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

the Childhood Liver Disease Research Network

doi:10.1002/hep.32777

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

the Childhood Liver Disease Research Network

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 R²to 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 R²from 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.

Original language	English (US)
Pages (from-to)	530-545
Number of pages	16
Journal	Hepatology
Volume	77
Issue number	2
DOIs	https://doi.org/10.1002/hep.32777
State	Published - Feb 2023

Funding

Binita M. Kamath consults for and received grants from Mirum and Albireo. She consults for Audiences. Daniel H. Leung received grant/research support from Abbvie, Gilead, and Mirum and has served as medical advisor for Vertex. He received grants from Mirum. Jean P. Molleston received grants from Mirum, Gilead, AbbVie, and Albireo. Kathleen M. Loomes consults for and received grants from Albireo, Mirum, and Travere Therapeutics. M. Kyle Jensen consults for Gerson Lehrman Group and Guidepoint Global. Phillip Rosenthal consults for and received grants from Albireo. He consults for Ambys. He received grants from AbbVie. Ronald J. Sokol consults for Albireo and Mirum. Saul J. Karpen consults for Albireo, Mirum, and Intercept. This work was supported by U01 grants from the NIDDK (DK 62445 [Mount Sinai School of Medicine], DK 62497 [Cincinnati Children's Hospital Medical Center], DK 62470 [Children's Healthcare of Atlanta], DK 62481 [The Children's Hospital of Philadelphia], DK 62456 [The University of Michigan], DK 84536 [Riley Hospital for Children], DK 84575 [Seattle Children's Hospital], DK 62500 [UCSF Children's Hospital], DK 62466 [Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC)], DK 62453 [Children's Hospital Colorado], DK 84538 [Children's Hospital Los Angeles], DK 62436 [Ann & Robert H Lurie Children's Hospital of Chicago], DK 103149 [Texas Children's Hospital], DK 103135 [The Hospital for Sick Children], and DK 103140 [University of Utah]). In addition, the project described was supported by the following NIH, NCATS, Clinical and Translational Sciences Award grants: University of Colorado UL1 TR002535, UCSF Children's Hospital UL1 TR001872, Children's Hospital of Pittsburgh of UPMC UL1 TR001857, The Children's Hospital of Philadelphia UL1 TR001878, Seattle Children's Hospital UL1 TR000423 and UL1 RR025014, Children's Healthcare of Atlanta UL1 TR002378, and Children's Hospital of Los Angeles UL1 TR00130.

ASJC Scopus subject areas

Hepatology

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10.1002/hep.32777

Cite this

@article{14596ed584234a778f6a6c00f074c969,

title = "Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic 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 R2to 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 R2from 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.",

author = "{the Childhood Liver Disease Research Network} and Leung, {Daniel H.} and Sridevi Devaraj and Goodrich, {Nathan P.} and Xinpu Chen and Deepthi Rajapakshe and Wen Ye and Victor Andreev and Minard, {Charles G.} and Danielle Guffey and Molleston, {Jean P.} and Bass, {Lee M.} and Karpen, {Saul J.} and Kamath, {Binita M.} and Wang, {Kasper S.} and Sundaram, {Shikha S.} and Philip Rosenthal and Patrick McKiernan and Loomes, {Kathleen M.} and Jensen, {M. Kyle} and Horslen, {Simon P.} and Bezerra, {Jorge A.} and Magee, {John C.} and Merion, {Robert M.} and Sokol, {Ronald J.} and Shneider, {Benjamin L.} and Estella Alonso and Lee Bass and Susan Kelly and Mary Riordan and Hector Melin-Aldana and Jorge Bezerra and Kevin Bove and James Heubi and Alexander Miethke and Greg Tiao and Julie Denlinger and Erin Chapman and Ronald Sokol and Amy Feldman and Cara Mack and Michael Narkewicz and Frederick Suchy and Sundaram, {Shikha S.} and {Van Hove}, Johan and Benigno Garcia and Mikaela Kauma and Kendra Kocher and Matthew Steinbeiss and Mark Lovell and Loomes, {Kathleen M.}",

year = "2023",

month = feb,

doi = "10.1002/hep.32777",

language = "English (US)",

volume = "77",

pages = "530--545",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

TY - JOUR

T1 - Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease

AU - the Childhood Liver Disease Research Network

AU - Leung, Daniel H.

AU - Devaraj, Sridevi

AU - Goodrich, Nathan P.

AU - Chen, Xinpu

AU - Rajapakshe, Deepthi

AU - Ye, Wen

AU - Andreev, Victor

AU - Minard, Charles G.

AU - Guffey, Danielle

AU - Molleston, Jean P.

AU - Bass, Lee M.

AU - Karpen, Saul J.

AU - Kamath, Binita M.

AU - Wang, Kasper S.

AU - Sundaram, Shikha S.

AU - Rosenthal, Philip

AU - McKiernan, Patrick

AU - Loomes, Kathleen M.

AU - Jensen, M. Kyle

AU - Horslen, Simon P.

AU - Bezerra, Jorge A.

AU - Magee, John C.

AU - Merion, Robert M.

AU - Sokol, Ronald J.

AU - Shneider, Benjamin L.

AU - Alonso, Estella

AU - Bass, Lee

AU - Kelly, Susan

AU - Riordan, Mary

AU - Melin-Aldana, Hector

AU - Bezerra, Jorge

AU - Bove, Kevin

AU - Heubi, James

AU - Miethke, Alexander

AU - Tiao, Greg

AU - Denlinger, Julie

AU - Chapman, Erin

AU - Sokol, Ronald

AU - Feldman, Amy

AU - Mack, Cara

AU - Narkewicz, Michael

AU - Suchy, Frederick

AU - Sundaram, Shikha S.

AU - Van Hove, Johan

AU - Garcia, Benigno

AU - Kauma, Mikaela

AU - Kocher, Kendra

AU - Steinbeiss, Matthew

AU - Lovell, Mark

AU - Loomes, Kathleen M.

PY - 2023/2

Y1 - 2023/2

N2 - 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 R2to 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 R2from 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.

AB - 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 R2to 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 R2from 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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U2 - 10.1002/hep.32777

DO - 10.1002/hep.32777

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AN - SCOPUS:85141397329

SN - 0270-9139

VL - 77

SP - 530

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JO - Hepatology

JF - Hepatology

IS - 2

ER -

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

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