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. 2003 Sep;74(9):1267–1271. doi: 10.1136/jnnp.74.9.1267

Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia

R Nemni 1, L Sanvito 1, A Quattrini 1, G Santuccio 1, M Camerlingo 1, N Canal 1
PMCID: PMC1738673  PMID: 12933932

Abstract

Objectives: Hepatitis C virus (HCV) infection is often associated with cryoglobulinaemia (CG). Peripheral neuropathy (PN) is a comparatively common complication of CG associated with HCV infection and it is thought to be attributable to nerve ischaemia. Only few HCV CG patients with PN have been reported. The recent finding of HCV RNA in nerve biopsy specimens has suggested a possible direct role of HCV in the pathogenesis of PN. The authors studied 51 HCV patients to determine the prevalence of CG and to clarify the possible mechanism by which HCV determines the PN.

Methods: All the patients were studied clinically, by laboratory tests and electrophysiologically. Twenty eight patients underwent sural nerve biopsy where both morphological and morphometric evaluation of the biopsy specimen was performed, as well as statistical analysis.

Results: CG was found in 40 of 51 cases (78%). Polyneuropathy was significantly prevalent in CG+ patients compared with CG- (18 of 40 compared with 1 of 11 patients; p=0.01). HCV CG- patients more frequently developed well defined mononeuropathy or multiple neuropathy when compared with HCV CG+ (10 of 11 compared with 22 of 40; p<0.03). HCV CG+ patients showed significantly higher proportion of rheumatoid factor positivity (p<0.001) and low C4 levels (p=0.001). Nerve biopsy was performed in 25 of 40 HCV CG+ patients and in 3 of 11 HCV CG- patients: epineurial vasculitis was present in 8 of 25 HCV CG+ (32%) and in 2 of 3 HCV CG-. Differential fascicular loss of axons was found in 10 of 25 CG+ (40%) and 1 of 3 CG-, signs of both demyelination and axonal degeneration were present in 7 of 25 CG+ (28%). No significant difference was found in neuropathological features, while histometrical analysis disclosed more severe involvement in CG+ patients.

Conclusions: These findings suggest that the presence of CG is a negative predictive factor for the associated PN. Morphological findings in the sural nerve from HCV CG- and CG+ are consistent with an ischaemic mechanism of nerve damage and are against a direct role of the virus in causing the associated PN.

