Advances in the clinical use of collagen as biomarker of liver fibrosis

ABSTRACT

Introduction

Hepatic fibrosis is the excessive synthesis and deposition of extracellular matrix including collagen in the tissue. Chronic liver insult leads to progressive parenchymal damage, portal hypertension, and cirrhosis. Determination of hepatic collagen by invasive liver biopsy is the gold standard to estimate severity and stage of fibrosis. However, this procedure is associated with pain, carries the risk of infection and bleeding, and is afflicted with a high degree of sampling error. Therefore, there is urgent need for serological collagen-derived markers to assess collagen synthesis/turnover.

Areas covered

Biochemical properties of collagens, cellular sources of hepatic collagen synthesis, and regulatory aspects in collagen expression. Markers are discussed suitable to estimate hepatic collagen synthesis and/or turnover. Discussed studies were identified through a PubMed search done in May 2020 and the authors’ topic knowledge.

Expert opinion

Hepatic fibrosis is mainly characterized by accumulation of collagen-rich scar tissue. Although traditionally performed liver biopsy is still standard in estimating hepatic fibrosis, there is evidence that noninvasive diagnostic scores and collagen-derived neo-epitopes provide clinical useful information. These noninvasive tests are less expensive than liver biopsy, better tolerated, safer, and more acceptable to patients. Therefore, these tests will lead to dramatic changes in diagnosis.

KEYWORDS:

• Hepatic stellate cells
• portal myofibroblasts
• TGF-β1
• Kupffer cells
• biomarker
• immunostain
• fibrogenesis
• extracellular matrix
• neo-epitope
• ELF score

Article highlights

• The estimation of hepatic collagen content is of fundamental importance to determine extent of fibrosis

• Although liver biopsy remains the gold standard for evaluation of hepatic fibrosis, non-invasive imaging and measurement of serum parameters will lead to fundamental changes in diagnosis

• Collagen fragments and neo-epitopes are useful to assess ECM synthesis and/or turnover

• Non-invasive tests are safer and more acceptable to the patients than liver biopsy

• There are several cellular sources for hepatic collagen in the liver

Abbreviations

aHSC:	=	activated hepatic stellate cell(s)
aKC:	=	activated Kupffer cell(s)
ALT:	=	alanine aminotransferase
AST:	=	aspartate aminotransferase
BDL:	=	bile duct ligation
CCl4:	=	carbon tetrachloride
CMP:	=	collagen mimetic peptide(s)
COMP:	=	Cartilage oligomeric protein
DAMP:	=	damage-associated molecular pattern
ECM:	=	extracellular matrix
ELF:	=	Enhanced Liver Fibrosis test
EMT:	=	epithelial-to-mesenchymal transition
HA:	=	hyaluronic acid
HSC:	=	hepatic stellate cell(s)
HCC:	=	hepatocellular carcinoma
HCV:	=	hepatic C virus
KC:	=	Kupffer cell(s)
LSEC:	=	liver sinusoidal endothelial cells
MFB:	=	myofibroblast(s)
MMP:	=	metalloproteinase(s)
MRE:	=	magnetic resonance elastography
MRI:	=	magnetic resonance imaging
NAFLD:	=	non-alcoholic fatty liver disease
NASH:	=	non-alcoholic steatohepatitis
PBC:	=	primary biliary cirrhosis
PC:	=	hepatocyte(s)
pF:	=	portal fibroblast(s)
pMF:	=	portal myofibroblast(s)
PIIINP:	=	propeptide of type III procollagen
PSC:	=	primary sclerosing cholangitis
TCA:	=	taurocholic acid
TGF-β:	=	transforming growth factor-β
TIMP-1:	=	tissue inhibitor of metalloproteinase-1
TLR:	=	toll-like receptor
US:	=	ultrasound
USE:	=	ultrasound elastrography

Declaration of interest

M Karsdal is the CEO of Nordic Bioscience, a company developing serological biochemical markers. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the German Research Foundation (SFB/TRR57, projects P13 and Q3) and the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF Aachen, O3‐1).