Authors

Daniel H Leung
Sridevi Devaraj
Nathan P Goodrich
Xinpu Chen
Deepthi Rajapakshe
Wen Ye
Victor Andreev
Charles G Minard
Danielle Guffey
Jean P Molleston
Lee M Bass
Saul J Karpen
Binita M Kamath
Kasper S Wang
Shikha S Sundaram
Philip Rosenthal
Patrick McKiernan
Kathleen M Loomes
M Kyle Jensen
Simon P Horslen
Jorge A Bezerra
John C Magee
Robert M Merion
Ronald J Sokol
Benjamin L Shneider
Estella Alonso
Lee Bass
Susan Kelly
Mary Riordan
Hector Melin-Aldana
Jorge Bezerra
Kevin Bove
James Heubi
Alexander Miethke
Greg Tiao
Julie Denlinger
Erin Chapman
Ronald Sokol
Amy Feldman
Cara Mack
Michael Narkewicz
Frederick Suchy
Shikha S Sundaram
Johan Van Hove
Benigno Garcia
Mikaela Kauma
Kendra Kocher
Matthew Steinbeiss
Mark Lovell
Kathleen M Loomes
David Piccoli
Elizabeth Rand
Pierre Russo
Nancy Spinner
Jessi Erlichman
Samantha Stalford
Dina Pakstis
Sakya King
Robert Squires
Rakesh Sindhi
Veena Venkat
Kathy Bukauskas
Patrick McKiernan
Lori Haberstroh
James Squires
Philip Rosenthal
Laura Bull
Joanna Curry
Camille Langlois
Grace Kim
Jeffery Teckman
Vikki Kociela
Rosemary Nagy
Shraddha Patel
Jacqueline Cerkoski
Jean P Molleston
Molly Bozic
Girish Subbarao
Ann Klipsch
Cindy Sawyers
Oscar Cummings
Simon P Horslen
Karen Murray
Evelyn Hsu
Kara Cooper
Melissa Young
Laura Finn
Binita M Kamath
Vicky Ng
Claudia Quammie
Juan Putra
Deepika Sharma
Aishwarya Parmar
Stephen Guthery
Kyle Jensen
Ann Rutherford
Amy Lowichik
Linda Book
Rebecka Meyers
Tyler Hall
Kasper S Wang
Sonia Michail
Danny Thomas
Catherine Goodhue
Rohit Kohli
Larry Wang
Nisreen Soufi
Daniel Thomas
Saul Karpen
Nitika Gupta
Rene Romero
Miriam B Vos
Rita Tory
John-Paul Berauer
Carlos Abramowsky
Jeanette McFall
Benjamin L Shneider
Sanjiv Harpavat
Paula Hertel
Daniel Leung
Mary Tessier
Deborah Schady
Laurel Cavallo
Diego Olvera
Christina Banks
Cynthia Tsai
Richard Thompson
Edward Doo
Jay Hoofnagle
Averell Sherker
Rebecca Torrance
Sherry Hall
John Magee
Robert Merion
Cathie Spino
Wen Ye

Publication Date

2-1-2023

Journal

Hepatology

DOI

10.1002/hep.32777

PMID

36069569

PMCID

PMC10151059

PubMedCentral® Posted Date

5-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Child, Liver, Matrix Metalloproteinase 7, Endoglin, Interleukin-8, Cholestasis, Liver Cirrhosis, Liver Diseases, Biomarkers, Alagille Syndrome, Elasticity Imaging Techniques, Alagille syndrome, alpha-1 antitrypsin deficiency, biliary atresia, cholestasis, cirrhosis, non-invasive, pediatric liver disease

Abstract

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS.

CONCLUSIONS: Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.

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