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

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

Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM 2002403

Method: 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)

C-Reactive Protein 0050180

Method: 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

Creatinine, Serum or Plasma 0020025

Method: Quantitative Enzymatic

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

Rheumatoid Factor 0050465

Method: Quantitative Immunoturbidimetry

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)

Complement Activity Enzyme Immunoassay, Total 0050198

Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

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

Complement activation can occur during blood draw (rare)

Complement Activity, Alternative Pathway (AH50) 2005373

Method: Semi-Quantitative Radial Immunodiffusion

Confirmatory tests for specific connective tissue disease

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

Connective Tissue Diseases Profile 0051668

Method: Semi-Quantitative Multiplex Bead Assay

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/PR3) with reflex to ANCA titer

Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR3 Antibodies 2002068

Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

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

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

There may be overlap between diseases and antibodies detected

No single test shows absolute specificity

LC-1 and soluble liver antigen (SLA) testing should be considered if panel tests are negative

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

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

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

Hepatitis B Virus Surface Antigen with Reflex to Confirmation 0020089

Method: 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

Hepatitis C Virus Antibody by CIA 2002483

Method: 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

Human Immunodeficiency Virus (HIV) Combo Antigen/Antibody (HIV-1/O/2) by CIA, Reflexive Panel 2012674

Method: 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

Protein Electrophoresis, Serum 0050640

Method: Quantitative Capillary Electrophoresis/Quantitative Spectrophotometry

Related Tests

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Sedimentation Rate, Westergren (ESR) 0040325

Method: Visual Identification

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

Cryoglobulin, Qualitative, with Reflex to Quantitative IgA, IgG, and IgM 2002063

Method: Qualitative Cold Precipitation/Quantitative Nephelometry

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

Cryoglobulin, Qualitative 0050185

Method: Qualitative Cold Precipitation

Initial screening for hepatobiliary inflammation

Hepatic Function Panel 0020416

Method: Quantitative Enzymatic/Quantitative Spectrophotometry

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

Screen for various metabolic and kidney disorders

Urinalysis, Complete 0020350

Method: Reflectance Spectrophotometry/Microscopy

Screening test to evaluate kidney function

Urea Nitrogen, Serum or Plasma 0020023

Method: Quantitative Spectrophotometry

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108

Method: Quantitative Electrochemiluminescent Immunoassay

Medical Experts

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; 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: Aug 2019]

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: October 2019

Cryoglobulinemia

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Differential Diagnosis

Monitoring

Background

Epidemiology

Classification

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Vasculitis in Adults Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Cryoglobulinemia. ARUP Consult^©. Retrieved December 5, 2019, from: https://arupconsult.com/content/cryoglobulinemia

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Cryoglobulinemia

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Differential Diagnosis

Monitoring

Background

Epidemiology

Classification

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Vasculitis in Adults Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult