Alcohol and Alcoholism Advance Access originally published online on August 30, 2005
Alcohol and Alcoholism 2005 40(6):511-514; doi:10.1093/alcalc/agh201
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SERUM GAMMA-GLUTAMYL TRANSFERASE IN ALCOHOLICS, MODERATE DRINKERS AND ABSTAINERS: EFFECT ON GT REFERENCE INTERVALS AT POPULATION LEVEL
Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital, and University of Tampere, FIN-60220 Seinäjoki, Finland
* Author to whom correspondence should be addressed at: Tel.: +358 6 415 4719; Fax: +358 6 415 4924; E-mail: onni.niemela{at}epshp.fi
(Received 2 June 2005; first review notified 15 July 2005; accepted in final revised form 8 August 2005)
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Aims: To clarify in the association between amount of ethanol consumption and serum gamma-glutamyl transferase (GT) levels. Methods: GT values were measured from 195 individuals with a wide variety of well-documented ethanol consumption assessed by detailed personal interviews using a time-line follow-back technique. These included 103 heavy drinkers (90 men, 13 women) and 92 healthy volunteers (54 men, 38 women) who were either abstainers (n = 30) or moderate drinkers (n = 62). For comparisons, data were collected from GT measurements for establishing GT reference intervals from 2485 healthy volunteers including 1156 abstainers and 1329 moderate drinkers. Results: GT values in the individuals whose mean ethanol consumption exceeded 40 g of ethanol per day were significantly higher than those in the moderate drinkers with a mean consumption of 1–40 g/day (P < 0.001) or in abstainers (P < 0.001). The GT values in the group of moderate drinkers also exceeded those of the abstainers (P < 0.001). The upper normal GT limits obtained from the data from abstainers were markedly lower (men 45 U/l, women 35 U/l) than those obtained from the population of moderate drinkers (men 66 U/l, women 40 U/l). Conclusions: Serum GT concentrations may respond to relatively low levels of ethanol consumption, which should be considered when defining GT reference intervals. The continuous increase in alcohol consumption at population level may lead to increased GT cut-off limits and hamper the detection of alcohol problems and liver affection in their early phase.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Gamma-glutamyl transferase (GT) is a commonly used laboratory parameter for detecting excessive alcohol consumption (Zein and Discombe, 1970
; Reyes and Miller, 1980). Although several studies have reported a positive correlation between the amount of alcohol consumed and serum GT levels, the reported sensitivities of this marker in previous literature have varied greatly, from 15 to 85% (Bagrel et al., 1979; Chick et al., 1981; Papoz et al., 1981; Persson et al., 1990; Leino et al., 1995; Anttila et al., 2004). Over the past decades, both the total ethanol consumption per capita and associated medical disorders have continued to increase. Simultaneously, the percentage of individuals fully abstaining from ethanol has decreased. In previous studies and in routine health care, reference intervals for GT determinations have been based on values obtained from mixed populations of apparently healthy moderate drinkers and abstainers, whereas only limited attention has been paid on the exact amounts of ethanol consumption in these individuals.
In this work we explored the relationship between ethanol consumption and GT values in individuals with a wide variety of ethanol consumption. Our data indicate distinct effects of mild to moderate ethanol consumption on serum GT levels, which should be considered in the clinical use of GT measurements as a marker of ethanol abuse and liver status.
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METHODS |
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Study protocol
Serum GT was first measured from a sample of 195 individuals (103 heavy drinkers: 90 men, mean age 42 ± 10 years; 13 women, mean age 40 ± 7 years, and 92 moderate drinkers or abstainers: 54 men, mean age 41 ± 16 years; 38 women, mean age 44 ± 19 years) who underwent detailed personal interviews using a time-line follow-back technique (interview sample). The heavy drinkers had a history of continuous ethanol consumption or binge drinking, the mean consumption being in the range of 40–539 g/day during the period of 4 weeks prior to sampling. In addition, this interview sample included 30 abstainers and 62 moderate drinkers with a mean daily ethanol consumption between 1 and 40 g/day. Measurements of GT levels were carried out using standard clinical chemical methods in an accreditated (SFS-EN 45001, ISO/IEC Guide 25) laboratory of Seinäjoki Central Hospital, Finland. For comparisons, data from a survey on 2485 apparently healthy individuals (1174 men, age 47 ± 18 years; 1311 women, age 47 ± 18 years) collected for establishing reference intervals in Nordic countries were also used as kindly provided by the project coordinator, Professor Pål Rustad, Fürst Medical Laboratory, Oslo, Norway. These subjects were classified as either abstainers (n = 1156: 471 men, age 49 ± 19 years; 685 women, age 49 ± 19 years) or moderate drinkers (n = 1329: 703 men, age 46 ± 17 years; 626 women, age 45 ± 16 years). In these subjects, the maximum amount of alcohol consumption during the 24 h period prior to sampling had been 24 g (two standard drinks). The survey excluded individuals who had clinical or laboratory evidence of current or recent illnesses or infections, who were pregnant, had donated blood during the past 5 months, or had used any prescription drugs during the preceding 1 week. Smoking was not allowed for 1 h prior to sampling. All GT measurements were carried out with homogeneous International Federation of Clinical Chemistry (IFCC) compatible measuring systems.
