Current Treatment Options in Gastroenterology

, Volume 9, Issue 6, pp 497–507 | Cite as

Treatment of hepatitis C cryoglobulinemia: Mission and challenges

  • Zeid Kayali
  • Douglas R. LaBrecque
  • Warren N. Schmidt

Opinion statement

Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-a and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Miescher PA, Huang YP, Izui S: Type-II cryoglobulinemia. Semin Hematol 1995, 32:80–85.PubMedGoogle Scholar
  2. 2.
    Weintrobe MM, Buell MV: Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 1933, 52:156.Google Scholar
  3. 3.
    Lerner AB, Watson CJ. Studies of cryoglobulins. Unusual purpura associated with the presence of high concentrations of cold precipitable serum globulin. Am J Med Sci 1947, 214:410–415.CrossRefPubMedGoogle Scholar
  4. 4.
    Meltzer M, Franklin EC, Elias K, et al.: Cryoglobulinemia- a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 1966, 40:837–856.PubMedCrossRefGoogle Scholar
  5. 5.
    Durand JM, Lefevre P, Harle JR, et al.: Cutaneous vasculitis and cryoglobulinaemia type II associated with hepatitis C virus infection. Lancet 1991, 337:499–500.PubMedCrossRefGoogle Scholar
  6. 6.
    Choo QL, Kuo G, Weiner AJ, et al.: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989, 244:359–362.PubMedCrossRefGoogle Scholar
  7. 7.
    Cacoub P, Fabiani FL, Musset L, et al.: Mixed cryoglobulinemia and hepatitis C virus. Am J Med 1994, 96:124–132.PubMedCrossRefGoogle Scholar
  8. 8.
    Monti G, Galli M, Invernizzi F, et al.: Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias. QJM 1995, 88:115–126.PubMedGoogle Scholar
  9. 9.
    Kayali Z, Buckwold VE, Zimmerman B, et al.: Hepatitis C, cryoglobulinemia, and cirrhosis: A meta-analysis. Hepatology 2002, 36:978–985. A comprehensive meta-analysis of published studies establishing the relationship between HCV, MC, and cirrhosis.PubMedGoogle Scholar
  10. 10.
    Lunel F, Musset L, Cacoub P, et al.: Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology 1994, 106:1291–1300.PubMedGoogle Scholar
  11. 11.
    Sene D, Limal N, Cacoub P: Hepatitis C virus-associated extrahepatic manifestations: a review. Metab Brain Dis 2004, 19:357–381. An in-depth discussion of HCV extrahepatic complications and the contribution of CGs. This is one of the best reviews of extrahepatic diseases due to HCV currently available.PubMedCrossRefGoogle Scholar
  12. 12.
    Brouet JC, Clauvel JP, Danon F, et al.: Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 1974, 57:775–788.PubMedCrossRefGoogle Scholar
  13. 13.
    Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992, 327:1490–1495.PubMedCrossRefGoogle Scholar
  14. 14.
    Schmidt WN, Stapleton JT, LaBrecque DR, et al.: Hepatitis C virus (HCV) infection and cryoglobulinemia: analysis of whole blood and plasma HCV-RNA concentrations and correlation with liver histology. Hepatology 2000, 31:737–744.PubMedCrossRefGoogle Scholar
  15. 15.
    Willson RA: Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 1997, 92:4–17.Google Scholar
  16. 16.
    Vassilopoulos D, Calabrese LH: Hepatitis C virus infection and vasculitis: implications of antiviral and immunosuppressive therapies. Arthritis Rheum 2002, 46:585–597. An excellent review of HCV extrahepatic complications of cryoglobulinemia, vasculitis, and treatment strategies.PubMedCrossRefGoogle Scholar
  17. 17.
    Schott P, Hartmann H, Ramadori G: Hepatitis C virusassociated mixed cryoglobulinemia. Clinical manifestations, histopathological changes, mechanisms of cryoprecipitation and options of treatment. Histol Histopathol 2001, 16:1275–1285.PubMedGoogle Scholar
  18. 18.
    D’Amico G: Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int 1998, 54:650–671.PubMedCrossRefGoogle Scholar
  19. 19.
    Tarantino A, Devecchi A, Montagnino G, et al.: Renal disease in essential mixed cryoglobulinemia. Longterm follow-up of 44 patients. Q J Med 1981, 50:1–30.PubMedGoogle Scholar
  20. 20.
    Kayali Z, Tan S, Shinkunas L, et al.: Risk factors for hepatitis C fibrosis: a prospective study of United States veterans compared with nonveterans. J Viral Hepat 2006, In press.Google Scholar
  21. 21.
    Saadoun D, Asselah T, Resche-Rigon M, et al.: Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C. Hepatology 2006, 43:1337–1345.PubMedCrossRefGoogle Scholar
  22. 22.
