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| {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} | | {{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}} |
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| ==Overview== | | ==[[Cryoglobulinemia overview|Overview]]== |
| '''Cryoglobulinemia''' is the presence of high amount of heavy [[globulin]]s (e.g. [[IgM]]) in the [[bloodstream]] which thicken or gel on exposure to cold. Cryoglobulins are circulating [[immunoglobulins]] or [[protein]]s that become insoluble at less than 4 degrees Celsius. The reaction is reversible; redissolution occurs at 37 degrees Celsius. Such proteins are called [[cryoglobulin]]s. 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]], [[arthralgia]]s 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.
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| ==Classification== | | ==[[Cryoglobulinemia historical perspective|Historical Perspective]]== |
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| Cryoglobulinemia is classically grouped into three types according to the Brouet classification.<ref name="pmid4216269">{{cite journal |author=Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M |title=Biologic and clinical significance of cryoglobulins. A report of 86 cases |journal=Am. J. Med. |volume=57 |issue=5 |pages=775–88 |year=1974 |pmid=4216269 |doi=}}</ref> | | ==[[Cryoglobulinemia classification|Classification]]== |
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| ===Type I=== | | ==[[Cryoglobulinemia pathophysiology|Pathophysiology]]== |
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| '''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]].<ref name="Ferri2002">{{cite journal |author=Ferri C, Zignego AL, Pileri SA |title=Cryoglobulins |journal=J. Clin. Pathol. |volume=55 |issue=1 |pages=4–13 |year=2002 |pmid=11825916 |doi=}}</ref> It can lead to a glomerulopathy that is distinct from light chain disease in amyloidosis.
| | ==[[Cryoglobulinemia differential diagnosis|Differentiating Cryoglobulinemia from other Diseases]]== |
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| ===Type II=== | | ==[[Cryoglobulinemia epidemiology and demographics|Epidemiology and Demographics]]== |
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| '''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). <ref name="Ferri2002"/>
| | ==[[Cryoglobulinemia risk factors|Risk Factors]]== |
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| ===Type III=== | | ==[[Cryoglobulinemia natural history|Natural History, Complications and Prognosis]]== |
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| '''Type III''' is also a mixed cryoglobulinemia (MC) where both the IgG and IgM are polyclonal.
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| 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.
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| ==Differential Diagnosis of Associated Disease States== | | ==Diagnosis== |
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| Cryoglobulins may be present in [[mycoplasma]] [[pneumonia]], [[multiple myeloma]], certain [[leukemia]]s, primary [[macroglobulinemia]], and some [[autoimmune disease]]s, such as [[systemic lupus erythematosus]] and [[rheumatoid arthritis]]. This is also found occasionally as a [[symptom]] in 35% of chronic [[hepatitis C]] infections.<ref>Pascual M, Perrin L, Giostra E, Schifferli JA. ''Hepatitis C virus in patients with cryoglobulinemia type II.'' J Infect Dis 1990;162:569-570. PMID 2115556.</ref>
| | [[Cryoglobulinemia history and symptoms|History and Symptoms ]] | [[ Cryoglobulinemia physical examination|Physical Examination]] | [[Cryoglobulinemia laboratory findings|Laboratory Findings]] | [[Cryoglobulinemia x ray|X Ray]] | [[Cryoglobulinemia CT|CT]] | [[Cryoglobulinemia MRI|MRI]] | [[Cryoglobulinemia ultrasound|Ultrasound]] | [[Cryoglobulinemia other imaging findings|Other Imaging Findings]] | [[Cryoglobulinemia other diagnostic studies|Other Diagnostic Studies]] |
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| == Pathophysiology & Etiology== | | ==Treatment== |
| | [[Cryoglobulinemia medical therapy|Medical Therapy]] | [[Cryoglobulinemia surgery |Surgery]] | [[Cryoglobulinemia primary prevention|Primary Prevention]] | [[Cryoglobulinemia secondary prevention|Secondary Prevention]] | [[Cryoglobulinemia cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Cryoglobulinemia future or investigational therapies|Future or Investigational Therapies]] |
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| It is important to note that these two different, yet highly representative, clinical syndromes generally reflect different types of underlying CG:
| | ==Case Studies== |
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| #Hyperviscosity is typically associated with CG due to hematological malignancies and monoclonal immunoglobulins.
| | [[Cryoglobulinemia case study one|Case #1]] |
| #"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.
