The cryoglobulinemias are caused by circulating immunoglobulins that undergo reversible precipitation from plasma or serum upon cooling (temperatures less than 37°C [98.6ºF]). Cryoglobulinemia is associated with multiple systemic disorders.

Three subtypes of cryoglobulins are characterized, according to immunoglobulin type:

• Type I cryoglobulins (10%-15% of cases) are monoclonal cryoglobulins typically made of IgM and sometimes IgA or IgG. Type I cryoglobulinemia is associated with B-cell lymphoproliferative disorders (most commonly multiple myeloma and Waldenström macroglobulinemia). The monoclonal cryoglobulins precipitate at lower temperatures, leading to vascular occlusion and ischemic damage of tissues. Typically, acral areas are affected.
• Type II (50%-60% of cases) and type III (30%-40% of cases) cryoglobulins are mixed cryoglobulins that consist of a rheumatoid factor (IgM) complexed with either a monoclonal IgG (type II) or a polyclonal IgG or non-immunoglobulin serum component (type III). Mixed cryoglobulinemias are caused by chronic B-cell activation that leads to immune complex formation (IgM / IgG) and deposition in small and medium vessels, resulting in vasculitis. The majority of cases (80%-90%) are associated with chronic hepatitis C virus (HCV) infection. Other infections (hepatitis B virus, HIV, Epstein-Barr virus, cytomegalovirus, leprosy, and, more rarely, other viral, bacterial, and parasitic infections) and rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome) have also been associated. Due to chronic B-cell stimulation, cryoglobulinemia is associated with the development of malignant B-cell lymphoproliferative disease, in particular non-Hodgkin lymphoma (35 times higher risk than the general population). When no underlying cause is identified, it is designated as essential mixed cryoglobulinemia.

Cryoglobulinemia is rare, with an estimate of fewer than 5 cases per 10 000 individuals in Europe and North America. It is more common in Southern Europe than in Northern Europe or North America. The time course is most often chronic but varies depending on the underlying condition and response to treatment. Overall survival in HCV-associated cryoglobulinemic vasculitis was found to be 75% at 5 years and 63% at 10 years in a cohort of 151 patients. Liver fibrosis, renal involvement, and severe vasculitis are associated with worse prognosis. Cryoglobulinemic vasculitis is sometimes associated with somatic mutations in the CARD11 or KLHL6 genes.