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Eugene R. Schiff, M.D., and Nuri Ozden, M.D.

Patients infected with the (HCV) who drink heavily are likely to suffer more severe injury, promoting disease progression to and increasing their risk for liver . Some research, although not conclusive, suggests that even moderate drinking may spur liver damage in HCV-infected patients. Research areas that have the greatest potential for developing more effective treatment options include HCV , immunology, animal models, and the mechanisms of liver injury. KEY WORDS: ; alcoholic beverage; chronic AODE (alcohol and other drug effects); amount of AOD use; ; risk factors; disease course; alcoholic liver cirrhosis; gender differences; biochemical mechanism; RNA; mutation; apoptosis; ; ; regulatory proteins; immune response; alcoholic fatty liver; treatment issues; treatment outcome;

epatitis C is an infectious liver the time of , male gender, are considerably more likely to test disease caused by the hepatitis obesity, abnormal accumulation of fat positive for HCV infection than those HC virus (HCV). The virus, in the liver (a condition known as fatty with less severe (Takase et which causes inflammation in the liver liver, or ), and excessive alco­ al. 1993). and can lead to more serious illness, hol consumption (Poynard et al. 2001). primarily is spread by intravenous This article discusses the mechanisms contact with the of an infected by which alcohol may exacerbate Levels of Alcohol person. About 4 million people in the HCV-infected patients’ risk of disease Consumption in HCV have been infected, progression, reviews issues in the Patients and the Risk of making it the Nation’s most common treatment of alcoholic patients with Further Liver Disease blood-borne disease, resulting in the HCV infection, and addresses impor­ of between 10,000 and 12,000 tant areas of future research. Several studies have indicated that people each year (National Institute heavy alcohol consumption accelerates of and Digestive and Kidney patients’ progression from chronic Diseases 2003). Those at heightened Epidemiology of Hepatitis HCV to cirrhosis (a condition in risk for HCV infection include intra­ C Among Alcoholics venous drug users, people who received blood transfusions or organ transplants Almost one-third of alcoholics with EUGENE R. SCHIFF, M.D., is chief of the before 1992 or clotting factors made clinical symptoms of liver disease have Division of , director of the before 1987, health care workers who been infected with HCV, which is Center for Liver Diseases, and a professor suffer needle-stick accidents, and infants four times the rate of HCV infection of medicine at the University of Miami born to mothers who are infected found in alcoholics who do not have School of Medicine, Miami, Florida. with HCV (Centers for Disease Con­ liver disease (Coelho-Little et al. trol and Prevention 1998). Several 1995; Mendenhall et al. 1991; Takase NURI OZDEN, M.D., is a clinical fellow factors may accelerate the progression et al. 1993). As shown in figure 1, in hepatology at the University of Miami of hepatitis C, including older age at people with more severe liver disease Center for Liver Diseases, Miami, Florida.

