Classification and external resources
ICD-10 D89.1
ICD-9 273.2
DiseasesDB 3207
MedlinePlus 000540
eMedicine med/480
MeSH D003449

Cryoglobulinemia[1] is a medical condition in which the blood contains large amounts of cryoglobulins - proteins that become insoluble at reduced temperatures. Cryoglobulins typically precipitate at temperatures below normal body temperature (37 degrees Celsius) and will dissolve again if the blood is heated. Cryoglobulinemia can be associated with various diseases such as multiple myeloma and hepatitis C infection.



Cryoglobulinemia is classically grouped into three types according to the Brouet classification.[2] Type I is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström macroglobulinemia.[3] Types II and III are strongly associated with infection by the hepatitis C virus.[3]

There are three different types of cryoglobulins that have been observed to form in the blood.[4]

Type Composition Percent Description
Type I isolated monoclonal immunoglobulins 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.[5]
Type II immunocomplexes formed by monoclonal IgM 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.[5]
Type III immunocomplexes formed by polyclonal IgM 25-30% of the reported cases These have very similar function to the type II cryoglobulins, however they are composed of polyclonal IgM and IgG molecules.[5]

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.[5]

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[6]


These proteins may be present in mycoplasma pneumonia,post streptococcal glomerulonephritis, 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.[7] 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.

See also


  1. ^ "cryoglobulinemia" at Dorland's Medical Dictionary
  2. ^ Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M (1974). "Biologic and clinical significance of cryoglobulins. A report of 86 cases". Am. J. Med. 57 (5): 775–88. doi:10.1016/0002-9343(74)90852-3. PMID 4216269. 
  3. ^ a b Ferri C, Zignego AL, Pileri SA (2002). "Cryoglobulins". J. Clin. Pathol. 55 (1): 4–13. doi:10.1136/jcp.55.1.4. PMC 1769573. PMID 11825916. 
  4. ^ "cryoglobulin" at Dorland's Medical Dictionary
  5. ^ a b c d Tedeschi A, Baratè C, Minola E, Morra E (2007). "Cryoglobulinemia". Blood Rev. 21 (4): 183–200. doi:10.1016/j.blre.2006.12.002. PMID 17289231. 
  6. ^ Tissot JD, Schifferli JA, Hochstrasser DF, et al. (1994). "Two-dimensional polyacrylamide gel electrophoresis analysis of cryoglobulins and identification of an IgM-associated peptide". J. Immunol. Methods 173 (1): 63–75. doi:10.1016/0022-1759(94)90284-4. PMID 8034987. 
  7. ^ Pascual M, Perrin L, Giostra E, Schifferli JA (1990). "Hepatitis C virus in patients with cryoglobulinemia type II". J. Infect. Dis. 162 (2): 569–70. doi:10.1093/infdis/162.2.569. PMID 2115556. 
  8. ^ Monti G, Galli M, Invernizzi F, et al. (February 1995). "Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias". QJM 88 (2): 115–26. PMID 7704562. 

External links