Clinical meaning
Cryoglobulins are immunoglobulins that precipitate at temperatures below 37°C and dissolve upon rewarming. Classification: Type I (monoclonal IgM or IgG, associated with lymphoproliferative disorders like Waldenström macroglobulinemia or multiple myeloma -- causes hyperviscosity). Type II (mixed, monoclonal IgM with rheumatoid factor activity against polyclonal IgG -- most common, strongly associated with hepatitis C virus, ~90%). Type III (mixed, polyclonal IgG and IgM -- associated with autoimmune diseases and chronic infections). Types II and III cause small-vessel vasculitis through immune complex deposition, complement activation, and endothelial injury, manifesting as palpable purpura, arthralgias, glomerulonephritis (membranoproliferative pattern), and peripheral neuropathy. The classic Meltzer triad of mixed cryoglobulinemia: purpura, weakness, and arthralgias.
Diagnosis & workup
Diagnostics & workup: - Cryoglobulin testing: specimen MUST be collected in pre-warmed tubes, transported at 37°C, and allowed to precipitate at 4°C for 72 hours (improper handling causes false negatives -- most common reason for negative result) - Cryocrit: quantifies the volume of cryoprecipitate as percentage of serum - Complement levels: low C4 with relatively preserved C3 is characteristic of mixed cryoglobulinemia (classical complement pathway activation) - Rheumatoid factor: elevated in Type II/III (IgM with RF activity) - Hepatitis C testing: HCV antibody and viral load (cause of 90% of mixed cryoglobulinemia) - Serum protein electrophoresis/immunofixation: identifies monoclonal component (Type I) - Renal biopsy if nephritis: membranoproliferative glomerulonephritis pattern with subendothelial deposits - Skin biopsy of purpura: leukocytoclastic vasculitis