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).


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 
  • 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


  • 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



  • 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


Types of Cryoglobulinemia
Type Percent Immunoglobulins Present Associated Disorders



Monoclonal immunoglobulins

  • IgM most common
  • IgG occasionally
  • IgA or Bence Jones protein rarely

Plasma cell dyscrasias – Waldenström and multiple myeloma most common

Lymphoproliferative diseases


(Mixed cryoglobulinemia)


Mixed cryoglobulins – monoclonal immunoglobulin directed against polyclonal immunoglobulin

  • IgM monoclonal


  • (Occasionally) IgG or IgA complexed with autologous normal IgG

Chronic hepatitis C (HCV), HIV

Autoimmune disorders (Sjögren)

Mixed cryoglobulinemia syndrome


(Mixed cryoglobulinemia)


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

Autoimmune diseases (eg, connective tissue, autoimmune hepatitis)


Lymphoproliferative disorders


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

ARUP Laboratory Tests

Preferred first-line reflex panel for the evaluation of ANCA-associated vasculitis

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)

Screening test to evaluate kidney function

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite), but only when concentrations are at or above those expected during acetaminophen overdose

Aid in the workup of suspected rheumatoid arthritis or undifferentiated inflammatory arthritides

Consider ordering this test in conjunction with cyclic citrullinated peptide (CCP) antibody, IgG to increase specificity and sensitivity

Rheumatoid arthritis panel is preferred test

Initial screening for functional ability of complement system; tests for defects in classical complement pathway

Does not evaluate individual components of alternative pathway

Complement activation can occur during blood draw (rare)

Initial screening for functional ability of complement system; tests for defects in alternative complement pathway

Complement activation can occur during blood draw (rare)

First-line testing for connective tissue disease

Panel includes dsDNA, IgG; Smith/RNP, IgG; Smith (ENA), IgG; SSA 52 and 60, IgG; SSB, IgG; Jo-1, IgG; Scl-70, IgG

Confirmatory tests for specific connective tissue disease

Components include Smith (ENA), Sm/RNP, SSA, SSB, Jo-1, RPP, centromere and Scl-70 antibodies

Recommended first-line panel for evaluation of autoimmune liver disease (ALD)

Negative results do not rule out disease

All interpretation of antibody patterns must be done in conjunction with clinical presentation

Components include mitochondrial M2 antibody, IgG; LKM-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG with reflex to SMA, IgG titer; soluble liver antigen antibody, IgG; ANA with HEp-2 substrate, IgG

Diagnose HBV

Can be ordered as part of acute hepatitis panel which includes HAV IgM, HBV core antibody IgM, HBV surface antigen, and HCV antibody

Preferred single-screening test for one-time screening of population born between 1945 and 1965 and individuals at risk for HCV

Positive results require confirmation by molecular testing (eg, hepatitis C virus by quantitative PCR or hepatitis C virus (HCV) by quantitative PCR with reflex to HCV genotype by sequencing

2014 CDC recommended algorithm for laboratory diagnosis of HIV infection

Fourth generation test screens for HIV-1 p24 antigen and antibodies to HIV-1 (groups M and O) and HIV-2

Repeatedly reactive HIV-1, 2 antigen/antibody screening results are confirmed with an HIV-1/HIV-2 antibody differentiation test

Negative or indeterminate results for HIV-1/2 antibody differentiation are confirmed with a quantitative NAAT test

Detect and quantify monoclonal protein (M-protein) in serum

Use in screening and monitoring of multiple myeloma and related disorders

Related Tests

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold

Initial screening for hepatobiliary inflammation

Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

Screening test to evaluate kidney function

Assess thyroid function

Identify risk in patients with palpable thyroid nodules


Additional Resources

Medical Experts



Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Pathology (Clinical), University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories