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Smoking and Alanine Aminotransferase Levels in Hepatitis C Virus Infection
Implications for Prevention of Hepatitis C Virus Progression
Chong-Shan Wang, MD, MPH;
Shan-Tair Wang, PhD;
Ting-Tsung Chang, MD;
Wei-Jen Yao, MD;
Pesus Chou, DrPH
Arch Intern Med. 2002;162:811-815.
ABSTRACT
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Background Alcohol consumption is a well-known risk factor for elevated ALT levels,
but the role of cigarette smoking is unclear.
Methods We collected a cross-sectional sample of 6095 inhabitants 35 years or
older in a community with hyperendemic hepatitis B and C virus infections.
We assayed levels of serum alanine aminotransferase (ALT), hepatitis B surface
antigen (HBsAg), and anti–hepatitis C virus antibody (anti-HCV). Multivariate
logistic regression was performed to determine the factors for elevated ALT
levels ( 40 U/L) among people with different hepatitis infection statuses.
Results Prevalence of elevated ALT levels in individuals who were seronegative
for both infections or seropositive for HBsAg or anti-HCV was 3.9%, 11.1%,
and 30.8%, respectively. Subjects with elevated ALT levels were more likely
to be seropositive for anti-HCV, male, and seropositive for HBsAg; to drink
alcohol; to smoke; and to have undergone blood transfusion (P<.05). An association was found between elevated ALT levels and
the consumption of cigarettes and alcohol among anti-HCV–seropositive
subjects. In multivariate logistic analyses, alcohol consumption (odds ratio
[OR], 2.2; 95% confidence interval [CI], 1.2-4.1) and smoking (OR, 1.8; 95%
CI, 1.1-2.7) were significantly associated with elevated ALT levels among
anti-HCV–seropositive subjects, but no such association was found among
HBsAg-seropositive subjects. The odds of elevated ALT levels were 7 times
higher (95% CI, 2.7-18.8) for the anti-HCV–seropositive patients who
smoked 1 or more packs of cigarettes per day and frequently drank alcohol
than for those who did not.
Conclusions Smoking and alcohol consumption are independently associated with elevated
ALT levels among anti-HCV–seropositive individuals but not among HBsAg-seropositive
individuals. Patients who are seropositive for anti-HCV are strongly advised
not to smoke and drink alcohol to reduce the possible risk for aggravating
the liver dysfunction.
INTRODUCTION
SERUM ALANINE aminotransferase (ALT) is the most suitable and useful
protein enzyme used in the evaluation of hepatocellular damage. It is also
a surrogate marker for disease severity or index of hepatic activity.1-2 Elevated ALT levels are associated
with obesity, sex, alcohol consumption, use of medication, and viral hepatitis
infection.2-4 Its
association with viral hepatitis infection makes the ALT level a useful indicator
of drug efficacy in the treatment of hepatitis B (HBV) and C virus (HCV).5-6
Alcohol consumption is a well-known risk factor for alcoholic liver
diseases, cirrhosis, and hepatoma, independent of HBV or HCV infection.7-8 An additive or possibly synergistic
effect exists between alcohol consumption and HCV on elevated ALT levels.9 However, the effect of smoking on the activity of
serum ALT among patients with HBV or HCV infection has not been widely reported.
Whether the effect is additive to that of alcohol consumption or depends on
hepatitis infection status remains unclear.
The aim of this study was to determine whether an association exists
between alcohol consumption and ALT level, and between cigarette smoking and
ALT level, and whether the relationships vary according to hepatitis infection
status. These questions are important because, if these risk behaviors have
different effects on ALT levels for different hepatitis infection statuses,
they could provide evidence of different viral activity under the influence
of alcohol consumption and/or cigarette smoking that could be helpful for
secondary prevention. Previous studies of elevated ALT levels were mostly
hospital based or conducted in regions with low prevalences of seropositivity
for hepatitis B surface antigen (HBsAg) or anti-HCV antibody. To our knowledge,
no large-scale population study on elevated ALT levels has been performed
in a community with a high prevalence of HBsAg and anti-HCV seropositivity.10 We surveyed a community with hyperendemic HBV and
HCV infection to determine the risk factors for elevated ALT levels.
