Cryoglobulinemia - Symptoms, Causes, Images, and Treatment Options

Diseases

Highlights & Basics

Key Highlights

Cryoglobulinemia may be asymptomatic or present acutely.
Mixed cryoglobulinemia (MC) is the most common type, and it is strongly associated with chronic hepatitis C virus (HCV) infection.
Clinical presentation includes a triad of purpura, weakness, and arthralgia. Multisystemic involvement may include the kidneys, liver, and nervous system.
Diagnosis is based on clinical and laboratory findings. Leukocytoclastic vasculitis is the histologic hallmark of MC.
Management of MC secondary to chronic HCV infection includes viral eradication strategies in addition to immunosuppression.

Lower extremity palpable purpura

From the personal collection of Dr GS Kaeley

Quick Reference

History & Exam
- Key Factors
- Other Factors
More information...
Diagnostics Tests
More information...
Treatment Options
More information...

Definition

Epidemiology

Etiology

Pathophysiology

Images

Lower extremity palpable purpura
Unusual case of hepatitis C-related cryoglobulin-induced digital gangrene

Citations

Key Articles

Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25.[Abstract][Full Text]
Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers. 2018 Aug 2;4(1):11.[Abstract]
American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Oct 2022 [internet publication].[Full Text]
Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023 Feb;42(2):359-70.[Abstract][Full Text]
Montero N, Favà A, Rodriguez E, et al. Treatment for hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database Syst Rev. 2018 May 7;(5):CD011403.[Abstract][Full Text]
Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022 Dec;102(6s):S129-205.[Full Text]

Other Online Resources

CDC: child and adolescent immunization schedule by age
CDC: adult immunization schedule by age

