Original Article

Cigarette smoking and serum liver enzymes: the role

of alcohol and inflammation

S Goya Wannamethee and A Gerald Shaper

Department of Primary Care and Population Health, UCL Medical School, Royal Free Campus, London NW3 2PF, UK
Corresponding author: Dr S Goya Wannamethee. Email: goya@pcps.ucl.ac.uk

Abstract
Background and aims: Smoking may affect the liver through inflammatory pathways and may aggravate the pathogenic
effects of alcohol on the liver. We have examined the relationship between cigarette smoking and liver enzymes and the role of
alcohol and C-reactive protein (CRP), a marker of inflammation.
Methods: The subjects consisted of 4595 men aged 40– 59 y with no history of coronary heart disease drawn from general
practices in 24 British towns.
Results: Cigarette smoking was significantly associated with increased levels of gamma-glutamyl transferase (GGT) and
alkaline phosphatase (ALP) (P , 0.0001) and was inversely associated with increased aspartate aminotransferase (AST) after
adjustment for alcohol intake, body mass index and physical activity. Compared with never smokers, heavy cigarette smokers
(40/day) were associated with increased odds of elevated GGT (23 IU/L) (adjusted odds ratio [OR] 1.56 [1.08, 2.27]), which
was abolished after adjustment for CRP (adjusted OR 1.27 [0.87, 1.86]). There was a significant interaction between smoking
and alcohol on GGT. In the absence of heavy drinking, there was no association between smoking and GGT after adjustment
for CRP. Among heavy drinkers, smoking was associated with increased levels of GGT independent of CRP. Smoking was
associated with increased odds of elevated ALP (11 IU/L) (adjusted OR 3.95 [2.77, 5.62]), which persisted after adjustment
for CRP and white cell count (adjusted OR 2.90 [1.99–4.23]), possibly reflecting increased bone cell activity.
Conclusion: The findings suggest that cigarette smoking does not cause liver injury, but may enhance the effects of alcohol
on liver cell injury in heavy drinkers.

Ann Clin Biochem 2010; 47: 321– 326. DOI: 10.1258/acb.2010.009303

Introduction some studies have reported significant associations

It is well established that alcohol consumption can cause
liver dysfunction and initiate liver disease.1 – 6 Basic and
clinical research suggests that cigarette smoking affects the
liver with numerous toxins in cigarettes altering enzymatic
and inflammatory pathways in hepatic physiology.7,8
Smoking is considered to be a risk factor for liver
cancer,9,10 has been shown to increase risk of cirrhosis10,11
and may adversely affect the progress of chronic liver dis-
eases.12 In addition, cigarette smoking may aggravate the
pathogenic effects of alcohol on the liver.10,13 – 15 The associ-
ation between smoking and liver function in the general
population is less clear. A few population studies have
examined the relationship between smoking and enzymes
measuring liver function such as gamma-glutamyl transfer-
ase (GGT), alanine aminotransferase (ALT), aspartate ami-
notransferase (AST) and alkaline phosphatase (ALP). Most
of these studies have shown no positive association
between smoking and ALT or AST, enzymes more specific
to the liver and indicators of liver damage.3,6 However,
between smoking and GGT3,4,16 – 21 and significant
smoking interactions with alcohol on GGT.4,22 Levels of
GGT are associated with inflammatory markers23,24 and
GGT is considered a marker of oxidative stress.25 Smoking
is strongly associated with inducing inflammation.26 The
lack of association of smoking with ALT and AST reported
in most studies suggests that smoking does not cause liver
damage, but may induce GGT in the liver possibly
through its influence on inflammation. A positive associ-
ation has been observed between smoking and ALP,27
but ALP is not specific to the liver and is also produced
in the bones and kidney.28,29 We have previously reported
an association between smoking and GGT.30 The aim of
this study was to examine the relationship between
smoking and liver enzymes GGT, AST and ALP, with par-
ticular focus on the combined effects of alcohol and
smoking on GGT and the role of C-reactive protein (CRP),
a marker of inflammation in the smoking– GGT relation-
ship. We hypothesized that the relationship between

