Cryoglobulinemia

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Overview
Cryoglobulinemia is the presence of high amount of heavy globulins (e.g. IgM) in the bloodstream which thicken or gel on exposure to cold. Cryoglobulins are circulating immunoglobulins or proteins that become insoluble at less than 4 degrees Celsius. The reaction is reversible; redissolution occurs at 37 degrees Celsius. Such proteins are called cryoglobulins. Cryoglobulinemia can lead to a medium-sized vessel vasculitis due to vascular deposition of circulating immune complexes. This leads to the triad of palpable purpura, arthralgias and peripheral neuropathy. The relationship of cryoglobulins and hepatitis C infection as well as B cell neoplasia provides an interesting link between infection, autoimmune disease and lymphoproliferative disorders.

Classification
Cryoglobulinemia is classically grouped into three types according to the Brouet classification.

Type I
Type I is is a monoclonal immunoglobulin and is most commonly encountered in patients with a plasma cell dyscrasia such as multiple myeloma or Waldenström macroglobulinemia. It can lead to a glomerulopathy that is distinct from light chain disease in amyloidosis.

Type II
Type II is essential mixed cryoglobulinemia and the cryoglobulins are a polyclonal IgG and a momoclonal IgM rheumatoid factor directed against IgG. Epstein-Barr Virus (EBV), HIV and Hepatitis B have been implicated but the majority is due to Hepatitis C (HCV).

Type III
Type III is also a mixed cryoglobulinemia (MC) where both the IgG and IgM are polyclonal. It is seen in various autoimmune disorders and lymphoreticular disease as well as hepatitis C in almost 50%. There is a 50% mortality rate at 15 years after diagnosis of MC.

Differential Diagnosis of Associated Disease States
Cryoglobulins may be present in mycoplasma pneumonia, 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.

Pathophysiology & Etiology
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.

History and Symptoms

 * Palpable purpura, arthralgias, and neuropathy are common findings.
 * Nonspecific systemic complaints, hepatosplenomegaly and hypocomplementemia are noted.
 * Low-grade Non-Hodgkins lymphomas may occur with increased frequency among these patients.
 * Renal disease occurs in 20% of patients at diagnosis and eventually develops in up to 60%, usually after the development of purpura.
 * Renal involvement is more common in Type II than Type III MC.
 * Most patients present with ayamptomatic hematuria and poteinuria, but frank nephrotic syndrome and acute renal failure can develop.
 * The characteristic findings on renal biopsy are
 * Intraluminal thrombi
 * Diffuse IgM deposition in the capillary loops
 * Subendothelial deposits in a “curvilinear” pattern on EM.
 * Only 14% develop end stage renal disease (ESRD) at 10 years after a renal biopsy demonstrates MC.
 * Recurrent MC can affect up to 70% of transplanted kidneys, but does not preclude transplantation since most of these grafts do not fail.

Electrolyte and Biomarker Studies

 * At least 20cc of blood should be drawn in the fasting state (lipids interfere) and sent to the lab in warm water.
 * The blood is spun at body temperature then the serum is cooled to see if a precipitate develops.
 * “Cryocrits” of up to 50% have been noted.
 * The cryoprecipitates is then analyzed for type of immune complex by immunofixation.
 * If anti-HCV and HCV RNA are negative but hepatits C is still suspected, the cryoprecipitate can be assayed directly for HCV RNA and anti-HCV antibody.
 * Spurious leukocytosis and thrombocytosis from the cryoglobulin particles have been noted if the sample is tested a lower temperature.
 * White blood cell count (WBC) of >40K normalize with warming of the blood.

Other Diagnostic Studies
Skin biopsy can be of value in establishing the diagnosis.

Treatment

 * The main indication for therapy is progressive end organ disease.

Acute Pharmacotherapies

 * Outside of the acute setting, immunosuppresive agents are thought to worsen the course of MC associated with HCV.
 * Interferon-alfa and ribavirin have been used in combination.
 * MC response, predictably, was related to the response rate of the underlying HCV to these agents.
 * Ribavirin should not be used in patients with glomerular filtration rate (GFR) <50 cc/min.

Future or Investigational Therapies

 * In patients with acute, severe disease, plasmapheresis has been used in conjunction with high dose steroids and cytoxan.
 * Uncontrolled studies demonstrated a reduction in creatinine in up to 87% of patients.

Acknowledgements
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