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).

Quick Answers for Clinicians

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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 
  • 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

Monitoring

  • Monitoring for complications associated predominantly with mixed cryoglobulinemia

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

Pathophysiology

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

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

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

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

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)

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

Complement activation can occur during blood draw (rare)

Confirmatory tests for specific connective tissue disease

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

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

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

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

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

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

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

Use in screening and monitoring of multiple myeloma and related disorders

Related Tests

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

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

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

Initial screening for hepatobiliary inflammation

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

Screen for various metabolic and kidney disorders

Screening test to evaluate kidney function

Assess thyroid function

Identify risk in patients with palpable thyroid nodules

Medical Experts

Contributor

Delgado

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

References

Additional Resources