Alcohol Unit, University La Sapienza, Rome, Italy, 1 Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy and 2 Pacific Institute for Research and Evaluation, Calverton, MD, USA
* Author to whom correspondence should be addressed at: Mauro Ceccanti, M.D., Dipartimento di Medicina Clinica, Policlinico U.I, Viale del Policlinico 155, 00100 Roma. Fax: 0039-06-49972096; E-mail: mauro.ceccanti{at}uniroma1.it
(First received 30 November 2004; returned 17 December 2004; revised 15 February 2005; accepted 21 March 2005)
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ABSTRACT |
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INTRODUCTION |
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TD in alcoholics is a well-known problem and contributes to nervous system impairment: TDP is the coenzyme of several intra-mitochondrial enzymes, involved in carbohydrate and lipid metabolism, such as piruvate dehydrogenase (PDH), alpha ketoglutarate dehydrogenase (-KGDH), and transketolase (TK) (Nishino and Itokawa, 1977
; Gubler, 1991
);
-KGDH impairment could have a key role in WernikeKorsakow syndrome (WKS) (Nishino and Itokawa, 1977
). Th-dependent enzymes are important in the biosynthesis of a number of cell constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defence and in the biosynthesis of pentoses, nucleic acid precursors (Butterworth, 1993
; Pannunzio et al., 2000
Thomson, 2000
; Lee et al., 2001
; Singleton and Martin, 2001
). TD has been implicated in central and peripheral WKS, in alcoholism-induced cognitive deficit and in alcohol peripheral neuropathies (Butterworth, 1993
; Cook et al., 1998
; Pannunzio et al., 2000
; Thomson, 2000
; Lee et al., 2001
; Singleton and Martin, 2001
). Glycerophosphorylcholine (GPC) depletion, triggered by TD, may be the primary biochemical lesion leading to WKS (Pannunzio et al., 2000
); other issues related to TD in alcoholics remain even further from resolution [e.g. in a group of heavy drinkers abnormally low TK protein activity was found, thus suggesting that (Butterworth, 1993
; Pannunzio et al., 2000
; Thomson, 2000
; Lee et al., 2001
; Singleton and Martin, 2001
) impaired Th utilization might lead to more severe brain damage in a specific subgroup of patients (Heap et al., 2002
)]. Experimental data suggest that TK activity, as well as the activity of other Th-utilizing enzymes, may be downregulated in TD (Butterworth, 1993
; Pekovich et al., 1998
; Heap et al., 2002
). Also Th phosphorylation (especially synthesis and accumulation of TDP) is impaired in alcoholics, mainly in the liver, as only Th and not its phosphates can easily cross hepatocyte membranes (Fig. 1) (Yoshioka et al., 1983
; Rindi et al., 1992
).
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In this study, erythrocyte TDP, as well as Th and TMP were assessed in a larger series of alcoholics, to determine whether erythrocyte TDP might serve as a useful marker of alcoholism. A puzzling problem is the role of TD in the pathogenesis of the alcohol withdrawal syndrome (AWS). High-dose Th administration is a mainstay of the AWS treatment in clinical settings (Schuckit, 2005), along with benzodiazepines (BDZs), but this is an empirical treatment, since the role of Th deficit in AWS is poorly understood and conflicting results have been reported [e.g. in alcoholics affected by delirium tremens, the most dangerous outcome of AWS, serum Th was lower than in uncomplicated alcoholics (Hoes, 1981
) while no difference was found for erythrocyte TK activity, a sensitive indicator of Th level, between alcoholics with severe AWS and controls (Nordentoft et al., 1993
; Heap et al., 2002
)].
In the present study, erythrocyte Th, TMP, and TDP levels were assessed to:
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PATIENTS AND METHODS |
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Subject characteristics are reported in Table 1 and occupations in Table 2. A detailed medical history was obtained using the Lifetime Drinking History instrument (LDH) (Skinner and Sheu, 1982), detailing the years of high-risk consumption, i.e. daily alcohol consumption >25 g for females, and 40 g for males at risk for the onset of alcohol-related pathologies (WHO, 2000
) Amount of alcohol consumption lifelong and during the last year was estimated by the LDH. Intake during the preceding month was estimated by the Alcohol Timeline Followback (TLFB) (Sobell and Sobell, 1955
). Previous episodes of AWS were carefully recorded. Self-reported occasional consumption of illegal psycho-active substances was investigated since in the last decades alcohol addiction has often been found in association with the use of other psycho-active drugs (Martin et al., 1993
). Physical examination was performed and body mass index (BMI) was calculated. Blood alcohol concentration (BAC) was assessed daily by breath-test (Pocket Alcolmeter Lion SD 400, MORGAN Italy) and TLFB was performed. AWS symptoms (tremors of the hands, agitation, etc.) were carefully investigated and AWS severity was assessed by Clinical Institute Withdrawal Assessment for Alcohol (CIWA-ar) test (Sullivan et al., 1989
) a structured questionnaire based on the semi-quantitative evaluation of the main symptoms of AWS. The highest CIWA-ar value found during the hospitalization was taken into account for statistics. BDZs were administered if the CIWA-ar score exceeded 10. None of the patients showed signs suggestive of WKS, like confusion, either in the whole series, or in the AWS subset: maybe the careful check-up of AWS symptoms, and the precocious administration of BDZs, prevented the onset of WKS in AWS subjects (Victor et al., 1989
).
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No subject under study (alcoholics or controls) had received vitamin supplementation before the blood draw. Informed consent was obtained from all the subjects enrolled in this study.
Samples
The blood samples employed for this study were taken on the first day in day-hospital. Samples were coded to guarantee personal privacy.
Methods
Assessment of Th and its esters. Blood samples (7 ml) were collected after overnight fasting in EDTA or heparin vacutainers on the first day of hospitalization. Erythrocytes were separated by centrifugation, washed in saline solution, and haemolysed. The improved method for the assessment of Th and its esters by HPLC fluorimetric detection is detailed elsewhere (Mancinelli et al., 2003). HBV and HCV markers were assessed in all the patients by ELISA and third generation RIBA tests. HCV-RNA was evaluated in patients with anti-HCV antibodies.
Statistical analyses. The significance of differences between groups was calculated by the MannWhitney U-test. Correlation significance was assessed by the Spearman's rho correlation coefficient. Three different Receiver Operating Characteristic (ROC) curves were calculated for Th, TMP, and TDP values. Three levels of sensitivity, specificity, and predictive values were calculated [95% confidence intervals (CI)] for different clinical purposes. To investigate relationships between the levels of Th and its esters and the AWS symptoms (assessed by the CIWA-ar test) and the biochemical tests, an analysis of variance ANOVA (one-way) with post hoc Bonferroni correction was performed on normalized data by ln-transformation. The one-sample KolmogorovSmirnov (KS) procedure was used to test the null hypothesis that the Th, TMP, and TDP data were normally distributed. The two-sample KS test was employed to compare cumulative distribution functions for two groups (alcoholics and controls) to detect differences in shapes and locations. The significance level for evaluating results was set at P 0.05. The statistical package SPSS 11.0 for Windows was employed.
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RESULTS |
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Biochemical markers yielding pathological results and gender differences are reported in Table 3. Significant gender differences were observed for ALT (P = 0.03), and ferritin (P = 0.04) and a tendency towards significance (P = 0.06) was observed for GT.
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A highly significant difference between alcoholics (59.59 ± 25.68 nmol/l) and controls (89.60 ± 22.70 nmol/l) was found on Th assay (P < 105) (Table 4). No significant difference between the mean values for alcoholics (2.64 ± 3.35 nmol/l) and for controls (4.21 ± 6.37 nmol/l) was found on the TMP assay (Table 4). The mean values for alcoholics on the TDP assay (123.78 ± 43.68 nmol/l) were significantly different from mean values for controls (222.24 ± 54.56 nmol/l): P < 105 (Table 4). No significant difference was found between cirrhosis group (n = 15) and the whole group of alcoholics (Table 4). ROC curves for Th, TMP, and TDP values were calculated for all subjects (Fig. 2), for males and females separately (Figs 3 and 4). For TDP, sensitivity across subjects was 84.1%, specificity 85.4%, positive predictive value 82.4%, and negative predictive value 88.0% (Table 5 and Fig. 2). Also a striking significant gender difference (Figs 3 and 4) was found (P < 0.0005). Areas under the curves (AUC) were also calculated (Table 6), creating multiple curves in order to compare three competing classification models. In the whole sample, the best models are TDP and Th, while for TMP the entirety interval lies below the others. If the sample is split into males and females, the results are very similar, but Th seems slightly better than TDP in females.
