CARBOHYDRATE-DEFICIENT TRANSFERRIN IS ELEVATED IN CATABOLIC FEMALE PATIENTS

Andreas Reif,*, Heike Keller, Marc Schneider, Stephan Kamolz, Armin Schmidtke and Andreas J. Fallgatter

Department of Psychiatry and Psychotherapy, Julius-Maximilians-University Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany

Received 14 April 2001; in revised form 21 May 2001; accepted 15 June 2001


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
— Serum carbohydrate-deficient transferrin (CDT) is currently widely used as a biochemical marker of alcohol misuse. However, various recent studies have questioned the diagnostic value of this parameter and reported low levels of both specificity and sensitivity, especially in women. Thus, we sought to identify sub-groups of female individuals in which CDT is elevated independently of alcohol consumption. Significantly increased CDT levels were found in catabolic disease states due to psychiatric disorders distinct from alcoholism. None of those patients reported frequent alcohol consumption. CDT therefore appears also to be increased by metabolic processes distinct from alcohol degradation. Possible biochemical mechanisms of this phenomenon are discussed. As a consequence of these findings, the measurement of CDT alone is not suitable to screen for alcohol misuse in catabolic subjects.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Serum carbohydrate-deficient transferrin (CDT) has over the past 20 years been described as a biochemical marker for alcohol consumption (van Eijk et al., 1983Go; Stibler et al., 1988Go; Stibler, 1991Go). Human transferrin comprises at least six different isoforms, with respect to the number of sialic acid side chains: penta-, tetra-, tri-, di-, mono- and asialo-transferrin (Wong and Regoeczi, 1977Go). In subjects with high levels of alcohol consumption, isoforms with 0–3 sialo residues are increased, whereas the 4 and 5 sialo forms are decreased (Stibler et al., 1979Go). The former are designated as CDT. The exact mechanism by which alcohol intake elevates CDT is not yet exactly known and seems to be a multi-step process (Sillanaukee et al., 2001Go): enzymes which glycosylate transferrin are inhibited by ethanol metabolites (Xin et al., 1995Go), enhanced loss of sialic acid groups occurs (Ghosh et al., 1993Go), and receptor-mediated CDT uptake might be inhibited (Petren and Vesterberg, 1988Go). To date, several commercial tests are available for clinical use, and the measurement of CDT is commonly applied in clinical and forensic medicine (Wetterling and Kanitz, 1997Go).

Initially, very high levels of both sensitivity and specificity have been reported, so that CDT was considered to be the best biomarker of alcoholism available (Stibler et al., 1986Go; Gjerde et al., 1988Go; Kapur et al., 1989Go; Kwoh-Gain et al., 1990Go; Lesch et al., 1996Go; Burke et al., 1998Go; Reynaud et al., 1998Go). However, follow-up studies failed to reproduce these promising results; a large number of studies demonstrated that CDT is not superior to gamma-glutamyltranspeptidase ({gamma}-GT) and mean corpuscular volume (MCV), which are not correlated to CDT (Helander et al., 1996Go), in the identification of alcohol misuse (Nilssen et al., 1992Go; Gronbaek et al., 1995Go; Aithal et al., 1998Go; Schmitt et al., 1998Go; Sillanaukee et al., 1998Go; Limin et al., 1999Go). This has been confirmed by two recent literature reviews (Salaspuro, 1999Go; Scouller et al., 2000Go). It also appeared that CDT has a worse predictive power in women compared to men; Schmitt et al. (1998) reported a sensitivity of 0% (at a specificity level of 95%) for females, and in a recent study CDT levels of peri-menopausal women were reported to have a sensitivity of 30% (van Pelt et al., 2000Go). Although some other studies found better values, it was consistently noted that CDT alone is not suitable as a biomarker of alcohol intake in women (Nystrom et al., 1992Go; Gronbaek et al., 1995Go; Yeastedt et al., 1998Go; Allen et al., 2000Go; Brathen et al., 2000Go). However, the cause for this gender-specific effect is not yet known and further investigations are needed to clarify this issue.

