Gene expression signature for biliary atresia and a role for interleukin‐8 in pathogenesis of experimental disease. Issue 1 (27th May 2014)

• Record Type: Journal Article
• Authors: Bessho, Kazuhiko; Mourya, Reena; Shivakumar, Pranavkumar; Walters, Stephanie; Magee, John C.; Rao, Marepalli; Jegga, Anil G.; Bezerra, Jorge A.
• Is Part Of: Hepatology. Volume 60:Issue 1(2014:Jul.)
• Page Start: 211
• Page End: 223
• Publication Date: 2014-05-27
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27045
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Biliary atresia (BA) 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 BA. Applying stringent statistical analysis to a genome‐wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age‐appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, <italic>IL8</italic> and <italic>LAMC2</italic> were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84‐1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver‐restricted increase in <italic>IL8</italic> was relevant to disease pathogenesis, we inactivated the signaling of <italic>IL8</italic> homologs by genetic targeting of the <italic>Cxcr2</italic> receptor in a murine model of experimental BA. Disruption of <italic>Cxcr2</italic> shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild‐type neonatal mice. <italic>Conclusion</italic>: The hepatic expression of <italic>IL8</italic> and <italic>LAMC2</italic> has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA. (H<sc>epatology</sc> 2014;60:211–223)</p> </abstract>