The Influence of Host Factors on the Outcome of HCV Infections

Key Learning Objectives

At the end of the session, the participants will be able to:

  • identify those host factors that influence HCV progression
  • consider the mechanisms whereby host factors can be modulated to beneficially alter the course of HCV
  • apply the presence or absence of certain host factors to decisions regarding whether to initiate and/or maintain anti-viral therapy
  • apply the presence or absence of certain host factors to counseling patients regarding their chronic HCV infections
  • use host factors to provide insights regarding the pathogenesis of HCV progression.

Abstract

The progression of any form of chronic viral hepatitis to cirrhosis is thought to depend on a combination of the virulence of the virus and so-called “host factors” that determine the threshold for hepatocyte injury and response to that injury. The viral levels of HCV in the liver do not correlate with histologic findings suggests that host factors may play a more important role in determining the rate of progression to cirrhosis. Host factors themselves can be divided into two broad categories; intrinsic and extrinsic. Of the former, the results of the largest clinical studies carried out to date suggest that age at the time of infection (beyond the age of 50 years), gender (males) and the immune competence of the host (immune-compromised) are the most important predictor variables of more rapid progression to cirrhosis. Of the extrinsic factors, alcohol has emerged as the most important and consistent determinant of progression to cirrhosis.

It should be noted, however, that the role, if any, of light or “social” alcohol consumption in HCV progression has yet to be determined. Although some data exist to implicate the presence or absence of other host factors (both intrinsic and extrinsic) such as HLA phenotypes, hemophilia, diabetes, hemochromatosis, smoking, environmental and geographic factors, for the most part, these data are limited or have been associated with conflicting reports. With the more established predictor variables in mind (age, gender, immune status and alcohol), it might be of therapeutic benefit to consider whether one specific component of the progressive process might serve as the target for non-antiviral therapy, particularly in individuals who fail to respond to antiviral agents.

For example, if older age, male gender, an immune-compromised state, and alcohol consumption all have a negative impact on the hepatic regenerative activity then theoretically, agents that enhance hepatic regeneration might be useful in preventing the progression of HCV infections to cirrhosis. On the other hand, if none of these factors have an adverse effect on hepatic regenerative activity then presumably, enhancing hepatic regeneration is unlikely to be of benefit in this condition. The same considerations would apply to the effects of host factors on hepatocyte necrosis and hepatic fibrinogenesis. These and other aspects of the host response to HCV will be discussed in detail.