    Gane EJ, Maertens G, Ducatteeuw A, et al.: Antibodies to hepatitis C virus envelope proteins correlate with hepatitis C viraemia after liver transplantation. Transplantation 1999, 67:78–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Rayhill SC, Kirby A, Voigt MD, et al.: Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C. Transplantation 2005, 80:448–456.PubMedCrossRefGoogle Scholar
  24. 24.
    Crovatto M, Ceselli S, Mazzaro C, et al.: HCV genotypes and cryoglobulinemia. Clin Exp Rheumatol 1995, 13(Suppl 13):S79-S82.PubMedGoogle Scholar
  25. 25.
    Frangeul L, Musset L, Cresta P, et al.: Hepatitis C virus genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia. J Hepatol 1996, 25:427–432.PubMedCrossRefGoogle Scholar
  26. 26.
    Zignego AL, Ferri C, Giannini C, et al.: Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia. Ann Intern Med 1996, 124:31–34.PubMedGoogle Scholar
  27. 27.
    Lindsay KL: Therapy of hepatitis C: overview. Hepatology 1997, 26(Suppl 1):S71-S77.CrossRefGoogle Scholar
  28. 28.
    Fried MW, Shiffman ML, Reddy KR, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, 347:975–982.PubMedCrossRefGoogle Scholar
  29. 29.
    Glue P, Rouzier-Panis R, Raffanel C, et al.: A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. Hepatology 2000, 32:647–653.PubMedCrossRefGoogle Scholar
  30. 30.
    Manns MP, McHutchinson JG, Gordon SC, et al.: Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001, 358:958–965.PubMedCrossRefGoogle Scholar
  31. 31.
    McHutchison JG, Gordon SC, Schiff ER, et al.: Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998, 339:1485–1492.PubMedCrossRefGoogle Scholar
  32. 32.
    Veldt BJ, Saracco G, Boyer N, et al.: Long term clinical outcome of chronic hepatitis C patients with sustained virological response to interferon monotherapy. Gut 2004, 53:1504–1508.PubMedCrossRefGoogle Scholar
  33. 33.
    National Institutes of Health (NIH) Panel: National Institutes of Health Consensus Statement of Management of Hepatitis C: 2002. Bethesda, MD: NIH; 2006:1–46.Google Scholar
  34. 34.
    Liang TJ, Rehermann B, Seeff LB, et al.: Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000, 132:296–305.PubMedGoogle Scholar
  35. 35.
    Bacon BR, McHutchison JG: Treatment issues with chronic hepatitis C: special populations and pharmacy strategies. Am J Manag Care 2005, 11(Suppl 10):S296-S306.PubMedGoogle Scholar
  36. 36.
    He Y, Katze MG: To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. Viral Immunol 2002, 15:95–119.PubMedCrossRefGoogle Scholar
  37. 37.
    Bonomo L, Casato M, Afeltra A, et al.: Treatment of idiopathic mixed cryoglobulinemia with alphainterferon. Am J Med 1987, 83:726–730.PubMedCrossRefGoogle Scholar
  38. 38.
    Casato M, Lagana B, Antonelli G, et al.: Long-term results of therapy with interferon-alpha for type-II essential mixed cryoglobulinemia. Blood 1991, 78:3142–3147.PubMedGoogle Scholar
  39. 39.
    Ferri C, Marzo E, Longombardo G, et al.: Interferonalpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 1993, 81:1132–1136.PubMedGoogle Scholar
  40. 40.
    Mazzaro C, Lacchin T, Moretti M, et al.: Effects of two different alpha-interferon regimens on clinical and virological findings in mixed cryoglobulinemia. Clin Exp Rheumatol 1995, 13(Suppl 13):S181-S185.PubMedGoogle Scholar
  41. 41.
    Migliaresi S, Tirri G: Interferon in the treatment of mixed cryoglobulinemia. Clin Exp Rheumatol 1995, 13(Suppl 13):S175-S180.PubMedGoogle Scholar
  42. 42.
    Misiani R, Bellavita P, Fenili D, et al.: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994, 330:751–756.PubMedCrossRefGoogle Scholar
  43. 43.
    Adinolfi LE, Utili R, Zampino R, et al.: Effects of longterm course of alpha-interferon in patients with chronic hepatitis C associated to mixed cryoglobulinaemia. Eur J Gastroenterol Hepatol 1997, 9:1067–1072.PubMedGoogle Scholar
  44. 44.
    Calleja JL, Albillos A, Moreno-Otero R, et al.: Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinaemia. Aliment Pharmacol Ther 1999, 13:1179–1186.PubMedCrossRefGoogle Scholar
  45. 45.
    Casaril M, Capra F, Gabrielli GB, et al.: Cryoglobulinemia in hepatitis C virus chronic active hepatitis: effects of interferon-alpha therapy. J Interferon Cytokine Res 1996, 16:585–588.PubMedGoogle Scholar
  46. 46.
    Casato M, Agnello V, Pucillo LP, et al.: Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood 1997, 90:3865–3873.PubMedGoogle Scholar
  47. 47.
    Cresta P, Musset L, Cacoub P, et al.: Response to interferon alpha treatment and disappearance of cryoglobulinaemia in patients infected by hepatitis C virus. Gut 1999, 45:122–128.PubMedCrossRefGoogle Scholar
  48. 48.