As the determination of CDT is more than twice as expensive as that of {gamma}-GT or MCV, and, even more importantly, a false-positive test result might have important consequences for the patient, we sought to identify conditions in which CDT is elevated independently of alcohol intake. Most noteworthy, several variables distinct from gender have been shown to have an influence on the CDT level, e.g. age, smoking status, obesity (Sillanaukee et al., 1998Go; Whitfield et al., 1998Go), hypertension (Fagerberg et al., 1994aGo), serum iron (De Feo et al., 1999Go) and insulin levels (Fagerberg et al., 1994bGo). However, most of these do not increase the CDT concentration above the cut-off value in teetotallers (Whitfield et al., 1998Go). As we had the clinical impression that serum CDT concentration is increased in women reporting recent weight loss, we screened all female patients who were in a catabolic (negative metabolic) state when attending our department. Our hypothesis was that catabolism of various aetiologies might result in elevated CDT levels in female (psychiatric) patients.


    SUBJECTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Female in-patients presenting at the admission ward of our department have been screened for elevated CDT levels if they reported a recent history of weight loss or showed clear clinical signs thereof. All of them suffered from psychiatric disorders distinct from alcoholism; only patients reliably denying any alcohol intake above one drink per week were included in the screening programme. Higher alcohol consumption was an exclusion criterion, as was a score of >=1 in the CAGE questionnaire (Mayfield et al., 1974Go; Ewing, 1984Go). Alcohol abstinence was confirmed by relatives or professional staff, when available; three patients did not have any opportunity to obtain alcoholic beverages, due to immobilization or placement in a closed ward. Serum CDT and other parameters were determined within the first 4 days after admission. Eleven patients matched all the inclusion criteria described above; they were between 20 and 86 years old with a mean age of 45 years. The recruitment interval was 5 months.

The causes of weight loss were varied, as were the psychiatric diagnoses (cf. Table 2Go). Patient #1 could not care for adequate food intake due to long-lasting dementia, whereas patient #2 refused to cook and eat, because of a paranoid schizophrenia resulting in a delusion of impoverishment. Patient #3 suffered from chronic malnutrition and neglect due to paranoid schizophrenia, and #4 reported that she refused to eat because of erotomania. Patient #5 suffered from anorexia nervosa. Patient #6 suffered from a personality disorder exaggerated by an acute polymorph psychotic disorder; additionally, she had juvenile diabetes. Due to both psychiatric diseases, she had very low compliance with respect to insulin treatment resulting in repetitive hypo- as well as hyperglycaemias and ketoacidosis. Patient #7 had ideas that both food and beverages were poisoned due to hebephrenic schizophrenia. Patient #8 had an obsession that she was not allowed to eat, as she had delusions that she would get punished for this by a former nurse (she suffered from paranoid schizophrenia for over 30 years); patient #9 had a severe case of anorexia nervosa with a body mass index (BMI) of 10 kg/m2. Patient #10 had an episode of schizoaffective disorder and lost 14 kg of weight due to maniform excitation, loss of appetite and altruistic overwork. Patient #11 had had anorexia nervosa for years, and concomitant chronic pancreatitis which explains her elevated {gamma}-GT value (cf. Table 1Go).


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Table 2. Carbohydrate-deficient transferrin (CDT) values of control psychiatric in-patients compared with the weight-loss group
 

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Table 1. Carbohydrate-deficient transferrin (CDT) concentrations in catabolic patients
 
For comparison, we investigated 24 female control subjects from the same ward and time interval, who have been screened routinely for excessive alcohol intake by the use of CDT; this group has been divided into abstinent/social drinkers [i.e. persons consuming alcohol not at all or socially, maximally twice a week, and not fulfilling any ICD-10 (World Health Organization, 1992Go) criterion for harmful alcohol use or alcohol dependence] and heavy drinkers (fulfilling the ICD-10 criteria for harmful alcohol use or alcohol dependence, drinking alcohol on a daily basis with frequent intoxications). The rationale for this division was an extensive open clinical interview including self-reported alcohol consumption, as well as information by relatives, when possible. One patient had to be excluded because of persisting uncertainties about her alcohol consumption (CDT value: 6.3%).

Determination of serum parameters
The concentration of CDT was performed in the routine laboratory of our department. As the assay method might substantially influence the sensitivity of the test (Sorvajarvi et al., 1996Go), we chose to utilize the %CDT method. By using this method, total transferrin levels are separately determined according to the protocol of the manufacturer. Therefore, changes in total transferrin concentrations have a smaller influence on the measured CDT value. The %CDT turbidimetric immunoassay by Bio-Rad was used (Bio-Rad Laboratories GmbH, Munich, Germany), which is based on the method by Axis Biochemicals. Briefly, serum transferrin is saturated by Fe3+ ions; as a result of this, transferrin isoforms are differentially charged, depending on the number of sialic acid groups. Thereafter, the samples are loaded onto an ion exchange column where transferrin isoforms are separated according to their different charges. The CDT isoforms are then detected turbidimetrically by the use of a polyclonal anti-human transferrin antibody. This test covers all six transferrin isoforms (penta-, tetra-, tri-, di-, mono- and a-sialo-transferrin) and reports CDT as a percentage of total transferrin. The assay has been calibrated by the manufacturer using a high-performance liquid chromatography (HPLC) method (r2 = 0.98 of %CDT against HPLC). The cut-off value for elevated CDT was 6% according to the manufacturer's protocol.

