Indications for Testing

  • Appropriate clinical signs and symptoms of cryoglobulinemia

Laboratory Testing

  • Initial testing – rule out other diseases or 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 determine if there is a monoclonal protein present


  • Skin biopsy demonstrating immune complex deposition to secure diagnosis in vasculitis

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 other diseases and not “essential” cryoglobulinemias as previously reported in medical literature.


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


  • Type I (25-35%) – monoclonal immunoglobulins consisting of IgM, occasionally IgG and, rarely, IgA or Bence Jones protein
  • Type II (25%) – mixed cryoglobulins where a monoclonal immunoglobulin is directed against a polyclonal immunoglobulin
    • Includes monoclonal IgM or occasionally IgG or IgA complexed with autologous normal IgG
    • Associated diseases – chronic hepatitis C (HCV), autoimmune disorders (Sjögren), other infections
  • Type III (50%) – mixed polyclonal proteins made of 2 or more immunoglobulins, none of which are homogeneous


Clinical Presentation

  • Target organs – may be involved in all types of cryoglobulinemia
    • Skin – purpura, petechiae, ulcers, cyanosis, Raynaud phenomena
    • Neurologic – mild sensory neuritis, peripheral neuropathy (most common in type III)
    • Renal – glomerulonephritis, proteinuria, hematuria 
    • Hepatic – hepatitis
    • Musculoskeletal – arthralgias
    • Otorhinolaryngological – xerostomia, xerophthalmia
  • Cryoglobulinemia types II and III –  vasculitic symptoms 
    • Results from the tendency of cryoglobulins to precipitate at low temperatures and occlude blood vessels
    • Vascular purpura (palpable purpura)
    • Bleeding tendencies
    • Cold-induced urticaria
    • Raynaud phenomenon
    • Digital pain and cyanosis
    • Skin ulcers
  • Essential mixed cryoglobulinemia – vasculitic syndrome resulting in purpura, arthralgia and weakness
    • 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
Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry
Diagnose rheumatoid arthritis (RA)

Negative results do not rule out RA

Complement Components 3 and 4 0050149
Method: Quantitative Immunoturbidimetry

Rule out autoimmune disease or complement deficiency

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

Rule out 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

Rule out 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

Rule out 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 

Rule out HBV

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

Rule out HCV

Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403
Method: Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Initial test in the evaluation of cryoglobulinemia after other etiologies have been ruled out

If qualitative is positive, Immunofixation Electrophoresis Typing and Quantitative IgA, IgG and IgM will be added

Confirms cryoglobulinemia but does not distinguish etiology

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

Confirms cryoglobulinemia but does not distinguish etiology

Perform serum electrophoresis

Cryoglobulin, Qualitative 0050185
Method: Qualitative Cold Precipitation

Confirms cryoglobulinemia but does not distinguish etiology

Perform serum electrophoresis

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Monitor for hepatocellular carcinoma (HCC)

Alpha Fetoprotein, Serum (Tumor Marker) 0080428
Method: Quantitative Chemiluminescent Immunoassay

Monitor for HCC

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Monitor glomerulonephritis

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Monitor glomerulonephritis

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Monitor glomerulonephritis

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

Monitor thyroid involvement

Thyroid Stimulating Hormone 0070145
Method: Quantitative Chemiluminescent Immunoassay

Monitor thyroid involvement

Thyroid Antibodies 0050645
Method: Chemiluminescent Immunoassay

Monitor thyroid involvement