Abstract
BACKGROUND—The severity, clinical course, and risk of hepatitis C virus (HCV) related chronic liver disease are still rather poorly defined. AIMS—To investigate the prevalence, risk factors, and severity of HCV related liver disease in the general population, and investigate whether infection with a specific genotype is associated with an increased risk of cirrhosis or hepatocellular carcinoma. METHODS—HCV RNA determination by polymerase chain reaction (PCR) and HCV genotyping were performed in all anti-HCV positive subjects belonging to the Dionysos study (6917 subjects). Diagnosis of cirrhosis and hepatocellular carcinoma was established by liver biopsy in all cases. All the data were analysed by univariate and multivariate statistics in all the cohort. To investigate the natural history of HCV infection, anti-HCV positive subjects were followed up every six months for three years with liver function tests and ultrasonograms. RESULTS—The overall prevalence of HCV RNA positivity was 2.3%. Positivity increased progressively with age, and was higher in women (ratio of men to women = 0.7). Genotypes 1b and 2a were the most frequent (42 and 24% of HCV RNA positive patients), with a prevalence of 1 and 0.6% respectively. Intravenous drug use, blood transfusions received before 1990, history of previous hepatitis among the cohabiting, and history of animal (mainly dogs) bites were significantly (p<0.05) associated with HCV infection, independently of age and sex. Multivariate analysis showed that, independently of age, sex, and alcohol intake, genotype 1b infection, with or without coinfection with other genotypes, is the major risk factor associated with the presence of cirrhosis and/or hepatocellular carcinoma. During the three years of follow up, 57 (35%) of the HCV RNA positive subjects had consistently normal alanine aminotransferase and γ-glutamyltransferase values. Two of the 22 HCV RNA positive cirrhotic patients, all drinking more than 90 g of alcohol a day, developed hepatocellular carcinoma (incidence rate = 3.0% per year). CONCLUSIONS—In the general population of Northern Italy, HCV infection is widespread, but only less than 50% of the anti-HCV positive subjects, particularly those infected with genotype 1b, are associated with a more severe liver disease. Alcohol consumption greater that 30 g a day significantly aggravates the natural course of the disease. Keywords: hepatitis C virus genotypes; Dionysos; liver disease; cirrhosis
Full Text
The Full Text of this article is available as a PDF (153.7 KB).
Figure 1 .
Distribution of different hepatitis C virus (HCV) genotypes in the HCV RNA positive subjects of the Dionysos cohort (n = 162).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alter M. J., Margolis H. S., Krawczynski K., Judson F. N., Mares A., Alexander W. J., Hu P. Y., Miller J. K., Gerber M. A., Sampliner R. E. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med. 1992 Dec 31;327(27):1899–1905. doi: 10.1056/NEJM199212313272702. [DOI] [PubMed] [Google Scholar]
- Bellentani S., Saccoccio G., Costa G., Tiribelli C., Manenti F., Sodde M., Saveria Crocè L., Sasso F., Pozzato G., Cristianini G. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997 Dec;41(6):845–850. doi: 10.1136/gut.41.6.845. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bellentani S., Tiribelli C., Saccoccio G., Sodde M., Fratti N., De Martin C., Cristianini G. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos Study. Hepatology. 1994 Dec;20(6):1442–1449. doi: 10.1002/hep.1840200611. [DOI] [PubMed] [Google Scholar]
