Unifying Concepts

Classification and Clinico-Pathological Characteristics of Different Cryoglobulinemias

Cryoglobulinemia is usually classified into three subgroups according to Ig composition: type I cryoglobulinemia is composed of only one isotype or subclass of immunoglobulin. Both type II and type III mixed cryoglobulins are immune complexes composed of polyclonal IgGs, the autoantigens, and mono- or polyclonal IgMs, respectively; the IgMs are the corresponding autoantibodies with rheumatoid factor (RF) activity.

Classification and clinico-pathological characteristics of different cryoglobulinemias

Cryoglobulins Composition Pathological findings Clinical associations
Type I cryoglobulinemia monoclonal Ig, mainly IgG, or IgM, or IgA self-aggregation through Fc fragment of Ig tissue histological alterations of underlying disorder -lymphoproliferative disorders:
MM, WM, CLL, B-cell NHL
Type II
mixed cryoglobulinemia
monoclonal IgM (or IgG, or IgA) with RF activity (often cross-idiotype WA-mRF) and polyclonal Ig (mainly IgG) -leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV, HBV, HIV)
-autoimmune/ lymphoproliferative disorders
-rarely ‘essential’
mixed cryoglobulinemia
oligoclonal IgM RF or mixture of poly/
monoclonal IgM (often cross-idiotype WA-mRF)
-leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV, HBV, HIV)
-autoimmune/ lymphoproliferative disorders
-rarely ‘essential’
Type III
mixed cryoglobulinemia
polyclonal mixed Ig (all isotypes) with RF activity of one polyclonal component (usually IgM) -leukocytoclastic vasculitis
-B-lymphocyte expansion with tissue infiltrates
-infections (mainly HCV)
-more often autoimmune disorders
-rarely ‘essential’

lymphoproliferative disorders: MM (multiple myeloma), WM (Waldenstrom’s macroglobulinemia), CLL (chronic lymphocytic leukemia), B-cell NHL (B-cell non-
Hodgkin’s lymphoma); Ig: immunoglobulin; RF: rheumatoid factor; HBV: hepatitis B virus; HCV: hepatitis C virus

Proposed criteria for the classification of mixed cryoglobulinemia (MC) patients

Criteria Major Minor
Serological Mixed cryoglobulins
Low C4
Rheumatoid factor +
Pathological Leucocytoclastic vasculitis Clonal B cell infiltrates (liver and/or bone marrow)
Clinical Purpura Chronic hepatitis
Membrano-proliferative glomerulonephritis
Peripheral neuropathy
Skin ulcers

“Definite” mixed cryoglobulinaemia syndrome:

  1. Serum mixed cryoglobulins (±low C4) + purpura + leucocytoclastic vasculitis.
  2. Serum mixed cryoglobulins (±low C4) + 2 minor clinical symptoms + 2 minor serological/pathological findings.

“Incomplete” or “possible” mixed cryoglobulinaemia syndrome:

  1. Mixed cryoglobulins or low C4 + 1 minor clinical symptom + 1 minor serological ±pathological findings.
  2. Purpura and/or leucocytoclastic vasculitis + 1 minor clinical symptom + 1 minor serological ±pathological findings.
  3. Two minor clinical symptoms + 2 minor serological ± pathological findings.

“Essential” or “secondary” mixed cryoglobulinaemia:
Absence or presence of well known disorders (infectious, immunological, or neoplastic) at the time of the diagnosis.



  1. Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25. [Medlne]
  2. Terrier B, Cacoub P. Cryoglobulinemia vasculitis: an update. Curr Opin Rheumatol. 2013 Jan;25(1):10-8. [Medline]


Created Sep 12, 2013.

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