for Health Care Providers
Hepatitis C and Alcohol
Alcohol and hepatitis C are certainly the two primary causes of cirrhosis and liver transplantation in the United States and Europe.(1,2) Many patients with hepatitis C from these regions also have a history of problematic alcohol use, and thus have liver injury from both agents. An unequivocal first step in the management of patients with HCV who have an alcohol problem is ensuring that alcohol cessation is put in place. This section describes what has been shown about the interaction between alcohol intake and chronic hepatitis C infection.
Several factors have made this area of study difficult:
- the fact that alcohol intake varies over time in nearly everyone, and is thus very difficult to quantify
- alcohol likely affects individuals differently (for example, it seems that only 20% of heavy drinkers develop cirrhosis).(3)
Alcohol and Liver Disease in Patients with HCV
Since the discovery of the hepatitis C virus in 1989,(4) heavy alcohol consumption and hepatitis C have been known to interact with each other in causing liver disease. Poynard et al (5) were among the first to demonstrate that heavy alcohol intake (50 grams/day or more in their study) contributes to fibrosis on liver biopsy in patients with HCV independent from other predictors. This intake is equivalent to 5 or more drinks per day (an average "drink"--one 12-oz beer, 5 oz of wine, or one 1.25 oz shot of hard liquor--contains approximately 10 grams of alcohol).
Numerous other studies have confirmed that heavy alcohol intake contributes to HCV-associated liver disease. Notable among them is the study by Roudot-Thoraval et al,(6) which evaluated more than 6,600 patients. Heavy alcohol intake in this study was associated with significantly more cirrhosis than was smaller amounts of alcohol intake. Another important study was that of Ostapowicz et al,(7) in which patients with HCV who had undergone a liver biopsy had a detailed lifetime alcohol history obtained. Daily alcohol intake was not associated with fibrosis in multivariate analysis, but patients with cirrhosis had greater total lifetime alcohol consumption than did patients who did not have cirrhosis.
Limitations of studies published to date have included grouping subjects by fixed categories of alcohol intake,(5) and using case-control methodology,(8) with cases often having cirrhosis and controls having little liver disease. Studies including light drinkers have had conflicting results. Ostapowicz et al (7) found no significant relationship between light or moderate alcohol intake and fibrosis on liver biopsy. A second prospective study, this one of inner-city injection drug users, found a statistically significant increase in the adjusted incidence of cirrhosis when 90-260 g/week were consumed, and a further increase when >260 g/week were consumed.(9)
Two recent studies suggest a similar role for light or moderate alcohol use on liver disease in patients with HCV. A group of 800 American patients who had lifetime alcohol use estimated at the time of liver biopsy were found to have more liver scarring if they had drunk >50 g/day of alcohol, and lower amounts of alcohol were associated with fibrosis, but to a lesser extent.(10) A French study of similar design found that quantity of alcohol drunk within 6 months prior to liver biopsy also was associated with fibrosis, and in a similar pattern: <31 g/day exerted some effect, 31-50 g/day a greater effect.(11)
Overall, data that light alcohol use leads to some increase in liver scarring in patients with hepatitis C are emerging, but this effect is less than that seen in heavy drinkers.
Alcohol and HCV Therapy
Active alcohol intake is considered a relative contraindication to interferon-based therapy.(12,13) This recommendation is based on the documented noncompliance of heavy drinkers with different medical therapies,(14) and the fact that the side effects of interferon therapy make it extremely difficult to comply with, even in patients without ongoing substance abuse.(15) Because abstinence prior to therapy is considered standard management, major trials of anti-hepatitis C therapy excluded active drinkers,(16,17) and did not evaluate alcohol history as a predictor variable in treatment response. As such, the effects of alcohol on HCV treatment response come only from much smaller studies.
Nearly all studies of the effect of alcohol on treatment responses have been with interferon monotherapy, and none has been blinded or randomized. Examples include two Japanese studies, one in which 16 of 53 patients were defined as heavy drinkers, and only 6% of all drinkers normalized their alanine aminotransferase (ALT) during treatment, compared with 30% of nondrinkers.(18) A second study found that ALT normalization segregated directly with alcohol intake, 53% in nondrinkers, 43% in those consuming <70 g/day of alcohol, and 0% in those consuming >70 g/day.(19)
More recently, an Italian study (20) required abstinence from alcohol for 6 months prior to and during interferon monotherapy. Sustained virological response was significantly reduced in those with >75 g/day alcohol consumption prior to abstinence (9%), compared with nondrinkers (33%). In the only published study examining the role of alcohol on response in patients treated with interferon and ribavirin, a German group (21) treated 81 patients whose alcohol use histories were characterized prior to, during, and after interferon and ribavirin therapy. Twenty-one patients (26%) reported alcohol use while on therapy, 6 requiring inpatient treatment for detoxification. No significant differences were found, however, in therapeutic outcome and ALT levels after treatment based on alcohol consumption before or during combination therapy.
In summary, published studies mostly suggest a negative effect of alcohol on the response to hepatitis C therapy. However, these were all small, nonrandomized, unblinded studies, so basing firm conclusions on them is difficult. Moreover, none of the studies reported patient compliance with therapy. As such, it remains unknown whether observed response differences seen in drinkers actually reflect biological differences, or whether the heavy drinkers were merely less compliant with therapy.
Alcohol and Hepatocellular Cancer in Patients with HCV
Heavy alcohol intake is clearly associated with cirrhosis, alone and particularly in combination with HCV. Cirrhosis has been shown to be the primary risk factor for hepatocellular carcinoma (HCC).(22) Thus, alcohol is clearly associated with HCC through causing cirrhosis. It remains unclear, however, whether alcohol leads to liver cancer independent from its effect on cirrhosis.
