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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

 


Alcohol May Affect Progression of Hepatitis C & Interferon Efficacy
 
http://www.natap.org/

 

 

The journal Hepatology published a NIH study in the July issue and study findings raise serious questions regarding alcohol use by Hepatitis C Virus-infected individuals. A second article was also published in this issue of Hepatology on alcohol use & Hepatitis C Virus, and both articles are discussed below.
 
NATIONAL INSTITUTES OF HEALTH PRESS RELEASE
 
ALCOHOL INCREASES HEPATITIS C VIRUS IN HUMAN CELLS
Drinking May Compromise Treatment Success

 
A team of NIH-supported researchers today report that alcohol increases replication of the hepatitis C virus (Hepatitis C Virus) in human cells and, by so doing, may contribute to the rapid course of Hepatitis C Virus infection. The researchers tested the actions of alcohol in Hepatitis C Virus replicon - viral Hepatitis C Virus-ribonucleic acid or Hepatitis C Virus-RNAs that, when introduced into human liver cell lines, replicate to high levels. In separate laboratory experiments they showed that:
 
-- alcohol increases Hepatitis C Virus replication at least in part by upregulating a key cellular regulator of immune pathways and function known as nuclear factor kappa B;
 
-- alcohol inhibits the anti-Hepatitis C Virus effect of interferon-alpha therapy; and
 
--treatment with the opioid antagonist naltrexone abolishes alcohol actions.
 
"These findings are immediately useful to clinicians for counseling Hepatitis C Virus-positive patients about alcohol use," said Ting-Kai Li, M.D., Director, National Institute on Alcohol Abuse and Alcoholism (NIAAA).
 
Clinicians have long observed a high incidence of Hepatitis C Virus infection in heavy drinkers, including those without other risk factors such as intravenous drug abuse or history of blood transfusions. In addition, the virus is more likely to persist in heavy drinkers and to lead to such complications as cirrhosis and liver cancer. Suspected mechanisms for the latter effects include alcohol's capacity to compromise immune function and enhance oxidative stress. The role of alcohol use in Hepatitis C Virus acquisition has been more of a mystery.
 
Alcohol potentiates hepatitis C virus replicon expression



 
Hepatology July 2003, Volume 38, Number 1
 
Ting Zhang1-2, Yuan Li1, Jian-Ping Lai1, Steven D. Douglas1, David S. Metzger3, Charles P. O'Brien3, Wen-Zhe Ho1. Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; the 2Department of Infectious Diseases, The Children's Hospital of Fudan University, Shanghai, China; and the 3Department of Psychiatry, The Center for Studies of Addiction, University of Pennsylvania School of Medicine, Philadelphia, PA.
 
ABSTRACT
 
Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (Hepatitis C Virus) effect of interferon alfa (IFN-) in patients with Hepatitis C Virus infection. It is unknown, however, whether alcohol enhances Hepatitis C Virus replication and promotes Hepatitis C Virus disease progression. The availability of the Hepatitis C Virus replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and Hepatitis C Virus replicon expression. We determined whether alcohol enhances Hepatitis C Virus RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased Hepatitis C Virus replicon expression. Alcohol also compromised the anti-Hepatitis C Virus effect of IFN-. Investigation of the mechanism(s) responsible for the alcohol action on Hepatitis C Virus replicon indicated that alcohol activated nuclear factor B (NF-B) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-B, abolished alcohol-induced Hepatitis C Virus RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on Hepatitis C Virus replicon expression. In conclusion, alcohol, probably through the activation of NF-B and the endogenous opioid system, enhances Hepatitis C Virus replicon expression and compromises the anti-Hepatitis C Virus effect of IFN-. Thus, alcohol may play an important role in vivo as a cofactor in Hepatitis C Virus disease progression and compromise IFN--based therapy against Hepatitis C Virus infection.
 
BACKGROUND
 
Hepatitis C virus (Hepatitis C Virus) is responsible for the vast majority of cases of transfusion-associated and community-acquired non-A, non-B hepatitis and infects an estimated 170 million people worldwide. The seroprevalence of anti-Hepatitis C Virus antibody in the United States has been estimated at 1.8%, which corresponds to approximately 4 million people. Hepatitis C Virus is the leading cause of chronic viral hepatitis in the United States, and Hepatitis C Virus-infected individuals are the major recipients of liver transplantation. Hepatitis C Virus, first molecularly cloned in 1989,1 is a positive-strand RNA virus of the flavivirus family with a genome size of ~10 kb, which encodes a number of structural (core, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. Hepatitis C Virus has at least 6 distinct but related genotypes with more than 50 subtypes, and genotype 1 is the most common in the United States, Europe, and most parts of Asia. Hepatitis C Virus typically escapes clearance by the host's immune system and leads to the establishment of a persistent infection in approximately 70% of infected individuals. The consequences of a subset of patients with chronic Hepatitis C Virus infection are cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of Hepatitis C Virus with interferon alfa (IFN-) and ribavirin is associated with a sustained response rate of less than 50%. These limited therapeutic efficacies and the absence of an effective Hepatitis C Virus vaccine underscore the importance of research on factors that enhance Hepatitis C Virus infection and compromise IFN--based therapy.
 
