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Recognizing And Treating Cryoglobulinemia

Cryoglobulinemia is a disorder in which cryoglobulins, immunoglobulins in the blood, become deposited in small and medium sized blood vessels at low temperatures. Cryoglobulins typically precipitate at temperatures lower than normal body temperature and dissolve when temperatures rise to or above normal body temperature. There are several types of cryoglobulins and various clinical presentations are associated with different cryoglobulin types. Cryoglobulinemia is associated with several diseases including multiple myeloma and hepatitis C infection.1

The Brouet classification divides cryoglobulinemia into three types based on the cryoglobulin composition:2

Type I cryoglobulinemia (simple cryoglobulinemia) consists of isolated monoclonal immunoglobulins (IgM). Type I is the least common, accounting for 10 to 15 percent of the total cases of cryoglobulinemia.2 

Type II cryoglobulinemia (mixed cryoglobulinemia) consists of immune complexes formed by monoclonal IgM or IgA, and polyclonal IgG. This is the most common form, accounting for 50 to 60 percent of all cases of cryoglobulinemia.2

Type III cryoglobulinemia (mixed cryoglobulinemia) consists of immune complexes of polyclonal IgM and IgG molecules. Type III accounts for 25 to 30 percent of cases of cryoglobulinemia.2 

Cryoglobulinemia is associated with several diseases including lymphoproliferative disorders, autoimmune disease and infections. Lymphoproliferative disorders associated with cryoglobulinemia include multiple myeloma, macroglobulinemia and certain leukemias.2 Infectious causes of cryoglobulinemia include mycoplasma pneumonia, Streptococcus, hepatitis C virus, hepatitis B virus and human immunodeficiency virus (HIV) infections.2,3 There is a strong association of cryoglobulinemia with hepatitis C infection with as many as 98 percent of patients with type II and type II cryoglobulinemia having hepatitis C infection.4 Additionally, cryoglobulinemia is a symptom in 35 percent of patients with chronic hepatitis C virus infections.5,6 

In cryoglobulinemia, temperature decreases lead to changes in cryoglobulin protein structure, lowering their solubility and leading to precipitation. Precipitation of cryoglobulin immune complexes leads to two main pathologic pathways: immune-mediated mechanisms (including vasculitis and activation of a systemic inflammatory response) and vascular slugging (including direct blocking and thrombosis of small arteries and capillaries and hyperviscosity syndrome).7

The clinical presentation of cryoglobulinemia is highly variable with symptoms occurring in numerous organ systems. The majority of manifestations of cryoglobulinemia affect the lower extremities. Lower extremity manifestations of cryoglobulinemia include cutaneous vasculitis and resultant skin changes; arthralgias and myalgias; peripheral neuropathy; and acrocyanosis. 

Cutaneous symptoms are the most common manifestation of cryoglobulinemia, occurring in nearly all cases. The most common cutaneous manifestations are petechiae and palpable purpura, which occur in 90 to 95 percent of patients.8-11 Researchers have reported ischemic necrosis in up to 40 percent of cases of cryoglobulinemia.8-11 Ulcerations are another relatively common cutaneous manifestation, occurring in 10 to 25 percent of cases of cryoglobulinemia.9-11 Cutaneous lesions are most common in the lower extremities.9-11

Musculoskeletal symptoms reportedly occur in more than 70 percent of patients with cryoglobulinemia.10,12,13 The most common musculoskeletal symptoms are arthralgia and myalgias. Arthralgias most commonly affect the hands, knees and ankles.10,12,13

Renal disease is the most serious complication of cryoglobulinemia. Renal damage occurs secondary to thrombosis and immune complex deposition. Renal disease reportedly occurs in 5 to 60 percent of patients with cryoglobulinemia.9 The most common clinical presentation of renal disease is proteinuria and hematuria.14 Untreated renal disease can lead to renal failure.14

Researchers have reported pulmonary symptoms in 40 to 50 percent of patients with cryoglobulinemia.9,10 Pulmonary symptoms include dyspnea, cough and chest pain.9,10 Examination findings include reduced forced expiratory flow rates and interstitial infiltrates on chest X-ray.15,16

Peripheral neuropathy is another very common manifestation of cryoglobulinemia. Ferri and colleagues showed neurologic exam changes in 48 percent of patients with cryoglobulinemia, electrophysiologic changes in 82 percent of patients and subjective symptoms in 91 percent of patients.17 Nerve injury occurs most commonly in sensory nerve fibers and is very rare in motor nerves.10  

