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Published on: August 23, 2022
In Utero Extrahepatic Bile Duct Damage and Repair: Implications for Biliary Atresia
Iris E M de Jong1,2, Rebecca G Wells1,2,3,4
1Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Insights
Biliary atresia (BA) in newborns may stem from an in utero damage-repair response. This process, involving redox stress, can lead to bile duct obstruction or duct recovery.
Area of Science:
- Neonatal cholestatic liver diseases
- Developmental biology
- Pediatric surgery
Background:
- Biliary atresia (BA) is a serious neonatal cholangiopathy affecting the extrahepatic bile duct (EHBD).
- The exact causes and mechanisms of BA remain incompletely understood.
- Evidence suggests initial damage to the EHBD occurs during fetal development.
Purpose of the Study:
- To explore the role of in utero damage and repair processes in the development of biliary atresia.
- To propose a unifying hypothesis for BA pathogenesis involving fetal wound healing.
- To identify potential therapeutic targets by viewing BA as a dysregulated repair response.
Main Methods:
- Review of existing literature on biliary atresia, fetal development, and wound healing.
- Conceptual framework development based on proposed damage-repair mechanisms.
- Analysis of the influence of developmental stages and birth on EHBD susceptibility.
Main Results:
- The fetal EHBD may be susceptible to damage during specific developmental windows.
- A fetal damage-repair response, involving redox stress, is proposed as a central mechanism in BA.
- This response can result in either EHBD obstruction (BA) or ductal repair and recovery.
Conclusions:
- Biliary atresia pathogenesis may be understood as a dysregulated in utero damage-repair response.
- Future research should focus on factors promoting ductal recovery versus fibrosis.
- This perspective offers novel therapeutic avenues for biliary atresia.
Abstract:
Biliary atresia (BA) is a cholangiopathy affecting the extrahepatic bile duct (EHBD) of newborns. The etiology and pathophysiology of BA are not fully understood; however, multiple causes of damage and obstruction of the neonatal EHBD have been identified. Initial damage to the EHBD likely occurs before birth. We discuss how different developmental stages in utero and birth itself could influence the susceptibility of the fetal EHBD to damage and a damaging wound-healing response. We propose that a damage-repair response of the fetal and neonatal EHBD involving redox stress and a program of fetal wound healing could-regardless of the cause of the initial damage-lead to either obstruction and BA or repair of the duct and recovery. This overarching concept should guide future research targeted toward identification of factors that contribute to recovery as opposed to progression of injury and fibrosis. Viewing BA through the lens of an in utero damage-repair response could open up new avenues for research and suggests exciting new therapeutic targets.
