Monitoring Relapse Drinking During Disulfiram Therapy by Assay of Urinary 5-Hydroxytryptophol

Screening for recent alcohol use by testing urine for the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) was performed in 10 methadone patients on disulfiram (Antabuse) maintenance therapy in an outpatient setting. Apart from alcohol ingestion, treatment with aldehyde dehydrogenase inhibitors such as disulfiram is the only known cause of an abnormally high 5HTOL/5HIAA ratio. After introduction of drug therapy, increased ratios were observed in all patients. The new higher level reached was relatively stable over time within the same patient but variable between patients. Four patients continued to consume alcohol, as evidenced by 5HTOL/5HIAA ratios well above the new individual plateau, while still taking 400 mg disulfiram 3 times per week under strict supervision. To try to achieve sobriety in two patients who drank frequently while on therapy, the disulfiram dose was doubled. Continued testing demonstrated this to increase the 5HTOL/5HIAA steady-state level further, and the absence of extreme values above this new baseline level indicated adherence to abstinence with possibly one single relapse. When disulfiram administration was discontinued, as planned, by five of the patients, four of them returned to drinking very soon. The present results show that during disulfiram maintenance the continuous inhibition of aldehyde dehydrogenase produces a new higher and dose-related 5HTOL to 5HIAA steady state level in urine, but relapse to drinking will still lead to further increased 5HTOL/5HIAA ratios. It is also suggested that an individual dose-titration regimen, whereby the disulfiram dose is raised gradually until 5HTOL/5HIAA testing indicates sobriety, will improve therapeutic effectiveness.     

Detection of Relapses in Alcohol-Dependent Patients: Comparison of Carbohydrate-Deficient Transferrin in Serum, 5-Hydroxytryptophol in Urine, and Self-Reports

In this study, detection of relapses in male alcohol-dependent patients by biochemical markers and self-reports of alcohol consumption were examined. The patients were trying to stay abstinent from alcohol for 6 months. Four of 15 patients dropped out from treatment after 50–110 days. Ratios of urinary 5-hydroxytryptophol (S-HTOL)/5-hydroxyindole-3-acetic acid and 5-HTOL/creatinine were measured daily and serum carbohydrate-deficient transferrin (CDT) once a week. Clinical ratings and self-reports about alcohol consumption were performed three times a week. According to the self-reports, 3 of the patients drank alcohol frequently, 5 of them sporadically, and 7 of the patients reported no alcohol intake at all. According to the 5-HTOL marker, 4 of the patients drank alcohol frequently, and 11 of them sporadically. No one had all urinary levels of 5-HTOL marker below the reference level. According to the CDT, 3 of the patients drank alcohol frequently, 3 sporadically, and in 9 of the patients no elevated levels of CDT were found. Elevated levels of CDT were preceded by increased values of 5-HTOL marker. The combined results suggested that no one of the patients was totally abstinent from alcohol during the treatment period. The 5-HTOL marker seemed to be useful to reveal recent alcohol drinking, and CDT proved to be useful to validate the patients' self-reports. Together the two biochemical markers showed complementary properties in early detection of relapse and treatment monitoring.     

Carbohydrate-Deficient Transferrin as an Alcohol Marker among Female Heavy Drinkers: A Population-Based Study

