Indications for Testing

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

Laboratory Testing

  • Initial testing – helpful in excluding other primary diseases, identifying organ dysfunction, or cryoglobulinemia-associated diseases
  • 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


  • 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" in the Clinical Background tab


  • Monitoring for complications associated predominantly with mixed cryoglobulinemia

Clinical Background

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).


  • Prevalence of mixed cryoglobulinemia – 1/100,000
  • Age – 40s-50s
  • Sex – M<F, 1:3
  • Ethnicity – more common in Southern European than Northern European/North American


  • Types of cryoglobulinemia



    Immunoglobulins Present

    Associated disorders



    Monoclonal immunoglobulins

    • IgM, usually
    • IgG, occasionally
    • IgA or Bence Jones protein, rarely


    (Mixed cryoglobulinemia)


    Mixed cryoglobulins – monoclonal immunoglobulin directed against polyclonal immunoglobulin

    • IgM monoclonal
    • OR (occasionally) IgG or IgA complexed with autologous normal IgG


    (Mixed cryoglobulinemia)


    Mixed polyclonal proteins – 2 or more immunoglobulins (none are homogeneous polyclonal IgM & IgG)


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
      • 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

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403
Method: Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Assess for cryoglobulinemia

If qualitative is positive, immunofixation electrophoresis typing and quantitative IgA, IgG and IgM will be added

Does not distinguish etiology for cryoglobulinemia

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Preferred test to detect inflammatory processes

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Aid in diagnosis of renal involvement in anti-GBM disease

Monitor renal failure

Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry
Assess for presence of rheumatoid arthritis (RA)

Negative results do not rule out RA

Complement Activity Enzyme Immunoassay, Total 0050198
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Rule out complement deficiency (classic pathway)

Complement Activity, Alternative Pathway (AH50) 2005373
Method: Semi-Quantitative Radial Immunodiffusion

Rule out complement deficiency (alternative pathway)

Connective Tissue Diseases Profile 0051668
Method: Semi-Quantitative Multiplex Bead Assay

Assess for the presence of autoimmune connective tissue disorders

Components include Smith (ENA) antibody, RNP (U1) (Ribonucleic Protein), SSA (Ro), SSB (La), Jo-1, Ribosomal P Protein, Centromere, Scleroderma (Scl-70)

Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies 2002068
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Initial evaluation for suspected ANCA-associated vasculitis

If screen is positive, titer and MPO/PR-3 antibodies testing will be added to aid in antibody determination

Autoimmune Liver Disease Evaluation with Reflex to Smooth Muscle Antibody (SMA), IgG by IFA 2007210
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Assess for presence of autoimmune hepatitis

Components include mitochondrial M2 antibody, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG; smooth muscle antibody, IgG titer

Hepatitis B Virus Surface Antigen with Reflex to Confirmation 0020089
Method: Qualitative Chemiluminescent Immunoassay 

Diagnose HBV

Hepatitis C Virus Antibody by CIA 2002483
Method: Qualitative Chemiluminescent Immunoassay

Diagnose HCV

Protein Electrophoresis, Serum 0050640
Method: Quantitative Capillary Electrophoresis

Rule out plasma cell dyscrasias

Perform in patients with cryoglobulinemia to identify specific immunoglobulins and determine presence of monoclonal proteins

Additional Tests Available
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Use to exclude other primary diseases, identifying organ dysfunction, or cryoglobulinemia-associated diseases

Cryoglobulin, Qualitative, with Reflex to Quantitative IgA, IgG, and IgM 2002063
Method: Qualitative Cold Precipitation/Quantitative Nephelometry

Confirms cryoglobulinemia but does not distinguish etiology

Consider serum electrophoresis

Cryoglobulin, Qualitative 0050185
Method: Qualitative Cold Precipitation

Confirms cryoglobulinemia but does not distinguish etiology

Consider serum electrophoresis

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Assess hepatic function

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Monitor renal disease

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Monitor renal disease

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108
Method: Quantitative Electrochemiluminescent Immunoassay

Monitor thyroid disease