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COMP serum levels: A new non-invasive biomarker of liver fibrosis in patients with chronic viral hepatitis

Published:January 15, 2017DOI:https://doi.org/10.1016/j.ejim.2017.01.007

      Highlights

      • Cartilage oligomeric matrix protein (COMP) is proposed as marker of liver fibrosis.
      • COMP levels are comparable with histology, transient elastography (TE), APRI, FIB-4.
      • COMP detects cirrhosis with the same accuracy as TE, APRI and FIB-4.
      • COMP measurements are not affected by inflammation and need no special equipment.
      • COMP is a sensitive, non-invasive, reproducible, low cost marker of liver fibrosis.

      Abstract

      Background & aims

      Recently we have shown that cartilage oligomeric matrix protein (COMP), a fibrillar collagen assembly regulator, is strongly associated with cirrhosis and hepatocellular carcinoma progression. Therefore, we assessed whether serum COMP levels can be used as a non-invasive fibrosis marker in patients with chronic viral hepatitis (CVH) and compared this marker with standard methods for disease stage assessment [histology, transient elastography (TE), APRI, FIB-4].

      Methods

      Sera from 116 CVH patients, 66 HBV [24 female; median age 53(22–76)] and 50 HCV [21 female; median age 48.5(25–69)] were investigated by COMP-ELISA. APRI and FIB-4 score was calculated in all along with TE. Liver biopsy was performed in 61. Patients were divided into two groups (F1/F2 and F3/F4) according to Metavir score.

      Results

      55/116 (47%) CVH patients were classified in F3/F4-group according to TE [14.3(9.3–75) kPa]. APRI score was >1.5 in 21/116 and FIB-4 > 3.25 in 20/116. Liver histology revealed 24/61 (39%) patients with significant fibrosis (stage 3–4), while 12/61 (19.7%) had cirrhosis. COMP levels correlated with TE measurements (r = 0.5; p < 0.001) and APRI score (r = 0.23; p < 0.02). The diagnostic accuracy of COMP in detecting cirrhosis was as good as TE, APRI and FIB-4 index (AUC 0.884) with sensitivity and specificity of 83.3% and 83.7% (cut-off 11.5 U/L).

      Conclusions

      COMP serum levels performed as well as TE, APRI and FIB4 score in detecting cirrhosis in CVH patients, suggesting COMP as a sensitive non-invasive, easy to perform biomarker of liver fibrosis. Further studies are needed in order to validate our findings in CVH patients.

      Abbreviations:

      ECM (extracellular matrix), CVH (chronic viral hepatitis), CHB (chronic hepatitis B), CHC (chronic hepatitis C), TE (transient elastography), LSM (liver stiffness measurement), COMP (cartilage oligomeric matrix protein), HCC (hepatocellular carcinoma), RA (rheumatoid arthritis), OA (osteoarthritis), SSc (systemic sclerosis), AST (aspartate aminotransferase), APRI (AST to Platelet Ratio Index), FIB-4 (Fibrosis-4 score), IQR (interquartile range), PLT (platelets), SD (standard deviation), MWU (Mann-Whitney U test), ANOVA (analysis of variance), ROC (receiver operating characteristic), AUC (area under the curve), aFP (alpha fetoprotein), ALP (alkaline phosphatase), ALT (alanine aminotransferase), PPV (positive predictive value), NPV (negative predictive value)

