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American Journal of Clinical Nutrition, Vol. 83, No. 6, 1351-1354, June 2006
© 2006 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Additive effects of moderate drinking and obesity on serum {gamma}-glutamyl transferase activity1,2,3

Katri Puukka, Johanna Hietala, Heidi Koivisto, Petra Anttila, Risto Bloigu and Onni Niemelä

1 From the Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, Seinäjoki, Finland, and the University of Tampere, Tampere, Finland (KP, JH, HK, PA, and ON), and the Department of Medical Informatics, University of Oulu, Oulu, Finland (RB)

2 Supported in part by a grant from the Finnish Foundation by Alcohol Studies (to ON).

3 Address reprint requests to O Niemelä, Seinäjoki Central Hospital Laboratory, FIN-60220 Seinäjoki, Finland. E-mail: onni.niemela{at}epshp.fi.

See corresponding editorial on page 1252.

See corresponding CME exam on page 1448.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: {gamma}-Glutamyl transferase (GGT) is a widely used index of liver induction and a marker of alcohol overconsumption. Obesity has also been suggested to elevate serum GGT activities.

Objective: The aim was to examine the links between moderate ethanol consumption, obesity, and GGT activities.

Design: GGT values were recorded from 2490 persons (1184 men and 1306 women) who reported either no alcohol use (abstainers) or 1–40 g ethanol consumption per day (moderate drinkers). The study population was additionally classified according to body mass index (BMI; in kg/m2) as follows: <19 (underweight), ≥19 and <25 (normal weight), ≥25 and <30 (overweight), and ≥30 (obese).

Results: Significant main effects of sex (P < 0.0001), drinking habits (P < 0.01), and BMI (P < 0.001) on serum GGT activities were observed. The values were higher in the men than in the women and higher in those with higher BMIs. The highest activities were found to occur in persons with moderate drinking combined with overweight or obesity. A significant positive correlation between GGT and BMI (P < 0.0001) was observed, which was stronger for the men (r = 0.24) than for the women (r = 0.15, P < 0.05 for the difference between correlations).

Conclusion: The data indicate that serum GGT activities may respond to moderate drinking and overweight in an additive manner; this should be considered in the clinical use of GGT measurements and when defining normal GGT values in health care.

Key Words: Ethanol • obesity • lipid peroxidation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
{gamma}-Glutamyl transferase (GGT) is commonly used as a biological marker for excessive alcohol consumption and as an index of liver induction due to ethanol, drug, or xenobiotic use (1-4). Several studies have reported a positive correlation between the amount of ethanol ingestion and serum GGT activities (5-8). Recent data have additionally suggested that serum GGT can also be considered a marker of oxidative stress (9).

Obesity is an increasingly common nutritional disorder in many industrialized countries affecting a major proportion of the adult population (10, 11). Over the past decades, although there has been an epidemic increase in the incidence of obesity, there has also been a simultaneous increase in the total per capita ethanol consumption and associated medical disorders (12). A growing body of evidence has indicated that obesity may also lead to increased serum GGT activities (13-17). However, the associations between body mass index (BMI), sex, alcohol consumption, and the interpretation of serum GGT activities in this context have remained unclear. The present study set out to explore the relations between ethanol consumption, overweight, and GGT activities in a large number of apparently healthy abstainers and moderate drinkers who were classified according to sex and BMI.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study protocol
Data from 2490 apparently healthy persons (1184 men, mean (±SD) age: 47 ± 18 y; 1306 women, aged 46 ± 18 y) collected for a survey for establishing enzyme reference intervals in Nordic countries were used. The study population was classified into either alcohol abstainers (n = 1160; 479 men aged 48 ± 19 y, and 681 women aged 48 ± 19 y) or moderate drinkers (n = 1330; 705 men aged 46 ± 17 y, and 625 women aged 45 ± 16 y) and further classified according to BMI (in kg/m2), as summarized in Table 1Go. In moderate drinkers, the amount of alcohol consumed varied between 1 and 40 g ethanol/d, and the maximum amount of alcohol consumed during the 24 h before sampling was 2 standard drinks. The survey excluded persons who had clinical or laboratory evidence of current or recent illnesses or infections, were pregnant, had donated blood in the past 5 mo, or had used any prescription drugs during the preceding week. Smoking was not allowed for 1 h before sampling. All GGT measurements were carried out with International Federation of Clinical Chemistry–compatible measuring systems.


