Serum markers of type III and IV procollagen processing predict recurrence of fibrosis in liver transplanted patients

Mette Juul Nielsen,Diana Julie Leeming,Aleksander Krag,Tim Zimmermann,Ida Falk Villesen,Morten Asser Karsdal,Natasja Stæhr Gudmann,Detlef Schuppan

doi:10.1038/s41598-019-51394-4

Abstract

Following liver transplantation (LT), 10–30% of patients develop recurrent cirrhosis (RC). There is an urgent need for predictive non-invasive markers for improved monitoring of these patients. Here we studied extracellular matrix biomarkers as predictors of RC after LT. Forty-seven LT patients were divided into groups of fast, intermediate or non-progressors towards RC (<1 year, 3–5 years or no advanced fibrosis >5 years after LT), assessed by follow-up liver biopsies. Markers of interstitial matrix type III and V collagen formation (PRO-C3 and PRO-C5), basement membrane type IV collagen formation (PRO-C4) and degradation (C4M) were assessed in serum samples collected 3, 6 and 12 months post-LT using specific ELISAs. PRO-C3, PRO-C4, and C4M were elevated in fast progressors compared to non-progressors 3 months after LT. C4M and PRO-C4 additionally differentiated between intermediate and fast progressors at 3 months. PRO-C3 was best predictor of survival, with LT patients in the highest PRO-C3 tertile having significantly shorter survival time. This shows that interstitial matrix and basement membrane remodeling in RC may be distinguishable. Markers originating from different sites in the extracellular matrix could be valuable tools for a more dynamic monitoring of patients at risk of RC. However, this needs validation in larger cohorts.

Highlights

Following liver transplantation (LT), 10–30% of patients develop recurrent cirrhosis (RC)
Other liver diseases recur after transplantation with incidence rates ranging from 10% to 50% including alcoholic liver disease (ALD)[3], primary sclerosing cholangitis (PSC)[4], primary biliary cholangitis (PBC)[4], autoimmune hepatitis (AIH)[4] and non-alcoholic steatohepatitis (NASH)[5]
Rapid recurrent cirrhosis after LT occurs in subjects with viral and non-viral etiologies of end-stage liver disease[1,3,4,5]

Summary

Introduction

Following liver transplantation (LT), 10–30% of patients develop recurrent cirrhosis (RC). PRO-C3 was best predictor of survival, with LT patients in the highest PRO-C3 tertile having significantly shorter survival time This shows that interstitial matrix and basement membrane remodeling in RC may be distinguishable. Markers originating from different sites in the extracellular matrix could be valuable tools for a more dynamic monitoring of patients at risk of RC. The (pro-)collagen fragments are released from the tissue into the circulation, where they can be identified by neo-epitope specific ELISAs to permit evaluation of the ECM remodeling during liver fibrosis, and potentially serve as prognostic biomarkers for. Measurements of these neo-epitopes have previously proved to be more sensitive and accurate than routinely used diagnostic and prognostic tools[11,12,13]

Methods

Results

Conclusion