Cryoglobulins are immune complexes that precipitate at low temperatures and are deposited on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, and peripheral nerves.¹ Manifestations vary according to type and range but the classical triad (Meltzer's triad) is purpura, weakness and arthralgias.²

Classification

Brouet's classification is:³

• Type I or simple cryoglobulinaemia, is caused by monoclonal antibody; usually IgM.
• Type II and type III cryoglobulinaemia are called mixed cryoglobulinaemia (MC). They make up 75% of cryoglobulinaemias. They contain rheumatoid factor (RF), which is usually IgM. The RF is monoclonal in type II and polyclonal in type III cryoglobulinaemia.

Epidemiology

• Essential mixed cryoglobulinaemia occurs in about 1 in 100,000 people.²
• It is more common in southern Europe and usually presents between about 40 and 60 years of age, with a female preponderance of 3:1.
• Since the identification of hepatitis C virus (HCV), it has been recognised as the cause of more than 90% of mixed cryoglobulinaemia (MC).¹
• It has been found to cluster in families and, rarely, after vaccination, especially against pneumococcus.

Presentation

Type I cryoglobulinaemia presents with:

• Acrocyanosis
• Retinal haemorrhage
• Severe Raynaud's phenomenon
• Arterial thrombosis

Types II and III cryoglobulinaemia produce:

• Arthralgias and arthritis in the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, knees, and ankles.
• Immune-complex glomerulonephritis.
• Vascular purpuric lesions.

Presenting features appear in the following list in decreasing frequency:

• Cutaneous symptoms of purpura, distal necrosis, cold urticaria and ulceration.
• Joint disease.
• Renal disease.
• Raynaud's phenomenon.
• Neurological symptoms including paraesthesia and peripheral neuropathy.
• Abdominal pain.
• Sicca.
• Acrocyanosis.
• Haemorrhage.
• Arterial thrombosis.
• Facial swelling.⁴

Associated diseases

The most important related disease seems to be hepatitis C.^5,6 This group is prolific and it has been suggested that essential cryoglobulinaemia is really due to hepatitis C.⁷

Cryoglobulinaemia may occur with specific diseases:

• Lymphoproliferative disorder: type I - multiple myeloma and Waldenström's macroglobulinaemia; types II and III - chronic lymphocytic leukaemia.
• Autoimmune disorders: primary Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus (SLE).
• Infectious disease: hepatitis C, HIV.

Differential diagnosis

• Antiphospholipid syndrome
• Chronic lymphocytic leukaemia
• Cirrhosis
• Glomerulonephritis
• Goodpasture's syndrome
• Haemolytic uraemic syndrome
• Hepatitis A, B or C
• Non-Hodgkin's lymphoma
• Multiple myeloma
• Polyarteritis nodosa
• Sarcoidosis
• SLE
• Waldenström's macroglobulinaemia.

Investigations

• Check for serum cryoglobulins. The blood must be kept warm and then serum incubated at 4°C. Type I tends to precipitate within the first 24 hours but type III may take a week. Correct handling is essential for reliable diagnosis.⁸
• Low C4 levels.
• Rheumatoid factor (RF): is positive in types II and III.
• Leukocytoclastic vasculitis detected by skin biopsy of recent vasculitic lesions.²
• FBC: leukocytosis may occur with infection or leukaemia. There may be anaemia.
• Urinalysis may show evidence of renal disease.
• U&Es: in case of renal disease.
• LFTs: if hepatitis is indicated, check serology.
• Antinuclear antibody: if SLE is suspected.
• ESR will be elevated with rouleaux formation.
• Electrophoresis of serum and urine if there is suspicion of an underlying gammopathy.

Further tests - if other diseases are suspected.

Management

General advice

Sufferers must avoid cold environments.

Pharmacological

• The aim is to limit precipitation of cryoglobulin and the inflammation that results. Asymptomatic cryoglobulinaemia does not require treatment unless there is renal or neurological damage.
• Non-steroidal anti-inflammatory drugs (NSAIDs) are used for arthralgia and fatigue.
• Immunosuppressive agents such as corticosteroids and/or cyclophosphamide or azathioprine are used when there is evidence of organ involvement such as vasculitis, renal disease, progressive neurological features, or severe skin disease. However, it is suggested that immunosuppression should be restricted to palliative care as it may facilitate viral replication.^2,9
• Plasmapheresis can be used for severe or life-threatening complications in combination with steroids and immunosuppression.¹⁰
• The first-line treatment for cryoglobulinaemia with HCV is pegylated interferon alfa and ribavirin.⁹ Alternatively, it may be appropriate to suppress the B-cell clonal expansion and cryoglobulin production, or just ameliorate the associated symptoms.¹¹ The choice of the most appropriate treatment is strictly related to the assessment of disease activity and the extent and severity of organ involvement.
• Rituximab is safe and effective.¹²

Complications

Lymphatic and hepatic malignancies may occur late in the illness.

Prognosis

Prognosis is worse in patients with renal disease, liver failure, lymphoproliferative disease and malignancies.²

Document references

1. Charles ED, Dustin LB; Hepatitis C virus-induced cryoglobulinemia. Kidney Int. 2009 Oct;76(8):818-24. Epub 2009 Jul 15. [abstract]
2. Ferri C; Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25. [abstract]
3. Brouet JC, Clauvel JP, Danon F, et al; Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974 Nov;57(5):775-88.
4. Nadruz W Jr, Carvalheira JB, Brenelli SL; A man with chronic facial swelling. Lancet. 2000 Apr 29;355(9214):1516.
5. Lunel F, Musset L, Cacoub P, et al; Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994 May;106(5):1291-300. [abstract]
6. Scotto G, Cibelli DC, Saracino A, et al; Cryoglobulinemia in subjects with HCV infection alone, HIV infection and HCV/HIV coinfection. J Infect. 2006 Apr;52(4):294-9. Epub 2005 Jul 18. [abstract]
7. Trendelenburg M, Schifferli JA; Cryoglobulins are not essential. Ann Rheum Dis. 1998 Jan;57(1):3-5.
8. Bakker AJ, Slomp J, de Vries T, et al; Adequate sampling in cryoglobulinaemia: recommended warmly. Clin Chem Lab Med. 2003 Jan;41(1):85-9. [abstract]
9. Kayali Z, Labrecque DR, Schmidt WN; Treatment of hepatitis C cryoglobulinemia: mission and challenges. Curr Treat Options Gastroenterol. 2006 Dec;9(6):497-507. [abstract]
10. Geltner D, Kohn RW, Gorevic P, et al; The effect of combination therapy (steroids, immunosuppressives, and plasmapheresis) on 5 mixed cryoglobulinemia patients with renal, neurologic, and vascular involvement. Arthritis Rheum. 1981 Sep;24(9):1121-7. [abstract]
11. Iannuzzella F, Vaglio A, Garini G; Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med. 2010 May;123(5):400-8. [abstract]
12. Bryce AH, Dispenzieri A, Kyle RA, et al; Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma. 2006 Sep;7(2):140-4. [abstract]