Matrix Metalloproteinase-7 as a Diagnostic Marker for Biliary Atresia: a Systematic Review and Meta-analysis

BackgroundBlood derived biomarkers have been extensively described as potential prognostic markers in idiopathic pulmonary fibrosis (IPF), but studies have been limited by analyses using data-dependent thresholds, inconsistent adjustment for confounders and an array of endpoints, thus often yielding ungeneralisable results. Meta-analysis of individual participant data (IPD) is a powerful tool to overcome these limitations. Through systematic review of blood derived biomarkers, sufficient studies with measurements of Matrix Metalloproteinase-7 (MMP-7) were identified to facilitate standardised analyses of the prognostic potential of this biomarker in IPF.MethodsElectronic databases were searched on 12th November 2020 to identify prospective studies reporting outcomes in patients with untreated IPF, stratified according to at least one pre-specified biomarker, measured at either baseline, or change over three months. Individual participant data (IPD) was sought for studies investigating MMP-7 as a prognostic factor. The primary outcome was overall mortality according to standardised MMP-7 z-scores, with a secondary outcome of disease progression in 12 months, all adjusted for age, gender, smoking and baseline FVC.ResultsIPD was available for nine studies out of twelve identified, reporting outcomes from 1664 participants. Baseline MMP-7 levels were associated with increased mortality risk (adjusted HR1.23, 95%CI 1.03;1.48, I2=64.3%) and disease progression (adjusted OR1.27, 95%CI 1.11;1.46, I2=5.9%). In limited studies, three-month change in MMP-7 was not associated with outcomes.ConclusionIPD meta-analysis demonstrated greater baseline MMP-7 levels were independently associated with an increased risk of poor outcomes in patients with untreated IPF, whilst short term changes did not reflect disease progression.

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Faculty Opinions recommendation of Diagnostic Accuracy of Serum Matrix Metalloproteinase-7 for Biliary Atresia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733879150.793556687 ◽

2019 ◽

Author(s):

Rebecca Wells

Keyword(s):

Matrix Metalloproteinase ◽

Diagnostic Accuracy ◽

Biliary Atresia ◽

Matrix Metalloproteinase 7

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Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature

Frontiers in Medicine ◽

10.3389/fmed.2020.617261 ◽

2020 ◽

Vol 7 ◽

Author(s):

Mark Nomden ◽

Leonie Beljaars ◽

Henkjan J. Verkade ◽

Jan B. F. Hulscher ◽

Peter Olinga

Keyword(s):

Immune Response ◽

Liver Fibrosis ◽

Pulmonary Fibrosis ◽

Matrix Metalloproteinase ◽

Biliary Atresia ◽

Adaptive Immune Response ◽

Cell Contact ◽

T Helper 1 ◽

Matrix Metalloproteinase 7

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.

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