Gerald Minuk, MD

Suggested Reading

  1. Romeo R, Colombo M, Rumi M, Soffredini R, Del Ninno E, Donato MF, et al. Lack of association between type of hepatitis C virus, serum load and severity of liver disease. J Viral Hepat 1996;3:183-90.
  2. McGuiness PH, Bishop GA, Painter DM, Chan R, McCaughan GW. Intrahepatic hepatitis C RNA levels do not correlate with degree of liver injury in patients with chronic hepatitis C. Hepatology 1996;23:676-87.
  3. Roudot-Thoraval F, Bastie A, Pawlotsky JM, Dhumeaux D and the Study Group for the Prevalence and the Epidemiology of Hepatitis C Virus. Epidemiological factors affecting the severity of hepatitis C virus-related liver disease: A French survey of 6,664 patients. Hepatology 1997;26:485-90.
  4. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR and DOSVIRC groups. Lancet 1997;349:825-32.
  5. Tong MJ, El-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-66.
  6. Crowe J, Doyle C, Fielding HF, Holloway H, Keegan M, Kelleher D, et al. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation (abstract). Gastroenterol 1995;108:1054A.
  7. Power JP, Lawlor E, Davidson F, Yap L, Kenny-Walsh E, Whelton MJ, et al. Hepatitis C viraemia in recipients of Irish intravenous anti-D immunoglobulin (Letter). Lancet 1994;344:1166-7.
  8. Dittmann S, Roggendorf M, Durkop J, Wiese M, Lorbeer B, Deinhardt F. Long-term persistence of hepatitis C virus antibodies in a single source outbreak. J Hepatol 1991;13:323-7.
  9. Yamakawa Y, Sata M, Suzuki H, Noguchi S, Tanikawa K. Higher elimination rate of hepatitis C virus among women. J Viral Hepat 1996;3:317-21.
  10. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology 1997;26(suppl 1):15S-20S.
  11. Cramp ME, Carucci P, Underhill J, Naoumov NV, Williams R, Donaldson PT. Association between HLA class II genotype and spontaneous clearance of hepatitis C viraemia. J Hepatol 1998;29:207-13.
  12. Preston FE, Jarvis LM, Markis M, Phillip L, Underwood JCE, Ludlam CA, et al. Heterogeneity of hepatitis C virus genotypes in hemophilia: relationship with chronic liver disease. Blood 1995;85:1259-62.
  13. Aledort LM, Levin PH, Hilgartner M, Blatt P, Spero JA, Goldberg GD, et al. A study of liver biopsies and liver disease among hemophiliacs. Blood 1985;66:367-73.
  14. Bianchi L, Desmet VJ, Popper H, Scheuer PJ, Aledort LM, Berk PD. Histologic patterns of liver disease in hemophiliacs, with special reference to morphologic characteristics of non-A, non-B hepatitis. Semin Liv Dis 1987;7:203-9.
  15. Assy N, Pettigrew NM, Lee SS, Chaudhary RK, Johnston J, Baruch Y, et al. Are chronic hepatitis C viral infections more benign in patients with hemophilia? Hepatology 1996;24:379A.
  16. Simo R, Hernandez C, Genesca J, Jardi R, Mesa J. High prevalence of hepatitis C virus infection in diabetic patients. Diabetes Care 1996;19:998-1000.
  17. Bonkovsky HL. Therapy of hepatitis C: other options. Hepatology 1997;26(suppl 1):143S-51S.
  18. Bonkovsky HL, Banner BF, Rothman AI. Iron and chronic viral hepatitis. Hepatology 1997;25:759-68.
  19. Arber N, Konikoff FM, Moshkowitz M, Baratz M, Hallak A, Santo M, et al. Increased serum iron and iron saturation without liver iron accumulation distinguish chronic hepatitis C from other chronic liver diseases. Dig Dis Sci 1994;39:2656-9.
  20. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffer LJ, Parker TI, Radick JL, et al. Hepatic iron concentration as a predictor of response to alpha interferon therapy in chronic HCV. Gastroenterol 1995;108:1104-9.
  21. Smith BC, Gorve J, Guzail MA, Day CP, Daly AK, Burt AD, et al. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 1998;27:1695-9.
  22. Seeff LB. Natural history of hepatitis C. Hepatology 1997;26(suppl 1):21S-8S.
  23. Serfaty L, Chazouilleres O, Poujol-Robert A, Morand-Joubert L, Dubois C, Chretien Y, et al. Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study. Hepatology 1997;26:776-9.
  24. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol in the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805-9.
  25. Sachithanandan S, Kay E, Leader M, Fielding JF. The effect of light drinking on HCV liver disease: the jury is still out. Biomed Pharmacother 1997;51:295-7.
  26. Chiba T, Matsuzaki Y, Abei M, Shoda J, Tanaka N, Osuga T, et al. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996;91:1195-1203.
