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 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.

Identification of diagnostic biomarkers and potential therapeutic targets for biliary atresia via WGCNA and machine learning methods

“…Bessho K et al reported that CXCL8 in the liver serves as a sensitive diagnostic biomarker, and perturbing the CXCL8-CXCR2 signature in the murine model could reduce the course of cholestasis and the risk of biliary obstruction, thereby increasing the overall survival ( 37 ). Leung DH et al reported that serum CXCL8 significantly correlates with liver stiffness in BA and can predict poor clinical outcomes ( 38 ). Thus, CXCL8 may be a diagnostic and prognostic biomarker and therapeutic target for BA.…”

Improving the quality of care in pediatric patients with cirrhosis

“…Transient elastography is used with increased frequency in children with chronic liver disease and is a noninvasive modality that may enhance our evaluation; however, there are limitations based on clinical availability, age cutoffs, nor has it become standard of care at all pediatric centers. The Childhood Liver Disease Research Network recently published a multicenter study investigating biomarkers of liver fibrosis and found there was a correlation with liver stiffness via transient elastography and biomarkers of fibrosis and that they varied based on type of pediatric cholestatic liver disease 13 . This study is a promising example of the research underway to better understand, monitor, and possibly intervene in a variety of pediatric chronic liver diseases and underscores the need for noninvasive tools to guide care.…”

Progress in Biomarkers Related to Biliary Atresia

“…Besides, Leung et al . 42 used shear wave velocity to measure liver stiffness, an indirect measure of fibrosis. They found that MMP-7 significantly correlates with increased liver stiffness in patients with BA ( n = 187), supporting the findings of Jiang et al .…”

“…It is worth noting that Lertudomphonwanit et al 16 and Jiang et al 32 used different systems to evaluate histological fibrosis. Besides, Leung et al 42 used shear wave velocity to measure liver stiffness, an indirect measure of fibrosis. They found that MMP-7 significantly correlates with increased liver stiffness in patients with BA (n = 187), supporting the findings of Jiang et al 32 and Chi et al 35 In addition, many researchers have tried to screen out high-risk children who may need liver transplantation after KPE based on their serum MMP-7 concentrations.…”

“…An increasing number of serum biomarkers with diagnostic and prognostic value in BA have been discovered and promoted in recent years. Most of them are listed in Table 3, 16,[31][32][33][34][35][36][37]40,42,52,54,59,69,70,72,[75][76][77]83,87,[92][93][94][95][96][97][98][99][100][102][103][104][105][106][107][108][110][111][112][113] including all the biomarkers mentioned in this review. Among them, MMP-7 is currently the most reliable biomarker for the diagnosis of BA, which may help clinicians assess the stage of liver fibrosis and predict post-KPE outcomes to a certain extent.…”