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PRO-C3 is an independent predictor of fibrosis stage in NAFLD. A PRO-C3 based score (ADAPT) accurately identifies patients with NAFLD and advanced fibrosis and is superior to APRI, FIB-4 and NFS. This article is protected by copyright. All rights reserved.

Emerging evidence suggests that altered components and posttranslational modifications of proteins in the extracellular matrix (ECM) may both initiate and drive disease progression. The ECM is a complex grid consisting of multiple proteins, most of which play a vital role in containing the essential information needed for maintenance of a sophisticated structure anchoring the cells and sustaining normal function of tissues. Therefore, the matrix itself may be considered as a paracrine/endocrine entity, with more complex functions than previously appreciated. The aims of this review are to 1) explore key structural and functional components of the ECM as exemplified by monogenetic disorders leading to severe pathologies, 2) discuss selected pathological posttranslational modifications of ECM proteins resulting in altered functional (signaling) properties from the original structural proteins, and 3) discuss how these findings support the novel concept that an increasing number of components of the ECM harbor signaling functions that can modulate fibrotic liver disease. The ECM entails functions in addition to anchoring cells and modulating their migratory behavior. Key ECM components and their posttranslational modifications often harbor multiple domains with different signaling potential, in particular when modified during inflammation or wound healing. This signaling by the ECM should be considered a paracrine/endocrine function, as it affects cell phenotype, function, fate, and finally tissue homeostasis. These properties should be exploited to establish novel biochemical markers and antifibrotic treatment strategies for liver fibrosis as well as other fibrotic diseases.collagen; cytokine; extracellular fibrogenesis; integrin; laminin; matrix metalloproteinase; posttranslational modification; proteoglycan; endocrine 45% OF ALL DEATHS IN THE DEVELOPED WORLD are associated with chronic fibroproliferative diseases (256, 378). Thus there is an increasing need to address fibroproliferative diseases because of their strong impact on the quality of life and health costs consequent to pain and organ failure, with an increased need for organ transplants despite dwindling availability, often followed by death. Moreover, their severity and perceived irreversibility in view of a current paucity of treatment options, coupled with a high prevalence in most and an orphan status in some fibrotic diseases, have just begun to attract biotechnology and big pharmaceutical companies to the field.The common denominator of fibroproliferative diseases is a dysregulated tissue remodeling leading to the excessive and abnormal accumulation of extracellular matrix (ECM) components, thereby generating an ECM with different structural and signaling properties in the affected tissues (285, 287, 289, 378 -380). Fibrosis can affect almost any organ or tissue and is therefore associated with a wide variety of diseases and injuries (287). Figure 1 illustrates the major fibroproliferative diseases with a significant impact on human health (20, ...

Highlights • Plasma PRO-C3 levels correlate with severity of steatohepatitis and fibrosis stage. • FIBC3 panel achieves good sensitivity and specificity for the identification of F≥3 fibrosis in NAFLD. • FIBC3 panel uses a single threshold value, eliminating indeterminate results and outperforming other non-invasive tools.

Pro-C3 is a useful test to predict fibrogenesis and monitor disease progression. Moreover, it could differentiate mild from moderate disease. Pro-C3 may become a promising blood parameter be included in future studies for monitoring disease progression and eventually for evaluation of potential antifibrotic therapies.

There is an unmet need for high‐quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non‐alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.

This newly developed serum assay specific for P4NP 7S was highly related to liver fibrosis and correlated to extent of hepatic fibrosis. This assay may improve fibrosis quantification.