Preview

Clinical Medicine (Russian Journal)

Advanced search
Open Access Open Access  Restricted Access Subscription Access

Mixed cryoglobulinemia associated with chronic HCV infection: problems of diagnosis and treatment

https://doi.org/10.30629/0023-2149-2025-103-2-137-145

Abstract

Mixed cryoglobulinemia is the most common extrahepatic manifestation of chronic HCV infection. Objective of the study. To investigate the frequency and diagnostic criteria of mixed cryoglobulinemia (MCG) associated with chronic HCV infection. Material and methods. The study included 83 patients with chronic HCV infection, aged 50.5 ± 12.6 years, of which 37 (44.6%) were men. The presence of cryoglobulins (CG) was examined, the cryocrit value was calculated, and rheumatoid factor (RF), complement component C4, and individual parameters of cellular immunity were determined. The frequency of MCG, its manifest forms, and immunological disorders were assessed, as well as the impact of antiviral therapy. Results. MCG was found in 61.4% of patients. Manifest forms of the disease were more frequently observed in the group of patients with a cryocrit of 1% or higher compared to those with a cryocrit of 0.5–0.99% (p < 0.017). In a multifactorial model, at a threshold cryocrit value of 0.5%, the detection of CG correlated with the duration of HCV infection (p = 0.001), and at a cryocrit value of 1%, it also correlated with a decrease in complement component C4 (p < 0.025). A sustained virological response (SVR) 12 weeks after the completion of therapy with direct-acting antiviral agents (DAAs) was achieved in 100% of patients. Despite the elimination of the virus, 29.4% of patients continued to have cryoglobulinemia. In 80% of patients with cryoglobulinemic vasculitis, immunological disorders persisted after the disappearance of CG. Conclusion. MCG develops in more than half of patients with chronic HCV infection and can be diagnosed with cryocrit values exceeding 0.5%. Early initiation of DAA therapy is a key factor in the prevention of MCG. The development of SVR does not exclude the persistence of MCG and immunological disorders in the early period after antiviral therapy, which necessitates mandatory long-term monitoring of these parameters.

About the Authors

I. M. Kim
G.N. Gabrichevsky National Research Centre for Epidemiology and Microbiology; Moscow City Clinical Hospital 52
Russian Federation

Moscow



P. O. Bogomolov
Moscow Region Scientific Research Clinical Institute named after M.F. Vladimirsky; A.I. Evdokimov Moscow State Medical University of Medicine and Dentistry
Russian Federation


M. V. Konopleva
National Research Centre for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
Russian Federation


T. A. Semenenko
National Research Centre for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
Russian Federation


N. A. Kokhanovskaya
National Research Centre for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
Russian Federation


E. I. Kaznacheeva
Clinical Diagnostic Laboratory INVITRO-Moscow
Russian Federation


A. P. Suslov
National Research Centre for Epidemiology and Microbiology named after Honorary Academician N.F. Gamaleya of the Ministry of Health of the Russian Federation
Russian Federation


A. A. Chernov
Moscow City Clinical Hospital 52
Russian Federation


A. D. Dushkin
Moscow City Clinical Hospital 52
Russian Federation


E. V. Kryukov
Military Medical Academy named after S.M. Kirov of the Ministry of Defense of the Russia
Russian Federation

 Saint Petersburg



M. L. Zubkin
G.N. Gabrichevsky National Research Centre for Epidemiology and Microbiology; Moscow City Clinical Hospital 52; Military Medical Academy named after S.M. Kirov Military Medical Academy (Moscow branch) of the Ministry of Defense of Russia
Russian Federation


References

1. Brouet J.C., Clauvel J.P., Danon F., Klein M., Seligmann M.. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am. J. Med. 1974;57(5):775–788. DOI: 10.1016/0002-9343(74)90852-3

2. Sargur R., White P., Egner W. Cryoglobulin evaluation: best practice? Ann. Clin. Biochem. 2010;47(Pt 1):8–16. DOI: 10.1258/acb.2009.009180

3. Vermeersch P., Gijbels K., Mariën G., Lunn R., Egner W., White P., Bossuyt X. A critical appraisal of current practice in the detection, analysis, and reporting of cryoglobulins. Clin. Chem. 2008;54(1):39–43. DOI : 10.1373/clinchem.2007.090134

4. Bunchorntavakul C., Mitraniy R., Reddy K.R. Advances in HCV and cryoglobulinemic vasculitis in the era of DAAs: are we at the end of the road? J. Clin. Exp. Hepatol. 2018;8(1):81–94. DOI: 10.1016/j.jceh.2017.11.012

5. Freitas-de Aguiar M., Faria-Janes A.L., Garcia-Brandes G.I., Takemi-Emori С., Gomes- Ferraz M.L., Coelho-Andrade L.E., Silva-de Souza A.W. Prevalence of cryoglobulinemia and cryoglobulinemic vasculitis in chronically HCV-infected Brazilian patients. Annals of Hepatology. 2019;18(5):685–692. DOI: 10.1016/j.aohep.2019.04.010

6. Ramos-Casals M., Stone J.H., Cid M.C., Bosch X. The cryoglobulinaemias. Lancet. 2012;28;379(9813):348–60. DOI: 10.1016/S0140-6736(11)60242-0

7. Sansonno D., Lauletta G., Montrone M., Tucci F.A., Nisi L., Dammacco F. Virological analysis and phenotypic characterization of peripheral blood lymphocytes of hepatitis C virus infected patients with and without mixed cryoglobulinemia. Clin. Exp. Immunol. 2006;143(2):288–96. DOI: 10.1111/j.1365-2249.2005.02987.x

8. Roccatello D., Saadoun D., Ramos-Casals M., Tzioufas A.G., Fervenza F.C., Cacoub P., Zignego A. L. and Ferri. C. Cryoglobulinaemia. Nature reviews disease primers.2018;4(11):1–14. DOI: 10.1038/s41572-018-0009-4

9. Dunaeva N.V., Neustroeva Yu.A., Tikhomirova T.A., Syssoev K.A., Alexeeva N.P., Lapin S.V., Esaulenko E.V.,Dobronravov V.A., Chukhlovin A.B., Totolian Areg A. Prevalence and risk factors in development of chronic hepatitis C-associated cryoglobulinemia Med immunologija. 2007;9(6):575–580. (In Russian). DOI: 10.15789/1563-0625-2007-6-575-580.