Annals of Clinical Biochemistry 2010; 47: 321– 326

322 Annals of Clinical Biochemistry Volume 47 July 2010
................................................................................................................................................
smoking and GGT may be associated with its effect on
inflammation.
Subjects and methods
The British Regional Heart Study is a large prospective
study of cardiovascular disease comprising 7735 men aged
40 –59 y drawn from general practices in each of 24 towns
in England, Wales and Scotland in 1978 –1980. The criteria
for selecting the town, the general practice and the subjects
as well as the methods of data collection have been
reported.31 Research nurses administered a standard ques-
tionnaire that included questions on lifestyle and medical
history. The men were asked to recall a doctor’s diagnosis
of coronary heart disease (CHD) (angina, myocardial infarc-
tion), stroke and diabetes. Physical measurements including
height and weight were made and venous non-fasting blood
samples were obtained to prepare serum for measurement
of biochemical and haematological variables. CRP measure-
ments were only available for men in the seventh to 24th
towns visited (n ¼ 4882). Details of lifestyle factor classifi-
cations have been reported.5,30 – 32 A physical activity score
was derived for each man and the men were initially
grouped into six broad categories based on their total
score (none, occasional, light, moderate, moderately vigor-
ous, vigorous).31 Men who reported none or occasional
were defined as ‘inactive’. Since CHD is strongly associated
with inflammation and smoking and to reduce the con-
founding effects of CHD, men with recall of doctor diagno-
sis of CHD have been excluded (n ¼ 266). We further
excluded men with missing data on smoking history and
men with no data on liver enzymes (n ¼ 21). After these
exclusions, data were available for a group of 4595 men.
Liver enzymes
The men attended the examination centre between 8:30 and
18:30. Blood samples (non-fasting) were taken into evacua-
ted tubes for measurement of biochemical and haematogi-
cal variables. All samples reached the Department of
Haematology, Queen Elizabeth Hospital, Birmingham by
the following morning and estimations were completed
by noon of that day. GGT was measured on serum with
a Technicon SMA 12/60 ‘Autoanalyzer’. The distribution
of GGT was skewed and log transformation was used.
Elevated GGT, AST and ALP were defined as the top fifth
of the distribution. ALT was not measured in the present
study.
CRP and white cell count
In 1531 men who were included in an earlier case-control
analysis,33 CRP protein was measured using a sensitive
enzyme immunoassay.34 In the remainder, CRP was
assayed by ultrasensitive nephelometry (Dade Behring,
Milton Keynes, UK) in Glasgow; intra- and interassay coef-
ficients of variation were 4.7% and 8.3%, respectively. Using
the results of a calibration study in 295 subjects whose
samples were assayed using both methods, the results of
the earlier CRP assays were adjusted to the Glasgow
assay, for which the current CRP international standard
was used, by subtracting 20.128 from the earlier log CRP
assay (87.9% of the original value). White cell count
(WCC) was measured with an automated blood cell
(Coulter, Miami, FL, USA) counter.
Smoking and alcohol consumption
Smoking
The men were initially classified into eight groups on the
basis of their smoking status at screening. (1) Never
smokers – those who had never smoked cigarettes and
did not currently smoke a pipe or cigars. (2) Primary
pipe/cigar smokers – those who had never smoked ciga-
rettes and currently smoked a pipe or cigars. (3)
Ex-cigarette smokers – those who used to smoke cigarettes
but did not currently smoke a pipe or cigars. (4) Secondary
pipe/cigar smokers – former cigarette smokers who cur-
rently smoked a pipe or cigars. (5 – 8) Current cigarette
smokers at four levels; 1 –19, 20, 21– 39 and 40 cigarettes
or more per day irrespective of whether they have ever
smoked a pipe or cigars. The smoking history has been
validated with cotinine concentrations.35
Alcohol consumption
The men were questioned about frequency and quantity of
alcohol intake, resulting in eight drinking categories: non-
drinkers, occasional drinkers (special occasions or 1– 2
drinks per month), weekend drinkers (1 – 2, 3 –6 or more
than 6 drinks per day) and men drinking daily or on most
days (1 – 2, 3– 6 or more than 6 drinks per day). The men
were then divided into five groups on the basis of their
estimated reported weekly intake:10 non-drinkers, occasional
drinkers (2 units/month), light (weekend 1 – 2/day, 3– 6/
day and daily 1 –2/day; 1 –15 units/week), moderate
(weekend .6 and daily 3 –6/day; 15 – 42 units/week) and
heavy (daily .6/day; .42 units/week). One UK unit of
alcohol (one drink) represents half a pint of beer, a single
measure of spirits or a glass of wine (8 – 10 g alcohol).
Statistical methods
Analysis of covariance was used to obtain adjusted means.
The distribution of GGT, AST, CRP and WCC were
skewed and log transformation was used and geometric
means presented. To assess the effects of cigarette
smoking, we excluded all non-cigarette smokers who
smoked pipe or cigars from the analyses ( primary and
secondary cigar smokers; groups 2 and 4; n ¼ 457). Tests
for trend across the cigarette smoking groups were assessed
by assigning ordinal values 1 –6 to the six smoking groups
never, ex, 1 – 19, 20, 21 –39 and 40þ/cigs/day. Similar tests
for trend were carried out across the alcohol groups (1 – 5).
Logistic regression was used to obtain adjusted relative
odds of having elevated levels of GGT, ALP and AST
(defined as the top fifth of the distribution of these
enzymes) for the smoking groups, with never smokers as
the reference group. Tests for interaction were assessed by
 Wannamethee and Shaper. Cigarette smoking and liver enzymes 323
................................................................................................................................................