Carbohydrate-deficient transferrin (CDT) has previously been reported to be an excellent marker of male alcoholics. Less is known of its efficiency among women and especially of early-phase alcohol abuse in nonselected populations. The present population-based study examined the diagnostic value of CDT among consecutive women, including 13 teetotallers, 135 social drinkers (mean alcohol consumption 45 ± 34 g/week), and 57 nonalcoholic heavy drinkers (197 ± 97 g/week). Sixty-two women with a well-documented history of chronic alcoholism (942 ± 191 g/week) were also studied, as well as 36 pregnant women used as a reference group. Two weeks of abstinence among 11 alcoholics was followed. The CDT (containing part of isotransferrin with pl = 5.7, 5.8, and 5.9) was separated by anion exchange chromatography and assayed by radioimmunoassay. In the whole material, CDT correlated significantly with alcohol consumption (r= 0.43, p < 0.001) but not with conventional markers (γ-glutamyltransferase, AST, ALT, and mean corpuscular volume). The CDT values of alcoholics (34 ± 20 units/liter) were significantly (p < 0.001) higher than those of teetotallers (19 ± 6 units/liter), social drinkers (20 ± 6 units/liter), or pregnant women (16 ± 13 units/ liter). Heavy drinkers also had higher values (25 ± 13 units/liter), but the difference did not reach statistic significance. The specificity of CDT was on the level of conventional markers when the cut-off value was increased from 26 to 29 units/liter. At a specificity of 95%, CDT found 19% of the heavy drinkers and 52% of the alcoholics; the best traditional marker, AST, with a specificity of 97%, found 7% and 56%, respectively. CDT was useful for follow-up of alcohol withdrawal when its initial value was elevated. In general, CDT (as well as conventional laboratory markers) does not seem to be sensitive enough in the detection of alcohol abuse in the female population. This is especially clear among nonalcoholic female heavy drinkers. CDT gives, however, additional information about alcohol abuse, and it may be recommended for parallel use with conventional markers in clinical use.     

Carbohydrate-Deficient Transferrin as a Marker of Alcohol Consumption in Male Patients with Liver Disease

Carbohydrate-deficient transferrin (CDT) has been proposed as a marker of alcohol abuse. However, its value in patients with associated liver disease is still controversial. The aim of the study was to investigate the usefulness of CDT as a marker of alcohol consumption in patients with liver disease. We measured serum levels of CDT and those of commonly used hematological and biochemical markers, mean corpuscular volume (MCV), transaminases (AST and ALT), and γ-glutamyltransferase in 179 male subjects divided into four groups: 45 active drinkers (13 with normal liver, 21 with fibrosteatosis, and 11 with liver cirrhosis), 45 abstinent chronic alcoholics (18 with and 27 without liver disease), 58 patients with nonalcoholic liver disease, and 31 healthy controls. Serum CDT in active alcoholics was 37.5 ± 3.6 units/liter, being significantly higher than that of abstinent alcoholics (20.3 ± 1.5 units/liter), patients with nonalcoholic liver disease (18.1 ± 1.1 units/liter), and controls (13.1 ± 0.8 units/liter). Contrary to the other markers, no significant differences were observed in CDT values in relation with the presence and severity of liver disease in either the active drinkers or in the abstinent alcoholics. The sensitivity and specificity of CDT as a marker of alcoholism in the series as a whole was 64% and 82%, respectively, similar to the best conventional marker, MCV (64 and 82%). In patients with liver disease, CDT maintained good sensitivity (72%) and specificity (83%). Receiver operating characteristic analysis confirmed that CDT had a similar diagnostic value to that of MCV, but better than γ-glutamyltransferase and transaminases for the detection of alcohol abusers. The good diagnostic efficacy of CDT remained unchanged when analyzing only patients with liver disease. We conclude that serum CDT is a good marker of alcoholism and is less influenced than the currently used biochemical markers for associated liver disease. Thus, CDT is an effective laboratory test to detect alcohol abuse regardless of the presence of alcoholic liver disease.     

