Biliary atresia is the most common cause of neonatal cholestasis. It results from a progressive fibroinflammatory cholangiopathy that leads to obliteration of the extrahepatic biliary system within weeks of birth. This obstruction leads to impaired bile flow, chronic cholestasis, reactive proliferation of intrahepatic bile ducts, and ongoing hepatocellular injury. When untreated, biliary obstruction will rapidly progress to end-stage cirrhosis, with growth failure and other consequences of chronic liver disease. Therefore, the initial challenge is to differentiate biliary atresia from other forms of neonatal cholestasis. Timely diagnosis is vital because the success of hepatic portoenterostomy in restoring bile drainage improves when surgery is performed before 3 mo of age. When surgery is effective in reducing the serum bilirubin level to <1 mg/dL within 3 mo after portoenterostomy, up to 53% of infants will have normal growth and minimal complications of cirrhosis (1,2). Unfortunately, this may represent only a small portion of all infants with biliary atresia; in most patients, liver disease progresses and requires liver transplantation for long-term survival. Thus, we are challenged to search systematically for pathogenic mechanisms of disease so that new medical therapies can be developed to stop disease progression.

The pathogenesis of biliary atresia is multifactorial (3–6). Although molecular mechanisms that regulate disease onset and progression are not known, patient- and animal-based studies have identified five mechanisms with potential pathogenic roles (Table 1). Collectively, these mechanisms support a “working model” in which a genetically susceptible subject undergoes destruction of the extrahepatic biliary system in response to environmental factors. Regardless of the triggering insult, the close association between inflammatory cells and injured bile ducts in infants with biliary atresia suggests that inflammatory cells may play a chief role in disease pathogenesis. Phenotypic characterization of these cells reveals important functional features of Kupffer cells and hepatic lymphocytes in biliary atresia. Kupffer cells may serve as antigen-presenting cells and produce IL-18, a cytokine that promotes a proinflammatory differentiation of lymphocytes (7–9). In agreement with this concept, some of the cells that infiltrate portal tracts in biliary atresia have been reported to consist of CD4+ (helper), CD8+ (cytotoxic), and CD56+ (natural killer) lymphocytes (7,10–12). Of interest, CD8+ lymphocytes were found in proliferated bile ducts of affected patients, although the cells did not express perforin or granzyme B, markers of functional activation (12). Further evidence supporting a functional commitment of lymphocytes is the unique hepatic transcriptional profile displaying the coordinated expression of genes that regulate proinflammatory differentiation of lymphocytes in infants early in the course of biliary atresia (13). The profile contained the overexpression of interferon-γ in affected infants, even when inflammatory infiltrates were similar to liver samples from age-matched infants with intra-hepatic cholestasis, suggesting different activation states of similar cell types. In this issue of Pediatric Research, Mack et al. add a comprehensive spatial and functional dimension to the relationship between bile ducts and inflammatory cells in infants with biliary atresia.

Table 1 Potential mechanisms involved in the pathogenesis of biliary atresia
Full size table

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