Document Detail


Gene expression signature for biliary atresia and a role for Interleukin-8 in pathogenesis of experimental disease.
MedLine Citation:
PMID:  24493287     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Biliary atresia is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to biliary atresia. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with biliary atresia at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls, and 7 normal controls, we identified 15 genes uniquely expressed in biliary atresia with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with biliary atresia distinctly from diseased controls with an area under the curve of 0.934 (95%CI: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of IL8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental biliary atresia. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. Conclusion: The hepatic expression of IL8 and LAMC2 has high sensitivity for biliary atresia at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental biliary atresia. (Hepatology 2014;).
Authors:
Kazuhiko Bessho; Reena Mourya; Pranavkumar Shivakumar; Stephanie Walters; John C Magee; Marepalli Rao; Anil G Jegga; Jorge A Bezerra
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-3
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  -     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 American Association for the Study of Liver Diseases.
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