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Biomarkers of Extracellular Matrix Remodeling in Liver Diseases

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Biomarkers in Liver Disease

Abstract

The common denominator, regardless of the underlying etiology, of chronic liver diseases is liver fibrosis. The hallmark of fibrosis is the accelerated accumulation of extracellular matrix proteins, ultimately leading to loss of organ function. The extracellular matrix consists of fibrous and nonfibrous macromolecules such as collagens, elastin, and proteoglycans.

During progressive fibrosis the balance of extracellular matrix remodeling is altered and leads to changes in quality, quantity, and distribution of extracellular matrix proteins in the liver. This results in excessive accumulation of fibrous tissue and an overall change in protein profile and liver structure and increase in extracellular matrix density. A cirrhotic liver may contain up to six times as much collagen as a healthy liver with type I and III collagen as the most abundant ones. The imbalanced extracellular matrix remodeling leads to a range of formation and disease-relevant degradation products of extracellular and intracellular proteins into the circulation. These fragments may provide information about the pathogenesis of disease and serve as serological biomarker targets. Clinically there is a need to identify early stages of liver fibrosis and particularly to detect patients with fast progressing fibrosis to prevent further progression.

In contrast to liver biopsy, serological markers are believed to reflect both the activity of the fibrotic processes as well as the total extracellular matrix mass undergoing remodeling. This chapter discusses the most common extracellular matrix remodeling markers such as hyaluronic acid, N-terminal procollagen type III, and type IV collagen as well as a novel alternative, called the protein fingerprint technology. This technology has received increased attention due to the diagnostic and prognostic potentials as serological biomarkers of extracellular matrix remodeling in various diseases, including chronic liver diseases.

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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:

Nonalcoholic 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:

Posttranslational modification

TIMP:

Tissue inhibitor of metalloproteinase

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Authors and Affiliations

  1. Nordic Bioscience, Biomarkers and Research, Herlev Hovedgade 205–207, DK-2730, Herlev, Denmark

    Mette J. Nielsen, Diana J. Leeming & Morten A. Karsdal

  2. Department of Gastroenterology and Hepatology, University of Southern Denmark, Odense University Hospital, Sdr. Boulevard 29, DK-5000, Odense C, Denmark

    Aleksander Krag

Authors
  1. Mette J. Nielsen
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  2. Diana J. Leeming
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  3. Morten A. Karsdal
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  4. Aleksander Krag
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Correspondence to Mette J. Nielsen , Diana J. Leeming or Morten A. Karsdal .

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Editors and Affiliations

  1. Department of Biomedical Science, Faculty of Science and Technology, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

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Nielsen, M.J., Leeming, D.J., Karsdal, M.A., Krag, A. (2017). Biomarkers of Extracellular Matrix Remodeling in Liver Diseases. In: Patel, V., Preedy, V. (eds) Biomarkers in Liver Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7675-3_14

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