Last updated: November 16, 2014
ICD9 Code: 273.2
Definition: These clinical syndromes are associated with the presence of coldprecipitable immunoglobulins (i.e., cryoglobulins).
Etiology: Cryoglobulins are produced by activated B cells, which may be oligoclonal or monoclonal. Some cases are associated with lymphoid malignancies, chronic immune-system disorders (e.g., RA or Sjögren’s syndrome), or infection (e.g., hepatitis, infective endocarditis). Cryoglobulins are classified as type I (monoclonal), type II (mixed monoclonal and polyclonal), or type III (mixed polyclonal). Disease association with each type is discussed under Cryoglobulins.
Pathology: Skin lesions often show leukocytoclastic vasculitis. Renal involvement is usually associated with a proliferative glomerulonephritis. Characteristic protein deposits in subendothelial regions are seen on electron microscopy. Serum samples contain reversibly precipitable immunoglobulins which may be monoclonal, polyclonal, or mixed. Hepatitis C or B antigenemia may be present.
Demographics: Most patients are in the fifth decade or older. Associations with an underlying disease, such as RA, follow the gender distribution characteristic of that disorder.
Cardinal Findings: Palpable purpura may be present on the lower extremities and rarely extends above the waist. Proteinuria may be present and in some cases can be accompanied by significant edema. Peripheral neuropathy with symptoms of pain, dysesthesia, or motor abnormalities may be the predominant finding in some patients. Cryoglobulinemia may present as a multisystem disorder with fever, cutaneous vasculitis, arthralgia, hepatosplenomegaly, lymphadenopathy, and glomerulonephritis.
Uncommon Manifestations: Raynaud’s phenomenon and hyperviscosity syndrome are uncommon manifestations of cryoglobulinemia.
Diagnostic Tests: Serum collection, processing, and characterization of cryoglobulins must be carried out using proper procedure. Complement levels should be measured. Some cryoglobulins may demonstrate rheumatoid factor activity and should be tested for it. Hepatic enzyme elevations may be related to liver involvement or underlying hepatitis C or B infection, which should be assayed. Peripheral neuropathy or mononeuritis can be confirmed by nerve conduction tests. In some cases, biopsy of a nerve that is abnormal on EMG testing is useful. Skin biopsy evidence of leukocytoclastic vasculitis supports the diagnosis of cryoglobulinemia.
Keys to Diagnosis: Palpable purpura in a dependent distribution is most suggestive of cryoglobulinemia. A systemic disorder with involvement of the skin, kidney, peripheral nerves, and liver should suggest the possibility of cryoglobulinemia.
Differential Diagnosis: Conditions that may mimic cryoglobulinemia include vasculitis (e.g., polyarteritis nodosa, Henoch-Schönlein purpura), SLE, and lymphoma. Henoch-Schönlein purpura is more likely to be seen in young adults or children. Isolated renal involvement may occur with cryoglobulinemia and often requires renal biopsy for definitive diagnosis and exclusion of other forms of glomerulonephritis.
Therapy: If an underlying disorder is identified, therapy should be aimed at that process. Hepatitis C may be treated with IFN-a/ribavirin. Acute complications of the cryoglobulins themselves, such as rapidly progressive renal failure or symptoms associated with hyperviscosity, should be treated with a course of intensive plasmapheresis. Cyclophosphamide and steroids are used to treat patients with renal or nervous system involvement.
Surgery: Surgery is only used for diagnostic biopsy such as kidney or nerve.
Prognosis: In the absence of renal or neurologic involvement, many patients remain stable for years. Rapidly progressive glomerulonephritis is associated with a poorer prognosis. All patients should be monitored for transformation to neoplastic disease.
Abel G, Zhang QX, Agnello V. Hepatitis C virus infection in type II mixed cryoglobulinemia. Arthritis Rheum 1993;36:1341–1349. PMID:8216392
Anaya JM, Talal N. Sjogren’s syndrome and connective tissue diseases associated with other immunologic disorders. In: Koopman WJ, ed. Arthritis and allied conditions: a textbook of rheumatology. 13th ed. Baltimore: Williams & Wilkins, 1997:1561–1580.
Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med 1974;57:775–788. PMID:4216269