Cryoglobulinemia pathophysiology

Jump to navigation Jump to search

Cryoglobulinemia Microchapters


Patient Information


Historical Perspective




Differentiating Cryoglobulinemia from other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications and Prognosis


Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings


X Ray




Other Imaging Findings

Other Diagnostic Studies


Medical Therapy


Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Cryoglobulinemia pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides


American Roentgen Ray Society Images of Cryoglobulinemia pathophysiology

All Images
Echo & Ultrasound
CT Images

Ongoing Trials at Clinical

US National Guidelines Clearinghouse

NICE Guidance

FDA on Cryoglobulinemia pathophysiology

CDC on Cryoglobulinemia pathophysiology

Cryoglobulinemia pathophysiology in the news

Blogs on Cryoglobulinemia pathophysiology

Directions to Hospitals Treating Cryoglobulinemia

Risk calculators and risk factors for Cryoglobulinemia pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]Feham Tariq, MD [3]


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 lymphoproliferation. Cryoglobulins have a tendency to redissolve on rewarming.


  • 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 lymphoproliferation.
  • 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 cryoglobulinemia is usually seen in patients suffering from disorders of lymphoproliferation such as:
    • Multiple myelomas (MM)
    • Monoclonal gammopathy of undetermined significance (MGUS)
    • Waldenstrom's macroglobulinemia
    • Chronic lymphocytic leukemia (CLL)

Mechanisms leading to precipitation of immunoglobulins (Ig)

The solubility of proteins depends upon concentration, hydrophobicity, size and surface charge, as well as the solution temperature, pH and ionic strength. The following mechanisms have been proposed to be implicated in the precipitation of immunoglobulins in patients suffering from type I cryoglobulinemia:

(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

  • An abnormal glycosylation event in the heavy chain hypervariable region apparently leads to precipitation of immunoglobulins in type I cryoglobulinemia.[1]

(ii) Reduced concentration of sialic acid

  • Increased content of hydrophobic amino acids, decreased tyrosine and sialic acid residues has been known to lead to decreased solubility of immunoglobulins (Ig).[2]

(iii) Deficiency of galactose in the Fc portion of the Ig

  • Decreased galactose concentration in the Fc portion of immunoglobulins leads to decreased plasma solubility of immunoglobulins.[3]
  • The terminal sialylation of these proteins is dependent on the presence of galactose residues, hence decreased galactose leads to decreased sialylation, which in turn promotes precipitation of immunoglobulins.[4]
  • The decreased glycosylation has also been linked to the increased nephrophilic nature of cryoglobulins.

(iv) Somatic Ig mutations

  • Somatic hypermutation in the variable regions of the heavy (VH) and light chains (VL)  may also contribute to the insolubility of immunoglobulins.
  • Increased intraclonal VH and/or VL gene diversity has been shown to be present in various patients suffering from hepatitis C associated mixed cryoglobulinemia.[5]

(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:

  1. Hyperviscosity is typically associated with CG due to hematological malignancies and monoclonal immunoglobulins.
  2. "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.


  1. "Atypical glycosylation of an IgG monoclonal cryoimmunoglobulin".
  2. Tomana M, Schrohenloher RE, Koopman WJ, Alarcón GS, Paul WA (March 1988). "Abnormal glycosylation of serum IgG from patients with chronic inflammatory diseases". Arthritis Rheum. 31 (3): 333–8. PMID 3358797.
  3. Trendelenburg M, Schifferli JA (August 2003). "Cryoglobulins in chronic hepatitis C virus infection". Clin. Exp. Immunol. 133 (2): 153–5. PMC 1808770. PMID 12869018.
  4. Otani M, Kuroki A, Kikuchi S, Kihara M, Nakata J, Ito K, Furukawa J, Shinohara Y, Izui S (November 2012). "Sialylation determines the nephritogenicity of IgG3 cryoglobulins". J. Am. Soc. Nephrol. 23 (11): 1869–78. doi:10.1681/ASN.2012050477. PMC 3482736. PMID 23024299.
  5. "" (PDF).

Template:WikiDoc Sources