Review: Cryoglobulins: An Important but Neglected Clinical Test

Cryoglobulin (CR) denotes a serum immunoglobulin that precipitates at temperatures below 37°C and dissolves on re-warming. CRs are heterogeneous in chemical composition and behave differently in vivo and in vitro. The majority are mixed antigen-antibody complexes that occur with high incidence in autoimmune and infectious disorders. Their measurement is important in the management of patients with vasculitis. CRs elicit variable symptoms in patients, mostly purpura, weakness, and arthralgias, and they require various methods of treatment. Sometimes CRs are not associated with any symptoms; but they can be associated with very severe conditions such as nephropathy and neuropathy. Treatment depends on the symptoms and causes, and on the phenotyping of the CR. Considering the high incidence of CR in diseases such as hepatitis C virus (HCV) infection, together with the high worldwide prevalence of this disease, it is clear that testing for CR is underutilized in clinical practice. CR testing has been neglected in routine clinical laboratories and by clinicians due to several factors, such as the lengthy time for serum CR analysis and failure to appreciate that low levels of CR can be associated with severe symptoms. In a series of 194 serum samples that gave positive tests for CR at our institution, the majority contained low CR concentrations (65% of the samples were type II with a mean of 372 mg/L and 39% of type III with a mean of 216 mg/L; reference range 0-60 mg/L). Case studies are presented to illustrate the importance of such low levels of CR. There is a need for more rapid and more reliable methods for quantification and phenotyping of low concentrations of serum CR. Based on our experience in the routine analysis, quantification, and phenotyping of serum CR, some practical solutions to these problems are presented.