The most documented extrahepatic manifestation of hepatitis C virus (HCV) infection is mixed cryoglobulinemia (MC). MC is characterised by the presence of temperature-sensitive protein complexes: in type II MC, cryoglobulins are composed of a monoclonal rheumatoid factor (usually, IgMk) against polyclonal IgG. In type III MC, all components are polyclonal. The presence of microheterogeneity and other new types of cryoglobulins is a novel and recent observation. The production of different autoantibodies and circulating immune complexes, including the cryoglobulins, are responsible for systemic vasculitis and various organ damage. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Finally, results of interferon and/or ribavirin treatments in MC patients represent an indirect proof for the pathogenetic link between MC and HVC infection. The discovery of the relation between HCV infection and MC shows the striking association between a viral infection and an autoimmune disease and, thus, a potential link between the systemic autoimmune and lymphoproliferative disorders.
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