- Benvegnù L., Pontisso P., Cavalletto D., Noventa F., Chemello L., Alberti A. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology. 1997 Jan;25(1):211–215. doi: 10.1053/jhep.1997.v25.pm0008985292. [DOI] [PubMed] [Google Scholar]
- Berg T., Hopf U., Stark K., Baumgarten R., Lobeck H., Schreier E. Distribution of hepatitis C virus genotypes in German patients with chronic hepatitis C: correlation with clinical and virological parameters. J Hepatol. 1997 Mar;26(3):484–491. doi: 10.1016/s0168-8278(97)80411-4. [DOI] [PubMed] [Google Scholar]
- Block G., Hartman A. M., Dresser C. M., Carroll M. D., Gannon J., Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol. 1986 Sep;124(3):453–469. doi: 10.1093/oxfordjournals.aje.a114416. [DOI] [PubMed] [Google Scholar]
- Bruno S., Silini E., Crosignani A., Borzio F., Leandro G., Bono F., Asti M., Rossi S., Larghi A., Cerino A. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study. Hepatology. 1997 Mar;25(3):754–758. doi: 10.1002/hep.510250344. [DOI] [PubMed] [Google Scholar]
- Bukh J., Miller R. H., Purcell R. H. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis. 1995 Feb;15(1):41–63. doi: 10.1055/s-2007-1007262. [DOI] [PubMed] [Google Scholar]
- Cammarota G., Maggi F., Vatteroni M. L., Da Prato L., Barsanti L., Bendinelli M., Pistello M. Partial nucleotide sequencing of six subtype 2c hepatitis C viruses detected in Italy. J Clin Microbiol. 1995 Oct;33(10):2781–2784. doi: 10.1128/jcm.33.10.2781-2784.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chiaramonte M., Stroffolini T., Caporaso N., Coppola R., Craxì A., Gaeta G. B., Sagnelli E., Zanetti A. R. Hepatitis-C virus infection in Italy: a multicentric sero-epidemiological study (a report from the HCV study group of the Italian Association for the Study of the Liver). Ital J Gastroenterol. 1991 Dec;23(9):555–558. [PubMed] [Google Scholar]
- Conry-Cantilena C., VanRaden M., Gibble J., Melpolder J., Shakil A. O., Viladomiu L., Cheung L., DiBisceglie A., Hoofnagle J., Shih J. W. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med. 1996 Jun 27;334(26):1691–1696. doi: 10.1056/NEJM199606273342602. [DOI] [PubMed] [Google Scholar]
- Cubeau J., Pequignot G. La technique du questionnaire alimentaire quantitatif utilisé par la section nutrition de l'I.N.S.E.R.M. Rev Epidemiol Sante Publique. 1980 Oct 30;28(3):367–372. [PubMed] [Google Scholar]
- De Bac C., Stroffolini T., Gaeta G. B., Taliani G., Giusti G. Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: a multicenter Italian study. Hepatology. 1994 Nov;20(5):1225–1230. doi: 10.1016/0270-9139(94)90761-7. [DOI] [PubMed] [Google Scholar]
- Dubois F., Desenclos J. C., Mariotte N., Goudeau A. Hepatitis C in a French population-based survey, 1994: seroprevalence, frequency of viremia, genotype distribution, and risk factors. The Collaborative Study Group. Hepatology. 1997 Jun;25(6):1490–1496. doi: 10.1002/hep.510250630. [DOI] [PubMed] [Google Scholar]
- Guillouzo A., Morel F., Langouët S., Maheo K., Rissel M. Use of hepatocyte cultures for the study of hepatotoxic compounds. J Hepatol. 1997;26 (Suppl 2):73–80. doi: 10.1016/s0168-8278(97)80499-0. [DOI] [PubMed] [Google Scholar]
- Kaur S., Rybicki L., Bacon B. R., Gollan J. L., Rustgi V. K., Carey W. D. Performance characteristics and results of a large-scale screening program for viral hepatitis and risk factors associated with exposure to viral hepatitis B and C: results of the National Hepatitis Screening Survey. National Hepatitis Surveillance Group. Hepatology. 1996 Nov;24(5):979–986. doi: 10.1002/hep.510240501. [DOI] [PubMed] [Google Scholar]
