Cryoglobulinemia pathophysiology: Difference between revisions
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=== Type I cryoglobulinemia (Monoclonal immunoglobulin) === | === Type I cryoglobulinemia (Monoclonal immunoglobulin) === | ||
'''Key background associations''' | |||
==== '''Key background associations''' ==== | |||
* Type I cryglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as: | * Type I cryglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as: | ||
** Multiple myeloma (MM) | ** Multiple myeloma (MM) | ||
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** Waldenstrom's macroglobulinemia | ** Waldenstrom's macroglobulinemia | ||
** Chronic lymphocytic leukemia (CLL) | ** Chronic lymphocytic leukemia (CLL) | ||
'''Chronic immune stimulation''' | |||
==== Mechanisms leading to precipitation of immunoglobulins (Ig) ==== | |||
'''(a) Chronic immune stimulation''' | |||
* The lymphoproliferative and hematological disorders listed above lead to chronic activation of the immune system and production of higher concentrations of monoclonal immunoglobulins (usually IgG or IgM) at temperatures below 37 degrees celcius. | * The lymphoproliferative and hematological disorders listed above lead to chronic activation of the immune system and production of higher concentrations of monoclonal immunoglobulins (usually IgG or IgM) at temperatures below 37 degrees celcius. | ||
'''Aggregation of immunoglobulins''' | '''(b) Aggregation of immunoglobulins''' | ||
* Self aggregation through Fc fragment of immunoglobulins is the proposed mechanism of production of cryoglobulins in type I cryoglobulinemia | * Self aggregation through Fc fragment of immunoglobulins is the proposed mechanism of production of cryoglobulins in type I cryoglobulinemia | ||
'''Modification of Ig heavy (H) and light (L) chains''' | '''(i) Modification of Ig heavy (H) and light (L) chains''' | ||
* | |||
'''Reduced concentration of sialic acid''' | '''(ii) Reduced concentration of sialic acid''' | ||
'''Deficiency of galactose in the Fc portion of the Ig''' | '''(iii) Deficiency of galactose in the Fc portion of the Ig''' | ||
'''Somatic Ig mutations''' | '''(iv) Somatic Ig mutations''' | ||
'''Non-specific Fc–Fc interactions''' | '''(v) Non-specific Fc–Fc interactions''' | ||
It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG: | It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG: | ||
Revision as of 15:59, 1 May 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Overview
Pathophysiology
Cryoglobulins are proteins (single or mixed immunoglobulins) that precipitate from serum and plasma when cooled. They are produced due to chronic immune system activation and lypmphoproliferation. Cryoglobulins have a tendency to redissolve on rewarming. The pathogenesis of cryoglobulinemia differs slightly based on the type of disorder and disease associations. The following are the major mechanisms involved in the pathogenesis of cryoglobulinemia:
Type I cryoglobulinemia (Monoclonal immunoglobulin)
Key background associations
- Type I cryglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as:
- Multiple myeloma (MM)
- Monoclonal gammopathy of undetermined significance (MGUS)
- Waldenstrom's macroglobulinemia
- Chronic lymphocytic leukemia (CLL)
Mechanisms leading to precipitation of immunoglobulins (Ig)
(a) Chronic immune stimulation
- The lymphoproliferative and hematological disorders listed above lead to chronic activation of the immune system and production of higher concentrations of monoclonal immunoglobulins (usually IgG or IgM) at temperatures below 37 degrees celcius.
(b) Aggregation of immunoglobulins
- Self aggregation through Fc fragment of immunoglobulins is the proposed mechanism of production of cryoglobulins in type I cryoglobulinemia
(i) Modification of Ig heavy (H) and light (L) chains
(ii) Reduced concentration of sialic acid
(iii) Deficiency of galactose in the Fc portion of the Ig
(iv) Somatic Ig mutations
(v) Non-specific Fc–Fc interactions
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.
- MC is closely associated with hepatitis C infection and is thought to activate B lymphocytes by binding to CD81.
- 80-95% of patients with MC have circulating anti-HCV antibodies or circulating HCV RNA in the serum or within the cryoprecipitate.
- Polyclonal IgG anti-HCV have been noted in the cryoprecipitate as well.
- Approximately 50% of patients with chronic hepatitis C and 15% with hepatitis B will have circulating MC (1/2 Type II, 2/3 Type III).
- It is unclear what the antigen trigger is for production of the MC, but it is though that the hepatitis C viral RNA itself may be the factor since it is found in high quantities in the cryoprecipitate.