Body weight, alcohol consumption and liver enzyme activity—a 4-year follow-up study

Duk-Hee Leea, Myung-Hwa Hab and David C Christianic

a Department of Preventive Medicine, College of Medicine, Kosin University, 34 Amnam-Dong, Suh-Gu, Pusan, Korea, 602–702. E-mail: ducky{at}ns.kosinmed.or.kr
b Health Care Center, Pohang Steel Company, Pohang, Korea.
c Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background This prospective study was performed in order to investigate the effect of baseline body mass index (BMI), BMI changes, baseline alcohol consumption, and changes in alcohol consumption on liver enzyme activity.

Methods This study population consisted of 6846 male workers in a steel manufacturing company who had undergone health examinations in 1994 and 1998.

Results The risk for elevated both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values over the four years increased with the baseline BMI and BMI changes, but not with alcohol consumption. Compared with the subject BMI <20, the adjusted odds ratios (OR) for those with baseline BMI 20–21.9, 22–24.9, 25– were 1.2, 1.6, 1.7 in AST and 1.4, 2.4, 2.8 in ALT, respectively. Compared with subjects who either lost or maintained their weight, the adjusted OR for men with slight, moderate, and heavy weight gain were 1.7, 2.6, 6.8 in AST and 2.4, 3.9, 11.3 in ALT, respectively. However gamma-glutamyl transferase (GGT) was associated with BMI changes and baseline alcohol consumption, not with baseline BMI and changes in alcohol consumption. Compared with subjects who lost or maintained weight, the adjusted OR for men with slight, moderate, and heavy weight gain were 2.4, 4.4 and 8.5, respectively. In comparison with non-drinkers, the adjusted OR for light, moderate and heavy drinkers were 1.8, 2.1 and 5.8, respectively.

Conclusion These data suggest that body weight, rather than alcohol consumption, may be the major factor in determining the serum level of liver enzymes. Even when body weight was not generally considered to be overweight, slight to moderate gains in weight were associated with increases in serum liver enzymes.

Keywords Liver enzymes, body weight, alcohol consumption, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase

Accepted 10 April 2001


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Alcohol is one of the factors most frequently associated with increased liver enzyme and the association between alcohol intake and alcohol-induced liver disease is well known. The Italian Dionysos study showed that alcohol was suspected to be the cause in 23% of all cases of liver disease, with a dose-dependent increase in the risk of developing liver disease.1,2 Conversely, two studies from Japan did not show a strong relationship between alcohol consumption and serum liver enzymes; specifically, aspartate aminotransferase (AST) and alanine aminotransferase (ALT).3,4

Obesity has also been identified as an important factor known to contribute to raised levels of serum liver enzyme in several cross-sectional studies.58 In the Dionysos study,9 it appeared that obesity rather than alcohol abuse was the main cause of raised values of ALT and the presence of fatty liver.

There have been a few studies evaluating the effects of the changes of alcohol consumption or the changes of body mass index (BMI) on the level of liver enzymes in a prospectively systematic way among apparently healthy people.1013 In these studies, the effect of the changes of alcohol consumption was very weak on liver enzyme, in comparison to that of the BMI change. This is an apparently surprising result given the strong association between alcohol consumption and serum liver enzymes consistently reported in many cross-sectional studies from western countries.1,2 Some clinical-based studies1416 have also showed that the effect of weight loss seemed to be more crucial in normalizing the liver enzyme than reduced alcohol consumption.

However, one study which analysed liver enzymes separately showed that the effect of body weight or alcohol consumption could be different depending upon which liver enzyme is assessed.10 In addition, most studies1013 published to date have usually focused on moderate or severe obesity, defined as a BMI >25. The aim of this prospective study was to investigate the association of baseline BMI, BMI changes, baseline alcohol consumption, and changes in alcohol consumption on serum liver enzyme activity in male workers, most of whom were in a normal range of BMI at baseline, at a large steel company in the Republic of Korea.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study population
All workers in this company are required to have an annual health check-up consisting of clinical and laboratory measurements. Throughout 1994, health check-ups were performed between 9:00 a.m. and noon after an overnight fast, in a health care centre at the factory. Male workers between 25 and 50 years old without definite liver disease or hepatitis B antigen were eligible for follow-up for this study. Of the 11 867 men who met these criteria, 8553 men (72.1% follow-up rate) were re-examined in 1998. Among these subjects, 8445 men without diseases requiring continuous medication became the base population for a cross-sectional analysis. For the incidence analysis, subjects with abnormal levels of liver enzyme activity at baseline defined as an AST over 33 U/L, ALT over 35 U/L, or gamma glutamyl transferase (GGT) over 50 U/L, were excluded. After all exclusions, 6846 men were included in the incidence analyses.

