INFO: Alcohol and Hepatitis C

[Guest guest]

Alcohol and Hepatitis C S. Lieber, M.D., M.A.C.P. S. Lieber, M.D., M.A.C.P., is chief of the Section of Liver Disease & Nutrition, Alcohol Research Center, Bronx, NY Medical Center and professor of medicine and pathology at Mt. Sinai School of Medicine, New York, New York.The preparation of this article was supported in part by National Institute on Alcohol Abuse and Alcoholism grants AA–11115 and AA–12867, by the Department of Veterans Affairs, and by the Kingsbridge Research Foundation. Infection with the hepatitis C virus (HCV) has become a leading cause of scarring of the liver (i.e., fibrosis) and cirrhosis in the United States. HCV-related cirrhosis (with its associated complications, such as liver cancer) is a major cause of death, although it develops slowly and occurs only in approximately one-third of HCV-infected patients. Alcohol can exacerbate HCV infection and the associated liver damage by causing oxidative stress and promoting fibrosis, thereby accelerating disease progression to cirrhosis. Furthermore, alcohol may exacerbate the side-effects associated with current antiviral treatment of HCV infection and impair the body's

immune defense against the virus. Of the HCV-infected people who do not consume alcohol, only a minority progresses to severe liver disease and requires antiviral treatment. Because alcohol potentiates the fibrosis- and cancer-inducing actions of HCV, alcoholics are particularly vulnerable to HCV infection and most in need of treatment. Key words: hepatitis C virus; chronic AODE (effects of alcohol or other drug use, abuse, and dependence); disease course; ethanol metabolism disorder; oxidative stress; fibrosis; hepatocyte; carcinoma; anti-infective agents; interferon; antioxidants; patient compliance Hepatitis is an inflammation of the liver that is characterized by jaundice, liver enlargement, abdominal and gastric discomfort, abnormal liver function, and other

symptoms. Although in many patients the diseased liver is able to regenerate its tissue and retain its function, severe hepatitis may progress to scarring of the liver tissue (i.e., fibrosis), cirrhosis, liver cancer (i.e., hepatocellular carcinoma), and chronic liver dysfunction. Hepatitis can have numerous causes, such as excessive alcohol consumption or infection by certain bacteria or viruses. One common cause of hepatitis is infection with one of several types of viruses (e.g., hepatitis A, B, or C viruses). With the development of new diagnostic tools, infections with the hepatitis C virus (HCV) have received increasing attention in recent years. In the United States, the number of deaths caused by HCV is increasing and may approach or even surpass the number of deaths from AIDS in the next few years (Alter 1997, 2000). HCV infection is becoming a leading cause of cirrhosis,

liver failure, and hepatocellular carcinoma, with incidence1 (1For a definition of this and other technical terms used in this article, see the glossary.) and prevalence rates of those complications highest among nonwhite racial and ethnic groups. Lifestyle and socioeconomic factors have been implicated in these ethnic and racial differences (Howell et al. 2000). In addition to genetic factors in the infected person ( et al. 2000), three independent factors are associated with an increased rate of disease progression to those life-threatening consequences. These factors include daily alcohol consumption of 50 grams or more (i.e., three or more standard drinks2). (2A standard drink is defined as 12 fluid

ounces (oz) of regular beer, 5 fluid oz of wine, or 1.5 fluid oz of distilled spirits (80 proof) and contains approximately 0.5 oz (14 grams) of pure alcohol (Dufour 1999). age at infection of more than 40 years, and male gender (Ostapowicz et al. 1998). These factors have a greater influence on fibrosis progression in HCV infection than the virus itself (Poynard et al. 1997). Early studies had reported that HCV infection (as well as infections with the hepatitis B virus) was particularly common among alcoholics, affecting 35 percent of alcohol-dependent people. However, those studies did not exclude the role of other potential risk factors, such as intravenous drug abuse and receipt of blood transfusions before 1990.3 (3Before 1990, no reliable tests for detecting HCV in the blood were available, leading to a risk of HCV infection through transfusion of contaminated blood. Since 1990, the introduction of improved blood screening tests has substantially reduced the risk of transfusion-related HCV infection (Lauer and 2001). To determine the association between alcoholism and HCV infection more conclusively, Rosman and colleagues (1996) screened alcoholic patients admitted for detoxification and patients attending a general medical clinic for the presence of hepatitis B and C viruses in the blood and for risk factors for infections with those viruses. The general medicine clinic patients were also screened for possible alcoholism, and those identified as nonalcoholic served as the control group for alcoholic patients who had no other known risk factors for viral hepatitis (e.g., intravenous drug use or

blood transfusions). The study found that actively drinking alcoholic patients were more likely to show evidence of HCV in the blood than control patients, suggesting that alcoholism in some way is a predisposing factor for HCV infection. This conclusion is consistent with the prior observation that the presence of inflammation in the liver is strongly associated with the presence of antibodies to HCV in alcoholic patients who have no other known risk factors for the infection (Rosman et al 1993). These observations are further supported and confirmed by studies of the epidemiology and natural history of HCV infection, which are discussed in the following section. This article explores the association between alcoholism and HCV infection in more detail. After reviewing the epidemiology and natural history of the infection, it discusses some of the mechanisms through which alcohol may

