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Gary DAVIS

Gary DAVIS. Alcohol in Chronic Hepatitis C:. Legal. or Prohibited ?. Gary L. Davis, M.D. Baylor University Medical Center Dallas, Texas USA. Questions. Is this really an issue? How many chronic hepatitis C patients used, use or abuse alcohol? Does alcohol impact the liver disease?

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Gary DAVIS

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  1. Gary DAVIS

  2. Alcohol in Chronic Hepatitis C: Legal or Prohibited ? Gary L. Davis, M.D. Baylor University Medical Center Dallas, Texas USA

  3. Questions • Is this really an issue? • How many chronic hepatitis C patients used, use or abuse alcohol? • Does alcohol impact the liver disease? • Does alcohol impair treatment outcome? • If alcohol is really a problem, then how much is too much?

  4. Background • 1.5-2% of US and Western Europeans are chronically infected with HCV • ~60% of the population use alcohol regularly1 • 5-7% in US are heavy or dependent alcohol users1(>2 drinks/day for men, >1 drink/day for women) 1Alcohol Epid Data System, NIAAA.

  5. ? Background • Of patients with chronic hepatitis C: • 60% have a history of prior heavy alcohol use1 • 28-37% continue use after diagnosis2 • Of patients with alcoholic liver disease: • 14-50% have HCV infection3 Jamal MM, et al. Dig Dis 2005; 23:285. Cambell JV, et al. Drug Alcohol Depend 2006; 81:259. Safdar K, Schiff ER. Sem Liver Dis 2004; 24:305.

  6. Impact of Alcohol on Liver Disease • 30-70% of deaths in patients with chronic hepatitis C have a history of heavy alcohol use1 • Alcohol is an independent risk factor of hepatic death in HCV patients (OR 1.4)2 • Rise in alcohol-related cirrhosis deaths in UK in 1990s was attributed to HCV3 • In advanced alcoholic liver disease, anti-HCV+ has less influence on survival than continued alcohol use, CTP score, or alcoholic hepatitis4 Harris H, et al. Epidemiol Infect 2006; 134:472.; Kobayashi M, et al. J Med Virol 2006; 78:459.; Henry J, et al. J Clin Pathol 2002; 55:704.; Pessione F, et al. Liver Int 2003; 23:45.

  7. If HCV infection results in higher liver-related mortality, then it must result in more progressive liver injury

  8. Impact of Alcohol on Liver Disease • Heavy alcohol intake in patients with chronic hepatitis C is associated with: • more severe periportal inflammation1 • more rapid progression of fibrosis2 • higher incidence of cirrhosis2 • greater risk of decompensation3,4 Hezode C, et al. Aliment Pharmacol Ther 2003; 17:1031. Wiley TE, et al. Hepatology 1998; 28:805. Delarocque-Astagneau E, Ann Epidemiol 2005; 15:551. Niederau C, et al. Hepatology 1998; 28:1687.

  9. Association of Alcohol with Fibrosis Progression in HCV Pts MontoA, et al. Hepatology 2004; 39:826.

  10. Association of Alcohol with Fibrosis Progression in HCV Pts MontoA, et al. Hepatology2004; 39:826.

  11. Impact of Alcohol on Liver Disease • Heavy alcohol intake in patients with chronic hepatitis C is associated with: • more severe periportal inflammation1 • more rapid progression of fibrosis2 • higher incidence of cirrhosis2 • greater risk of decompensation3,4 Hezode C, et al. Aliment Pharmacol Ther 2003; 17:1031. Wiley TE, et al. Hepatology 1998; 28:805. Delarocque-Astagneau E, Ann Epidemiol 2005; 15:551. Niederau C, et al. Hepatology 1998; 28:1687.

  12. Impact of Alcohol on Liver Disease • Heavy alcohol use increases risk of cirrhosis 2 to 150 fold1-3 Roudot-Thoraval F, et al. Hepatology 1997; 26:485.; Corrao G, et al. Hepatology 1998; 27:914.; Stroffllini T, et al. J Viral Hepat 2006; 13:351.

  13. Impact of Alcohol and HCV on Risk of Cirrhosis Corrao G, Arico S. Hepatology 1998; 27:914

  14. Impact of Alcohol on Liver Disease • Heavy alcohol use increases risk of cirrhosis 2 to 150 fold1-3 • Only duration of HCV infection has a greater influence on progression4 • Concurrent or past alcohol use explains most of the increased mortality in HIV-HCV coinfection5 and perhaps fibrosis in the obese6 Roudot-Thoraval F, et al. Hepatology 1997; 26:485.; Corrao G, et al. Hepatology 1998; 27:914.; Stroffllini T, et al. J Viral Hepat 2006; 13:351. Poynard T, et al. J Hepatol 2001; 34:730.; Salmon-Ceron D, et al. J Hepatol 2005; 42:799.; Ruhl CE, et al. Clin Gastroenterol Hepatol 2005; 3:1260.

