cryoglobulins

Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below normal body temperature and dissolve when warmed. They can be detected in serum, and cryoglobulinemia refers to the clinical syndrome caused by these precipitates, often through immune complex–mediated vasculitis.

Cryoglobulinemia is classified into three main types. Type I consists of a single monoclonal immunoglobulin, usually IgM or IgG, and is most often associated with hematologic malignancies such as Waldenström macroglobulinemia or multiple myeloma. Type II is a mixed cryoglobulin containing a monoclonal IgM with rheumatoid factor activity bound to polyclonal IgG and is frequently linked to hepatitis C virus infection. Type III is also mixed but comprises polyclonal IgM and polyclonal IgG, with associations to chronic infections, autoimmune diseases, or inflammatory conditions. Mixed types (II and III) commonly present with systemic vasculitis.

Clinically, cryoglobulinemia can cause palpable purpura, arthralgia, weakness, and fatigue, with possible Raynaud phenomenon and peripheral neuropathy. Renal involvement, including membranoproliferative glomerulonephritis, and other organ manifestations may occur. The pathophysiology involves immune complex deposition in small to medium vessels and complement consumption, leading to inflammation.

Diagnosis requires proper sample handling: blood should be drawn and kept at 37°C until serum is separated to prevent false-negative results, then cryoglobulins are precipitated by cooling and quantified, with immunofixation used to type the immunoglobulins. Evaluation for underlying diseases (hepatitis C testing, autoimmune markers, hematologic malignancies) is standard.

Treatment targets the underlying condition and the inflammatory vasculitis. Antiviral therapy for hepatitis C, therapy for hematologic disease, and immunosuppressive regimens (steroids, rituximab) are used; plasmapheresis may be employed in severe cases. Prognosis varies with the underlying disease and organ involvement.