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

Cryoglobulinemia[1] or cryoglobulinaemia is a medical condition in which the blood contains large amounts of cryoglobulins – proteins (mostly immunoglobulins themselves) that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells. Cryoglobulins typically precipitate at temperatures below normal body temperature (37 °C) and will dissolve again if the blood is heated. The precipitated clump can block blood vessels and cause toes and fingers to become gangrenous. Cryoglobulinemia can be associated with various diseases such as multiple myeloma and hepatitis C infection.[2] Cryoglobulins usually consist of IgM directed against the Fc region of IgG.[3]


Cryoglobulinemia is classically grouped into three types according to the Brouet classification.[4] Type I is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström macroglobulinemia.[5] Types II and III are strongly associated with infection by the hepatitis C virus.[5] Type III is strongly associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis.

There are three different types of cryoglobulins that have been observed to form in the blood.[6]

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 (Bence Jones protein); or, they may accumulate in blood serum in the event of renal failure.[7]
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 or IgA, 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.[7]
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.[7]

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.[7]

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[8]


These proteins may be present in Mycoplasma pneumonia pneumonitis, 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 as a symptom in 35% of chronic hepatitis C infections.[9][10] It can also occur in hepatitis B and human immunodeficiency virus infections.[11] It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG:

See also[edit]


  1. ^ "Cryoglobulinemia" at Dorland's Medical Dictionary
  2. ^ Peveling-Oberhag, J.; Arcaini, L.; Hansmann, M. L.; Zeuzem, S. (2013). "Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management". Journal of Hepatology. 59 (1): 169–177. PMID 23542089. doi:10.1016/j.jhep.2013.03.018. 
  3. ^ Adam M Tritsch MD. Herbert S Diamond, MD, ed. "Cryoglobulinemia". 
  4. ^ 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. PMID 4216269. doi:10.1016/0002-9343(74)90852-3. 
  5. ^ a b Ferri C, Zignego AL, Pileri SA (2002). "Cryoglobulins". J. Clin. Pathol. 55 (1): 4–13. PMC 1769573Freely accessible. PMID 11825916. doi:10.1136/jcp.55.1.4. 
  6. ^ "Cryoglobulin" at Dorland's Medical Dictionary
  7. ^ a b c d Tedeschi A, Baratè C, Minola E, Morra E (2007). "Cryoglobulinemia". Blood Rev. 21 (4): 183–200. PMID 17289231. doi:10.1016/j.blre.2006.12.002. 
  8. ^ 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. PMID 8034987. doi:10.1016/0022-1759(94)90284-4. 
  9. ^ Franco Dammacco & Domenico Sansonno (September 12, 2013). "Review Article: Therapy for Hepatitis C Virus–Related Cryoglobulinemic Vasculitis". N Engl J Med. 369 (11): 1035–1045. PMID 24024840. doi:10.1056/NEJMra1208642. 
  10. ^ 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. PMID 2115556. doi:10.1093/infdis/162.2.569. 
  11. ^ Liang TJ (May 2009). "Hepatitis B: the virus and disease". Hepatology (Baltimore, Md.). 49 (5 Suppl): S13–21. PMC 2809016Freely accessible. PMID 19399811. doi:10.1002/hep.22881. Retrieved 2011-12-08. 
  12. ^ 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. 

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