-mediated fibro-obliteration of the extrahepatic and intrahepatic biliary tree in most patients and defective morphogenesis of the biliary system in the remainder. The determinants of the outcome of portoenterostomy include the age at surgery, the center's experience, the presence of associated congenital anomalies, and the postoperative occurrence of cholangitis. A number of screening strategies in infants have been studied. The most promising are early measurements of serum conjugated bilirubin and a stool color card given to new parents that alerts them and their primary care provider to alcholic stools. This report summarizes a National Institutes of Health workshop held on September 12 and 13, 2006, in Bethesda, MD, that addressed the issues of outcomes, screening, and pathogenesis of biliary atresia.

Figures

Fig. 1

Liver histology of a patient with biliary atresia at 8 weeks of age. The biopsy shows an expanded and fibrotic portal tract (outlined by the arrows), with inflammation, biliary proliferation (outlined by the black arrowheads), and bilirubinostasis within a ductal structure (indicated by a blue arrowhead). Hematoxylin and eosin were used; the original magnification was ×100.

Fig. 2

Proposed model of virus-induced, T cell–mediated autoreactivity leading to bile duct epithelial injury in biliary atresia. The viral infection of the bile duct epithelia (BDE) (1) results in an initial injury to the cells. Virus particles phagocytosed by macrophages or dendritic cells (2) are presented to naive T cells in local lymph nodes, in which the activation and interleukin-2 (IL-2)–stimulated proliferation of virus-specific CD4+ T cells ensues (3). These activated CD4+ T cells travel back to the original site of exposure and elicit T cell effector functions (4), including interferon-γ–induced macrophage stimulation and activation of cytotoxic CD8+ T cells. The macrophages release TNF-α, nitric oxide (NO), and reactive oxygen species, whereas the CD8+ T cells release granzyme and perforin; together, they result in further BDE injury through apoptotic or necrotic pathways. Previously sequestered or altered BDE antigens released from this initial injury are now phagocytosed by macrophages or dendritic cells and presented to autoreactive T cells (5), causing further activation of this T cell–mediated immune cascade (6) and progressive destruction of BDE. Adapted from Sokol RJ, Mack C. Etiopathogenesis of biliary atresia. Sem Liv Dis 2001;21:S17-S124. Reproduced by permission of the authors.

Fig. 3

Comparison of serum bilirubin concentrations in infants with breast milk–associated jaundice (primarily indirect hyperbilirubinemia) and biliary atresia (primarily direct hyperbilirubinemia). As the indirect bilirubin falls during the first month of life in an infant with biliary atresia who is also breast-fed, it may appear that there is an overall improvement in jaundice. Thus, the diagnosis may be delayed, and the delay may lead to late referral for the evaluation of cholestasis.