HOMOCYSTEINE LEVELS IN PATIENTS CLASSIFIED ACCORDING TO LESCH'S TYPOLOGY

STEFAN BLEICH1,*, KRISTINA BAYERLEIN1, UDO REULBACH1, THOMAS HILLEMACHER1, DOMINIKUS BÖNSCH1, BIRGIT MUGELE2, JOHANNES KORNHUBER1 and WOLFGANG SPERLING1

1 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen–Nuremberg and 2 Department of Addiction Klinikum am Europakanal, Erlangen, Germany

* Author to whom correspondence should be addressed at: Friedrich-Alexander, University of Erlangen–Nuremberg, Department of Psychiatry and Psychotherapy, Schwabachanlage 6, D-91054 Erlangen, Germany. Tel.: +49 9131 8534597; Fax: +49 9131 8534105; E-mail: stefan.bleich{at}psych.imed.uni-erlangen.de

(Received 13 April 2004; first review notified 25 June 2004; in revised form 30 June 2004; accepted 9 August 2004)


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: It has been suggested that elevated total plasma homocysteine levels might be useful to predict alcohol withdrawal seizures. The typology by Lesch distinguishes between four subtypes of which type 1 suffers from marked withdrawal symptoms, including alcohol withdrawal seizures. This study was undertaken to investigate total plasma homocysteine levels in actively drinking patients with alcoholism who were classified according to Lesch's typology. Subjects and methods: We determined total plasma homocysteine levels in 144 non-abstinent chronic alcoholics (115 men, 29 women; aged 22–67 years). Patients were classified in Lesch's typology (LT) and were divided into two groups: LT 1 (n = 27) and LT 2–4 (n = 117). Within the groups, patients with or without a history of alcohol withdrawal seizures were differentiated. Results: All patients with a history of alcohol withdrawal seizures had significantly elevated plasma homocysteine concentrations at admission when compared with those without seizures (Mann–Whitney U, P < 0.001). Furthermore, patients classified as LT 1 who suffered from an alcohol withdrawal seizure (n = 12) had significantly higher plasma homocysteine levels (Z = –2.31, P = 0.02) when compared to the corresponding types 2–4 (n = 24). Using a logistic regression analysis, withdrawal seizures were best predicted by a high homocysteine level at admission but even more pronounced in LT 1 (Wald's chi-squared [{chi}2] = 10.7; odds ratio [OR] 1.24; 95% confidence interval [CI] 1.03–1.51; P < 0.001) when compared with LT 2–4 ({chi}2 = 10.6; OR 1.06; 95%CI 1.03–1.14; P = 0.004). Conclusion: To our knowledge, this is the first study evaluating homocysteine levels in patients who were classified according to Lesch's typology. Homocysteine levels on admission may be a useful screening method to identify actively drinking patients at risk of alcohol withdrawal seizures, especially in alcoholics with Lesch type 1.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is difficult to pinpoint single characteristics associated with vulnerability to major psychiatric disorders, including alcoholism. Taking into account social, mental and somatic factors, the typology by Lesch distinguishes between the following four subtypes (Lesch et al., 1990Go): type 1 (Model of Allergy) has marked withdrawal symptoms, including alcohol withdrawal seizures. Type 2 (Model of Anxiety or Conflict) exhibits pre-morbid conflicts and anxiety. Type 3 (Alcohol as Antidepressant) emerges from a permissive alcoholic milieu and shows pre-alcoholic mood changes. Type 4 (Alcohol as Adaptation) has pre-morbid cerebral injuries and serious social problems. In 1990, a decision tree was developed for diagnosing the typology and is now available as a computer version in most European languages (Lesch et al., 1990Go).

There is growing evidence that chronic alcoholism, especially in non-abstinent patients, is associated with hyperhomocysteinaemia (Hultberg et al., 1993Go; Bleich et al. 2000aGo; de la Vega et al., 2001Go). The reasons for the increase of plasma homocysteine levels and its significant correlation with the blood alcohol concentration, regardless of whether beer, wine or spirits have been consumed (Bleich et al., 2000bGo; 2001Go), are most likely complex ones in alcohol-dependent patients. In the metabolism, homocysteine is either trans-sulfurated into cystathionine or it is remethylated to methionine by methionine synthase (MS). In actively drinking alcoholics, an impairment of remethylation of homocysteine is brought about on account of a dysfunction of MS, due to an alcohol-induced vitamin deficiency (folic acid, vitamin B12), as well as a direct inhibition of MS due to acetaldehyde, the product of oxidative degradation of alcohol (Kenyon et al., 1998Go).

