Cryoglobulinemia

  • Diagnosis
  • Algorithms
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

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

Laboratory Testing

  • Initial testing – exclude other primary diseases, 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

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" in the Clinical Background tab
  • Monitoring for complications associated predominantly with mixed 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

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
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.

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

Limitations 

Does not distinguish etiology for cryoglobulinemia

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Limitations 

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

Rheumatoid Factor 0050465
Method: Quantitative Immunoturbidimetry

Limitations 

Negative results do not rule out RA

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

Limitations 

Does not evaluate individual components of the alternative pathway

Complement activation can occur during blood draw (rare) 

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

Limitations 

Complement activation can occur during blood draw (rare) 

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

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

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

Limitations 

Negative results do not rule out disease

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

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

Follow-up 

LC-1 and SLA testing should be considered if panel tests are negative

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

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

Human Immunodeficiency Virus (HIV) Combo Antigen/Antibody (HIV-1/O/2) by ELISA, Reflexive Panel 2012674
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Qualitative Immunoassay/Quantitative Polymerase Chain Reaction

Protein Electrophoresis, Serum 0050640
Method: Quantitative Capillary Electrophoresis

Guidelines

American Society for Clinical Pathology. Choosing Wisely - Five Things Physicians and Patients Should Question. An initiative of the ABIM Foundation. [Last revision Feb 2015; Accessed: Jan 2016]

Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, Flores-Suarez LF, Gross WL, Guillevin L, Hagen EC, Hoffman GS, Jayne DR, Kallenberg CG, Lamprecht P, Langford CA, Luqmani RA, Mahr AD, Matteson EL, Merkel PA, Ozen S, Pusey CD, Rasmussen N, Rees AJ, Scott DG, Specks U, Stone JH, Takahashi K, Watts RA. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65(1): 1-11. PubMed

General References

Braun GS, Horster S, Wagner KS, Ihrler S, Schmid H. Cryoglobulinaemic vasculitis: classification and clinical and therapeutic aspects. Postgrad Med J. 2007; 83(976): 87-94. PubMed

Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008; 3: 25. PubMed

Motyckova G, Murali M. Laboratory testing for cryoglobulins. Am J Hematol. 2011; 86(6): 500-2. PubMed

Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012; 379(9813): 348-60. PubMed

Sargur R, White P, Egner W. Cryoglobulin evaluation: best practice? Ann Clin Biochem. 2010; 47(Pt 1): 8-16. PubMed

Takada S, Shimizu T, Hadano Y, Matsumoto K, Kataoka Y, Arima Y, Inoue T, Sorano S. Cryoglobulinemia (review). Mol Med Rep. 2012; 6(1): 3-8. PubMed

Tedeschi A, Baratè C, Minola E, Morra E. Cryoglobulinemia. Blood Rev. 2007; 21(4): 183-200. PubMed

Medical Reviewers

Last Update: August 2016