PREVALENCE AND RISK FACTORS IN DEVELOPMENT OF CHRONIC HEPATITIS C-ASSOCIATED CRYOGLOBULINEMIA

Abstract. The aim of the study was to assess prevalence and risk factors for cryoglobulinemia associated with chronic hepatitis C in St.-Petersburg. Patients and methods. We studied 121 patients with chronic hepatitis C, including 53 men and 68 women with median age of 39±13 years. The median hepatitis duration was 3 years (range 0.5 to 34 years). In this group 25 (20,7%) had cirrhosis. Results. 37,2% (45/121) patients had circulating cryoglobulins. A low levels of crioglobulins (cryocrit 1-4%) were detected more frequently. Cryoglobulinaemic patients showed more frequent rates rheumatoid factors activity (р = 0,001), a higher levels of bilirubin (р = 0,003) and a γ-gamma-glutamyltransferase (р = 0,031). The presence of cryoglobulins was not correlated with HCV genotype (HCV 1a – 20,8% vs 20,7%, 1b – 29,2% vs 27,6%, 2 – 4,2% vs 6,9%, 3a – 20,8 vs 34,5%, mixt – 20,8% vs 6,9%, not identified – 4,1% vs 3,4%, in cryopositive vs cryonegative patients respectively, р = 0,7). By multivariate analysis hepatitis duration (Exp (B) = 1,07, 95% Cl 1,0-1,13, р = 0,049) and cirrhosis (Exp (B) = 6,2, 95% Cl 2,25-16,8, р < 0,001) could independently predict the presence of cryoglobulins. Conclusion. Our study demonstrates high prevalence of serum cryoglobulins in patients with chronic hepatitis C in St.-Petersburg and independent association between duration of hepatitis and advanced cirrhosis with development of cryoglobulinemia.

1. Константинова Н.А. Криоглобулины и патология. – М.: Медицина, 1999. – 176 с.

2. Игнатова Т.М., Апросина З.Г., Серов В.В., Мухин Н.А., Крель П.Е., Семенкова Е.Н., Попова И.В., Танащук Е.Л. Внепеченочные проявления хронического вирусного гепатита С // Терапевт. арх. – 1998. – № 11. – C. 9-16.

3. Неустроева Ю.А., Тихомирова Т.А., Дунаева Н.В., Лапин С.В., Тотолян А.А. Оптимизация полуколичественного метода выявления криоглобулинов в условиях клинико-диагностической лаборатории // Клин. лаб. диагностика. – 2007. – № 1. – С. 37-41.

4. Agnello V. The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection // Springer Semin. Immunopathol. – 1997. – Vol. 19, N 1. – P. 111-129.

5. Almirall J., Amengual M.J., Lopez T., Andreu X., Oristrell J., Sala M., Luelmo J., Dalmau B. Type II essential mixed cryoglobulinemia and renal disease. Hepatitis C virus association // Nefrologia. – 2002. – Vol. 22, N 6. – P. 531-539.

6. Antonescu C., Mayerat C., Mantegani A., Frei P.C., Spertini F., Tissot J.-D. Hepatitis C virus (HCV) infection: serum rheumatoid factor activity and HCV genotype correlate with cryoglobulin clonality // Blood. – 1998. – Vol. 92, N 9. – P. 3486-3488.

7. Cicardi M., Cesana B., Del Ninno E., Pappalardo E., Silini E., Agostoni A., Colombo M. Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C // J. Viral Hepat. – 2000. – Vol. 7, N 2. – P. 138-143.

8. D’Amico G., Fornasieri A. Cryoglobulinemia // Therapy in nephrology and hypertension: a companion to Brenner and Rector’s The kidney / Ed. by Brady H.R., Wilcox C.S. – USA: W.B.Saunders Company, 1999. – Chap. 18. – P. 125-129.

9. Ducoulombier D., Roque-Afonso A.-M., Di Liberto G., Penin F., Kara R., Richard Y., Dussaix E., Feray C. Frequent compartmentalization of hepatitis C virusvariants in circulating B cells and monocytes // Hepatology. – 2004. – Vol. 39. – P. 817-825.

10. Ferri C., Giuggioli D., Cazzato M., Sebastiani M., Mascia M.T., Zignego A.L. HCV-related cryoglobulinemic vasculitis: an update on its etiopathogenesis and therapeutic strategies // Clin. Exp. Rheumatol. – 2003. – Vol. 21, Suppl. 31. – P. 78-84.

11. Ferri C., Sebastiani M., Giuggioli D., Cazzato M., Longombardo G., Antonelli A., Puccini R., Michelassi C., Zignego A.L. Mixed cryoglobulinemia: demographic, clinical, and serologic features and survival in 231 patients // Semin. Arthritis Rheum. – 2004. – Vol. 33, N 6. – P. 355-374.

12. Frangeul L., Musset L., Cresta P., Cacoub P., Huraux J.M., Lunel F. Hepatitis C virus genotypes and subtypes in patients with hepatitis C, with and without cryoglobulinemia // J. Hepatol. – 1996. – Vol. 25, N 4. – P. 427-432.

13. Gad A., Tanaka E., Matsumoto A., el-Hamid Serwah A., Ali K., Makledy F., el-Gohary A., Orii K., Ijima A., Rokuhara A., Yoshizawa K., Nooman Z., Kiyosawa K. Factors predisposing to the occurrence of cryoglobulinemia in two cohorts of Egyptian and Japanese patients with chronic hepatitis C infection: ethnic and genotypic influence // J. Med. Virol. – 2003. – Vol. 70, N 4. – P. 594-599.

14. Hilgard P., Treichel U., Dries V., Dienes H.P., Gerken G. Cryoglobulin-associated uptake of hepatitis C virus into human hepatocytes // Hepatogastroenterology. – 2005. – Vol. 52, N 65. – P. 1534-1540.

15. Hwang S.-J., Chu C.-W., Huang D.-F., Lan K.-H., Chang F.-Y., Lee S.-D. Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis C // Tissue Antigens. – 2002. – Vol. 59. – P. 31-37.

16. Iagnocco A., Coari G., Mammarella M., Basili S., Donnarumma L., Valesini G., Paoletti V. Joint sonographi in asymptomatic patients with HCV correlated hepatitis // Clin. Exp. Rheumatology. – 2004. – Vol. 22, N 1. – P. 43-48.

17. Kayali Z., Buckwold V.E., Zimmerman B., Schmidt W.N. Hepatitis C, cryoglobulinemia and cirrhosis: a meta-analysis // Hepatology. – 2002. – Vol. 36, N 4. – P. 978-985.

18. Kosmas N., Kontos A., Panayiotakopoulos G., Dimitrakopoulos A., Kordossis T. Decreased prevalence of mixed cryoglobulinemia in the HAART era among HIV-positive, HCV-negative patients // J. Med. Virol. – 2006. – Vol. 78, N 10. – P. 1257-1261.

19. Kronenberger B., R ster B., Elez R., Weber S., Piiper A., Lee J.-H., Roth W.K., Zeuzem S. Interferon alfa down-regulates CD81 in patients with chronic hepatitis C // Hepatology. – 2001. – Vol. 33, N 6. – P. 1518-1526.

20. Liakina V., Speiciene D., Irnius A., Naraskeviciene J., Barakauskiene A., Semuchiniene T. Prevalence of cryoglobulinemia in patients with chronic HCV infection // Med. Sci. Monit. – 2002. – Vol. 8, N 1. – P. 31-36.

21. Lunel F., Musset L., Cacoub P., Frangeul P., Cresta P., Perrin M., Grippon P., Hoang C., Piette J.C., Huraux J.-H., Opolon P. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage // Gastroenterology. – 1994. – Vol. 106. – P. 1291-1300.

22. Moldvay J., Deny P., Pol S., Brechot C., Lamas E. Detection of hepatitis C virus RNA in peripheral blood mononuclear cells of infected patients by in situ hybridization // Blood. – 1994. – Vol. 83, N 1. – P. 269-273.

