Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease
Authors: Leung Daniel H. , Devaraj Sridevi , Goodrich Nathan P. , Chen Xinpu , Rajapakshe Deepthi , Ye Wen , Andreev Victor , Minard Charles G. , Guffey Danielle , Molleston Jean P. , Bass Lee M. , Karpen Saul J. , Kamath Binita M. , Wang Kasper S. , Sundaram Shikha S. , Rosenthal Philip , McKiernan Patrick , Loomes Kathleen M. , Jensen M. Kyle , Horslen Simon P. , Bezerra Jorge A. , Magee John C. , Merion Robert M. , Sokol Ronald J. , Shneider Benjamin L. ,   The Childhood Liver Disease Research Network, Alonso Estella , Bass Lee , Kelly Susan , Riordan Mary , Melin‐Aldana Hector , Bezerra Jorge , Bove Kevin , Heubi James , Miethke Alexander , Tiao Greg , Denlinger Julie , Chapman Erin , Sokol Ronald , Feldman Amy , Mack Cara , Narkewicz Michael , Suchy Frederick , Sundaram Shikha S. , Van Hove Johan , Garcia Benigno , Kauma Mikaela , Kocher Kendra , Steinbeiss Matthew , Lovell Mark , Loomes Kathleen M. , Piccoli David , Rand Elizabeth , Russo Pierre , Spinner Nancy , Erlichman Jessi , Stalford Samantha , Pakstis Dina , King Sakya , Squires Robert , Sindhi Rakesh , Venkat Veena , Bukauskas Kathy , McKiernan Patrick , Haberstroh Lori , Squires James , Rosenthal Philip , Bull Laura , Curry Joanna , Langlois Camille , Kim Grace , Teckman Jeffery , Kociela Vikki , Nagy Rosemary , Patel Shraddha , Cerkoski Jacqueline , Molleston Jean P. , Bozic Molly , Subbarao Girish , Klipsch Ann , Sawyers Cindy , Cummings Oscar , Horslen Simon P. , Murray Karen , Hsu Evelyn , Cooper Kara , Young Melissa , Finn Laura , Kamath Binita M. , Ng Vicky , Quammie Claudia , Putra Juan , Sharma Deepika , Parmar Aishwarya , Guthery Stephen , Jensen Kyle , Rutherford Ann , Lowichik Amy , Book Linda , Meyers Rebecka , Hall Tyler , Wang Kasper S. , Michail Sonia , Thomas Danny , Goodhue Catherine , Kohli Rohit , Wang Larry , Soufi Nisreen , Thomas Daniel , Karpen Saul , Gupta Nitika , Romero Rene , Vos Miriam B. , Tory Rita , Berauer John‐Paul , Abramowsky Carlos , McFall Jeanette , Shneider Benjamin L. , Harpavat Sanjiv , Hertel Paula , Leung Daniel , Tessier Mary , Schady Deborah , Cavallo Laurel , Olvera Diego , Banks Christina , Tsai Cynthia , Thompson Richard , Doo Edward , Hoofnagle Jay , Sherker Averell , Torrance Rebecca , Hall Sherry , Magee John , Merion Robert , Spino Cathie , Ye Wen 
Published: September 2022

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 R
2 = 0.437; adding IL‐8 and MMP‐7 improved R
2 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 R
2 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.