fitting a smoking alcohol interaction term in the regression
model, with smoking fitted continuously.
Results
In the 4595 men with no history of CHD (myocardial infarc-
tion or angina), the geometric mean (interquartile range) for
GGT and AST were 14.9 (10 –20) and 8.87 (18 –25) IU/L,
respectively. The mean (standard deviation) for ALP was
8.87 (2.99) IU/L. GGT was significantly correlated with
AST (r ¼ 0.46; P , 0.0001) and ALP (r ¼ 0.19; P , 0.0001).
AST and ALP were also significantly correlated (r ¼ 0.15;
P , 0.0001).
Table 1 shows the relationship between smoking status
and lifestyle factors and liver enzymes (GGT, AST and
ALP), excluding primary and secondary pipe cigar
smokers. Smoking was strongly and positively associated
with GGT and ALP, but inversely associated with AST. A
dose –response relationship with GGT was seen in
smokers. Alcohol and body mass index (BMI) were strongly
associated with GGT and AST. Physical activity was inver-
sely associated with GGT and ALP. The positive association
between smoking and GGT and ALP and the inverse asso-
ciation with AST remained significant after further adjust-
ment for alcohol, BMI and physical activity.
A significant strong positive association was seen
between smoking and CRP and WCC (Table 2).
Adjustment for CRP abolished the relationship between
smoking and GGT, but made minor differences to the
relationships seen with AST and ALP. Further adjustment
for WCC slightly attenuated the positive association and
inverse association seen between smoking and ALP and
AST, respectively, but these associations remained
significant.
Table 3 shows the relationship between smoking and the
odds of having high GGT (top fifth), high ALP or high AST.
The odds of having high GGT increased slightly with
increasing cigarettes smoked/day, but was only signifi-
cantly raised in heavy smoker (40þ/day). Adjustment
for CRP attenuated the associations to non-significance. By
contrast, the odds of having high ALP were significantly
increased in all smokers and there was a dose– response
relationship among smokers. Adjustment for CRP and
WCC reduced the association, but a strong positive relation-
ship remained. An inverse association was seen with high
AST, which persisted after adjustment for CRP and WCC.
We also examined the possible interaction between
alcohol and smoking on GGT.
Table 4 shows the combined effect of smoking and
alcohol on GGT with and without adjustment for CRP. A
significant interaction was seen between smoking alcohol