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Selected References

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  1. Adinolfi L. E., Utili R., Attanasio V., Zampino R., Ragone E., Tripodi M. F., Ruggiero G. Epidemiology, clinical spectrum and prognostic value of mixed cryoglobulinaemia in hepatitis C virus patients: a prospective study. Ital J Gastroenterol. 1996 Jan;28(1):1–9. [PubMed] [Google Scholar]
  2. Apartis E., Léger J. M., Musset L., Gugenheim M., Cacoub P., Lyon-Caen O., Pierrot-Deseilligny C., Hauw J. J., Bouche P. Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection? J Neurol Neurosurg Psychiatry. 1996 Jun;60(6):661–666. doi: 10.1136/jnnp.60.6.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Betourné C., Buge A., Dechy H., Dorra M., Dournon E., Rancurel G. Neuropathies périphériques au cours d'un myélome à IgA et d'une cryoglobulinémie mixte. Traitement par plasmaphérèses itératives. Nouv Presse Med. 1980 Apr 26;9(19):1369–1371. [PubMed] [Google Scholar]
  4. Bonetti B., Invernizzi F., Rizzuto N., Bonazzi M. L., Zanusso G. L., Chinaglia G., Monaco S. T-cell-mediated epineurial vasculitis and humoral-mediated microangiopathy in cryoglobulinemic neuropathy. J Neuroimmunol. 1997 Mar;73(1-2):145–154. doi: 10.1016/s0165-5728(96)00191-9. [DOI] [PubMed] [Google Scholar]
  5. Bonetti B., Scardoni M., Monaco S., Rizzuto N., Scarpa A. Hepatitis C virus infection of peripheral nerves in type II cryoglobulinaemia. Virchows Arch. 1999 Jun;434(6):533–535. doi: 10.1007/s004280050380. [DOI] [PubMed] [Google Scholar]
  6. 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 Nov;57(5):775–788. doi: 10.1016/0002-9343(74)90852-3. [DOI] [PubMed] [Google Scholar]
  7. Cacoub P., Renou C., Rosenthal E., Cohen P., Loury I., Loustaud-Ratti V., Yamamoto A. M., Camproux A. C., Hausfater P., Musset L. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l'Hepatite C. Medicine (Baltimore) 2000 Jan;79(1):47–56. doi: 10.1097/00005792-200001000-00005. [DOI] [PubMed] [Google Scholar]
  8. Chad D., Pariser K., Bradley W. G., Adelman L. S., Pinn V. W. The pathogenesis of cryoglobulinemic neuropathy. Neurology. 1982 Jul;32(7):725–729. doi: 10.1212/wnl.32.7.725. [DOI] [PubMed] [Google Scholar]
  9. Crotta Stefania, Stilla Annalisa, Wack Andreas, D'Andrea Annalisa, Nuti Sandra, D'Oro Ugo, Mosca Marta, Filliponi Franco, Brunetto R. Maurizia, Bonino Ferruccio. Inhibition of natural killer cells through engagement of CD81 by the major hepatitis C virus envelope protein. J Exp Med. 2002 Jan 7;195(1):35–41. doi: 10.1084/jem.20011124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dyck P. J., Benstead T. J., Conn D. L., Stevens J. C., Windebank A. J., Low P. A. Nonsystemic vasculitic neuropathy. Brain. 1987 Aug;110(Pt 4):843–853. doi: 10.1093/brain/110.4.843. [DOI] [PubMed] [Google Scholar]
  11. Ferri C., Greco F., Longombardo G., Palla P., Moretti A., Marzo E., Fosella P. V., Pasero G., Bombardieri S. Antibodies to hepatitis C virus in patients with mixed cryoglobulinemia. Arthritis Rheum. 1991 Dec;34(12):1606–1610. doi: 10.1002/art.1780341221. [DOI] [PubMed] [Google Scholar]
  12. Garcia-Bragado F., Fernandez J. M., Navarro C., Villar M., Bonaventura I. Peripheral neuropathy in essential mixed cryoglobulinemia. Arch Neurol. 1988 Nov;45(11):1210–1214. doi: 10.1001/archneur.1988.00520350048015. [DOI] [PubMed] [Google Scholar]
  13. Gemignani F., Pavesi G., Fiocchi A., Manganelli P., Ferraccioli G., Marbini A. Peripheral neuropathy in essential mixed cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 1992 Feb;55(2):116–120. doi: 10.1136/jnnp.55.2.116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gemignani Franco, Melli Giorgia, Inglese Cristina, Marbini Adriana. Cryoglobulinemia is a frequent cause of peripheral neuropathy in undiagnosed referral patients. J Peripher Nerv Syst. 2002 Mar;7(1):59–64. doi: 10.1046/j.1529-8027.2002.02007.x. [DOI] [PubMed] [Google Scholar]
  15. Lidove O., Cacoub P., Maisonobe T., Servan J., Thibault V., Piette J. C., Léger J. M. Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia. Ann Rheum Dis. 2001 Mar;60(3):290–292. doi: 10.1136/ard.60.3.290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Logothetis J., Kennedy W. R., Ellington A., Williams R. C. Cryoglobulinemic neuropathy. Incidence and clinical characteristics. Arch Neurol. 1968 Oct;19(4):389–397. doi: 10.1001/archneur.1968.00480040055005. [DOI] [PubMed] [Google Scholar]
  17. Lunel F., Musset L., Cacoub P., Frangeul L., Cresta P., Perrin M., Grippon P., Hoang C., Valla D., Piette J. C. Cryoglobulinemia in chronic liver diseases: role of hepatitis C virus and liver damage. Gastroenterology. 1994 May;106(5):1291–1300. doi: 10.1016/0016-5085(94)90022-1. [DOI] [PubMed] [Google Scholar]
  18. Migliaresi S., Di Iorio G., Ammendola A., Ambrosone L., Sanges G., Ugolini G., Sampaolo S., Bravaccio F., Tirri G. Interessamento del sistema nervoso periferico nella crioglobulinemia mista HCV-correlata. Reumatismo. 2001;53(1):26–32. doi: 10.4081/reumatismo.2001.26. [DOI] [PubMed] [Google Scholar]
  19. Nemni R., Corbo M., Fazio R., Quattrini A., Comi G., Canal N. Cryoglobulinaemic neuropathy. A clinical, morphological and immunocytochemical study of 8 cases. Brain. 1988 Jun;111(Pt 3):541–552. doi: 10.1093/brain/111.3.541. [DOI] [PubMed] [Google Scholar]
  20. Paoletti V., Donnarumma L., De Matteis A., Mammarella A., Labbadia G., Musca A., Francia A. Peripheral neuropathy without cryoglobulinemia in patients with hepatitis C virus infection. Panminerva Med. 2000 Sep;42(3):175–178. [PubMed] [Google Scholar]
  21. Trejo O., Ramos-Casals M., García-Carrasco M., Yagüe J., Jiménez S., de la Red G., Cervera R., Font J., Ingelmo M. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore) 2001 Jul;80(4):252–262. doi: 10.1097/00005792-200107000-00004. [DOI] [PubMed] [Google Scholar]
  22. Vallat J. M., Desproges-Gotteron R., Leboutet M. J., Loubet A., Gualde N., Treves R. Cryoglobulinemic neuropathy: a pathological study. Ann Neurol. 1980 Aug;8(2):179–185. doi: 10.1002/ana.410080208. [DOI] [PubMed] [Google Scholar]
  23. Vital C., Deminière C., Lagueny A., Bergouignan F. X., Pellegrin J. L., Doutre M. S., Clement A., Beylot J. Peripheral neuropathy with essential mixed cryoglobulinemia: biopsies from 5 cases. Acta Neuropathol. 1988;75(6):605–610. doi: 10.1007/BF00686206. [DOI] [PubMed] [Google Scholar]
  24. Walport M. J. Complement. First of two parts. N Engl J Med. 2001 Apr 5;344(14):1058–1066. doi: 10.1056/NEJM200104053441406. [DOI] [PubMed] [Google Scholar]
  25. Zaltron S., Puoti M., Liberini P., Antonini L., Quinzanini M., Manni M., Forleo M. A., Rossi S., Spinetti A., Zanini B. High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinaemia. Ital J Gastroenterol Hepatol. 1998 Aug;30(4):391–395. [PubMed] [Google Scholar]

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