Since the discovery of the association of hepatitis C virus (HCV) with mixed cryoglobulinaemia, the use of this term is more ambiguous than ever on the one hand; on the other hand, there is less ambiguity as 80% of what previously was classified as essential mixed cryoglobulinaemia (EMC) is now known as secondary to HCV infection. The ambiguity is generated mainly by the heterogeneity of mixed cryoglobulins that were originally defined as containing IgG- anti-IgG (rheumatoid factor (RF)) immune complexes. Early studies focused on these RF containing mixed cryoglobulins; most of the recent studies, which are predominantly studies on patients with HCV infection, include cryoglobulins characterised for mixed isotypes of immunoglobulins but not for RF activity.

Meltzer, Franklin and colleagues1 first coined the term “mixed cryoglobulins” for the cryoglobulinaemia composed of IgG and IgM RF that accompanied the syndrome of palpable purpura, arthralgias, and weakness. Studies performed by Franklin’s group and by others implicated the cryoglobulin components in the immune complex mediated vascular and glomerular lesions that occur in many patients with this syndrome. The Meltzer-Franklin syndrome, as it is now called, was also called essential mixed cryoglobulinaemia to distinguish it from similar mixed cryoglobulinaemia that was known to occur secondary to a variety of infectious, autoimmune, and malignant diseases.

Shortly after Meltzer et al 1 published their study, the great immunologist, Kunkel2 noted that cryoglobulins might be a sensitive and, by far, the simplest method for the detection of immune complex because certain complexes may be soluble at 37°C but precipitate on standing at 4°C. Mixed cryoglobulinaemia came to imply immune complex disease. This implication was, in fact, true for the Meltzer-Franklin syndrome because immune complexes, that is, IgG-IgM RF, were demonstrated in the mixed cryoglobulins, and components of the complex were …