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

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The Human Gut-Liver-Axis in Health and Disease

Abstract

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.

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Abbreviations

ALD:

Alcoholic liver disease

ALT:

Alanine aminotransferase

AST:

aspartate aminotransferase

AUC:

Area under receiver operator characteristics curve

BIPED:

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

C3M:

Type III collagen degradation fragment

ECM:

Extracellular matrix

ELF:

Enhanced liver fibrosis

FACIT:

fibril-associated collagens

FDA:

Food and drug administration

HA:

Hyaluronic acid

HALT-C:

Hepatitis C Antiviral Long-term Treatment against Cirrhosis

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HSC:

Hepatic stellate cells

MMP:

Matrix metalloproteinase

NAFLD:

Non-alcoholic liver disease

NPV:

Negative predictive value

PIIINP:

N-terminal type III collagen propeptide

PPV:

Positive predictive value

Pro-C3:

True type III collagen formation fragment

PTM:

Post-translational modification

TIMP:

Tissue inhibitor of metalloproteinase

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Authors and Affiliations

  1. Nordic Bioscience, Biomarkers and Research, Herlev, Denmark

    Mette Juul Nielsen, Morten A. Karsdal & Diana Julie Leeming

  2. Department of Gastroenterology and Hepatology, University of Southern Denmark, Odense University Hospital, Odense, Denmark

    Aleksander Krag

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  1. Mette Juul Nielsen
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Correspondence to Mette Juul Nielsen .

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  1. Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark

    Aleksander Krag

  2. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark

    Torben Hansen

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Nielsen, M.J., Karsdal, M.A., Krag, A., Leeming, D.J. (2019). Extracellular Matrix Remodeling with Focus on Biochemical Markers in Liver Fibrosis: Limitations and Possibilities. In: Krag, A., Hansen, T. (eds) The Human Gut-Liver-Axis in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-98890-0_15

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