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Abundant Expression of Lysyl Oxidase-Like 2 Protein in Intra-Hepatic Bile Ducts of Infants with Biliary Atresia

Honigbaum, Stefany*; Zhu, Qingfeng; Layman, Andrew; Anders, Robert A.; Schwarz, Kathleen B.*

Journal of Pediatric Gastroenterology and Nutrition: June 7, 2019 - Volume Publish Ahead of Print - Issue - p
doi: 10.1097/MPG.0000000000002414
Original Article: Hepatology: PDF Only
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ABSTRACT Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be anti-fibrotic in animals. Objectives: to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues. Methods: Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared to non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed. Results: Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 (p ≤ 0.001) for non-BA and distribution of bile duct staining score of 3.0 vs. 2.8 (p = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 vs 3.1 for non-BA. Non-hepatic pediatric tissue displayed minimal to no LOXL2 staining. Conclusions: There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extra-hepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

*Department of Pediatrics

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.

Address correspondence and reprint requests to Kathleen B. Schwarz, MD, CMSC 2- 116, 600 North Wolfe St. Baltimore, Md. 21287 (e-mail: kschwarz@jhmi.edu).

Received 5 July, 2018

Accepted 13 May, 2019

Conflict of interest disclosure: R Anders does consulting for Adaptive Biotechnologies; KB Schwarz does consulting for Gilead, Roche Genentech, and Up to Date and has research grants from Gilead, BMS, Roche Genentech, and NIDDK; the remaining authors have no conflicts of interest

Financial support: This work was completed with the assistance of monetary support the American College of Gastroenterology (ACG) Clinical Research Award 2014, the Johns Hopkins Hospital Pediatric Liver Center Gift Fund (including support from the Zachary Meehan Foundation for biliary atresia research, the Sydney Moss BA 5K, and the Colleen Mitchell BA 5K). and the GI SPORE P50 CA062924

Guarantor of the article: Kathleen B. Schwarz is accepting full responsibility for the conduct of the study.

Specific author contributions: Stefany Honigbaum planned and conducted the study, selected the patients and controls, analyzed the data and drafted the manuscript. Robert Anders planned and conducted the study, interpreted the histology and performed the immunohistochemistry assisted by Qingfeng Zhu and Andrew Layman, analyzed the data and critiqued the manuscript. Kathleen Schwarz planned and supervised the conduct of the study, analyzed the data and critiqued the manuscript.

I, Stefany Honigbaum, approved the final draft submitted,

I, Qingfeng Zhu, approved the final draft submitted.

I, Andrew Layman, approved the final draft submitted.

I Robert A Anders approved the final draft submitted.

I, Kathleen B. Schwarz, approved the final draft submitted.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org).

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,