Blood Reviews
Volume 21, Issue 4 , Pages 183-200 , July 2007

Cryoglobulinemia

  • Alessandra Tedeschi

      Affiliations

    • Department Oncology/Haematology, Division of Haematology, Nigurda Ca’ Granda Hospital Milano, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +390264442668; fax: +390264442033.
  • ,
  • Claudia Baratè

      Affiliations

    • Department Oncology/Haematology, Division of Haematology, Nigurda Ca’ Granda Hospital Milano, Italy
  • ,
  • Ernesto Minola

      Affiliations

    • Department of Pathology, Niguarda Ca’ Granda Hospital, Milano, Italy
  • ,
  • Enrica Morra

      Affiliations

    • Department Oncology/Haematology, Division of Haematology, Nigurda Ca’ Granda Hospital Milano, Italy

References 

  1. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull John Hopkins Hosp. 1933;52:156–165
  2. Lerner AB, Watson CJ. Studies of cryoglobulins. Unusual purpura associated with the presence of a high concentrations of cryoglobulin (cold precipitate serum globulin). Am J Med Sci. 1947;314:410–415
  3. Meltzer M, Franklin EC. Cryoglobulinemia: a study of 29 patients. IgG and IgM cryoglobulins and factors effecting cryoprecipitability. Am J Med. 1966;40:828–836
  4. Brouet JC, Clauvel JP, Dannnon F, Klein M, Seligmann M. Biological and clinical significance of cryoglobulins: a report of 86 cases. Am J Med. 1974;57:775–788
  5. Montagnino G. Reappraisal of the clinical expression of mixed cryoglobulinemia: Springer Semin Immunopathol 1988;10:1–19.
  6. Tissot JD, Schifferli JA, Hochstrasser DF, et al. Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide. J Immunol Meth. 1994;173:63–75
  7. Musset L, Diemert MC, Taibi F, et al. Characterization of cryoglobulins by immunoblotting. Clin Chem. 1992;38:798–802
  8. Musset L, Duarte F, Gaillard O, et al. Immunochemical characterization of monoclonal IgG containinig mixed cryoglobulinemia. Clin Immunol Immunopathol. 1994;70:166–170
  9. Kallemuchikkal U, Gorevic PD. Evaluation of cryoglobulins. Arch Pathol Lab Med. 1999;123:119–125
  10. Vitali C, Ferri C, Nasti P, La Civita L, et al. Hypercomplementaemia as a marker of the evolution from benign to malignant B-cell proliferation in patients with type II mixed cryoglobulinemia. Br J Rheumatol. 1994;33:791–792
  11. Maire MA, Mittey M, Lambert PH. The presence of cryoprecipitable immunoglobulins in normal human sera may reflect specific molecular interactions. Autoimmunity. 1989;37:187–192
  12. Levo Y, Gorevic PD, Kassab HJ, et al. Association between hepatitis B virus and essential mixed cryoglobulinemia. N Engl J Med. 1977;297:946–947
  13. Galli M, Monti G, Invernizzi F, et al. Hepatitis B virus-related markers in secondary and in essential mixed cryoglobulinemias: a multicentric study of 596 cases:. Ann Ital Med Int. 1992;7:209–214
  14. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol. 2002;55:4–13
  15. Galli M, Invernizzi F, Chemotti M, et al. Cryoglobulins and infectious diseases. Ric Clin Lab. 1986;16:301–313
  16. Dammacco F, Sansonno D, Piccoli C, Tucci FA, Ravanelli V. The cryoglobulins an overview. Eur J Clin Invest. 2001;31:628–638
  17. Horcajada JP, Garcia Bengoechea M, Cilla G, Etxaniz P, Cuadrado E, Arenas JL. Mixed cryoglobulinemia in patients with chronic hepatitis C infection: prevalence, significance and relationship with different viral genotypes. Ann Med. 1999;31:352–358
  18. Lunnel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver disease: role of hepatitis C and liver damage. Gastroenterology. 1994;106:1230–1291
  19. Gabrielli A, Manzin A, Candela M, et al. Active hepatitis C virus infection in the bone marrow and peripheral blood mononuclear cells from patients with mixed cryoglobulinemia. Clin Exp Immunol. 1994;97:87–93
  20. Sansonno D, Cornacchiulo V, Iacobelli AR, et al. Localization of hepatitis virus C antigens in liver and skin tissues of chronic hepatitis C virus infected patients with mixed cryoglobulinemia. Hepatology. 1995;21:305–312
  21. Pileri P, Uematsu Y, Campagnoli S, et al. Binding of hepatitis C virus on CD81. Science. 1998;282:938–941
