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Hepatitis C and Alcohol

Introduction

The alcoholic patient is no less subject to the spectrum of hepatobiliary disorders that may afflict the nonalcoholic patient and, in some cases, may be predisposed to liver injury because of specific socioeconomic, epidemiologic, or metabolic risk factors.

Prevalence of Anti-HCV Markers

Multiple studies have clearly demonstrated a high prevalence of anti-HCV among alcoholic patients with liver disease. (1-5) Testing with supplemental assays (e.g., recombinant immunoblot assay [RIBA]) confirmed that 8~5 percent of alcoholic patients with liver disease have anti-HCV (RIBA+). The prevalence of anti-HCV is sevenfold higher among alcoholics than in the population at large (10 percent vs. 1.4 percent), but is even higher in those with liver disease (30 percent). Most of those with liver disease have detectable HCV RNA which may also be present in some anti-HCV(-)patients. Anti-HCV(+)(RIBA+) patients are likely to have HCV RNA detected, which is indicative of active viral infection, usually associated with some degree of necroinflammatory changes, with or without fibrosis, regardless of alanine aminotransferase (ALT) levels.

HCV Correlation With Severity of Liver Injury

The prevalence of anti-HCV(RIBA+) correlates with the severity of liver injury seen in alcoholic patients. Anti-HCV positivity (RIBA+) correlated positively and significantly with cirrhosis, cellular unrest, periportal inflammation, and piecemeal necrosis, in contrast to anti-HBc, which did not correlate with any of these histologic features, in a large Veterans Administration (VA) study. (6) In a study of 144 alcoholic patients, a prevalence of 20 percent anti-HCV positivity in alcoholic fibrosteatosis, 21.4 percent in alcoholic hepatitis, and 42.6 percent in alcoholic cirrhosis, as compared to 2.2 percent in alcoholic patients without liver disease, was noted. (7) Histologic features, with the exception of sinusoidal cellularity, were comparable in alcoholic patients with and without anti-HCV. Nishiguchi et al. performed both immunoblot and HCV RNA determinations among 80 alcoholic patients with liver disease. (8) Patients with cirrhosis and HCV RNA had higher ALT activity than comparable patients without HCV RNA. The HCV RNA(+) patients had higher histologic activity indices (Knodell) than those without detectable HCV RNA. The presence of HCV RNA conferred a more severe degree of periportal and bridging necrosis, intralobular de~eneration, focal necrosis. and Dortal inflammation.

Effect of Abstinence on Alcoholic Patients with Histologic Evidence of Chronic Hepatitis

In HCV RNA(+) alcoholic patients with histologic evidence of chronic hepatitis, abstinence was not followed by resolution of aminotransferase elevation, which has been observed in both anti-HCV(+) HCV RNA(-) and anti-HCV(-), HBsAg(-) alcoholic patients with similar histologic features. (9) This suggests that chronic hepatitis C infection perpetuates the liver damage in these alcoholic patients who have abstained. Nevertheless, serum HCV RNA levels will decrease with abstinence. (10)

Epidemiology of Hepatitis C Among Alcoholic Patients

The epidemiology of hepatitis C among alcoholic patients with bonafide viral C infection has not been definitively characterized. Intravenous drug abuse (IVDA) is the most common risk factor. Yet there has not been a good explanation for the disproportionately high prevalence of HCV among alcoholic patients with liver disease without a history of IVDA. (11) Caldwell et al. found the prevalence of anti-HCV similar among patients with alcoholic liver disease who had high risk factors as compared to those without identifiable modes of parenteral transmission. (12)

Effect of Alcohol on HCV Replication

A critical question is whether or not alcohol and hepatitis C infection are synergistic in a combined liver injury. In some patients, there are both histologic features of alcoholic liver injury and chronic viral hepatitis, but in most studies the predominant pattern is chronic hepatitis. (13) Alcohol may enhance the replication of hepatitis C and produce a more severe injury independent of the direct alcohol-induced toxic injury. There is a correlation between HCV RNA levels and amount of alcohol consumed. (14) Alcoholic patients with HCV infection have higher hepatic iron concentrations, which may be germane to increased HCV replication. (15) Clinical evidence of hepatic activity and viral levels is significantly greater in those consuming greater than 10g of alcohol per day. (16)