232 Alcohol Research & Health Hepatitis C and Alcohol

which fibrous scar tissue replaces healthy liver tissue), and (specifically, hepatocellular carcinoma, the most common form of liver can­ cer). Although fewer studies have examined the effects of moderate drinking on the course of liver disease in HCV patients, there is some indi­ cation that alcohol consumption in the moderate-to-heavy range may increase HCV-infected patients’ risk of developing liver and cirrho­ sis. Research on whether gender has any effect on alcohol consumption and liver disease progression in HCV patients is very limited. cent Positive for the Anti-HCV the Anti-HCV Antibody for cent Positive Cirrhosis Per In a study of 2,235 HCV-infected Alcoholic Cirrhosis Hepatocellular patients, Poynard and colleagues (1997) Fibrosis Carcinoma observed that patients who drank heav­ ily (more than 50 grams [g] of alcohol, Figure 1 Patients with more severe have a significantly higher or 4.2 drinks, per day1) tended to show prevalence of HCV infection (as assessed by anti-HCV antibody tests). much more advanced liver scarring (i.e., fibrosis, a defining feature of cirrhosis) SOURCE: Takase et al. 1993. than those who did not drink as heavily. In addition, the researchers identified a group of “rapid fibrosers,” who were 4 more likely to be male, heavy drinkers, and infected with HCV after age 40. Wiley and colleagues (1998) observed that HCV-infected patients 3 who drank heavily were significantly HCV + Alcohol more likely to develop cirrhosis than those who were not heavy drinkers. HCV In addition, among patients who did 2 develop cirrhosis, the disease emerged considerably sooner for patients who drank heavily than for those who did Fibrosis Grade not (see figure 2). 1 Bellentani and colleagues (1999) analyzed hepatitis virus markers (includ­ ing the virus’s genetic material, HCV RNA, and to the virus), 0 0 5 10 15 20 25 30 35 40 alcohol intake, and clinical and bio­ chemical evidence of liver disease in Years Since HCV Infection a random sample of 6,917 people in northern Italy. Regardless of HCV Figure 2 Relationship between fibrosis severity (grades 1–4) and years of HCV infection. Patients who reported significant alcohol consumption (more status, subjects who were heavy drinkers than 40 g of alcohol per day, or 3.3 drinks, for women; and more than (which the authors defined as drink­ 60 g of alcohol per day, or about 5 drinks, for men) experienced markedly ing more than 30 g, or 2.5 drinks, faster disease progression than patients who did not report significant alcohol intake. 1 The National Institute on and (NIAAA) defines a as 11–14 g of alcohol. This corresponds to approximately one shot of 80-proof SOURCE: Wiley et al. 1998. alcohol (about 14 g alcohol), one glass of wine (11 g), or one 12-oz. beer (12.8 g).