exacerbate the consequences of HCV infection. The article also discusses current treatment approaches for HCV infection, particularly among drinkers. EPIDEMIOLOGY AND NATURAL HISTORY OF HCV INFECTION It is estimated that HCV infects some 170 million people worldwide, and in the United States an estimated 2.7 million people have HCV infection (Lauer and 2001). Nevertheless, the virus has attracted major attention among researchers and clinicians only over the last two or three decades, mainly because initially no reliable diagnostic tools were available. Moreover, the early stages of the infection are relatively benign, and severe manifestations (e.g., cirrhosis) occur only in a minority of the infected people and after long periods of time (i.e., up to

20 to 30 years) (Di Bisceglie 2000). As a result of this delay, clinicians currently note a peak of severe and life-threatening complications of HCV infection (e.g., end-stage cirrhosis and liver cancer), although maximal rates of infections may have occurred three or four decades ago. Of the people infected with HCV, only a minority eventually develop serious, life-threatening complications (see figure 1). Thus, approximately 15 to 25 percent of infected people recover spontaneously. An additional 20 to 25 percent of infected people exhibit a stable, nonprogressive chronic hepatitis that is virtually asymptomatic and, therefore, does not require antiviral treatments, particularly because the side-effects of currently available

treatments may be more severe than the symptoms of the disease itself. Figure 1 The progression of hepatitis C (HCV) infection and the proportion of initially infected patients who develop each disease stage. Approximately two-thirds of the people suffering an acute infection experience a relativity benign disease course; that is, the infection resolves on its own, does not progress, or

responds to antiviral treatment. Conversely, approximately one-third of people infected with HCV develop cirrhosis, and many later die of complications from the cirrhosis (i.e., decompensated cirrhosis) or from liver cancer (i.e., hepatocellular carcinoma [HCC]). The proportions shown here provide only a general indication of how this disease progresses. The actual prognosis may vary strikingly in each patient, depending on numerous factors, including the patient's genetic makeup; gender; age at onset of the infection; presence or absence of antiviral treatment; and, especially, concomitant alcohol use. These factors also affect the duration of disease progression, which, from the onset of the infection to the end- stages of disease, may last from 10 to 30 years.+ In 50 to 60 percent of HCV-infected patients the disease

may progress with time. Of those patients, about one-half to three-fourths show a sustained reduction in their virus levels in response to state-of-the-art antiviral treatment (i.e., a combination of the medications interferon-alpha and ribavirin) (Fried et al. 2001). The response to treatment depends on the specific strain of HCV with which the patient is infected. Six distinct HCV strains exist that differ in their genetic makeup (i.e., genotype). In the United States, the most commonly found genotypes are called 1a, 1b, 2, and 3. Among patients infected with these HCV strains, those infected with HCV genotypes 1a or 1b show lower response rates to treatment (i.e., 46 percent) than do patients infected with HCV genotypes 2 or 3 (i.e., 76 percent). Treatment failure and, consequently, disease progression to cirrhosis, liver failure, or hepatocellular carcinoma, occurs in

approximately 25 to 30 percent of patients originally infected with HCV (see figure 1). Because these patients will develop serious and potentially fatal health consequences, it is essential to devise ways to identify them before they enter the advanced stages of the disease in order to initiate early treatment and avoid those factors that promote rapid disease progression toward the end-stages. Because of the potentially serious consequences of HCV infection, prevention is an important concern. The primary prevention approach obviously is to avoid the main sources of infection, such as intravenous drug abuse or transfusion of contaminated blood. Another prevention approach would be to avoid sexual promiscuity, which promotes acquisition of the disease (Alter 2000) in ways that have not yet been well defined. In addition to these "classic" risk factors, other factors can

significantly increase the rate of infection, its persistence, or the rapid evolution of the disease toward the dismal end-stages. Although some of these factors (e.g., genetic factors, gender, and age at infection) cannot be controlled, avoidance of other factors could have a tremendous impact on the spread and incidence of HCV infection. Among these controllable risk factors, none is more important than alcohol consumption. EFFECT OF ALCOHOLISM ON HCV INFECTION Researchers first became aware of the major effect of alcoholism on HCV infection when they noted that alcoholism was associated with HCV (but not hepatitis even in people who did not show classic risk factors, such as

intravenous drug abuse or blood transfusions (Rosman et al. 1996; also see Schiff 1997). In addition to promoting the acquisition or persistence of HCV, alcohol subsequently was shown to affect the two major processes that are harbingers of rapid and severe progression of liver disease and of the patient's deterioration, namely inflammation and fibrosis. Effects of Alcoholism on HCV Acquisition and Persistence In addition to the high incidence of HCV infection in heavy drinkers even in the absence of classic risk factors, other observations suggest that heavy alcohol consumption enhances the ability of the virus to enter and persist in the body. For example, several studies demonstrated a correlation between the presence of virus in the blood (i.e., viremia) and the amount of alcohol patients