  27. Benvegnu L, Fattovich G, Noventa F, Tremolada F, Chemello L, Cecchetto A, et al. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 1994;74:2442-8.
  28. Shiratori Y, Shiina S, Zhang PY, Ohno E, Okudaira T, Payawal DA, et al. Does dual infection by hepatitis B and C viruses play an important role in the pathogenesis of hepatocellular carcinoma in Japan? Cancer 1997;80:2060-7.
  29. Weltman MD, Brotodihardjo A, Crewe EB, Farrell GC, Bilous M, Grierson JM, et al. Coinfection with hepatitis B and C or B, C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment. J Viral Hepat 1995;2:39-45.
  30. Fong TL, Di Bisceglie AM, Waggoner JG, Banks SM, Hoofnagle JH. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B. Hepatology 1991;14:64-7.
  31. Chiba T, Matsuzaki Y, Abei M, Shoda J, Tanaka N, Osaga T, et al. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 1996;91:119-203.
  32. Rockstroh JK, Woitas RP, Spengler U. Human immunodeficiency virus and hepatitis C virus coinfection. Eur J Med Res 1998;3:269-77.
  33. Thomas DL, Shih JW, Alter HJ, Vlahov D, Cohn S, Hoover DR, et al. Effect of human immuno-deficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 1996;174:690-5.
  34. Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo JA, Garcia-Bengoechea M, Hernandez-Quero J, Rey C, Abad MA, Rodriguez M, Sales Gilabert M, Gonzalez F, Miron P, Caruz A, Relimpio F, Torronterasa R, Leal M, Lissen E. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 1997;26:1-5.
  35. Pol S, Lamorthe B, Thi NT, Thiers V, Carnot F, Zylberberg H, et al. Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users.
  36. Maddrey WC. Isoniazid-induced liver disease. Sem Liv Dis 1981;1:129-33.
  37. Patel T, Roberts LR, Jones BA, Gores GJ. Dysregulation of apoptosis as a mechanism of liver disease: an overview. Sem Liv Dis 1998;18:105-14.
  38. Bucher NL. Regeneration of Mammalian Liver. Eds. GH Bourne, JF Danielli. Review of Cytology 1963;15:246-97.
  39. Van Thiel DH, Stauber R, Gavaler JS, Francavilla A. Hepatic Regeneration: Effects of age, sex, hormone status, prolactin and cyclosporine. Dig Dis Sci 1991;36:1309-12.
  40. Van Thiel DH, Stauber R, Gavalier JS, Francavilla A. Hepatic Regneration: Effects of age, sex, hormone status, prolactin and cyclosporine. Dig Dis Sci 1991;36:1309-12.
  41. DuBois DB, Gretch D, dela Rosa C, Lee W, Fine J, Blagg CR, et al. Quantitation of hepatitis C viral RNA in sera of hemodialysis patients: gender-related differences in viral load. Am J Kidney Dis 1994;24:795-801.
  42. Sarich TC, Adams SP, Zhou T, Wright JM. Isoniazid-induced hepatic necrosis and steatosis in rabbits: absence of effect of gender. Can J Physiol Pharmacol 1997; 75:1108-11.
  43. Gong Y, Zhang M, Minuk GY. Regulation of transforming growth factor beta1 gene expression and cell proliferation in human hepatocellular carcinoma cells (PLC/PRF/5) by tamoxifen. J Hepatology 1998 (submitted).
  44. Sporn MB, Roberts AB. Transforming growth factor-B. Multiple actions and potential clinical applications. JAMA 1989;262:938-41.
  45. Pessione E, Degos F, Marcellin P, Duchatelle V, Njapoum C, Martinot-Peignoux M, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology 1998;27:1717-22.
  46. Haydon GH, Jarvis LM, Blair CS, Simmonds P, Harrison DJ, Simpson KJ, et al. Clinical significance of intrahepatic hepatitis C virus levels in patients with chronic HCV infection. Gut 1998;42:570-75.
  47. Corrao G, Arico S. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology 1998;27:914-9.
  48. Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998;27:1730-5.
  49. Cooksley WGE. Chronic liver disease: do alcohol and hepatitis C virus interact? J Gastro Hepat 1996;11:187-92.
  50. Diehl AM, Chacon M, Wagner P. The effect of chronic ethanol feeding on ornithine decarboxylase activity and liver regeneration. Hepatology 1988;8:237-42.
  51. Duguay L, Coutu D, Hetu C, Joly JG. Inhibition of liver regeneration by chronic alcohol administration. Gut 1982;23:8-13.
  52. Popper H, Lieber CS. Histogenesis of alcoholic fibrosis and cirrhosis in the baboon. Am J Pathol 1980;98:695-716.
  53. Mezey E, Potter JJ, Slusser RJ, et al. Changes in hepatic collagen metabolism in rats produced by chronic ethanol feeding. Lab Invest 1977;36:206-14.

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