10. Bonacci M., Lens S., Londoño M.C., Mariño Z., Cid M.C., Ramos-Casals M., Sánchez-Tapias J.M., Forns X., Hernández-Rodríguez J. Virologic, clinical, and immune response outcomes of patients with hepatitis C virus-associated cryoglobulinemia treated with direct-acting antivirals. Clin. Gastroenterol. Hepatol.2017;15(4):P.575–583. DOI: 10.1016/j.cgh.2016.09.158

11. Bonacci M., Lens S., Mariño Z., Londoño M.C., Rodriguez-Tajes S., Sánchez-Tapias J.M. et al. Long-term outcomes of patients with HCV-associated cryoglobulinemic vasculitis after virologic cure. Gastroenterology. 2018;155(2):311–315. DOI: 10.1053/j.gastro.2018.04.024

12. Carrat F., Fontaine H., Dorival C, Simony M., Diallo A., Hezode C. et al. French ANRS CO22 Hepather cohort. Clinical outcomes in patients with chronic hepatitis C after direct-acting anti-viral treatment: a prospective cohort study. Lancet. 2019; 393(10179):1453–64 . DOI: 10.1016/S0140-6736(18)32111-1

13. Dammacco F., Lauletta G., Vacca A. The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements. Clinical and Experimental Medicine. 2023;23:255– 272. DOI: 10.1007/s10238-022-00808-1

14. Singh S., Facciorusso A., Loomba R., Falck-Ytter Y.T. Magnitude and kinetics of decrease in liver stiff ness after antiviral therapy in patients with chronic hepatitis C: a systematic review and meta-analysis. Clin. Gastroenterol. Hepatol.2018;16:27–38.e4. DOI: 10.1016/j.cgh.2017.04.038

15. Gragnani, L., Lorini S., Marri S., Vacchi C., Madia F., Monti M., Ferri C., Zignego A.L. Predictors of long-term cryoglobulinemic vasculitis outcomes 160 after HCV eradication with direct-acting antivirals in the real-life. Autoimmunity Reviews. 2022;21(1):102923. DOI: 10.1016/j.autrev.2021.102923

16. Cacoub, P., Ahmed S.N.S, Ferfar Y. Pol S., Thabut D., Hezode C. et al. Long-term efficacy of interferon-free antiviral treatment regimens in patients with hepatitis C virus–associated cryoglobulinemia vasculitis. Clinical Gastroenterology and Hepatology. 2019;17(3):518–526 . DOI: 10.1016/j.cgh.2018.05.021

17. Comarmond C., Cacoub P., Saadoun D. Treatment of chronic hepatitis C-associated cryoglobulinemia vasculitis at the era of direct-acting antivirals. Therap. Adv. Gastroenterol. 2020;13:1756284820942617. DOI: 10.1177/1756284820942617

18. Del Padre M., Todi L, Mitrevski M., Marrapodi R., Colantuono S., Fiorilli M., Casato M., Visentini M. Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia. Blood. 2017;130(1):35-38. DOI: 10.1182/ blood-2017-03-771238

19. Visentini M., Del Padre M., Colantuono S., Yang B., Minafò Y.A., Antonini S. et al. Long-lasting persistence of large B-cell clones in hepatitis C 165 virus-cured patients with complete response of mixed cryoglobulinaemia vasculitis. Liver International. 2019;39(4):628– 632. DOI: 10.1111/liv.14053

20. Comarmond C., Garrido M., Pol S., Desbois A.C., Costopoulos M., Le Garff-Tavernier M. et al. Direct-acting antiviral therapy restores immune tolerance to patients with hepatitis C virus-induced cryoglobulinemia vasculitis. Gastroenterology.2017;152(8): 2052–2062. DOI: 10.1053/j.gastro.2017.02.037

21. Gavrisheva S.V., Abdurahmanov D.T., Bulanov N.M., Tanashhuk E.L., Rozina T.P., Nikulkina E.N.et al. Efficacy of direct-acting antiviral drugs in the treatment of patients with hepatitis C virus-associated cryoglobulinemic vasculitis: results of a long-term follow-up. Nauchno-prakticheskaja revmatologija. 2023;61(2):181– 187. (In Russian). DOI: 10.47360/1995-4484-2023-181-187


Review

For citations:


Kim I.M., Bogomolov P.O., Konopleva M.V., Semenenko T.A., Kokhanovskaya N.A., Kaznacheeva E.I., Suslov A.P., Chernov A.A., Dushkin A.D., Kryukov E.V., Zubkin M.L. Mixed cryoglobulinemia associated with chronic HCV infection: problems of diagnosis and treatment. Clinical Medicine (Russian Journal). 2025;103(2):137-145. (In Russ.) https://doi.org/10.30629/0023-2149-2025-103-2-137-145

Views: 78


ISSN 0023-2149 (Print)
ISSN 2412-1339 (Online)