  22. Crovatto M, Ceselli S, Mazzaro C, et al. HCV genotypes and cryoglobulinemia. Clin Exp Rheumatol. 1995;13(Suppl 13):S79–S82
  23. Pawlotsky JM, Roudot-Thoraval F, Simmonds P, et al. Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann Int Med. 1995;122:169–173
  24. Chang M, Williams O, Mittler J, et al. Dynamics of hepatitis C virus replication in human liver. Am J Pathol. 2003;163:433–444
  25. Sansonno D, Lauletta G, Montrone M, Tucci FA, Nisi L, Dammacco F. Virological anlysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus infected patients with and without mixed cryoglobulinemia. Clin Exp Immunol. 2006;143:288–296
  26. Morra E. Cryoglobulinemia. Hematology Am Soc Hematol Educ Program. 2005;368–372
  27. Petracca R, Falugi F, Galli G, et al. Structure-function analysis of hepatitis C virus envelope-CD81 binding. J Virol. 2000;74:4824–4830
  28. Rosa D, Saletti G, De Gregorio E, et al. Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci USA. 2005;102:18544–18549
  29. Mazzaro C, Tirelli U, Pozzato G. Hepatitis C virus and non Hodgkin’s lymphoma 10 years later. Dig Liv Dis. 2005;37:219–226
  30. Sansonno D, Lauletta G, De Re V, et al. Intrahepatic B cell clonal expansions and extrahepatic manifestations of chronic HCV infection. Eur J Immunol. 2004;34:126–136
  31. Dispenzieri A, Gorevic PD. Cryoglobulinemia. Hematol Oncol Clin North Am. 1999;13:1315–1349
  32. Franzin F, Efremov DG, Pozzato G, Tulissi P, Batista F Burrone O. Clonal B-cell expansion in peripheral blood of HCV-infected patients. Br J Hematol. 1995;90:548–552
  33. De Re V, De Vita S, Marzotto A, et al. Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor-producing cells that occur mainly in type II cryoglobulinemia. Blood. 2000;96:3578–3584
  34. Ivanovsky M, Silvestri F, Pozzato G, et al. Somatic hypermutation, clonal diversità and preferential expression of the VH 51p1/V L kv325 immunoglobulin gene combination in hepatitis C associated immunocytomas. Blood. 1998;91:2433–2442
  35. De Re V, De Vita S, Sansonno D, Gasparotto D, Simula MP. Type II mixed cryoglobulinemia as an oligo rather than a mono B-cell disorder: evidence from GeneScan and MALDI-TOF analyses. Rheumatology. 2006;45:685–693
  36. Ferri S, Dal Pero F, Bortoletto G, et al. Detailed analysis of the E2-IgM complex in hepatitis C-related type II mixed cryoglobulinemia. J Viral Hepatol. 2006;13:166–176
  37. Zignego AL, Ferri C, Giannelli F, et al. Prevalence of bcl-2 rearrangement in patients with hepatitis C virus-related mixed cryoglobulinemia with or without B-cell lymphomas. Ann Intern Med. 2002;137:571–580
  38. Kitay Y, Amiel A, Hilzenrat N, et al. Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II. Blood. 2000;96:2910–2912
  39. Monteverde A, Ballarè M, Pileri S. Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia Springer Semin Immunopathol 1997;19:99–110.
  40. Ellis M, Rathaus M, Amiel A, Manor Y, Klein A, Lishner M. Monoclonal lymphocyte proliferation and bcl-2 rearrangement in essential mixed cryoglobulinaemia. Eur J Clin Invest. 1995;25:833–837
  41. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long term follow-up of 40 patients. Am J Med. 1980;69:287–308
  42. Monti G, Galli M, Invernizzi F, et al. Cryoglobulinemias: a multicentre study of the early clinical and laboratori manifestations of primary and secondary disease. GISC Italian Group for the study of Cryoglobulinemias. QJM. 1995;88:115–126
  43. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia:study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001;80:252–262
  44. Rieu V, Cohen P, Andrè M H, et al. Characteristic and outcome of 49 patients with symptomatic cryoglobulinemia. Rheumatology. 2002;41:290–300
  45. Sene D, Ghillani-Dalbin P, Thibault V, et al. Longterm corse of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol. 2004;31:2199–2206
  46. Ferri C, Sebastiani M, Giuggioli D et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 321 patients Seminars Arthritis and rheumatism 2004;33:355–374.