Most recently, it has been suggested that homocysteine levels on admission may be a useful screening method to identify patients with chronic alcoholism at risk of withdrawal seizures (Bleich et al., 2000cGo; Kurth et al., 2001Go). The Lesch classification can be assessed at admission. A history of withdrawal seizures and withdrawal symptoms makes it possible to differentiate between type 1 and type 2. If it is not possible to determine an appropriate medical history, a period of five days should be allowed to pass before classification into type 1 or type 2. As this decision tree is to be classified in the order of type 4, type 3, type 1 and type 2, type 3 and type 4 patients can also have epileptic withdrawal seizures, while type 2 patients must not display withdrawal seizures (Lesch et al., 1990Go; Poldrugo and Lesch, 1994Go). Thus, from a clinical point of view, this is a limitation of Lesch's typology as a useful guide to identify alcoholic patients at risk of seizures in early alcohol withdrawal. Therefore, the aim of this study was to evaluate homocysteine levels in different types according to the typology of Lesch. The hypothesis was that alcoholics with a history of alcohol withdrawal seizures, who were classified as type 1 by Lesch, reveal higher homocysteine levels.


    SUBJECTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study was approved by the Ethics Committee of the Medical Faculty of the University of Erlangen–Nuremberg and written, informed consent was obtained from all patients before participating in any part of the study. The present prospective, open, case–control study with a naturalistic design included 144 non-abstinent chronic alcoholics, 115 men and 29 women, aged 22–67 years (mean: 44 years). Study design, laboratory methods and nutritional assessments were performed with minor modifications as previously described (Bleich et al., 2000aGo). Briefly, all patients were active drinkers and had an established diagnosis of alcohol dependence according to the Diagnostic Statistical Manual for Mental Disorders (DSM-IV) with a history of alcohol consumption ranging from 6–47 (mean: 19.2) years. Mean daily ethanol intake was 208 g (SD 141), this quantity being derived according to Cravo et al. (1996)Go. Because of the close relationship between blood alcohol concentration and plasma homocysteine levels (Bleich et al., 2000aGo), patients without BAC at admission were excluded. The patients were all seen as inpatients in a closed detoxification unit, stopped drinking immediately before admission and were taking no vitamin supplements or other drugs before being enrolled in the study. Abstinence during withdrawal was monitored by alcohol and drug screening. In addition, the patients' nutritional assessment according to Baker et al. (1982)Go revealed no abnormalities (with the exception of five patients with decreased folate levels who were considered malnourished; data not shown). After admission, patients were detoxified in all cases with the same psychotropic medication (clomethiazole and carbamazepine in daily mg doses up to 10 days after admission). To assess the severity of withdrawal, we used the withdrawal syndrome scale for alcohol and related psychoactive drugs (WSA) (Kristensen et al., 1986Go). No significant differences between the groups in respect to WSA scoring and dosage of withdrawal medication were found (data not shown). Patients with any known other risk factors for hyperhomocysteineamia such as nutritional status, medication (i.e. methotrexate), endocrinological conditions and other diseases (i.e. thromboembolic and cardiovascular diseases) as well as patients with any other psychiatric comorbidity were not included in the study.

Patients were initially divided into four groups (types 1–4) according to Lesch's typology (LT) (computerized allocation according to the decision tree; Lesch et al., 1990Go). Within the groups, patients with or without a history of alcohol withdrawal seizures were differentiated. As there were no significant differences in respect to variables at admission (i.e. plasma homocysteine, age, vitamins, blood alcohol concentration, %CDT) between the Lesch types 2, 3, and 4, these types were drawn together into one group (Lesch types 2–4 [LT 2–4]).

