Cryoglobulinemia

Indications for Testing

Appropriate clinical signs and symptoms are present

Laboratory Testing

Initial testing to rule out other diseases or associated diseases
- Rheumatoid factor – rheumatoid arthritis (RA)
- Complement components 3 & 4 (C3, C4) – complement deficiency
- Antinuclear antibody test (ANA) with extractable nuclear antigen (ENA) – systemic lupus erythematous or other autoimmune connective tissue disorders
- Antineutrophil cytoplasmic antibodies – vasculitis
- Antimitochondrial antibody – autoimmune hepatitis
- HCV, HBV – viral hepatitis B & C
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 immunoglobular trace amounts of polyclonal immunoglobulins
Serum protein electrophoresis should be performed in patients with cryoglobulinemia to identify the specific immunoglobulins present and determine if there is a monoclonal protein present

Histology

Skin biopsy demonstrating immune complex deposition to secure diagnosis in vasculitis

Differential Diagnosis

See "Clinical conditions that may be associated with cryoglobulinemia" in the Clinical Background tab

Monitoring for complications associated predominantly with mixed cryoglobulinemia
- Chronic hepatitis with cirrhosis – hepatocellular carcinoma (HCC) monitoring (transaminases, alpha-fetoprotein and liver ultrasonography)
- Glomerulonephritis – urinalysis, blood urea nitrogen/creatinine
- Thyroid involvement – thyroid stimulating hormone, antibody testing
- Skin ulcers – consider arterial/venous Doppler evaluations; repeat testing for vasculitis

The majority of cryoglobulinemias are secondary manifestations of other diseases and not “essential” as previously reported.

Epidemiology

Prevalence of mixed cryoglobulinemia – 1/100,000
Age – 40s-50s
Sex – M<F, 1:3
Ethnicity – more common in Southern Europe than Northern Europe/North America

Classification

Type I (25-35%) – monoclonal immunoglobulins consisting of IgM, occasionally IgG and, rarely, IgA or Bence Jones protein
- Associated diseases – plasma cell dyscrasia, monoclonal gammopathy of unknown significance, lymphoproliferative diseases
Type II (25%) – mixed cryoglobulins where a monoclonal immunoglobulin is directed against a polyclonal immunoglobulin
- Includes monoclonal IgM or occasionally IgG or IgA complexed with autologous normal IgG
- Associated diseases – chronic hepatitis C (HCV), autoimmune disorders (Sjögren), other infections
Type III (50%) – mixed polyclonal proteins made of 2 or more immunoglobulins, none of which are homogeneous
- Includes polyclonal IgM and IgG
- Associated disorders – autoimmune diseases (eg, connective tissue, hepatitis), HCV, lymphoproliferative, other infections (HBV, Epstein-Barr virus, cytomegalovirus)

Pathophysiology

Cryoglobulins are proteins that reversibly precipitate at 0-4°C and resolubilize upon warming

Low levels of cryoglobulins may also 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

Bacterial

Fungal

Coccidioides

Parasitic

Clinical Presentation

Target organs – may be involved in all types of cryoglobulinemia
- Skin – purpura, petechiae, ulcers, cyanosis, Raynaud phenomena
- Neurologic – mild sensory neuritis, peripheral neuropathy (most common in type III)
- Renal – glomerulonephritis, proteinuria, hematuria
- Hepatic – hepatitis
- Musculoskeletal – arthralgias
- Otorhinolaryngological – xerostomia, xerophthalmia
Predominant symptoms related to cryoglobulinemia types II and III result from the tendency of cryoglobulins to precipitate at low temperatures and occlude blood vessels, resulting in vasculitic symptoms
- Vascular purpura (palpable purpura)
- Bleeding tendencies
- Cold-induced urticaria
- Raynaud phenomenon
- Digital pain and cyanosis
- Skin ulcers
Essential mixed cryoglobulinemia – vasculitic syndrome resulting in purpura, arthralgia and weakness
- Often associated with lymphadenopathy, hepatosplenomegaly and renal failure
- Triad of purpura, weakness and arthralgias

Tests generally appear in the order most useful for common clinical situations

Test name: Rheumatoid Factor

ARUP #: 0050465

Methodology: Quantitative Immunoturbidimetry

Use:

Diagnose RA

Limitations:

Negative results do not rule out RA

Test name: Complement Components 3 & 4

ARUP #: 0050149

Methodology: Quantitative Immunoturbidimetric

Use:

