Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma

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

Figure 1

Cartilage oligomeric matrix protein antigen values in the non-cirrhotic and cirrhotic patients in total and according to the etiology of liver disease. Cartilage oligomeric matrix protein (COMP) antigen titers were significantly higher compared to non-cirrhotic patients irrespectively of the etiology of liver disease. Bars indicate median values with interquartile range. CHB: Chronic hepatitis B; CHC: Chronic hepatitis C; AIH: Autoimmune hepatitis; PBC: Primary biliary cirrhosis; ALD: Alcoholic liver disease.

Figure 2

The follow-up schedule diagram of the 187 patients enrolled in the study. HCC: Hepatocellular carcinoma.

Figure 3

Kaplan-Meier analysis of patients according to cartilage oligomeric matrix protein antigen values (cartilage oligomeric matrix protein-positive vs cartilage oligomeric matrix protein-negative). Only, three patients, that were cartilage oligomeric matrix protein (COMP)-negative, developed cirrhosis during follow-up (A). A trend for more rapid development of decompensation in COMP-positive patients was noticed (B). The rates of HCC development (C) and liver-related mortality (D) are significantly higher in COMP-positive group compared to COMP-negative group by log-rank test. HCC: Hepatocellular carcinoma.