Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease

• Type of Material: Article
• Authors: Miriam Vos, Emory University; Nitika Gupta, Emory University; Rene Romero, Emory University; Carlos Abramowsky, Emory University; John-Paul Berauer, Emory University; Daniel H Leung, Baylor College of Medicine; Sridevi Devaraj, Baylor College of Medicine; Nathan P Goodrich, Arbor Research Collaborative for Health; Xinpu Chen, Baylor College of Medicine; Deepthi Rajapakshe, Baylor College of Medicine; Wen Ye, University of Michigan; Victor Andreev, Arbor Research Collaborative for Health, Ann Arbor; Charles G Minard, Baylor College of Medicine; Danielle Guffey, Baylor College of Medicine; Jean P Molleston, Indiana University; Lee M Bass, Northwestern University; Saul Karpen, Emory University; Binita M Kamath, University of Toronto; Kasper S Wang, Children’s Hospital Los Angeles; Skikha S Sundaram, Children’s Hospital Colorado and University of Colorado; Philip Rosenthal, University of California San Francisco; Patrick McKiernan, Children’s Hospital of Pittsburgh; Kathleen M Loomes, University of Pennsylvania; Kyle M Jensen, University of Utah; Simon P Horslen, University of Washington; Jorge A Bezerra, University of Cincinnati; John C Magee, University of Michigan Hospitals and Health Centers; Robert M Merion, Arbor Research Collaborative for Healt; Ronald J Sokol, Children’s Hospital Colorado and University of Colorado; Benjamin L Shneider, Baylor College of Medicine
• Language: English
• Date: 2022-11-03
• Publisher: WILEY
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2023 American Association for the Study of Liver Diseases.
• Final Published Version (URL): http://dx.doi.org/10.1002/hep.32777
• Title of Journal or Parent Work: HEPATOLOGY
• Volume: 77
• Issue: 2
• Start Page: 530
• End Page: 545
• Keywords: BILIARY ATRESIA; EXPRESSION; INFANTS; CIRRHOSIS; Science & Technology; FIBROSIS; INTERLEUKIN-8; Gastroenterology & Hepatology; TRANSIENT ELASTOGRAPHY; Life Sciences & Biomedicine; ENDOGLIN; MEDIATORS

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.