Measurement
Information on lifestyle factors including cigarette smoking, alcohol consumption, exercise, and medical history were obtained by self-reported questionnaires. Each year, all workers were asked to complete the same, or slightly modified, questionnaire. For each questionnaire, changes spotted by a computerized data system (which contained information from previous years) were confirmed by a nurse in a direct interview.

The workers were asked how many times per week or per month they consumed alcohol and the typical quantities consumed. They were asked to estimate the amount in terms of soju, a popular Korean liquor. Based on this information the amount of alcohol consumed per week was calculated. All subjects were divided into four groups by the baseline amount of alcohol consumption (non-drinker; light drinker, 1–180 g/week; moderate drinker, 181–360 g/week; heavy drinker, 361+ g/week). The population was stratified into four groups by changes in alcohol consumption (decreased, no change, increased 1–90 g/week, increased 91+ g/week). The BMI value, defined as weight (kg)/height (m2), was used as a weight index; and during weighing, almost all subjects wore the standard company uniform. Subjects were classified into four groups according to baseline BMI or BMI change, respectively. The criteria for the former were: <20 kg/m2; 20–21.9 kg/m2; 22–24.9 kg/m2; and >=25 kg/m2. Criteria for the latter were: weight loser or maintainer, <=0 kg/m2 or 0 kg/m2; slight weight gainer, 0.1–1.0 kg/m2; moderate weight gainer, 1.1–2.0 kg/m2; heavy weight gainer, >2.0 kg/m2.

Venous blood samples were obtained from a cubital vein after overnight 12 hours fasting. The serum samples were kept at 4°C and analysed within 48 hours. Laboratory tests were performed with an automatic analyser (Hitachi 7170, Japan) by optimized methods based on the recommendations of the Korean Society for Clinical Chemistry, at 37°C. Our normal ranges (U/L) for men were as follows: AST <=33; ALT <=35; GGT <=50.

Statistical analyses
The relationship between alcohol consumption and BMI, and the prevalence and incidence of elevated liver enzyme were analysed by multiple logistic regression, using the SAS statistical program, version 6.12. In the incidence analyses, we included four main variables (baseline BMI, baseline alcohol consumption, BMI change, change in alcohol consumption), covariates (age, cigarette smoking [pack-years], exercise [frequency/week], baseline AST or ALT or GGT [baseline for the dependent variable]), and interaction terms between main factors. There were no interaction terms that reached statistical significance; therefore, these terms were dropped from the final model. We included baseline AST or ALT or GGT as covariates because amounts of changes of these enzymes during 4 years were dependent upon the baseline value of these enzymes. Those with relatively high values of serum liver enzymes at baseline, although in normal range, tended to increase more than those with low values. In the prevalence analyses, two main variables (baseline BMI, baseline alcohol consumption) and covariates (age, cigarette smoking [pack-years], exercise [frequency/week]) were included in the final model. The P-values used are two-sided, and values <0.05 were regarded as statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Baseline characteristics (Table 1Go)
Table 1Go shows the baseline characteristics of the subjects. The mean age of the subjects was 38.3 years and 84.2% of subjects were within the normal range of BMI. The prevalence of elevated liver enzyme at baseline was 7.8% in AST, 15.6% in ALT, and 4.4% in GGT.


