Incidence, character and clinical relevance of mixed cryoglobulinaemia in patients with chronic hepatitis C virus infection

Abstract

SUMMARYHepatitis C virus (HCV) infection has been implicated in the pathogenesis of mixed cryoglobulinaemia. Several studies have shown the presence of anti-HCV antibodies and HCV-RNA in both sera and cryoglobulins of such patients. However, the prevalence and clinical significance of cryoglobulins remain uncertain in patients with chronic HCV infection. We have studied 113 consecutive patients referred for assessment because of the presence of anti-HCV antibody in serum for the presence of cryoglobulinaemia and ascertained their clinical relevance and immunochemical properties. Twentyone of 113 (19%) had detectable cryoglobulins with a mean protein concentration of 0 . 38 g/l (range 0 . 15-3 . 34 g/l). Most of these patients were asymptomatic. The cryoglobulins were of type III in 19 (91%) and of type II in two patients (9%). The latter two patients had the highest concentration of cryoglobulins, subnormal C4 and C1q levels suggesting classical pathway activation and vasculitis with renal impairment. The cryoglobulin IgG subclasses were mainly IgG1 and IgG3. HCV-RNA was detected more frequently in the sera of cryoglobulin-positive patients than in cryoglobulin-negative patients. This study showed that mixed cryoglobulinaemia is common in chronic HCV infection, and is predominantly type III. Evidence of systemic or renal disease was rare except in those with type II cryoglobulinaemia, and this may reflect either the concentration of the cryoprecipitate or the presence of a monoclonal complement-activating IgM paraprotein. The detection of HCV-RNA in the majority of the cryoprecipitates further supports the important role of HCV in the etiopathogenesis of essential mixed cryoglobulinaemia, although the mechanism is at present unclear.

Autoantibody profile in individuals with chronic hepatitis C

“…For example, anti-HCV antibodies and viral RNA were isolated from the cryoprecipitate of a large number of patients with this disorder 30 . In this work, the testing for cryoglobulins was positive in 2.1% of the patients, which differs from the results in other studies showing that the prevalence of cryoglobulins in patients with HCV ranges from 35 to 54% 13,[31][32][33] . Such differences may be justified by technical difficulties in sample processing, which involves the cooling of serum samples at 4°C for at least 72 h and the observation of a precipitate formation that is reversible by heat.…”

“…Such differences may be justified by technical difficulties in sample processing, which involves the cooling of serum samples at 4°C for at least 72 h and the observation of a precipitate formation that is reversible by heat. The most common sources of error are false-negative results due to loss of the cryoprecipitate during transport and storage 32 . Therefore, more than one sample should be assessed in patients with negative results and in cases of high clinical suspicion.…”

The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders

“…They found no clinical signs or symptoms of systemic vasculitis in a cohort of 135 hemophiliacs with chronic HCV infection. In accordance with previous studies, 36,[50][51][52][53] we identified a positive correlation between genotype 1, the presence of chronic hepatitis or severe liver disease, the duration of hepatitis C, and the risk of producing serum cryoglobulins.…”

“…[50][51][52][53] Serum cryoglobulins have been detected in 19% to 55% of patients with chronic HCV infection. Such cryoglobulins may be clinically significant and associated with a systemic vasculitic disorder in 12% to 30% of cases.…”

Involvement of chemokines and type 1 cytokines in the pathogenesis of hepatitis C virus–associated mixed cryoglobulinemia vasculitis neuropathy

“…This is consistent with previous data obtained from peripheral blood mononuclear cells (9) and liver (10), ruling out the possibility of a discrepancy between the response of peripheral, liver, and nerve T cells that could occur because of compartmentalization of T cells. These data are also concordant with the observation that the major IgG isotypes in HCV-associated type II and type III MC are mainly IgG1 and IgG3 subclasses (24,25). TNF␣ has been shown to drive the differentiation of dendritic cell subsets that will present the Fc fragment of immunoglobulins, eventually leading to the generation of rheumatoid factor (anti-Ig Fc response) (26), which is typical of MC vasculitis.…”