Aetiology

Type l cryoglobulinaemia is usually associated with lymphoproliferative disorders. Types ll and lll (or mixed cryoglobulinaemia [MC]) may be associated with infectious or autoimmune disorders.[1][2] Only a small subset of patients with MC present with isolated cryoglobulinaemia, the so-called 'essential' cryoglobulinaemia.

Lymphoproliferative disorders

  • Type l cryoglobulinaemia is usually associated with multiple myeloma, Waldenstrom's macroglobulinaemia, chronic lymphocytic leukaemia, and B-cell non-Hodgkin's lymphomas.[7]​​

  • The most common lymphoproliferative disorders associated with MC are Hodgkin's and non-Hodgkin's lymphomas. Non-Hodgkin's lymphoma is associated with hepatitis C virus (HCV) infection in 50% of patients with cryoglobulinaemia.[9]

Infection

  • HCV infection may account for up to 90% of all cases of MC.[10][11][12] The highest rates of HCV infection in MC are found in the Mediterranean region.[13][14]

  • In patients with chronic HCV, cryoglobulinaemia may be found in 20% to 56% of cases, but less than one third of these are symptomatic.[2][4][15]

  • Studies of HCV-negative cryoglobulinaemia have revealed that the common viral non-HCV associations include hepatitis B and human immunodeficiency virus (HIV) infection.[2][3] Rarely, MC may be triggered by other bacterial, parasitic, or fungal infections.[7][16]​​

Autoimmune disorders

  • The most common autoimmune conditions associated with MC include Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, undifferentiated connective tissue disease, and vasculitis.[9][17]

  • Overlap with co-existent HCV infection, especially with Sjogren's syndrome and polyarteritis nodosa, has been noted.

Pathophysiology

Type l cryoglobulins are monoclonal antibodies produced by autonomous malignant B-cells. These cryoglobulins are composed of a single monoclonal immunoglobulin (Ig). IgM paraprotein is seen more frequently than IgG paraprotein. IgA isotype is rarely seen.[2]

In type II cryoglobulinaemia, monoclonal IgM forms a complex with polyclonal IgG. In type lll, polyclonal IgMs complex with polyclonal IgGs. The IgM in mixed cryoglobulinaemia (MC), but not in type I, has rheumatoid factor activity (monoclonal in type II and polyclonal in type III).[18]

In MC, cryoprecipitation may occur due to several factors. IgG 3 isotype antibodies have a unique physicochemical property that allows them to self-associate via Fc-Fc interactions, independently of their specificities. This property may be necessary to confer cryoglobulin activity. However, other factors such as temperature, pH, cryoglobulin concentration, covalent bonding, and sialylation of residues may also contribute.[1][19] Type l cryoglobulins, which are usually monoclonal IgG and IgM, may self-aggregate due to the physicochemical properties of the immunoglobulins.[1]

The pathogenic expression of symptomatic cryoglobulinaemia is presumed to be due to immune complex deposition. However, clinical expression does not seem to correlate with cryocrit levels or with concentration of rheumatoid factor in MC.[1]

Classification

Brouet classification[5]

Cryoglobulinaemia is usually classified into 3 types according to Ig composition:

  • Type l: isolated monoclonal Igs.

  • Type ll: monoclonal Ig with polyclonal activity towards other Igs, usually IgM reactive to IgG.

  • Type lll: polyclonal Ig of more than one type.

MC encompasses type ll and lll cryoglobulins.

Immunoblotting has revealed that there may be a subset of patients with oligoclonal IgM complexing with IgG. This has been described as type ll-lll cryoglobulinaemia.[4]

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