Cryoglobulinemia Clinical Presentation

  • Author: Adam M Tritsch, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 18, 2012
 

History

  • Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given their usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include acrocyanosis, retinal hemorrhage, severe Raynaud phenomenon with digital ulceration, livedo reticularis, purpura, and arterial thrombosis.
  • Specific clinical manifestations associated with types II and III cryoglobulinemia include joint involvement (usually, arthralgias in the proximal interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles), fatigue, myalgias, renal immune-complex disease, cutaneous vasculitis, and peripheral neuropathy.
  • Typical presentations and reported frequencies include the following:
    • Cutaneous: These manifestations are nearly always present in cryoglobulinemia. Observed lesions have a predilection for dependent areas (particularly the lower extremities) and include erythematous macules and purpuric papules (90-95%), as well as ulcerations (10-25%).[16, 22, 15, 23] Lesions in nondependent areas are more common in type I cryoglobulinemia (head and mucosa), as are livedo reticularis, Raynaud phenomenon, and ulcerations. Nailfold capillary abnormalities are common and include dilatation, altered orientation, capillary shortening, and neoangiogenesis.[24] See the image below. Rash on lower extremities typical of cutaneous smaRash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.
    • Musculoskeletal: Symptoms such as arthralgias and myalgias are rare in type I cryoglobulinemia and are common in types II and III disease. Frank arthritis and myositis are rare. Arthralgias commonly affect the proximal interphalangeal and metacarpophalangeal joints of the hands, knees, and ankles. Musculoskeletal symptoms are described in more than 70% of persons with cryoglobulinemia.[25, 26, 22]
    • Renal: Renal disease may occur secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%. Histologically, membranoproliferative glomerulonephritis is almost always the lesion in mixed cryoglobulinemia. Clinically, isolated proteinuria and hematuria are more common than nephrotic syndrome, nephritic syndrome, or acute renal failure. Renal involvement is one of the most serious complications of cryoglobulinemia and typically manifests early in the course of the disease (within 3-5 y of diagnosis). Failure to treat may result in renal failure.[16, 27, 28]
    • Pulmonary: A reduction in forced expiratory flow rates and the presence of interstitial infiltrates revealed by chest radiographs are common in mixed cryoglobulinemia. Approximately 40-50% of patients are symptomatic with dyspnea, cough, or pleuritic pain. Severe pulmonary disease is rare.[29, 30, 31, 32]
    • Neuropathy: Neuropathy is common in types II and III disease (as determined with electromyographic and nerve conduction studies), affecting 70-80% of patients. Symptomatic disease was once reported as less common (5-40%); however, more recently, subjective symptoms have been reported up to 91% of patients. Sensory fibers are more commonly affected than motor fibers, with pure motor neuropathy in approximately 5% of patients.[33, 22, 34, 35]
    • Abdominal pain: Abdominal pain has been reported in 2-22% of patients. Vasculitis of the small mesenteric vessels that leads to acute abdomen has been reported.
    • Sicca symptoms have been reported in 4-20% of patients.[22, 29]
    • Acrocyanosis has been reported in up to 9% of patients.
    • Arterial thrombosis has been reported in 1% of patients.
  • Meltzer triad, ie, purpura, arthralgia, and weakness, was first described in 1966 by Meltzer and Franklin in cases of essential mixed cryoglobulinemia. This triad is generally seen with types II and III cryoglobulinemia and is seen in up to 25-30% of patients.[36, 22]
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Physical

  • Skin manifestations
    • Ischemic necrosis (40% in type I, 0-20% in mixed types)
    • Palpable purpura (15% in type I, 80% in mixed types)
    • Livedoid vasculitis (1% in type I, 14% in type III)
    • Cold-induced urticaria (15% in type I, 10% in type III)
    • Hyperkeratotic spicules in areas exposed to cold
    • Scarring of tip of nose, pinnae, fingertips, and toes
    • Acrocyanosis
    • Nailfold capillary abnormalities
  • Pulmonary manifestations
  • Gastrointestinal manifestations
    • Abdominal pain (2-22%)
    • Hemorrhage
    • Hepatomegaly or signs of cirrhosis (ie, palmar erythema, abdominal wall collateral vessels, spider angiomata)
    • Splenomegaly
  • Renal manifestations
    • Membranoproliferative glomerulonephritis described in all types (more common in type II)
    • Intraluminal cryoglobulin deposition
    • Hypertension
    • Nephrotic-range proteinuria with resultant edema
  • Joint manifestations
    • Arthralgias (5% of type I, 20-58% of mixed)
    • Frank arthritis and progressive joint deformity (distinctly rare)
  • Nervous system manifestations
    • Sensorimotor neuropathy
    • Visual disturbances
    • CNS involvement (rare, although pseudotumor cerebri and cerebral vascular events have been described)
  • Other manifestations - Fever
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Causes

  • Disease associations variable based on type of cryoglobulinemia
    • Type I is observed in lymphoproliferative disorders (eg, multiple myeloma, Waldenström macroglobulinemia).
    • Types II and III are observed in chronic inflammatory diseases such as chronic liver disease, infections (chronic HCV infection), and coexistent connective-tissue diseases (SLE, Sjögren syndrome). Mixed cryoglobulinemia is rarely associated with lymphoproliferative disorders.
  • Infection
  • Autoimmune diseases
  • Lymphoproliferative disorders - Waldenström macroglobulinemia, multiple myeloma, lymphoma, leukemia (eg, chronic lymphocytic leukemia, hairy cell leukemia)
  • Liver diseases - Hepatitis A, B, and C (30-98% of patients with HCV infection have cryoglobulins, especially type II); cirrhosis
  • Familial
  • Essential
  • Experimental - Postvaccination (eg, pneumococcal vaccine)
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Contributor Information and Disclosures
Author

Adam M Tritsch, MD  Resident Physician, Department of Internal Medicine, Eisenhower Army Medical Center, Fort Gordon, Georgia

Adam M Tritsch, MD, is a member of the following medical societies: American College of Physicians

Disclosure: Amgen Stocks None

Coauthor(s)

Craig Ainsworth, MD  Chief of Medical Residents, Department of Internal Medicine, Eisenhower Army Medical Center

Craig Ainsworth, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

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.

Specialty Editor Board

Kristine M Lohr, MD, MS  Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Lawrence H Brent, MD  Associate Professor of Medicine, Jefferson Medical College of 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 for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Alex J Mechaber, MD, FACP  Senior 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  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh 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: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Timothy M Straight, MD, to the development and writing of this article.

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Rash on lower extremities typical of cutaneous small-vessel vasculitis due to cryoglobulinemia secondary to hepatitis C infection.
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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