Cryoglobulinemia

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

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

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

Vasculitis in Adults Testing Algorithm

  • 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 mixed cryoglobulinemia – 1/100,000
  • 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
      • 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

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

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

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

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

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

Protein Electrophoresis, Serum 0050640
Method: Quantitative Capillary Electrophoresis

Additional Tests Available

Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Comments

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

Comments

Confirms cryoglobulinemia but does not distinguish etiology

Consider serum electrophoresis

Cryoglobulin, Qualitative 0050185
Method: Qualitative Cold Precipitation

Comments

Confirms cryoglobulinemia but does not distinguish etiology

Consider serum electrophoresis

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Comments

Assess hepatic function

Urinalysis, Complete 0020350
Method: Reflectance Spectrophotometry/Microscopy

Comments

Monitor renal disease

Urea Nitrogen, Serum or Plasma 0020023
Method: Quantitative Spectrophotometry

Comments

Monitor renal disease

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

Comments

Monitor thyroid disease

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 J, Falk R, Bacon P, Basu N, Cid M, Ferrario F, Flores-Suarez L, Gross W, Guillevin L, Hagen E, Hoffman G, Jayne D, Kallenberg C, Lamprecht P, Langford C, Luqmani R, Mahr A, Matteson E, Merkel P, Ozen S, Pusey C, Rasmussen N, Rees A, Scott D, Specks U, Stone J, Takahashi K, Watts R. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65(1): 1-11. PubMed

General References

Braun G, Horster S, Wagner K, 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 J, Cid M, 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: December 2015