Treatment of cryoglobulinemia includes treating underlying disease and limiting tissue damage due to precipitating cryoglobulins. Authors have proposed numerous treatment modalities but very little literature exists regarding the efficacy of various treatment modalities.18 Some have recommended immunosuppressive therapy for patients with severe organ system damage, rapidly progressing disease and disabling skin lesions.18 Immunosuppressive therapy typically combines corticosteroids with either rituximab (Rituxan, Genentech) or cyclophosphamide.19 Plasmapheresis is indicated for severe or life-threatening complications due to hyperviscosity syndrome, life-threatening cryoglobulinemia and patients with rapidly progressive renal disease.19

In Conclusion

Cryoglobulinemia is a disorder resulting in deposition of cryoglobulins at lower temperatures, leading to tissue damage by both immune-mediated mechanisms and direct vascular injury. A majority of the clinical manifestations of cryoglobulinemia affect the lower extremities and include cutaneous vasculitis with petechiae, palpable purpura and ulceration; arthralgias and myalgia; and peripheral neuropathy. Cryoglobulinemia is most commonly associated with hepatitis C virus infection but is also associated with other infections, lymphoproliferative disorders and autoimmune diseases.


1. Peveling-Oberhag J, Arcaini L, Hansmann ML, Zeuzem S. Hepatitis C-associated B-cell non-Hodgkin lymphomas. Epidemiology, molecular signature and clinical management. J Hepatology. 2013;59(1):169169:1

2. Tedeschi A, Baratc C, Minola E, Morra E. Cryoglobulinemia. Blood Rev.  2007;21(4):183:007;

3. Schifferli JA, French EL, Tissot JD. Hepatitis C virus infection, cryoglobulinemia, and glomerulonephritis. Advances in Nephrology. 1995;24:107–24:

4. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992;117(7):5737n In

5. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis. 1990; 162(2):569:90;

6. Dammacco F, Sansonno D. Review article: therapy for hepatitis C virus–related cryoglobulinemic vasculitis. N Engl J Med. 2013; 369(11):1035: 369d

7. Ramos-Casalas M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet. 2012; 379(9813):348-60.

8. Daoud MS, Gibson LE, Daoud S, el-Azhary RA. Chronic hepatitis C and skin diseases: a review. Mayo Clin Proc. 1995;70(6):55995;7

9. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974; 57(5):775-88.

10. Monti G, Galli M, Invernizzi F, Pioltelli P, Saccardo F, Monteverde A, et al. Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias. QJM. 1995; 88(2):115-26.

11. Cohen SJ, Pittelkow MR, Su WP. Cutaneous manifestations of cryoglobulinemia: clinical and histopathologic study of seventy-two patients. J Am Acad Dermatol. 1991;25(1):21-7.

12. Ramos-Casals M, Trejo O, García-Carrasco M, Cervera R, Font J. Mixed cryoglobulinemia: new concepts. Lupus. 2000;9(2):83-91.

13. Weinberger A, Berliner S, Pinkhas J. Articular manifestations of essential cryoglobulinemia. Semin Arthritis Rheum. 1981;10(3):224-9.

14. Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995; 47(2):618-23.

15. Bombardieri S, Paoletti P, Ferri C, Di Munno O, Fornal E, Giuntini C. Lung involvement in essential mixed cryoglobulinemia. Am J Med. 1979; 66(5):748-56.

16. Viegi G, Fornai E, Ferri C, Di Munno O, Begliomini E, Vitali C, et al. Lung function in essential mixed cryoglobulinemia: a short-term follow-up. Clin Rheumatol. 1989; 8(3):331-8.

17. Ferri C, La Civita L, Cirafisi C, Siciliano G, Longombardo G, Bombardieri S, et al. Peripheral neuropathy in mixed cryoglobulinemia: clinical and electrophysiologic investigations. J Rheumatol. 1992; 19(6):889-95.

18. Ferri C, Zignego AL, Pileri SA. Cryoglobulins. J Clin Pathol. 2002; 55(1):4–:20

19. Fervenza FC, Leise MD, Roccatello D, Kyle RA. Treatment of the mixed cryoglobulinemia syndrome. In (Post TW, ed.): UpToDate, UpToDate, Waltham, MA.


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