- Kobayashi M., Kumada H., Chayama K., Arase Y., Saitou S., Tsubota A., Koida I., Ikeda K., Hashimoto M., Iwasaki S. Prevalence of HCV genotype among patients with chronic liver diseases in the Tokyo metropolitan area. J Gastroenterol. 1994 Oct;29(5):583–587. doi: 10.1007/BF02365439. [DOI] [PubMed] [Google Scholar]
- Mangia A., Cascavilla I., Lezzi G., Spirito F., Maertens G., Parlatore L., Saracco G., Rizzetto M., Andriulli A. HCV genotypes in patients with liver disease of different stages and severity. J Hepatol. 1997 Jun;26(6):1173–1178. doi: 10.1016/s0168-8278(97)80449-7. [DOI] [PubMed] [Google Scholar]
- Midanik L. The validity of self-reported alcohol consumption and alcohol problems: a literature review. Br J Addict. 1982 Dec;77(4):357–382. doi: 10.1111/j.1360-0443.1982.tb02469.x. [DOI] [PubMed] [Google Scholar]
- Nousbaum J. B., Pol S., Nalpas B., Landais P., Berthelot P., Bréchot C. Hepatitis C virus type 1b (II) infection in France and Italy. Collaborative Study Group. Ann Intern Med. 1995 Feb 1;122(3):161–168. doi: 10.7326/0003-4819-122-3-199502010-00001. [DOI] [PubMed] [Google Scholar]
- Okamoto H., Sugiyama Y., Okada S., Kurai K., Akahane Y., Sugai Y., Tanaka T., Sato K., Tsuda F., Miyakawa Y. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infectious sources. J Gen Virol. 1992 Mar;73(Pt 3):673–679. doi: 10.1099/0022-1317-73-3-673. [DOI] [PubMed] [Google Scholar]
- Okamoto H., Tokita H., Sakamoto M., Horikita M., Kojima M., Iizuka H., Mishiro S. Characterization of the genomic sequence of type V (or 3a) hepatitis C virus isolates and PCR primers for specific detection. J Gen Virol. 1993 Nov;74(Pt 11):2385–2390. doi: 10.1099/0022-1317-74-11-2385. [DOI] [PubMed] [Google Scholar]
- Paton A., Saunders J. B. ABC of alcohol. Definitions. Br Med J (Clin Res Ed) 1981 Nov 7;283(6301):1248–1250. doi: 10.1136/bmj.283.6301.1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pontisso P., Ruvoletto M. G., Nicoletti M., Tisminetzky S., Gerotto M., Levrero M., Artini M., Baldi M., Ballardini G., Barbara L. Distribution of three major hepatitis C virus genotypes in Italy. A multicentre study of 495 patients with chronic hepatitis C. J Viral Hepat. 1995;2(1):33–38. doi: 10.1111/j.1365-2893.1995.tb00069.x. [DOI] [PubMed] [Google Scholar]
- Pozzato G., Kaneko S., Moretti M., Crocè L. S., Franzin F., Unoura M., Bercich L., Tiribelli C., Crovatto M., Santini G. Different genotypes of hepatitis C virus are associated with different severity of chronic liver disease. J Med Virol. 1994 Jul;43(3):291–296. doi: 10.1002/jmv.1890430318. [DOI] [PubMed] [Google Scholar]
- Prati D., Capelli C., Zanella A., Mozzi F., Bosoni P., Pappalettera M., Zanuso F., Vianello L., Locatelli E., de Fazio C. Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection. Gastroenterology. 1996 Jan;110(1):178–183. doi: 10.1053/gast.1996.v110.pm8536854. [DOI] [PubMed] [Google Scholar]
- Puoti C., Magrini A., Filippi T., Aldegheri L. Do symptomless HCV carriers spread infection to their relatives? Lancet. 1995 Sep 23;346(8978):843–843. doi: 10.1016/s0140-6736(95)91657-1. [DOI] [PubMed] [Google Scholar]
- Reshef A., Epstein L. M. Reliability of a dietary questionnaire. Am J Clin Nutr. 1972 Jan;25(1):91–95. doi: 10.1093/ajcn/25.1.91. [DOI] [PubMed] [Google Scholar]
- Riboli E., Péquignot G., Repetto F., Axerio M., Raymond L., Boffetta P., Zubiri A., Del Moral A., Estève J., Tuyns A. J. A comparative study of smoking, drinking and dietary habits in population samples in France, Italy, Spain and Switzerland. I. Study design and dietary habits. Rev Epidemiol Sante Publique. 1988;36(3):151–165. [PubMed] [Google Scholar]
