Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jul 18, 2015; 7(14): 1875-1883
Published online Jul 18, 2015. doi: 10.4254/wjh.v7.i14.1875
Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma
Gary L Norman, Nikolaos K Gatselis, Zakera Shums, Christos Liaskos, Dimitrios P Bogdanos, George K Koukoulis, George N Dalekos
Gary L Norman, Zakera Shums, Inova Diagnostics, Inc., San Diego, CA 92131, United States
Nikolaos K Gatselis, Christos Liaskos, George N Dalekos, Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, 41110 Larissa, Thessaly, Greece
Dimitrios P Bogdanos, Division of Rheumatology, School of Medicine, University of Thessaly, 41110 Larissa, Thessaly, Greece
Dimitrios P Bogdanos, Division of Transplantation Immunology and Mucosal Biology, Institute of Liver Studies, King’s College London School of Medicine, Denmark Hill Campus, London SE5 9RJ, United Kingdom
George K Koukoulis, Department of Pathology, School of Medicine, University of Thessaly, 41110 Larissa, Thessaly, Greece
Author contributions: Norman GL, Gatselis NK, Bogdanos DP and Dalekos GN had the original idea, designed the study and wrote the first draft of the paper; Shums Z, Liaskos C and Gatselis NK performed the laboratory analysis, collect the data and did the statistical analysis; Koukoulis GK did the interpretation of the histological data of the patients and along with Dalekos GN and Norman GL made the final critical revision of the manuscript for important intellectual content; all authors have seen and approved the final draft of the paper.
Institutional review board statement: The study was reviewed and approved by the Ethical Committee Review Board of the School of Medicine of Thessaly University. All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Norman GL and Shums Z are employees of Inova Diagnostics Inc. They have a pending patent application US 2012/0183981 relevant to the present study. Inova Diagnostics Inc. provided funds to Norman GL and Shums Z (ELISA kits) for the support of this study. All other authors have no disclosures relevant to this manuscript. Other authors have declared that no competing interest exists.
Data sharing statement: No additional data are available (all relevant data are within the paper).
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: George N Dalekos, MD, PhD, Professor, Head, Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Biopolis, 41110 Larissa, Greece. dalekos@med.uth.gr
Telephone: +30-24-13502285 Fax: +30-24-13501557
Received: April 14, 2015
Peer-review started: April 24, 2015
First decision: May 13, 2015
Revised: May 29, 2015
Accepted: June 30, 2015
Article in press: July 2, 2015
Published online: July 18, 2015
Processing time: 101 Days and 18.4 Hours
Abstract

AIM: To assess serum cartilage oligomeric matrix protein (COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma (HCC).

METHODS: A COMP enzyme-linked immunosorbent assay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range (IQR)] duration of 96.5 (102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group.

RESULTS: COMP positivity (> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7% (14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age (P < 0.001), advanced fibrosis (P = 0.001) and necroinflammatory activity (P = 0.001), higher aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.02), γ-glutamyl transpeptidase (P = 0.003), alkaline phosphatase (P = 0.001), bilirubin (P < 0.05), international normalized ratio (P = 0.002) and alpha-fetoprotein levels (P < 0.02), and lower albumin (P < 0.001), and platelet count (P = 0.008). COMP levels [median (IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8 (7.9) U/L vs 9.8 (4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis (OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development (P = 0.007) and higher incidence of liver-related death (P < 0.001).

CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.

Keywords: Hepatic fibrosis; Hepatocellular carcinoma; Viral hepatitis; Enzyme-linked immunosorbent assay; Biomarker; Cirrhosis

Core tip: We report our first results regarding the utility of serum cartilage oligomeric matrix protein (COMP), an antigen over-expressed in developing liver, as a novel non-invasive marker of liver fibrosis and risk of progression to hepatocellular carcinoma (HCC). HCC is the third leading cause of cancer deaths worldwide, therefore non-invasive tests of fibrosis, as well as tests that can predict which patients are at high risk to develop HCC are needed. Our results suggest that COMP levels are associated with cirrhosis and a worse prognosis, thus serum COMP may assist clinicians as a non-invasive biomarker for risk assessment in surveillance programs.