Hepatitis C virus infection and cryoglobulinaemia.

Mixed cryoglobulins (CG) are serum proteins that precipitate at low temperature and are commonly classified into two types according to the presence (type II) or not (type III) of monoclonal immunoglobulins. Mixed CG are observed in a wide variety of diseases. Some mixed cryoglobulinaemia occurs without evidence of an underlying disease and is considered as essential mixed cryoglobulinaemia (EMC). Many studies have underlined the possible involvement of liver diseases in the pathogenesis of cryoglobulinaemia and particularly viral hepatitis. Recently, it has been shown that 50 to 80% of patients with EMC are in fact infected with HCV. It has also been shown that CG may be found in about 50% of patients infected with HCV. HCV-RNA genomic sequences are specifically concentrated in CG as well as IgG reactive with HCV-related proteins, and monoclonal IgM with rheumatoid factor (RF) activity. The monoclonal IgM RF detected in HCV infected patients is highly restricted to the same cross-idiotype OWAO. In addition to hepatocytes, HCV-RNA has been found in both peripheral blood and BM mononuclear cells. These cells could represent a reservoir of virus and may play a major role in viral persistence; they also could act as effectors of tissue injury in various organs. HCV shows high genomic variability. It is not clear whether these genetic variations have a significant clinical impact (i.e. severity of the disease) but there is evidence that they may influence both the efficacy of the host immune response and the interferon treatment response. The role of viral factors has been studied but a clear relationship between the presence of cryoglobulinaemia, the viral load or the HCV genotype have not been demonstrated. The frequency of clinical symptoms related to mixed cryoglobulinaemia reported in the literature is extremely variable according to the series. The striking association between HCV infection and mixed type II CG (usually considered as a benign lymphoproliferative disorder) and the occurrence of HCV infection in patients with NHL suggest that HCV could be involved in the pathogenesis of some malignant lymphoproliferative disease. The progression to malignancy probably involves the accumulation of multiple mutations facilitated by chronic antigenic stimulation. The efficacy of anti-viral treatment on both CG levels and related symptoms argue strongly that HCV is involved in the production of CG.