Alcohol is the most commonly used and abused drug in the United States. Alcohol abuse significantly affects morbidity and mortality from infectious diseases. Alcohol consumption accelerates liver damage, diminishes therapeutic response to IFN-, and increases the rate of hepatocellular carcinoma in patients with chronic Hepatitis C Virus infection. Alcohol added in vivo and in vitro also impairs liver parenchymal cells and various functions of immune cells, including monocytes, T cells, and natural killer cells, which contribute to hepatocyte damage in chronic Hepatitis C Virus infection. Alcohol consumption and viral hepatitis infection, both recognized as major causes of liver disease worldwide, frequently coexist in patients with chronic liver disease. Alcohol and Hepatitis C Virus most likely act synergistically to promote the development and progression of liver damage. There is little direct information available concerning the effects of alcohol abuse on Hepatitis C Virus replication in hepatic cells. This lack of knowledge about the impact of alcohol abuse on Hepatitis C Virus is a major barrier to fundamental understanding of Hepatitis C Virus-related morbidity and mortality in alcohol abusers with Hepatitis C Virus infection. Thus, it is critical to investigate the impact of alcohol abuse on Hepatitis C Virus replication in the target cells such as hepatic cells. We investigated whether alcohol enhances Hepatitis C Virus RNA expression in Hepatitis C Virus replicon containing cell lines. We also studied whether the in vitro addition of alcohol to these cells compromises the anti-Hepatitis C Virus effect of IFN-.



 
Discussion by authors
 
Alcohol abuse is a major cofactor in the development of Hepatitis C Virus associated liver disease. Chronic alcohol abuse mediates liver damage as a result of increase in production of proinflammatory cytokines. In the setting of chronic Hepatitis C Virus infection, alcohol ingestion has an additional effect of diminishing immune clearance and increasing viral burden to hasten the onset of cirrhosis and hepatocellular carcinoma. Serum Hepatitis C Virus RNA levels were significantly higher in habitual alcohol drinkers with chronic Hepatitis C Virus infection than in infrequent alcohol drinkers with chronic Hepatitis C Virus. Hepatitis C Virus RNA levels were significantly higher in alcohol drinkers than abstainers, and the number of responders in IFN therapy decreased as alcohol intake increased. These in vivo data strongly support the hypothesis that alcohol plays a role as a cofactor in promoting Hepatitis C Virus RNA expression.
 
Clinical trials indicate a therapeutic benefit of IFN- treatment in chronic Hepatitis C Virus infection.13,18 Currently available combination therapy with IFN- and ribavirin is, however, effective in less than 50% of treated subjects. Although a history of alcohol abuse is not a contraindication to clinical therapy, continued alcohol use during therapy adversely affects response to Hepatitis C Virus treatment. Heavy alcohol consumption reduces the efficacy of IFN- therapy for chronic Hepatitis C Virus infection, and this adverse effect of alcohol drinking on efficacy might be reversed, partly, by abstinence for a long period before treatments. Thus, it is important to identify whether alcohol is one of the cofactors that are responsible for the failure of IFN- treatment. The Hepatitis C Virus replicon system has been successfully used to examine the anti-Hepatitis C Virus effect of IFN-. IFN- inhibits Hepatitis C Virus RNA expression in Huh.8 cells, as shown by a declined Hepatitis C Virus RNA expression over time. Our data showing that IFN- significantly inhibited (up to 90%) Hepatitis C Virus RNA expression in Huh.8 cells further confirms this observation. Thus, the Huh.8 cell line is an excellent in vitro model for studying whether alcohol interferes with the anti-Hepatitis C Virus effect of IFN- on Hepatitis C Virus RNA expression. We hypothesized that alcohol abuse may have a negative impact on the anti-Hepatitis C Virus effect of IFN-. Our data support this hypothesis, showing that alcohol compromised the anti-Hepatitis C Virus effect of IFN- in Huh.8 cells. This finding suggests the possibility that alcohol may reduce efficacy of IFN- therapy in vivo. The mechanism(s) responsible for the IFNÑmediated therapeutic effect remain unclear. Thus, further studies are critical to determine the mechanism(s) responsible for the anti-Hepatitis C Virus ability of IFN- and whether alcohol has the ability to interfere with the mechanism(s) involved in IFN- action against Hepatitis C Virus.
 
Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C
 
Hepatology July 2003, Volume 38, Number
Cristina Rigamonti. Internal Medicine Unit, Ospedale Maggiore della Caritˆ, Novara, Italy
 
"...the data presented are the first evidence that even moderate alcohol consumption worsens oxidative stress in patients with chronic hepatitis C and suggest that oxidative injury might be one of the mechanisms by which alcohol contributes to the progression of chronic hepatitis CÉ.."
 
