Definitions

Cryoglobulins: a group of immunoglobulins (IgM, IgG, IgA) that precipitate in vitro at cold (< 37°C).
Cryoglobulinemia: a condition characterized by elevated serum cryoglobulin concentration
Cryoglobulinemic vasculitis: a vasculitis caused by the deposition of temperature-dependent IgG and IgM immunoglobulins/immune complexes (i.e., cryoglobulins), with subsequent inflammation of surrounding tissue

Etiology

Strong association with Hepatitis C Virus (HCV) (>90% of mixed cryoglobulinemia cases).
Other triggers: HIV, HBV, autoimmune diseases (Sjögren syndrome, SLE), lymphoproliferative disorders (Waldenström macroglobulinemia, MM).

Mechanism (Types II/III Mixed Cryo):
- Chronic antigen (HCV) drives clonal B-cell proliferation.
- Pathologic IgM with RF activity binds polyclonal IgG complexes.
- Complexes precipitate at <37°C in cooler microvasculature.
Vascular Damage:
- Immune-complex deposition in small vessels triggers classical complement activation -> severe consumption of C4.
- Neutrophil recruitment -> LCV (skin), MPGN (kidney), and ischemic vasa nervorum infarction (nerves).

Meltzer Triad: Palpable purpura, arthralgias, and weakness (present in ~30% of pts).
Cutaneous: Palpable purpura (predominantly on lower extremities), livedo reticularis, Raynaud phenomenon, digital ulcers/necrosis.
Renal: Membranoproliferative glomerulonephritis (MPGN) in 50% of pts (presents with hematuria, proteinuria, HTN, and progressive AKI). c
Neurologic: Painful, symmetric sensory or sensorimotor peripheral neuropathy (paresthesias, burning sensation).
Systemic: Fatigue, low-grade fever, hepatosplenomegaly.

Initial Labs: Serum cryoglobulins, positive Rheumatoid Factor (RF) (IgM directed against IgG), elevated ESR/CRP.
- Complement levels: Characteristically extremely low C4 (C3 is often normal or only mildly decreased). c
- High-Yield Lab Note: Blood sample must be kept warm at 37°C during collection, transport, and processing to prevent premature cryoglobulin precipitation (which causes false-negative results).
Confirmatory/Gold Standard: Biopsy of involved organ.
- Skin: Leukocytoclastic vasculitis.
- Kidney: MPGN with subendothelial immune complex deposits (“wire loops”) and intraluminal cryoglobulin thrombi.
Secondary Screening: HCV RNA, HBV serologies, HIV testing, SPEP/UPEP to rule out underlying monoclonal gammopathies.

IgA Vasculitis: Pediatric focus, normal complements, IgA deposits, prominent GI colic.
Polyarteritis Nodosa (PAN): Associated with HBV, medium-vessel microaneurysms, spares glomeruli, normal complements.
Granulomatosis with Polyangiitis (GPA): Sinus/cavitary lung lesions, c-ANCA (+), normal complements.
SLE: ANA/anti-dsDNA (+), both C3 and C4 profoundly low, malar rash.

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