      Keywords

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      References

        • Henderson N.C.
        • Forbes S.J.
        Hepatic fibrogenesis: from within and outwith.
        Toxicology. 2008; 254: 130-135https://doi.org/10.1016/j.tox.2008.08.017
        • Lee Y.A.
        • Wallace M.C.
        • Friedman S.L.
        Pathobiology of liver fibrosis: a translational success story.
        Gut. 2015; 64: 830-841https://doi.org/10.1136/gutjnl-2014-306842
        • Friedman S.L.
        Mechanisms of hepatic fibrogenesis.
        Gastroenterology. 2008; 134: 1655-1669https://doi.org/10.1053/j.gastro.2008.03.003
        • Schuppan D.
        • Afdhal N.H.
        Liver cirrhosis.
        Lancet. 2008; 371: 838-851https://doi.org/10.1016/S0140-6736(08)60383-9
        • Rockey D.C.
        • Caldwell S.H.
        • Goodman Z.D.
        • Nelson R.C.
        • Smith A.D.
        Liver biopsy.
        Hepatology. 2009; 49: 1017-1044https://doi.org/10.1002/hep.22742
        • Bedossa P.
        • Carrat F.
        Liver biopsy: the best, not the gold standard.
        J Hepatol. 2009; 50: 1-3https://doi.org/10.1016/j.jhep.2008.10.014
        • Castera L.
        Noninvasive methods to assess liver disease in patients with hepatitis B or C.
        Gastroenterology. 2012; 142 (e4): 1293-1302
        • Branchi F.
        • Conti C.B.
        • Baccarin A.
        • Lampertico P.
        • Conte D.
        • Fraquelli M.
        Non-invasive assessment of liver fibrosis in chronic hepatitis B.
        World J Gastroenterol. 2014; 20: 14568-14580https://doi.org/10.3748/wjg.v20.i40.14568
        • Schiavon Lde L.
        • Narciso-Schiavon J.L.
        • de Carvalho-Filho R.J.
        Non-invasive diagnosis of liver fibrosis in chronic hepatitis C.
        World J Gastroenterol. 2014; 20: 2854-2866https://doi.org/10.3748/wjg.v20.i11.2854
        • Lampertico P.
        • Maini M.
        • Papatheodoridis G.
        Optimal management of hepatitis B virus infection – EASL Special Conference.
        J Hepatol. 2015; 63: 1238-1253https://doi.org/10.1016/j.jhep.2015.06.026
        • European Association for Study of Liver
        EASL recommendations on treatment of hepatitis C 2015.
        J Hepatol. 2015; 63: 199-236
        • Castera L.
        • Foucher J.
        • Bernard P.H.
        • et al.
        Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations.
        Hepatology. 2010; 51: 828-835https://doi.org/10.1002/hep.23425
        • Pinzani M.
        • Vizzutti F.
        • Arena U.
        • Marra F.
        Technology insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography.
        Nat Clin Pract Gastroenterol Hepatol. 2008; 5: 95-106https://doi.org/10.1038/ncpgasthep1025
        • Norman G.L.
        • Gatselis N.K.
        • Shums Z.
        • et al.
        Cartilage oligomeric matrix protein: a novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma.
        World J Hepatol. 2015; 7: 1875-1883https://doi.org/10.4254/wjh.v7.i14.1875
        • Oldberg A.
        • Antonsson P.
        • Lindblom K.
        • Heinegård D.
        COMP (cartilage oligomeric matrix protein) is structurally related to the thrombospondins.
        J Biol Chem. 1992; 267: 22346-22350
        • Hedbom E.
        • Antonsson P.
        • Hjerpe A.
        • Aeschlimann D.
        • Paulsson M.
        • Rosa-Pimentel E.
        • et al.
        Cartilage matrix proteins. An acidic oligomeric protein (COMP) detected only in cartilage.
        J Biol Chem. 1992; 267: 6132-6136
        • Halász K.
        • Kassner A.
        • Mörgelin M.
        • Heinegård D.
        COMP acts as a catalyst in collagen fibrillogenesis.
        J Biol Chem. 2007; 282: 31166-31173https://doi.org/10.1074/jbc.M705735200
        • Mann H.H.
        • Ozbek S.
        • Engel J.
        • Paulsson M.
        • Wagener R.
        Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias.
        J Biol Chem. 2004; 279: 25294-25298https://doi.org/10.1074/jbc.M403778200
        • Di Cesare P.
        • Hauser N.
