Approach

Cryoglobulinaemia may be asymptomatic or present acutely. Mixed cryoglobulinaemia (MC) was first described as a triad of purpura, weakness, and arthralgia.[20] However, the clinical presentation of cryoglobulinaemia varies from asymptomatic to a cryoglobulinaemic syndrome consisting of purpura and leukocytoclastic vasculitis with multiple organ involvement.[4]

The pace and extent of evaluation depends on the presentation. Type l cryoglobulinaemia is usually associated with lymphoproliferative disorders. MC is associated with infectious or autoimmune disorders, particularly chronic hepatitis C virus (HCV) infection.[1][2] If a patient is diagnosed with a haematological malignancy while being evaluated for cryoglobulinaemia, referral to a haematologist is imperative.

Clinical evaluation

Careful clinical evaluation may provide clues to the type of cryoglobulinaemia and its complications:

  • The presence of acrocyanosis; Raynaud's phenomenon; skin ulcers; gangrene; and, less frequently, purpura, renal disease, or a neurological disorder should raise the possibility of type l cryoglobulinaemia.[1] This may be complicated by life-threatening hyperviscosity syndrome, which may present with bleeding, visual disturbances, diplopia, ataxia, headache, and confusion. Signs of retinal haemorrhage and retinal vein thrombosis may be seen.[21][22]

  • MC should be suspected in patients with signs and symptoms consistent with small- to medium-vessel vasculitis. These include the presence of purpura, mononeuritis multiplex, or glomerulonephritis.[23] It may suggest a more rapid work-up with particular attention to multiple organ function.[24] Other manifestations may include arthralgia, sicca syndrome, weakness, or hypertension in those with renal involvement.[Figure caption and citation for the preceding image starts]: Lower extremity palpable purpuraFrom the personal collection of Dr GS Kaeley [Citation ends].com.bmj.content.model.Caption@7fde768c[Figure caption and citation for the preceding image starts]: Unusual case of hepatitis C-related cryoglobulin-induced digital gangreneAbdel-Gadir A, Patel, K, Dubrey SW. Cryoglobulinaemia induced digital gangrene in a case of hepatitis C. BMJ Case Reports. 2010 [Citation ends].com.bmj.content.model.Caption@436e57b7

Isolation of cryoglobulins

  • The detection of serum cryoglobulins is necessary to classify the cryoglobulinaemic syndrome. Because cryoglobulins precipitate below normal body temperature, the collection and processing of the sample is critical.

  • Blood sampling (10-20 mL of blood is required), clotting, and serum separation should be carried out at 37°C (98.6°F). The serum sample is then stored at 4°C (39.2°F) for 24-72 hours and observed for the formation of a white precipitate (cryoglobulins). An aliquot of the cryoprecipitate should be re-warmed to 37°C (98.6°F) for 24 hours to test for the reversibility of cryoprecipitation.

Initial investigations

  • The Ig cryoprecipitate is isolated and analysed by immunoelectrophoresis or immunofixation. Cryoprecipitate measurement methods vary, and cryocrit levels do not correlate with disease activity.[1][4] However, a sudden decrease of cryoglobulin levels with increased levels of C4 may signal the evolution of a lymphoproliferative disorder.[25] This is thought to reflect the change of benign polyclonal B cells that produce antibodies to malignant B cells that no longer produce immunoglobulins.[4]

  • Other markers of activity are rheumatoid factor, complement C1q, C3, C4, CH50 (total complement activity), and acute-phase reactants (C-reactive protein and erythrocyte sedimentation rate [ESR]).​[4][6]​​[26] Findings may include IgM rheumatoid factor positive, elevated ESR, and normocytic normochromic anaemia. Complement C1q and C4 may be low.

  • The evaluation for organ involvement should include a full blood count, a comprehensive chemistry panel, and a urinalysis. An ECG and chest x-ray are indicated in patients with suspected multi-organ involvement.[4]

  • The aetiology of vasculitis should be assessed by performing the following tests: antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies, extractable nuclear antigen antibody (ENA), double-stranded deoxyribonucleic acid (dsDNA) antibodies, complement assay, and specific biopsies (e.g., IgA deposits on skin or kidney are suggestive of Henoch-Schonlein purpura).

  • If a viral cause is suspected, testing for HCV antibody and hepatitis B is recommended.[4]

Further investigations

  • Autoimmune testing may include antibodies such as ANA, Sjogren's syndrome antigens (SSA, SSB), and ENA, depending on clinical presentation.[4][27]

  • Testing for HIV is recommended if a viral cause is suspected.[4]

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