Effect of Alcohol on Progression of Chronic Viral C Hepatitis to Cirrhosis and Hepatocellular Carcinoma

There is a more rapid development of cirrhosis and hepatocellular carcinoma in the alcoholic with chronic HCV infection. (17,18) The period from transfusion to the diagnosis of cirrhosis is shorter in the heavy drinker. The risk for the development of hepatocellular carcinoma in alcoholic cirrhotics is 8.3 times higher in the HCV(+) patients than HCV(-) patients, and the prevalence of anti-HCV among alcoholics with HCC is 50-70 percent. (20,21) Therefore, alcohol may modify the replication of HCV as well as the oncogenicity of HCV in hepatocellular carcinoma.

Interferon Therapy in Alcoholic Patients with Chronic Hepatitis C

Among alcoholic patients with chronic hepatitis C who remained abstinent during therapy with interferon, there was a significantly lower rate of HCV RNA clearance in those who consumed more than 70g/day of ethanol as compared to lass than 70g/day drinkers or nondrinkers. (22) A similar experience noted zero HCV RNA clearance in those consuming >70g/day up to the time of interferon therapy. (23)

Conclusion

The most common type of nonalcoholic liver disease seen in alcoholic patients is chronic viral hepatitis C. Evidence accumulated thus far supports the concept that superimposed hepatitis C infection confers a more severe liver injury in alcoholic patients, possibly by enhancing viral replication. The progression of the liver disease is more rapid and the risk for the development of hepatocellular carcinoma, once cirrhosis has developed, is high. It remains to be proven whether or not successful antiviral therapy will change the natural history and improve the prognosis in such patients who abstain. Regardless, part of the mystery of why some alcoholics develop liver disease while most do not can be explained by the presence of chronic viral C hepatitis.

