Cryoglobulinemia and Chronic HCV Infection: An Evolving Story



Cryoglobulinemia was identified and named many years ago by clinicians who related the in vitro precipitation of globulins from serum incubated in the cold with diseases. One major point was that there was no evidence for a known disease in many patients with “mixed” cryoglobulins. Thus, the terminology “mixed essential cryoglobulinemia” became accepted. The discovery of HCV as the causative agent of mixed essential cryoglobulinemia allowed not only the introduction of a new nomenclature (largely removing the designation “essential”), but studies of the relationship between this viral disease and the emergence of pathological clones of B cells.


Rheumatoid Factor Renal Tubular Acidosis Mixed Cryoglobulinemia Essential Mixed Cryoglobulinemia Mixed Cryoglobulins 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Heidelberger M, Kendall FE (1929) A quantitative study of the precipitin reaction between type III pneumococcus polysaccharide and purified homologous antibody. J Exp Med 50:809–823PubMedCrossRefGoogle Scholar
  2. 2.
    Wintrobe MM, Buell MV (1933) Hypoproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52:156–165Google Scholar
  3. 3.
    Lospalluto J, Dorward B, Miller W Jr, Ziff M (1962) Cryoglobulinemia based on interaction between a gamma macroglobulin and 7s gamma globulin. Am J Med 32:142–147PubMedCrossRefGoogle Scholar
  4. 4.
    Meltzer M, Franklin EC (1966) Cryoglobulinemia: a study of twentynine patients. I. IgG and IgM cryoglobulins and factors affecting cryoprecipitability. Am J Med 40:828–836PubMedCrossRefGoogle Scholar
  5. 5.
    Meltzer M, Franklin EC, Elias K, McCluskey RT, Cooper N (1966) Cryoglobulinemia: a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med 40:837–856PubMedCrossRefGoogle Scholar
  6. 6.
    Brouet JC, Clauvel JP, Danon F et al (1974) Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med 57:775–788PubMedCrossRefGoogle Scholar
  7. 7.
    Gorevic PD (1986) Mixed cryoglobulinemia: an update of recent clinical experience. In: Ponticelli C, Minetti L, D’Amico G (eds) Antiglobulins, cryoglobulins and glomerulonephritis. Martinus Nijhoff, DordrechtGoogle Scholar
  8. 8.
    Tissot JD, Schifferli JA, Hochstrasser DF, Pasquali C, Spertini F, Clément F, Frutiger S, Paquet N, Hugues GJ, Schneider P (1994) Two-dimentional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide. J Immunol Methods 173:63–75PubMedCrossRefGoogle Scholar
  9. 9.
    Agnello V, Barnes JL (1986) Human rheumatoid factor crossidiotypes. I. WA and BLA are heat-labile conformational antigens requiring both heavy and light chains. J Exp Med 164:1809–1814PubMedCrossRefGoogle Scholar
  10. 10.
    Brouet JC (1983) Les cryoglobulinémies. Presse Med 12:2991–2996PubMedGoogle Scholar
  11. 11.
    Levo Y, Gorevic PD, Kassab HJ, Tobias H, Franklin EC (1977) Liver involvement in the syndrome of mixed cryoglobulinemia. Ann Intern Med 87:287–292PubMedCrossRefGoogle Scholar
  12. 12.
    Pascual M, Perrin L, Giostra E, Schifferli JA (1990) Hepatitis C virus in patients with cryoglobulinemia type II (letter). J Infect Dis 162:569–570PubMedCrossRefGoogle Scholar
  13. 13.
    Ferri C, Greco F, Longombardo G, Palla P, Moretti A, Marzo E, Fosella PV, Pasero G, Bombardieri S (1991) Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum 34:1606–1610PubMedCrossRefGoogle Scholar
  14. 14.
    Agnello V, Chung RT, Kaplan LM (1992) A role for hepatitis C virus infection in type II mixed cryoglobulinemia. N Engl J Med 327:1490–1495PubMedCrossRefGoogle Scholar
  15. 15.
    Alter HE (1992) New kit on the block: evaluation of second generation assays for detection of antibody to the hepatitis C virus. Hepatology 15:350–353PubMedCrossRefGoogle Scholar
  16. 16.
    Ferri C, Palla P, Greco F, Marzo E, Longombardo G, Moretti A (1991) Hepatitis C virus antibodies in mixed cryoglobulinemia (letter). Clin Exp Rheumatol 9:95–96PubMedGoogle Scholar
  17. 17.
    Bambara LM, Carletto A, Biasi D, Pacor ML, Caramaschi P (1991) Cryoglobulinemia and hepatitis C virus (HCV) infection (letter). Clin Exp Rheumatol 9:96–97PubMedGoogle Scholar
