Abstract
Background
There is much controversy surrounding the natural history of hepatitis C virus (HCV) infection.
Aims
The aim of this review was to review the natural history of HCV infection.
Methods
Published English literature was searched via pubmed and then reviewed.
Results
Approximately, 75–85% of HCV-infected persons will progress to chronic HCV infection. The rate of chronic HCV infection is affected by a person’s age, gender, race, and viral immune response. Once chronic HCV infection develops, there are external and host factors that can increase the risk of progression of liver disease. Progression of chronic HCV infection is not linear in time, probably because many cofactors change the rate of development of fibrosis, cirrhosis, and hepatocellular carcinoma. Factors linked with aggressive disease progression include age at infection, duration of infection, heavy alcohol use, co-infections with HIV or hepatitis B virus, male sex, steatosis, insulin resistance (and factors associated with the metabolic syndrome), and host genetics. However, the relative importance of many and varied factors remains uncertain, and further research efforts should be directed toward design of predictive models for effective risk stratification. Interferon-based therapy, particularly among those achieving a sustained virologic response (SVR), is associated with improved fibrosis and inflammation scores, reduced incidence of hepatocellular carcinoma, and prolonged life expectancy.
Conclusions
Despite the progress in understanding the factors affecting the natural history of HCV infection, a great deal remains to be learnt.
Similar content being viewed by others
References
Thimme R, Oldach D, Chang KM, et al. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001;194(10):1395–1406
Loomba R, Rivera MM, McBurney R, et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment Pharmacol Ther 2011;33(5):559–565
Wright TL, Hsu H, Donegan E, et al. Hepatitis C virus not found in fulminant non-A, non-B hepatitis. Ann Intern Med 1991;115(2):111–112
Kanda T, Yokosuka O, Imazeki F, et al. Acute hepatitis C virus infection, 1986–2001: a rare cause of fulminant hepatitis in Chiba, Japan. Hepatogastroenterology 2004;51(56):556–558
Amin J, Law MG, Micallef J, et al. Potential biases in estimates of hepatitis C RNA clearance in newly acquired hepatitis C infection among a cohort of injecting drug users. Epidemiol Infect 2007;135(1):144–150
Bellentani S, Tiribelli C. The spectrum of liver disease in the general population: lesson from the Dionysos study. J Hepatol 2001;35(4):531–537
Thomson EC, Smith JA, Klenerman P. The natural history of early hepatitis C virus evolution; lessons from a global outbreak in HIV-1 infected individuals. J Gen Virol 2011;92:2227–2236
Thomas DL, Astemborski J, Rai RM, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000;284(4):450–456
Bigger CB, Guerra B, Brasky KM, et al. Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees. J Virol 2004;78:13779–13792
Keller BC, Johnson CL, Erickson AK, et al. Innate immune evasion by hepatitis C virus and West Nile virus. Cytokine Growth Factor Rev 2007;18:535–544
Post J, Ratnarajah S, Lloyd AR. Immunological determinants of the outcomes from primary hepatitis C infection. Cell Mol Life Sci 2009;66:733–756
Shoukry NH, Grakoui A, Houghton M, et al. Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003;197:1645–1655
Zeremski M, Hooker G, Shu MA, et al. Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection. J Hepatol 2011;55:545–552
Romero-Gomez M, Eslam M, Ruiz A, et al. Genes and hepatitis C: susceptibility, fibrosis progression and response to treatment. Liver Int 2011;31(4):443–460
Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461(7265):798–801
Missiha SB, Ostrowski M, Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008;134(6):1699–1714
Tong MJ, el-Farra NS, Reikes AR, et al. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463–1466
Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990;12:671–675
Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002;36(5 Suppl 1):S35–S46
Thein HH, Yi Q, Dore GJ, et al. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology 2008;48:418–431
Lawson A, Trent Hepatitis C Study Group. A comparison of the natural history and outcome of treatment for Asian and non-Asian hepatitis C-infected patients. J Viral Hepat 2011;18:e270–e277
Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998;75(3):347–354
Kiyosawa K. Trend of liver cirrhosis as precancerous lesions. Hepatol Res 2002;24:40–45
Alazawi W, Cunningham M, Dearden J, et al. Systematic review: outcome of compensated cirrhosis due to chronic hepatitis C infection. Aliment Pharmacol Ther 2010;32(3):344–355