Fasting total homocysteine in plasma (reference value <15 µmol/l) was measured by an enzyme-linked immunosorbent assay (Axis Homocysteine EIA, IBL-No.: AX 513 01; Axis, Germany/Norway) according to Frantzen et al. (1998)Go. Carbohydrate-deficient transferrin (CDT) at admission and after 10 days was assessed to identify chronic heavy alcohol consumption and monitoring abstinence. The %CDT turbidimetric immunoassay (reference value <2.6%, Axis–Shield, Norway) with assessment of the relative amount of CDT (primarily the asialo, monosialo and disialo transferrin isoforms) in proportion to total transferrin was performed (Helander et al., 2001Go). Blood samples of vitamins (folate, vitamin B12) and blood alcohol concentrations (BAC) were also taken at admission. All fasting blood samples were promptly centrifuged following collection. Plasma was stored at –80°C. Vitamin B12 and serum folate concentrations were measured by chemiluminescence using Chiron kits (Chiron Diagnostics, Fernwald, Germany) on a Chiron ACS:180 automated analyser.

Statistical analyses
Comparisons were made using the Kruskal–Wallis test and the Mann–Whitney test for independent samples. Logistic regression analysis was made using SCORE and STEPWISE options. The results are presented as central tendencies (CI ± SD). A P-value of <0.05 was considered significant.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Plasma homocysteine levels were significantly different at admission when comparing the four groups (LT 1–4). (Kruskal–Wallis test: d.f. 3; {chi}2 = 10.14; P < 0.05.) However, no significant differences among the groups in respect to age, BAC, lifetime drinking (LD), years of drinking (YD), %CDT, or vitamin (folate, B12) levels were found ({chi}2 = 1.7023.51; P = 0.23–0.64). Furthermore, there were no significant changes in any of the above listed variables (including plasma homocysteine) when comparing the LT 2–4 (Kruskal–Wallis: d.f. 2; {chi}2 = 0.27–8.85; P = 0.12–0.88) (For descriptive data see Table 1). For further statistical evaluation, we therefore compared the LT 1 against the cumulative values of variables of LT 2–4 (Table 2).


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Table 1. Comparison of variables of actively drinking alcoholic patients classified to Lesch types (LT) 2,3, and 4 (LT 2–4). Each group is further divided into patients with and without a history of alcohol withdrawal seizures

 

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Table 2. Comparison of variables of actively drinking alcoholic patients classified to Lesch type 1 (LT 1) and Lesch types 2–4 (LT 2–4). Each group is further divided into patients with and without a history of alcohol withdrawal seizures

 
As shown in Figs 1 and 2, patients with a history of alcohol withdrawal seizures had significantly elevated plasma homocysteine concentrations at admission ('means' as central tendencies, CI) in both LT 1 (Mann–Whitney U: CI 55.8 ± 30.7 vs 21.5 ± 10.3 µmol/l; Z = –3.86; P < 0.001) and LT 2–4 (CI 39.7 ± 21.9 vs 24.4 ± 12.5 µmol/l; Z = –3.96; P <0.001) (Figs 1,2).



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Fig. 1. Total plasma homocysteine levels in alcoholics classified as Lesch type 1 (LT 1) with (seizure +, n = 12) and without (seizure –, n = 15) a history of alcohol withdrawal seizures. *Significant; LT 1 patients with seizures had significantly higher homocysteine levels when compared to LT 1 patients without seizures (Mann–Whitney U-test: Z = –3.86; P < 0.001).

 


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Fig. 2. Total plasma homocysteine levels in alcoholics classified as Lesch types 2–4 (LT 2–4) with (seizure +, n = 24) and without (seizure –, n = 93) a history of alcohol withdrawal seizures. *Significant; LT 2–4 patients with seizures had significantly higher homocysteine levels when compared to LT 2–4 patients without seizures (Mann–Whitney U-test: Z = –3.96; P < 0.001).

