Cryoglobulinemia – Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Cryoglobulinemia is a state characterized by the presence of cryoglobulins in a patient’s serum.
  • Cryoglobulins are circulating immunoglobulins that precipitate at cold temperatures (below 37°C) and dissolve on rewarming.
  • Clinical symptoms are often secondary to either small vessel occlusion and a hyperviscosity syndrome in Type I cryoglobulins, or the formation of cryoglobulin-containing immune complexes leading to vasculitis in Type II and Type III cryoglobulins (i.e., “mixed cryoglobulinemia”):
    • Type I
      • Monoclonal immunoglobulin (Ig); IgM is most common
      • 10–15% of all cryoglobulinemia
      • Less frequently IgG, IgA, free Ig light chains
    • Type II
      • Monoclonal IgM with rheumatoid factor activity (anti-IgG), which forms an immune complex with polyclonal IgG
      • 50–60% of all cryoglobulinemia
      • Monoclonal fraction rarely IgG or IgA
    • Type III:
      • Polyclonal IgM with rheumatoid factor activity (anti-IgG), which forms an immune complex with polyclonal IgG
      • 25–30% of cryoglobulinemia


  • No adequate epidemiological studies regarding overall prevalence
  • Healthy patients may have low concentrations of cryoglobulins present in the serum (<0.06 g/L)
  • Clinically relevant cryoglobulinemia is far more common in patients with chronic infections and/or inflammation

Risk Factors

  • Type I: Associated with lymphoproliferative disorders:
    • Multiple myeloma
    • Waldenström’s macroglobulinemia
    • Chronic lymphocytic leukemia (CLL)
    • Monoclonal gammopathy of unknown significance (MGUS)
    • B-cell lymphoma
  • Type II (mixed cryoglobulinemia):
    • Main association with hepatitis C
    • 40–90% of patients with mixed cryoglobulinemia are hepatitis C positive
    • Higher association with hepatitis C compared to type III cryoglobulinemia
    • Also associated with Sjögren’s syndrome, HIV, and other autoimmune/connective tissue disease
  • Type III (mixed cryoglobulinemia):
    • Like Type II, also associated with chronic infection and inflammatory states:
      • Autoimmune disease: SLE, RA, IBD
      • Infection: EBV, CMV, TB, HIV, subacute endocarditis
    • Significant hepatitis C virus association, just less than type II


  • Exact mechanism of cold insolubility in these cryoproteins is unknown. Hypotheses include reduced concentrations of sialic acid and galactose in the Fc region of Ig, as well as steric conformation changes due to temperature variation.
  • Type I:
    • An underlying lymphoproliferative disorder causes monoclonal B cell proliferation.
    • B cells produce cryoglobulin, which precipitates, causing hyperviscosity and vessel damage.
  • Types II and III:
    • B cell hyperactivation (from hepatitis C virus or another chronic inflammatory state) produces immunoglobulin with rheumatoid factor activity, which leads to immune complex formation.
    • Immune complex deposition and subsequent complement activation causes small-vessel damage.


Hepatitis C correlation:

  • Hepatitis C virus displays lymphotropism. The E2 capsid protein of HCV binds site to CD81, a site present on hepatocytes, T lymphocytes, and B lymphocytes.
  • Patients infected with HCV who have mixed cryoglobulinemia (MC) have been found to have higher viral loads than patients with HCV and no MC.

