cryoglobulinemias

Cryoglobulinemias are a group of disorders characterized by the presence of cryoglobulins—immunoglobulins that precipitate at temperatures below body temperature and dissolve upon warming—in the serum. These cryoglobulins can deposit in small vessels and trigger immune complex–mediated vasculitis with multisystem involvement.

Classification comprises three main types. Type I cryoglobulinemia consists of a single monoclonal immunoglobulin and is typically associated with hematologic malignancies such as multiple myeloma or lymphoma. Type II is a mixed cryoglobulinemia with a monoclonal IgM that has rheumatoid factor activity and polyclonal IgG. Type III is a mixed cryoglobulinemia with polyclonal IgM with rheumatoid factor activity and polyclonal IgG. Mixed cryoglobulinemias (types II and III) are strongly linked to chronic hepatitis C infection, though other infections, autoimmune diseases, and lymphoproliferative disorders can also contribute.

Clinical features commonly include a triad of palpable purpura, arthralgia or arthritis, and fatigue. Vasculitic skin lesions may be accompanied by peripheral neuropathy, and renal involvement can manifest as membranoproliferative glomerulonephritis. Cold-induced symptoms such as Raynaud phenomenon may occur. Additional organ involvement, including liver or pulmonary disease, may be seen in some cases.

Pathophysiology centers on immune complex deposition and complement consumption, leading to small-vessel vasculitis. Cryoglobulins are temperature-sensitive, so sample handling is important and cryocrit or cryoprecipitate quantification is used in testing. Laboratory evaluation often reveals low C4 with variable C3.

Diagnosis requires demonstration of cryoglobulins in serum, usually with cryoprecipitation at low temperature, along with assessment for underlying etiologies such as hepatitis C infection, autoimmune diseases, or hematologic disorders.

Management targets both the underlying cause and the vasculitic process. Antiviral therapy for hepatitis C can induce remission in many cases of mixed cryoglobulinemia. Immunosuppressive therapy, including corticosteroids, is used for active vasculitis; rituximab is effective in several patients. Plasmapheresis may be necessary in cryoglobulinemic crisis or severe renal involvement. Prognosis varies with type and the underlying disease; mixed cryoglobulinemias associated with effective antiviral therapy have better outcomes. Cryoglobulinemia remains relatively rare outside endemic settings.