Cryoglobulinemia

The majority of cryoglobulinemias are secondary manifestations of another disease and are, therefore, not usually essential cryoglobulinemia as previously reported in medical literature. In the presence of vascular involvement (usually small vessel), the disease is termed cryoglobulinemic vasculitis (Chapel Hill, 2012).

Epidemiology

• Prevalence of clinically significant cryoglobulinemia – 1/100,000
  • May be seen at much higher prevalence in patients with chronic infections (eg, HCV, HIV)
• Age – 40s-50s
• Sex – M<F, 1:3
• Ethnicity – more common in Southern European than Northern European/North American

Classification

Pathophysiology

• Cryoglobulins
  • Proteins reversibly precipitate at 0-4°C and resolubilize upon warming
  • Low concentrations may occur in apparently healthy individuals
  • Clinical conditions that may be associated with cryoglobulinemia

    Clinical Conditions that May Be Associated with Cryoglobulinemia
    Infections	Lymphoproliferative Diseases	Autoimmune Diseases	Vasculitides
    Viral Cytomegalovirus Epstein-Barr virus Hepatitis A virus Hepatitis B virus Hepatitis C virus HIV Bacterial Babesia microti Borrelia burgdorferi Coxiella burnetii Mycobacterium leprae Poststreptococcal nephritis Subacute bacterial endocarditis Treponema pallidum ​Plasmodium malariae Fungal Coccidioides Parasitic Echinococcus spp Leishmania spp Plasmodium spp Schistosoma spp Toxoplasma gondii Trypanosoma cruzi	B-cell and T/NK-cell lymphomas Castleman disease Chronic lymphocytic leukemia Chronic myeloid leukemia Cold agglutinin disease Hodgkin lymphoma Myelodysplastic syndrome Plasma cell dyscrasias Thrombocytopenic thrombotic purpura	Autoimmune hepatitis Autoimmune thyroiditis Primary biliary cirrhosis Inflammatory myopathies (eg, polymyositis) Endomyocardial fibrosis Inflammatory bowel disease Pemphigus vulgaris Primary antiphospholipid syndrome Pulmonary fibrosis Rheumatoid arthritis Sarcoidosis Sjögren syndrome Systematic lupus erythematosus Systemic sclerosis	Eosinophilic granulomatosis with polyangiitis IgA vasculitis (Henoch-Schönlein purpura) Polyarteritis nodosa Giant cell arteritis (temporal arteritis) Microscopic polyangitis

Clinical Presentation

• Cryoglobulinemic vasculitis
  • Most common with types II and III
  • Predominantly small vessel involvement – capillaries, venules or arterioles
  • Pathophysiology – tendency of cryoglobulins to precipitate at low temperatures and occlude blood vessels
• Vascular purpura (palpable purpura)
  • Skin, glomeruli and peripheral nerves most often involved – more common and frequent in type I
    • Skin
      • Vascular purpura
      • Cold-induced urticaria
      • Digital pain/cyanosis
      • Raynaud phenomenon
      • Skin ulcers
    • Renal
      • Glomerulonephritis – hematuria, proteinuria, casts
    • Peripheral nerves
      • Neuropathies
    • Other
      • Musculoskeletal – arthralgias
      • Hepatic – hepatitis
      • Otorhinolaryngological–xerostomia, xerophthalmia
• Essential mixed cryoglobulinemia – vasculitis
  • Triad of purpura, weakness, and arthralgias
  • Often associated with lymphadenopathy, hepatosplenomegaly, and renal failure