        • Lehman D.
        • Pasumarti S.
        • Paulsson M.
        Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon.
        FEBS Lett. 1994; 354: 237-240
        • Xiao Y.
        • Kleeff J.
        • Guo J.
        • Gazdhar A.
        • Liao Q.
        • Di Cesare P.E.
        • et al.
        Cartilage oligomeric matrix protein expression in hepatocellular carcinoma and the cirrhotic liver.
        J Gastroenterol Hepatol. 2004; 19: 296-302
        • Kelman A.
        • Lui L.
        • Yao W.
        • Krumme A.
        • Nevitt M.
        • Lane N.E.
        Association of higher levels of serum cartilage oligomeric matrix protein and N-telopeptide crosslinks with the development of radiographic hip osteoarthritis in elderly women.
        Arthritis Rheum. 2006; 54: 236-243https://doi.org/10.1002/art.21527
        • Williams F.M.
        • Spector T.D.
        Biomarkers in osteoarthritis.
        Arthritis Res Ther. 2008; 10: 101https://doi.org/10.1186/ar2344
        • Skoumal M.
        • Haberhauer G.
        • Feyertag J.
        • Kittl E.M.
        • Bauer K.
        • Dunky A.
        Serum levels of cartilage oligomeric matrix protein (COMP): a rapid decrease in patients with active rheumatoid arthritis undergoing intravenous steroid treatment.
        Rheumatol Int. 2006; 26: 1001-1004https://doi.org/10.1007/s00296-006-0117-4
        • Morozzi G.
        • Fabbroni M.
        • Bellisai F.
        • Pucci G.
        • Galeazzi M.
        Cartilage oligomeric matrix protein level in rheumatic diseases: potential use as a marker for measuring articular cartilage damage and/or the therapeutic efficacy of treatments.
        Ann N Y Acad Sci. 2007; 1108: 398-407
        • Yamamoto M.
        • Takahashi H.
        • Suzuki C.
        • Naishiro Y.
        • Yamamoto H.
        • Imai K.
        • et al.
        Cartilage oligomeric matrix protein in systemic sclerosis.
        Rheumatology (Oxford). 2007; 46: 1858-1859https://doi.org/10.1093/rheumatology/kem254
        • Gardner H.
        • Shearstone J.R.
        • Bandaru R.
        • Crowell T.
        • Lynes M.
        • Trojanowska M.
        • et al.
        Gene profiling of scleroderma skin reveals robust signatures of disease that are imperfectly reflected in the transcript profiles of explanted fibroblasts.
        Arthritis Rheum. 2006; 54: 1961-1973https://doi.org/10.1002/art.21894
        • Hesselstrand R.
        • Andréasson K.
        • Wuttge D.M.
        • Bozovic G.
        • Scheja A.
        • Saxne T.
        Increased serum COMP predicts mortality in SSc: results from a longitudinal study of interstitial lung disease.
        Rheumatology (Oxford). 2012; 51: 915-920https://doi.org/10.1093/rheumatology/ker442
        • Liao Q.
        • Kleeff J.
        • Xiao Y.
        • Di Cesare P.E.
        • Korc M.
        • Zimmermann A.
        • et al.
        COMP is selectively up-regulated in degenerating acinar cells in chronic pancreatitis and in chronic-pancreatitis-like lesions in pancreatic cancer.
        Scand J Gastroenterol. 2003; 38: 207-215
        • Magdaleno F.
        • Arriazu E.
        • de Galarreta M.R.
        • Chen Y.
        • Ge X.
        • Conde de la Rosa L.
        • et al.
        Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis.
        J Hepatol. 2016; https://doi.org/10.1016/j.jhep.2016.06.003
        • Bedossa P.
        • Poynard T.
        • The French METAVIR Cooperative Study Group
        An algorithm for grading activity in chronic hepatitis C.
        Hepatology. 1996; 24: 289-293https://doi.org/10.1002/hep.510240201
        • Zachou K.
        • Gampeta S.
        • Gatselis N.K.
        • Oikonomou K.
        • Goulis J.
        • Manoussakis M.N.
        • et al.
        Anti-SLA/LP alone or in combination with anti-Ro52 and fine specificity of anti-Ro52 antibodies in patients with autoimmune hepatitis.
        Liver Int. 2015; 35: 660-672https://doi.org/10.1111/liv.12658
        • Gabeta S.
        • Norman G.L.
        • Gatselis N.
        • Liaskos C.
        • Papamichalis P.A.