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Self-reported occasional consumption of illegal drugs is reported in Table 8. No significant difference was found between the alcoholics using illegal drugs and the others. A biochemical assessment of nutritional status was performed. Albumin and BMI values were within normal limits, while the levels of ferritin and lymphocytes (Table 9) suggested a status of mild malnutrition (Blackburn et al., 1977).
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DISCUSSION |
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No significant difference was found for Th or its esters between patients consuming alcohol only and patients consuming illicit drugs occasionally. Further exploration of this topic, as well as of the gender differences found in this study, would prove fruitful.
No significant and reliable positive correlation was found between Th and its esters and the lifelong amount of AWS episodes or CIWA-ar values. This negative result may be in some way biased, since early prophylactic administration of Th (few hours after the first-day blood draw) could have prevented the TD worsening due to the increased Th metabolic demands in AWS subjects, thus maybe decreasing the severity of AWS symptoms. However, while the hypothesis that Th and its esters could be a main factor of AWS was not supported by our findings, the administration of Th remains a mainstay component of AWS treatment. At present Th treatment is advisable in all heavy drinkers, since post-mortem findings have demonstrated that TD sufficient to cause irreversible brain damage remains non-diagnosed ante-mortem in 8090% of patients (Thomson, 2000). Moreover, carbohydrate repletion in malnourished alcoholics, without Th supplementation, can precipitate acute TD (Thomson, 2000
).
Conflicting results were obtained from the nutritional assessment: BMI and albumin values were within normal limits, while lymphocyte and ferritin values suggested moderate malnutrition. Normal albuminaemia in alcoholics may be a surprise finding since albumin synthesis is depressed in alcoholics but the serum albumin levels are severely decreased only in ChildPugh stage C cirrhosis subjects. Such patients were not included in our study. The reliability of BMI in the assessment of body composition is a debated matter, mainly when modifications of total body water are crucial, as in alcoholics. Our data may be biased by water retention, common in heavily drinking alcoholics (like most of our patients), since the assessment of body weight (BMI: body weight/body height2) cannot distinguish between fat, muscle, or water. Indeed, only a few patients under study were homeless or very low-income subjects. Most held a regular job and maintained a good income and, therefore, poverty-related starvation (often the cause of malnutrition in alcoholics) can be dismissed in our series. Further, unemployed (32% of our series) and even homeless patients were assisted by public or private charities. Lymphocyte depletion could be an early-stage finding of alcoholism malnutrition, or rather might be related to alcohol-induced impairment of the immune system. Further research is needed.
Significant partial correlations were found between Th and TMP and some commonly used markers of alcoholism, MCV, AST, and ALT. No correlation was found for TDP, the active form of Th, and GT, the more popular marker of alcoholism.
Considering the striking significance of TDP decrease in alcoholics, erythrocyte TDP could be proposed as a new candidate marker of alcoholism. In our opinion, since alcoholism is extremely prevalent in many countries procedures designed to allow early diagnosis are needed. A reliable marker of alcoholism could be very helpful for the diagnosis, but none of the established markers is adequate in its own right to support the diagnosis of alcoholism (Ewing et al., 1984; Schuckit et al., 1994
; Hillman et al., 1998
; Schmitt et al., 1998
; Allen et al., 2000
; Bean et al., 2001
; Sharpe, 2001
; Sasso et al., 2004
).
Diagnosis of alcoholism in non-compliant subjects may be informed by clinical interview, physical signs of alcohol intake or alcohol-related physical damage (Sharpe, 2001), self-reported screening measures, (Nilssen and Forde, 1991
; Schuckit et al., 1994
; Stockwell et al., 1994
; Storgaard et al., 1994
) and biomarkers of heavy drinking (Cohen and Kaplan, 1979
; Ewing, 1984
; Orrego et al., 1985
; Conigrave et al., 1995
; Hillman et al., 1998
; Macchia et al., 1991
, Macchia et al., 1997
; Mancinelli et al., 1994
; Schmitt et al., 1998
; Allen et al., 2000
; Bean et al., 2001
; Sharpe, 2001
; Sasso et al., 2004
). Unfortunately, none of them is fully satisfactory (Allen et al., 2000
; Bean et al., 2001
; Sharpe, 2001
).