Transferrin Isoform Distribution: Gender and Alcohol Consumption

Transferrin (Tf) has different isoforms based on the degree of sialylation of its two N-linked oligosaccharide chains. The least sialylated isoforms of Tf; with 0 (asialo Tf), 1 (monosialo Tf), and 2 (disialo Tf) sialic acids are referred to as carbohydrate-deficient transferrin (COT). CDT has been reported to be a specific and sensitive marker for the detection and monitoring of alcohol abuse. However, the possible differences between the three CDT isoforms in males and females relative to alcohol consumption has not been known. The present study included 82 males (M) and 43 females (F) with well documented drinking habits. The Tf isoforms were separated by FPLC and measured by RIA in the collected fractions, as well as by a commercially available method (CDTect RIA). The results were expressed as relative values and absolute values. Female low consumers compared to male low consumers had higher levels of asialo Tf (p < 0.01) and monosialo Tf (p < 0.01), but not of disialo Tf or sum of asialo, monosialo, and disialo Tf. Male high consumers and chronic consumers compared to male low consumers had 53% and 219% higher levels of asialo Tf, 4% and 28% higher monosialo Tf, 57% and 148% higher disialo Tf, and 48% and 134% higher sum of CDT isoforms, respectively. The corresponding increases in females were for asialo Tf 68% and 249%, for monosialo Tf 36% and 58%, for disialo Tf 54% and 225%, and for sum of CDT isoforms 52% and 192%, respectively. For both genders, total Tf, trisialo Tf, and the levels of more sialylated transferrin isoforms were constant when comparing the consumption groups. Results expressed as relative values and absolute values were in good agreement In conclusion, the present study indicates that alcohol consumption strongly increases the levels of asialo Tf and disialo Tf and slightly increases the level of monosialo Tf. However, women had higher asialo Tf and monosialo Tf levels than men. Alcohol consumption does not increase trisialo or more sialyated Tf subfractions. Expressing the CDT results as absolute or relative values made no obvious difference in diagnostic efficiency.     

Urinary Level of L-Fucose as a Marker of Alcoholic Liver Disease

The urinary levels of L-fucose were measured in 93 alcoholics: 20 of these were without liver disease, 57 with noncirrhotic alcoholic liver disease, and 16 with alcoholic liver cirrhosis. In addition, patients with cirrhosis due to viral infection, and healthy subjects were evaluated. The mean urinary L-fucose concentration showed significantly higher values in patients with alcoholic liver disease and alcoholic liver cirrhosis when compared with the healthy subjects or the chronic alcoholics without liver disease ( p < 0.001). The urinary L-fucose level was also significantly higher ( p < 0.001) in cases of alcoholic liver cirrhosis than in noncirrhotic alcoholic liver disease (384 ± 97 vs. 240 ± 95 μmol/g of creatinine). No difference was observed between the healthy subjects and chronic alcoholics without liver disease (143 ± 29 vs. 155 ± 60 μmol/g of creatinine). The urinary level of L-fucose was significantly higher with alcoholic cirrhosis (384 ± 97 μmol/g of creatinine) than with viral cirrhosis (265 ± 42 μmol/g of creatinine) ( p < 0.001). The measurement of urinary L-fucose may be a useful marker of alcoholic liver disease.     

Retrospective Self-Report of Alcohol Consumption: Test-Retest Reliability by Telephone

The Timeline Follow-Back (TLFB) is an interview technique for obtaining detailed retrospective self-reports of alcohol consumption with excellent reliability for various composite variables when both administrations are in person. Because the telephone offers practical advantages over face-to-face interviewing for follow-up assessments in longitudinal studies of problem drinkers, this study was undertaken to compare the test-retest reliability of a 12-week TLFB interview when the second administration was by telephone to that when the second interview was in person. In addition, because the reliability of the TLFB has been previously assessed using composite variables, we examined the reliability of the TLFB at the item level. Research participants were 30 adult medical patients who drank frequently, and 75 college students who were problem drinkers. Test-retest reliability as measured by intraclass correlation was generally high, 0.79 or greater for the number of days of drinking > 6 standard drinks, 0.90 or greater for the number of abstinent days, and 0.80 or greater for the greatest number of drinks consumed on any 1 day, in both the most recent 4-week interval and in the entire 12-week interval. Test-retest correlation coefficients for composite variables derived from the interview data were not systematically affected by whether the second interview was in person or by telephone. Furthermore, item-level correlations were also substantial. Findings support the use of the telephone for follow-up interviews, potentially reducing costs of longitudinal studies and facilitating multisite studies with centralized data collection, and lend further general support to the reliability of the TLFB.     

