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Multicenter Study
. 2023 Feb 1;77(2):530-545.
doi: 10.1002/hep.32777. Epub 2022 Nov 3.

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

Daniel H Leung  1 , Sridevi Devaraj  2 , Nathan P Goodrich  3 , Xinpu Chen  2 , Deepthi Rajapakshe  2 , Wen Ye  4 , Victor Andreev  3 , Charles G Minard  5 , Danielle Guffey  5 , Jean P Molleston  6 , Lee M Bass  7 , Saul J Karpen  8 , Binita M Kamath  9 , Kasper S Wang  10 , Shikha S Sundaram  11 , Philip Rosenthal  12 , Patrick McKiernan  13 , Kathleen M Loomes  14 , M Kyle Jensen  15 , Simon P Horslen  16 , Jorge A Bezerra  17 , John C Magee  18 , Robert M Merion  3 , Ronald J Sokol  11 , Benjamin L Shneider  1 , 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; Childhood Liver Disease Research Network
Affiliations
Multicenter Study

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

Daniel H Leung et al. Hepatology. .

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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Figures

Figure 1.
Figure 1.
Boxplots of selected biomarker concentrations (IL-8, MMP-7, CTGF, Endoglin) by diagnosis (control, BA, A1AT, ALGS).
Figure 2.
Figure 2.
Spearman correlations and scatter plots among biomarker concentrations and liver stiffness measurements for participants with BA. The numbers in the upper triangle of the grid display the Spearman correlation coefficients for pairs of variables. The size of the font corresponds to the magnitude of the correlation and the symbols below the numbers indicate significance levels after using multiple comparisons correction for false discovery rate: * p<0.05; **p<0.01;***p<0.001 The lower triangle of the grid displays scatter plots with LOESS lines.
Figure 3.
Figure 3.
Boxplots for selected biomarkers (IL-8, MMP-7, CTGF, Endoglin) by diagnosis (control, BA, A1AT, ALGS) and liver stiffness measurement category.
Figure 4.
Figure 4.
Spearman correlations between biomarker concentrations and laboratory measurements for BA participants. The size of the font corresponds to the magnitude of the correlation and the symbols below the numbers indicate significance levels after using multiple comparisons correction for false discovery rate: * p<0.05;**p<0.01; ***p<0.001
See this image and copyright information in PMC

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