Soluble inflammatory markers as predictors of liver histological changes in patients with chronic hepatitis C virus infection

  • A. S. Moura
  • R. A. Carmo
  • A. L. Teixeira
  • V. H. R. Leite
  • M. O. C. Rocha


Host immune response seems to be mainly responsible for the progression of liver disease among patients with hepatitis C virus (HCV) infection. Immune activation involves the release of cytokines and their receptors that can be measured in plasma samples. The study aimed to evaluate the association between plasma levels of chemokines and soluble tumor necrosis factor receptors (sTNFR) and liver histological changes among patients with chronic HCV infection. Seventy-one treatment-naive patients were included. Plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL9, CXCL10, sTNFR1, and sTNFR2 were measured and liver histological findings were reviewed. Plasma levels of CXCL9, sTNFR1, and sTNFR2 were significantly associated with liver fibrosis, with higher median levels found among patients with moderate/severe fibrosis (F ≥ 2) if compared to those with no or mild fibrosis (p = 0.014; p = 0.012; p = 0.009, respectively). Plasma sTNFR2 levels were significantly associated with necroinflammatory activity, with higher median levels among patients with moderate/severe activity (A ≥ 2) if compared to those with no or mild activity (2.34 ng/mL vs. 1.99 ng/mL; p = 0.019). In conclusion, plasma levels of CXCL9, sTNFR1, and sTNFR2 were independently associated with liver histological changes, suggesting a role of TNF activation and Th1-type cell-mediated immune response in the pathogenesis of HCV infection.


  1. 1.
    Brown RS Jr, Gaglio PJ (2003) Scope of worldwide hepatitis C problem. Liver Transpl 9:S10–S13CrossRefPubMedGoogle Scholar
  2. 2.
    Lauer GM, Walker BD (2001) Hepatitis C virus infection. N Engl J Med 345:41–52CrossRefPubMedGoogle Scholar
  3. 3.
    Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, Vidaud M, Bricaire F, Opolon P, Katlama C, Poynard T (1999) Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 30:1054–1058CrossRefPubMedGoogle Scholar
  4. 4.
    Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J (2003) Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology 125:1695–1704CrossRefPubMedGoogle Scholar
  5. 5.
    Poynard T, Bedossa P, Opolon P (1997) Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 349:825–832CrossRefPubMedGoogle Scholar
  6. 6.
    Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J (2001) Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol 34:730–739CrossRefPubMedGoogle Scholar
  7. 7.
    Friedman SL (1999) Cytokines and fibrogenesis. Semin Liver Dis 19:129–140CrossRefPubMedGoogle Scholar
  8. 8.
    Friedman SL (2003) Liver fibrosis—from bench to bedside. J Hepatol 38(Suppl 1):S38–S53CrossRefPubMedGoogle Scholar
  9. 9.
    Napoli J, Bishop GA, McGuinness PH, Painter DM, McCaughan GW (1996) Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology 24:759–765CrossRefPubMedGoogle Scholar
  10. 10.
    Ghany MG, Kleiner DE, Alter H, Doo E, Khokar F, Promrat K, Herion D, Park Y, Liang TJ, Hoofnagle JH (2003) Progression of fibrosis in chronic hepatitis C. Gastroenterology 124:97–104CrossRefPubMedGoogle Scholar
  11. 11.
    Chang KM, Rehermann B, Chisari FV (1997) Immunopathology of hepatitis C. Springer Semin Immunopathol 19:57–68CrossRefPubMedGoogle Scholar
  12. 12.
    Neuman MG, Benhamou JP, Malkiewicz IM, Ibrahim A, Valla DC, Martinot-Peignoux M, Asselah T, Bourliere M, Katz GG, Shear NH, Marcellin P (2002) Kinetics of serum cytokines reflect changes in the severity of chronic hepatitis C presenting minimal fibrosis. J Viral Hepat 9:134–140CrossRefPubMedGoogle Scholar
  13. 13.
    Neuman MG, Benhamou JP, Bourliere M, Ibrahim A, Malkiewicz I, Asselah T, Martinot-Peignoux M, Shear NH, Katz GG, Akremi R, Benali S, Boyer N, Lecomte L, Le Breton V, Le Guludec G, Marcellin P (2002) Serum tumour necrosis factor-alpha and transforming growth factor-beta levels in chronic hepatitis C patients are immunomodulated by therapy. Cytokine 17:108–117CrossRefPubMedGoogle Scholar
  14. 14.
