BASICS
DESCRIPTION
- Cryoglobulins (CGs) consists of immunoglobulins (Igs) and complement precipitating in serum and plasma.
- CGs precipitate at cold temperatures 98.6 ░F (<37 ░C) and dissolve on rewarming.
- Clinical symptoms are often secondary to either small vessel occlusion and a hyperviscosity syndrome in type I CGs or the formation of CG-containing immune complexes leading to vasculitis in type II and type III CGs.
- Brouet classification categorizes CGs by clonality and rheumatoid factor (anti-IgG) activity:
- Type I
- Monoclonal Ig; IgM is most common.
- Less frequently IgG, IgA, free Ig light chains
- Type II
- Monoclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig
- Monoclonal fraction is rarely IgG or IgA.
- Type III
- Polyclonal IgM with rheumatoid factor activity, which forms an immune complex with polyclonal Ig (1)
EPIDEMIOLOGY
- Healthy patients may have low concentrations of CGs present in the serum (<0.06 g/L).
- Clinically relevant cryoglobulinemia is far more common in patients with chronic infections or inflammation.
Incidence
- Distribution (percentage of all cases) of CG:
- Type I CG: 10-15%
- Type II CG: 50-60%
- Type III CG: 30-40%
Prevalence
- Mixed CG (CGs type II and type III) is female (1:100,000) > male: (3:1); onset in 6th decade
- Heterogenous geographic distribution: highest incidence in areas with increased hepatitis C virus (HCV) infection (2)[B]
ETIOLOGY AND PATHOPHYSIOLOGY
- 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 CG, which precipitates, causing hyperviscosity and vessel damage.
- Types II and III
- B-cell hyperactivation or hyperproliferation (from HCV or another chronic inflammatory state) produce Ig with rheumatoid factor activity, which leads to immune complex formation.
- Immune complex deposition and subsequent complement activation causes small vessel damage.
- HCV correlation
- HCV 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.
- Disease manifestations of CG may arise due to the following causes:
- Chronic immune stimulation or lymphoproliferation resulting in the increased production of CGs (3)[A]
- Immune complex formation among CGs with antigens
- Insufficient clearance of CGs and their immune complexes
- Consider small vessel vasculitis: may present with necrosis at cold exposed areas (4)[A]
RISK FACTORS
- Hematologic/lymphoproliferative diseases (type I CG)
- HCV infection (type II CG > type III CG), other chronic infections (mixed CG)
GENERAL PREVENTION
Prevent or manage progression of underlying disease, if applicable. á
COMMONLY ASSOCIATED CONDITIONS
- Infections:
- Viral (commonly hepatitis C, hepatitis B, HIV), bacterial, fungal, parasitic (rare)
- Hematologic/lymphoproliferative diseases:
- Non-Hodgkin/Hodgkin lymphoma
- Chronic leukemia
- Multiple myeloma
- Waldenstr Âm macroglobulinemia
- Autoimmune/chronic inflammatory diseases:
- Sj Âgren syndrome
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Inflammatory bowel disease (IBD) (5)[C]
DIAGNOSIS
- Type I
- Commonly asymptomatic
- More frequent association with signs of peripheral vessel occlusion (e.g., Raynaud phenomenon, acrocyanosis, livedo reticularis, purpura, ulcers, gangrene), less with signs of vasculitis
- Types II and III: mixed cryoglobulinemia syndrome
- Caused by immune complex-mediated vasculitis
- Characterized by Meltzer triad
- Purpura
- Weakness
- Arthralgias
- Multiple organ involvement is common:
- Cutaneous vasculitis, purpura, with/without necrosis (3)[B]
- Membranoproliferative glomerulonephritis (nephropathy)
- Peripheral neuropathy
HISTORY
- Constitutional/nonspecific: fever, myalgias, arthralgia, malaise, generalized weakness, sensory changes
- Hyperviscosity: blurring of vision, headache, vertigo, dizziness, diplopia, ataxia, confusion, dementia, stroke
- Vasculitis: peripheral neuropathy, palpable purpura, other end-organ involvement (e.g., kidneys, liver)
- Past medical history: risk factors for hepatitis C, lymphoproliferative disorders
PHYSICAL EXAM
- Skin: purpura (intermittent, nonblanching, palpable, beginning in legs), ulcers, Raynaud phenomenon, livedo reticularis, acrocyanosis
- GI: hepatomegaly
- Lymph: lymphadenopathy, splenomegaly
- Extremities: synovitis, signs of peripheral vascular occlusion
- Neurologic: peripheral neuropathy
DIFFERENTIAL DIAGNOSIS
- Possible causes of small vessel vasculitis: Henoch-Sch Ânlein purpura, lupus vasculitis, rheumatoid vasculitis, Sj Âgren syndrome vasculitis, hypocomplementemic urticarial vasculitis, Beh žet syndrome, Goodpasture syndrome, serum sickness vasculitis, drug-induced immune complex vasculitis, infection-induced immune complex vasculitis, antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitis, paraneoplastic syndrome-associated vasculitis, IBD-associated vasculitis
- Possible causes of hyperviscosity: Waldenstr Âm macroglobulinemia, polycythemia, sickle cell anemia, malaria, babesiosis (6)
DIAGNOSTIC TESTS & INTERPRETATION
Important to rule out other small vessel vasculitis (see "Differential Diagnosis"Ł) á
Initial Tests (lab, imaging)
- General
- CBC with peripheral smear
- Electrolytes
- Liver function tests (LFTs)
- Hepatitis B and C serology
- BUN, creatinine
- Urinalysis
- Rheumatoid factor
- ESR
- C-reactive protein
- Specific
- Serologic test for CGs (blood collection and initial storage needs to be at 98.6 ░F [37 ░C]); following detection of CGs, further testing including electrophoresis and immunofixation should be completed.