  47. Bryce AH, Kyle RA, Dispenzieri A, et al. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol. 2006;81:511–518
  48. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005;5:227–236
  49. Daghestani L, Pomeroy C. Renal manifestations of hepatitis C infection. Am J Med. 1999;106:347–354
  50. D’Amico G, Colasanti C, Ferrario F, Sinico RA. Renal involvement in essential mixed cryoglobulinemia. Kidney Int. 1989;54:1004–1014
  51. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemia glomerulonephritis. Kidney Int. 1995;47:618–623
  52. Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med. 1993;328:465–470
  53. Beddhu S, Bastacky S, Johnson JP. The clinical and morphological spectrum of renal cryoglobulinemia. Medicine. 2002;81:398–409
  54. Fornasieri A, D’Amico G. Type II mixed cryoglobulinemia, hepatitis C infection, and glomerulonephritis. Nephrol Dial Transplant. 1996;11:25–30
  55. Sansonno D, Lauletta G, Montrone M, Grandaliano G, Schena FP, Dammacco F. Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated with laser capture microdissection. Clin Exp Immunol. 2005;140:498–506
  56. Germignani F, Melli G, Inglese C, Marbini A. Cryoglobulinemia is a frequent cause of peripheral neuropathy in undiagnosed referral patients. Peripher Nerv Syst. 2002;7:59–64
  57. Ferri C, La Civita L, Cirafisi C, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol. 1992;19:889–895
  58. Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry. 2005;76:1410–1414
  59. Santoro L, Manganelli F, Briani C, et al. Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population. J Neurol Neurosurg Psychiatry. 2006;77:626–629
  60. Migliaresi S, Di Iorio G, Ammendola A, et al. Peripheral nervous system involvement in HCV-related mixed cryoglobulinemia. Reumatismo. 2001;53:26–32
  61. Ammendola A, Sampaolo S, Ambrosone L, et al. Peripheral neuropathy in hepatitis related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle nerve. 2005;31:382–385
  62. Chad D, Pariser K, Bradley WG, et al. The pathogenesis of cryoglobulinemic neuropathy. Neurology. 1982;32:725–729
  63. Bonetti B, Invernizzi F, Rizzuto N, et al. T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy. J Neuroimmunol. 1997;73:145–154
  64. Origgi L, Vanoli M, Carbone A, et al. Central nervous system involvement in patients with HCV-related cryoglobulinemia. Am J Med Sci. 1998;315:208–210
  65. Petty GW, Duffy J, Huston J. Cerebral ischemia in patients with hepatitis C virus infection and mixed cryoglobulinemia. Mayo Clin Proc. 1996;71:671–678
  66. Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neuropsycological tests. J Rheumatol. 2005;3:484–488
  67. Ramos-Casals M, De Vita S, Tzioufas AG. Hepatitis C virus, Sjögren’s syndrome and B-cell lymphoma: linking infection, auttoimmunity and cancer. Autoimmun Rev. 2005;4:8–15
  68. Tzioufas AG, Manoussakis MN, Costello R. Cryoglobulinemia in autoimmune rheumatic disease. Evidence of circulating monoclonal cryoglobulins in patients with primary Sjögren’s syndrome. Arthritis Rheum. 1986;29:1098–1104
  69. Agnello V. Mixed cryoglobulinemia after hepatitis C virus: more or less ambiguity. Ann Rheumatol Dis. 1998;57:701–702
  70. Kayali Z, Buckwold VE, Zimmerman B, et al. Hepatitis C, cryoglobulinemia, and cirrhosis: a meta-analysis. Hepatology. 2002;36:978–985
  71. Saadoun D, Asselah T, Resche-Rigon M, et al. Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C. Hepathology. 2006;43:1337–1345
  72. Ferri C, Marzo E, Longobardo G, et al. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood. 1993;81:1132–1136
  73. Misiani R, Bellavita P, Fenili D, et al. Interferon-alpha-2 therapy in cryoglobulinemia patients associated with hepatitis C virus. N Eng J Med. 1994;330:751–756
  74. Dammacco F, Sansonno D, Han JH, et al. Natural Interferon-α versus its combination with 6-Methyl-Prednisolone in therapy of type II mixed cryoglobulinemia: a long term randomized controlled study. Blood. 1994;84:3336–3343
  75. Cohen P, Nguyen QT, Deny P, et al. Treatment of mixed cryoglobulinemia with recombinant interferon-alpha and adjuvant therapies. A prospective study on 20 patients. Ann Med Interne. 1996;147:81–86
