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Cryoglobulinemia Clinical Presentation

  • Author: Adam M Tritsch, MD; Chief Editor: Herbert S Diamond, MD  more...
Updated: Jun 15, 2016


Specific clinical manifestations associated with type I cryoglobulinemia are related to hyperviscosity and thrombosis, as would be expected given the usual high concentrations of immunoglobulins and limited interference with complement function. These manifestations include the following:

  • Acrocyanosis
  • Retinal hemorrhage
  • Severe Raynaud phenomenon with digital ulceration
  • Livedo reticularis
  • Purpura
  • Arterial thrombosis

Specific clinical manifestations associated with types II and III cryoglobulinemia include the following:

  • Joint involvement (usually, arthralgias in the proximal interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles)
  • Fatigue
  • Myalgias
  • Renal immune-complex disease
  • Cutaneous vasculitis
  • Peripheral neuropathy

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.[25, 26]

Cutaneous manifestations

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%).[19, 26, 18, 27]

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.[28] See the image below.

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

Musculoskeletal manifestations

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.[29, 30, 26]

Renal manifestations

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.[19, 31, 32]

Pulmonary manifestations

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.[33, 34, 35, 36]


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.[37, 26, 38, 39]

Other manifestations

Patients with cryoglobulinemia may also present with the following:

  • 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 [26, 33]
  • Acrocyanosis has been reported in up to 9% of patients
  • Arterial thrombosis has been reported in 1% of patients
  • A high incidence of new cases of thyroid autoimmunity and dysfunction hase been found in patients (particularly women) with hepatitis C–associated mixed cryoglobulinemia. [40]


Skin manifestations include the following:

  • 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 include the following:

  • Dyspnea
  • Cough
  • Pleurisy
  • Pleural effusions
  • Bronchiectasis

Gastrointestinal manifestations include the following:

  • Abdominal pain (2-22%)
  • Hemorrhage
  • Hepatomegaly or signs of cirrhosis (ie, palmar erythema, abdominal wall collateral vessels, spider angiomata)
  • Splenomegaly

Renal manifestations include the following:

  • Membranoproliferative glomerulonephritis described in all types (more common in type II)
  • Intraluminal cryoglobulin deposition
  • Hypertension
  • Nephrotic-range proteinuria with resultant edema

Joint manifestations include the following:

  • Arthralgias (5% of type I, 20-58% of mixed)
  • Frank arthritis and progressive joint deformity (distinctly rare)

Nervous system manifestations include the following:

  • Sensorimotor neuropathy
  • Visual disturbances
  • CNS involvement (rare, although pseudotumor cerebri and cerebral vascular events have been described)

Fever is another manifestation.



Disease associations vary with the type of cryoglobulinemia, as follows:

  • 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.

Infections associated with cryoglobulinemia include the following:

  • Viral - Hepatitis A, B, and C (see Differentials); HIV; Epstein-Barr virus (EBV); cytomegalovirus (CMV); adenovirus; chikungunya
  • Bacterial - Endocarditis, streptococcal infections, syphilis, Lyme disease, leprosy, Q fever, brucellosis
  • Fungal -Coccidioidomycosis
  • Parasitic -Malaria, toxoplasmosis, others

Other disorders associated with cryoglobulinemia include the following:

  • Autoimmune diseases - SLE, rheumatoid arthritis, Sjögren syndrome
  • Vasculitis -Polyarteritis nodosa (especially hepatitis B–associated), Henoch-Schönlein purpura
  • Lymphoproliferative disorders - Waldenström macroglobulinemia, multiple myeloma, lymphoma, leukemia (eg, chronic lymphocytic leukemia, hairy cell leukemia)
  • Renal diseases -Proliferative glomerulonephritis
  • Liver diseases - Hepatitis A, B, and C (30-98% of patients with HCV infection have cryoglobulins, especially type II); cirrhosis

Cryoglobulinemia may occur as a familial or idiopathic disorder. Finally, cases have been reported following vaccination (eg, with pneumococcal vaccine).

Contributor Information and Disclosures

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: Partner received stocks from Amgen for none.


Colin C Edgerton, MD Clinical Assistant Professor, Department of Medicine, Medical College of Georgia; Clinical Assistant Professor, Department of Medicine, Uniformed Services University

Colin C Edgerton, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, Clinical Immunology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, American College of Rheumatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Janssen<br/>Serve(d) as a speaker or a member of a speakers bureau for: Genentech; Pfizer; Mallinckrodt.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; 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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Interim Chief, 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, American College of Rheumatology

Disclosure: Nothing to disclose.


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.

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.

Timothy M Straight, MD Instructor, Department of Medicine, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

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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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