Heavy Episodic Drinking and Alcohol Consumption in French Colleges: The Role of Perceived Social Norms

Background:  The effect of normative perceptions (social norms) on heavy episodic drinking (HED) behavior is well known in the U.S. college setting, but little work is available in other cultural contexts. The objective of this study is therefore to assess whether social norms of alcohol use are related to HED in France, taking account of other influential predictors.
Methods:  A cross-sectional survey was carried out among 731 second-year university students in the Paris region to explore the role of 29 potential alcohol use risk factors. The probability of heavy episodic drinking and the frequency of HED among heavy episodic drinkers were modeled independently. Monthly alcohol consumption was also assessed.
Results:  Of the students, 56% overestimate peer student prevalence of HED (37% for alcohol drinking prevalence). HED frequency rises with perceived peer student prevalence of HED. Other social norms associated with HED are perceived friends' approval of HED (increasing both HED probability and HED frequency) and perceived friend prevalence of alcohol drinking (increasing HED probability only). Cannabis and tobacco use, academic discipline, gender, and the number of friends are also identified as being associated with HED.
Conclusions:  Overestimation of peer student prevalence is not uncommon among French university students. Furthermore, perceived peer student prevalence of HED is linked to HED frequency, even after adjusting for other correlates. Interventions correcting misperceived prevalences of HED among peer students have therefore the potential to reduce the frequency of HED in this population.     

Voluntary Alcohol Consumption in BXD Recombinant Inbred Mice: Relationship to Alcohol Metabolism

Studies were initiated to characterize behaviorally and biochemically C57BL/6J and DBA/2J inbred mice, as well as BXD Recombinant Inbred (RI) strains derived from them. The C57BL/6J, DBA/2J, and 7 BXD RI strains were tested for voluntary alcohol consumption (VAC) by receiving 4 days of forced exposure to a 10% (w/v) solution of alcohol, followed by 3 weeks of free choice between water and 10% alcohol. Measures of VAC included the absolute intake of alcohol (g/kg), as well as alcohol preference. A wide range of VAC was displayed by the various BXD RI strains with a continuous (rather than bimodal) distribution, indicating that there is likely to be additive effects of several genes involved in regulating alcohol-related behaviors. Kinetic characteristics of aldehyde dehydrogenase and catalase in liver and brain of the C57BL/6J, DBA/2J, and BXD strains of mice were determined to test the hypothesis that the genetic regulation of the levels of alcohol-metabolizing enzymes mediate differences in VAC. Aldehyde dehydrogenase activity was determined spectrophotometrically by observing the change in absorption at 340 nm. Catalase activity was determined by measuring oxygen production with a Yellow Springs Biological Oxygen monitor and oxygen electrode. There was a strong negative relationship between VAC and brain catalase activity in the BXD RI and parental strains. These data suggest that RI strains are likely to be useful genetic models in the examination of quantitative trait loci controlling VAC and other responses to alcohol.     

Modeling the Distribution and Consequences of Alcohol Consumption

This paper is based on the session "Modeling the Distribution and Consequences of Alcohol Consumption" that was held on May 12-14, 1997 at the International Workshop on Consumption Measures and Models for Use in Policy Development and Evaluation, Bethesda, MD. The session chair was Paul J. Gruenewald; presenters were Timo Alanko, Bryan Johnstone, Paul J. Gruenewald, Susan Bondy, Thomas Harford, Raul Caetano, and Maria Elena Medina-Mora; and the discussants were Jiirgen Rehm and Bryan Johnstone.     

Fetal Cerebral Circulation as Target of Maternal Alcohol Consumption

Alcohol (ethanol [EtOH]) is one of the most widely used psychoactive substances worldwide. Alcohol consumption during pregnancy may result in a wide range of morphological and neurodevelopmental abnormalities termed fetal alcohol spectrum disorders (FASD), with the most severe cases diagnosed as fetal alcohol syndrome (FAS). FAS and FASD are not readily curable and currently represent the leading preventable causes of birth defect and neurodevelopmental delay in the United States. The etiology of FAS/FASD remains poorly understood. This review focuses on the effects of prenatal alcohol exposure (PAE) on fetal cerebrovascular function. A brief introduction to the epidemiology of alcohol consumption and the developmental characteristics of fetal cerebral circulation is followed by several sections that discuss current evidence documenting alcohol‐driven alterations of fetal cerebral blood flow, artery function, and microvessel networks. The material offers mechanistic insights at the vascular level itself into the pathophysiology of PAE.     