Vol. 27, No. 3, 2003 233 per day) for more than 10 years were day (Donato et al. 2002). Other research above the median level (4.8 g of alco­ three times as likely to have cirrhosis has shown that HCV-infected patients hol, or less than one drink per day) than those who were not heavy drinkers. who drink heavily are more likely to showed more liver scarring (fibrosis) Among HCV-positive subjects, 32 develop liver cancer at a younger age than patients whose alcohol consump­ percent of those who were heavy than are those who drink less. For tion was below the median level. drinkers had cirrhosis, compared with example, Noda and colleagues (1996) Hézode and colleagues (2003) also 10 percent of those who were not observed that patients who drank at found that the severity of fibrosis in heavy drinkers. There were five cases least 46 g of alcohol (3.8 drinks) daily patients with chronic HCV was corre­ of hepatocellular carcinoma, all in the were diagnosed with hepatocellular lated with the amount of alcohol con­ heavier drinking group. carcinoma an average of 26 years after sumed (see figure 3). Finally, a recent Seeff and colleagues (2001) studied developing transfusion-associated HCV, study of 180 patients with untreated 1,030 patients who had been enrolled in whereas those who drank less than 46 chronic hepatitis C confirmed these a prospective investigation of transfusion- g per day were diagnosed with cancer findings (Zarski et al. 2003). associated HCV conducted in the an average of 31 years after transfusion. United States between 1968 and 1980. And Kubo and colleagues (1997) Gender and Disease Progression In a followup investigation conducted found that, among HCV-infected an average of 15 years after transfusions patients with hepatocellular carcinoma, The data regarding the contribution had occurred, the researchers found that heavy drinkers had more advanced of gender to the progression of HCV 17 percent of patients infected with tumors and died sooner after diagno­ in alcoholics is quite limited. Chronic transfusion-associated HCV had sis than did nondrinkers. hepatitis C often is milder in women developed cirrhosis, compared with than in men, but women may be more 3.2 percent of patients with transfu- Moderate-to-Heavy Drinking and sensitive than men to the adverse sion-associated non-A, non-B, and Disease Progression effects of alcohol (Becker et al. 1996). non-C hepatitis, and 2.8 percent of uninfected patients. Alcohol use greatly Most studies have evaluated the effect exacerbated patients’ risk of progression of extremely heavy drinking on the Histologic Features of from chronic hepatitis to cirrhosis. progression of HCV infection to other Chronic Hepatitis C in Patients with both transfusion-associated liver disease, with little emphasis on Alcoholic Patients HCV and a history of heavy alcohol the effects of moderate drinking on use were 31 times more likely to disease progression. However, some As discussed above, there is strong develop cirrhosis than control subjects studies have found indications that evidence that heavy alcohol consump- without a history of alcohol abuse. moderate-to-heavy alcohol consump­ tion—and perhaps even moderate Perhaps the most dramatic demon­ tion also may increase the risk of consumption—increases the risk that stration that alcohol multiplies HCV- developing liver fibrosis and cirrhosis HCV infection will progress to more infected patients’ risk of cirrhosis came in patients infected with HCV. serious liver disease. In patients infected from a study by Corrao and Arico (1998). Ostapowicz and colleagues (1998) with HCV, alcohol consumption has Of 285 cirrhotic subjects, only 1.4 specified no particular threshold level a direct effect on liver histology. percent (4 subjects) were HCV-positive above which the risk of disease progres­ Specifically, patients with HCV who and nondrinkers, compared with 11.2 sion increases but found that, among are drinkers show greater liver necrosis, percent (32 subjects) who were both patients with chronic HCV infection, inflammation, fibrosis, and fatty infil­ HCV-positive and heavy drinkers. those who had cirrhosis reported higher tration than HCV patients who do People infected with both HCV lifetime and total alcohol consump­ not drink. Further, alcohol consump­ and HIV are more likely to develop tion than those HCV patients who tion and fatty liver have been shown cirrhosis than are patients who are did not have cirrhosis. to act together to increase fibrosis in infected only with HCV, and alcoholism Several other studies have examined patients infected with HCV, especially further potentiates this mechanism the effects of moderate drinking on in those who are obese and diabetic (Di Martino et al. 2001). HCV progression.2 Assessing HCV- (Monto et al. 2002). infected patients who drank less than Liver Cancer 40 g of alcohol (3.3 drinks) per day, Westin and colleagues (2002) found Mechanisms of Liver Injury An Italian survey showed that alcohol that patients whose alcohol intake was in C intake doubles the risk of hepatocellular Infection carcinoma in HCV-infected patients 2 In these studies, definitions of moderate drinking differ who drink 41 to 80 g of alcohol per from current Federal guidelines, which consider moderate Although researchers do not fully day (between 3.4 and 6.7 drinks) and drinking to be no more than one drink per day for women, understand how alcohol consumption and no more than two drinks per day for men (U.S. quadruples the risk for patients who Department of Agriculture and the U.S. Department of accelerates liver injury in patients drink more than 80 g of alcohol per Health and Human Services 1995). with HCV infection, it is likely that

234 Alcohol Research & Health Hepatitis C and Alcohol

several factors are involved. The fol­ •Mutations of the HCV virus (forming (1997) noted that chronic alcohol lowing mechanisms have been proposed: what are known as quasi-species). feeding in mice inhibited immune Alcoholics infected with HCV show responses (specifically, responses •Increased replication of HCV in greater quasi-species complexity than by T-helper cells and cytotoxic T- the liver. As illustrated in figure 4, do nonalcoholics with HCV infection. ) that play a pivotal role some research (although not all) In alcoholic HCV patients, such in removal of HCV from the body has found that greater alcohol increased viral complexity might (i.e., HCV clearance). consumption is related to higher make it difficult for the immune HCV RNA blood concentrations system to control the mutated •Viral gene mutations. (Pessione et al. 1998). Moreover, , leading to progressive injury as shown in figure 5, when people (Takahashi et al. 2001). •Fatty liver. Accumulation of fat in infected with HCV who drank the liver is common in patients with more than 10 g of alcohol (about •Increased programmed cell HCV. Examining a large group of 5.8 drinks) per day abstained from (apoptosis) of liver cells. Apoptotic patients with HCV infection, Serfaty alcohol or substantially reduced death of liver cells, which can ulti­ and colleagues (2002) found that their consumption for 4 months mately lead to liver fibrosis, is increased fibrosis progressed about twice as before treatment, HCV RNA levels by alcohol consumption in people with quickly among drinkers with steatosis dropped; the decline in HCV infection (Szabo 2003). as among drinkers without steatosis or HCV RNA among subjects who nondrinkers with or without steatosis. drank less than or equal to 10 g •Higher levels of inflammation and of alcohol (less than one drink) immunoregulatory proteins (specifi­ •Accumulation of excess iron in body per day before abstaining was not cally, interleukin, tumor necrosis tissues (i.e., ). Alcohol statistically significant (Cromie factor, and interferon). In research consumption increases iron stores in et al. 1996). with mice, Geissler and colleagues the liver, and iron overload seems to contribute to HCV disease progres­ sion by inducing fibrosis (Piperno et al. 1998).

