Recent developments in etiology and disease modeling of biliary atresia: a narrative review

Abstract

Biliary atresia (BA) is a rare but severe fibroinflammatory disease of the extrahepatic and the intrahepatic bile ducts. Without prompt interventions, BA has fatal outcomes and is the most common indicator for pediatric liver transplantation (LTx). While the mainstay of treatment involves surgically correcting the extrahepatic biliary obstruction via Kasai hepato-portoenterostomy (KHPE), activation of a multitude of biological pathways and yet-to-be-determined etiology in BA continue to foster liver inflammation, cirrhosis and need for LTx. However, important caveats still exist in our understandings of the biliary pathophysiology, the rapidity of liver fibrosis and progression to liver failure, largely due to limited knowledge of the triggers of biliary injury and the inability to accurately model human BA. Although inconclusive, a large body of existing literature points to a potential viral infection in the early peri- or postnatal period as triggers of epithelial injury that perpetuates the downstream biliary disease. Further confounding this issue, are the lack of in-vivo and in-vitro models to efficiently recapitulate the cardinal features of BA, primarily liver fibrosis. To overcome these barriers in BA research, new directions in recent years have enabled (I) identification of additional triggers of biliary injury linked mostly to environmental toxins, (II) development of models to investigate liver fibrogenesis, and (III) translational research using patient-derived organoids. Here, we discuss recent advances that undoubtedly will stimulate future efforts investigating these new and exciting avenues towards mechanistic and drug discovery efforts and disease-preventive measures. The implications of these emerging scientific investigations and disease modeling in severe fibrosing cholangiopathies like BA are enormous and contribute substantially in our understandings of this rare but deadly disease. These findings are also expected to facilitate expeditious identification of translationally targetable pathways and bring us one step closer in treating an infant with BA, a population highly vulnerable to life-long liver related complications.

Keywords: Biliary atresia (BA); fibrosis; mouse models; neonatal cholestasis; triggers of biliary atresia.

Figure 1

Triggers and outcomes of hepatobiliary pathogenesis in experimental biliary atresia. Flowchart (A) depicts the primary model of experimental BA involving intraperitoneal RRV infection of newborn mice. EHBD manifestations of biliary disease follow a biological continuum from inflammation to segmental atresia and are associated with intrahepatic portal inflammation. (B) Newly identified chemical triggers of BA induce rapid development of severe cholestasis upon oral or dermal exposures. Extrahepatic duct injury is associated with vanishing common bile duct similar to human BA and development of liver fibrosis. Chemical BA model represents a unique approach to investigate very early immunopathogenic mechanisms driving EHBD atresia. (C) depicts recently described in-vivo, in-vitro and ex-vivo activities of the plant toxin, biliatresone, towards cholangiocytes. Biliatresone promotes abnormal cellular pathologies of the extra- but not intrahepatic ducts. BA, Biliary atresia; RRV, rhesus rotavirus; EHBD, extrahepatic bile duct.

Figure 2

Pre-clinical models for investigating EHBD pathogenesis and liver fibrosis. Panel (A) defines the available models for investigating extrahepatic biliary pathogenesis with specific advantages and outcomes of the individual model systems. Panel (B) shows recent advances in disease modeling for investigating the pathophysiology of liver fibrosis involving in-vivo and in-vitro approaches. These models elucidate features of obstructive cholangiopathies, bridging fibrosis and gene dysregulations associated with liver fibrosis. EHBD, extrahepatic bile duct.