Extracellular Matrix Remodeling with Focus on Biochemical Markers in Liver Fibrosis: Limitations and Possibilities

  • Mette Juul NielsenEmail author
  • Morten A. Karsdal
  • Aleksander Krag
  • Diana Julie Leeming


Liver fibrosis is the common factor of liver diseases regardless of the underlying cause. Continuous accumulation of extracellular matrix (ECM) proteins will eventually lead to organ failure. The extracellular matrix is composed of fibrous and non-fibrous collagens, elastin, and proteoglycans. In advanced stages of fibrosis the balance of the ECM remodeling is disturbed resulting in alterations of the quality and constitution of ECM liver proteins. As a result, the extracellular matrix density maximizes and a superfluous build-up of fibrous tissue as well as a general change in the protein profile and liver structure occurs. In fact, compared with a healthy liver, a cirrhotic liver may comprise nearly six times as much collagen; where type I and III collagens are the most plentiful. Formation and disease relevant degradation products of extracellular and intracellular proteins released into the circulation are the result of the extracellular matrix remodeling. Serving as serological biomarker targets these fragments can hold valuable clues about the disease pathogenesis. Being able to identify early signs of liver fibrosis with the aim of stopping further progression is a clinical need. Unlike in histology, serological markers can potentially mirror both the activity of the fibrotic processes and the total extracellular matrix mass going through a modification. The most prevalent ECM remodeling markers such as hyaluronic acid, N-terminal procollagen type III, and type IV collagen will be discussed in the following chapter. A novel alternative: The Protein Fingerprint Technology will also be introduced. This technology has become widely recognized for its ability to identify and quantify disease-specific protein fragments in body liquids, demonstrating a sound potential as a serological biomarker of extracellular matrix remodeling in fatty liver diseases with fibrosis.


Extracellular matrix Remodeling Fibrosis Collagen Biomarkers Neo-epitope 



Alcoholic liver disease


Alanine aminotransferase


aspartate aminotransferase


Area under receiver operator characteristics curve


Burden of disease, Investigative, Prognostic, Efficacy of intervention, Diagnostic


Type III collagen degradation fragment


Extracellular matrix


Enhanced liver fibrosis


fibril-associated collagens


Food and drug administration


Hyaluronic acid


Hepatitis C Antiviral Long-term Treatment against Cirrhosis


Hepatitis B virus


Hepatitis C virus


Hepatic stellate cells


Matrix metalloproteinase


Non-alcoholic liver disease


Negative predictive value


N-terminal type III collagen propeptide


Positive predictive value


True type III collagen formation fragment


Post-translational modification


Tissue inhibitor of metalloproteinase


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mette Juul Nielsen
    • 1
    Email author
  • Morten A. Karsdal
    • 1
  • Aleksander Krag
    • 2
  • Diana Julie Leeming
    • 1
  1. 1.Nordic Bioscience, Biomarkers and ResearchHerlevDenmark
  2. 2.Department of Gastroenterology and HepatologyUniversity of Southern Denmark, Odense University HospitalOdenseDenmark

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