References
1. Koff RS, Dienstag JL. Extrahepatic manifestations of hepatitis C and the association with alcoholic liver disease. Semin Liver Dis 1995;15(1):101-9.
2. Befrits R, Hedman M, Blomquist L, Allander T, Grillner L, Kinnman N, Rubio C, Hultcrantz R. Chronic hepatitis C in alcoholic patients: prevalence, genotypes, and correlation to liver disease. Scand J Gastroenterol 1995;30(1 1):1 1 13-8.
3. Mendenhall CL, Moritz T, Rouster S, Roselle G, Polito A, Quan S, KiNelle RK, and the VA Cooperative Study Group 275. Epidemiology of hepatitis C among veterans with alcoholic liver disease. Am J Gastroenterol 1 993 ;88(7): 1 022-6.
4. Coelho-Little ME, Jeffers LJ, Bernstein DE, Goodman JJ, Reddy KR, deMedina M, Li X, Hill M, LaRue S, Schiff ER. Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. Alcohol Clin Exp Res 1995;19(5):]173-6.
5. Caldwell SH, Li X, Rourk RM, Millar A, Sosnowski KM, Sue M, Barritt AS, McCallum RW, Schiff ER. Hepatitis C infection by polymerase chain reaction in alcoholics: false-positive ELISA results and the influence of infection on a clinical prognostic score. Am J Gastroenterol 1993;88(7):1016-21.
6. Mendelhall CL, Seeff L, Diehl AM, Ghosen SJ, French SW, Gartside PS, et al. Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. Hepatology 1991;14(4):581-9.
7. Pares A, Barrera JM, Caballeria J, Ercilla G, Bruguera M, Caballeria L, Castillo R, Rodes J. Hepatitis C virus antibodies in chronic alcoholic patients: association with severity of liver injury. Hepatology 1990; 1 2(6): 1 295 - 9.
8. Nishiguchi S, Kuroki T, Yabusako T, Seki S, Kobayashi K, Monna T, Otani S, et al. Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease. Hepatology 1991; 14(6):985-9.
9. Takase S, Takada N, Enomoto N, et al. Different types of chronic hepatitis in alcoholic patients: does chronic hepatitis induced by alcohol exist? Hepatology 1991;13:876-81.
10. Sata M, Fukuizumi K, Uchimura Y, Nakano H, Ishii K, Kumashiro R, Mizokami M, Lau JYN, Tanikawa K. Hepatitis C virus infection in patients with clinically diagnosed alcoholic liver diseases. J Viral Hepatitis 1996;3:143-8.
11. Rosman AS, Waraich A, Galvin K, Casiano J, Paronetto F, Liever CS. Alcoholism is associated with hepatitis C but not hepatitis B in an urban population. Am J Gastroenterol 1996;91(3):498-505.
12. Caldwell SH, Jeffers LJ, Ditomaso A, Millar A, Clark RM, Rabassa A, Reddy KR, deMedina M, Schiff ER. Antibody to hepatitis C is common among patients with alcoholic liver disease with and without risk factors. Am J Gastroenterol 1991;86(9):1219-23.
13. Uchimura Y, Sata M, Kage M, Abe H, Tanikawa K. A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease. Liver 1995;15(6):300-6.
14. Oshito M, Takei Y, Kawano S, Hijioka T, Masuda E, Goto M, Nishimuro Y, Nagui H, Ito S, Tsuji S, Fusamoto H, Kamada T. Endogenous nitric oxide attenuates ethanol-induced perturbation of hepatic circulation in the isolated perfused rat liver. Hepatology 1994;20:961-5.
15. Izumi N, Enomoto N, Uchihara M, Murakami T, Ono K, Noguchi 0, Miyake S, Nouchi T, Fujisawa K, Marumo F, Sato C. Hepatic iron contents and response to interferon-a in patients with chronic hepatitis C. Dig Dis Sci 1996;41(5):989-94.
16. Cromie SL, Jenkins PJ, Bowden DS, Dudley FJ. Chronic hepatitis C: effect of alcohol on hepatic activity and viral titre. J Hepatol 1996;25:821-6.
17. Takase S, Tsutsumi M, Kawahara H, et al. The alcohol-altered liver membrane antibody and hepatitis C virus infection in the progression of alcoholic liver disease. Hepatology 1993;17:9-13.
18. Noda K, Yoshihara H, Suzuki K, Yamada Y, Kasahara A, Hayashi N, Fusamoto H, Kamada T. Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma-its relationship to alcohol drinking and the age of transfusion. Alcohol Clin Exp Res 1996;2(1):95A-IOOA.
19. Sato Y, Okabe K. Studies on the incidence of hepatocellular carcinoma in heavy drinkers with liver cirrhosis [abstract]. Alcohol Alcohol 1993;(1B Suppl): 109-14.
20. Nalpas B, Feitelsol M, Brechot C, Rubin E. Alcohol, hepatotropic viruses, and hepatocellular carcinoma [editorial]. Alcohol Clin Exp Res 1995;19(5);1089-95.
21. Miyakawa H, Sato C, Izumi N, Tazawa J, Ebata A, Hattori K, Sakai H, Ikeda T, Hirata R, Sakai Y, et al. Hepatitis C virus infection in alcoholic liver cirrhosis in Japan: its contribution to the development of hepatocelluar carcinoma. Alcohol Alcohol 1993;(1A Suppl):85-90.
22. Okazaki T, Yoshihara H, Suzuki K, Yamada Y, Tsujimura T, Kawano K, Yamada Y, Abe H. Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol 1994;29(11):1039-43 .
23. Ohnishi K, Matsuo S, Matsutani K, Itahashi M, Kakihara K, Suzuki K, Ito S, Fujiwara K. Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol 1996;91(7): 1374-9.

SOURCE: From the NIH Consensus Development Conference on Management of Hepatitis C
Title: Hepatitis C and Alcohol;Author: Eugene R. Schiff, M.D.


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