Evaluation of serological markers of extracellular matrix remodeling in primary sclerosing cholangitis

Background & aim:

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with progression to liver cirrhosis in the majority of patients. PSC shows a remarkably variable course making it challenging for clinicians to identify patients at risk for rapid disease progression. We aimed to evaluate the prognostic utility of three biomarkers of interstitial extracellular matrix (C3 M, PRO-C3) and fibril-associated collagen (PRO-C16) remodeling in patients with primary sclerosing cholangitis.

Methods:

Serum samples from 250 large-duct primary sclerosing cholangitis patients (of which 183 [72.3%] with IBD) recruited 2004 – 2016 and 20 healthy controls were analyzed. In 27 PSC patients a follow-up serum samples (mean 5.5 years, 3 – 10 years) were assessable. neo-epitope biomarkers of collagen type III formation and degradation (PRO-C3 and C3 M, respectively) and type XVI formation (PRO-C16) were assessed and compared with regard to laboratory and clinical parameters.

Results:

The final study cohort comprises 250 PSC patients. 183 (73.2%) patients had concomitant IBD and 69 (27.6%) patients presented dominant strictures at time of serum collection. Of the evaluated biomarkers PRO-C3 and PRO-C3/C3 M ratio were significantly elevated in PSC patients compared to healthy controls (24.6 ng/ml vs. 8.1 ng/ml, P < 0.0001). PRO-C3 and PRO-C3/C3 M were elevated in all PSC subtypes, independent of presence of concomitant IBD phenotypes (PRO-C3: control: 8.1 ng/ml; no IBD: 20.4 ng/ml; UC: 26.8 ng/ml; CD: 20.1 ng/ml, p < 0.01; PRO-C3/C3 M ratio control: 0.8; no IBD: 2.0; UC: 2.5; CD: 1.8, p < 0.05;). Only PRO-C16 could separate PSC patients with and without IBD, (p = 0.007) After a mean follow-up period of 5.5 years in a subgroup of 27 patients C3 M showed an significant increase during the course of disease, when compared to baseline (C3 M: baseline 10.4 ng/ml vs. FU 12.7 ng/ml, p = 0.04) In patients with presence of dominant strictures in the bile ducts at serum collection PRO-C3/C3 M ratio were significantly elevated (PRO-C3/C3 M: no DS 1.79 vs. DS 3.32; p = 0.003).

Conclusions:

Serum markers of extracellular matrix remodeling are elevated in primary sclerosing cholangitis patients compared to healthy controls. Collagen type III formation and turnover (PRO-C3, PRO-C/C3 M) is significantly elevated in PSC patients with dominant strictures, while PRO-C16 specifically related to the IBD phenotype of the patients irrespective of PSC status. These results indicate that specific ECM biomarkers might relate to different pathophysiological aspects of PSC-IBD, and assessement of serum markers of extracellular matrix remodeling might be a valuable tool for early identification of patients at risk for rapid disease progression.