Commonly Associated Conditions

  • NOTE: See above for specific association by cryoglobulinemia type classification
  • Infections:
    • Viral: Hepatitis C, hepatitis B, hepatitis A, HIV, Epstein-Barr virus, VZV, cytomegalovirus, HTLV-1, adenovirus, influenza virus, parvovirus B19, rubella virus
    • Bacterial: Lyme disease, syphilis, Q fever, poststreptococcal nephritis, subacute bacterial endocarditis, leprosy, TB, brucella
    • Fungal: Coccidiomycosis
    • Parasitic: Kala-azar toxoplasmosis, echinococcosis, malaria, schistosomiasis, trypanosomiasis
  • Hematologic disease:
    • Non-Hodgkin lymphoma
    • Chronic lymphocytic leukemia
    • Multiple myeloma
    • Waldenström’s macroglobulinemia
    • Hodgkin lymphoma
    • Chronic myeloid leukemia
    • Castleman disease
    • Thrombocytopenic thrombotic purpura
    • Cold agglutinin disease
  • Autoimmune diseases:
    • Sjögren syndrome
    • Systemic lupus erythematosus
    • Polyarteritis nodosa
    • Systemic sclerosis
    • Rheumatoid arthritis
    • Autoimmune thyroiditis
    • Temporal arteritis
    • Dermatomyositis/polymyositis
    • Henoch-Schönlein disease
    • Sarcoidosis
    • Inflammatory bowel disease
    • Pemphigus vulgaris

Cryoglobulinemia, Immunoglobulin G, Hepatitis C virus, Immunoglobulin M, HCV, b cell lymphoma, chronic lymphocytic leukemia, vessel occlusion, cryoglobulins, hyperviscosity syndrome, multiple myeloma,


  • Type I:
    • Commonly asymptomatic
    • More frequent association with signs of peripheral vessel occlusion, less with signs of vasculitis. Think of Raynaud’s phenomenon, acrocyanosis, livedo reticularis, purpura, ulcers, gangrene.
  • Types II and III: Mixed cryoglobulinemia syndrome
    • Caused by immune complex-mediated vasculitis
    • Characterized by Meltzer’s triad:
      • Purpura
      • Weakness
      • Arthralgias
    • Multiple organ involvement is common:
      • Cutaneous vasculitis, purpura
      • Membranoproliferative glomerulonephritis (nephropathy)
      • Peripheral neuropathy


  • Constitutional/nonspecific: Fever, myalgias, arthralgia, malaise, generalized weakness, sensory changes
  • Hyperviscosity: Blurring of vision, headache, vertigo, dizziness, diplopia, ataxia, confusion, dementia, stroke
  • Past medical history: Risk factors for hepatitis C, lymphoproliferative disorders

Physical Exam

  • Skin: Purpura (intermittent, palpable, beginning in legs), ulcers, Raynaud phenomenon, livedo reticularis, acrocyanosis
  • Gastrointestinal: Hepatomegaly, splenomegaly
  • Endocrine: Lymphadenopathy
  • Extremities: Synovitis, signs of peripheral vascular occlusion
  • Neurological: Peripheral neuropathy

Diagnostic Tests & Interpretation

Important to rule out other small-vessel vasculitis (see sectionDifferential Diagnosis) (1)


Initial lab tests

  • General:
    • Complete blood count (CBC), with peripheral smear
    • Electrolytes
    • Liver function tests (LFTs)
    • Blood urea nitrogen (BUN), creatinine
    • Urinalysis
    • Rheumatoid factor
  • Specific:
    • Serological test for cryoglobulins (blood collection and initial storage needs to be at 37°C); following detection of cryoglobulins, further testing including electrophoresis and immunofixation should be completed.
    • Serum complement levels (low C4, normal or slightly decreased C3)
    • Serologic tests for hepatitis B and C
    • Rheumatologic (e.g., antinuclear antibody, ANCA)

Diagnostic Procedures/Surgery

Check main organ systems involved:

  • Kidneys: Proteinuria, microscopic hematuria, arterial hypertension common at diagnosis
  • Nervous system: Peripheral neuropathy in types II and III cryoglobulinemia
  • Liver: Normal or increased liver enzymes, steatosis, chronic hepatitis, cirrhosis

Pathological Findings

  • Renal biopsy: Most common type of nephropathy is membranoproliferative glomerulonephritis
  • Bone marrow: May be indicated for type I cryoglobulinemia; examination often reveals underlying hematological condition
  • Liver biopsy: Inflammation is graded; fibrosis is staged

