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Clinical Chemistry 44: 2120-2125, 1998;
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(Clinical Chemistry. 1998;44:2120-2125.)
© 1998 American Association for Clinical Chemistry, Inc.

Enzymes and Protein Markers

Intra- and interindividual variability of carbohydrate-deficient transferrin, {gamma}-glutamyltransferase, and mean corpuscular volume in teetotalers

Anders Helander1,a, Erling Vabö1, Klas Levin2, and Stefan Borg1

1 Department of Clinical Neuroscience, Karolinska Institute, Center for Dependency Disorders at St. Görans & Karolinska Hospital, S-10229 Stockholm, Sweden.

2 Nova Medical Calab, St. Görans Hospital, S-11281 Stockholm, Sweden.
a Address correspondence to this author at: Alcohol & Drug Dependence Unit, St. Görans Hospital, S-11281 Stockholm, Sweden. Fax 46-8-6721994; e-mail anders.helander{at}bekl.csso.sll.se.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
 References
 
Blood samples for determination of the biochemical alcohol markers carbohydrate-deficient transferrin (CDT) in serum, {gamma}-glutamyltransferase (GGT) in serum, and erythrocyte mean corpuscular volume (MCV) were collected once every 1–2 weeks over ~5 months from 10 female and 4 male teetotalers. Mean values for serum CDT (using the CDTectTM assay) ranged from 9.9 to 29.4 units/L (median, 14.2 units/L), and the highest results were obtained in the women. The mean values for serum GGT ranged from 0.15 to 0.49 µkat/L (median, 0.30 µkat/L, or 18 U/L) except for one woman with a very high mean of 3.07 µkat/L. For MCV, the mean values ranged from 79.5 to 91.5 fL. Two women showed several CDT results above the upper reference limit (mean values, 27.6 and 29.4 units/L, respectively); however, their GGT and MCV values fell within the reference intervals. One of these women exhibited an increased total transferrin concentration (mean value, 5.38 g/L), which was possibly related to the use of oral contraceptives and/or a low serum iron concentration. When the CDTect value was expressed relative to total transferrin, a ratio within the reference interval was observed for this woman but not for the other woman with increased CDTect values. The present study demonstrates a considerable variation between individuals in CDT, GGT, and MCV without drinking any alcohol. The results also show that these baseline values are fairly constant over time within the same individual.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Conclusions
 References
 
Measuring an abnormal microheterogeneity of the iron transport glycoprotein transferrin in serum has become an accepted laboratory method for detection of excessive alcohol consumption during the previous weeks (1)(2). The most abundant transferrin isoform contains two biantennary carbohydrate chains with a total of four terminal sialic acid residues (tetrasialotransferrin); however, continuous heavy drinking increases the formation of isoforms with less sialic acid, hence the name "carbohydrate-deficient" transferrin (CDT).1 To render CDT concentrations above the conventional reference limit for abnormal values, a regular intake of at least 50–80 g of ethanol per day for 1 week or longer is required (1)(2). During abstention, the serum CDT concentration normalizes, with a half-life of ~1.5–2 weeks (1). Although CDT sometimes shows only marginally higher or even similar sensitivity relative to the laboratory test currently used most widely for alcohol abuse, the activity of the liver enzyme {gamma}-glutamyltransferase (GGT, EC 2.3.2.2), the major advantage is that CDT produces considerably less false-positive test results (i.e., a superior diagnostic specificity). Apart from being increased by chronic drinking, there are many non-alcohol-related causes of a raised GGT, such as severe liver disease, certain medications, obesity, and smoking, thereby limiting its diagnostic specificity (3)(4)(5).

The cutoff limit used to differentiate between health-related and abnormal values for biochemical markers is traditionally calculated as the mean plus or minus two standard deviations of the values in an apparently healthy control population (light/moderate social drinkers). It should be noted that this practice will yield a specificity of <100% because a small fraction of the control values will always lie outside the reference interval. Additionally, although the response in CDT to a given dose of alcohol is known to vary considerably between individuals, people with low baseline values of CDT may be able to drink much more alcohol on average than those with high baseline values before exceeding the upper reference limit. However, during long-term monitoring with repeated sampling in outpatient treatment programs, the sensitivity of biochemical alcohol markers can be enhanced considerably by introducing individualized reference limits instead of the conventional, population-based a priori cutoffs (6)(7). This strategy, which uses each individual's baseline—or abstinence—value as the starting point, not only facilitates early detection of relapse into heavy drinking but also improves the reliability of the test results.