  15. Impact of Alcohol on HCC Risk • HCV infection is the most common cause of hepatocellular carcinoma in the US – Europe • Risk of HCC is higher with concurrent HCV infection and alcohol use1-2 • Donato: Relative risk for HCC3 • Alcohol = 5; HCV = 30; HCV + alcohol = 66 Simonetti RG, et al. Ann Intern Med 1992; 116:97. Ikeda K, et al. J Hepatol 1998; 28:930. Donato F, et al. Cancer Causes Control 1999; 10:417.

  16. Impact of Alcohol on HCC Risk Reference Donato F, et al. Hepatology 1997; 26:579.

  17. Impact of Alcohol on HCC Risk • HCC occurs earlier in heavy drinkers1 • Niederau: HCV duration and cirrhosis, not alcohol, are the major risk factors for HCC2 Whether alcohol has a direct carcinogenic effect or contributes by simply enhancing progression to cirrhosis is not known Noda K, et al. Alcohol Clin Exp Res 1996; 20(1 Suppl):95A. Niederau C, et al. Hepatology 1998; 28:1687.

  18. Alcohol and Interferon Response • Difficult to assess since most studies have excluded significant alcohol and it is a common reason not to treat1 • Most studies find that alcohol decreases response to interferon-based therapy2-4 and this effect is alcohol dose-dependent2-3 Nguyen HA, et al. Am J Gastroenterol 2002; 97:1813.; Chang A, et al. Pharmacol Ther 2005; 22:701.; Tabone M, et al. J Viral Hepat 2002; 9:288.; Okazaki T, et al. Scand J Gastroenterol 1994; 29:1039-1043.

  19. Alcohol and Interferon Response • Odd’s ratio of sustained viral response: ORTreatmentComparison • Anand 1.5 IFN/Riba 0 vs any alcohol • Chang 3.0 Peg/Riba 0-29 vs >30 g/d • Tabone 1.7, 3.7 IFN 0 vs mild vs heavy (all w/ >6m abstinence)

  20. Alcohol and Interferon Response • Poor treatment response largely related to early treatment discontinuation (~40%)1-2 • When full course is completed, SVR is similar regardless of alcohol intake1 Anand BS, et al. Gastroenterology 2006;130:1607. Cheung RC, et al. Am J Gastroenterol 2005; 100:2186.

  21. Mechanism of Interaction Between Alcohol and HCV • Effects of immune function • Oxidative stress and lipid peroxidation

  22. Mechanism of Interaction Between Alcohol and HCV • Alcohol effects on immune function • Global effects on innate and adaptive responses • Depresses dendritic cell function • Increased IL-10 expression • Impaired proliferation of CD4 and CD8 cells • Reduced production of endogenous interferons and interferon-stimulated genes (ISGs)

  23. HCV Replication and Inflammation + - Alcohol Impairs Adaptive Immune Function IL-10 Cellular Immune Response Hepatocyte

  24. Alcohol Inhibits Endogenous IFN and ISG Production NFκβ-dependent inhibition NFκβ-dependent inhibition Type 1 IFN

  25. Mechanism of Interaction Between Alcohol and HCV • Additive induction of lipid peroxidation in mice by chronic ethanol and HCV core expression Perlemuter G, et al. J Hepatol 2003; 39:1020.

  26. <0.05 <0.05 <0.01 Mechanism of Interaction Between Alcohol and HCV • Oxidative stress and liver injury increases proportional to alcohol intake in HCV patients **, # *, # ** * # # AAHP-HAS = Ig aby to HAS-bound arachadonic acid hydroperoxide Ox-Cl = oxidized cardiolipin; Moderate EtOH <50 g/d, heavy EtOH >50 g/d * = p<0.01 vs controls, ** = p<0.05 vs controls, # = p<0.01 vs HCV/no EtOH; Rigaminti C, et al. Hepatology 2003; 38:42.

  27. Summary Regarding the effect of alcohol in patients with chronic hepatitis C: • 10/10 studies show a detrimental effect on inflammation, fibrosis progression, cirrhosis, and decompensation • 9/10 articles suggest alcohol facilitates development of hepatocellular carcinoma • 2/3 studies demonstrate increased HCV RNA • 4/4 articles show impaired response to interferon-based antiviral therapy

  28. Conclusions • Alcohol abuse should be discouraged on its own merits, regardless of whether liver disease is present • Studies are variable in design, definitions of alcohol use and abuse, and power • Detrimental effects of alcohol are dose-dependent with greatest impact at >20-50 g/d • However, deleterious effects are even present at daily intake less than 20 gm/day

  29. Clinical Recommendations:How Much is Too Much? • The data, limited as it is, does not support any safe level of daily alcohol consumption in patients with chronic hepatitis C • The effects of sporadic and limited alcohol use have not been carefully studied • The prudent recommendation to patients is to avoid alcohol consumption altogether

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