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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.

Introduction

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 cirrhosis^10,11 and may adversely affect the progress of chronic liver diseases.¹² In addition, cigarette smoking may aggravate the pathogenic effects of alcohol on the liver.^10,13–15 The association 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 transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (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, some studies have reported significant associations between smoking and GGT^3,4,16–21 and significant smoking interactions with alcohol on GGT.^4,22 Levels of GGT are associated with inflammatory markers^23,24 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 association 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 particular 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 relationship. We hypothesized that the relationship between 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 questionnaire 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 infarction), 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 measurements were only available for men in the seventh to 24th towns visited (n = 4882). Details of lifestyle factor classifications 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 vigorous, 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 confounding effects of CHD, men with recall of doctor diagnosis of CHD have been excluded (n = 266). We further excluded men with missing data on smoking history and men with no data on liver enzymes (n = 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 evacuated tubes for measurement of biochemical and haematogical 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 coefficients 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 −0.128 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 cigarettes 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 currently 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 = 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 40+/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 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 infarction 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 = 0.46; P < 0.0001) and ALP (r = 0.19; P < 0.0001). AST and ALP were also significantly correlated (r = 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 inversely associated with GGT and ALP. The positive association between smoking and GGT and ALP and the inverse association with AST remained significant after further adjustment for alcohol, BMI and physical activity.

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
30+	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/ vigorous	868	14.0	14.2	21.8	21.5	8.66	8.86
		<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 = 53; missing data on alcohol n = 2

*Primary and secondary pipe cigar smokers excluded (n = 457)

^†Geometric mean

^‡Adjusted for age and each of the other lifestyle factors

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 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 mean CRP* (mg/L)	Age-adjusted mean WCC* (×10⁹/L)	Adjusted^† mean GGT* (IU/L)	Adjusted^† mean ALP (IU/L)	Adjusted^† 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 = 0.58	P < 0.0001 (P < 0.0001)	P < 0.0001 (P = 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 = 457)

*Geometric mean

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

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 significantly raised in heavy smoker (40+/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 relationship remained. An inverse association was seen with high AST, which persisted after adjustment for CRP and WCC.

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	+CRP	Adjusted	+CRP	+WCC	Adjusted	+CRP	+WCC
Smoking
Never	1.00	1.00	1.00	1.00	1.00	1.00	1.00	1.00
Ex	1.04 (0.83, 1.31)	1.00 (0.79, 1.26)	1.33 (1.04, 1.68)	1.27 (0.99, 1.61)	1.23	1.08 (0.88, 1.33)	1.06 (0.86, 1.31)	1.11 (0.90, 1.38)
1–20	1.11 (0.88, 1.40)	0.92 (0.73, 1.17)	2.05 (1.62, 2.57)	1.71 (1.35, 2.16)	1.47 (1.14, 1.89)	0.65 (0.52, 0.82)	0.60 (0.48, 0.76)	0.73 (0.57, 0.93)
21–39	1.19 (0.89, 1.50)	0.99 (0.74, 1.33)	2.25 (1.70, 2.97)	1.86 (1.60, 2.47)	1.58 (1.16, 2.14)	0.80 (0.61, 1.06)	0.74 (0.56, 0.98)	0.90 (0.66, 1.22)
≥40	1.56 (1.08, 2.27)	1.27 (0.87, 1.86)	3.95 (2.77, 5.62)	3.21 (2.24, 4.60)	2.90 (1.99, 4.23)	0.90 (0.62, 1.57)	0.82 (0.56, 1.21)	1.00 (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 = 457)

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 and GGT, with the strongest relationship seen in the heaviest drinkers. Adjustment for CRP abolished the relationships 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 interaction was seen between smoking, BMI and GGT or between smoking physical activity and GGT.

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	40+/day	Trend for smoking	P-value interaction
Model A
Alcohol intake
Non/occ.	12.4	12.7	13.5	12.7	14.0	P = 0.06	P = 0.04
Light	13.9	14.3	14.2	14.0	14.0	P = 0.35
Moderate	15.3	16.8	16.8	16.7	18.1	P = 0.05
Heavy	19.3	18.1	21.1	23.3	23.5	P = 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 = 0.88	P = 0.006
Light	14.3	14.7	13.9	14.4	13.6	P = 0.44
Moderate	15.8	16.9	16.3	16.3	17.3	P = 0.58
Heavy	19.5	18.2	19.7	22.9	23.0	P = 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 = 457)

By contrast, no interaction was seen between alcohol and smoking and ALP (P = 0.92). The strong positive association 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 enzymes^{2–4,7,16–22} 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 significant 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 ALT^3,6 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 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 oxidative 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 cigarette 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 cellular 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 synergistic effects of smoking and alcohol on liver cancer and alcoholic 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 leukocyte 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 cigarette smoking and GGT was largely due to inflammation. The positive association between smoking and ALP independent 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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Cigarette smoking and serum liver enzymes: the role of alcohol and inflammation

Abstract

Background and aims

Methods

Results

Conclusion

Introduction

Subjects and methods

Liver enzymes

CRP and white cell count

Smoking and alcohol consumption

Smoking

Alcohol consumption

Statistical methods

Results

Discussion

DECLARATIONS

References