eMedicine Specialties > Rheumatology > Vasculitis

Cryoglobulinemia: Differential Diagnoses & Workup

Author: Craig Ainsworth, MD, Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, GA
Coauthor(s): Colin C Edgerton, MD, Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Chief of Rheumatology Service, Eisenhower Army Medical Center; Robert John Oglesby, MD, Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Contributor Information and Disclosures

Updated: Jul 17, 2009

Differential Diagnoses

Antiphospholipid Syndrome
Hepatitis C
Chronic Lymphocytic Leukemia
Hepatitis, Viral
Churg-Strauss Syndrome
Lymphoma, Non-Hodgkin
Cirrhosis
Microscopic Polyangiitis
Giant Cell Arteritis
Multiple Myeloma
Glomerulonephritis, Acute
Polyarteritis Nodosa
Glomerulonephritis, Diffuse Proliferative
Sarcoidosis
Goodpasture Syndrome
Serum Sickness
Hemolytic-Uremic Syndrome
Systemic Lupus Erythematosus
Hepatitis A
Waldenstrom Hypergammaglobulinemia
Hepatitis B

Other Problems to Be Considered

Consider an active infection (ie, viral, bacterial, fungal, parasitic) or a systemic vasculitic process, particularly with evidence of skin lesions, renal disease, or both.

Workup

Laboratory Studies

  • Evaluation for serum cryoglobulins
    • The blood specimen must be obtained in warm tubes (37°C) in the absence of anticoagulants.
    • Allow the blood sample to clot before removal of serum with centrifugation (at 37°C).
    • The period required for the serum sample to incubate (at 4°C) depends on the type of cryoglobulin present, as follows:
      • Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL).
      • Type III cryoglobulins may require 7 days to precipitate a small sample (<1 mg/mL).
    • Repeat centrifugation to determine cryocrit (volume of precipitate as a percentage of original serum volume).
    • Cryoglobulin concentration may be determined via spectrophotometric analysis. Specific immunologic assays may be used to identify cryoglobulin components (immunoglobulins, light chains, clonality).
  • Urinalysis: Abnormalities may represent evidence of renal disease.
  • Complete blood cell count: Leukocytosis may be a manifestation of concomitant infection or leukemia. Anemia may be present.
  • Serum chemistry: Patients with renal insufficiency may present with elevated serum creatinine levels and electrolyte abnormalities.
  • Liver function studies: Liver function studies may reveal evidence of underlying hepatitis; obtain hepatitis serology.
  • RF: RF is positive in types II and III.
  • Antinuclear antibody (ANA): ANA is indicated upon clinical suspicion of underlying connective-tissue disease (SLE, Sjögren syndrome).
  • Erythrocyte sedimentation rate (ESR): Elevations may be secondary to rouleaux formation.
  • Complement evaluation (CH50, C3, C4): Patients may display hypocomplementemia (especially low C4 levels).
  • Other studies: Consider serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and quantitative immunoglobulin upon suspicion for underlying gammopathy.
  • Serum viscosity: Measure serum viscosity if symptoms warrant.
  • Further diagnostic laboratory tests: Consider further testing based on the level of suspicion for other associated disease. For example, a recent study demonstrated that patients with mixed cryoglobulinemia associated with HCV infection have elevated levels of interferon-inducible protein 10 and that these levels correlate with disease activity.36

Imaging Studies

  • A chest radiograph may reveal interstitial involvement or pleural effusions.
  • CT imaging may be considered upon high suspicion of underlying malignancy.
  • Transesophageal echocardiography should be obtained if bacterial endocarditis is suspected.
  • Angiography may be considered to evaluate for evidence of vasculitis.

Procedures

  • Tissue biopsy may be required for diagnosis when patients with vasculitis, renal disease, or both are evaluated.
  • Electromyography and nerve conduction studies may be used to confirm neuropathy when history or physical examination findings are suggestive.
  • Further diagnostic procedures (eg, bone marrow biopsy, liver or kidney biopsy) usually depend on coexistent disease, especially HCV infection.

Histologic Findings

Skin: Purpura are histologically characterized by dermal vasculitis that extends variably to the subcutaneous interstitial space. HCV-associated proteins have been found in vasculitic skin biopsy samples, suggesting a role for these antigens in pathogenesis of the lesions.

Other organs: Autopsy studies have revealed unsuspected vasculitis of multiple organs (heart, lung, gastrointestinal tract, central nervous system, liver, muscle, adrenals).14 Histologic evaluation of affected lung, kidney, and muscle reveals eosinophilic material in the lumen of small vessels with frequent extension into the vessel intima and inflammation of the vessel wall.37

Although biopsy samples generally exhibit inflammatory vascular changes (eg, leukocytoclastic vasculitis in patients with vasculitic purpura), intraluminal cryoglobulin deposits may be observed, especially in renal glomeruli.

Renal biopsy sample that shows membranoproliferat...

Renal biopsy sample that shows membranoproliferative glomerulonephritis in a patient with hepatitis C–associated cryoglobulinemia (hematoxylin and eosin; magnified X 200).

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Renal biopsy sample that shows membranoproliferat...

Renal biopsy sample that shows membranoproliferative glomerulonephritis in a patient with hepatitis C–associated cryoglobulinemia (hematoxylin and eosin; magnified X 200).

More on Cryoglobulinemia

Overview: Cryoglobulinemia
Differential Diagnoses & Workup: Cryoglobulinemia
Treatment & Medication: Cryoglobulinemia
Follow-up: Cryoglobulinemia
Multimedia: Cryoglobulinemia
References
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Further Reading

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Keywords

cryoglobulinemia, cryoproteinemia, cryoglobulins, immunoglobulins, essential cryoglobulinemia, simple cryoglobulinemia, type I cryoglobulinemia, type II cryoglobulinemia, type III cryoglobulinemia, mixed cryoglobulinemia, essential cryoglobulinemia, idiopathic cryoglobulinemia, hepatitis C virus, HCV, secondary cryoglobulinemia, glomerulonephritis, chronic vasculitis, cryoprecipitation, systemic lupus erythematosus, SLE, Sjögren syndrome, Sjögren's syndrome, hyperviscosity, thrombosis, acrocyanosis, retinal hemorrhage, Raynaud phenomenon, Raynaud's phenomenon, livedo reticularis, purpura, arterial thrombosis, multiple myeloma, Waldenström macroglobulinemia, Waldenström's macroglobulinemia, chronic liver disease

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Contributor Information and Disclosures

Author

Craig Ainsworth, MD, Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, GA
Craig Ainsworth, MD is a member of the following medical societies: American College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Colin C Edgerton, MD, Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Chief of Rheumatology Service, Eisenhower Army Medical Center
Colin C Edgerton, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Robert John Oglesby, MD, Chief of Rheumatology Service, Department of Medicine, Walter Reed Army Medical Center; Associate Professor of Medicine, Uniformed Services University of the Health Sciences
Robert John Oglesby, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and Arthritis Foundation
Disclosure: Nothing to disclose.

Medical Editor

Kristine M Lohr, MD, MS, Program Director, Professor, Department of Internal Medicine, Division of Rheumatology and Women's Health, University of Kentucky School of Medicine
Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and American Medical Women's Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Lawrence H Brent, MD, Associate Professor of Medicine, Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association of Immunologists, American College of Physicians, and American College of Rheumatology
Disclosure: Genentech Honoraria Speaking and teaching; Genentech Grant/research funds Other; Amgen Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Immunology Honoraria Speaking and teaching

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

 
 
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