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Table 1 Baseline characteristics of the cohort (n = 8436)
 
Cross-sectional analyses (Table 2Go)
The prevalence of elevated liver enzyme showed clear dose-response relationships with BMI in 1994 for all three liver enzymes. Compared with those with BMI <20, the adjusted odds ratios for BMI 20–21.9, 22–24.9, 25 or more were as follows: 1.7 (95% confidence interval [CI] : 1.1–2.5), 2.9 (95% CI : 2.0–4.1), 7.1 (95% CI : 4.9–10.4) in AST, respectively; 1.8 (95% CI : 1.3–2.4), 5.0 (95% CI : 3.7–6.8), 14.2 (95% CI : 10.4–19.4) in ALT, respectively; and 1.7 (95% CI : 0.8–3.5), 4.5 (95% CI : 2.3–8.5), 12.6 (95% CI : 6.6–24.1) in GGT, respectively. GGT also showed a dose-response relationship with the amount of alcohol consumption, however, AST and ALT showed little or no statistically significant relationship. In comparison with non-drinkers, the adjusted odds ratios in GGT were as follows: 2.1 (95% CI : 1.4–3.1) for light drinkers, 3.1 (95% CI : 2.0–4.9) for moderate drinkers, 5.9 (95% CI : 3.5–10.0) for heavy drinkers.


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Table 2 Adjusteda odds ratio (aOR) of prevalence of elevated liver enzyme by body mass index (BMI) and alcohol consumption at baseline (n = 8436)
 
Incidence analyses (Table 3Go)
During the follow-up periods 4.3%, 14.1% and 2.6% of the subjects developed abnormal liver enzyme levels of AST, ALT and GGT, respectively. The risk of developing both abnormal AST and abnormal ALT values increased with baseline BMI and the increase BMI. The magnitude of the effect of the change in body weight was much larger than that of baseline body weight. Compared with subjects with BMI <20, the adjusted odds ratios for men with baseline BMI 20–21.9, 22–24.9, 25– were as follows: 1.2 (95% CI : 0.8–1.8), 1.6 (95% CI : 1.1–2.4), 1.7 (95% CI : 1.0–2.8) in AST, respectively; 1.4 (95% CI : 1.0–1.9), 2.4 (95% CI : 1.8–3.2), 2.8 (95% CI : 2.0–4.0) in ALT, respectively. Compared with the weight losers or maintainers, the adjusted odds ratios for slight weight gainers, moderate weight gainers, and heavy weight gainers were as follows: 1.7 (95% CI : 1.2–2.5), 2.6 (95% CI : 1.9–3.7), 6.8 (95% CI : 4.6–10.0) in AST, respectively; 2.4 (95% CI : 2.0–2.9), 3.9 (95% CI : 3.2–4.9), 11.3 (95% CI : 8.6–14.8) in ALT, respectively. However, baseline alcohol consumption and the change of alcohol consumption did not show any notable relationship with either AST or ALT, even though there was a slight relationship with baseline alcohol consumption.


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Table 3 Adjusteda odds ratios (aOR) of incidence of elevated liver enzyme by baseline body mass index (BMI), BMI change, baseline alcohol consumption, and change in alcohol consumption (n = 6846)
 
GGT showed a marked difference from both AST and ALT with regard to alcohol consumption and/or BMI. There were clear dose-response relationships with BMI changes and baseline alcohol consumption, but not baseline BMI and the changes of alcohol consumption, even though the changes of alcohol consumption affected slightly the incidence of abnormal GGT. Compared with weight losers or maintainers, the adjusted odds ratios for slight weight gainers, moderate weight gainers, and heavy weight gainers were 2.4 (95% CI : 1.5–3.9), 4.4 (95% CI : 2.7–7.1) and 8.5 (95% CI : 4.6–15.7), respectively. In comparison with non-drinkers, the adjusted odds ratios were 1.8 (95% CI : 0.9–3.7) for light drinkers, 2.1 (95% CI : 0.9–4.8) for moderate drinkers, and 5.8 (95% CI : 2.3–14.7) for heavy drinkers.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We explored the relationships between BMI and alcohol consumption, and the prevalence and/or incidence of abnormal serum liver enzyme activity in both cross-sectional and prospective designs. First, serum activity of both AST and ALT showed strong dose-response relationships with body weight rather than with alcohol consumption. In particular, the association of enzymes with BMI changes was much stronger than that with baseline BMI. Regarding alcohol consumption, there was only a weak relationship with baseline alcohol consumption and no relationship with the changes of alcohol consumption. A second major finding was that serum GGT activity was related to both the baseline amount of alcohol consumed and the changes of body weight, while there were only weak or no relationships with the changes of alcohol consumption and the baseline BMI.

