• Cryoglobulins (CGs) consist of immunoglobulins (Igs) and complement precipitating in serum and plasma.
  • CGs precipitate at cold temperatures 98.6°F (<37°C) and dissolve on rewarming.
  • Clinical symptoms are often secondary to small vessel occlusion or a hyperviscosity syndrome in type I CGs or the formation of CG-containing immune complexes leading to vasculitis in type II and type III CGs.
  • Brouet classification categorizes CGs by clonality and rheumatoid factor (anti-IgG) activity:
    • Type I
      • Monoclonal Ig; IgM is most common.
      • Less frequently IgG, IgA, free Ig light chains
    • Type II
      • Monoclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig
      • Monoclonal fraction is rarely IgG or IgA.
    • Type III
      • Polyclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig


  • Healthy patients may have low concentrations of CGs present in the serum (<0.06 g/L).
  • Clinically relevant cryoglobulinemia is far more common in patients with chronic infections or inflammation.

Distribution (percentage of all cases) of CG:

  • Type I CG: 10–15%
  • Type II CG: 50–60%
  • Type III CG: 30–40%


  • Mixed CG (CGs type II and type III) is female: (1:100,000) > male: (3:1); onset in 6th decade
  • Heterogenous geographic distribution: highest incidence in areas with increased hepatitis C virus (HCV) infection (1)[B]

Etiology and Pathophysiology

  • Exact mechanism of cold insolubility in these cryoproteins is unknown. Hypotheses include reduced concentrations of sialic acid and galactose in the Fc region of Ig as well as steric conformation changes due to temperature variation.
  • Type I
    • An underlying lymphoproliferative disorder causes monoclonal B-cell proliferation.
    • B cells produce CG, which precipitates, causing hyperviscosity and vessel damage.
  • Types II and III
    • B-cell hyperactivation or hyperproliferation (from HCV or another chronic inflammatory state) produces Ig with rheumatoid factor activity, which leads to immune complex formation.
    • Immune complex deposition and subsequent complement activation causes small vessel damage.
    • HCV correlation
      • HCV displays lymphotropism. The E2 capsid protein of HCV binds site to CD81, a site present on hepatocytes, T lymphocytes, and B lymphocytes.
      • Patients infected with HCV who have mixed cryoglobulinemia (MC) have been found to have higher viral loads than patients with HCV and no MC.
  • Disease manifestations of CG may arise due to the following causes:
    • Chronic immune stimulation or lymphoproliferation resulting in the increased production of CGs (2)[A]
    • Immune complex formation among CGs with antigens
    • Insufficient clearance of CGs and their immune complexes
    • Consider small vessel vasculitis: may present with necrosis at cold exposed areas

Risk Factors

  • Hematologic/lymphoproliferative diseases (type I CG)
  • HCV infection (type II CG > type III CG), other chronic infections (mixed CG)
  • HIV
  • Connective tissue disease

General Prevention

Prevent or manage progression of underlying disease, if applicable.

Commonly Associated Conditions

  • Infections:
    • Viral (commonly hepatitis C, hepatitis B, HIV), bacterial, fungal, parasitic (rare)
  • Hematologic/lymphoproliferative diseases:
    • Non-Hodgkin/Hodgkin lymphoma
    • Chronic leukemia
    • Multiple myeloma
    • Waldenström macroglobulinemia
  • Autoimmune/chronic inflammatory diseases:
    • Sjögren syndrome
    • Systemic lupus erythematosus
    • Rheumatoid arthritis
    • Inflammatory bowel disease (IBD) (3)[C]

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