SUBJECTS AND METHODS
In A-Lein, a township of about 30 000 in southern Taiwan, patients
with serious liver diseases abound, and mortality due to hepatoma is more
than double the average in Taiwan,11 which
exceeds 30 cases per 100 000 per year. This rate is at least 6 times
higher than that of the countries in low-risk areas such as northern Europe
and the United States.12 In a community-wide
hepatitis screening of the 8800 adults 35 years or older in A-Lein, the prevalence
of anti-HCV seropositivity was found to be approximately 17% and of HBsAg
seropositivity to be approximately 13%.10 The
study lasted from January 1, 1996, through December 31, 1997. Intensive health
promotion activities for hepatitis screening were held before blood samples
and questionnaires were collected. Villagers came voluntarily during this
period. We have found no differences in the age, sex, health behaviors, or
prevalence of HBV and HCV between the responders and nonresponders. A total
of 6095 persons participated in this hepatitis screening program, a response
rate of 69.3%.
The questionnaire asked about demographic data, average daily consumption
of cigarettes, the habit of alcohol consumption, and blood transfusions. The
habit of drinking alcohol was subclassified as frequent, occasional, or rare.
Cigarette consumption was defined as (1) equal to or greater than 1 pack per
day (PPD), (2) less than 1 PPD, (3) abstained (stopped 6 months before
this study), or (4) never smoked. The town had no reported cases of human
immunodeficiency virus infection and was believed to have no or a negligible
number of intravenous drug abusers among the target population. Very few people
who were seropositive for HBsAg or anti-HCV had received interferon therapy.
Serum samples were sent to the Tainan Blood Center of the Chinese Blood
Service Foundation, Tainan, Taiwan, to test for HBsAg and anti-HCV markers
and ALT levels. Seropositivity for HBsAg was determined by means of an enzyme
immunoassay method (Version I; Murex, London, England). Seropositivity for
anti-HCV was tested by means of the third-generation Murex anti-HCV enzyme
immunoassay method, which contains the antigen from the HCV core and nonstructural
3, 4, and 5 regions. Levels of ALT were measured by means of a kinetic UV
test for clinical chemistry analyzers (Olympus System Reagent; Olympus Diagnostica
GmbH, Mills, Ireland). The cutoff value for diagnosis of elevated ALT level
was set at 40 U/L according to the suggestion of the Blood Center of the Chinese
Blood Service Foundation; this standard was also adopted by the National Health
Insurance Bureau for eligibility of claims about liver disorders. The same
cutoff value has been used for identifying communities with a high prevalence
of HCV infection.13 In this study, HBsAg seropositivity
also indicates anti-HCV seronegativity; anti-HCV seropositivity also indicates
HBsAg seronegativity; and seronegativity describes the negative status for
both infections.
Univariate analysis and multiple logistic regression were used to determine
the association of risk factors for elevated ALT levels (<40 vs 40
U/L). Multivariate logistic analysis was used to determine the risk factors
for elevated ALT levels among seronegative, HBsAg-seropositive, and anti-HCV–seropositive
individuals. The factors included in the multivariate logistic regression
analysis were sex, stratified age (<40, 40-49, 50-59, and 60 years),
alcohol and cigarette consumption, and blood transfusion. In multivariate
logistic regression analysis, individuals with coinfection (HBsAg and anti-HCV
seropositivity) were not included. We analyzed all results using Stata software.14
RESULTS
Of the 6095 community members who participated in this study, 9.2% had
elevated ALT levels (40 U/L). The prevalences of elevated ALT levels in
individuals who were seronegative, seropositive for HBsAg, and seropositive
for anti-HCV and coinfected were 3.9%, 11.1%, 30.8%, and 23.1%, respectively.
Individuals who were seropositive for HBsAg were 3 times more likely to have
elevated ALT levels than seronegative individuals (odds ratio [OR], 3.1; 95%
confidence interval [CI], 2.3-4.1). Individuals who were seropositive for
anti-HCV were 11 times more likely to have elevated ALT levels than seronegative
individuals (OR, 11.0; 95% CI, 8.9-13.5). In addition, individuals who were
male, habitual (frequent) drinkers of alcohol, or habitual smokers of cigarettes
(1 PPD) or who had undergone a blood transfusion were more likely to have
elevated serum ALT levels (P<.05) (Table 1). The mean and median levels of ALT in the various comparison
groups are also shown in Table 1.
Among these variables, anti-HCV–seropositive and coinfected individuals
and those with frequent alcohol consumption had higher mean and median ALT
levels.