Ethical considerations
The procedure was approved by the 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 mean ± SD. Comparisons were made with Kruskal-Wallis test and Dunn's Multiple Comparison Test or Mann–Whitney test when comparing two groups. Correlations were calculated with Pearson product–moment correlation coefficients. Reference intervals were calculated after logarithmic transformation as previously described (Horn and Pesce, 2003). A P-value <0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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In the total population, serum GT concentrations (mean ± SD) in the groups of heavy drinkers drinking 40–80 g (68 ± 54 U/l) or >80 g (167 ± 254 U/l) of ethanol per day significantly exceeded the levels of both abstainers (P < 0.001) and moderate drinkers (P < 0.001) (Fig. 1). Male alcoholics had slightly higher GT values (166 ± 267 U/l) than female alcoholics (130 ± 163 U/l), although the difference between genders did not reach significance. Interestingly, GT values in the group of moderate drinkers with a daily consumption of 1–40 g (28 ± 23 U/l) also exceeded the values obtained from the group of abstainers (24 ± 17 U/l) (P < 0.001). The correlation between ethanol consumption and GT values, as calculated from the individuals interviewed with the time-line follow-back method, was significant (r = 0.35, P < 0.001).
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Figure 2 demonstrates the previously established changes in national GT reference intervals in Finland in comparison with the yearly changes in ethanol consumption at population level. The data on GT reference intervals, as calculated from the individuals classified according to ethanol consumption data in the detailed personal interviews, are summarized in Table 1. The upper normal limits were found to be on average 43% higher, when the individuals with moderate drinking are contrasted with the population of abstainers. The upper normal limits for men were higher than those for women and the age group
40 years had higher levels than the age group 18–39 years in both genders. However, the correlation between GT levels and age per se did not reach significance (r = 0.097).
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The effect of the choice of the reference population on the estimated diagnostic sensitivity of GT as a marker of excessive ethanol consumption is demonstrated in Fig. 3. When the heavy drinkers are contrasted with abstainers, 69% of heavy drinkers become correctly classified. If the reference interval and definition of normal values would be based on moderate drinkers, the sensitivity remains at a level of 56%. In separate analyses of men and women, the corresponding percentages were 68 and 54% for men and 77 and 69% for women, showing essentially similar changes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Alcohol abuse and alcoholism rank as one of the most serious health problems in most Western countries (Room et al., 2005
). Therefore, a high priority should be given to reduction in the prevalence of alcoholism through more effective diagnosis and early intervention. Objective methods for detecting excessive ethanol consumption in health care are necessary for a majority of heavy drinkers who have not self-identified as having alcohol problems.
Studies in the past have shown that a number of biochemical parameters are altered in alcoholics, of which serum GT has emerged as one of the most efficient tests (Bagrel et al., 1979; Chick et al., 1981; Papoz et al., 1981; Bernadt et al., 1982; Leino et al., 1995; Anttila et al., 2004). The present study indicates that even moderate amounts of ethanol consumption influence serum GT concentrations at population level and this phenomenon may significantly affect the interpretation and the establishment of common reference intervals for GT measurements in health care. The data support the view that in order to improve the diagnostic potential of laboratory markers of excessive ethanol consumption and liver status, the reference intervals of each test should be based on healthy individuals who abstain from ethanol. Since a gold standard for a bona fide social drinker currently does not exist, the concepts of moderate drinking and social drinking should also be defined more accurately and the proportions of abstainers and moderate drinkers considered separately when selecting reference individuals in future studies.