 
Furthermore, Table 2 shows that patients classified as type 1 who suffered from an alcohol withdrawal seizure in their history (n = 12) had significantly higher plasma homocysteine (HCY) levels (CI 55.8 ± 30.7 µmol/l; Z = 22.31; P = 0.02) when compared to the corresponding types 2–4 (HCY 39.7 ± 21.9 µmol/l). Because the increase of the higher homocysteine levels within LT 1 might be due to a significantly higher BAC at admission in patients with a history of seizures (282 ± 110 vs 202 ± 81 mg/dl; Z = –2.10; P = 0.037), no significant differences of BAC were found between the two groups (LT 1 vs LT 2–4) with seizures (282 ± 110 vs 216 ± 113 mg/dl; Z = –1.91; P > 0.05). Furthermore, we did not observe a significant association (Spearman's rho) between BAC at admission and plasma homocysteine levels in LT 1, 3, or 4 patients with ({rho} = 0.050–0.60; P = 0.20–0.88) and without ({rho} = 0.07–0.52; P = 0.13–0.80) seizures. A significant correlation between BAC and homocysteine levels was found in patients classified as LT 2 for both seizure patients ({rho} = 0.62; P = 0.013) and non seizure patients ({rho} = 0.41; P = 0.001). No significant differences were seen in any of the other investigated variables such as age, %CDT, vitamin levels (folate, B12), YD, or LD (see Table 2). After 10 days of withdrawal treatment and further abstinence, there was a significant decrease of homocysteine levels in both LT 1 (Wilcoxon; from 55.8 ± 30.7 to 11.3 ± 2.6 µmol/l; Z = 24.54; P < 0.001) and LT 2–4 (from 39.7 ± 21.9 to 10.1 ± 3.2 µmol/l; Z = –7.82; P < 0.001) patients with seizures. In addition, significant decreases were seen in respect to their %CDT and vitamin levels (Table 1). There were no significant changes of variables such as plasma homocysteine, %CDT, or vitamins when comparing LT 1 with LT 2–4 patients (Mann–Whitney U; see Table 2).

Logistic regression
All variables in Table 2 were fed into a logistic regression analysis. By using the SCORE and STEPWISE procedures, the best-fitting model was tested. No variables (such as age, sex, BAC, vitamins, LD, YD, %CDT) except the homocysteine levels met the 0.05 significance level for entry into the model. Thus, in this model, the criterion ‘seizure’ was best predicted by a high homocysteine level in both LT 1 (Wald's {chi}2 = 10.7; OR 1.24; 95%CI 1.03–1.51; P < 0.001) and LT 2–4 (Wald's {chi}2 = 10.6; OR 1.06; 95%CI 1.03–1.14; P = 0.004), respectively.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We observed an ethanol-associated hyperhomocysteinemia in the majority of investigated patients suffering from chronic alcoholism which is in line with previous studies (Bleich et al., 2000aGo). The degree of the plasma homocysteine levels in alcoholics has been shown to be strongly determined by the degree of alcoholization (Bleich et al., 2000aGo). However, in the present study we did not find a significant correlation between plasma homocysteine levels and BAC (exception: patients categorized as LT 2), which is possibly due to the relatively small sample sizes in the other groups. To our knowledge, this is the first study evaluating plasma homocysteine levels in patients classified according to Lesch's typology. In total, 12 patients (44%) typed as LT 1 and 24 patients (21%) classified as other Lesch types (2–4) with an intermediate hyperhomocysteinemia (levels >30 mmol/l) at admission suffered from a withdrawal seizure in their medical history, whereby the highest homocysteine levels were found in LT 1. We observed that only elevated homocysteine levels at admission could significantly predict seizures, which is also in line with recent findings (Bleich et al., 2000cGo; Kurth et al., 2001Go).

Unfortunately, little is known about how to predict the course of alcohol withdrawal and alcohol withdrawal seizures. Until recently, various risk factors and/or predictors, such as repeated alcohol withdrawals (‘kindling’ model) (Brown et al., 1988Go), alcohol level on admission (Vinson and Menezes, 1991Go), hazardous alcohol drinking (Brathen et al., 1999Go), genetic factors (Schaumann et al., 1994Go), reduced white matter volume in the temporal lobes in alcohol-related seizures (Sullivan et al., 1996Go), age, duration of disease or previous cerebral damage (to list a few), have been discussed. However, most of the known predictors have proven to be less useful.

