Etiology

Type I cryoglobulinemia is usually associated with lymphoproliferative disorders. Types II and III (or mixed cryoglobulinemia [MC]) may be associated with infectious or autoimmune disorders.[1][2] Only a small subset of patients with MC present with isolated cryoglobulinemia, the so-called "essential" cryoglobulinemia.

Lymphoproliferative disorders

  • Type I cryoglobulinemia is usually associated with multiple myeloma, Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphomas.[7]​​

  • The most common lymphoproliferative disorders associated with MC are Hodgkin and non-Hodgkin lymphomas. Non-Hodgkin lymphoma is associated with hepatitis C virus (HCV) infection in 50% of patients with cryoglobulinemia.[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, cryoglobulinemia may be found in 20% to 56%, but less than one third of these are symptomatic.[2][4][15]

  • Studies of HCV-negative cryoglobulinemia 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 syndrome, systemic lupus erythematosus, systemic sclerosis, undifferentiated connective tissue disease, and vasculitis.[9][17]

  • Overlap with coexistent HCV infection, especially with Sjogren syndrome and polyarteritis nodosa, has been noted.

Pathophysiology

Type I 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 cryoglobulinemia, monoclonal IgM forms a complex with polyclonal IgG. In type III, polyclonal IgMs complex with polyclonal IgGs. The IgM in mixed cryoglobulinemia (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. IgG3 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 I 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 cryoglobulinemia 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]

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

  • Type I: isolated monoclonal Igs.

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

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

MC encompasses type II and III cryoglobulins.

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

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