Digestive and Liver Disease
Volume 41, Issue 1 , Pages 67-70, January 2009

Alcohol and viral hepatitis: A mini-review

  • S. Gitto

      Affiliations

    • Department of Medicine, University of Bologna, Italy
    • Internal Medicine Unit, Saint’Orsola-Malpighi Hospital, Bologna, Italy
    • ,
  • L. Micco

      Affiliations

    • Department of Medicine, University of Bologna, Italy
    • Internal Medicine Unit, Saint’Orsola-Malpighi Hospital, Bologna, Italy
    • ,
  • F. Conti

      Affiliations

    • Department of Medicine, University of Bologna, Italy
    • Internal Medicine Unit, Saint’Orsola-Malpighi Hospital, Bologna, Italy
    • ,
  • P. Andreone

      Affiliations

    • Department of Medicine, University of Bologna, Italy
    • Internal Medicine Unit, Saint’Orsola-Malpighi Hospital, Bologna, Italy
    • Corresponding Author InformationCorresponding author at: Dipartimento di Medicina Clinica, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. Tel.: +39 051 6363618; fax: +39 051 345806.
    • ,
  • M. Bernardi

      Affiliations

    • Department of Medicine, University of Bologna, Italy
    • Internal Medicine Unit, Saint’Orsola-Malpighi Hospital, Bologna, Italy

Received 3 April 2008; accepted 5 May 2008. published online 04 July 2008.

Article Outline

Abstract 

Due to their high prevalence in the general population, alcohol use and abuse can be associated with hepatitis B and C virus infections and it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver disease. There is evidence that alcohol abuse accelerates the progression of liver fibrosis and affects the survival of patients with chronic hepatitis C. The mechanism by which alcohol worsens hepatitis C virus-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response could play a relevant role. Alcohol abuse also seems to reduce both sensitivity to interferon and adherence to treatment. It sounds reasonable to presume that the mechanisms enhancing liver damage in patients affected by hepatitis B are similar to those involved in hepatitis C virus infection. However, more studies are warranted to improve our knowledge about the interaction between alcohol intake and hepatitis B virus infection. In conclusion alcohol abuse is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of hepatocellular carcinoma, and higher mortality. Abstinence could reverse some of these deleterious effects.

Keywords: Alcohol, Chronic hepatitis, Cirrhosis, Hepatitis B, Hepatitis C

 

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1. Introduction 

Alcohol abuse is an important problem for the public health, with a significant morbidity and mortality [1]. Hepatitis B (HBV) and C (HCV) viruses are the two most frequent causes of chronic hepatitis worldwide, and lead to most cases of end-stage liver disease and hepatocellular carcinoma (HCC) [2], [3]. Due to their high prevalence in the general population, alcohol use and abuse are often associated with hepatitis virus infections, and, in these cases, it has been demonstrated that alcohol plays a role as a co-morbid factor in the development of liver damage and disease progression [1].

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2. Alcohol and chronic hepatitis C 

Most subjects (>75%) exposed to HCV develop chronic infection [4]. The severity of HCV-related liver disease is variable; in most cases, however, the disease either runs an indolent course or only leads to a significant liver damage as a late event [5]. In chronic alcoholics, the prevalence of anti-HCV antibody positivity is higher than in the general population [6]. Chronic alcohol consumption is frequently associated to intravenous drug use, which is the main risk factor for HCV infection [7]. Moreover, studies assessing the prevalence of HCV infection in hospitalized patients, demonstrated an independent association between alcohol abuse and anti-HCV seropositivity, irrespective of serum HCV-RNA positivity [8]. There is strong evidence that alcohol abuse not only accelerates the progression of liver fibrosis, but even affects the survival of patients with chronic hepatitis C. Namely, the fibrosis progression rate with a daily alcohol intake exceeding 50g increased by 34% with respect to no drinkers [9] and alcohol abuse predicted fibrosis progression [5] and decompensation [10]. Moreover, excessive alcohol consumption is associated with an increased rate of liver-related deaths [11], [12], [13] and death occurring at an earlier age [14].