• Oxidative stress. Alcohol stimulates the production of reactive oxygen- containing molecules (i.e., oxygen radicals). Heavy alcohol use also depletes the body’s supply of molecules that normally defend tissues against damage caused by oxygen radicals (i.e., antioxidants). This state, known as oxidative stress, may accelerate Patients (%) liver damage in patients with HCV (Rigamonti et al. 2003). (For more information about how alcohol use can lead to oxidative stress and sub­ sequent liver injury, see the article by Nanji and French in the next issue of Alcohol Research & Health, [Vol. 27, No. 4].) Alcohol Intake (grams/day) •Depression of the immune system Figure 3 Alcohol consumption and liver fibrosis in patients with chronic HCV. by alcohol. More advanced fibrosis (stages 2 through 4) was observed in 29 percent of patients who reported no alcohol intake, 34.4 percent of those who had minimal intake, 38.2 percent of those who had mild intake, and 67.6 percent of those who were moderate drinkers. Correspondingly, Treatment Issues the incidence of less advanced fibrosis (stages 0 through 1) decreased with increasing alcohol consumption. Heavy alcohol use can be detrimental to HCV-infected patients’ long-term SOURCE: Hézode et al. 2003. response to interferon therapy (see the sidebar for discussion of interferon

Vol. 27, No. 3, 2003 235 treatment for HCV). It is likely that better to treatment than do those who However, this study indicated that alcohol affects HCV treatment effec­ continue to drink. In one study, heavy when HCV-infected alcoholic patients tiveness both because drinking tends drinkers who did not abstain from who normally drank heavily (70 or to interfere with patients’ adherence to drinking before interferon treatment more grams of alcohol, or at least 5.8 therapy and because alcohol interferes showed a total lack of HCV RNA drinks, per day) abstained from alcohol with interferon therapy’s antiviral actions. clearance, whereas those who normally consumption during interferon therapy, drank heavily but abstained from their rate of HCV RNA clearance was Abstention Before Interferon drinking before interferon treatment markedly lower than was the case for Treatment showed some improvement in HCV HCV-infected nondrinkers (see figure RNA clearance (and the virus completely 6). These results were confirmed by a Some research has indicated that heavy disappeared in 15.8 percent of heavy recent Italian study (Tabone et al. 2002) drinkers who abstain from alcohol drinkers who abstained before treat­ in which 150 patients with chronic before interferon treatment respond ment) (Mochida et al. 1996). HCV underwent interferon treatment