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  		TABLE 1 Main characteristics of the study population1

 
The study was approved by the Seinäjoki Central Hospital institutional review board. Informed consent was obtained from the participants, and the study was carried out according to the provisions of the Declaration of Helsinki.

Statistical methods
Values are expressed as means ± SDs. Comparisons were made with Kruskal-Wallis test and Dunn's multiple comparison test or with Mann-Whitney test in a comparison of 2 groups. Correlations were calculated with Pearson product–moment correlation coefficients and the differences between correlations with z tests for correlation coefficients. The analyses were carried out with GRAPHPAD PRISM version 3.03 (GraphPad Software, San Diego, CA) statistical software. SPSS version 12.0 for Windows statistical software (SPSS Inc, Chicago, IL) was used for the 2- and 3-factor analyses after natural logarithmic transformation of GGT values to obtain symmetrical distributions. A P value < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Significant main effects of sex (P < 0.0001), drinking habits (P < 0.01), and BMI (P < 0.001) on serum GGT activities were observed. Data for the groups of abstainers and moderate drinkers classified further according to BMI are shown in Figure 1Go. GGT activities were found to significantly increase with increasing BMI. The highest values occurred in those with moderate drinking combined with overweight or obesity. Although the magnitude of GGT changes in men appeared to exceed those observed in women, a 3-factor interaction (sex x BMI x drinking status) on the between-subjects effects for all of these factors with GGT as the dependent variable was not significant. The 2-factor interactions (sex x drinking status, sex x BMI, or drinking status x BMI) were also not significant.


Figure 1
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  		FIGURE 1. Mean (±SD) distributions of {gamma}-glutamyl transferase (GGT) activities in men (A) and women (B) classified according to alcohol consumption and body mass index (BMI; in kg/m2). A significant main effect of sex (P < 0.0001), drinking status (P < 0.01), and BMI (P < 0.001) was observed. Neither the 3-factor interaction (sex x BMI x drinking status) nor the 2-factor interactions (sex x BMI, sex x drinking status, or BMI x drinking status) were significant.

 
The correlations between GGT and BMI were significant for both men (r = 0.24, P < 0.0001) and women (r = 0.15, P < 0.0001). The correlation observed for men was also significantly different from that of women (P < 0.05). Computing the partial correlation coefficients with control for sex, drinking status, or both, also yielded significant correlations (r = 0.25, P < 0.0001; r = 0.31, P < 0.0001; and r = 0.26, P < 0.0001, respectively).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Morbidity and mortality related to excessive ethanol consumption and obesity are increasingly pervasive public health problems that extend across the entire spectrum of body weights and different levels of ethanol consumption. However, only few studies have investigated the combined effects of moderate ethanol consumption and obesity on the biochemical variables that reflect health status (14, 18, 19).

The present data in a large population of abstainers and moderate drinkers indicated distinct additive effects of moderate alcohol consumption and overweight on serum GGT activities. These findings are consistent with the view that obesity together with ethanol consumption may lead to an increase in metabolic burden and risk of liver problems. Although the primary role of hepatic GGT is to metabolize extracellular reduced glutathione, recent studies have indicated that GGT enzyme induction may also be closely associated with the generation of reactive oxygen species (ROS) (20). Enhanced oxidant stress has been recently linked with obesity-associated metabolic syndrome and generation of fatty liver (21, 22). Interestingly, recent studies conducted both in experimental animals and in humans have indicated that the ethanol-inducible cytochrome enzyme, CYP2E1, may also be induced by obesity alone because free fatty acids can serve as substrates (23-27). This may create oxidative stress and render the liver more susceptible toward oxidative stress and associated cellular injury. Thus, the generation of fatty change in livers of alcoholic persons and in patients with nonalcoholic fatty liver disease appears to share several common pathogenic features both on cytochrome enzyme induction and generation of ROS (24, 25, 28, 29). In experimental animals, high-fat diets together with ethanol consumption enhanced oxidative stress and aggravated alcoholic liver injury (30). In humans, obesity has been shown to potentiate the severity of alcohol-induced liver damage, although the mechanisms of interaction by adiposity and ethanol are still unknown (11, 29, 31). It is possible that enhanced serum GGT activities could be regarded as a sign of generalized metabolic induction and activation of the body's defense mechanisms against the metabolic burden (32-34). GGT is an ectoenzyme that can be released from the cell membrane even without cell death. In light of previous findings by Speisky et al (34), GGT on the sinusoidal side of hepatocytes could provide a mechanism whereby glutathione released from periportal hepatocytes is broken down into readily oxidizable cysteine, replenishing this glutathione precursor for pericentral hepatocytes. The pericentral area is known to be the primary site of alcohol-induced CYP2E1 induction and of generation of ROS in the liver. Thus, increases in GGT may provide a compensatory hepatic mechanism to protect the pericentral hepatocytes against oxidative damage. Because ROS also increase in fatty liver and obesity, similar mechanisms may apply in both the alcohol- and obesity-induced increases in GGT and in the possible synergistic effects of alcohol abuse and overweight.