The mechanism by which alcohol worsens HCV-related liver disease has not been fully clarified, but enhanced viral replication, increased oxidative stress, cytotoxicity and impairment of immune response have been proposed.

In an experimental replicon system, alcohol metabolites potentiated the expression of viral proteins [15]. However, when the influence of alcohol on HCV replication was evaluated in patients, divergent results emerged [9], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27]. In fact, serum HCV-RNA levels in alcoholics were either increased [9], [18], [22], [26] or comparable with respect to those found in abstinent patients [16], [19], [20], [21], [25], [27]. Likewise, either no effect [24] or a decrease in viral load [19], [20] followed abstinence by patients with previous alcohol consumption. A recent meta-analysis [28] suggested that such variable results were amenable to differences in the definition of amount of alcohol consumption, duration of alcohol intake, presence or absence of active drinking at the time of evaluation, and duration of abstinence prior the assessment. The conclusion was that available data do not support an effect of alcohol consumption on serum HCV-RNA levels. Thus a controlled prospective study was deemed necessary to assess the effect of alcohol on viral replication in a conclusive way [28].

Both HCV and alcohol stimulate hepatic oxidative stress and their combined action may boost the liver fibrogenic cell activation, with consequent acceleration of fibrogenesis [29]. Perlemuter et al. demonstrated that chronic alcohol administration to HCV core transgenic mice led to additive hepatic lipid peroxidation, synergistic induction of the pro-fibrogenetic cytokine TGF-β1, and activation of hepatic stellate cells [30]. Coherently, an even moderate alcohol consumption stimulated oxidative stress, suggesting a role for alcohol-induced oxidative damage in the worsening of chronic hepatitis C evolution [31].Immune response is definitely affected by alcohol [32]. Experimental data suggest that the alcohol-induced impairment of immunity may account for the high rate of viral infection chronicization in alcohol abusers [33]. Moreover, mice chronically exposed to ethanol showed a reduced cellular immune response to HCV core and non-structural proteins. This alteration led to impaired dendritic cells maturation, and a tendency to generate a Th2-immune response [32].Other mechanisms likely play a role in enhancing liver injury in alcoholic patients infected by HCV. Namely, steatosis, which is known to enhance the liver metabolic stress [34], is a feature of both alcoholic liver disease and chronic hepatitis C. Iron is another known hepatotoxic agent, and its overload is often present in alcohol abusers [35], [36]. At last, there is evidence suggesting that alcohol promotes apoptosis in infected hepatocytes [37].

Alcohol abuse also seems to affect the treatment outcome of chronic hepatitis C, as reduces the response to interferon [38], a finding that likely results through different mechanisms, involving both sensitivity to interferon and adherence to treatment. It has been proposed that alcohol acts synergistically with HCV core protein and oxidative stress in inhibiting the cellular response to interferon though an interference with the JAK-STAT signalling pathway [39]. On the other hand, while adherence to treatment and rates of sustained virological response were similar in non-drinkers and past alcohol users, patients with a short-term abstinence, more frequently discontinued treatment and had a reduced rate of sustained virological response [40]. Subgroup analysis, excluding patients with early dropout, indicated that the rate of sustained virological response was not impaired in alcohol users able to complete the full course of treatment [40]. These results strongly suggest that alcohol intake primarily acts by decreasing patient compliance, while a reduced sensitivity to interferon likely plays a minor role.

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3. Alcohol and chronic hepatitis B 

HBV infection affects more than 360 millions people worldwide, representing the first cause of chronic liver disease [41]. The effects of alcohol intake in chronic hepatitis B are less clear than in chronic hepatitis C. In the transgenic mice model, viral replication is enhanced by alcohol consumption [42], suggesting that alcohol up-regulates HBV gene expression and replication. This would promote not only higher viral loads, but also trigger an antiviral immune response leading to severe bouts of liver disease.

