Cryoglobulinemia

Diagnosis

Indications for Testing

• Appropriate clinical signs and symptoms of cryoglobulinemia

Laboratory Testing

• Initial testing – rule out other diseases or associated diseases
  • Rheumatoid factor – rheumatoid arthritis
  • 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 trace amounts of polyclonal immunoglobulins
• Serum protein electrophoresis – 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

Clinical Background

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

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
  • Consists of IgM, occasionally IgG, and rarely IgA or Bence Jones protein
  • Associated diseases – plasma cell dyscrasia, monoclonal gammopathy of undetermined 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, autoimmune 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 Cytomegalovirus Epstein-Barr virus Hepatitis A virus Hepatitis B virus Hepatitis C virus HIV Bacterial Borrelia burgdorferi Coxiella burnetii Lepromatous leprosy Poststreptococcal nephritis Subacute bacterial endocarditis Treponema pallidum 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 Non-Hodgkin lymphoma Multiple myeloma Myelodysplasia Thrombocytopenic thrombotic purpura Waldenström macroglobulinemia	Autoimmune hepatitis Autoimmune thyroiditis Biliary cirrhosis Dermatomyositis-polymyositis Endomyocardial fibrosis Inflammatory bowel disease Pemphigus vulgaris Primary antiphospholipid syndrome Pulmonary fibrosis Rheumatoid arthritis Sarcoidosis Sjögren syndrome Systematic lupus erythematosus Systemic sclerosis	Churg-Strauss syndrome Henoch-Schönlein purpura Polyarteritis nodosa Temporal arteritis

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
• Cryoglobulinemia types II and III –  vasculitic symptoms 
  • Results from the tendency of cryoglobulins to precipitate at low temperatures and occlude blood vessels
  • 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
  • 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Cryoglobulin, Qualitative, with Reflex to Quantitative IgA, IgG, and IgM 2002063 Method: Qualitative Cold Precipitation/Quantitative Nephelometry	Confirms cryoglobulinemia but does not distinguish etiology Perform serum electrophoresis
Cryoglobulin, Qualitative 0050185 Method: Qualitative Cold Precipitation	Confirms cryoglobulinemia but does not distinguish etiology Perform serum electrophoresis
Hepatic Function Panel 0020416 Method: Quantitative Enzymatic/Quantitative Spectrophotometry	Monitor for hepatocellular carcinoma (HCC)
Alpha Fetoprotein, Serum (Tumor Marker) 0080428 Method: Quantitative Chemiluminescent Immunoassay	Monitor for HCC
Urinalysis, Complete 0020350 Method: Reflectance Spectrophotometry/Microscopy	Monitor glomerulonephritis
Urea Nitrogen, Serum or Plasma 0020023 Method: Quantitative Spectrophotometry	Monitor glomerulonephritis
Creatinine, Serum or Plasma 0020025 Method: Quantitative Enzymatic	Monitor glomerulonephritis
Thyroid Stimulating Hormone with reflex to Free Thyroxine 2006108 Method: Quantitative Electrochemiluminescent Immunoassay	Monitor thyroid involvement
Thyroid Stimulating Hormone 0070145 Method: Quantitative Chemiluminescent Immunoassay	Monitor thyroid involvement
Thyroid Antibodies 0050645 Method: Chemiluminescent Immunoassay	Monitor thyroid involvement