Cryoglobulins are proteins that become insoluble at reduced temperatures- less than 4 degrees Celsius. Cryoglobulinaemia is the presence of large amounts of cryoglobulin in the blood. It can be associated with various diseases.

Cryoglobulins will dissolve again if the blood is heated to around 37 degrees Celsius.


Cryoglobulinemia is classically grouped into three types according to the Brouet classification. Type I is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström macroglobulinemia. Types II and III are strongly associated with infection by the hepatitis C virus.

There are three different types of cryoglobulins that have been observed to form in the blood. Type I is composed of isolated monoclonal immunoglobulins, while types II and III are immunocomplexes formed by monoclonal or polyclonal IgM respectively. Types II and III have rheumatoid factor (RF) activity and bind to polyclonal immunoglobulins. These two types are referred to as mixed cryoglobulinemia (MC). When the temperature is raised, the precipitated cryoglobulins will dissolve back into the serum.

  • Type I cryoglobulins make up 10-15% of the total cases. These are composed of a single monoclonal immunoglobulin paraprotein (usually IgM). Sometimes, these are represented by light chains only and can be extracted from the urine, or they will accumulate in blood serum in the event of renal failure.
  • Type II cryoglobulins account for 50-60% of reported cases. They usually have a polyclonal component, usually IgG, and a monoclonal component, usually IgM, which has an RF function. The IgM can recognize intact IgG or either the Fab region or Fc region of IgG fragments. This is why most type II cryoglobulins are IgM-IgG complexes.
  • Type III cryoglobulins account for 25-30% of the reported cases. These have very similar function to the type II cryoglobulins, however they are composed for polyclonal IgM and IgG molecules.

In 2006 it was discovered that there are unusual cryoglobulins that show a microheterogeneous composition, with an immunochemical structure that cannot be fit into any of the classifications. A classification of a type II-III variant has been proposed because they are composed of oligoclonal IgMs with traces of polyclonal immunoglobulins


These proteins may be present in mycoplasma pneumonia, multiple myeloma, certain leukemias, primary macroglobulinemia, and some autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. This is also found occasionally as a symptom in 35% of chronic hepatitis C infections. It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG:

Hyperviscosity is typically associated with CG due to hematological malignancies and monoclonal immunoglobulins. "Meltzer's triad" of palpable purpura, arthralgia and myalgia is generally seen with polyclonal CGs seen in essential-, viral-, or connective tissue disease-associated CG.


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