In the clinical ground, the effects of alcohol on the progression of fibrosis in chronic hepatitis B have not been examined in detail, but current evidence suggests that high alcohol intake by HBsAg positive patients is associated with an increase in liver necroinflammatory changes [43] and a greater alteration of liver tests [44]. Moreover, alcohol abuse in patients with chronic hepatitis B is associated with increased risk of cirrhosis and HCC [42], [45]. At last, Marcellin et al. found a strong association between alcohol consumption and mortality in these patients [14].

As a whole, even though a lower amount of data on the effects of alcohol consumption in HBV infected patients is available, it sounds reasonable to presume that the mechanisms enhancing liver damage are similar to those involved in HCV infection, such as enhanced oxidative stress, faint immune response, and activation of pro-inflammatory cytokine pathways. It is also likely that alcohol abuse impairs the response to therapy in chronic hepatitis B, as it does in patients with chronic hepatitis C. However, more experimental and clinical studies are warranted to improve our knowledge on the consequences of the interaction between alcohol intake and HBV infection (Table 1).

Table 1. Mechanisms by which alcohol worsens virus induced liver disease
MechanismHCVHBV
Enhanced viral replicationDebated [9], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]Demonstrated [42]
Increased oxidative stressDemonstrated [29], [30], [31]Not demonstrated
Impaired immune responseDemonstrated [32], [33]Not demonstrated
Induction of steatosisDemonstrated [34]Not demonstrated
Hepatocyte apoptosisDemonstrated [37]Not demonstrated
Iron overloadDemonstrated [35], [36]Not demonstrated
Decreased antiviral therapy responseDemonstrated [38], [39], [40]Not demonstrated

Numbers of corresponding references are reported in square brackets.

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4. Conclusions 

Alcohol abuse has a strong negative influence on the fate of patients with viral chronic hepatitis, as it is associated with an accelerated progression of liver injury, leading to an earlier development of cirrhosis, higher incidence of HCC, and higher mortality. Alcohol abuse also impairs the response to interferon treatment. Abstinence may reverse some of these deleterious effects, and may improve the response to antiviral treatment.

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Practice points 


•Alcohol plays a role as a co-morbid factor in the development of virus induced liver disease.

•Alcohol accelerates the progression of hepatitis C liver disease through mechanisms such as increased oxidative stress, cytotoxicity, impairment of immune system and reduction of response to anti-viral treatment.

•The mechanisms of alcohol damage in hepatitis B seem to be similar to those involved in hepatitis C.

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Research agenda 


•Controlled prospective studies are necessary to assess the effect of alcohol on HCV replication.

•Experimental and clinical studies would be useful to better understand the interaction between alcohol and hepatitis B.

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Conflict of interest statement 

None declared.