Interestingly, the present data suggest distinct differences in serum GGT responses as a result of moderate alcohol consumption and overweight in groups consisting either of men or women. Although there may be sex-dependent differences in the metabolic consequences of ethanol intake and fat accumulation, the 3-factor analysis and 2-factor analyses on the interactions between sex, BMI, and drinking status with GGT as the dependent variable were not significant. Sex steroids have been shown to play a role in cytochrome enzyme expression and regulation of oxidant stress status in the liver (35, 36). Unfortunately, information on the type of alcoholic beverages consumed by the study subjects was not available in the present study. Because recent studies conducted in persons who consume >5 drinks/d have indicated a reduced risk for alcoholic cirrhosis in wine drinkers (37), future studies should address whether GGT responses would differ based on moderate drinking of wine, beer, or liquor. Increasing age also influences GGT activities, and, therefore, studies conducted in populations with wide age distributions should also explore the biological significance of such responses.

Studies in the past decades have shown that serum GGT is a sensitive clinical marker of alcohol abuse (5-8, 38-40). These data show that even moderate amounts of ethanol consumption elevate serum GGT activities, especially when occurring together with obesity. Although the correlation observed between self-reported alcohol consumption and GGT values has typically been in the order of 0.3–0.4 (5-8, 41), the present data show that a nearly similar correlation (r = 0.2–0.3) may be achieved between GGT and BMI. It should, however, be noted that a correlation of 0.7 can be reached between GGT activities and alcohol consumption when the amount of ethanol ingestion is monitored for prolonged periods with daily ethanol analyses (42).

The effects of obesity on GGT activities should also be considered in the interpretation and establishment of common reference intervals for GGT measurements in health care. Upper normal limits for such assays have usually been based on values obtained from mixed populations of apparently healthy moderate drinkers and abstainers. The present data supports the view that to improve the diagnostic potential of GGT measurements, reference intervals should, in fact, be based on healthy persons who abstain from ethanol consumption and are not significantly overweight. Additional improvement might be achieved if BMI-based reference intervals could be made available.

In conclusion, the present data supports the view that changes in drinking behavior and the continuing increase in the prevalence of obesity may elevate mean serum GGT activities at the population level. Future studies to address the prognostic implications of such responses as possible indicators of enhanced oxidative stress and whether it is possible to formulate BMI- based guidelines for safer alcohol consumption appear warranted (29). A critical reevaluation of reference intervals for GGT measurements as a biochemical marker of alcohol consumption and liver induction may also be necessary.


   ACKNOWLEDGMENTS
 
We thank Pål Rustad, Fürst Medical Laboratory, Oslo, Norway, for providing data on GGT measurements from the Nordic NORIP Survey on enzyme reference intervals. We thank Timo Marjomäki, University of Jyväskylä, for help with the statistical analyses.

KP and JH contributed equally to this work and were involved in the study design, material collection, data analyses, and drafting the manuscript. HK and RB were involved in the data analyses. PA was involved in the material collection. ON was involved in the study design and writing the manuscript. None of the authors had any conflicts of interest.


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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 9, 2005. Accepted for publication January 12, 2006.


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