- Silini E., Bono F., Cividini A., Cerino A., Bruno S., Rossi S., Belloni G., Brugnetti B., Civardi E., Salvaneschi L. Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities. Hepatology. 1995 Feb;21(2):285–290. [PubMed] [Google Scholar]
- Silini E., Bottelli R., Asti M., Bruno S., Candusso M. E., Brambilla S., Bono F., Iamoni G., Tinelli C., Mondelli M. U. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a case-control study. Gastroenterology. 1996 Jul;111(1):199–205. doi: 10.1053/gast.1996.v111.pm8698200. [DOI] [PubMed] [Google Scholar]
- Simmonds P., Alberti A., Alter H. J., Bonino F., Bradley D. W., Brechot C., Brouwer J. T., Chan S. W., Chayama K., Chen D. S. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology. 1994 May;19(5):1321–1324. [PubMed] [Google Scholar]
- Simmonds P. Variability of hepatitis C virus. Hepatology. 1995 Feb;21(2):570–583. doi: 10.1002/hep.1840210243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sirchia G., Almini D., Bellobuono A., Giovanetti A. M., Marconi M., Mercuriali F., Mozzi F., Parravicini A., Pizzi M., Zanuso F. Prevalence of hepatitis C virus antibodies in Italian blood donors. The Italian Cooperative Group. Vox Sang. 1990;59(1):26–29. doi: 10.1111/j.1423-0410.1990.tb02109.x. [DOI] [PubMed] [Google Scholar]
- Stevens C. E., Taylor P. E., Pindyck J., Choo Q. L., Bradley D. W., Kuo G., Houghton M. Epidemiology of hepatitis C virus. A preliminary study in volunteer blood donors. JAMA. 1990 Jan 5;263(1):49–53. [PubMed] [Google Scholar]
- Stroffolini T., Menchinelli M., Taliani G., Dambruoso V., Poliandri G., Bozza A., Lecce R., Clementi C., Ippolito F. M., Compagnoni A. High prevalence of hepatitis C virus infection in a small central Italian town: lack of evidence of parenteral exposure. Ital J Gastroenterol. 1995 Jun;27(5):235–238. [PubMed] [Google Scholar]
- Stuyver L., van Arnhem W., Wyseur A., Hernandez F., Delaporte E., Maertens G. Classification of hepatitis C viruses based on phylogenetic analysis of the envelope 1 and nonstructural 5B regions and identification of five additional subtypes. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10134–10138. doi: 10.1073/pnas.91.21.10134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takada A., Tsutsumi M., Okanoue T., Matsushima T., Komatsu M., Fujiyama S. Distribution of the different subtypes of hepatitis C virus in Japan and the effects of interferon: a nationwide survey. J Gastroenterol Hepatol. 1996 Mar;11(3):201–207. doi: 10.1111/j.1440-1746.1996.tb00063.x. [DOI] [PubMed] [Google Scholar]
- Takada N., Takase S., Enomoto N., Takada A., Date T. Clinical backgrounds of the patients having different types of hepatitis C virus genomes. J Hepatol. 1992 Jan;14(1):35–40. doi: 10.1016/0168-8278(92)90128-c. [DOI] [PubMed] [Google Scholar]
- Watson J. P., Brind A. M., Chapman C. E., Bates C. L., Gould F. K., Johnson S. J., Burt A. D., Ferguson J., Simmonds P., Bassendine M. F. Hepatitis C virus: epidemiology and genotypes in the north east of England. Gut. 1996 Feb;38(2):269–276. doi: 10.1136/gut.38.2.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zein N. N., Rakela J., Krawitt E. L., Reddy K. R., Tominaga T., Persing D. H. Hepatitis C virus genotypes in the United States: epidemiology, pathogenicity, and response to interferon therapy. Collaborative Study Group. Ann Intern Med. 1996 Oct 15;125(8):634–639. doi: 10.7326/0003-4819-125-8-199610150-00002. [DOI] [PubMed] [Google Scholar]
- Zeuzem S., Teuber G., Lee J. H., Rüster B., Roth W. K. Risk factors for the transmission of hepatitis C. J Hepatol. 1996;24(2 Suppl):3–10. [PubMed] [Google Scholar]