Bruno S, Crosignani A, Maisonneuve P, et al. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study. Hepatology 2007;46:1350–1356
Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998;28:1687–1695
Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997;112:463–472
Omland LH, Jepsen P, Krarup H, et al. Increased mortality among persons infected with hepatitis C virus. Clin Gastroenterol Hepatol 2011;9:71–78
Amin J, Law MG, Bartlett M, et al. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006;368:938–945
Hissar SS, Kumar M, Tyagi P, et al. Natural history of hepatic fibrosis progression in chronic hepatitis C virus infection in India. J Gastroenterol Hepatol 2009;24(4):581–587
Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121–124
Poynard T, Ratziu V, Charlotte F, et al. Rate and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol 2001;34:730–739
Nguyen GC, Segev DL, Thuluvath PJ. Racial disparities in the management of hospitalized patients with cirrhosis and complications of portal hypertension: a national study. Hepatology 2007;45:1282–1289
Scott JD, McMahon BJ, Bruden D, et al. High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives. Clin Infect Dis 2006;42:945–952
Kobayashi M, Ikeda K, Hosaka T, et al. Natural history of compensated cirrhosis in the Child–Pugh class A compared between 490 patients with hepatitis C and 167 with B virus infections. J Med Virol 2006;78:459–465
Asselah T, Bieche I, Laurendeau I, et al. Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 2005;129:2064–2075
Bitetto D, Fabris C, Fornasiere E, et al. IL28B rs12979860 C > T polymorphism affects the evolution of chronic Hepatitis C. Hepatology 2010;52(Suppl):438A
Del Campo JA, Maraver Zamora M, Ramirez-Lorca R, et al. Real LM.IL28B polymorphism predicts sustained virological response in hepatitis C but is not associated with fibrosis or viral load. Hepatology 2010;52(Suppl):748A
Thompson AJ, Clark PJ, Fellay J, et al. IL28B genotype is not associated with advanced hepatic fibrosis in chronic hepatitis C patients enrolled in the ideal study. Hepatology 2010;52:2243–2244
Marabita F, Aghemo A, De Nicola S, et al. Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Hepatology 2011;54(4):1127–1134
Huang H, Shiffman ML, Cheung RC, et al. Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C. Gastroenterology 2006;130:1679–1687
Harris DR, Gonin R, Alter HJ, et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001;134:120–124
Ishida JH, Peters MG, Jin C, et al. Influence of cannabis use on severity of hepatitis C disease. Clin Gastroenterol Hepatol 2008;6:69–75
Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001;33:562–569
Freedman ND, Everhart JE, Lindsay KL, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology 2009;50:1360–1369
Modi AA, Feld JJ, Park Y, et al. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 2010;51:201–209
Everhart JE, Lok AS, Kim HY, et al. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology 2009;137:549–557
Kobayashi M, Tanaka E, Sodayama T, et al. The natural course of chronic hepatitis C: a comparison between patients with genotype 1 and 2 hepatitis C viruses. Hepatology 1996;23:669–695
Bruno S, Silini E, Crosignani A, et al. Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study. Hepatology 1997;25:754–758
Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004;53:406–412
Bochud PY, Cai T, Overbeck K, et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol 2009;51:655–666
De Nicola S, Aghemo A, Rumi MG, et al. HCV genotype 3: an independent predictor of fibrosis progression in chronic hepatitis C. J Hepatol 2009;51:964–966
Benvegnu L, Pontisso P, Cavalletto D, et al. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology 1997;25:211–215
Poynard T, Ratziu V, Charlotte F, et al. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol 2001;34:764–767
Harris HE, Eldridge KP, Harbour S, et al. Does the clinical outcome of hepatitis C infection vary with the infecting hepatitis C virus type? J Viral Hepatol 2007;14:213–220
Nousbaum JB, Pol S, Nalpas B, et al. Hepatitis C virus type 1b (II) infection in France and Italy. Collaborative Study Group. Ann Intern Med 1995;122:161–168
Hatzakis A, Katsoulidou A, Kaklamani E, et al. Hepatitis C virus 1b is the dominant genotype in HCV-related carcinogenesis: a case-control study. Int J Cancer 1996;68:51–53
Mihm S, Fayyazi A, Hartmann H, et al. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 1997;25:735–739
Kamal S, Nasser I. Hepatitis C genotype 4: what we know and what we don’t yet know. Hepatology 2008;47:1371–1383
Antaki N, Craxi A, Kamal SM, et al. The neglected hepatitis C virus genotype 4, 5 and 6: an international consensus report. Liver Int 2010;30:342–355
Kamal SM, Turner B, He Q, et al. Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum marker of fibrosis. Hepatology 2006;43:771–779