It is well established that, in about 20% to 25% of the patients with chronic hepatitis C, the disease will progress to cirrhosis or even to hepatocellular carcinoma within 20 years from infection.1 Among the factors that contribute to the evolution of hepatitis C, the role of alcohol consumption has received increasing attention (for review, see Vento and Cainelli and Peters and Terrault). An alcohol intake exceeding 40 g/d for women and 60 g/d for men increases by 2- to 3-fold the risk of developing cirrhosis, independently from the duration of Hepatitis C Virus infection. According to Corrao and Aric˜, the interaction between ethanol and hepatitis C virus (Hepatitis C Virus) in promoting cirrhosis is additive for lifetime daily alcohol intake of 50 g/d but becomes synergistic when alcohol consumption exceeds 125 g/d. Nonetheless, a recent report suggests that even moderate alcohol intake (below 30-40 g/d) can promote the progression of fibrosis in patients with Hepatitis C Virus infection. In addition, heavy alcohol consumption has also an additive effect with chronic hepatitis C in increasing the risk of hepatocellular carcinoma.
 
Despite the finding that the capacity of ethanol to worsen the evolution of Hepatitis C Virus infection is well documented, the mechanisms involved are still poorly understood. It has been proposed that alcohol might favor viral replication8; however, other mechanisms are also likely to be involved. Recent studies have documented an association between Hepatitis C Virus infection and the presence of both liver and serum markers of oxidative stress. Furthermore, the expression of Hepatitis C Virus core protein in transgenic mice or in hepatoma cells lines alters the liver antioxidant status and promotes lipid peroxidation. Ethanol is also known to stimulate the production of reactive oxygen species and hydroxyethyl free radicals and to lower hepatic antioxidant defense. The implication of oxidative damage in human alcohol liver injury is supported by several reports showing an increase in lipid peroxidation markers in patients with alcoholic liver disease. Furthermore, immunohistochemistry has shown the presence of lipid peroxidation products in the areas of liver fatty infiltration, focal necrosis, and fibrosis.
 
These observations prompted us to investigate whether ethanol intake might potentiate oxidative stress in patients with chronic hepatitis C. One of the problems encountered in performing retrospective investigations with serum samples stored frozen for several years is that autooxidation can affect the direct measurement of lipid peroxidation. In the present study, we took advantage of the immunogenic properties of proteins complexed with lipid peroxidation products to evaluate the presence of antibodies against lipid peroxidation-derived antigens as markers of oxidative stress. Indeed, recent studies have shown that the titers of circulating IgG against epitopes derived from the binding of lipid peroxidation products to human albumin or low-density lipoproteins are significantly increased in patients with alcoholic liver disease. Moreover, alcoholic patients also display a significant increase in antibodies that recognize oxidized cardiolipin (Ox-CL).
 
ABSTRACT
 
The mechanisms by which alcohol consumption worsens the evolution of chronic hepatitis C (CHC) are poorly understood. We have investigated the possible interaction between hepatitis C virus (Hepatitis C Virus) and ethanol in promoting oxidative stress. Circulating IgG against human serum albumin (HSA) adducted with malondialdehyde (MDA-HSA), 4-hydroxynonenal (HNE-HSA), or arachidonic acid hydroperoxide (AAHP-HSA) and against oxidized cardiolipin (Ox-CL) were evaluated as markers of oxidative stress in 145 CHC patients with different alcohol consumption, 20 Hepatitis C Virus-free heavy drinkers (HD) without liver disease, and 50 healthy controls. Anti-MDA IgG was increased in CHC patients irrespective of alcohol intake as well as in the HD group. CHC patients with moderate alcohol intake (<50 g ethanol/d), but not HD, also had significantly higher values of anti-AAHP-HSA, anti-HNE-HSA, and anti-Ox-CL IgG (P < .05) than controls. A further elevation (P < .001) of these antibodies was evident in CHC patients with heavy alcohol intake (>50 g ethanol/d). Anti-AAHP and anti-Ox-CL IgG above the 95th percentile in the controls were observed in 24% to 26% of moderate and 58% to 63% of heavy drinkers but only in 6% to 9% of the abstainers. The risk of developing oxidative stress during CHC was increased 3-fold by moderate and 13- to 24-fold by heavy alcohol consumption. Heavy drinking CHC patients had significantly more piecemeal necrosis and fibrosis than abstainers. Diffuse piecemeal necrosis was 4-fold more frequent among alcohol-consuming patients with lipid peroxidation-related antibodies than among those without these antibodies. In conclusion, even moderate alcohol consumption promotes oxidative stress in CHC patients, suggesting a role for oxidative injury in the worsening of CHC evolution by alcohol.