Cryoglobulinemia

Diagnosis

Indications for Testing

Clinical signs and symptoms of cryoglobulinemia (eg, skin ulcers, digital pain, Raynaud disease)

Laboratory Testing

• Initial testing – exclude other primary diseases and identify organ dysfunction or cryoglobulinemia-associated diseases 
  • C-reactive protein (CRP)
    • If CRP is not available, order erythrocyte sedimentation rate (ESR)
    • Preferred test to detect inflammatory processes (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
  • Rheumatoid arthritis – rheumatoid factor
  • Complement deficiency – AH50, CH50, individual complement testing
  • Systemic lupus erythematous (SLE) or other autoimmune connective tissue disorders – antinuclear antibody test (ANA), C3 and C4 concentrations
  • ANCA-associated vasculitis – antineutrophil cytoplasmic antibodies (ANCA)
  • Autoimmune hepatitis – antimitochondrial antibody
  • Viral testing
    • Hepatitis C virus (HCV)
    • Hepatitis B virus (HBV)
    • HIV
• Cryoglobulin testing – circulating cryoglobulins present
  • Type I – characterized by monoclonal immunoglobulins
  • Type II – monoclonal heavy chain, an associated light chain, and polyclonal immunoglobulins
  • Type III – only trace amounts of polyclonal immunoglobulins
• Serum protein electrophoresis – identify the specific immunoglobulins present and assess for monoclonal protein to rule out plasma cell dyscrasia

Histology

• Skin biopsy – immune complex deposition noted
  • May also demonstrate small vessel vasculitis
• Bone marrow biopsy may be necessary to rule out malignancy

Differential Diagnosis

• See Clinical conditions that may be associated with cryoglobulinemia
• Vasculitis
• Skin lesions

Monitoring

• Monitoring for complications associated predominantly with mixed cryoglobulinemia
  • Chronic hepatitis with cirrhosis – hepatocellular carcinoma monitoring (transaminases, alpha fetoprotein, and liver ultrasonography)
  • Glomerulonephritis – urinalysis, blood urea nitrogen (BUN)/creatinine
  • Thyroid disease – thyroid stimulating hormone, antibody testing
  • Skin ulcers – consider arterial/venous Doppler evaluations; repeat testing for vasculitis

Background

Epidemiology

• Prevalence of clinically significant cryoglobulinemia – 1/100,000
  • May be seen at much higher prevalence in patients with chronic infections (eg, hepatitis C virus [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

  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 polyangiitis

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