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
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ABSTRACT |
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INTRODUCTION |
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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., 1986; Gjerde et al., 1988
; Kapur et al., 1989
; Kwoh-Gain et al., 1990
; Lesch et al., 1996
; Burke et al., 1998
; Reynaud et al., 1998
). However, follow-up studies failed to reproduce these promising results; a large number of studies demonstrated that CDT is not superior to gamma-glutamyltranspeptidase (
-GT) and mean corpuscular volume (MCV), which are not correlated to CDT (Helander et al., 1996
), in the identification of alcohol misuse (Nilssen et al., 1992
; Gronbaek et al., 1995
; Aithal et al., 1998
; Schmitt et al., 1998
; Sillanaukee et al., 1998
; Limin et al., 1999
). This has been confirmed by two recent literature reviews (Salaspuro, 1999
; Scouller et al., 2000
). 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., 2000
). 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., 1992
; Gronbaek et al., 1995
; Yeastedt et al., 1998
; Allen et al., 2000
; Brathen et al., 2000
). 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 -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., 1998
; Whitfield et al., 1998
), hypertension (Fagerberg et al., 1994a
), serum iron (De Feo et al., 1999
) and insulin levels (Fagerberg et al., 1994b
). However, most of these do not increase the CDT concentration above the cut-off value in teetotallers (Whitfield et al., 1998
). 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.
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SUBJECTS AND METHODS |
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The causes of weight loss were varied, as were the psychiatric diagnoses (cf. Table 2). 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
-GT value (cf. Table 1
).
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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., 1996), 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, 8598 fl; -GT,
28 U/l; uric acid, 2.47.0 g/l; total cholesterol, 140220 mg/l; total triglycerides, 74172 mg/l.
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RESULTS |
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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 1 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 2, 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.
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DISCUSSION |
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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 1). 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., 1998
; Allen et al., 2000
), might also be elevated in malnutrition, due to decreased cobalamine or folic acid intake. When
-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., 1998
). Thus, CDT proves to be useful only in combination with other routine laboratory parameters, as suggested by other groups (Nilssen et al., 1992
; Aithal et al., 1998
; Yeastedt et al., 1998
; Allen et al., 2000
; van Pelt et al., 2000
). 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., 1998
), 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., 1993; Xin et al., 1995
). 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, 1988
). Acetoacetate and acetaldehyde bear structural similarities (Fig. 1
). 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., 1998
), 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., 1994b
). 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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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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