Rule out autoimmune disease or complement deficiency

Test name: Connective Tissue Diseases Profile

ARUP #: 0051668

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

Rule out autoimmune connective tissue disorders

Components include Smith (ENA) antibody; RNP (U1) (Ribonucleic Protein); SSA (Ro); SSB (La); Jo-1; Ribosomal P Protein; Centromere; Scleroderma (Scl-70)

Test name: Anti-Neutrophil Cytoplasmic Antibody with Reflex to Titer and MPO/PR-3 Antibodies

ARUP #: 2002068

Methodology: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

Rule out vasculitis

If screen is positive, titer and MPO/PR-3 antibodies testing will be added to aid in antibody determination

Test name: Autoimmune Hepatitis Panel Plus with Reflex to Titers

ARUP #: 0055351

Methodology: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Use:

Rule out autoimmune hepatitis

Components include anti-nuclear antibodies (ANA) IgG screen with reflex to IFA titer; f-actin (smooth muscle) antibody, IgG; liver-kidney microsoluble antibody, IgG; mitochondrial M2 antibody, IgG (ELISA); anti-neutrophil cytoplasmic antibody, IgG; and soluble liver antigen antibody, IgG

Test name: Hepatitis B Virus Surface Antigen with Reflex to Confirmation

ARUP #: 0020089

Methodology: Qualitative Chemiluminescent Immunoassay

Use:

Rule out HBV

Test name: Hepatitis C Virus Antibody by CIA

ARUP #: 2002483

Methodology: Qualitative Chemiluminescent Immunoassay

Use:

Rule out HCV

Test name: Cryoglobulin, Qualitative with Reflex to IFE Typing and Quantitative IgA, IgG, and IgM

ARUP #: 2002403

Methodology: Qualitative Cold Precipitation/ Qualitative IFE/Quantitative Nephelometry

Use:

First test in the evaluation of cryoglobulinemia after other etiologies have been ruled out

Confirm cryoglobulinemia

Limitations:

Confirms cryoglobulinemia but does not distinguish etiology

Follow-up:

If qualitative is positive, Immunofixation Electrophoresis Typing and Quantitative IgA, IgG and IgM will be added

Test name: Protein Electrophoresis, Serum

ARUP #: 0050640

Methodology: Quantitative Capillary Electrophoresis

Use:

Rule out plasma cell dyscrasias

Perform in patients with cryoglobulinemia to identify specific immunoglobulins and determine presence of monoclonal proteins

Additional Tests Available

Test name: Cryoglobulin, Qualitative with Reflex to Quantitative IgA, IgG, & IgM

ARUP #: 2002063

Methodology: Qualitative Cold Precipitation/Quantitative Nephelometry

Comments:

Confirms cryoglobulinemia but does not distinguish etiology

Serum electrophoresis should be performed

Test name: Cryoglobulin, Qualitative

ARUP #: 0050185

Methodology: Qualitative Cold Precipitation

Comments:

Confirms cryoglobulinemia but does not distinguish etiology

Serum electrophoresis should be performed

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Comments:

Monitor for HCC

Test name: Alpha Fetoprotein, Serum (Tumor Marker)

ARUP #: 0080428

Methodology: Quantitative Chemiluminescent Immunoassay

Comments:

Monitor for HCC

Test name: Urinalysis, Complete

ARUP #: 0020350

Methodology: Reflective Photometry/Microscopic by Yellow IRIS

Comments:

Monitor glomerulonephritis

Test name: Urea Nitrogen, Serum or Plasma

ARUP #: 0020023

Methodology: Quantitative Spectrophotometry

Comments:

Monitor glomerulonephritis

Test name: Creatinine, Serum or Plasma

ARUP #: 0020025

Methodology: Quantitative Enzymatic

Comments:

Monitor glomerulonephritis

Test name: Thyroid Stimulating Hormone

ARUP #: 0070145

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

Monitor thyroid involvement

Test name: Thyroid Antibodies

ARUP #: 0050645

Methodology: Chemiluminescent Immunoassay

Comments:

Monitor thyroid involvement

General

Delgado, Julio C., MD, MS. Medical Director, Protein Immunology at ARUP Laboratories; Associate Director, Histocompatibility and Immunogenetics Laboratory and Assistant Professor of Pathology, University of Utah

Comprehensive Review: July 2011
Last Update: February 2012

Connective Tissue Diseases

Epstein-Barr Virus

Hepatitis, Autoimmune

Hepatitis B Virus

Hepatitis C Virus

Inflammatory Bowel Disease

Mixed Connective Tissue Disease

Plasma Cell Dyscrasias

Vasculitis