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References 

  1. Gramenzi A, Caputo F, Biselli M, Kuria F, Loggi E, Andreone P, et al. Alcoholic liver disease – pathophysiological aspects and risk factors. Aliment Pharmacol Ther. 2006;24:1151–1161
  2. Weisberg IS, Brown RS, Sigal SH. Hepatitis B and end-stage liver disease. Clin Liv Dis. 2007;11:893–916
  3. Feld JJ, Liang TJ. Hepatitis C: identifying patients with progressive liver injury. Hepatology. 2006;43:5194–5206
  4. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GN, Gao F, Moyer LA, et al. The prevalence of hepatitis C in the United States, 1988 through 1994. N Engl J Med. 1999;341:556–562
  5. Zarski JP, Mc Hutchison J, Bronowicki JP, Sturm N, Garcia-Kennedy R, Hodaj E, et al. Rate of natural disease progression in patients with chronic hepatitis C. J Hepatol. 2003;38:307–314
  6. Takase S, Takada N, Sawada M, Tsutsumi M, Takada A. Relationship between alcoholic liver disease and HCV infection. Alcohol Alcohol. 1993;28:77–84
  7. Galperim B, Cheinquer H, Stein A, Fonseca A, Lunge V, Ikuta N. Prevalence of hepatitis C virus in alcoholic patients: role of parenteral risk factors. Arq Gastroenterol. 2006;43:71–72
  8. Austin GE, Jensen B, Leete J, De L’Aune W, Bhatnagar J, Racine M, et al. Prevalence of hepatitis C virus seropositivity among hospitalized US veterans. Am J Med Sci. 2000;319:353–359
  9. Poynard T, Bedossa P, Opolon P The OBSVIRIC, METAVIR, CLINIVIR, and DOSVIRIC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:825–832
  10. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. J Am Med Assoc. 2000;284:450–456
  11. Kim WR, Gross JB, Poterucha JJ, Locke GR, Dickson ER. Outcome of hospital care of liver disease associated with hepatitis C in the United States. Hepatology. 2001;33:201–206
  12. Tsui JI, Pletcher MJ, Vittinghoff E, Seal K, Gonzales R. Hepatitis C and hospital outcomes in patients admitted with alcohol-related problems. J Hepatol. 2006;44:262–266
  13. Harris HE, Ramsay ME, Andrews N, Eldridge KP. Clinical course of hepatitis C virus during the first decade of infection: cohort study. Br Med J. 2002;324:450–453
  14. Marcellin P, Pequignot F, Delarocque-Astagneau E, Zarski JP, Ganne N, Hillon P, et al. Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption. J Hepatol. 2008;48:200–207
  15. Zhang T, Li Y, Lai JP, Douglas SD, Metzger TS, O’Brien CP, et al. Alcohol potentiates hepatitis C virus replicon expression. Hepatology. 2003;38:57–65
  16. Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805–809
  17. Sawada M, Takada A, Takase S, Takada N. Effects of alcohol on the replication of hepatitis C virus. Alcohol Alcohol. 1993;28:85–90
  18. Oshita M, Hayashi N, Kasahara A, Hagiwara H, Mita E, Naito M, et al. Increased serum hepatitis C virus RNA levels among alcoholic patients with hepatitis C. Hepatology. 1994;20:1115–1120
  19. Cromie SL, Jenkins PJ, Bowden DS, Dudley FJ. Chronic hepatitis C: effect of alcohol on hepatic activity and viral titre. J Hepatol. 1996;25:821–826
  20. Sata M, Fukuizumi K, Uchimura Y, Nakano H, Ishii K, Kumashiro R, et al. Hepatitis C virus infection in patients with clinically diagnosed alcoholic liver disease. J Viral Hepatol. 1996;3:143–148
  21. Ohnishi K, Matsuo S, Matsutani K, Itahashi M, Kakihara K, Suzuki K, et al. Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol. 1996;91:1374–1379
  22. Yoshihara H, Noda K, Kamada T. Interrelationship between alcohol intake, hepatitis C, liver cirrhosis, and hepatocellular carcinoma. Recent Dev Alcohol. 1998;14:457–469
  23. Pessione F, 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;27:1717–1722
  24. Anand BS, Velez M. Influence of chronic alcohol abuse on hepatitis C virus replication. Dig Dis. 2000;18:168–171
  25. Khan KN, Yatsuhashi H. Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol Alcohol. 2000;35:286–295
