Clinical Background
The majority of cryoglobulinemias are secondary manifestations of other diseases and not “essential” as previously reported.
Classification
- Type I (25%) - monoclonal immunoglobulins, consisting of IgM, occasionally IgG and, rarely, IgA or Bence Jones protein
- Associated diseases - plasma cell dyscrasia, MGUS, lymphoproliferative diseases
- Type II (25%) - mixed cryoglobulins, where a monoclonal immunoglobulin is directed against a polyclonal immunoglobulin
- Includes monoclonal IgM or, occasionally, IgG or IgA, complexed with autologous normal IgG
- Associated diseases - hepatitis C virus (HCV), autoimmune disorders, other infections
- Type III (50%) - polyclonal proteins made of 2 or more immunoglobulins, none of which are homogeneous
- Includes polyclonal IgM and IgG
- Associated disorders - autoimmune, HCV, lymphoproliferative, other infections
Pathophysiology
- Cryoglobulins, proteins that reversibly precipitate at 0-4° C, are usually associated with plasma cell and lymphoproliferative disorders, but may also occur in:
- Connective tissue diseases
- Hepatitis C infection
- Other infections such as infectious mononucleosis and cytomegalovirus disease
- Low levels of cryoglobulins may also occur in apparently healthy individuals
Refer to Cryoglobulinemia topic at www.arupconsult.com for a table of Clinical Conditions that may be associated with Cryoglobulinemia
Clinical Presentation
- Target organs - skin, nerves, kidney, liver
- Symptoms related to cryoglobulinemia Types II and III result from the tendency of cryoglobulins to precipitate at low temperatures, which occlude blood vessels, resulting in vasculitic symptoms
- Vascular purpura (palpable purpura)
- Bleeding tendencies
- Cold-induced urticaria
- Raynaud phenomenon
- Digital pain and cyanosis
- All cryoglobulins can lead to renal disease such as glomerulonephritis
- Essential mixed cryoglobulinemia, a vasculitic syndrome, results in purpura, arthralgia and weakness
- Often associated with lymphadenopathy, hepatosplenomegaly and renal failure
See Also
Diagnosis
Diagnosis
- Indications for testing
- Appropriate clinical signs and symptoms are present
- Laboratory testing
- Cryoglobulin testing - positive circulating cryoglobulins
- Serum protein electrophoresis should be preformed in patients with cryoglobulinemia to identify the specific immunoglobulins present and determine if there is a monoclonal protein present
- Histology studies
- Skin biopsy demonstrating immune complex deposition to secure diagnosis in vasculitis
Tests generally appear in the order most useful for common clinical situations
| Test name: Cryoglobulin, Qualitative with Reflex to Quantitative IgA, IgG, & IgM
|
| ARUP #: 0050187 |
| Methodology: Nephelometry/Cold Precipitation
|
Use: First test to order in the evaluation of cryoglobulinemiaConfirm cryoglobulinemia |
| Limitations: Not helpful in distinguishing etiology of cryoglobulinemia |
| Follow-up:
Serum electrophoresis should be performed
|
| Test name: Cryoglobulin, Qualitative
|
| ARUP #: 0050185 |
| Methodology: Cold Precipitation
|
| Use: Confirm cryoglobulinemia |
| Limitations: Not helpful in distinguishing etiology of cryoglobulinemia |
| Follow-up:
Serum electrophoresis should be performed
|
References
Cited References
Tedeschi A, Barate C, Minola E, Morra E. Cryoglobulinemia. Blood Rev.
2007;
21(
4):
183-200.
General References
Amdo TD, Welker JA. An approach to the diagnosis and treatment of cryofibrinogenemia. Am J Med.
2004;
116(
5):
332-337.
Braun GS, Horster S, Wagner KS, Ihrler S, Schmid H. Cryoglobulinaemic vasculitis: classification and clinical and therapeutic aspects. Postgrad Med J.
2007;
83(
976):
87-94.
Cacoub P, Costedoat-Chalumeau N, Lidove O, Alric L. Cryoglobulinemia vasculitis. Curr Opin Rheumatol.
2002;
14(
1):
29-35.
Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol.
2006;
18(
1):
54-63.
Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol.
2002;
55(
1):
4-13.
Gertz MA. Cold agglutinin disease and cryoglobulinemia. Clin Lymphoma.
2005;
5(
4):
290-293.
Shihabi ZK. Cryoglobulins: an important but neglected clinical test. Ann Clin Lab Sci.
2006;
36(
4):
395-408.
Stone MJ, Merlini G, Pascual V. Autoantibody activity in Waldenstrom's macroglobulinemia. Clin Lymphoma.
2005;
5(
4):
225-229.
Trendelenburg M, Schifferli JA. Cryoglobulins in chronic hepatitis C virus infection. Clin Exp Immunol.
2003;
133(
2):
153-155.
Medical Reviewers
Hill, Harry R., M.D. Group Medical Director, Laboratory of Immunology, ARUP Laboratories, and Executive Director of the ARUP Institute for Clinical and Experimental Pathology; Professor and Division Head, Clinical Pathology, University of Utah
Litwin, Christine, M.D. Medical Director, Immunology at ARUP Laboratories; Professor, Clinical Pathology, University of Utah
Comprehensive Review: July 2008
Last Update: July 2008