When the stability of CDT over time was compared by sequential measurements in control subjects (light/moderate social drinkers and one teetotaler) and alcohol-dependent individuals undergoing treatment in an outpatient program, the single lowest coefficient of variation was observed for the teetotaler (7). This observation suggested that occasional intake of small to moderate amounts of alcohol can cause increases in the CDT concentration, leading to a greater intraindividual fluctuation (8). To determine the intra- and interindividual variability of CDT at baseline, i.e., without drinking any alcohol, serial monitoring was performed in teetotalers. For comparison, measurements of two other routinely available clinical tests of excessive drinking, GGT and the mean corpuscular volume of erythrocytes (MCV), were also evaluated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Conclusions
 References
 
subjects
Ten female and five male Caucasian teetotalers with no history of excessive drinking (all being members of a local temperance society) participated in this study as paid volunteers. Their ages ranged from 19 to 69 years (mean, 42 years), and they were all healthy and not taking any regular medication, except for two women who used oral contraceptives (estrogens). None of the women were pregnant. Informed consent was obtained from all participants, and the study was approved by the Ethics Committee at the Karolinska Hospital.

Venous blood samples for determination of MCV and serum CDT and GGT were drawn from individuals once every 1–2 weeks over a period of ~5 months (between January and June). All samples were collected on the same time of day and by the same nurse; however, the sampling procedure was not further standardized. One man dropped out after only a few weeks, and the data for this subject were excluded from the study. The blood samples for MCV determination were kept at room temperature and analyzed within 4 h after they were drawn. Serum samples for CDT and GGT determination were frozen within 4 h after collection and stored at -20 °C until use. Samples were then thawed overnight at 4 °C, and analysis was performed in single analytical runs. The total number of blood samples obtained from each subject ranged from 15 to 22 (mean, 18 samples). Altogether, 252 blood samples were collected.

measurements
Measurement of CDT in serum was carried out in duplicate using a commercial test kit (CDTectTM, Pharmacia & Upjohn Diagnostics) based on the initial separation of transferrin isoforms by microanion exchange chromatography on disposable microcolumns. Quantification of CDT was carried out by a double antibody radioimmunoassay. In this method, the CDT content is expressed as an absolute amount (in units/liter; according to the manufacturer, 1 unit of CDT in the CDTect assay refers to ~1 mg transferrin) of the transferrin isoforms with pI values >5.7 (asialo-, monosialo- and part of disialotransferrin). The reference limits between health-related and abnormal CDT values were 20 units/L for men and 27 units/L for women. The analytical precision (intraassay CV) of the method was 6.1% (n = 15). To assess the possible influence on CDT of variations in the serum transferrin concentration, total transferrin was quantified in five samples from each subject (the samples were evenly distributed throughout the 5-month collection period).

GGT, MCV, and serum transferrin (traceable to CRM 470) were determined at the local clinical chemistry laboratory, using accredited routine methods. The upper reference limit for GGT was 0.8 µkat/L for healthy women and 1.3 µkat/L for healthy men (1 µkat = 60 U); the intraassay CV of the measurements was 0.95% (n = 14) at 1.9 µkat/L. The corresponding limit for MCV was 96 fL for both men and women, and the interassay CV of the measurements was 0.75% (n = 12) at 87 fL. The standard reference interval for serum total transferrin was 1.94–3.26 g/L, and the intraassay CV of the method was 2.5% (n = 5).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Conclusions
 References
 
The individual mean values and ranges for CDT, GGT, and MCV in serial blood samples (n = 15–22/subject) collected from 14 healthy teetotalers over a period of ~5 months are shown in Fig. 1 . Although there were large variations in the baseline values for all three alcohol markers, the relative variability over time within the same subject was not markedly different between those with higher and lower means. The mean values for CDT ranged from 9.9 to 29.4 units/L (median, 14.2 units/L), and the highest results were obtained in the women, showing a mean value of 17.5 units/L compared with 11.4 units/L in the men (Fig. 1a ). That nondrinking women have ~30–50% higher concentrations of CDT (with the CDTect method) than nondrinking men is known already from previous studies (9)(10)(11), and this apparently is the result of a gender-based difference in the absolute amounts of asialo- and monosialotransferrin isoforms (12). The intra- and interindividual CVs for CDT are given in Table 1 . The intraindividual value agreed well with earlier findings for light/moderate social drinkers and abstaining alcoholics (7); however, the interindividual CV was much higher in this study.