Clinical findings are a poor indicator of alcohol misuse, unless it is quite recent. Clinical interview information and self-reported measures of drinking and its effects, while reported as reliable in several studies, may easily be feigned by alcoholics unwilling to admit their dependence. This is particularly true if they are well educated, have lengthy histories of psychological care, or have made several previous attempts to stop drinking in rehabilitation settings (Blackburn et al., 1977).
Thus, biomarkers of alcoholism are probably the best tools for the diagnosis of alcoholism in non-compliant subjects, since they are completely independent of the attitude of the patient. Several markers have been proposed [e.g. GT, MCV, and the AST/ALT ratio (Sullivan et al., 1989
; Hillman, 1998
; Allen et al., 2000
; Sharpe, 2001
)]. Indeed, some new biological markers for alcohol abuse have been more recently proposed. Carbohydrate-deficient transferrin (CDT) is probably the most studied of these new markers but conflicting results for CDT's sensitivity and accuracy, ranging from <20% to 100%, have been reported (Stibler et al., 1991
; Nystrom et al.,1992
; Aithal et al., 1998
; Schmitt et al., 1998
; Merkerk et al., 1999
; Allen et al., 2000
; Walter et al., 2001
; Sharpe, 2001
). Also markers based on the detection of acetaldehyde modified proteins (acetaldehyde adducts) have been suggested (Nilssen and Forde, 1991
; Stockwell et al., 1994
; Latvala et al., 2001
). At present, among the most recent markers, the most interesting are ethyl-glucuronide and fatty acid ethyl esters in hair and/or in plasma (Laposata, 1997
; Worrall et al., 1998
; Skopp et al., 2000
; Wurst et al., 2004
).
Beyond problems with sensitivity and/or specificity, many traditional alcohol biomarkers are biased, mainly in specific population groups to include women, young people, and social drinkers (Nystrom et al., 1992; Allen et al., 2000
). The most recent markers, while very promising, need further investigation. At present, the best clinical approach to a suspected alcoholic is conjoint use of them with CDT and the best self-reported procedures, such as the Michigan Alcoholism Screening Test (MAST) (Nilssen and Forde, 1991
) or Alcohol Use Disorders Identification Test (AUDIT) (Allen et al., 1997
). Obviously, this strategy is expensive and time consuming and misdiagnosis of alcoholism cannot be fully avoided.
Unfortunately, the method for the assessment of TDP is also time consuming and requires skilful operators (Tallaksen et al., 1991; Hervé et al., 1994
). Enhanced reliability and practicability were obtained by our recently described procedure (Mancinelli et al., 2003
). The cost/benefit ratio, in terms of better clinical management of the patient, argues for wider use of TDP and Th in studies on alcoholism and nutritional impairment. This marker may assist early diagnosis in difficult cases when other biological markers do not yield a reliable answer. The diagnostic power of TDP assessment is high (Sgouros et al., 2004
). We have found a sensitivity value of 85% and a specificity of 84%. This finding may be somewhat biased (spectrum bias), as contrasting two extreme groups will over-estimate test sensitivity and/or specificity (Lijmer et al., 1999
): thus, further research is needed in non-extreme groups, as moderate drinkers, adolescent drinkers, etc. As Th deficiency may be caused by a number of other conditions occurring separately from alcohol misuse (celiac sprue, Crohn's disease, short bowel syndrome, etc.) (Leevy et al., 1965
; Thomson et al., 2002
) or in conjunction with it, all of them have to be excluded in any patient, a simple task in most cases. Moreover, the low levels of Th and its esters could be related to liver disease, rather than to alcohol dependence: this could be a debated point for alcoholic cirrhosis, since low levels of Th were found in HCV cirrhosis (Levy et al., 2002
), but not in non-alcoholic liver steatosis.
In conclusion, the values of Th and TDP were not correlated to CIWA-ar values or to levels of alcohol intake, while the diagnostic power of Th and TDP was fully confirmed. TDP seems a marker independent of the common markers of alcoholism, as it is not correlated to GT and is weakly correlated to AST, ALT, and MCV. The hypothesis that TDP may be a reliable marker of alcoholism is supported by our findings.
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