Last Updated: 2023-07-07

Author(s): Anzengruber F., Navarini A.

ICD11: 4B22

Landsteiner, 1903; Lerner & Watson, 1947

  • Cryoglobulin disease, cryoglobulinemia, cryoglubulinemia

  • Agglutination of immunoglobulins on exposure to cold (4°Celsius) with subsequent vasculitis of the small vessels → cryoglobulins
    • the process is reversible at 37°Celsius

Division into 3 types:

  • Type I (approx.15%): Monoclonal cryoglobulin, mostly IgM (e.g. multiple myeloma, Waldenström's disease)
  • Type II ( approx. 60%): Mono- and polyclonal immunoglobulins (hepatitis C, SLE, systemic scleroderma, Sjögren's syndrome)
  • Type III (approx. 25%): Polyclonal immunoglobulins (mostly in autoimmune diseases, rheumatic disease)

  1. Essential cryoglobulinaemia (idopathic)
  2. Secondary cryoglobulinaemia:
    • Infections (over  80% of cases association to hepatitis C, syphilis) 
    • Autoimmune diseases (a. o. SLE, rheumatoid arthritis, ulcerative colitis)
    • Neoplasms (a. o. malignant lymphomas, plasmacytoma)
  3. Association to hepatitis C, syphilis.a. SLE, rheumatoid arthritis, ulcerative colitis)
  4. Neoplasms (a. o. malignant lymphoma, plasmacytoma)

  • The clinic depends on the predominant immune complexes
    • Type I: especially acrocyanosis, necrosis of the acras, Raynaud's symptoms, erythema elevatum diutinum, livedo reticularis, livedo racemosa
    • Type II, III: Acrally accentuated, palpable small- and large-area purpura, muscle and joint complaints, polyneuropathy


  • Late symptom or in severe course: glomerulonephritis

  • Histories
  • Clinical
  • Lab:
    • Sharply elevated ESR at 37°Celsius, slowed at 4°Celsisus
    • Agglutination of immune complexes at cool temperatures
    • Cryoglobulin concentration mostly > 1 g/l (normal value < 100 mg/l)
  • Eventual detection of hepatitis C infection, hepatitis serology
  • Sample biopsy of the skin
  • Immune electrophoresis

  • Vasculitis of the small vessels (capillaries, venules, arterioles)
  • Picture of a leukocytoclastic vasculitis
  • Immune complex deposits (IgM and IgG) on the vessel walls of the skin
  • Lymphocytic infiltrations within as well as perivascularly of the vessel walls

  • Glomerulonephritis

  • Chronic, recurrent course over months, years

  1. Baumgärtel MW. Diagnostik, klinisches Spektrum und Verlauf der Kryoglobulinämie. Eine Untersuchung anhand 1 640 konsekutiver Patienten einer hämatoimmunologischen Spezialambulanz. Dissertation der RWTH Aachen. 1998
  2. Schwartzenberg S et al. (2003) Generalized vasculitis, thrombocytopenia, and transient lymphoproliferative disorder caused by idiopathic mixed cryoglobulinemia. Am J Med Sci 326: 47-50
  3. Lospalluto J, Dorward B, Miller W, Jr, Ziff M. Cryoglobulinemia based on interaction between a gamma macroglobulin and 7S gamma globulin. Am J Med. 1962;32:142–145. doi: 10.1016/0002-9343(62)90191-2.
  4. Dammacco F, Sansonno D. Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol. 1997;15:97–119. doi: 10.1007/BF02828280.
  5. Lunel F, Musset L, Cacoub P, Frangeul L, Cresta P, Perrin M, Grippon P, Hoang C, Valla D, Piette JC. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994;106:1291–300.
  6. Bonnet F et al. (2003) Prevalence of cryoglobulinemia and serological markers of autoimmunity in human immunodeficiency virus infected individuals: a cross-sectional study of 97 patients. J Rheumatol 30: 2005-2010