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).

Tabs Content

Clinical Overview

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
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

Types of cryoglobulinemia

Types of Cryoglobulinemia
Type	Percent	Immunoglobulins Present	Associated Disorders
I	5-20%	Monoclonal immunoglobulins IgM most common IgG occasionally IgA or Bence Jones protein rarely	Plasma cell dyscrasias – Waldenström and multiple myeloma most common Lymphoproliferative diseases
II (Mixed cryoglobulinemia)	40-60%	Mixed cryoglobulins – monoclonal immunoglobulin directed against polyclonal immunoglobulin IgM monoclonal OR (Occasionally) IgG or IgA complexed with autologous normal IgG	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

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 Echinococcus spp Leishmania spp Plasmodium spp Schistosoma spp Toxoplasma gondii Trypanosoma cruzi	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
Essential mixed cryoglobulinemia – vasculitis
- Triad of purpura, weakness, and arthralgias
- Often associated with lymphadenopathy, hepatosplenomegaly, and renal failure

ARUP Lab Tests

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

Recommended Use

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

Reflex pattern – if qualitative is positive, immunofixation electrophoresis typing and quantitative IgA, IgG, and IgM will be added

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Recommended Use

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

Creatinine, Serum or Plasma 0020025
Method: Quantitative Enzymatic

Recommended Use

Screening test to evaluate kidney function

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

Recommended Use

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

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

Recommended Use

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

Limitations

Does not evaluate individual components of alternative pathway

Complement activation can occur during blood draw (rare)

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

Recommended Use

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

Limitations

Complement activation can occur during blood draw (rare)

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

Recommended Use

Confirmatory tests for specific connective tissue disease

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

Recommended Use

Preferred reflex panel for managing patients with a known diagnosis of vasculitis; may be assistive in evaluating suspected vasculitis

Preferred reflex panel for workup of suspected vasculitis is ANCA-associated vasculitis profile (ANCA/MPO/PR-3) with reflex to ANCA titer

Panel includes ANCA, IgG; myeloperoxidase antibody; and serine protease 3 antibody

Reflex pattern – if screen is positive, then 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

Recommended Use

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

Components include mitochondrial M2 antibody, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG with reflex to smooth muscle antibody, IgG titer

Reflex pattern – if F-Actin, IgG result is 20 units or greater, then smooth muscle antibody, IgG titer will be added

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 soluble liver antigen (SLA) testing should be considered if panel tests are negative

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

Recommended Use

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

Reflex pattern – if results for HBsAg screen are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation will be added

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

Recommended Use

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

Human Immunodeficiency Virus (HIV) Combo Antigen/Antibody (HIV-1/O/2) by CIA, Reflexive Panel 2012674
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Immunoassay/Quantitative Polymerase Chain Reaction

Recommended Use

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 PCR test

Reflex pattern – 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 PCR test

Protein Electrophoresis, Serum 0050640
Method: Quantitative Capillary Electrophoresis

Recommended Use

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

Use in screening and monitoring of multiple myeloma and related disorders

Medical Reviewers

Delgado, Julio, MD, MS, Chief Medical Officer; Director of Laboratories; Chief, Division of Clinical Pathology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

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
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jun 2018]

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

Testing Algorithms

Vasculitis in Adults Testing Algorithm

Read more about Vasculitis in Adults Testing Algorithm

Content Review:

July 2017

Last Update: September 2018


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	Cryoglobulinemia. ARUP Consult^©. Retrieved October 15, 2018, from: https://arupconsult.com/content/cryoglobulinemia