Hepatitis C Infection: Disease Characteristics, Testing, and Treatment

The symptoms and course of hepatitis C vary greatly. Many The standard treatment for symptomatic hepatitis people who are infected with the virus show no symptoms C infection is a combination of the drugs pegylated (although they can still infect others), whereas some interferon (peginterferon) and (National Institutes people may experience , weakness, fever, , of Health 2002). Strict abstinence from alcohol is abdominal pain, poor appetite, muscle and joint pain, or important during treatment. yellowing of the skin and eyes () (National Institutes Currently, the best indicator of effective treatment of Health 2002). About 75 percent of patients who are is a sustained virological response (SVR), defined by infected with HCV develop chronic infection (Centers for the absence of detectable virus 24 weeks after the end Disease Control and Prevention 1998). Between 10 and of treatment. Early viral response (a minimum 2 log 40 percent of HCV patients develop cirrhosis (a condition decrease in during the first 12 weeks of in which normal liver cells are replaced by scar tissue) within treatment) is predictive of SVR, and patients who fail 20 to 40 years, and 1 to 3 percent develop liver cancer. to achieve an early viral response at week 12 should Many patients who develop cirrhosis show no discontinue the treatment. Genotype 1 requires 1 year symptoms of the disease and can expect long-term of treatment, whereas genotypes 2 and 3 require a 6­ survival (Di Bisceglie 2000). Data from a cohort of month course. In research with patients who did not European patients with cirrhosis followed for an aver­ consume alcohol during the therapy, SVR rates of 42 age of 5 years showed that only 7 percent developed to 46 percent for genotype 1 and 76 to 82 percent for hepatocellular carcinoma, and 18 percent experienced genotypes 2 and 3 have been obtained (Di Bisceglie symptomatic (Fattovich et al. 1997). and Hoofnagle 2002). There currently is no for hepatitis C. — Eugene R. Schiff and Nuri Ozden References Testing and Treatment Centers for Disease Control and Prevention. Recommendations for pre­ Blood tests can diagnose HCV infection, either by vention and control of hepatitis C virus (HCV) infection and HCV-relat- detecting antibodies to the virus or by detecting the ed chronic disease. Morbidity and Mortality Weekly Reports 47:1–39, 1998. presence and quantity of the virus’s genetic material DI BISCEGLIE, A.M. Natural history of hepatitis C: Its impact on clini­ (HCV RNA) itself (National Institutes of Health cal management. Hepatology 31:1014–1018, 2000.

2002). is quite helpful for evaluating the DI BISCEGLIE, A.M., AND HOOFNAGLE, J.H. Optimal therapy of hep­ disease’s severity prior to initiating treatment. Liver atitis C. Hepatology 36(5 Suppl. 1):S121–127, 2002. have little value in predicting fibrosis. FATTOVICH, G.; GIUSTINA, G.; DEGOS, F.; ET AL. Morbidity and mor­ There are six known genetic variants (genotypes) tality in compensated cirrhosis type C: A retrospective follow-up study of HCV, which vary geographically in their rate of of 384 patients. 112:463–472, 1997. occurrence. Genotypes 1 (which accounts for 70 to 75 National Institutes of Health. National Institutes of Health Consensus percent of cases), 2, and 3 constitute the majority of Development Conference statement: Management of hepatitis C: genotypes in the United States. 2002—June 10–12, 2002. Hepatology 36(5 Suppl. 1):S3–20, 2002.

236 Alcohol Research & Health Hepatitis C and Alcohol

for 1 year after 6 months of abstinence transferrin.) Although all patients treatment, compared with 20 percent from alcohol. (Abstinence was verified had abstained from alcohol before of light drinkers and 33 percent of by analyzing blood levels of a biologi­ beginning treatment, only 9 percent nondrinkers. The factors that most cal marker of heavy alcohol consump­ of (normally) heavy drinkers exhibited strongly predicted a poor response to tion known as carbohydrate-deficient a sustained response to the interferon interferon treatment were the specific type of HCV infection (patients with HCV genotype 1b were least respon­ 140 sive), patients’ age, and their lifetime alcohol intake. 120

) Treatment Recommendations 5 100 The evidence is strong that continued heavy alcohol intake during interferon 80 treatment adversely affects treatment effectiveness. Further, depression, irri­ 60 tability, and anxiety—side effects that occur in 20 to 30 percent of patients 40 who receive interferon treatment— may be especially difficult to manage