The present data indicate that the estimated upper normal limits for GT measurements would be 
40% higher if the data based on moderate drinkers would be used as the basis of the reference population instead of abstainers. In accordance with this view, a recent NORIP survey from the Nordic countries showed markedly increased GT reference values (Stromme et al., 2004). The diagnostic sensitivity of GT measurements as a marker of excessive ethanol consumption would obviously improve if reference intervals would be based on the data from abstainers. This work indicates that 13% of alcoholics would escape detection if moderate drinkers are used as the reference population, instead of abstainers. Thus, there may be a need for revising the reference range downwards. It may, however, be argued that setting a lower limit could worsen the specificity of GT assays and lead to a high number of false positive values. According to this work, 11% of the moderate drinkers would have shown increased values. However, there may be individuals who are in the upper range of the limits of social drinking. Since the data are based on self-reports, we cannot rule out occult alcohol abuse in these subjects. It should be noted, however, that future studies are clearly warranted to explore the independent effect of various possible sources of unspecificity on GT values, such as obesity or diabetes in individuals reporting either moderate drinking or no drinking. Our preliminary analyses on moderate drinkers with different degrees of obesity have indicated potentiation of GT activities in individuals with significant obesity (data not shown). The associations between GT, moderate drinking, and obesity have previously been examined by Kornhuber et al. (1989) who also concluded that the definition of GT normal values may need to be readdressed. The correlation (r = 0.35) between alcohol consumption per se and GT values in this study is consistent with previous observations (Bagrel et al., 1979; Chick et al., 1981; Papoz et al., 1981; Leino et al., 1995; Anttila et al., 2004). The correlation was, however, essentially similar in women (r = 0.36) and men (r = 0.32), though some earlier studies have reported higher correlations in populations consisting of men only (Papoz et al., 1981; Anton and Moak, 1994; Sillanaukee et al., 1998). The diagnostic sensitivity of GT has usually been shown to be lower for women than for men (Anton and Moak, 1994; Yersin et al., 1995; Mundle et al., 2000). Based on the present data, these findings may in part be explained by the definition of reference intervals. Furthermore, GT values in women may increase at lower levels of alcohol consumption as a result of women's increased vulnerability to the toxic effects of alcohol (Anton et al., 1998).
The advent of carbohydrate-deficient transferrin (CDT) testing has recently imposed a new challenge to the use of GT measurements because CDT has shown higher specificities than GT in several trials. Although CDT has become an increasingly important tool for assessing excessive ethanol consumption, it appears that CDT and GT frequently increase in different individuals (Anton et al., 2002; Anttila et al., 2003; Neumann and Spies, 2003). Some studies have concluded that GT is more efficient in identifying female alcoholics than CDT (Anton and Moak, 1994, Anton et al., 2002). Therefore, it seems at this time that CDT alone does not cover all the needs for an alcohol marker in routine clinical practice, and other markers, especially GT are needed as well.
Taken together, the present data indicate that the changes in drinking behaviour at population level may parallel increases in recommended GT cut-offs, which may subsequently lead to problems in recognizing excessive alcohol consumption in its early phase. Therefore, a critical re-evaluation of reference intervals even in the use of the well-established biochemical markers of alcohol consumption may be necessary in order to improve the assessment and treatment of patients with early-stage alcohol problems.
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ACKNOWLEDGEMENTS |
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The help of professor Pål Rustad, Fürst Medical Laboratory, Oslo, Norway, for providing data on GT measurements in the Nordic NORIP Survey for establishing reference intervals is gratefully acknowledged. The studies were supported in part by a grant from the Finnish Foundation for Alcohol Studies.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Anton, R. F. and Moak, D. H. (1994) Carbohydrate-deficient transferrin and gamma-glutamyltransferase as markers of heavy alcohol consumption: gender differences. Alcoholism: Clinical and Experimental Research 18, 747–754.[CrossRef][Web of Science][Medline]
Anton, R. F., Stout, R. L., Roberts, J. S. et al. (1998) The effect of drinking intensity and frequency on serum carbohydrate-deficient transferrin and gamma-glutamyl transferase levels in outpatient alcoholics. Alcoholism: Clinical and Experimental Research 22, 1456–1462.[CrossRef][Web of Science][Medline]
Anton, R. F., Lieber, C. and Tabakoff, B. (2002) Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study. Alcoholism: Clinical and Experimental Research 26, 1215–1222.[CrossRef][Web of Science][Medline]
Anttila, P., Järvi, K., Latvala, J. et al. (2003) A new modified gamma-%CDT method improves the detection of problem drinking: studies in alcoholics with or without liver disease. Clinica Chimica Acta 338, 45–51.[CrossRef][Web of Science][Medline]
Anttila, P., Järvi, K., Latvala, J. et al. (2004) Method-dependent characteristics of carbohydrate-deficient transferrin measurements in the follow-up of alcoholics. Alcohol and Alcoholism 39, 59–63.
