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).
Diagnosis
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
- C-reactive protein (CRP)
- If CRP is not available, order erythrocyte sedimentation rate (ESR)
- Preferred test to detect inflammatory processes (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
- Rheumatoid arthritis – rheumatoid factor
- Complement deficiency – AH50, CH50, individual complement testing
- Systemic lupus erythematous (SLE) or other autoimmune connective tissue disorders – antinuclear antibody test (ANA), C3 and C4 concentrations
- ANCA-associated vasculitis – antineutrophil cytoplasmic antibodies (ANCA)
- Autoimmune hepatitis – antimitochondrial antibody
- Viral testing
- Hepatitis C virus (HCV)
- Hepatitis B virus (HBV)
- HIV
- C-reactive protein (CRP)
- 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
- Vasculitis
- Skin lesions
Monitoring
- 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
Background
Epidemiology
- 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
Classification
Type | Percent | Immunoglobulins Present | Associated Disorders |
---|---|---|---|
I |
5-20% |
Monoclonal immunoglobulins
|
Plasma cell dyscrasias – Waldenström and multiple myeloma most common Lymphoproliferative diseases |
II (Mixed cryoglobulinemia) |
40-60% |
Mixed cryoglobulins – monoclonal immunoglobulin directed against polyclonal immunoglobulin
OR
|
Chronic hepatitis C (HCV), HIV Autoimmune disorders (Sjögren) Mixed cryoglobulinemia syndrome |
III (Mixed cryoglobulinemia) |
40-50% |
Mixed polyclonal proteins – ≥2 immunoglobulins (none are homogeneous polyclonal IgM & IgG) |
Autoimmune diseases (eg, connective tissue, autoimmune hepatitis) HCV Lymphoproliferative disorders |
Pathophysiology
- Cryoglobulins
- Proteins reversibly precipitate at 0-4°C and resolubilize upon warming
- Low concentrations may occur in apparently healthy individuals
Clinical Conditions That May Be Associated with Cryoglobulinemia Infections Lymphoproliferative Diseases Autoimmune Diseases Vasculitides Viral
- Cytomegalovirus
- Epstein-Barr virus
- Hepatitis A virus
- Hepatitis B virus
- Hepatitis C virus
- HIV
Bacterial
- Babesia microti
- Borrelia burgdorferi
- Coxiella burnetii
- Mycobacterium leprae
- Poststreptococcal nephritis
- Subacute bacterial endocarditis
- Treponema pallidum
- Plasmodium malariae
Fungal
- Coccidioides
Parasitic
- B-cell and T/NK-cell lymphomas
- Castleman disease
- Chronic lymphocytic leukemia
- Chronic myeloid leukemia
- Cold agglutinin disease
- Hodgkin lymphoma
- Myelodysplastic syndrome
- Plasma cell dyscrasias
- Thrombocytopenic thrombotic purpura
- Autoimmune hepatitis
- Autoimmune thyroiditis
- Primary biliary cirrhosis
- Inflammatory myopathies (eg, polymyositis)
- Endomyocardial fibrosis
- Inflammatory bowel disease
- Pemphigus vulgaris
- Primary antiphospholipid syndrome
- Pulmonary fibrosis
- Rheumatoid arthritis
- Sarcoidosis
- Sjögren syndrome
- Systematic lupus erythematosus
- Systemic sclerosis
- Eosinophilic granulomatosis with polyangiitis
- IgA vasculitis (Henoch-Schönlein purpura)
- Polyarteritis nodosa
- Giant cell arteritis (temporal arteritis)
- Microscopic polyangiitis
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
- Skin
- Skin, glomeruli, and peripheral nerves most often involved – more common and frequent in type I
- 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
Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay
Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold
Qualitative Cold Precipitation/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry
Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)
Quantitative Immunoturbidimetry
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
Quantitative Enzymatic Assay
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
Quantitative Immunoturbidimetry
Initial screening for functional ability of complement system; tests for defects in classical complement pathway
Complement activation can occur during blood draw (rare)
Quantitative Immunoturbidimetry
Initial screening for functional ability of complement system; tests for defects in alternative complement pathway
Complement activation can occur during blood draw (rare)
Semi-Quantitative Radial Immunodiffusion
First-line testing for connective tissue disease
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody (IFA)/Semi-Quantitative Multiplex Bead Assay
Confirmatory tests for specific connective tissue disease
Components include Smith (ENA), Sm/RNP, SSA, SSB, Jo-1, RPP, centromere and Scl-70 antibodies
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay
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
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
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
Qualitative Chemiluminescent Immunoassay
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
Qualitative Chemiluminescent Immunoassay
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
Qualitative Chemiluminescent Immunoassay/Qualitative Immunoassay/Quantitative Transcription-Mediated Amplification
Detect and quantify monoclonal protein (M-protein) in serum
Use in screening and monitoring of multiple myeloma and related disorders
Quantitative Capillary Electrophoresis/Colorimetry
Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold
Qualitative Cold Precipitation/Quantitative Nephelometry
Aid in evaluation of patients with vasculitis, macroglobulinemia, or multiple myeloma in whom symptoms occur with exposure to cold
Qualitative Cold Precipitation
Initial screening for hepatobiliary inflammation
Quantitative Enzymatic Assay/Quantitative Spectrophotometry
Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total
Screening test to evaluate kidney function
Quantitative Spectrophotometry
Assess thyroid function
Identify risk in patients with palpable thyroid nodules
Quantitative Electrochemiluminescent Immunoassay
References
17308210
Braun GS, Horster S, Wagner KS , et al. Cryoglobulinaemic vasculitis: classification and clinical and therapeutic aspects. Postgrad Med J. 2007;83(976):87-94.
Choosing Wisely
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Dec 2020]
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Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008;3:25.
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Motyckova G, Murali M. Laboratory testing for cryoglobulins. Am J Hematol. 2011;86(6) 500-502.
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Ramos-Casals M, Stone JH, Cid MC , et al. The cryoglobulinaemias. Lancet. 2012;379(9813):348-360.
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Sargur R, White P, Egner W. Cryoglobulin evaluation: best practice? Ann Clin Biochem. 2010;47(Pt 1):8-16.
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Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6(1):3-8.
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Tedeschi A, Baratè C, Minola E , et al. Cryoglobulinemia. Blood Rev. 2007;21(4):183-200.
Medical Experts
Delgado

Peterson

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