Serum HCV RNA (mEq x 10 Serum HCV RNA for patients with a history of alcoholism, 20 predisposing them to begin drinking again (Zdilar et al. 2000). Despite this 0 risk, however, the data do not support 0 691 70 139 140 209 >210 withholding interferon therapy for Alcohol Consumption (g) chronic HCV from patients with a history of alcoholism or heavy drink­ Figure 4 As (self-reported) alcohol consumption increases, mean blood HCV ing if they remain abstinent and have RNA levels also increased in patients with chronic HCV infection. adequate psychosocial support during treatment. Likewise, light-to-moderate SOURCE: Pessione et al. 1998. drinkers should not be excluded from HCV treatment, nor should a period of abstinence before starting therapy be enforced in this patient population.

) Directions for Future Research

A recent National Institute on Alcohol Abuse and Alcoholism conference (Mor­ gan et al. 2003) identified areas of Serum HCV RNA (copies/mL x 10 (copies/mL research with the greatest potential for leading to more effective treatment options. Conference recommendations for Group 1 Group 2 Group 1 Group 2 research within these areas were as follows: At Initial After Abstaining From Evaluation Alcohol for 4 Months Clinical Studies Figure 5 Reversibility of the increase in blood HCV RNA levels following a 4-month alcohol-free diet. Group 1 consisted of subjects who drank less than or equal •Determine how variations in the to 10 grams (g) of alcohol per day when the study began; subjects in Group amount and pattern of drinking, 2 consumed 10 g of alcohol or more per day at the outset of the study. combined drinking and smoking, and nutritional deficiencies affect SOURCE: Cromie et al. 1996. HCV-infected patients’ risk of liver injury, disease progression, and death.

Vol. 27, No. 3, 2003 237 •Evaluate the effectiveness of alco­ •Determine the source of proteins, of HCV infection and of alcoholic hol cessation programs in patients known as , that act as liver disease that reproduce disease with HCV. antibody-mediated (humoral) processes found in humans. messengers between liver cells, and •Specify how alcohol affects patients’ their role in liver cell injury and Summary response to interferon treatment, regeneration in HCV-infected patients who use alcohol. including chemical interactions and Excessive alcohol consumption among day-to-day changes in virus activity patients infected with chronic hepati­ •Evaluate the effect of alcohol and during treatment. tis C is likely to result in more severe HCV infection on fatty liver and liver injury, promoting cirrhosis and determine how steatosis contributes increasing the risk for development of HCV Virology to liver disease. liver cancer (specifically, hepatocellular carcinoma). Although the mechanisms •Determine how alcohol use and •Determine how alcohol affects by which chronic hepatitis C progresses HCV infection influence various viral replication, clearance, and to more severe liver disease in alcoholic types of liver cells (i.e., , persistence and the evolution of patients have not been clearly estab­ Kupffer cells, endothelial cells, and new HCV quasi-species. lished, they may include an alcohol- hepatic stellate cells). induced increase in viral replication; •Examine whether alcohol use leads to rapid mutation of HCV, leading to • Characterize the effect of human greater dominance of more harmful greater viral complexity; increased liver cells (i.e., hepatocytes) on genetic variants of HCV. liver-cell death and inflammatory overall human pathophysiology in response; suppression of immune response to alcohol and HCV. •Determine whether alcohol inter­ responses; accumulation of fat in the liver; and accumulation of excess iron acts with the HCV viral proteins •Identify genetic factors that affect in body tissues. to alter the virus’s genetic activity. the severity of alcohol- and HCV- In addition to greatly heightening induced liver disease. HCV-infected patients’ risk of serious Immunology liver disease, heavy drinking during anti­ Model Systems viral (interferon) treatment has been •Identify the effects of alcohol on shown to impede patients’ responses to immune responses to HCV, includ­ •Develop animal models (using living therapy. Abstaining from drinking before ing changes in quality, behavior, and animals and laboratory cell cultures) and during treatment improves patients’ survival of immune cell populations both within and outside the liver.