Table 1 Smoking, alcohol, BMI and physical activity and mean levels of liver enzymes in 4138 men with no pre-existing coronary heart disease
GGT (IU/L)† AST (IU/L)† ALP (IU/L)
N Unadjusted Adjusted‡ Unadjusted Adjusted‡ Unadjusted Adjusted‡
Smoking
Never 987 13.9 14.3 22.0 22.0 8.25 8.29
Ex 1226 15.0 14.7 22.0 22.0 8.64 8.59
1– 19 708 15.2 15.3 21.1 21.1 9.08 9.07
20 518 15.2 15.2 20.9 20.7 9.49 9.49
21– 39 512 16.1 15.6 21.3 21.1 9.40 9.41
40 193 17.1 16.4 21.5 21.1 9.74 9.81
,0.0001 0.0006 0.005 0.006 ,0.00001 ,0.0001
Alcohol
None 262 12.7 12.6 21.3 21.1 9.18 9.17
Occ. 970 12.9 12.8 20.5 20.5 9.03 9.01
Light 1328 14.0 14.2 21.1 21.1 8.63 8.72
Moderate 1114 16.6 16.4 22.2 20.7 8.86 8.76
Heavy 462 20.9 20.3 23.8 23.8 9.09 8.85
,0.0001 ,0.0001 ,0.0001 ,0.0001 0.54 0.03
BMI
,25 1946 13.5 13.6 20.9 21.1 8.76 8.76
25– 27.49 1872 16.0 15.8 21.8 21.8 8.93 8.96
30þ 320 19.1 18.9 24.3 24.0 8.84 8.99
,0.0001 ,0.0001 ,0.0001 ,0.0001 0.65 0.24
Physical activity
None 364 16.3 15.6 22.0 22.0 9.23 9.06
Occ. 1184 15.6 15.5 21.8 22.0 9.09 9.01
Light 998 14.9 14.9 21.1 21.1 8.80 8.75
Moderate 666 14.2 14.4 21.3 21.3 8.69 8.72
Moderatelyvigorous/ 868 14.0 14.2 21.8 21.5 8.66 8.86
vigorous
,0.0001 ,0.0001 0.40 0.16 ,0.0001 0.08

BMI, body mass index; GGT, gamma-glutamyl transferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase
Missing data on physical activity n ¼ 53; missing data on alcohol n ¼ 2

Primary and secondary pipe cigar smokers excluded (n ¼ 457)
†
Geometric mean
‡
Adjusted for age and each of the other lifestyle factors
324 Annals of Clinical Biochemistry Volume 47 July 2010
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Table 2 Smoking and age adjusted levels of CRP, WCC and adjusted mean GGT, ALP and AST in men with no pre-existing coronary heart disease
Age-adjusted Age-adjusted Adjusted† Adjusted† Adjusted†
mean CRP (mg/L) mean WCC (3109/L) mean GGT (IU/L) mean ALP (IU/L) mean AST (IU/L)
Smoking
Never 0.87 6.17 14.8 8.46 (8.54) 22.2 (21.89)
Ex 1.08 6.49 15.0 8.69 (8.70) 22.2 (21.96)
1– 19 1.56 7.46 15.0 8.97 (8.90) 20.9 (21.26)
20 1.96 7.92 14.6 9.30 (9.24) 20.7 (20.88)
21– 39 1.85 8.00 15.0 9.26 (9.16) 21.1 (21.48)
40 2.10 8.00 15.8 9.63 (9.54) 21.1 (21.46)
P , 0.0001 P , 0.0001 P ¼ 0.58 P , 0.0001 P , 0.0001
(P , 0.0001) (P ¼ 0.004)

CRP, C-reactive protein; WCC, white cell count; GGT, glutamyl transferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; BMI, body mass index
For ALP and AST additional adjustment made for WCC (figures in brackets)
Primary and secondary pipe cigar smokers excluded (n ¼ 457)