- Serum complement levels (low C4, normal or slightly decreased C3)
- Rheumatologic (e.g., antinuclear antibody, ANCA)
Diagnostic Procedures/Other
Check the main organ systems involved: á
- Kidneys: proteinuria, microscopic hematuria, and arterial hypertension common at diagnosis
- Nervous system: peripheral neuropathy in type II CG and type III CG
- Liver: normal or increased liver enzymes, steatosis, chronic hepatitis, cirrhosis
Test Interpretation
- Renal biopsy: Most common type of nephropathy is membranoproliferative glomerulonephritis.
- Bone marrow: may be indicated for type I cryoglobulinemia; examination often reveals underlying hematologic condition.
- Liver biopsy: investigation for underlying hepatitis
- Skin biopsy: leukocytoclastic vasculitis
TREATMENT
- Goals:
- Symptomatic management of vasculitis and/or hyperviscosity and limit damage caused by circulating immune complexes
- Limit or suppress B-lymphocyte proliferation.
- Eradicate HCV (if applicable, CGs types II and III) (2)[C].
- General measures:
- Most important to treat underlying disease
- Asymptomatic: Observe.
- Mild disease: cold avoidance, analgesics
- Moderate to severe or recalcitrant disease: plasmapheresis, steroids, cytotoxic agents (cyclophosphamide); rituximab
MEDICATION
Specific CG treatment regimens are largely empiric due to lack of long-term multicenter, randomized, controlled trials, although consensus guidelines suggest the following: á
- Type I
- Treatment of underlying lymphoproliferative disease as appropriate (chemotherapy, radiation therapy) (7,8)[B]
- Non malignancy-associated: oral prednisone or cyclophosphamide
- Types II and III
- Antiviral HCV therapy as appropriate: Pegylated interferon-╬▒ and ribavirin have shown satisfactory response; hepatitis B treatment as appropriate (consider tenofovir, entecavir)
- Treatments are reserved for severe, recalcitrant CG (e.g., glomerulonephritis, skin ulcers, peripheral neuropathy) in infectious and non-infection-related populations:
- Rituximab (chimeric monoclonal antibody directed against CD20) has shown potential in relapse and long term control (9)[C].
ONGOING CARE
DIET
Mixed CG: Low-antigen content (LAC) diet is suggested for symptomatic improvement (no meat except turkey; no eggs, dairy products, or food additives; no preservatives; no beverages except water; diet is mostly fruits and vegetables). The hypothesized mechanism is a reduction in antigen input load for the reticuloendothelial system which allows that system to more efficiently process circulating immune complexes. á
PATIENT EDUCATION
Vasculitis Foundation: http://www.vasculitisfoundation.org/ á
PROGNOSIS
- In mixed CG, overall prognosis worse with severe disease (glomerulonephritis, neuropathy, vasculitis), underlying lymphoproliferative disease.
- Mean survival: 50-60% at 10 years after diagnosis
- In patients with noninfectious mixed CG vasculitis, the main prognostic factors are age >65 years, pulmonary and GI involvement, and renal failure (6)[B].
- In patients with HCV-associated mixed CG vasculitis, the main cause of mortality remains renal disease, whereas immunosuppression significantly increases death due to infectious causes. Response to antiviral treatment incurs decreased mortality due to cryoglobulinemia vasculitis.