Mechanisms of Liver Injury

•Determine what factors activate the liver cells that deposit fibrous material at the site of injury and cause scarring (i.e., hepatic stellate cells). These fac­ tors may include the patient’s immune response to HCV infection, the spe­

cific HCV genotype, and oxidative and Biochemical Virological (%) Response to Treatment stress triggered by alcohol use.

•Identify factors (including comple­ Alcoholics Nonalcoholics mentary medicines) that may inhibit Figure 6 Six months after completion of a 24-week course of interferon treatment, stellate cell activation and fibrosis in HCV-infected patients who were not alcoholics showed significantly bet­ HCV-infected patients who use alcohol. ter virological and biochemical responses to therapy than did alcoholic patients. (Response to therapy was assessed by measuring blood levels •Clarify the roles that alcohol and of the virus itself [HCV RNA] and of the alanine aminotrans­ HCV infection play in oxidative ferase [ALT], a marker for liver inflammation.) stress, lipid peroxidation, and dis­ SOURCE: Mochida et al. 1996. ruption of cell function.

238 Alcohol Research & Health Hepatitis C and Alcohol

response to antiviral therapy, although on cellular immune responses to hepatitis C virus METAVIR, CLINIVIR, and DOSVIRC groups. this improvement is not total. In light core protein are reversed by genetic immunizations Lancet 349:825–832, 1997. augmented with -expressing plasmids. of these findings, alcoholic patients Journal of Immunology 159(10):5107–5113, 1997. POYNARD, T.; RATZIU, V.; CHARLOTTE, F.; ET AL. should be advised to abstain from fur­ Rates and risk factors of liver fibrosis progression ther alcohol consumption and should HÉZODE, C.; LONJON, I.; ROUDOT-THORAVAL, in patients with chronic hepatitis C. Journal of be alcohol free for at least 6 months F.; ET AL. Impact of moderate alcohol consump­ Hepatology 34:730–739, 2001. tion on histological activity and fibrosis in patients before beginning interferon therapy. with chronic hepatitis C, and specific influence of RIGAMONTI, C.; MOTTARAN, E.; REALE, E.; ET Future research should further examine steatosis: A prospective study. Alimentary Pharma­ AL. Moderate alcohol consumption increases the effects of light and moderate drink­ cology and Therapeutics 17(8):1031–1037, 2003. oxidative stress in patients with chronic hepatitis ing on features of the hepatitis C virus; KUBO, S.; KINOSHITA, H.; HIROHASHI, K.; ET AL. C. Hepatology 38:42–49, 2003. alcohol’s effect on virus activity and High malignancy of hepatocellular carcinoma in SEEFF, L.B.; HOLLINGER, F.B.; ALTER, H.J.; ET AL. alcoholic patients with hepatitis C virus. Surgery response to treatment; patients’ immune Long-term mortality and morbidity of transfu- 121(4):425–429, 1997. responses to the virus; mechanisms of sion-associated non-A, non-B, and type C hepati­ fibrosis in response to HCV infection MENDENHALL, C.L.; SEEFF, L.; DIEHL, A.M.; ET tis: A National Heart, Lung, and Blood Institute and alcohol use; and animal models of AL. Antibodies to virus and hepatitis C collaborative study. Hepatology 33:455–463, 2001. HCV infection that may shed greater light virus in alcoholic hepatitis and cirrhosis: Their on disease processes in humans. ■ prevalence and clinical relevance. The VA Coop­ SERFATY, L.; POUJOL-ROBERT, A.; CARBONELL, erative Study Group (No. 119). Hepatology N.; ET AL. Effect of the interaction between 14:581–589, 1991. steatosis and alcohol intake on liver fibrosis pro­ gression in chronic hepatitis C. American Journal References MOCHIDA, S.; OHNISHI, K.; MATSUO, S.; ET AL. of Gastroenterology 97(7):1807–1812, 2002. 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