Geometric mean
†
Adjusted for age, BMI, alcohol intake, physical activity and CRP

and GGT, with the strongest relationship seen in the heavi-
est drinkers. Adjustment for CRP abolished the relation-
ships between smoking and GGT, except in heavy
drinkers. By contrast, alcohol was positively related to
GGT within all smoking categories, with the highest levels
in heavy smokers and heavy drinkers. No significant inter-
action was seen between smoking, BMI and GGT or
between smoking physical activity and GGT.
By contrast, no interaction was seen between alcohol and
smoking and ALP (P ¼ 0.92). The strong positive associ-
ation between smoking and ALP was seen within all
alcohol categories even after adjustment for CRP and
WCC (data not shown).
Discussion
In this study of middle-aged British men, we have shown
that cigarette smoking is associated with increased levels
of GGT and ALP, but was inversely associated with AST.
These findings confirm several previous studies that have
reported on the association between smoking and liver
enzymes2 – 4,7,16 – 22 and extend these findings by examining
the role of inflammation and the synergistic effects of
alcohol drinking. The association between smoking and
GGT was to a large extent associated with inflammation,
except in the presence of heavy drinking. There was a sig-
nificant interaction between cigarette smoking and alcohol
on GGT. By contrast the association between smoking and
ALP was only partially explained by inflammation and
was seen irrespective of alcohol intake.
Despite the strong positive association between smoking
and alcohol intake, which was strongly and positively
associated with AST, we observed an inverse relationship
between smoking and AST, which persisted even after
adjustment for BMI and alcohol intake. The nature of this
inverse association is not clear, but has been observed in
previous studies.7 Although we did not have measures of
ALT, a more specific marker of liver injury, most studies
have observed inverse or no association between smoking
and ALT3,6 or non-alcoholic fatty liver disease,36 suggesting
that smoking does not cause liver injury.
The cross-sectional findings of a positive association
between smoking and GGT are consistent with reports
from several previous population studies. Although GGT
has been widely used as a test for hepatobiliary diseases
and heavy drinking, it is also strongly influenced by
obesity and recent reviews have suggested that GGT may
be an indicator of oxidative stress.25 It is well established
that cigarette smoking induces inflammation30 and oxidative

Table 3 Smoking and adjusted relative odds of having elevated GGT (23 IU/L), elevated ALP (11 IU/L) and elevated AST (26 IU/L) in men with
no pre-existing coronary heart disease
High GGT High ALP High AST
Adjusted 1CRP Adjusted 1CRP 1WCC Adjusted 1CRP 1WCC
Smoking
Never 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Ex 1.04 1.00 1.33 1.27 1.23 1.08 1.06 1.11
(0.83, 1.31) (0.79, 1.26) (1.04, 1.68) (0.99, 1.61) (0.88, 1.33) (0.86, 1.31) (0.90, 1.38)
1– 20 1.11 0.92 2.05 1.71 1.47 0.65 0.60 0.73
(0.88, 1.40) (0.73, 1.17) (1.62, 2.57) (1.35, 2.16) (1.14, 1.89) (0.52, 0.82) (0.48, 0.76) (0.57, 0.93)
21– 39 1.19 0.99 2.25 1.86 1.58 0.80 0.74 0.90
(0.89, 1.50) (0.74, 1.33) (1.70, 2.97) (1.60, 2.47) (1.16, 2.14) (0.61, 1.06) (0.56, 0.98) (0.66, 1.22)
40 1.56 1.27 3.95 3.21 2.90 0.90 0.82 1.00
(1.08, 2.27) (0.87, 1.86) (2.77, 5.62) (2.24, 4.60) (1.99, 4.23) (0.62, 1.57) (0.56, 1.21) (0.65, 1.47)
Trend 0.04 0.88 ,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001 ,0.0001

CRP, C-reactive protein; WCC, white cell count; GGT, glutamyl transferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; BMI, body mass index
Adjusted for age, BMI, alcohol intake and physical activity
Primary and secondary pipe cigar smokers excluded (n ¼ 457)
 Wannamethee and Shaper. Cigarette smoking and liver enzymes 325
................................................................................................................................................