Seto WK, Lai CL, Fung J, et al. Natural history of chronic hepatitis C: genotype 1 versus genotype 6. J Hepatol 2010;53(3):444–448
Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334–1337
Lambrecht RW, Sterling RK, Naishadham D, et al. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 2011;140:1490–1500
Di Bisceglie AM, Thompson J, Smith-Wilkaitis N, et al. Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon. Hepatology 2001;33:704–707
Shakil AO, Conry-Cantilena C, Alter HJ, et al. Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group. Ann Intern Med 1995;123:330–337
Kuzushita N, Hayashi N, Katayama K, et al. Increased frequency of HLA DR13 in hepatitis C virus carriers with persistently normal ALT levels. J Med Virol 1996;48:1–7
Silini E, Bono F, Cividini A, et al. Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities. Hepatology 1995;21:285–290
Prati D, Capelli C, Zanella A, et al. Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection. Gastroenterology 1996;110:178–183
Alberti A, Noventa F, Benvegnù L, et al. Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection. Ann Intern Med 2002;137:961–964
Shindo M, Arai K, Sokawa Y, et al. The virological and histological states of anti-hepatitis C virus-positive subjects with normal liver biochemical values. Hepatology 1995;22:418–425
Shiffman ML, Diago M, Tran A, et al. Chronic hepatitis C in patients with persistently normal alanine transaminase levels. Clin Gastroenterol Hepatol 2006;4:645–652
Tarao K, Takemiya S, Tamai S, et al. Relationship between the recurrence of hepatocellular carcinoma (HCC) and serum alanine aminotransferase levels in hepatectomized patients with hepatitis C virus-associated cirrhosis and HCC. Cancer 1997;79(4):688–694
Ghany MG, Lok AS, Everhart JE, et al. Predicting clinical and histologic outcomes based on standard laboratory tests in advanced chronic hepatitis C. Gastroenterology 2010;138:136–146
Bonis PA, Tong MJ, Blatt LM, et al. A predictive model for the development of hepatocellular carcinoma, liver failure, or liver transplantation for patients presenting to clinic with chronic hepatitis C. Am J Gastroenterol 1999;94:1605–1612
Khan MH, Farrell GC, Byth K, et al. Which patients with hepatitis C develop liver complications? Hepatology 2000;31:513–520
Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132(7):517–524
Yoshida H, Arakawa Y, Sata M, et al. Interferon therapy prolonged life expectancy among chronic hepatitis C patients. Gastroenterology 2002;123(2):483–491
Yoshida H, Tateishi R, Arakawa Y, et al. Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C. Gut 2004;53(3):425–430
Camm`a C, Di Bona D, Schepis F, et al. Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: a meta-analysis of individual patient data. Hepatology 2004;39(2):333–342
Everson GT, Balart L, Lee SS, et al. Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis. Alimentary Pharmacol Ther 2008;27(7):542–551
Okanoue T, Itoh Y, Kirishima T, et al. Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma for five years and improves the long-term survival of chronic hepatitis C patients. Hepatol Res 2002;23:62–77
Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med 1999;131(3):174–181
Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142(2):105–114
Cardoso AC, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with advanced fibrosis. J Hepatol 2010;52(5):652–657
Singal AK, Singh A, Jaganmohan S, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol 2010;8(2):192–199
Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child–Pugh class A hepatitis C virus induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010;51(6):2069–2076
Kasahara A, Tanaka H, Okanoue T, et al. Interferon treatment improves survival in chronic hepatitis C patients showing biochemical as well as virological responses by preventing liver-related death. J Viral Hepatol 2004;11(2):148–156
Deuffic-Burban S, Deltenre P, Louvet A, et al. Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France. J Hepatol 2008;49(2):175–183
Wright M, Goldin R, Fabre A, et al. Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross-sectional and longitudinal study. Gut 2003;52:574–579
Kim WR, Poterucha JJ, Benson JT, et al. The impact of competing risks on the observed rate of chronic hepatitis C progression. Gastroenterology 2004;127:749–755
Poynard T, Ratziu V, Kim N, et al. Age and gender will survive to competing risks as fibrosis factors. Gastroenterology 2005;128:519–520
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sarin, S.K., Kumar, M. Natural history of HCV infection. Hepatol Int 6, 684–695 (2012). https://doi.org/10.1007/s12072-012-9355-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12072-012-9355-6