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  		Figure 1. Distribution of individual mean values and ranges for serum CDT, using the CDTect assay (a), serum GGT (b), and MCV (c) in serial blood samples collected from 14 healthy teetotalers (subjects A–N) over a 5-month period.

The number of samples collected from each subject ranged from 15 to 22 (mean, 18 samples/subject). The dashed lines indicate the upper reference limits.


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  		Table 1. Coefficients of intraindividual total (analytical + biological) variation (CVTW), intraindividual biological variation (CVBW), interindividual biological variation (CVBB), and reference values from the literature for S-GGT, B-MCV, S-CDT, S-transferrin (S-Tf), and the S-CDT/Tf ratio in 14 healthy teetotalers over a 5-month period.

In two of the women (subjects M and N), several CDT values exceeded the upper reference limit used to indicate prolonged heavy drinking, the respective mean values being 27.6 and 29.4 units/L. Both women showed GGT and MCV values within the reference intervals. Although transferrin synthesis and glycosylation are two distinct processes, an association between serum CDT and total transferrin concentrations has been reported (10)(13)(14). The results of the present study (Fig. 2 a and Table 1Up ) confirm that the serum transferrin concentration is fairly stable over time within the same individual (15). However, two women (subjects L and N) exhibited transferrin concentrations above the upper reference limit of 3.26 g/L for healthy adult individuals (the mean values ± SD were 3.74 ± 0.24 g/L and 5.38 ± 0.18 g/L, respectively). These were the only subjects taking oral contraceptives (estrogens), which are known to be associated with a ~12–16% increase on average in serum transferrin synthesis (the reference interval for women using estrogens is 2.25–3.85 g/L) (16)(17)(18) and possibly also with the amount of CDT (19), although this was not confirmed by others (11)(20). If these two subjects were excluded from the calculations, the interindividual CV value for serum transferrin concentration was markedly reduced, thereby approaching that reported by others (Table 1Up ) (21). When the ratio of CDT (CDTect) to total transferrin was calculated in units/gram (Fig. 2b ), only subject M showed a relative value above the reference range for healthy adults for this ratio (6.4 ± 1.7 units/g) reported by Sorvajärvi et al. (14). This suggests that the abnormal test result according to the CDTect assay for subject N can be explained by the increased total transferrin concentration, which may in turn be related to intake of oral contraceptives and/or a low serum iron concentration (9.9 ± 3.2 µmol/L). However, the cause of the high CDT (CDTect) values in subject M remains unknown but may possibly involve partial coelution of the trisialotransferrin isoform in the initial microcolumn fractionation step (22).



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  		Figure 2. Distribution of individual mean values and ranges for serum total transferrin (a) and the ratio of CDT (using the CDTect assay) (b) to total transferrin in 5 blood samples collected from 14 healthy teetotalers (subjects A–N) over a 5-month period.

The dashed lines indicate the upper reference limits. The expected limit for the CDTect/transferrin ratio is calculated from the results (mean + 2 SD) of Sorvajärvi et al. (14). The two women using oral contraceptives (estrogens) are indicated by a *.

Although CDT is considered a very specific marker for recent excessive alcohol consumption, values outside the reference interval are occasionally found even without prior heavy drinking. Known or likely causes for false-positive CDT results include severe hepatic failure (usually primary biliary cirrhosis and chronic viral hepatitis), the uncommon transferrin D variant, a rare inherited defect in glycoprotein metabolism, and transplantation (1)(10)(23)(24)(25)(26)(27)(28). During pregnancy and, as indicated above, oral estrogen administration and also in iron deficiency anemia, there is a general increase in total transferrin concentration, which could yield false-positive results if absolute CDT values are used (29)(30). On the other hand, using relative values (%CDT) might, at least theoretically, yield false-negative results in women who abuse alcohol during pregnancy because most of the increase in transferrin synthesis is accounted for by the highly sialylated isoforms (15), leading to a gradual decline in relative CDT content over time (31). Whether the CDT result should preferably be expressed as an absolute amount (units or milligrams CDT/liter serum) or the amount relative to total transferrin (%CDT) has been a matter of some debate. In general, correlation studies with the two different ways of expressing the CDT result have shown good agreement, and the small variations in diagnostic efficiency observed are mostly not important in clinical practice (14)(32)(33). However, in the present study, expressing CDT as the relative amount helped to identify one individual who consistently showed false-positive results with the CDTect assay. In cases where the CDT result and the clinical experience are not congruent, an independent CDT method based on HPLC or isoelectric focusing should be recommended because the visible measurements of the latter procedures reduce the risk of obtaining false-positive results caused by genetic variants or other chromatographic interferences.