  76. 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
  77. Mazzaro C, Carniello GS, Colle R, et al. Interferon therapy in HCV-positive mixed cryoglobulinemia: viral and host factors contributing to efficacy of therapy. Ital J Gastroenterol Hepatol. 1997;29:343–350
  78. Lidove O, Cacoub P, Hausfaster P, et al. Cryoglobulinemia and hepatitis C: worsening of peripheral neuropathy after interferon alpha treatment. Gastroenterol Clin Biol. 1999;23:403–406
  79. Cid MC, Hernandez-Rodriguez J, Robert J et al. Interpheron-alpha may exacerbate cryoglobulinemia-related ischemic manifestations:an adverse effect potentially related to its anti-angiogenic activity. Arthritis Rheum 199;42:1051–1055.
  80. Sherman KE, O’Brien J, Gutierrez AG, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679–2685
  81. Durand JM, Cacoub P, Lunel-Fabiani F, et al. Ribavirin in hepatitis C related cryoglobulinemia. J Rheumatol. 1998;25:1115–1117
  82. Calleja JL, Albillos A, Moreno-Otero R, et al. Sustained response to interferon-alpha plus ribavirin in hepatitis C virus-associated symptomatic mixed cryoglobulinemia. Aliment Pharmacol Ther. 1999;13:1179–1186
  83. 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;27:2172–21178
  84. Donada C, Crucitti A, Donadon V, et al. Interferon and ribavirin combination therapy in patients with chronic hepatitis C and mixed cryoglobulinemia. Blood 198;92:2983-2984.
  85. 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;30:1775–1780
  86. Mazzaro C, Zorat F, Caizzi M, et al. Treatment with peg-interferon alpha-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia: a pilot study. J Hepatol. 2005;42:632–638
  87. Cacoub P, Saadoun D, Limal N, Sene D, Lidove O, Piette JC. Pegylate and interferon-alpha-2b and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthitis Rheumatism. 2005;52:911–915
  88. Alric L, Plaisier E, Thèbault S, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kydney Dis. 2004;43:617–623
  89. Mazzaro C, Franzin F, Tulissi P, et al. Regresssion of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer. 1996;77:2604–2613
  90. Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes associated with type II cryoglobulinemia and HCV infection: a new entity?. Blood. 2005;105:74–76
  91. Kelaidi C, Rollot F, Park S, et al. Response to antiviral treatment in hepatitis C virus-associated marginal zone lymphomas. Leukemia. 2004;18:1711–1716
  92. Vallisa D, Bernuzzi P, Arcaini L, et al. Role of anti hepatitis C virus (HCV) treatment in HCV related low-grade, B-cell, non-Hodgkin’s lymphoma: a multicenter Italian Trial. J Clin Oncol. 2005;23:468–473
  93. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Eng J Med. 2002;347:89–94
  94. Levine AM, Shimodaira S, Lai MM. Treatment of HCV related mantle cell lymphoma with ribavirin and pegylate interferon-alpha. N Eng J Med. 2003;349:2078–2079
  95. Pietrogrande M, Ferri C. The low antigen content diet in treatment of essential mixed cryoglobulinemia. Conn Tiss Dis. 1999;11:61–66
  96. Sansonno D, De Re V, Lauletta G, Tucci AF, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon-α with an anti-CD20. Blood. 2003;101:3818–3826
  97. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003;101:3827–3834
  98. Bryce AH, Dispenzieri A, Kyle RA, et al. Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma. 2006;7:140–144
  99. Lamprecht P, Lerin-Lozano C, Merz H, et al. Rituximab induces remission in refractory HCV associated cryoglobulinemic vasculitis. Ann Rheumatic Dis. 2003;62:1230–1233
  100. Basse G, Ribes D, Kamar N, et al. Rituximab therapy for mixed cryoglobulinemia in seven renal transplanted patients. Transplant Proc. 2006;38:2308–2310
  101. Quartuccio L, Soardo G, Romano G, et al. Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinemia: efficacy and safety in the absence of steroids. Rheumatology. 2006;45:842–846

PII: S0268-960X(06)00076-2

doi: 10.1016/j.blre.2006.12.002

Blood Reviews
Volume 21, Issue 4 , Pages 183-200 , July 2007