All other parameters were determined in the same laboratory by established techniques for routine measurements, with a Vitros Chemistry Systems 750XRC apparatus. MCV was calculated as the quotient between the haematocrit and the number of erythrocytes as determined with a Sysmex K1000 apparatus. Reference ranges were as follows: MCV, 85–98 fl; {gamma}-GT, <=28 U/l; uric acid, 2.4–7.0 g/l; total cholesterol, 140–220 mg/l; total triglycerides, 74–172 mg/l.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Within 5 months, 11 female patients were admitted to our admission ward and reported weight loss in recent weeks, or showed clear clinical signs thereof and conceded decreased food intake in an open clinical interview. All of them consumed less than one alcoholic drink per week. We investigated whether CDT is elevated in these subjects, being in a catabolic state (exclusion criteria are given in the Subjects and methods section).

Of 11 patients, seven were found to have CDT levels above the cut-off value (6%). Thus, the sensitivity of elevated CDT concentrations for catabolic metabolism in abstinent patients was 63%. In all patients, other known markers for alcohol misuse have been determined for comparison. Weight as well as height have been measured and the body mass index (BMI) has been calculated using the formula BMI = weight (kg)/[height (m)]2. Table 1Go summarizes all investigated parameters. The mean ± SD serum CDT concentration of this group was 6.7 ± 1.8%; CDT concentrations and BMI, as well as other laboratory parameters, were not correlated.

During the same time-frame, the CDT value of 24 other female in-patients of the same ward has been determined routinely to screen for alcohol misuse. According to their self-reported history of alcohol consumption and the clinician's impression, this group has been divided into abstinent/social and heavy drinkers according to the rationale given in the Subjects and methods section. One patient has been excluded as her drinking status remained unclear; none of these patients reported recent weight loss. In Table 2Go, the CDT value, the main psychiatric diagnosis and the drinking status of those patients is presented. The mean ± SD CDT value of abstinent/ social drinkers was 4.4 ± 1.0%, and for heavy drinkers 5.8 ± 2.2, respectively. The CDT values of the abstinent/social and the heavy drinkers did not differ significantly (P = 0.075, two-tailed Student's t-test). The CDT value had a sensitivity for heavy alcohol consumption of 33% (at a cut-off level of 6%). In abstinent/social drinkers, only one patient was found to have an increased CDT concentration, thus the specificity of CDT was 91% when abstinent/social drinkers were the ‘healthy’ control group. Considering CDT as a marker for excessive alcohol intake, its specificity when calculated for the weight-loss group was as low as 36%, i.e. seven false-positive test results in 11 patients.


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The determination of CDT is currently commonly applied to screen for alcohol misuse. However, there is an increasing body of evidence that this marker has lower levels of sensitivity and specificity than previously described (Salaspuro, 1999Go; Scouller et al., 2000Go). Additionally, a range of confounding variables has emerged (Whitfield et al., 1998Go) and it appears that this marker is much less valid in female, than in male, subjects (Allen et al., 2000Go). The specificity for women ranges from 57 to 100% with a mean of 87 ± 12% (calculated from the values given in Allen et al., 2000Go). Equally important is the corresponding level of sensitivity. In the present study, we found sensitivity levels of 33% for women. Consistent with this, CDT sensitivity levels for women from 19 to 86% have been reported (mean ± SD: 47 ± 18%; Allen et al., 2000Go). Thus, the diagnostic value of CDT for female subjects is fairly poor. The low level of sensitivity might easily cause a diagnostic bias when CDT is applied as a biomarker for alcohol consumption. A false-positive test result might have severe consequences for the patient, especially in forensic psychiatry. It is therefore of extreme importance to identify disease states in which CDT is elevated independently of alcohol consumption.