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Table 1. Distribution of ALT and Univariate Analysis of Risk Factors
for Abnormal Liver Function*
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In multivariate logistic regression analysis of the risk factors for
elevated ALT levels stratified by hepatitis infection status, no significant
factor affected HBsAg-seropositive subjects, whereas alcohol consumption (OR,
2.2; 95% CI, 1.2-4.1) cigarette smoking (OR, 1.8; 95% CI, 1.1-2.7), and being
aged 50 to 59 years (OR, 1.4; 95% CI, 1.0-2.0; P
= .045) were significant factors associated with elevated ALT levels among
anti-HCV–seropositive subjects (Table
2). Among seronegative subjects, being male (OR, 1.5; 95% CI, 1.0-2.2),
drinking alcohol (OR, 2.7; 95% CI, 1.6-4.5), being aged 40 to 49 years (OR,
1.7; 95% CI, 1.2-2.5), and having undergone a blood transfusion (OR, 1.6;
95% CI, 1.0-2.4) were significant factors for elevated ALT levels, but those
in older stratified age groups were less likely to have elevated ALT levels
(OR, 0.98; 95% CI, 0.97-0.99).
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Table 2. Logistic Regression Analysis of Risk Factors for Elevated
ALT Levels Stratified by Status of Hepatitis Infection*
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The additive effect of cigarette and alcohol consumption on elevated
ALT levels was found among anti-HCV–seropositive subjects. The risk
(70.0%) was highest among those who habitually smoked 1 PPD or more and who
frequently drank alcohol (Figure 1). The odds of elevated ALT levels were 7 times higher (95% CI, 2.7-18.8) for
that group than for those who did neither. An association between the prevalence
of elevated ALT levels and the levels of alcohol drunk and cigarettes smoked
was found in the anti-HCV–seropositive group but not in the HBsAg-seropositive
group. Figure 1 also shows that
the ALT level is more elevated for heavy smokers (1 PPD) than for frequent
drinkers who did not smoke (50.0% vs 44.4%).
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Prevalence of elevated alanine aminotransferase levels stratified
by the levels of cigarette smoking (smoking) and alcohol consumption (drinking)
among persons who were seropositive for anti–hepatitis C virus antibody.
PPD indicates packs of cigarettes per day. Levels of alcohol consumption are
described in the "Subjects and Methods" section.
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COMMENT
This study demonstrates that consumption of cigarettes and alcohol are
associated with elevated ALT levels among anti-HCV–seropositive subjects
but not among HBsAg-seropositive subjects. Furthermore, cigarette smoking
and alcohol consumption had an additive effect on the prevalence of elevated
ALT levels in these patients. These results indicate that cigarette smoking
and alcohol consumption are closely associated with the prevalence of elevated
ALT levels in anti-HCV–seropositive individuals. The prevalence of elevated
ALT levels for those who only smoked heavily (1 PPD) is not less than
the prevalence for those who only drank frequently (50.0% vs 44.4%), which
implies that smoking, like alcohol consumption, is an independent promoting
factor for hepatic necroinflammation. A plausible explanation for the significant
effect of cigarette smoking on hepatic necroinflammation is that the liver
is a target organ for the chemicals in tobacco and alcohol. Patients who were
seropositive for anti-HCV with elevated ALT levels require repeated hospital
visits for biochemical tests, ultrasonography, and medical treatment, and
hepatocellular carcinoma is more likely to develop than in those with normal
ALT levels.15-16 Therefore, abstinence
from smoking and alcohol consumption by anti-HCV–seropositive individuals
could probably help to slow their progression into advanced liver diseases
and minimize their need for health care services. At present, treatment for
chronic HCV infection is recommended for patients with persistently elevated
ALT levels,17 and no rationale exists for treating
anti-HCV–seropositive patients with normal ALT levels.18
Patients who are seropositive for anti-HCV and who have active, heavy alcohol
intake are not recommended for treatment, because alcohol increases viremia
and interferes with the response to treatment.9
It is also rational to advise all anti-HCV–seropositive patients, particularly
those with elevated ALT levels, to stop smoking to eliminate the additive
effect that smoking has on HCV antibodies. Whether this will cause elevated
ALT levels to return to normal in some patients needs further study. However,
to suggest that they abstain from smoking before initiating expensive and
unpleasant anti-HCV treatment might be a cost-effective measure and might
increase treatment response.
A high prevalence of HCV infection and rate of viral replication, rapid
changes in histological progression of liver lesions, and increased carcinogenesis
have been noted in patients with alcoholic liver diseases.8-9,19
People who habitually smoked cigarettes showed a higher prevalence of HCV
infection than those who did not, and multivariate logistic regression showed
smoking to be a significant risk factor for acquiring HCV infection.10 Cigarette smoking is also highly associated with
the development of hepatocellular carcinoma.15, 20
Nevertheless, the effect of smoking on the necroinflammatory activity of anti-HCV–seropositive
patients is not fully understood. Smoking has been shown to influence all
aspects of the immune systems, including alterations of humoral and cellular
immunity.21 Further study is needed to determine
whether cigarette smoking has effects similar to those of alcohol consumption
on the increase of viral replication, the worsening of histological progression,
and the immunosuppression within anti-HCV–seropositive individuals.