Table 4 Combined effect of alcohol and smoking on mean (geometric) GGT (IU/L) adjusted for age, BMI and physical activity (Model A) and in
addition for CRP (Model B)
Smoking
Never Ex 1 –20/day 21– 39/day 401/day Trend for smoking P-value interaction
Model A
Alcohol intake
Non/occ. 12.4 12.7 13.5 12.7 14.0 P ¼ 0.06 P ¼ 0.04
Light 13.9 14.3 14.2 14.0 14.0 P ¼ 0.35
Moderate 15.3 16.8 16.8 16.7 18.1 P ¼ 0.05
Heavy 19.3 18.1 21.1 23.3 23.5 P ¼ 0.004
Trend P , 0.0001 P , 0.0001 P , 0.0001 P , 0.0001 P , 0.0001
Model B
Non/occ. 12.8 12.9 13.1 12.2 13.2 P ¼ 0.88 P ¼ 0.006
Light 14.3 14.7 13.9 14.4 13.6 P ¼ 0.44
Moderate 15.8 16.9 16.3 16.3 17.3 P ¼ 0.58
Heavy 19.5 18.2 19.7 22.9 23.0 P ¼ 0.002
Trend for alcohol P , 0.0001 P , 0.0001 P , 0.0001 P , 0.0001 P , 0.0001

CRP, C-reactive protein; GGT, glutamyl transferase; BMI, body mass index
Primary and secondary pipe cigar smokers excluded (n ¼ 457)

stress.26 The rise in GGT associated with smoking was
largely due to inflammation, suggesting that raised GGT
in non-heavy drinking smokers is a measure of general oxi-
dative stress. A few reports have suggested an interaction of
alcohol consumption and smoking on GGT,4,22 as was seen
in the current study. The positive association between ciga-
rette smoking and GGT was only seen in heavy drinkers
after adjustment for CRP. Thus, smoking appears to increase
the effects of heavy drinking on GGT. Oxidative stress is
well recognized to play a pivotal role in the development
of alcoholic liver disease.37 Our findings are in keeping
with the suggestion that oxidative stress in the liver
caused by heavy drinking may be aggravated and enhanced
by cigarette smoking, resulting in more severe hepatic cellu-
lar injury.22 The particularly hazardous effect of heavy
drinking and smoking on GGT, which is a risk factor for
liver cancer and cirrhosis,38 may contribute to the synergis-
tic effects of smoking and alcohol on liver cancer and alco-
holic cirrhosis reported in several studies.11,14,15,39
ALP was strongly influenced by smoking but not alcohol,
consistent with other studies.7,27 ALP is an important
enzyme mainly derived from the liver and bones, but is
also present in the kidneys and the leukocytes.28,29 Part of
the association between smoking and ALP was explained
by inflammatory markers CRP and in particular the leuko-
cyte count (WCC), which is known to be influenced by
smoking, but there remained an apparent independent
effect. The association with elevated ALP was seen even
after exclusion of men with raised GGT, suggesting that
raised ALP associated with smoking may reflect bone cell
activity.40
In conclusion, we have shown that cigarette smoking is
associated with increased GGT and ALP but not AST. In
the absence of heavy drinking, the association between ciga-
rette smoking and GGT was largely due to inflammation.
The positive association between smoking and ALP inde-
pendent of inflammation may reflect bone cell activity.
There was a synergistic effect of heavy drinking and
smoking on GGT levels. These findings suggest that
cigarette smoking does not directly cause liver injury, but
may in the presence of heavy drinking enhance the effects
of alcohol on liver cell injury.
DECLARATIONS
Competing interest: None.
Funding: The British Heart Foundation. The British
Regional Heart Study is a British Heart Foundation
Research Group. RG/08/013/25942.
Contributorship: SGW and AGS developed the study idea.
SGW carried out the statistical analysis of the paper and
wrote the initial draft of the paper. AGS contributed to
the writing of the paper. Both authors approved the final
version for publication.
Guarantor: SGW.
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