Alcohol Consumption and Stroke: Benefits and Risks

The complex relationship between alcohol consumption and stroke includes both benefits and risks. Regular light-to-moderate consumption of alcohol seems to decrease the risk for ischemic stroke by reducing atherothrombotic events, but the undertying mechanism is still unclear. Recent and current (but not previous) heavy drinking increases the risk for both hemorrhagic and ischemic strokes. Young and middle-aged men are stricken more often than women or elderly persons, probably because they are more often current heavy drinkers. Alcoholic cardiomyopathy is a cause of cardioembolic brain infarction. Cardiac arrhythmias caused by regular heavy drinking or binge drinking can precipitate thrombus formation and propagate already existing thrombi from the heart. The maintenance of high blood pressure by heavy drinking may promote cerebral arterial degeneration, but the effect of drinking habits on aneurysm formation is not known. Acute increases in systolic blood pressure and/or alterations in cerebral arterial tone could serve as mechanisms triggering hemorrhagic strokes during alcoholic intoxication. We lack studies to show that prevention of heavy drinking can efficiently influence the occurrence of strokes.     

Urinary Dolichol—A Doubtful Marker of Alcoholism

The purpose of this study was to replicate the results of Pullarkat and Raguthu and Roine et al. who found elevated levels of urinary dolichol (long-chain 2,3-dihydropolyprenols) in chronic alcoholic patients. We investigated a sample of 21 alcohol-dependent inpatients voluntarily entering detoxification treatment. Urinary dolichol was only slightly increased as compared to 21 healthy controls. When dolichol was related to urinary creatinine no differences between alcoholic patients and controls could be found. Under conditions of confirmed abstinence the slightly elevated levels of dolichol returned to normal within 2 weeks. Compared with the sensitivity of gamma-glutamyltransferase which ranges from 72-85%, the value of urinary dolichol (sensitivity 9-19%) as a biochemical marker of alcoholism must be doubted.     

The Role of the Flushing Response in the Relationship Between Alcohol Consumption and Insulin Resistance

Background: Facial flushing responses to drinking, because of intolerance to alcohol, are observed in some people, especially Asians. This study examined the role of flushing responses in the relationship between alcohol consumption and insulin resistance (IR). Methods: Participants in this cross‐sectional analysis included 624 Korean men (80 nondrinkers, 306 nonflushing drinkers, and 238 flushing drinkers) who were free of cardiovascular disease and diabetes. Data on the flushing response to drinking and alcohol consumption were collected from medical records. IR was estimated using the Homeostasis Model Assessment (HOMA_IR). On the basis of comparisons with nondrinkers, the risk of IR according to the quantity of alcohol consumed per week was analyzed among nonflushers and flushers. Results: After adjusting for age, exercise status, smoking status, BMI, waist circumference, blood pressure, high‐density lipoprotein cholesterol, and triglycerides using a logistic regression model, we found a low risk of IR among nonflushers who consumed ≤4 drinks (1 drink = 14 g of alcohol) per week (OR = 0.3). In contrast, a higher risk of IR was associated with nonflushers who consumed >20 drinks per week (OR = 3.5). On the other hand, only a higher risk of IR was associated with flushers who consumed >12 drinks per week (>12 to 20 drinks: OR = 4.7; >20 drinks: OR = 3.5). Conclusions: The amount of drinking associated with the development of IR in flushers was lower than in nonflushers. Additionally, no positive effect of moderate drinking on IR was observed in flushers. The findings support acetaldehyde‐derived mechanisms in the development of alcohol‐related IR.