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Clinical manifestations and diagnosis of essential mixed cryoglobulinemia

INTRODUCTION

Cryoglobulins are immunoglobulins that precipitate in the cold and dissolve on rewarming. The biochemical characteristics that promote cryoprecipitation are not well understood, but three different types of cryoglobulins have been described [1,2]:

  • Type I, in which there is a monoclonal immunoglobulin that is most often due to underlying multiple myeloma or Waldenstrom's macroglobulinemia [3]. In multiple myeloma, cryoglobulin-induced glomerular disease must be distinguished from primary amyloidosis and from light chain deposition disease. (See "Types of renal disease in multiple myeloma".)

  • Type II or essential mixed cryoglobulinemia, in which the cryoglobulin contains both a polyclonal IgG (which may either act as an antigen or be directed against an antigen) and a monoclonal IgM rheumatoid factor directed against the IgG. Most cases are due to chronic infection with hepatitis C virus) [4-8], although infection with hepatitis B virus and Epstein-Barr virus have been implicated in some patients [4,9,10].
  • Type III, in which there is also a mixed cryoglobulin, but both the IgG and the rheumatoid factor IgM are polyclonal. This condition is often seen in chronic inflammatory and autoimmune disorders (such as lupus and leukocytoclastic vasculitis), lymphoproliferative malignancies, and, in as many as one-half of cases, HCV infection [5,6,8,11].

This topic review will discuss the clinical characteristics of type II or essential mixed cryoglobulinemia. The treatment of this disorder is discussed separately. (See "Treatment of essential mixed cryoglobulinemia".)

RELATIONSHIP TO HCV INFECTION

Hepatitis C virus infection has been found in the majority of patients with essential mixed cryoglobulinemia:
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References Top
  1. 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.
  2. D'Amico, G, Colasanti, G, Ferrario, F, Sinico, RA. Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989; 35:1004.
  3. Paueksakon, P, Revelo, MP, Horn, RG, Shappell, S. Monoclonal gammopathy: Significance and possible causality in renal disease. Am J Kidney Dis 2003; 42:87.
  4. Lunel, F, Musset, L, Cacoub, P, et al. Cryoglobulinemia in chronic liver diseases: Role of HCV and liver damage. Gastroenterology 1994; 106:1291.
  5. Agnello, V, Chung, RT, Kaplan, LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992; 327:1490.
  6. Pozzato, G, Mazzaro, C, Crovatto, M, et al. Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia. Blood 1994; 84:3047.
  7. Misiani, R, Bellavita, P, Fenili, D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117:573.
  8. Roccatello, D, Fornasieri, A, Giachino, O, et al. Multicenter study on hepatitis C virus-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis 2007; 49:69.
  9. Kawakami, T, Ooka, S, Mizoguchi, M, et al. Remission of hepatitis B virus-related cryoglobulinemic vasculitis with entecavir. Ann Intern Med 2008; 149:911.
  10. Enomoto, M, Nakamishi, T, Ishii, M, et al. Entecavir to treat hepatitis B-associated cryoglobulinemic vasculitis. Ann Intern Med 2008; 149:912.
  11. 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.
  12. Dimitrakopoulos, AN, Kordossis, T, Hatzakis, A, Moutsopoulos, HM. Mixed cryoglobulinemia in HIV-infection: The role of HIV-1. Ann Intern Med 1999; 130:226.
  13. Sansonno, D, De Vita, S, Iacobelli, AR, Cornacchiulo, V. Clonal analysis of intrahepatic B cells from HCV-infected patients with and without mixed cryoglobulinemia. J Immunol 1998; 160:3594.
  14. Frankel, AH, Singer, DRJ, Winearls, CG, et al. Type II essential mixed cryoglobulinemia: Presentation, treatment and outcome in 13 patients. Q J Med 1992; 82:101.
  15. 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 neuropsychological tests. J Rheumatol 2005; 32:484.
  16. Nash, JW, Ross, P, Neil Crowson, A, et al. The histopathologic spectrum of cryofibrinogenemia in four anatomic sites. Skin, lung, muscle, and kidney. Am J Clin Pathol 2003; 119:114.
  17. Manganelli, P, Salaffi, F, Subiaco, S, et al. Bronchoalveolar lavage in mixed cryoglobulinaemia associated with hepatitis C virus. Br J Rheumatol 1996; 35:978.
  18. Viegi, G, Fornai, E, Ferri, C, et al. Lung function in essential mixed cryoglobulinemia: a short-term follow-up. Clin Rheumatol 1989; 8:331.
  19. Lee, LN, Lo, SC, Lau, HP, et al. Hepatitis C-associated cryoglobulinaemia presenting with refractory hypertensive crisis and acute pulmonary oedema. Med J Aust 2005; 182:38.
  20. Suzuki, R, Morita, H, Komukai, D, et al. Mixed cryoglobulinemia due to chronic hepatitis C with severe pulmonary involvement. Intern Med 2003; 42:1210.
  21. Jara, LJ, Vera-Lastra, O, Calleja, MC. Pulmonary-renal vasculitic disorders: differential diagnosis and management. Curr Rheumatol Rep 2003; 5:107.
  22. Sinico, RA, Winearls, CG, Sabadini, E, et al. Identification of glomerular immune complexes in cryoglobulinemia glomerulonephritis. Kidney Int 1988; 34:109.
  23. Fulpius, T, Berney, T, Lemoine, R, et al. Glomerulopathy induced by IgG3 anti-trinitrophenyl monoclonal cryoglobulins derived from non-autoimmune mice. Kidney Int 1994; 45:962.
  24. Sansonno, D, Gesualdo, L, Manno, C, et al. Hepatitis C virus-related proteins in kidney tissue from hepatitis C virus-infected patients with cryoglobulinemic membranoproliferative glomerulonephritis. Hepatology 1997; 25:1237.
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