    Yoshioka K, Kakumu S, Arao M, Tsutsumi Y, Inoue M (1989) Tumor necrosis factor alpha production by peripheral blood mononuclear cells of patients with chronic liver disease. Hepatology 10:769–773CrossRefPubMedGoogle Scholar
  15. 15.
    Neuman MG, Benhamou JP, Marcellin P, Valla D, Malkiewicz IM, Katz GG, Trepo C, Bourliere M, Cameron RG, Cohen L, Morgan M, Schmilovitz-Weiss H, Ben-Ari Z (2007) Cytokine–chemokine and apoptotic signatures in patients with hepatitis C. Transl Res 149:126–136CrossRefPubMedGoogle Scholar
  16. 16.
    Zylberberg H, Rimaniol AC, Pol S, Masson A, De Groote D, Berthelot P, Bach JF, Bréchot C, Zavala F (1999) Soluble tumor necrosis factor receptors in chronic hepatitis C: a correlation with histological fibrosis and activity. J Hepatol 30:185–191CrossRefPubMedGoogle Scholar
  17. 17.
    Brockhaus M, Schoenfeld HJ, Schlaeger EJ, Hunziker W, Lesslauer W, Loetscher H (1990) Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A 87:3127–3131CrossRefPubMedGoogle Scholar
  18. 18.
    Hohmann HP, Remy R, Brockhaus M, van Loon AP (1989) Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha). J Biol Chem 264:14927–14934PubMedGoogle Scholar
  19. 19.
    Porteu F, Brockhaus M, Wallach D, Engelmann H, Nathan CF (1991) Human neutrophil elastase releases a ligand-binding fragment from the 75-kDa tumor necrosis factor (TNF) receptor. Comparison with the proteolytic activity responsible for shedding of TNF receptors from stimulated neutrophils. J Biol Chem 266:18846–18853PubMedGoogle Scholar
  20. 20.
    Lien E, Liabakk NB, Johnsen AC, Nonstad U, Sundan A, Espevik T (1995) Polymorphonuclear granulocytes enhance lipopolysaccharide-induced soluble p75 tumor necrosis factor receptor release from mononuclear cells. Eur J Immunol 25:2714–2717CrossRefPubMedGoogle Scholar
  21. 21.
    Joyce DA, Gibbons DP, Green P, Steer JH, Feldmann M, Brennan FM (1994) Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes. Eur J Immunol 24:2699–2705CrossRefPubMedGoogle Scholar
  22. 22.
    Lantz M, Malik S, Slevin ML, Olsson I (1990) Infusion of tumor necrosis factor (TNF) causes an increase in circulating TNF-binding protein in humans. Cytokine 2:402–406CrossRefPubMedGoogle Scholar
  23. 23.
    Tilg H, Vogel W, Dinarello CA (1995) Interferon-alpha induces circulating tumor necrosis factor receptor p55 in humans. Blood 85:433–435PubMedGoogle Scholar
  24. 24.
    Fabris C, Del Forno M, Falleti E, Toniutto P, Pirisi M (1999) Kinetics of serum soluble tumour necrosis factor receptor (TNF-R) type-I and type-II after a single interferon-alpha (IFN-alpha) injection in chronic hepatitis C. Clin Exp Immunol 117:556–560CrossRefPubMedGoogle Scholar
  25. 25.
    Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry SF (1992) Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl Acad Sci U S A 89:4845–4849CrossRefPubMedGoogle Scholar
  26. 26.
    Luster AD (1998) Chemokines–chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–445CrossRefPubMedGoogle Scholar
  27. 27.
    Baggiolini M, Dewald B, Moser B (1997) Human chemokines: an update. Annu Rev Immunol 15:675–705CrossRefPubMedGoogle Scholar
  28. 28.
    Mackay CR (1997) Chemokines: what chemokine is that? Curr Biol 7:R384–R386CrossRefPubMedGoogle Scholar
  29. 29.
    Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115CrossRefPubMedGoogle Scholar
  30. 30.
    Kunkel SL (1999) Through the looking glass: the diverse in vivo activities of chemokines. J Clin Invest 104:1333–1334CrossRefPubMedGoogle Scholar
  31. 31.
    Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354:610–621CrossRefPubMedGoogle Scholar
  32. 32.
    Ono SJ, Nakamura T, Miyazaki D, Ohbayashi M, Dawson M, Toda M (2003) Chemokines: roles in leukocyte development, trafficking, and effector function. J Allergy Clin Immunol 111:1185–1199CrossRefPubMedGoogle Scholar
  33. 33.
