Updated: 8/1/2020

Mixed Cryoglobulinemia

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  • A 40-year-old gentleman presents with bilateral lower extremity swelling and rash. He complains of general fatigue and weight loss in the past few months. He has a past medical history of untreated hepatitis C. On physical exam, he has a purpuric rash bilaterally on his lower extremities and upper extremities and acrocyanosis of his fingers. He is found to have proteinuria and hematuria with low serum complement levels. His creatinine is 2.0 mg/dL (baseline was 0.9 mg/dL). He is started on interferon and ribavirin for the untreated hepatitis C.
  • Hyperviscosity syndrome resulting from cryoglobulins (single or mixed immunoglobulins) in the blood
  • Pathogenesis
    • proteins, mainly immunoglobulins, precipitate at cold temperatures
    • IgM antibody (but different from cold agglutinin disease) deposition
      • often against anti-hepatitis C IgG 
    • precipitated clumps can block blood vessels
  • Epidemiology
    • females:male ratio is 3:1
    • mean age 42-52
  • Associated conditions
    • most commonly underlying hepatitis C
    • less commonly hepatitis B
    • endocarditis
    • Sjogren's syndrome
    • multiple myeloma
    • MGUS
    • lymphoproliferative disorder
  • Symptoms
    • similar to other vasculitidies
      • fever, malaise, weight loss, and myalgias
    • renal disease
      • membranoproliferative glomerulonephritis
    • joint pain
    • peripheral neuropathy
    • dermatologic
      • purpura with or without ulcerations
      • livedo reticularis
      • acrocyanosis
    • retinal hemorrhage
    • no GI symptoms (in contrast to Henoch-Schonlein purpura)
  • ↑ ESR
  • ↓ Complement level
    • in particular, C4
  • Can have + rheumatoid factor
  • Cryoglobulins isolated from serum 
  • Tissue biopsy of organ sometimes necessary for diagnosis
    • hyaline thrombi occluding small blood vessels
  • Urine studies
    • most commonly isolated proteinuria and hematuria
Differential Diagnosis
  • HSP
  • Cold agglutinin disease
  • Acute glomerulonephritis
  • Other vasculitidies
  • Treat underlying hepatitis C (interferon and ribavirin)
  • For severe disease
    • pulse prednisone
    • plasmapheresis
Prognosis, Prevention, and Complications
  • Prognosis
    • depends on concomitant disease
    • good if underlying hepatitis C successfully treated
    • worst in those with renal disease or lymphoproliferative disease
  • Complications
    • renal failure
    • infection
    • cardiovascular disease


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