help button home button Am J Pathol International Conference on Pathology of Chest Diseases
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2007.070073 on June 28, 2007

Published online before print June 28, 2007
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
ajpath.2007.070073v1
171/2/641    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fabris, L.
Right arrow Articles by Strazzabosco, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fabris, L.
Right arrow Articles by Strazzabosco, M.
(American Journal of Pathology. 2007;171:641-653.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070073

Analysis of Liver Repair Mechanisms in Alagille Syndrome and Biliary Atresia Reveals a Role for Notch Signaling

Luca Fabris*{dagger}, Massimiliano Cadamuro*{dagger}, Maria Guido{ddagger}, Carlo Spirli*§, Romina Fiorotto*{dagger}§, Michele Colledan*, Giuliano Torre*, Daniele Alberti*, Aurelio Sonzogni*, Lajos Okolicsanyi{dagger} and Mario Strazzabosco*§

From CeLiveR, Gastroenterology and Liver Transplant Unit,* Ospedali Riuniti di Bergamo, Bergamo, Italy; the Departments of Surgical and Gastroenterological Sciences{dagger} and Pathology,{ddagger} University of Padova, Padova, Italy; and the Liver Center,§ the Department of Internal Medicine, Yale University, New Haven, Connecticut

Patients with Alagille syndrome (AGS), a genetic disorder of Notch signaling, suffer from severe ductopenia and cholestasis, but progression to biliary cirrhosis is rare. Instead, in biliary atresia (BA) severe cholestasis is associated with a pronounced "ductular reaction" and rapid progression to biliary cirrhosis. Given the role of Notch in biliary development, we hypothesized that defective Notch signaling would influence the reparative mechanisms in cholestatic cholangiopathies. Thus we compared phenotype and relative abundance of the epithelial components of the hepatic reparative complex in AGS (n = 10) and BA (n = 30) using immunohistochemistry and computer-assisted morphometry. BA was characterized by an increase in reactive ductular and hepatic progenitor cells, whereas in AGS, a striking increase in intermediate hepatobiliary cells contrasted with the near absence of reactive ductular cells and hepatic progenitor cells. Hepatocellular mitoinhibition index (p21waf1/Ki67) was similar in AGS and BA. Fibrosis was more severe in BA, where portal septa thickness positively correlated with reactive ductular cells and hepatic progenitor cells. AGS hepatobiliary cells failed to express hepatic nuclear factor (HNF) 1ß, a biliary-specific transcription factor. These data indicate that Notch signaling plays a role in liver repair mechanisms in postnatal life: its defect results in absent reactive ductular cells and accumulation of hepatobiliary cells lacking HNF1ß, thus being unable to switch to a biliary phenotype.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2007 by the American Society for Investigative Pathology.