HCV and Mixed Cryoglobulinemia

Hepatitis C virus (HCV) infection has been shown to be associated with essential mixed cryoglobulinemia. Thirty-six to 54% of patients with chronic HCV infection have detectable cryoglobulins in the sera, but 60 to 80% of patients with essential mixed cryoglobulinemia (EMC) are HCV positive. HCV RNA and HCV antigens are 100-1000 fold increased in cryoglobulins and EMC is cured by successful treatment of HCV infection.

The exact mechanism by which chronic HCV infection specifically leads to EMC is unknown. The hypotheses include:

1. HCV leads to general immune stimulation and, by chance, Rheumatoid Factor, polyclonal and monoclonal are produced or
2. There is immunologic cross-reactivity between some HCV antigen and RF. The latter is more likely as the RF is often monoclonal and identical in most HCV infected patients.

Clinical manifestations of EMC in 257 HCV infected patients:

Purpura	                                     88 - 100 %
Arthralgia	                             51 -  70 %
Weakness	                             61 - 100 %
Peripheral neuropathy	     25 -  69 %
Rental involvement                  8 -  54 %
Raynaud's	                             10 -  35 %

Laboratory features of HCV and EMC:

» Higher levels of cryoglobulins more significant
» Low total hemolytic complement, marked depression of C1 and C4
» Rheumatoid factor positive, monoclonal in Type 1I and polyclonal in Type III
» Not associated with any specific sub-type of HCV or any specific severity of liver disease or HLA type

HCV and Non-Hodgkin’s Lymphoma:

» Several studies have suggested an association between HCV infection and Non-Hodgkin’s Lymphoma, especially low-grade. The vast majority of these patients have EMC first and the hypothesis is that with chronic stimulation of B cells, one B cell line eventually mutates, activating oncogenes.


» Response to IFN similar to that observed in patients without EMC

Linda Scully, MD
Associate Professor
Department of Medicine
University of Ottawa


1. Agnello et al. A role for hepatitis C virus infection in Type II cryoglobulinemia. N Engl J Med 1977;296:1501.
2. Misiani et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Inter Med 1992;117:573.
3. Agnello. Hepatitis C virus infection and Type II cryoglobulinemia: an immunologic perspective. Hepatology 1997;26:1375.

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