In this study, the prevalence of elevated ALT levels was about 3 times
higher for those who habitually smoked 1 PPD or more and frequently drank
alcohol than for those who did neither. In addition, 75.2% of those anti-HCV–seropositive
subjects who did not smoke cigarettes or drink alcohol had ALT levels within
the normal range. The reason for a greater prevalence of normal ALT levels
among these anti-HCV–seropositive individuals could be that more of
them were seronegative for HCV RNA and they had less change in histological
findings in the liver. As a result, they might be less liable to development
of chronic disease than those who do consume cigarettes or alcohol.1, 17, 22 In addition, they
might be more likely to recover from an acute HCV infection and become seronegative
for HCV RNA because of better host immunity. A clear correlation exists between
alcohol consumption and liver HCV RNA levels.9
Whether a correlation also exists between smoking levels and liver HCV RNA
levels requires further study. The prevalence of cigarette smoking is much
higher than that of alcohol consumption (27.2% vs 5.5%) in this study, but
the effect of smoking on anti-HCV–seropositive people is almost overlooked
in practice. It will be helpful for secondary prevention to suggest that anti-HCV–seropositive
patients abstain from cigarette smoking as well as alcohol consumption.
Confounding factors might exist in this study. First, because smokers
might use health care services more often than nonsmokers,23
they might be given more medications or medical injections that could result
in different genotypes of HCV infections or that could produce hepatic necroinflammation
and thereby cause more elevated ALT levels.2
Second, smokers were more likely to have a lower socioeconomic status than
nonsmokers and therefore were more likely to work in more hazardous environments
that cause more elevated ALT levels.2
Some limitations exist in this community-wide population study. First,
because the amounts of cigarette and alcohol consumption were self-reported,
a bias toward underestimation might exist due to social stigmata associated
with the reporting of these adverse lifestyle practices. Misclassification
of alcohol consumption might have occurred, because information about the
amount of alcohol consumed was not obtained. Second, the duration of cigarette
and alcohol consumption was not recorded, but duration is associated with
liver damage that can cause elevated ALT levels. Third, polymerase chain reaction
analysis for HCV RNA levels was not performed to elucidate the relationship
between the actual viral status or viral titers and past infections. Finally,
this cross-sectional study may blur etiologic associations; hence, a long-term
prospective study is needed to see the effects of cigarette smoking, the combined
effects of smoking and alcohol consumption, and the effects of abstinence
on HCV infection.
CONCLUSIONS
Alcohol and cigarette consumption are independently associated with
elevated ALT levels among anti-HCV–seropositive individuals but not
among HBsAg-seropositive individuals. This finding will be useful for secondary
prevention among anti-HCV–seropositive patients to slow further progression
into advanced liver diseases and to decrease excessive use of health care
services. Abstention from cigarettes and alcohol by anti-HCV–seropositive
patients might be a cost-effective measure before initiation of treatment
for anti-HCV seropositivity. The detailed biological effect of smoking on
the necroinflammation, viral loads, histological progression, and hepatocarcinogenesis
among anti-HCV–seropositive patients needs further evaluation.
AUTHOR INFORMATION
Accepted for publication July 31, 2001.
This study was supported by the C. T. Hsu Cancer Research Foundation,
Taipei City, Taiwan.
We thank the A-Lein Community Health Promotion Committee, Kaohsiung
County, Taiwan; the staff and volunteers of the A-Lein Community Health Center,
Kaohsiung County, for their assistance in data collection; and the Tainan
Blood Center of the Chinese Blood Service Foundation, Tainan City, Taiwan,
for assistance with laboratory analysis.
Corresponding author and reprints: Pesus Chou, DrPH, National Yang-Ming
University, Institute of Public Health, Shih-Pai, Taipei 112, Taiwan, Republic
of China (e-mail: pschou{at}ym.edu.tw or wangcsh{at}mail.ncku.edu.tw).
From the A-Lein Community Health Center, Kaohsiung County, Taiwan (Dr
C.-S. Wang); the Institute of Public Health, Department of Medicine, Colleges
of Medicine (Drs C.-T. Wang and S.-T. Wang), the Institute of Public Health,
Division of Gastroenterology, Department of Internal Medicine (Dr Chang),
and the Department of Nuclear Medicine, College of Medicine (Dr Yao), National
Cheng Kung University, Tainan, Taiwan; and the Community Medicine Research
Center and Institute of Public Health, National Yang-Ming University, Taipei,
Taiwan (Dr Chou).
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