A number of studies have suggested that alcohol is associated with HCC independent of its association with cirrhosis. Aizawa et al (23) included histological stage in their multivariate model, and found alcohol to be associated with HCC independent of histological stage. However, stage had often been ascertained 5-15 years prior to HCC diagnosis. A large, case-control study of patients with HCV (24) found that alcohol consumption >60 g/day was associated with twice the risk of HCC as was abstinence or light alcohol consumption. A cross-sectional study from France, however, found that alcohol use was not independently associated with HCC, only cirrhosis was.(6) A recent, population-based study from Taiwan confirmed the importance of HCV as a risk factor for HCC, with having an antibody to HCV multiplying the risk of liver cancer 3.6-fold. Alcohol intake added to this risk, with a further threefold increased incidence of HCC in patients with HCV who drank alcohol.(25)
Alcohol has also been linked to outcomes in patients diagnosed with HCC. In a Japanese cohort of 53 patients who underwent resection of HCC, (26) patients who continued to consume >80 g/day of alcohol had a significantly diminished median disease-free survival (12.6 months) compared with those drinking <80 g/day (25.4 mos).
To summarize, drinking alcohol has been linked to HCC development in patients with chronic hepatitis C. The demonstration of this association at a population level, as well as the association between alcohol and HCC recurrence, suggests a direct link between alcohol and HCC independent of the effect of alcohol on fibrosis, but this has not been proven.
Patients with chronic hepatitis C infection likely should not drink alcohol. Heavy alcohol use has been found in multiple studies to be associated with fibrosis progression and cirrhosis. Light and moderate alcohol consumption also seem to contribute to liver disease.
Both past and current heavy alcohol use also have been associated with a decrease in patients' responses to interferon-based therapy, but studies largely have been retrospective and small, and have not addressed the question of whether patient compliance with therapy is also affected by alcohol. Alcohol intake in patients with HCV also has been linked to HCC. This may be principally through the association between alcohol and cirrhosis; studies have not demonstrated a link between alcohol and HCC independent from the association between alcohol and cirrhosis. Future studies with careful quantification and documentation of the timing of alcohol intake will shed additional light on all these questions.
- Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health 2000;90:1562-1569.
- Prieto M, Berenguer M, Rimola A, et al. Liver transplantation in hepatitis C: a Spanish multicenter experience. Eur J Gastroenterol Hepatol 1998;10:771-776.
- Lelbach WK. Organic pathology related to volume and patterns of alcohol use. In: Gibbins RS, Israel Y, Kalant H, et al, eds. Research Advances in Alcohol and Drug Problems. Vol. 1. New York: John Wiley & Sons, 1974, pp 93-198.
- Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood borne non-A, non-B viral hepatitis genome. Science 1989, 244:359-362.
- Poynard T, Bedossa P, Opolon P, OBSVIRC, METAVIR, CLINIVIR, DOSVIRC. Natural History of Liver Fibrosis Progression in patients with Chronic Hepatitis C. Lancet 1997;349:825-32.
- Roudot-Thoraval F, Bastie A, Pawlotsky J-M, et al. Epidemiological factors affecting the severity of hepatitis C virus-related liver disease: a French survey of 6,664 patients. Hepatology 1997, 26: 485-490.
- 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(6):1730-5.
- 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.
- Thomas DL, Astemborski J, Rai RM, et al.The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000, 284: 450-456.
- Monto A, Patel K, Bostrom A, et al. Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology 2004, 39: 826-834.
- Hezode C, Lonjon I, Roudot-Thoraval F, et al. Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study. Aliment Pharmacol Ther 2003, 17: 1031-1037.
- National Institutes of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology 1997, 26:2S-10S.
- National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002. Hepatology 2002, 36:S3-S20.
- Marco A, Cayla JA, Serra M, et al. Predictors of adherence to tuberculosis treatment in a supervised therapy programme for prisoners before and after release. Study Group of Adherence to Tuberculosis Treatment of Prisoners.. Eur Respir J 1998, 12: 967-971
- Dusheiko G. Side effects of alpha interferon in chronic hepatitis C. Hepatology 1997, 26:112S-121S.
- Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C. Lancet 2001, 358:958-965.
- Fried MW, Shiffman ML, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.. N Engl J Med 2002, 347:975-982.
- Oshita M, Hayashi N, Kasahara A, et al. Increased Serum Hepatitis C Virus RNA Levels Among Alcoholic Patients with Chronic Hepatitis C. Hepatology 1994;20(5):1115-1120.
- Okazaki T, Yoshihara H, Suzuki K, et al. Efficacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol 1994;29(11):1039-43.
- Tabone M, Sidoli L, Laudi C, et al. Alcohol abstinence does not offset the strong negative effect of lifetime alcohol consumption on the outcome of interferon therapy. J Viral Hepatitis 2002, 9: 288-294.
- Schaefer M, Schmidt F, Folwaczny C, et al. Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.. Hepatology 2003, 37: 443-451.
- Kew MC, Popper H.Relationship between hepatocellular carcinoma and cirrhosis. Semin Liver Dis 1984, 4:136-146.
- Aizawa Y, Shibamoto Y, Tagaki I, et al. Analysis of factors affecting the appearance of hepatocellular carcinoma on patients with chronic hepatitis C. Cancer 2000; 89:53-9.
- Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime alcohol intake and hepatitis virus infections in men and women. Am J Epidemiol 2002, 155:323-331.
- Sun C-A, Wu D-M, Lin C-C, et al. Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: a prospective study of 12,008 men in Taiwan.Am J Epidemiol 2003, 157: 674-682.
- Okada S, Ishii H, Nose H, et al. Effect of heavy alcohol intake on long-term results after curative resection of hepatitis C virus-related hepatocellular carcinoma.Jpn J Cancer Res 1996, 87:867-873.