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  • Cryoglobulins are immunoglobulins that precipitate in the cold and disolve on rewarming

Three Types of Cryoglobulins

  • Type I Cryoglobulin: monoclonal antibody that does not have rheumatoid factor activity
    • Associated with lymphoma, Waldenström’s macroglobulinemia, and multiple myeloma
    • Because type I cryoglobulins do not easily activate complement, patients with type I are asymptomatic until the level of cryoglobulinemia is sufficiently high to cause hyperviscosity syndrome
  • Type II Cryoglobulin: monoclonal rheumatoid factor (antibody that binds to the Fc fragment of IgG)
    • Associated with lymphoproliferative diseases, rheumatic diseases, and chronic infections (HCV > HBV)
  • Type III Cryoglobulin: polyclonal rheumatoid factor (antibody that binds to the Fc fragment of IgG)
    • Associated with rheumatic diseases and chronic infections

Essential Cryoglobulinemia

  • When disease occurs without an associated predisposing condition

Mixed Cryoglobulinemia

  • Refers to type II and III cryoglobulinemia
  • Mixed Cryoglobulinema frequently presents as hypersensitivity (leukocytoclastic) vasculitis
  • Most patients diagnosed with type II or type III mixed essential cryoglobulinemia have the disease as an immune response to chronic hepatitis C infection (and less commonly, hepatitis B)
    • The role of hepatitis C virus is suggested by finding that the cryoglobulins in these patients are enriched with anti–hepatitis C antibody and hepatitis C RNA
    • Moreover, antviral therapy can remit the disease in some patients


  • PFT’s
    • Increased DLCO: during active diffuse alveolar hemorrhage
  • Open Lung Biopsy (OLB)
    • Tissue Ab staining: granular pattern (IgG)
  • CXR/Chest CT Patterns
    • Interstitial infiltrates: may appear due to ILD or chronic/ recurrent DAH
    • Diffuse or patchy focal alveolar infiltrates: seen in cases with DAH
  • Serology
    • ANA/RF: variable
    • Anti-DNA/ANCA/Anti-GBM: negative
    • C3/C4/CH50: decreased-normal
    • Cryocrit (need to deliver warm to lab): positive
    • HBsAg:
  • ESR: usually elevated
  • CBC: anemia (iron deficiency) is usually present/leukocytosis
  • Urinalysis: abnormal
  • Renal Bx: proliferative glomerulonephritis, crescents
    • Immunofluorescence: positive, granular

Clinical Presentations (vary based on types of cryoglobulins)

Type I Cryoglobulinemia

  • Hyperviscosity

Type II/III Cryoglobulinemia

  • Arthritis (see Arthritis, [[Arthritis]])
  • Dermal Hypersensitivity (Leukocytoclastic) Vasculitis (see Vasculitis, [[Vasculitis]])
    • Diagnosis
      • Pathology: dermal leukocytoclastic vasculitis -> perivascular polymorphonuclear infiltration with tissue extravasation and fragmentation in the dermis
    • Clinical
      • Splinter Hemorrhages
      • Recurrent Lower Extremity Purpura (see Purpura, [[Purpura]])
  • Interstitial Pulmonary Fibrosis (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]])
    • Epidemiology: most common pulmonary manifestation
    • Physiology: likely due to immune complex-mediated systemic vasculitis
    • Diagnosis:
      • Pathology: inflammation and fibrosis of alveolar walls
    • Clinical
      • Dyspnea
  • Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])
    • Epidemiology: extremely rare (only a few reported cases)
    • Diagnosis
      • Pathology: pulmonary capillaritis
    • Clinical: symptoms usually present for only days-weeks before presentation
      • Chest Pain
      • Cough
      • Dyspnea
      • Hemoptysis: may be absent initially in some cases even after significant bleed
  • Glomerulonephritis (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Neuropathy (see Peripheral Neuropathy, [[Peripheral Neuropathy]])
  • Hepatitis


Treatment of Type I Cryoglobulinemia-Related Hyperviscosity

  • Plasmapheresis
  • Chemotherapy (if associated with an underlying malignancy)

Treatment of Type II/III (Mixed) Cryoglobulinemia-Related Vasculitis

  • Prednisone
  • Cytoxan

Treatment of Type II/III (Mixed) Cryoglobulinemia Associated with Hepatitis C

  • Brief use of prednisone, followed by 6 mo of interferon alfa has produced clinical and liver function test improvement
  • However, relapse of liver disease and vasculitis often occurs when interferon alfa is stopped


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