Several cross-sectional and clinical studies58 have shown consistently that the increased serum activity of various liver enzymes is related to overweight or obesity. The results of a few prospective studies10,12,1416 also confirmed this association. However, earlier studies usually focused on moderate or severe obesity with BMI >25. In this prospective study, higher levels of adiposity as assessed by baseline BMI and BMI change were monotonically related to an increase in the incidence of elevated serum liver enzymes, especially AST and ALT, even though most of our subjects had a BMI within the normal range. Our study allows a more precise quantification of the dose-response relationship than has been possible previously due to the large sample size. Also, we explored the association of baseline BMI and BMI change simultaneously and showed that the effect of BMI change was a more important factor in developing abnormal liver enzymes than was baseline BMI. To our knowledge, this is the first study to report these findings. Among our subjects, those with higher baseline BMI tended to experience an increase in body weight less than those with lower baseline BMI. Hence, one of these factors should be considered as a confounder when interpreting associations with the other. Although Bruns et al.10 assessed the effect of body weight change, they did not consider these two covariates concurrently as possible confounders.

Among liver enzymes, the serum activities of ALT were more clearly related to BMI than were the other enzymes. These findings were similar to those observed in other studies.7,9,10 On the basis of such observations, Wejstal et al.17 suggested that ALT values should be corrected for body weight, especially when ALT measurements are used as a surrogate test in screening for non-A, non-B hepatitis. According to another study,18 AST values also should be corrected for body weight because in various animal species, ranging from mice to cattle, the expected enzymatic activity can be expressed as a function of a power of the weight.

AST and ALT had a surprisingly weak or non-existent relationship with alcohol consumption in both the cross-sectional and longitudinal analyses in our study; although the relationship between alcohol consumption and GGT was clear, as expected. The studies9,10,19 from western countries reported that the magnitude of the effect of alcohol consumption was similar to, or slightly smaller than, that of obesity. This could be because the total alcohol consumption in our subjects might have been lower than in other studies. Alternatively, Asians may be less sensitive to alcohol than Caucasians. Studies3,4 from Japan also reported that alcohol consumption was not significantly related to ALT or AST.

The Serum GGT level showed a strong relationship only with BMI change, but not baseline BMI. The importance of BMI change means that the effects of adiposity might be temporary. A 7-year longitudinal population study from Norway also showed that the change in BMI was the single strongest determinant of change in GGT.12 Our study suggested that liver enzymes could be influenced by a slight weight change even within normal range.

One of the most interesting findings of this study was that GGT showed a relationship only with baseline alcohol consumption, not change in alcohol consumption, the opposite finding to the relationship observed for BMI. As far as we know, though, there has been no previous study exploring the relationships between both baseline and the changes of alcohol consumption, and liver enzyme concurrently, the results of some studies support our finding. As a screening test for alcoholism and alcohol abuse, the sensitivity of GGT has been considered to be acceptable, but its specificity is poor.20 In contrast to this, GGT has been found to have reasonable specificity but low sensitivity to changes in alcohol consumption.21 The Tromsø study12 in Norway also reported a strong relationship between alcohol consumption and GGT in a cross-sectional setting, but a surprisingly weak association between the changes of alcohol consumption and the changes of GGT in longitudinal analyses. They interpreted this as reflecting the imprecision of their alcohol questions, which may have introduced random measurement errors that obscured the true changes in alcohol consumption. However, our result suggested that it could be a real association. Some investigators22,23 have suggested that elevated GGT activity in drinkers is probably related more closely to the biological effects of alcohol than to the amount of alcohol consumption.

In conclusion, these data indicate that body weight rather than alcohol consumption may be the major factor in determining the level of liver enzyme, though some ethnic differences may need to be taken into consideration. In particular, even slight or moderate gains in weight, and levels of body weight not generally considered to be overweight, were associated with increases of liver enzyme. With regard to the alcohol consumption, further study is needed to clarify the reason for the small effect of changes in alcohol consumption on GGT.


KEY MESSAGES

  • The risk for elevated both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values increased with the baseline BMI and BMI changes, but not with alcohol consumption.
  • Gamma-glutamyl transferase (GGT) was associated with BMI changes and baseline alcohol consumption, not with baseline BMI and changes in alcohol consumption.
  • Body weight, rather than alcohol consumption, may be the major factor in determining the serum level of liver enzymes.

 


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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