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| * MC is closely associated with hepatitis C infection and is thought to activate B lymphocytes by binding to CD81.
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| * 80-95% of patients with MC have circulating anti-HCV antibodies or circulating HCV RNA in the serum or within the cryoprecipitate.
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| * Polyclonal IgG anti-HCV have been noted in the cryoprecipitate as well.
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| * 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).
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| * 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.
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| == History and Symptoms ==
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| *Palpable [[purpura]], [[arthralgias]], and [[neuropathy]] are common findings.
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| *Nonspecific systemic complaints, [[hepatosplenomegaly]] and hypocomplementemia are noted.
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| *Low-grade [[Non-Hodgkins lymphoma]]s may occur with increased frequency among these patients.
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| *Renal disease occurs in 20% of patients at diagnosis and eventually develops in up to 60%, usually after the development of purpura.
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| *:* Renal involvement is more common in Type II than Type III MC.
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| *:* Most patients present with ayamptomatic [[hematuria]] and [[poteinuria]], but frank [[nephrotic syndrome]] and [[acute renal failure]] can develop.
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| * The characteristic findings on renal biopsy are
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| *:# Intraluminal thrombi
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| *:# Diffuse [[IgM]] deposition in the capillary loops
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| *:# Subendothelial deposits in a “curvilinear” pattern on EM.
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| * Only 14% develop end stage renal disease ([[ESRD]]) at 10 years after a renal biopsy demonstrates MC.
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| * Recurrent MC can affect up to 70% of transplanted kidneys, but does not preclude transplantation since most of these grafts do not fail.
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| == Laboratory Findings ==
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| === Electrolyte and Biomarker Studies ===
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| * At least 20cc of blood should be drawn in the fasting state (lipids interfere) and sent to the lab in warm water.
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| *:* The blood is spun at body temperature then the serum is cooled to see if a precipitate develops.
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| *:*:* “Cryocrits” of up to 50% have been noted.
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| *:* The cryoprecipitates is then analyzed for type of immune complex by immunofixation.
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| *:* 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.
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| *:* Spurious leukocytosis and thrombocytosis from the cryoglobulin particles have been noted if the sample is tested a lower temperature.
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| *:* [[White blood cell]] count ([[WBC]]) of >40K normalize with warming of the blood.
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| === Other Diagnostic Studies ===
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| Skin biopsy can be of value in establishing the diagnosis.
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| == Treatment ==
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| * The main indication for therapy is progressive end organ disease.
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| === Acute Pharmacotherapies ===
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| * Outside of the acute setting, immunosuppresive agents are thought to worsen the course of MC associated with HCV.
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| *:* Interferon-alfa and ribavirin have been used in combination.
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| * MC response, predictably, was related to the response rate of the underlying HCV to these agents.
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| * Ribavirin should not be used in patients with glomerular filtration rate (GFR) <50 cc/min.
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| == Future or Investigational Therapies ==
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| * In patients with acute, severe disease, plasmapheresis has been used in conjunction with high dose steroids and cytoxan.
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| *:* Uncontrolled studies demonstrated a reduction in creatinine in up to 87% of patients.
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| == Acknowledgements == | | == Acknowledgements == |
| The content on this page was first contributed by: {{CMG}} | | The content on this page was first contributed by: {{CMG}} |
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| ==Related Chapters== | | ==Related Chapters== |
| Line 109: |
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| {{Immune disorders}} | | {{Immune disorders}} |
| {{Blood}} | | {{Blood}} |
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