  18. 18.
    Durand JM, Lefevre P, Harle JR, Boucrat J, Vitvitski L, Soubeyrand J (1991) Cutaneous vasditis and cryoglobulinemia type II associated with hepatitis C virus infection (letter). Lancet 337:499–500PubMedCrossRefGoogle Scholar
  19. 19.
    Casato M, Taliani G, Pucillo LP, Goffredo F, Lagana B, Bonomo L (1991) Cryoglobulinemia and hepatitis C virus (letter). Lancet 337:1047–1048PubMedCrossRefGoogle Scholar
  20. 20.
    Arribas JR, Barbado FJ, Zapico R, Sendino A, Gonzalez I, Vazquez JJ (1991) Association between hepatitis C virus and mixed cryoglobulinemia. Rev Infect Dis 13:770–771PubMedCrossRefGoogle Scholar
  21. 21.
    Disdier P, Harle JR, Weiller PJ (1991) Cryoglobulinemia and hepatitis C infection (letter). Lancet 338:1151–1152PubMedCrossRefGoogle Scholar
  22. 22.
    Pechère-Bertschi A, Perrin L, de Saussure P, Widmann JJ, Giostra E, Schifferli JA (1992) Hepatitis C: a new etiology for cryoglobulinemia type II. Clin Exp Immunol 89:419–422PubMedCrossRefGoogle Scholar
  23. 23.
    Ferri C, Greco F, Longombando G, Palla P, Moretti A, Marzo E, Mazzoni A, Pasero G, Bombardieri S, Highfield P, Corbishley T (1991) Association between hepatitis C virus and mixed cryoglobulinemia. Clin Exp Rheumatol 9:621–624PubMedGoogle Scholar
  24. 24.
    Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M, Vedramin G, Comotti B, Tanzi E, Scudeller G, Zanetti A (1992) Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573–577PubMedCrossRefGoogle Scholar
  25. 25.
    McFarlane IG, Smith HM, Johnson PJ, Bray GP, Vergani D, Williams R (1990) Hepatitis C virus antibodies in chronic active hepatitis: pathogenetic factor or false-positive result? Lancet 335:754–757PubMedCrossRefGoogle Scholar
  26. 26.
    Qi M, Steiger G, Schifferli JA (1992) A calcium dependent cryoglobulin IgM kappa/polyclonal IgG. J Immunol 149:2345–2351PubMedGoogle Scholar
  27. 27.
    Schifferli JA, Amos N, Pusey CD, Sissons JGP, Peters DK (1983) Metabolism of autologous and homologous IgG in patients with mixed essential cryoglobulinemia type II. Absence of fast elimination of IgG. Clin Exp Immunol 51:305–316PubMedGoogle Scholar
  28. 28.
    Schifferli JA, Ng YC, Estreicher J, Walport MJ (1988) The clearance of tetanus toxoid/anti-tetanus toxoid immune complexes from the circulation of humans: complement- and erythrocyte CR1-dependent mechanisms. J Immunol 140:899–904PubMedGoogle Scholar
  29. 29.
    Madi N, Steiger G, Estreicher J, Schifferli JA (1991) Defective immune adherence and elimination of hepatitis B surface Ag/Ab complexes in patients with mixed essential cryoglobulinaemia type II. J Immunol 147:495–502PubMedGoogle Scholar
  30. 30.
    Schifferli JA, Steiger G, Polla L, Didierjean L, Saurat JH (1985) Activation of the alternative pathway of complement by skin immune deposits. J Invest Dermatol 85:407–411PubMedCrossRefGoogle Scholar
  31. 31.
    Fulpius T, Berney T, Lemoine R et al (1994) Glomerulopathy induced by IgG3 anti-trinitrophenyl monoclonal cryoglobulins derived from non-autoimmune mice. Kidney Int 45:962–971PubMedCrossRefGoogle Scholar
  32. 32.
    Sansonno D, Gesualdo L, Manno C, Schena FP, Dammacco F (1997) Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 25:1237–1244PubMedCrossRefGoogle Scholar
  33. 33.
    Agnello V, Abel G (1997) Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis Rheum 40:2007–2015PubMedCrossRefGoogle Scholar
  34. 34.
    Terrier B, Saadoun D, Sène D et al (2009) Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus-related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum 30:2531–2540CrossRefGoogle Scholar
  35. 35.
    Bonomo L, Casato M, Afeltra A, Caccavo D (1987) Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 83:726–730PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  1. 1.Division of Internal Medicine, Department of MedicineUniversity Hospital BaselBaselSwitzerland
  2. 2.Clinic for Internal Medicine and Laboratory for Clinical ImmunologyUniversity Hospital BaselBaselSwitzerland

Personalised recommendations