Differential Diagnosis

  • Possible causes of small-vessel vasculitis: Henoch-Schönlein purpura, lupus vasculitis, rheumatoid vasculitis, Sjögren syndrome vasculitis, hypocomplementemic urticarial vasculitis, Behçet syndrome, Goodpasture syndrome, serum sickness vasculitis, drug-induced immune complex vasculitis, infection-induced immune complex vasculitis, ANCA-associated vasculitis, paraneoplastic syndrome-associated vasculitis, inflammatory bowel disease-associated vasculitis
  • Possible causes of hyperviscosity: Waldenstrom macroglobulinemia, polycythemia, sickle cell anemia, malaria, babesiosis


  • Most important to treat underlying disease
  • Treat according to individual patient and severity of symptoms
  • Mild disease treated with cold avoidance, analgesics, nonsteroidal anti-inflammatory drugs
  • Intensive therapy with steroids, plasmapheresis, or cytotoxic agents only for organ-threatening or recalcitrant disease
  • Type I:
    • Cytotoxic treatment of lymphoproliferative disease as appropriate
  • Types II and III:
    • Antiviral hepatitis C treatment as appropriate


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  • Hepatitis C-associated:
    • Antiviral therapy: Combination therapy of pegylated interferon (PEG-INF)α and ribavirin
  • Non-hepatitis C-associated:
    • Immunosuppression, low-dose corticosteroids
  • Rituximab: this chimeric monoclonal antibody directed against CD20 has shown some efficacy in treating both type I and mixed cryoglobulinemias, and should be considered in severely symptomatic patients.

Additional Treatment


  • For severe clinical manifestations of disease
  • Used alongside immunosuppressive treatment to avoid rebound phenomena

Ongoing Care


At least one small study has suggested that a low antigen content (LAC) diet can be helpful in improving the symptoms of cryoglobulinemia. The hypothesized mechanism is a reduction in antigen input load for the reticuloendothelial system that allows that system to more efficiently process circulating immune complexes.

Patient Education


There seems to be no increased morbidity or mortality risk with cryoglobulinemia over the associated underlying conditions.


1. Sargur R, White P, Egner W et al. Cryoglobulin evaluation: best practice? Ann. Clin. Biochem. 2010;47:8–16.

Additional Reading

Alpers CE, Smith KD et al. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens. 2008;17:243–9.

Dammacco F, Sansonno D, Piccoli C, et al. The cryoglobulins: an overview. Eur J Clin Invest. 2001;31:628–38.

Dispenzieri A et al. Symptomatic cryoglobulinemia. Curr Treat Options Oncol. 2000;1:105–18.

Ferri C, Antonelli A, Mascia MT et al. B-cells and mixed cryoglobulinemia. Autoimmun Rev. 2007;7:114–20.

Sansonno D, Carbone A, De Re V et al. Hepatitis C virus infection, cryoglobulinaemia, and beyond. Rheumatology (Oxford). 2007.

Tedeschi A, Baratè C, Minola E, et al. Cryoglobulinemia. Blood Rev.2007.



  • 273.1 Monoclonal paraproteinemia
  • 273.2 Other paraproteinemias


  • 30911005 cryoglobulinemia (disorder)
  • 38675009 monoclonal cryoimmunoglobulinemia (disorder)
  • 44371002 mixed polyclonal cryoimmunoglobulinemia (disorder)

Clinical Pearls

  • Cryoglobulins are circulating immunoglobulins that precipitate at cold temperatures (below 37°F) and dissolve on rewarming.
  • Type I: Associated with lymphoproliferative disorders (e.g., multiple myeloma, Waldenstrom macroglobulinemia, MGUS, CLL)
  • Type II (mixed cryoglobulinemia): Main association with hepatitis C (40–90% are hepatitis C positive)
  • Type III (mixed cryoglobulinemia): High association with chronic infection and inflammatory states
  • Initial laboratory evaluation: CBC with peripheral smear, electrolytes, LFTs, BUN, creatinine, urinalysis, rheumatoid factor
  • Specific:
    • Serological test for cryoglobulins (blood collection and initial storage needs to be at 37°C); electrophoresis and immunofixation if cryoglobulins present
    • Serum complement levels (low C4, normal or slightly decreased C3)
    • Serologic tests for hepatitis B and C
    • Rheumatologic (ANA, ANCA)

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