Mixed Cryoglobulinemia

MIXED CRYOGLOBULINEMIA

Circulating cryoglobulins are immunoglob-ulins that precipitate at cold temperatures and dissolve on rewarming. Three types of cryoglobulins have been described. Type I refers to monoclonal immunoglobulin that is associated with multiple myeloma or Waldenstrom’s macroglobulinemia. Type II, or essential mixed cryoglobulinemia, refers to cryoglobulin, which contains both polyclonal IgG (as an antigen or formed against another circulating antigen) and monoclonal IgM rheumatoid factor against the IgG. Most cases have been associated with chronic hepatitis C virus infection. Type III is also a mixed cryoglobulin, but both the IgG and rheumatoid IGM are polyclonal. This latter type is associated with hepatitis C infection, autoimmune disorders (e.g., lupus), and lymphopro-liferative disorders. Although hepatitis C antibodies were found in the precipitates in both type II and III, antibodies to HIV-1 can be found as well.

Clinical symptoms of mixed cryoglob-ulinemia are related to the deposition of the cryoglobulins in medium-sized arteries. Palpable purpura is a major skin finding. Other symptoms include polyarthralgias, hepatosplenomegaly, lymphadenopathy, peripheral neuropathy, and hypocom-plementemia. About 20 percent of cases will have renal involvement. MPGN is commonly seen, including the presence of precipitated cryoglobulins that may occlude the capillary loops. Immunofluo-rescence will show diffuse deposition of IgM in capillary loops. Electron microscopy will show subendothelial deposits, which may have a “fingerprint” appearance.

Until the discovery of hepatitis C and HIV-1 in cryglobulin precipitates, steroids and cytotoxic drugs (cyclophos-phamide or chlorambucil) were main-stays of treatment. These drugs are now reserved for severe cases of progressive renal failure, necrotic extremities that may require amputation, and severe neuropathy. Plasmapheresis is initially done to remove circulating cryoglobulins. Pulse steroids and cytotoxic agents are used to prevent new antibody formation. Anti-viral therapy is directed to hepatitis C and HIV disease to prevent further cry-oglobulin formation.