Bile ductule formation in fetal, neonatal, and infant livers compared with extrahepatic biliary atresia

The cell of origin of intrahepatic bile ducts during fetal development remains a subject of controversy, although there has been recent evidence that they form from hepatocytes. However, the origin of neoductules and ducts in the setting of liver disease has not been extensively investigated in humans. Using anticytokeratins characteristic of hepatocytes and bile ducts, we repeated earlier studies of fetal development to compare ductule formation in normal developing and newborn livers with the ductules formed during extrahepatic biliary atresia. We utilized an antibody to proliferating cell nuclear antigen (PCNA) staining to determine which cells were in active DNA synthesis (S phase) during fetal development and liver disease progression. The results indicated that hepatocytes undergo a phenotypic switch (metaplasia) to form ductular cells during fetal development. There was no ductular cell replication in the fetal livers. In contrast, both bile ductular metaplasia and proliferation were observed in biliary atresia. Therefore, both a limiting plate phenotypic switch to ductules and replication of ductular cells play a role in the increase in the ductules seen in the progression to biliary cirrhosis. Bile ductular proliferation in biliary atresia, however, was less than that seen in hepatocytes, whereas the number of bile ductules increased and the relative proportion of hepatocytes diminished as the accompanying periductular fibrosis progressed to cirrhosis.