    Hartmann H, Schott P, Polzien F, et al.: Cryoglobulinemia in chronic hepatitis C virus infection: prevalence, clinical manifestations, response to interferon treatment and analysis of cryoprecipitates [in German]. Z Gastroenterol 1995, 33:643–650.PubMedGoogle Scholar
  49. 49.
    Polzien F, Schott P, Mihm S, et al.: Interferon-alpha treatment of hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 1997, 27:63–71.PubMedCrossRefGoogle Scholar
  50. 50.
    Tanaka K, Aiyama T, Imai J, et al.: Serum cryoglobulin and chronic hepatitis C virus disease among Japanese patients. Am J Gastroenterol 1995, 90:1847–1852.PubMedGoogle Scholar
  51. 51.
    Naarendorp M, Kallemuchikkal U, Nuovo GJ, et al.: Longterm efficacy of interferon-alpha for extrahepatic disease associated with hepatitis C virus infection. J Rheumatol 2001, 28:2466–2473.PubMedGoogle Scholar
  52. 52.
    Dammacco F, Sansonno D, Han JH, et al.: Natural interferon-alpha versus its combination with 6-methylprednisolone in the therapy of type II mixed cryoglobulinemia: a long-term, randomized, controlled study. Blood 1994, 84:3336–3343.PubMedGoogle Scholar
  53. 53.
    Lauta VM, DeSangro MA: Long-term results regarding the use of recombinant interferon alpha-2b in the treatment of II type mixed essential cryoglobulinemia. Med Oncol 1995, 12:223–230.PubMedGoogle Scholar
  54. 54.
    Cacoub P, Lidove O, Maisonobe T, et al.: Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2002, 46:3317–3326.PubMedCrossRefGoogle Scholar
  55. 55.
    Mazzaro C, Zorat F, Comar C, et al.: Interferon plus ribavirin in patients with hepatitis C virus positive mixed cryoglobulinemia resistant to interferon. J Rheumatol 2003, 30:1775–1781.PubMedGoogle Scholar
  56. 56.
    Zuckerman E, Keren D, Slobodin G, et al.: Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferon-alpha. J Rheumatol 2000, 27:2172–2178.PubMedGoogle Scholar
  57. 57.
    Schmidt WN, LaBrecque DR, Voigt MD, et al.: Combination antiviral therapy in patients with chronic hepatitis C and cryoglobulinemia. Hepatology 2001, 34:421A.Google Scholar
  58. 58.
    Luxon BA, Grace M, Brassard D, Bordens R: Pegylated interferons for the treatment of chronic hepatitis C infection. Clin Ther 2002, 24:1363–1383.PubMedCrossRefGoogle Scholar
  59. 59.
    Mazzaro C, Zorat F, Caizzi M, et al.: Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol 2005, 42:632–638.PubMedCrossRefGoogle Scholar
  60. 60.
    Cacoub P, Saadoun D, Limal N, et al.: PEGylated interferon alfa-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2005, 52:911–915.PubMedCrossRefGoogle Scholar
  61. 61.
    Casato M, Lagana B, Antonelli G, et al.: Long-term results of therapy with interferon-alpha for type II essential mixed cryoglobulinemia. Blood 1991, 78:3142–3147.PubMedGoogle Scholar
  62. 62.
    Campise M, Tarantino A: Glomerulonephritis in mixed cryoglobulinaemia: what treatment? Nephrol Dial Transplant 1999, 14:281–283.PubMedCrossRefGoogle Scholar
  63. 63.
    Ferri C, Zignego AL, Pileri SA: Cryoglobulins. J Clin Pathol 2002, 55:4–13.PubMedGoogle Scholar
  64. 64.
    Garini G, Allegri L, Carnevali L, et al.: Interferon-alpha in combination with ribavirin as initial treatment for hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis. Am J Kidney Dis 2001, 38:E35.PubMedGoogle Scholar
  65. 65.
    Lamprecht P, Gause A, Gross WL: Cryoglobulinemic vasculitis. Arthritis Rheum 1999, 42:2507–2516.PubMedCrossRefGoogle Scholar
  66. 66.
    D’Amico E, Chincoli C, Cacciatore P, et al.: Effects of combined antiviral therapy on asymptomatic mixed cryoglobulinemia in naive patients with chronic hepatitis C virus infection: a preliminary study. Dig Dis Sci 2005, 50:2344–2347.PubMedCrossRefGoogle Scholar
  67. 67.
    Quartuccio L, Soardo G, Romano G, et al.: Treatment of glomerulonephritis in type II mixed cryoglobulinemia with rituximab. Arthritis Rheum 2004, 50:S235.Google Scholar
  68. 68.
    Zaja F, De Vita S, Mazzaro C, et al.: Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003, 101:3827–3834.PubMedCrossRefGoogle Scholar
  69. 69.
    Murai H, Inaba S, Kira J, et al.: Hepatitis C virus associated cryoglobulinemic neuropathy successfully treated with plasma exchange. Artif Organs 1995, 19:334–338.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  • Zeid Kayali
  • Douglas R. LaBrecque
    • 1
  • Warren N. Schmidt
  1. 1.Division of GI/Hepatology, Department of Internal MedicineUniversity of Iowa Hospitals and ClinicsIowa CityUSA

Personalised recommendations