    Larrubia JR, Benito-Martínez S, Calvino M, Sanz-de-Villalobos E, Parra-Cid T (2008) Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. World J Gastroenterol 14:7149–7159CrossRefPubMedGoogle Scholar
  34. 34.
    Moura AS, Carmo RA, Teixeira AL, Rocha MOC (2009) Soluble inflammatory markers as predictors of hepatocellular damage and therapeutic response in chronic hepatitis C. Braz J Infect Dis 13:375–382CrossRefPubMedGoogle Scholar
  35. 35.
    Bonecchi R, Bianchi G, Bordignon PP, D’Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187:129–134CrossRefPubMedGoogle Scholar
  36. 36.
    Koziel MJ (1999) Cytokines in viral hepatitis. Semin Liver Dis 19:157–169CrossRefPubMedGoogle Scholar
  37. 37.
    Apolinario Fernández de Sousa A, García Monzón C (2003) Role of chemokines in the pathogenesis of liver diseases. Rev Esp Enferm Dig 95:614–620PubMedGoogle Scholar
  38. 38.
    Rehm J (1998) Measuring quantity, frequency, and volume of drinking. Alcohol Clin Exp Res 22:4S–14SCrossRefPubMedGoogle Scholar
  39. 39.
    Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 24:289–293CrossRefPubMedGoogle Scholar
  40. 40.
    Brunt EM (2004) Nonalcoholic steatohepatitis. Semin Liver Dis 24:3–20PubMedGoogle Scholar
  41. 41.
    Brunt EM (2001) Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 21:3–16CrossRefPubMedGoogle Scholar
  42. 42.
    Sousa-Pereira SR, Teixeira AL, Silva LC, Souza AL, Antunes CM, Teixeira MM, Lambertucci JR (2006) Serum and cerebral spinal fluid levels of chemokines and Th2 cytokines in Schistosoma mansoni myeloradiculopathy. Parasite Immunol 28:473–478CrossRefPubMedGoogle Scholar
  43. 43.
    Porteu F, Hieblot C (1994) Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils. J Biol Chem 269:2834–2840PubMedGoogle Scholar
  44. 44.
    Itoh Y, Okanoue T, Ohnishi N, Sakamoto M, Nishioji K, Nakagawa Y, Minami M, Murakami Y, Kashima K (1999) Serum levels of soluble tumor necrosis factor receptors and effects of interferon therapy in patients with chronic hepatitis C virus infection. Am J Gastroenterol 94:1332–1340CrossRefPubMedGoogle Scholar
  45. 45.
    Kakumu S, Okumura A, Ishikawa T, Yano M, Enomoto A, Nishimura H, Yoshioka K, Yoshika Y (1997) Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease. Clin Exp Immunol 109:458–463CrossRefPubMedGoogle Scholar
  46. 46.
    Kallinowski B, Haseroth K, Marinos G, Hanck C, Stremmel W, Theilmann L, Singer MV, Rossol S (1998) Induction of tumour necrosis factor (TNF) receptor type p55 and p75 in patients with chronic hepatitis C virus (HCV) infection. Clin Exp Immunol 111:269–277CrossRefPubMedGoogle Scholar
  47. 47.
    Spinas GA, Keller U, Brockhaus M (1992) Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest 90:533–536CrossRefPubMedGoogle Scholar
  48. 48.
    Diez-Ruiz A, Tilz GP, Zangerle R, Baier-Bitterlich G, Wachter H, Fuchs D (1995) Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis. Eur J Haematol 54:1–8CrossRefPubMedGoogle Scholar
  49. 49.
    Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, Lau JY (1997) The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C. J Immunol 158:1473–1481PubMedGoogle Scholar
  50. 50.
    Kountouras J, Zavos C, Chatzopoulos D (2003) Apoptosis in hepatitis C. J Viral Hepat 10:335–342CrossRefPubMedGoogle Scholar
  51. 51.
    Kaplanski G, Farnarier C, Payan MJ, Bongrand P, Durand JM (1997) Increased levels of soluble adhesion molecules in the serum of patients with hepatitis C. Correlation with cytokine concentrations and liver inflammation and fibrosis. Dig Dis Sci 42:2277–2284CrossRefPubMedGoogle Scholar
  52. 52.
    Zeremski M, Petrovic LM, Chiriboga L, Brown QB, Yee HT, Kinkhabwala M, Jacobson IM, Dimova R, Markatou M, Talal AH (2008) Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. Hepatology 48:1440–1450CrossRefPubMedGoogle Scholar
  53. 53.
    Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH (1999) Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 163:6236–6243PubMedGoogle Scholar
  54. 54.
    Apolinario A, Majano PL, Alvarez-Pérez E, Saez A, Lozano C, Vargas J, García-Monzón C (2002) Increased expression of T cell chemokines and their receptors in chronic hepatitis C: relationship with the histological activity of liver disease. Am J Gastroenterol 97:2861–2870CrossRefPubMedGoogle Scholar
  55. 55.
    Wasmuth HE, Lammert F, Zaldivar MM, Weiskirchen R, Hellerbrand C, Scholten D, Berres ML, Zimmermann H, Streetz KL, Tacke F, Hillebrandt S, Schmitz P, Keppeler H, Berg T, Dahl E, Gassler N, Friedman SL, Trautwein C (2009) Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology 137:309–319CrossRefPubMedGoogle Scholar
  56. 56.
    Butera D, Marukian S, Iwamaye AE, Hembrador E, Chambers TJ, Di Bisceglie AM, Charles ED, Talal AH, Jacobson IM, Rice CM, Dustin LB (2005) Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. Blood 106:1175–1182CrossRefPubMedGoogle Scholar
  57. 57.
    Apolinario A, Diago M, Lo Iacono O, Lorente R, Pérez C, Majano PL, Clemente G, García-Monzón C (2004) Increased circulating and intrahepatic T-cell-specific chemokines in chronic hepatitis C: relationship with the type of virological response to peginterferon plus ribavirin combination therapy. Aliment Pharmacol Ther 19:551–562CrossRefPubMedGoogle Scholar
  58. 58.
    Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR (1998) The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. J Clin Invest 101:746–754CrossRefPubMedGoogle Scholar
  59. 59.
    Park MK, Amichay D, Love P, Wick E, Liao F, Grinberg A, Rabin RL, Zhang HH, Gebeyehu S, Wright TM, Iwasaki A, Weng Y, DeMartino JA, Elkins KL, Farber JM (2002) The CXC chemokine murine monokine induced by IFN-gamma (CXC chemokine ligand 9) is made by APCs, targets lymphocytes including activated B cells, and supports antibody responses to a bacterial pathogen in vivo. J Immunol 169:1433–1443PubMedGoogle Scholar
  60. 60.
    Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B (1996) Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 184:963–969CrossRefPubMedGoogle Scholar
  61. 61.
    Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM (1995) Human Mig chemokine: biochemical and functional characterization. J Exp Med 182:1301–1314CrossRefPubMedGoogle Scholar
  62. 62.
    Clark-Lewis I, Mattioli I, Gong JH, Loetscher P (2003) Structure–function relationship between the human chemokine receptor CXCR3 and its ligands. J Biol Chem 278:289–295CrossRefPubMedGoogle Scholar
  63. 63.
    Boccato S, Pistis R, Noventa F, Guido M, Benvegnù L, Alberti A (2006) Fibrosis progression in initially mild chronic hepatitis C. J Viral Hepat 13:297–302CrossRefPubMedGoogle Scholar
  64. 64.
    Fontaine H, Nalpas B, Poulet B, Carnot F, Zylberberg H, Brechot C, Pol S (2001) Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C. Hum Pathol 32:904–909CrossRefPubMedGoogle Scholar
  65. 65.
    Iredale JP (2003) Regulating hepatic inflammation: pathogen-associated molecular patterns take their toll. Hepatology 37:979–982CrossRefPubMedGoogle Scholar
  66. 66.
    Harvey CE, Post JJ, Palladinetti P, Freeman AJ, Ffrench RA, Kumar RK, Marinos G, Lloyd AR (2003) Expression of the chemokine IP-10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation. J Leukoc Biol 74:360–369CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • A. S. Moura
    • 1
    • 4
  • R. A. Carmo
    • 2
  • A. L. Teixeira
    • 1
  • V. H. R. Leite
    • 3
  • M. O. C. Rocha
    • 1
  1. 1.Postgraduate Program on Infectious Diseases and Tropical Medicine, Medical SchoolFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Orestes Diniz Referral Center for Infectious Diseases—Belo Horizonte City Health DepartmentBelo HorizonteBrazil
  3. 3.Anatomic Pathology Department, Medical SchoolFederal University of Minas GeraisBelo HorizonteBrazil
  4. 4.Belo HorizonteBrazil

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