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Cryoglobulinaemia

Post your experience

Cryoglobulins are antibodies that show reversible precipitation at low temperatures. It is postulated that the resultant aggregates and immune complexes outstrip reticuloendothelial-clearing activity and tissue damage results from immune complex deposition and complement activation.1 Manifestations vary according to type and range from acrocyanosis and retinal haemorrhage to hypertension and renal disease.1

There are several types and variable clinical pictures. The Brouet classification2 is:

  • Type I or simple cryoglobulinaemia, is caused by monoclonal antibody, usually IgM, but less often IgG, IgA or light chains.
  • Type II and type III cryoglobulinaemia are called mixed cryoglobulinaemia. 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.
  • It usually presents between about 40 and 60 years of age with a female preponderance of 3:2.
  • In people with hepatitis C infection (HCV), the prevalence of cryoglobulinaemia is 40 to 50%.3
  • The relative proportions are roughly:
    • type I =25%
    • type II =25%
    • type III =50%
Presentation

Features

Type I cryoglobulinaemia presents with:

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

The approximate frequencies are:

  • Cutaneous symptoms of purpura, distal necrosis, cold urticaria, and ulceration (50-100%)
  • Joint disease (35-70%)
  • Renal disease (10-60%)
  • Raynaud's phenomenon (30-50%)
  • Neurological symptoms including paraesthesia and peripheral neuropathy (10-30%)
  • Abdominal pain (2-25%)
  • Sicca (10-15%)
  • Acrocyanosis (10%)
  • Haemorrhage (5-10%)
  • Arterial thrombosis (1%)

Meltzer's triad is purpura, arthralgia, and weakness.

Signs

Skin:

  • Ischaemic necrosis
  • Palpable purpura
  • Scarring of tip of nose, pinna, fingertips, and toes
  • Acrocyanosis

Lungs:

  • Rhonchi
  • Pleural effusion

Gastrointestinal:

Renal disease may present as:

Neurological:

  • Peripheral neuropathy
  • Visual disturbances

Fever can also occur.

Associated diseases
  • Cryoglobulinaemia may occur with a specific disease such as a lymphoproliferative disorder, autoimmune or infectious disease, or it can be idiopathic when it is called essential cryoglobulinaemia.
  • It can run in families and rarely after vaccination, especially against pneumococcus.

Type I occurs in lymphoproliferative disorders including multiple myeloma and Waldenström's macroglobulinemia.

Type II and III occur in lymphoproliferative disorders including chronic lymphocytic leukaemia as well as chronic liver disease, infections, and connective tissue diseases.

Infections include:

The most important related disease seems to be hepatitis C.4 This group is so important that it has been suggested that essential cryoglobulinaemia is really due to hepatitis C.5

Autoimmune diseases are usually:

Vasculitis includes:

Differential diagnosis

The differential diagnosis includes looking for the underlying cause of the cryoglobulinaemia:

Hepatitis C infection is very common in those with HIV and a study has suggested that it is the HCV that is important and not the HIV.6 This may be a reflection of the efficacy of HAART7 (highly active antiretroviral therapy).

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
  • FBC: leucocytosis may occur with infection or leukaemia. There may be anaemia.
  • Urinalysis may show evidence of renal disease.
  • U&E: in case of renal disease.
  • LFTs: may show hepatitis. If so get serology for hepatitis.
  • Rheumatoid Factor: RF is positive in type II and III.
  • Antinuclear antibody: if SLE suspected.
  • ESR will be elevated with rouleaux formation.
  • Complement levels may be reduced, especially C4.
  • Electrophoresis of serum and urine if there is suspicion of an underlying gammopathy.

Further tests will be required if other diseases are suspected.

Management

Non-drug

Sufferers must avoid cold environments.

Drug

  • 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.
  • Secondary cryoglobulinaemia is managed by treating the underlying disease. Otherwise treatment is suppression of the immune response.
  • 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.3
  • Plasmapheresis can be used for severe or life-threatening complications in combination with steroids and immunosuppression.9
  • Interferon-alfa (IFN-a) works in patients with cryoglobulinaemia associated with hepatitis C and possibly chronic myelogenous leukemias and low-grade lymphomas. The first line treatment for cryoglobulinaemia with HCV is pegylated interferon-alpha and ribavirin.3
  • Ritumaxib appears to be safe and effective.10
Prognosis

Prognosis depends on the underlying cause like lymphoproliferative disorders, hepatitis B or C. Renal involvement has an adverse effect. In one study11 the median time from diagnosis to death was just over 3 years.


Document references
  1. Edgerton C, Straight T, Oglesby J; Cryoglobulinemia. eMedicine, December 2007.
  2. 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.
  3. 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]
  4. 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]
  5. Trendelenburg M, Schifferli JA; Cryoglobulins are not essential. Ann Rheum Dis. 1998 Jan;57(1):3-5.
  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. Kosmas N, Kontos A, Panayiotakopoulos G, et al; Decreased prevalence of mixed cryoglobulinemia in the HAART era among HIV-positive, HCV-negative patients. J Med Virol. 2006 Oct;78(10):1257-61. [abstract]
  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. 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]
  10. 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]
  11. Rieu V, Cohen P, Andre MH, et al; Characteristics and outcome of 49 patients with symptomatic cryoglobulinaemia. Rheumatology (Oxford). 2002 Mar;41(3):290-300. [abstract]

Internet and further reading Acknowledgements EMIS is grateful to Dr Richard Draper for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2009.
Document ID: 2021
Document Version: 21
Document Reference: bgp1282
Last Updated: 20 Mar 2009
Planned Review: 20 Mar 2011

The authors and editors of this article are employed to create accurate and up to date content reflecting reliable research evidence, guidance and best clinical practice. They are free from any commercial conflicts of interest. Find out more about updating.

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