  26. Loguercio C, Di Pierro M, Di Marino MP, Federico A, Disalvo D, Crafa E, et al. Drinking habits of subjects with hepatitis C virus-related chronic liver disease: prevalence and effect on clinical, virological and pathological aspects. Alcohol Alcohol. 2000;35:296–301
  27. Romero-Gòmez M, Grande L, Nogales MC, Fernández M, Chavez M, Castro M. Intrahepatic hepatitis C virus replication is increased in patients with regular alcohol consumption. Dig Liver Dis. 2001;33:698–702
  28. Anand BS, Thornby J. Alcohol has no effect on hepatitis C virus replication: a meta-analysis. Gut. 2005;54:1468–1472
  29. Otani K, Korenaga M, Beard MR, Li K, Qian T, Showalter LA, et al. Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology. 2005;128:96–107
  30. Perlemuter G, Lettéron P, Carnot F, Zavala F, Pessayre D, Nalpas B, et al. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model. J Hepatol. 2003;39:1020–1027
  31. Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F, et al. Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology. 2003;38:42–49
  32. Aloman C, Gehring S, Wintermeyer P, Kuzushita N, Wands JR. Chronic ethanol consumption impairs cellular immune responses against HCV NS5 protein due to dendritic cell dysfunction. Gastroenterology. 2007;132:698–708
  33. Piasecki BA, Lewis JD, Reddy KR, Bellamy SL, Porter SB, Weinrieb RM, et al. Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population. Hepatology. 2004;40:892–899
  34. Farrell GC, Larter CZ. Non alcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–S112
  35. Brittenham GM. Iron chelators and iron toxicity. Alcohol. 2003;30:151–158
  36. Corengia C, Galimberti S, Bovo G, Vergani A, Arosio C, Mariani R, et al. Iron accumulation in chronic hepatitis C: relation of hepatic iron distribution, HFE genotype and disease course. Am J Clin Pathol. 2005;124:846–853
  37. Pianko S, Patella S, Sievert W. Alcohol consumption induces hepatocyte apoptosis in patients with chronic hepatitis C infection. J Gastroenterol Hepatol. 2000;15:798–805
  38. Mochida S, Ohnishi K, Matsuo S, Kakihara K, Fujiwara K. Effect of alcohol intake on the efficacy of interferon therapy in patients with chronic hepatitis C as evaluated by multivariate logistic regression analysis. Alcohol Clin Exp Res. 1996;20:371–377
  39. Di Bona D, Cippitelli M, Fionda C, Cammà C, Licata A, Santoni A, et al. Oxidative stress inhibits IFN-alpha-induced antiviral gene expression by blocking the JAK-STAT pathway. J Hepatol. 2006;45:271–279
  40. Anand BS, Currie S, Dieperink E, Bini EJ, Shen H, Ho SB, et al. VA-HCV-001 Study Group Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenterology. 2006;130:1607–1616
  41. Kondili LA, Tosti ME, Szklo M, Costantino A, Cotichini R, Resuli B, et al. The relationships of chronic hepatitis and cirrhosis to alcohol intake, hepatitis B and C, and delta virus infection: a case-control study in Albania. Epidemiol Infect. 1998;12:391–395
  42. Larkin J, Clayton MM, Liu J, Feitelson MA. Chronic ethanol consumption stimulates hepatitis B virus gene expression and replication in transgenic mice. Hepatology. 2001;34:792–797
  43. Murata T, Takanari H, Watanabe S, Tanaka T, Suzuki S. Enhancement of chronic viral hepatitis changes by alcohol intake in patients with persistent HBs-antigenemia. Am J Clin Pathol. 1990;94:270–273
  44. Nomura H, Kashiwagi S, Hayashi J, Kajiyama W, Ikematsu H, Noguchi A, et al. An epidemiologic study of effects of alcohol in the liver in hepatitis B surface antigen carriers. Am J Epidemiol. 1988;128:277–284
  45. Corrao G, Torchio P, Zambon A, Ferrari P, Aricò S, di Orio F Collaborative Groups for the Study of Liver Diseases in Italy. Exploring the combined action of lifetime alcohol intake and chronic hepatotropic virus infections on the risk of symptomatic liver cirrhosis. Eur J Epidemiol. 1998;14:447–456

PII: S1590-8658(08)00196-5

doi:10.1016/j.dld.2008.05.009

Digestive and Liver Disease
Volume 41, Issue 1 , Pages 67-70, January 2009

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