Differential Diagnosis

This is a vascular disorder secondary to the presence of cryoglobulins. Cryoglobulins are immunoglobulins that precipitate at low temperatures, and this phenomenon is reversible upon warming. There are two types of cryoglobulins. Type I cryoglobulins are single, monoclonal proteins, and their presence is associated with multiple myeloma, macroglobulinemia, and rarely, other lymphocytic malignancies. Type II cryoglobulins are composed of more than one class of immunoglobulins. Type II disease may be primary or associated with an underlying disease process.

Type I cryoglobulins are easily detected on serum protein electrophoresis and appear as monoclonal components. Often, this disorder is present without symptoms; however, Raynaud's phenomenon, livedo reticularis, purpura or ischemic ulcers may be associated with this disorder. The aforementioned symptoms are believed to result from hyperviscosity and plugging of the microcirculation when the body is cooled and cryoglobulin precipitation is induced. Vasculitis is a rare complication of type I disease. Immunoglobulins associated with this disorder are, in decreasing order of frequency, as follows: IgG > IgM > IgA.

Type II cryoglobulins are composed of more than one class of immunoglobulins; therefore, this disorder is referred to as mixed cryoglobulinemia. Mixed cryoglobulins may be further subdivided into those in which one component is monoclonal and those in which all components are polyclonal. There appears to be little clinical significance to this distinction however. Type II disease occurs twice as frequently as type I disease. IgM and IgG molecules are frequently encountered in mixed cryoglobulins; however, antigens such as hepatitis B virus, other infecting agents, or nuclear and complement proteins may also be present. The IgM portion often has antiglobulin activity (rheumatoid factor), which is responsible for the complex formation and the cryoprecipitation.  This condition is also seen with chronic hepatitis C infection.

Symptoms of cryoglobulinemia include palpable purpura, urticaria, skin ulcers, arthralgias, glomerulonephritis, neuropathy, hepatomegaly, splenomegaly, lymphadenopathy, and Raynaud's phenomenon. Less commonly, thyroiditis, Sjogrens syndrome, pneumonitis, or pericarditis may be associated. The course is variable and depends on which organ systems are involved and which underlying disease initiated the cryoglobulinemia. Progressive glomerulonephritis is a most serious complication.

Associated lab abnormalities include elevated serum gammaglobulins, a positive rheumatoid factor, and low complement levels. The ESR is markedly elevated. The leukocyte count may be spuriously elevated in patients with cryoglobulinemia when done by the model S Coulter Counter. Frequently, hepatitis B virus is present although, hepatitis A, hepatitis C, Epstein-Barr virus, cytomegalovirus, and HIV may also be involved. A serum sample should be tested for the presence of cryoglobulins in patients who have connective tissue disease, infections, or neoplasms, who develop cutaneous or renal lesions, or who have evidence of a vasculitis.

Treatment is directed toward curing the underlying illness. In patients with primary or viral induced disease, the choice of therapy depends on the severity of disease. Symptomatic therapy is indicated for patients who manifest arthralgia or mild purpura. The presence of neuropathy or progressive renal disease mandates more aggressive therapy with high-dose corticosteroids, immunosuppressives, or plasmapheresis.