reported they consumed (i.e., self-reported alcohol consumption, or SRAC) (see figure 2). Furthermore, moderation of alcohol consumption was shown to result in a decrease in the number of virus particles in the blood (i.e., the viral titer) (Cromie et al. 1996). Researchers do not yet fully understand the mechanism through which alcohol affects the viral titer. It is well known, however, that alcohol impairs the function of certain components of the body's immune system (Ince and Wands 1999). An impaired immune function, in turn, may influence the ability of the virus to persist in the body rather than be eliminated by immune cells. Figure 2 Relationship between hepatitis C virus (HCV) levels in the blood and self-reported alcohol consumption (SRAC) (in grams of alcohol per week*) during a typical week in the month preceding the HCV measurement. Greater alcohol consumption was associated with higher virus levels in the blood. *One standard drink (i.e., 12 fluid ounces of beer, 5 fluid ounces of wine, or 1.5 fluid ounces of distilled spirits) contains approximately 14 grams (0.5 ounces) of pure alcohol.NOTE: Statistical significance: r = 0.26, p<0.0001.SOURCE: Pessione et al. 1998, with permission. Another mechanism through which alcohol consumption may favor the progression and exacerbation of HCV infection is oxidative stress. The term "oxidative stress" refers to the presence of excessive levels of highly reactive molecules called free radicals in the cell or a lack of molecules called antioxidants that can eliminate those free radicals. (For more information on oxidative stress, see the sidebar below.) Various studies have indicated that through as yet unknown mechanisms, HCV infection itself can lead to oxidative stress (Larrea et al. 1998), which contributes to the virus's ability to persist in the body. This virus-induced oxidative stress, in turn, may be exacerbated by the breakdown (i.e., metabolism) of alcohol in the liver, which can generate free radicals that contribute to oxidative stress (Lieber 1997) and which are a major cause of alcohol-related hepatic injury (Lieber 2001). OXIDATION AND FORMATION OF FREE RADICALS The breakdown of nutrients (e.g., carbohydrates, proteins, and fats) as well as other molecules (e.g., alcohol) frequently involves chemical reactions that use oxygen and/or hydrogen (i.e., oxidation reactions). Generally speaking, oxidation reactions are those that add oxygen to or remove hydrogen from a substance (or both). For example, the metabolism of alcohol involves two oxidation reactions. First, one enzyme converts alcohol (chemically referred to as ethanol) to acetaldehyde by removing hydrogen. Then, a second enzyme converts acetaldehyde to acetate by removing

additional hydrogen and adding oxygen. Two major enzyme systems are involved in ethanol metabolism in the liver. The first one involves the enzyme alcohol dehydrogenase. The second system, which is activated mainly after heavy alcohol consumption, is the microsomal ethanol-oxidizing system (MEOS). Particularly the MEOS, however, sometimes generates not only stable, nontoxic molecules but also highly unstable (i.e., reactive) and potentially harmful molecules, called free radicals. Many of these molecules contain oxygen and are called oxygen radicals. Common oxygen radicals include superoxide (O2.), hydrogen peroxide (H2O2), and hydroxyl radicals (OH.). The presence of excess levels of oxygen radicals is called oxidative stress. If unchecked, oxygen radicals can damage cells by attacking vital cell components,

such as the fat and protein constituents of the cell wall and the cell's genetic material. For example, oxidative stress can induce enhanced metabolism of fat molecules (i.e., lipid peroxidation) that may generate biologically active molecules. Some of these molecules, in turn, may contribute to the development of fibrosis. Because the formation of oxygen radicals is a natural process that occurs during many metabolic processes, cells have developed several protective mechanisms to prevent radical formation or to detoxify radicals. These mechanisms employ molecules called antioxidants, which are found in foods or generated by the body itself. Commonly found antioxidants include vitamin E, vitamin C, and glutathione (GSH). These compounds have several mechanisms of action. For example, GSH can neutralize oxygen radicals by transferring hydrogen to the reactive

molecules, thus creating a more stable chemical structure. Using their internal antioxidants, cells can deal with normal levels of oxygen radical formation. When oxygen radical formation is greater than normal or antioxidant levels are lower than normal, however, oxidative stress occurs that may contribute to cell death and tissue damage, such as fibrosis of the liver. Chronic alcohol consumption can increase oxidative stress in several ways. For example, alcohol metabolism by the MEOS is associated with the generation of oxygen radicals. Moreover, animal models demonstrated that chronic alcohol consumption reduces the levels of various antioxidants, including GSH (Colell et al. 1998; Nanji and Hiller-Sturmhöfel 1997). Accordingly, treatment with potent antioxidants or with compounds to enhance the body's ability to generate antioxidants may relieve oxidative stress

and counteract the fibrosis-inducing effects of alcohol and other conditions (e.g., infection with the hepatitis C virus). -ne Hiller-Sturmhöfelhttp://pubs.niaaa.nih.gov/publications/arh25-4/245-254.htm