Homocysteine is a simple sulfur-containing amino acid that has recently received a great deal of attention for neurodegenerative diseases such as Alzheimer's disease (Seshadri et al., 2002Go) and alcoholism associated brain atrophy (Bleich et al., 2003aGo). There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory amino acids such as glutamate, aspartate and homocysteine have been shown to be increased in patients with chronic alcoholism (Tsai et al., 1998Go; Bleich et al., 2004Go). Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with an active drinking pattern. Taking into account that homocysteine levels are elevated but steadily decrease during early alcohol withdrawal (Bleich et al., 2000aGo) this may possibly explain why alcoholism-associated disorders (e.g. brain atrophy) no longer progress during abstinence (O'Neill et al., 2001Go).

Our results are consistent with the hypothesis that the up-regulation of NMDA receptor systems following chronic alcohol consumption may mediate the seizures associated with ethanol withdrawal (Grant et al., 1990Go; Hoffman et al., 1992Go) and it is conceivable that excitotoxicity, possibly causing brain damage and withdrawal symptomatology (i.e. seizures), can be induced by rebound activation of NMDA receptor-mediated neurotransmission upon the removal of ethanol's inhibitory effect.

Both intra- and extracellular pathophysiological mechanisms that can basically be distinguished lead to homocysteine-induced neuronal excitotoxicty.

First, the mechanisms of excitotoxicity via overstimulation of NMDA receptors and the resulting apoptotic cell damage. Moreover, alcohol consumption leads to a disturbed permeability of the blood-brain barrier (Kornhuber et al., 1987Go). Thus, in hyperhomocysteinaemic patients, disruption of the blood–brain barrier results in exposure of the brain to near plasma levels of homocysteine (Lipton et al., 1997Go), leading to NMDA mediated excitotoxicity (Lipton et al., 1997Go; Mattson and Shea, 2003Go) with associated changes such as an impaired signal-to-noise ratio or long-term potentiation (Bleich et al., 2003bGo). In accordance with the profile of action of homocysteine, generalized epileptic seizures can be triggered in animal experiments by systemic administration of both homocysteine and its breakdown products (i.e. homocysteic acid) (Kubová et al., 1995Go; Folbergrová et al., 1997Go, 2000Go).

Second, various direct or indirect neurotoxic mechanisms that are not mediated by ionotropic NMDA receptors. These toxic effects are preceded by the ubiquitous intracellular accumulation of homocysteine, which is observed in chronic ethanol exposure (Barak et al., 2001Go) and then leads to extracellular overcharging of excitatory amino acids via anionic membrane transporters. Furthermore, homocysteine is rapidly taken up by neurons via a specific Na+-dependent membrane transporter (Grieve et al., 1992Go), a further mechanism that results in accumulation of homocysteine within the cell.

Taking into account the relatively high potential of homocysteine to induce seizures we would like to recommend the possible usefulness of anticonvulsive strategies as an additional approach in alcohol withdrawal treatment. For example, benzodiazepines are accepted throughout the world in the therapy of alcohol withdrawal and, when administered at an adequate dose, have a sufficient antiepileptic potential. Furthermore, hyperhomocysteinemia is a treatable condition taking into account that folate therapy will reliably reduce plasma homocysteine levels. Thus, the administration of B vitamins might also be useful in patients undergoing alcohol withdrawal. Homocysteine levels on admission may be a useful screening method to identify actively drinking patients at risk of alcohol withdrawal seizures, especially in alcoholics with LT 1. The elevated excitability of the NMDA receptor mediated neurotransmission is also under intense discussion in relation to prophylaxis against recurrence. Acamprosate, as an NMDA antagonist, shows a marked improvement in relapse rates, whereby it has been shown that particularly type 1 patients benefit from the administration of acamprosate (Lesch and Walter, 1996Go; Lesch et al., 2001Go).


    ACKNOWLEDGEMENTS
 
We acknowledge the support of a grant to S.B. from Axis–Shield, Norway (CT-H2003). (The sponsor had no role in the study design, data collection, data analysis, data interpretation or writing of the report.) None of the authors had financial or personal conflicts of interest.


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 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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