REFERENCES
11 Krishnamurthy áK, Mohapatra áS, Mishra áTK, et al. Early onset mixed cryoglobulinemia in hepatitis C. Indian J Pathol Microbiol. 2015;58(3):381-383.22 Takada áS, Shimizu áT, Hadano áY, et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6(1):3-8.33 Porres-Aguilar áM, Rodriguez-Castro áCE, Osvaldo áP, et al. Finger necrosis due to cryoglobulinemic vasculitis in association with membranous nephropathy. Proc (Bayl Univ Med Cent). 2015;28(1):72-74.44 Owen áRG, Treon áSP, Al-Katib áA, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's macroglobulinemia. Semin Oncol. 2003;30(2):110-115.55 Giuggioli áD, Manfredi áA, Colaci áM, et al. Systemic sclerosis and cryoglobulinemia: our experience with overlapping syndrome of scleroderma and severe cryoglobulinemic vasculitis and review of literature. Autoimmun Rev. 2013;12(11):1058-1063.66 Sunderk Âtter áC, Pappelbaum áKI, Ehrchen áJ. Cutaneous symptoms of various vasculitides [in German]. Hautarzt. 2015;66(8):589-598.77 Pietrogrande áM, De Vita áS, Zignego áAL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev. 2011;10(8):444-454.88 Terrier áB, Krastinova áE, Marie áI, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119(25):5996-6004.99 Quartuccio áL, Zuliani áF, Corazza áL, et al. Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: long-term follow up data of a randomized controlled multicentre study. J Autoimmun. 2015;63:88-93.
ADDITIONAL READING
- Alpers áCE, Smith áKD. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens. 2008;17(3):243-249.
- Anis áS, Abbas áK, Mubarak áM, et al. Vasculitis with renal involvement in essential mixed cryoglobulinemia: case report and mini-review. World J Clin Cases. 2014;2(5):160-166.
- Damoiseaux áJ. The diagnosis and classification of the cryoglobulinemic syndrome. Autoimmun Rev. 2014;13(4-5):359-362.
- De Vita áS. Treatment of mixed cryoglobulinemia: a rheumatology perspective. Clin Exp Rheumatol. 2011;29(1 Suppl 64):S99-S103.
- Della Rossa áA, Cioffi áE, Elefante áE, et al. Systemic vasculitis: an annual critical digest of the most recent literature. Clin Exp Rheumatol. 2014;32(3 Suppl 82):S98-S105.
- Fabrizi áF, Dixit áV, Messa áP. Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies. J Med Virol. 2013;85(6):1019-1027.
- Ferri áC, Antonelli áA, Mascia áMT, et al. B-cells and mixed cryoglobulinemia. Autoimmun Rev. 2007;7(2):114-120.
- Ferri áC, Cacoub áP, Mazzaro áC, et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011;11(1):48-55.
- Humphries áK, Darling áJM, Barritt áASIV. Membranoproliferative glomerulonephritis, type II cryoglobulinemia and triple therapy for hepatitis C: a case series and review of the literature. Dig Dis Sci. 2014;59(8):2007-2012.
- Landau áD, Scerra áS, Sene áD, et al. Causes and predictive factors of mortality in a cohort of patients with hepatitis C virus-related cryoglobulinemic vasculitis treated with antiviral therapy. J Rheumatol. 2010;37(3):615-621.
- Monti áG, Saccardo áF, Castelnovo áL, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study. Autoimmun Rev. 2014;13(6):609-614.
- Motyckova áG, Murali áM. Laboratory testing for cryoglobulins. Am J Hematol. 2011;86(6):500-502.
- Pietrogrande áM, De Vita áS, Zignego áAL, et al. Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients. Autoimmun Rev. 2011;10(8):444-454.
- Ramos-Casals áM, Stone áJH, Cid áMC, et al. The cryoglobulinaemias. Lancet. 2012;379(9813):348-360.
- Saadoun áD, Resche Rigon áM, Thibault áV, et al. Peg-IFN╬▒/ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: results at week 24. Ann Rheum Dis. 2014;73(5):831-837.
- Sneller áMC, Hu áZ, Langford áCA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum. 2012;64(3):835-842.
- Takada áS, Shimizu áT, Hadano áY, et al. Cryoglobulinemia (review). Mol Med Rep. 2012;6(1):3-8.
- Terrier áB, Krastinova áE, Marie áI, et al. Management of noninfectious mixed cryoglobulinemia vasculitis: data from 242 cases included in the CryoVas survey. Blood. 2012;119(25):5996-6004.
CODES
ICD10
D89.1 Cryoglobulinemia á
ICD9
273.2 Other paraproteinemias á
SNOMED
- cryoglobulinemia (disorder)
- Monoclonal cryoimmunoglobulinemia (disorder)
- Mixed polyclonal cryoimmunoglobulinemia (disorder)
CLINICAL PEARLS
- CGs are circulating Igs that precipitate at cold temperatures (below 37 ░C) and dissolve on rewarming.
- Type I: associated with lymphoproliferative disorders (e.g., multiple myeloma, Waldenstr Âm macroglobulinemia, monoclonal gammopathy of undetermined significance, and chronic lymphocytic leukemia)
- 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 workup for underlying etiology:
- Serologic test for CGs
- Serum complement levels (low C4, normal or slightly decreased C3)
- Serologic tests for hepatitis B and C, HIV
- Rheumatologic (antinuclear antibodies, ANCA)