23. Morsica G., Tambussi G., Sitia G., Novati R., Lazzarin A., Lopalco L., Mukenge S. Replication of hepatitis C virus in B lymphocytes (CD19+) // Blood. – 1999. – Vol. 94, N 3. – P. 1138-1139.

24. Muratori L., Gibellini D., Lenzi M., Cataleta M., Muratori P., Morelli M.C., Bianchi F.B. Quantification of hepatitis C virus infected peripheral blood mononuclear cells by in situ reverse transcriptasepolymerase chain reaction // Blood. – 1996. – Vol. 88, N 7. – P. 2768-2774.

25. Pascual M., Perrin L., Giostra E., Schifferli J. Hepatitis C virus in patients with cryoglobulinaemia type II // J. Infect. Dis. – 1990. – Vol. 162. – P. 569-570.

26. Pawlotsky J.-M., Ben Yahia M., Andre C., Voisin M.-C., Intrator L., Roudot-Thoraval F., Deforges L., Duvoux C., Zafrani E-S., Duval J., Dhumeaux D. Immunological disorders in C virus chronic active hepatitis: a prospective case-control study // Hepatology. – 1994. – Vol. 19, N 4. – P. 841-848.

27. Rizos E., Dimos G., Liberopoulos E.N., Elisaf M.S., Drosos A.A. Cryoglobulinemic purpura in visceral leishmaniasis // Rheumatol. Int. – 2005. – Vol. 25, N 6. – P. 469-471.

28. Saadoun D., Sellam J., Ghillani-Dalbin P., Crecel R., Piette J.-C., Cacoub P. Increased risks of lymphoma and death among patients with non-hepatitis C virusrelated mixed cryoglobulinemia // Arch. Intern. Med. – 2006. – Vol. 166. – P. 2101-2108.

29. Saadoun D., Asselah T., Resche-Rigon M., Charlotte F., Bedossa P., Valla D., Piette J.C., Marcellin P., Cacoub P. Cryoglobulinemia is associated with steatosis and fibrosis in chronic hepatitis C // Hepatology. – 2006. – Vol. 43, N 6. – P. 1337-1345.

30. Schmidt W.N., Stapleton J.T., LaBrecque D.R., Mitros F.A., Kirby P.A., Phillips M., Brashear D. Hepatitis C virus (HCV) infection and cryoglobulinemia: analysis of whole blood and plasma HCV-RNA concentrations and correlation with liver histology // Hepatology. – 2000. – Vol. 31. – P. 737-744.

31. Trejo O., Ramos-Casals M., Lopez-Guillermo A., Garcia-Carrasco M., Yagie J., Cervera R., Font J., Ingelmo M. Hematologic malignancies in patients with cryoglobulinemia: association with autoimmune and chronic viral diseases // Semin. Arthritis Rheum. – 2003. – Vol. 33, N 1. – P. 19-28.

32. Wintrobe M., Buell M. Hyperproteinemia associated with multiple myeloma. With report of a case in with anextraordinary hyperproteinemia was associated with thrombosis of the retinal veins and symptoms suggesting Raynaud’s disease // Bull. of the John Hopkins Hosp. – 1933. – Vol. 52. – P. 156-165.

33. Wong V.S., Egner W., Elsey T., Brown D., Alexander G.J. Incidence, character and clinical relevance of mixed cryoglobulinemia in patients with chronic hepatitis C virus infection // Clin. Exp. Immunol. – 1996. – Vol. 104, N 1. – P. 25-31.

34. Zignego A.L., Ferri C., Giannini C., Monti M., La Civita L., Careccia G., Longombardo G., Lombardini F., Bombardieri S., Gentilini P. Hepatitis C virus genotype analysis in patients with type II mixed cryoglobulinemia // Ann. Intern. Med. – 1996. – Vol. 124, Iss. 1, Part 1. – P. 31-34.