We present here cases of non-alcohol-drinking female patients in whom CDT was elevated due to a catabolic state. The underlying psychiatric diseases were predominantly anorexia nervosa and schizophrenia spectrum disorders. Malnutrition in industrialized countries is becoming rare; however, it can be found frequently in psychiatric hospitals due to eating disorders, delusions or compulsions. Recently, a study by Agelink et al. (1999) suggested CDT as a highly specific parameter for alcohol misuse in schizophrenic patients. Considering the results of the present study, a catabolic state should be considered when CDT alone is found to be elevated. Notably, the BMI was not a marker for recent malnutrition (cf. Table 1Go). The overall constellation of laboratory parameters has to be taken into account; MCV, another alcoholism parameter, which has recently been suggested to be diagnostically equal to CDT (Schmitt et al., 1998Go; Allen et al., 2000Go), might also be elevated in malnutrition, due to decreased cobalamine or folic acid intake. When {gamma}-GT is increased too, this could indicate increased alcohol intake; low uric acid, cholesterol and triglyceride values suggest malnutrition, but tend to be elevated in alcoholics (Burke et al., 1998Go). Thus, CDT proves to be useful only in combination with other routine laboratory parameters, as suggested by other groups (Nilssen et al., 1992Go; Aithal et al., 1998Go; Yeastedt et al., 1998Go; Allen et al., 2000Go; van Pelt et al., 2000Go). Nonetheless, serum parameters can only support a clinician's diagnosis of alcohol dependence, never substantiate it. Screening questionnaires, like the CAGE test, have proven to be useful (Aithal et al., 1998Go), and can be carried out quickly and at almost no cost, and should therefore be used first-line in the diagnostic hierarchy.

Why is CDT elevated in catabolic states? Glycosyltransferases, enzymes which are involved in the glycosylation of transferrin, are inhibited by the ethanol metabolite acetaldehyde (Ghosh et al., 1993Go; Xin et al., 1995Go). This results in decreased synthesis of fully glycosylated transferrin and contributes to the elevation of CDT in subjects with excessive alcohol intake. In catabolic states, ketones are formed, one of which is acetoacetate (Stryer, 1988Go). Acetoacetate and acetaldehyde bear structural similarities (Fig. 1Go). Therefore, it is possible that acetoacetate could also inhibit glycosyltransferases, resulting in an increase of CDT (Scheme 1). Interestingly, patient #6 had type I diabetes with repeating ketoacidosis, which supports this theory. A recent study found no influence of diabetes on CDT (Meerkerk et al., 1998Go), but usually diabetic patients attending a general practice (as in this report) are not expected to suffer from diabetic decompensations resulting in ketoacidosis. It would therefore be interesting to determine CDT in non-compliant patients suffering from juvenile diabetes, especially in correlation with ketones. In line with this suggestion, elevated CDT was found to be negatively correlated with fasting plasma insulin in hypertensive men (Fagerberg et al., 1994bGo). Although our hypothesis has yet to be proven, it provides a basis for future basic research, e.g. biochemical experiments investigating the possible inhibition of glycosyltransferases by acetoacetate. Additional mechanisms could of course include deficient availability of carbohydrates in catabolic states or other mechanisms not yet known.



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Fig. 1. Proposed mechanism for the elevation of carbohydrate-deficient transferrin (CDT) in catabolic states. Transferrin is glycosylated by specific enzymes, called glycosyltransferases. These are inhibited by acetaldehyde (right), a metabolite of ethanol (Ghosh et al., 1993Go; Xin et al., 1995Go), resulting in an increase in CDT. The ketone acetoacetate (left), which is formed in catabolic states, might also inhibit the enzymes due to its structural similarity to acetaldehyde, resulting also in increased CDT. The formulae of both acetaldehyde and acetoacetate are displayed to point out their structural similarity.

 
Obviously, some uncertainties about both the exact drinking status and the precise nutritional history do exist in the present study due to the fact that we utilized a retrospective study design. According to these methodological problems, it would be fruitful to reproduce the findings presented in this pilot study by the use of a prospective study design with a greater number of both male and female patients by the use of a matched controls study design. A replication study investigating the possible CDT increase in patients suffering from anorexia nervosa is presently under way, and preliminary data indicate the validity of our findings. Taken together, we conclude that CDT is not suitable as a marker for alcohol intake in catabolic female patients; furthermore, when CDT is elevated, recent weight loss should be considered and CAGE-positivity, {gamma}-GT, MCV, uric acid, cholesterol and triglycerides have also to be determined.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
We thank Dr Lothar G. Fröhlich for his valuable help in preparing this manuscript.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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