ImmunologyTier 1Medical Sciences concept

Cryoglobulinaemia - types and complement associations

Core concept

Cryoglobulins = immunoglobulins that reversibly precipitate in the cold and redissolve on rewarming -- classified by clonality of the immunoglobulin(s) involved
Type I: single monoclonal immunoglobulin (usually IgM) -- associated with lymphoproliferative disease (myeloma, Waldenstrom's)
Type II: monoclonal IgM (with rheumatoid factor activity) + polyclonal IgG -- mixed cryoglobulinaemia, strongly associated with Hepatitis C

Type	Composition	Main association	Complement pattern
I	Monoclonal only	Myeloma, Waldenstrom's, lymphoma	Complement usually normal
II	Monoclonal IgM (RF activity) + polyclonal IgG	Hepatitis C (~90% of mixed cryo), lymphoproliferative disease	Low C4, relatively preserved C3
III	Polyclonal IgM + polyclonal IgG	Autoimmune disease (SLE, Sjogren's), chronic infection	Low C4, relatively preserved C3

Types II and III together = "mixed cryoglobulinaemia" -- both feature immune-complex-mediated vasculitis and share the disproportionately low C4 pattern (classical pathway consumption)
The low-C4-with-preserved-C3 pattern is the discriminator from other complement-consuming states (e.g. active SLE nephritis typically drops both C3 and C4)

Clinical triad (mixed cryoglobulinaemia): palpable purpura, arthralgia, weakness (Meltzer's triad) -- plus renal involvement (membranoproliferative glomerulonephritis) and peripheral neuropathy in more severe disease
Any patient with cryoglobulinaemic vasculitis should be tested/treated for Hepatitis C -- antiviral therapy for HCV is first-line management of type II disease, often resolving the vasculitis
Trap: sample handling artefact -- blood must be kept at 37C during clotting and transport, and only separated/tested warm; cryoglobulin can be missed (false negative) if allowed to cool before processing

Type I overlaps with the monoclonal gammopathy/myeloma work-up -- same clonal immunoglobulin, different clinical syndrome (hyperviscosity/cold-precipitation vs marrow infiltration)
Rheumatoid factor positivity is intrinsic to type II (the monoclonal IgM itself has RF activity) -- distinct from RF as a marker of rheumatoid arthritis
Complement pattern parallels other immune-complex diseases (SLE) but the isolated/disproportionate C4 depletion is a specific pointer toward cryoglobulinaemia or hereditary angioedema-type classical pathway activation

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