Abstract
Background and AimsNon-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis.MethodsWe performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis.ResultsSeventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long’s test).ConclusionsWe have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.
Highlights
Liver fibrosis is the main cause of chronic liver disease (CLD)-related morbidity and mortality
We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum hyaluronic acid (HA), PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test)
The funders had no Seventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively)
Summary
Liver fibrosis is the main cause of chronic liver disease (CLD)-related morbidity and mortality. A number of non-invasive methods of fibrosis assessment have been identified and widely validated, including imaging techniques and serum biomarkers. The use of non-invasive biomarkers for excluding advanced fibrosis to reduce the number of liver biopsies has been incorporated into clinical practice guidelines, they are still considered insufficiently accurate for assessing intermediate stages of fibrosis, disease progression or the effect of therapy[1]. Transient elastography, which can reliably identify advanced fibrosis, is one of the most frequently used non-invasive methods; its use is largely limited to specialist centres due to the need for specialised instrumentation and expertise. Serum panels offer several advantages over liver biopsy, as they are quantitative and have the potential to reflect the dynamic nature of fibrogenesis, providing a more sensitive assessment of the dynamic changes associated with fibrosis progression/regression compared to static fibrosis stage. The aim of this study was to identify novel serum biomarkers of advanced fibrosis
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