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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.
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