For many years, the activity of GGT in serum has been the most widely used laboratory test for detection of alcohol abuse. The major disadvantage of GGT is that it can be increased by a variety of other conditions besides heavy drinking, thereby reducing its diagnostic specificity. Nonetheless, many of the confounding factors are well known today and can often be controlled for in clinical situations. In the present study, the mean values for serum GGT ranged from 0.15 to 0.49 µkat/L (median value, 0.30 µkat/L, or 18 U/L), except for one women (subject E) showing an abnormally high mean of 3.07 µkat/L (Fig. 1bUp ). These results are in good agreement with earlier findings in teetotalers (34)(35), and both intra- and interindividual CVs were concordant with reference values from the literature (Table 1Up ) (36). The woman with increased GGT showed an initial value of 3.4 µkat/L, and the GGT value peaked in the third sample (7.2 µkat/L, or 432 U/L), after which there was a gradual decline until the last three specimens, which were 1.0, 0.8, and 1.3 µkat/L, respectively. The reason for her abnormally high and fluctuating GGT values is unknown; however, it may at least partly be related to her weight (a body mass index of 30 kg/m, compared with a reference value of <=25 kg/m) (37). However, her corresponding concentrations of CDT (range, 8–12 units/L) and MCV (88–92 fL) were stable and fell within reference limits during the entire 5-month observation period (Fig. 1Up ).

An increased erythrocyte MCV is often observed in alcoholic patients, and this hematological marker has been widely used as an indicator of alcohol abuse (38). However, the sensitivity of MCV is much too low to motivate its use as the sole evidence of heavy drinking, and there are also several other explanations for increased values besides excessive alcohol consumption. The mean values for MCV in the present study ranged from 79.5 to 91.5 fL (Fig. 1cUp ). All test results fell within the reference interval except for patient F, who showed three consecutive values of 97 fL, i.e., being just above the upper reference limit. The intra- and interindividual CVs were small (Table 1Up ), which agree with previous results (36). The smaller variability in MCV over time compared with the CDT, GGT, and transferrin values may be related to the long life span of erythrocytes in the circulation (~120 days).

The present study performed on healthy teetotalers demonstrates a considerable variation between individuals in their baseline values of the alcohol markers CDT, GGT, and MCV. The results also show that without drinking any alcohol the changes over time within the same individual are generally not very large.


   Conclusions
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
References
 
Although based on a limited number of subjects, the considerable variability in baseline values of CDT, GGT, and MCV between subjects found in the present study is in line with previous observations. The highest relative individual fluctuation was observed for the serum activity of GGT, which is not surprising considering the many factors besides heavy drinking known to influence this assay. On the basis of the present data, it would appear that during monitoring of alcohol-dependent subjects in outpatient treatment programs, instead of using population-based a priori reference limits to distinguish between health-related and abnormal values for biochemical markers, following changes relative to the individual baseline or abstinence value will improve the importance of laboratory data in early detection of relapse to drinking (i.e., a gain in diagnostic sensitivity) (6)(7)(8)(39)(40)(41). In addition, because some people have baseline values outside the reference interval even without prior excessive drinking, this strategy also improves the reliability of the test results yielding a higher diagnostic specificity.


   Acknowledgments
 
We thank Ulla Lindström and Helen Dahl for skillful clinical and technical assistance. S. Borg is one of the inventors and a patent holder of the CDTect method and obtains royalties for sales outside of Sweden.


   Footnotes
 
1 Nonstandard abbreviations: CDT, carbohydrate-deficient transferrin; GGT, {gamma}-glutamyltransferase; and MCV, mean corpuscular volume of erythrocytes.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Conclusions
 References
 

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