        • Garagounis A.
        • et al.
        IgA anti-b2GPI antibodies in patients with autoimmune liver diseases.
        J Clin Immunol. 2008; 28: 501-511https://doi.org/10.1007/s10875-008-9211-6
        • Zachou K.
        • Oikonomou K.
        • Renaudineau Y.
        • Chauveau A.
        • Gatselis N.
        • Youinou P.
        • et al.
        Anti-α actinin antibodies as new predictors of response to treatment in autoimmune hepatitis type 1.
        Aliment Pharmacol Ther. 2012; 35: 116-125https://doi.org/10.1111/j.1365-2036.2011.04908.x
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
        J Hepatol. 2012; 57: 167-185https://doi.org/10.1016/j.jhep.2012.02.010
        • Boursier J.
        • Brochard C.
        • Bertrais S.
        • Michalak S.
        • Gallois Y.
        • Fouchard-Hubert I.
        • et al.
        Combination of blood tests for significant fibrosis and cirrhosis improves the assessment of liver-prognosis in chronic hepatitis C.
        Aliment Pharmacol Ther. 2014; 40: 178-188https://doi.org/10.1111/apt.12813
        • Tsochatzis E.A.
        • Crossan C.
        • Longworth L.
        • Gurusamy K.
        • Rodriguez-Peralvarez M.
        • Mantzoukis K.
        • et al.
        Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C.
        Hepatology. 2014; 60: 832-843https://doi.org/10.1002/hep.27296
        • Lurie Y.
        • Webb M.
        • Cytter-Kuint R.
        • Shteingart S.
        • Lederkremer G.Z.
        Non-invasive diagnosis of liver fibrosis and cirrhosis.
        World J Gastroenterol. 2015; 21: 11567-11583https://doi.org/10.3748/wjg.v21.i41.11567
        • Zarski J.P.
        • Sturm N.
        • Guechot J.
        • Paris A.
        • Zafrani E.S.
        • Asselah T.
        • et al.
        Comparison of nine blood tests and transient elastography for liver fibrosis in chronic hepatitis C: the ANRS HCEP-23 study.
        J Hepatol. 2012; 56: 55-62https://doi.org/10.1016/j.jhep.2011.05.024
        • Castera L.
        • Pinzani M.
        Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango?.
        Gut. 2010; 59: 861-866https://doi.org/10.1136/gut.2010.214650
        • Lin Z.H.
        • Xin Y.N.
        • Dong Q.J.
        • Wang Q.
        • Jiang X.J.
        • Zhan S.H.
        • et al.
        Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis.
        Hepatology. 2011; 53: 726-736https://doi.org/10.1002/hep.24105
        • Zhu X.
        • Wang L.C.
        • Chen E.Q.
        • Chen X.B.
        • Chen L.Y.
        • Liu L.
        • et al.
        Prospective evaluation of FibroScan for the diagnosis of hepatic fibrosis compared with liver biopsy/AST platelet ratio index and FIB-4 in patients with chronic HBV infection.
        Dig Dis Sci. 2011; 56: 2742-2749https://doi.org/10.1007/s10620-011-1659-1
        • Xiao G.
        • Yang J.
        • Yan L.
        Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis.
        Hepatology. 2015; 61: 292-302https://doi.org/10.1002/hep.27382
        • Cales P.
        • Veillon P.
        • Konate A.
        • Mathieu E.
        • Ternisien C.
        • Chevailler A.
        • et al.
        Reproducibility of blood tests of liver fibrosis in clinical practice.
        Clin Biochem. 2008; 41: 10-18
        • Andréasson K.
        • Hesselstrand R.
        • Saxne T.
        • Holmberg A.
        • Norrgren H.
        • Jönsson G.
        Cartilage oligomeric matrix protein: a new promising biomarker of liver fibrosis in chronic hepatitis C.
        Infect Dis. 2015; 47: 915-918
        • Vallet-Pichard A.
        • Mallet V.
        • Nalpas B.
        • Verkarre V.
        • Nalpas A.
        • Dhalluin-Venier V.
        • et al.
        FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and Fibrotest.
        Hepatology. 2007; 46: 32-36
        • Wai C.T.
        • Greenson J.K.
        • Fontana R.J.
        • et al.
        A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.
        Hepatology. 2003; 38: 518-526https://doi.org/10.1053/jhep.2003.50346