Referenced Articles

1. Dispenzieri A, Gorevic PD. Cryoglobulinemia. Hematol Oncol Clin North Am. 1999 Dec;13(6):1315-49.[Abstract]
2. Tedeschi A, Barate C, Minola E, et al. Cryoglobulinemia. Blood Rev. 2007 Jul;21(4):183-200. [Abstract]
3. Gorevic P, Kassab H, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long term follow-up in 40 patients. Am J Med. 1980 Aug;69(2):287-308.[Abstract]
4. Ferri C. Mixed cryoglobulinemia. Orphanet J Rare Dis. 2008 Sep 16;3:25.[Abstract][Full Text]
5. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974 Nov;57(5):775-88.[Abstract]
6. Silva F, Pinto C, Barbosa A, et al. New insights in cryoglobulinemic vasculitis. J Autoimmun. 2019 Dec;105:102313.[Abstract]
7. Roccatello D, Saadoun D, Ramos-Casals M, et al. Cryoglobulinaemia. Nat Rev Dis Primers. 2018 Aug 2;4(1):11.[Abstract]
8. Monti G, Saccardo F, Castelnovo L, et al. Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the origgio study. Autoimmun Rev. 2014 Jun;13(6):609-14.[Abstract]
9. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001 Jul;80(4):252-62.[Abstract]
10. Sise ME, Bloom AK, Wisocky J, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016 Feb;63(2):408-17.[Abstract][Full Text]
11. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med. 1992 Oct 1;117(7):573-7.[Abstract]
12. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005 Apr;5(4):227-36.[Abstract]
13. Ramos-Casals M, Stone JH, Cid MC, et al. The cryoglobulinaemias. Lancet. 2012 Jan 28;379(9813):348-60.[Abstract]
14. Dammacco F, Sansonno D. Mixed cryoglobulinemia as a model of systemic vasculitis. Clin Rev Allergy Immunol. 1997 Spring;15(1):97-119.[Abstract]
15. Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum. 2004 Jun;33(6):355-74.[Abstract]
16. Dammacco F, Lauletta G, Vacca A. The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements. Clin Exp Med. 2023 Jun;23(2):255-72.[Abstract][Full Text]
17. Mascia MT, Ferrari D, Campioli D, et al. Non HCV-related mixed cryoglobulinemia. Dig Liver Dis. 2007 Sep;39(suppl 1):S61-4.[Abstract]
18. Napodano C, Gulli F, Rapaccini GL, et al. Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins. Adv Clin Chem. 2021;104:299-340.[Abstract][Full Text]
19. Kuroda Y, Kuroki A, Kikuchi S, et al. A critical role for sialylation in cryoglobulin activity of murine IgG3 monoclonal antibodies. J Immunol. 2005 Jul 15;175(2):1056-61.[Abstract][Full Text]
20. Monti G, Galli M, Invernizzi F, 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 Feb;88(2):115-26.[Abstract]
21. Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinaemia. Lancet Oncol. 2003 Nov;4(11):679-85.[Abstract]
22. Wintrobe M, Buell M. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp. 1933;52:156-65.
23. Ferri C, Mascia M. Cryoglobulinemic vasculitis. Curr Opin Rheumatol. 2006 Jan;18(1):54-63.[Abstract]
24. Suresh E. Diagnostic approach to patients with suspected vasculitis. Postgrad Med J. 2006 Aug;82(970):483-8.[Abstract][Full Text]
25. Vitali C, Ferri C, Nasti P, et al. Hypercomplementaemia as a marker of the evolution from benign to malignant B cell proliferation in patients with type II mixed cryoglobulinaemia. Br J Rheumatol. 1994 Aug;33(8):791-2.[Abstract]
26. Lamprecht P, Moosig F, Gause A, et al. Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis. Ann Rheum Dis. 2001 Apr;60(4):385-90.[Abstract][Full Text]
27. Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. Sjogren syndrome associated with hepatitis C virus: a multicenter analysis of 137 cases. Medicine (Baltimore). 2005 Mar;84(2):81-9.[Abstract]
28. Leone N, Pellicano R, Ariata Maiocco I, et al. Mixed cryoglobulinemia and chronic hepatitis C virus infection: the rheumatic manfestations. J Med Virol. 2002 Feb;66(2):200-3. [Abstract]
29. Lormeau C, Falgarone G, Roulot D, et al. Rheumatologic manifestations of chronic hepatitis C infection. Joint Bone Spine. 2006 Dec;73(6):633-8.[Abstract]
30. Bombardieri M, Alessandri C, Labbadia G, et al. Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with rheumatoid arthritis from patients with chronic hepatitis C infection-associated polyarticular involvement. Arthritis Res Ther. 2004;6(2):R137-41. [Abstract][Full Text]
31. Sidana S, Rajkumar SV, Dispenzieri A, et al. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. Am J Hematol. 2017 Jul;92(7):668-73.[Abstract][Full Text]
32. Ammendola A, Sampaolo S, Ambrosone L, et al. Peripheral neuropathy in hepatitis-related mixed cryoglobulinemia: electrophysiologic follow-up study. Muscle Nerve. 2005 Mar;31(3):382-5.[Abstract]
33. Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1410-4.[Abstract][Full Text]
34. Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: a multicenter case-control study using magnetic resonance imaging and neurophysiological tests. J Rheumatol. 2005 Mar;32(3):484-8.[Abstract]
35. Saadoun D, Landau DA, Calabrese LH, et al. Hepatitis C-associated mixed cryoglobulinemia: a crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford). 2007 Aug;46(8):1234-42. [Abstract][Full Text]
36. Tarantino A, Campise M, Banfi G, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995 Feb;47(2):618-23.[Abstract][Full Text]
37. Beddhu S, Bastacky S, Johnson JP, et al. The clinical and morphologic spectrum of renal cryoglobulinemia. Medicine (Baltimore). 2002 Sep;81(5):398-409.[Abstract]
38. Kay J, McCluskey RT. Case records of the Massachusetts General Hospital. Case 31-2005. A 60-year-old man with skin lesions and renal insufficiency. N Engl J Med. 2005 Oct 13;353(15):1605-13.[Abstract]
