Cryoglobulinemia can be associated with an immune-complex mediated, small-vessel vasculitis. Cryoglobulins are abnormal proteins in the blood. If you have cryoglobulinemia (kry-o-glob-u-lih-NEE-me-uh), these proteins may clump together at temperatures below 98.6 F (37 C).

Chronic infec­tion with hepatitis C is the most common underlying condition; cryoglobulinemic vasculitis also can occur with other chronic infections (such as subacute bacterial endo­carditis, osteomyelitis, HIV, and hepatitis B), with connec­tive tissues diseases (especially Sjögren syndrome), and with lympho-proliferative disorders. The cryoglobulins associated with vasculitis are cold-precipitable immune complexes consisting of rheumatoid factor and IgG (rheu­matoid factor is an autoantibody to the constant region of IgG).


The rheumatoid factor component can be monoclo­nal (type II cryoglobulins) or polyclonal (type III cryo­globulins). (Type I cryoglobulins are cryoprecipitable monoclonal proteins that lack rheumatoid factor activity; these cause cold-induced hyperviscosity syndromes, not vasculitis, and are associated with B-cell lymphoproliferative diseases.)


The symptoms of cryoglobulinemia vary depending on the organ systems affected. Some people may have no signs except for elevated cryoglobulin levels detected in a blood test. However, when symptoms are present, they typically include the following:

  • Rash with red spots and/or purplish discoloration from bleeding under the skin, mostly affecting the lower legs. Hives may develop, as well as open sores (ulcers) and loss of tissue (necrosis).
  • Severe fatigue
  • Joint pain
  • Numbness, tingling and/or burning sensation of the extremities, especially hands and feet, caused by nerve damage
  • Muscle pain and weakness
  • Discoloration of hands in cold temperatures
  • Swollen lymph nodes
  • Abdominal pain
  • Kidney damage (Note: A patient can have kidney damage without having symptoms; therefore, patients with vasculitis of any form should have regular urine tests.)

When the brain is involved, a patient may experience headaches or strokes. Heart involvement can cause chest pain and congestive heart failure (difficulty breathing, swelling of the legs).


Antiviral regimens that do not include interferon are first-line therapy for hepatitis C–associated cryoglobulinemic vasculitis that is neither life- nor organ-threatening. Patients with severe cryoglobulinemic vasculitis (eg, exten­sive digital gangrene, extensive neuropathy, and rapidly progressive glomerulonephritis) and hepatitis C should receive immunosuppressive therapy with corticosteroids and either rituximab or cyclophosphamide as well as interferon-free antiviral therapy; plasma exchange may provide additional benefit in selected cases.


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