Bagrel, A., d'Houtaud, A., Gueguen, R. et al. (1979) Relations between reported alcohol consumption and certain biological variables in an "unselected" population. Clinical Chemistry 25, 1242–1246.
Bernadt, M. W., Mumford, J., Taylor, C. et al. (1982) Comparison of questionnaire and laboratory tests in the detection of excessive drinking and alcoholism. The Lancet 1, 325–328.[Web of Science][Medline]
Chick, J., Kreitman, N. and Plant, M. (1981) Mean cell volume and gamma-glutamyl-transpeptidase as markers of drinking in working men. The Lancet 1, 1249–1251.[Web of Science][Medline]
Horn, P. S. and Pesce, A. J. (2003) Reference intervals: an update. Clinica Chimica Acta 334, 5–23.[CrossRef][Web of Science][Medline]
Kornhuber, J., Kornhuber, H. H., Backhaus, B. et al. (1989) The normal values of gamma-glutamyltransferase are falsely defined up to now: on the diagnosis of hypertension, obesity and diabetes with reference to "normal" consumption of alcohol. Versicherungsmedizin 41, 78–81.[Medline]
Leino, A., Impivaara, O., Irjala, K. et al. (1995) Health-based reference intervals for ALAT, ASAT and GT in serum, measured according to the recommendations of the European Committee for Clinical Laboratory Standards (ECCLS). The Scandinavian Journal of Clinical and Laboratory Investigation 55, 243–250.
Mundle, G., Munkes, J., Ackermann, K. et al. (2000) Sex differences of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and mean corpuscular volume in alcohol-dependent patients. Alcoholism: Clinical and Experimental Research 24, 1400–1405.[CrossRef][Web of Science][Medline]
Neumann, T. and Spies, C. (2003) Use of biomarkers for alcohol use disorders in clinical practice. Addiction 98 (Suppl. 2), 81–91.
Papoz, L., Warnet, J. M., Pequignot, G. et al. (1981) Alcohol consumption in a healthy population. Relationship to gamma-glutamyl transferase activity and mean corpuscular volume. The Journal of the American Medical Association 245, 1748–1751.
Persson, J., Magnusson, P. H. and Borg, S. (1990) Serum gamma-glutamyl transferase (GGT) in a group of organized teetotallers. Alcohol 7, 87–89.[CrossRef][Web of Science][Medline]
Reyes, E. and Miller, W. R. (1980) Serum gamma-glutamyl transpeptidase as a diagnostic aid in problem drinkers. Addictive Behaviors 5, 59–65.[CrossRef][Web of Science][Medline]
Room, R., Babor, T. and Rehm, J. (2005) Alcohol and public health. The Lancet 365, 519–530.[Web of Science][Medline]
Sillanaukee, P., Aalto, M. and Seppä, K. (1998) Carbohydrate-deficient transferrin and conventional alcohol markers as indicators for brief intervention among heavy drinkers in primary health care. Alcoholism: Clinical and Experimental Research 22, 892–896.[CrossRef][Web of Science][Medline]
Stromme, J. H., Rustad, P., Steensland, H. et al. (2004) Reference intervals for eight enzymes in blood of adult females and males measured in accordance with the International Federation of Clinical Chemistry reference system at 37°C: part of the Nordic Reference Interval Project. The Scandinavian Journal of Clinical and Laboratory Investigation 64, 371–384.
Yersin, B., Nicolet, J. F., Dercrey, H. et al. (1995) Screening for excessive alcohol drinking. Comparative value of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and mean corpuscular volume. Archives of Internal Medicine 155, 1907–1911.
Zein, M. and Discombe, G. (1970) Serum gamma-glutamyl transpeptidase as a diagnostic aid. The Lancet 2, 748–750.[CrossRef][Web of Science][Medline]
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