39. D'Amico G. Renal involvement in hepatitis C infection: cryoglobulinemic glomerulonephritis. Kidney Int. 1998 Aug;54(2):650-71.[Abstract][Full Text]
40. Della Rossa A, Tavoni A, Bombardieri S. Hyperviscosity syndrome in cryoglobulinemia: clinical aspects and therapeutic considerations. Semin Thromb Hemost. 2003 Oct;29(5):473-7.[Abstract]
41. Chan AO, Lau JS, Chan CH, et al. Cryoglobulinaemia: clinical and laboratory perspectives. Hong Kong Med J. 2008 Feb;14(1):55-9.[Abstract][Full Text]
42. Amdo TD, Welker JA. An approach to the diagnosis and treatment of cryofibrinogenemia. Am J Med. 2004 Mar 1;116(5):332-7.[Abstract]
43. Shah H, Bilodeau M, Burak KW, et al. The management of chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver. CMAJ. 2018 Jun 4;190(22):E677-87.[Abstract][Full Text]
44. European Association for the Study of the Liver, Clinical Practice Guidelines Panel: Chair:, EASL Governing Board representative:, et al. EASL recommendations on treatment of hepatitis C: final update of the series(☆). J Hepatol. 2020 Nov;73(5):1170-218.[Abstract][Full Text]
45. Cacoub P, Desbois AC, Comarmond C, et al. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. Gut. 2018 Nov;67(11):2025-34.[Abstract]
46. El-Serag HB, Christie IC, Puenpatom A, et al. The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection. Aliment Pharmacol Ther. 2019 Jun;49(11):1442-7. [Abstract]
47. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. Oct 2022 [internet publication].[Full Text]
48. Gragnani L, Fabbrizzi A, Triboli E, et al. Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: a prospective, controlled pilot study. Dig Liver Dis. 2014 Sep;46(9):833-7.[Abstract]
49. Saadoun D, Resche Rigon M, Pol S, et al. PegIFNalfa/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis. J Hepatol. 2015 Jan;62(1):24-30.[Abstract]
50. Cornella SL, Stine JG, Kelly V, et al. Persistence of mixed cryoglobulinemia despite cure of hepatitis C with new oral antiviral therapy including direct-acting antiviral sofosbuvir: a case series. Postgrad Med. 2015 May;127(4):413-7. [Abstract]
51. Emery JS, Kuczynski M, La D, et al. Efficacy and safety of direct acting antivirals for the treatment of mixed cryoglobulinemia. Am J Gastroenterol. 2017 Aug;112(8):1298-308.[Abstract]
52. Saadoun D, Thibault V, Si Ahmed SN, et al. Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study. Ann Rheum Dis. 2016 Oct;75(10):1777-82.[Abstract]
53. Gragnani L, Visentini M, Fognani E, et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. Hepatology. 2016 Nov;64(5):1473-82. [Abstract][Full Text]
54. Bonacci M, Lens S, Mariño Z, et al. Long-term outcomes of patients with HCV-associated cryoglobulinemic vasculitis after virologic cure. Gastroenterology. 2018 Aug;155(2):311-5;e6. [Abstract]
55. Muchtar E, Magen H, Gertz MA. How I treat cryoglobulinemia. Blood. 2017 Jan 19;129(3):289-98.[Abstract][Full Text]
56. Tavoni A, Mosca M, Ferri C, et al. Guidelines for the management of essential mixed cryoglobulinemia. Clin Exp Rheumatol. 1995 Nov-Dec;13(suppl 13):S191-5.[Abstract]
57. Saadoun D, Delluc A, Piette JC, et al. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008 Jan;20(1):23-8. [Abstract]
58. De Vita S, Quartuccio L, Isola M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum. 2012 Mar;64(3):843-53.[Abstract][Full Text]
59. Quartuccio L, Bortoluzzi A, Scirè CA, et al. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol. 2023 Feb;42(2):359-70.[Abstract][Full Text]
60. Montero N, Favà A, Rodriguez E, et al. Treatment for hepatitis C virus-associated mixed cryoglobulinaemia. Cochrane Database Syst Rev. 2018 May 7;(5):CD011403.[Abstract][Full Text]
61. Colantuono S, Mitrevski M, Yang B, et al. Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Clin Rheumatol. 2017 Mar;36(3):617-23. [Abstract]
62. Visentini M, Tinelli C, Colantuono S, et al. Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: phase II clinical trial and systematic review. Autoimmun Rev. 2015 Oct;14(10):889-96.[Abstract]
63. Saleh F, Ko HH, Davis JE, et al. Fatal hepatitis C associated fibrosing cholestatic hepatitis as a complication of cyclophosphamide and corticosteroid treatment of active glomerulonephritis. Ann Hepatol. 2007 Jul-Sep;6(3):186-9.[Abstract][Full Text]
64. Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022 Dec;102(6s):S129-205.[Full Text]
65. Scarpato S, Tirri E, Naclerio C, et al. Plasmapheresis in cryoglobulinemic neuropathy: a clinical study. Dig Liver Dis. 2007 Sep;39(suppl 1):S136-7.[Abstract]
66. Stone MJ. Waldenstrom's macroglobulinemia: hyperviscosity syndrome and cryoglobulinemia. Clin Lymphoma Myeloma. 2009 Mar;9(1):97-9. [Abstract]
67. Thiel J, Peters T, Mas Marques A, et al. Kinetics of hepatitis C (HCV) viraemia and quasispecies during treatment of HCV associated cryoglobulinaemia with pulse cyclophosphamide. Ann Rheum Dis. 2002 Sep;61(9):838-41.[Abstract][Full Text]
68. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis resistant to intermittent intravenous pulse cyclophosphamide therapy. Scand J Rheumatol. 2000;29(3):201-2.[Abstract]
69. Michael AB, Lawes M, Kamalarajan M, et al. Cryoglobulinaemia as an acute presentation of Waldenstrom's macroglobulinaemia. Br J Haematol. 2004 Mar;124(5):565.[Abstract]
70. Ferri C, Mannini L, Bartoli V, et al. Blood viscosity and filtration abnormalities in mixed cryoglobulinemia patients. Clin Exp Rheumatol. 1990 May-Jun;8(3):271-81.[Abstract]
71. Antonelli A, Ferri C, Fallahi P, et al. Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia. QJM. 2004 Aug;97(8):499-506.[Abstract][Full Text]