Associations of ADH1B and ALDH2 genotypes and alcohol flushing with drinking history, withdrawal symptoms, and ICD-10 criteria in Japanese alcohol-dependent men.

OBJECTIVES: Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2 ) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2 ) alleles in East Asians, we evaluated how the ADH1B / ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD). METHODS: We evaluated how the ADH1B / ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men. RESULTS: The ADH1B*1/*1 group and ALDH2*1/*1 group were 1-5 years younger than the ADH1B*2 (+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for 'tolerance' and 'withdrawal symptoms'. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1-2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status. CONCLUSION: The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited.

National burden of gambling in Japan: an estimation from an online-based cross-sectional investigation and national epidemiological survey.

BACKGROUND: Gambling is a popular leisure activity in many countries, often expected to boost regional economies. Nevertheless, its negative impacts remain a significant concern. Gambling disorder is recognized as the most severe consequence; however, even non- or low-risk gamblers may also face negative impacts. This study aimed to estimate the number of Japanese gamblers experiencing gambling-related harm (GRH) and its distribution across six life domains, financial, relational, emotional, health, social and other aspects, based on the severity of their problem gambling risk. METHODS: This cross-sectional study relied on an online survey conducted between August 5 and 11, 2020. Participants aged 20 years and above, who engaged in gambling during 2019 were recruited via a market research company. The survey assessed the prevalence of GRH 72 items among four gambler risk groups (non-problem, low-, moderate-, and high-risk), as categorized by the Problem Gambling Severity Index. The data was adjusted for population weighting using representative national survey data: the 2017 Comprehensive Survey of Living Conditions and the 2017 Epidemiological Survey on Gambling Addictions. RESULTS: Out of the 28,016 individuals invited to the survey, 6,124 participated in the screening, 3,113 in the main survey, and 3,063 provided valid responses. After adjusting the survey data, it was estimated that 39.0 million (30.8%) of Japan's 126.8 million citizens gambled in 2019. Among them, 4.44 million (11.4%) experienced financial harm, 2.70 million (6.9%) health harm, 2.54 million (6.5%) emotional harm, 1.31 million (3.4%) work/study harm, 1.28 million (3.3%) relationship harm, and 0.46 million (1.2%) other harm. Although high-risk gamblers experienced severe harm at the individual level, over 60% of gamblers who experienced GRHs were non- and low-risk gamblers, with the exception of other harm, at the population level. CONCLUSIONS: The study highlighted the prevention paradox of gambling in Japan. While national gambling policies primarily focus on the prevention and intervention for high-risk gamblers, a more effective approach would involve minimizing GRH across the entire population.

Influence of ADHD, especially attention-deficit characteristics, on the course of alcohol-dependent individuals.

BACKGROUND: While several studies have revealed that neurodevelopmental disorders have a high probability of overlapping with substance use disorders, the effects of neurodevelopmental disorders on the courses of substance use disorders have hardly been examined. METHODS: This study targeted 637 alcohol-dependent individuals who received inpatient treatment and whose drinking situations were followed for 12 months after hospital discharge using mailed questionnaires. The comorbidity of psychiatric disorders and the characteristics associated with the neurodevelopmental disorders were assessed using several measurements at the time of hospital admission. The effects of neurodevelopmental disorders on the drinking courses of the subjects were then estimated. RESULTS: The presence of a current depressive episode or any anxiety disorder significantly lowered the abstinence rates during the follow-up period (p = 0.0195 and p = 0.0214, respectively). ADHD traits as assessed using the ADHD Self-report Scale (ASRS) predicted a significantly poorer abstinence rate (p = 0.0296). Similarly, attention-deficit characteristics assessed objectively through interviews predicted a significantly lower abstinence rate (p = 0.0346), and a sensitivity analysis enhanced these results (p = 0.0019). When the drinking patterns were classified into three groups, the subjects with attention-deficit characteristics had a significantly higher rate of "Recurrence" and lower rates of "Abstinence" and "Controlled drinking" (p = 0.013). In a multivariate proportional hazards analysis, the ASRS score was significantly correlated with the re-drinking risk (p = 0.003). CONCLUSION: ADHD traits had significant effects on not only abstinence rates, but also on drinking pattern. The presence of ADHD traits, especially attention-deficit characteristics, influenced the drinking courses of alcohol-dependent individuals after hospital treatment.

Alcohol dependence severity determines the course of treatment-seeking patients.

BACKGROUND: While accumulating evidence suggests a relation between the severity of alcohol dependence and the risk of its recurrence, the impact of dependence severity on the course of the disorder has not been carefully evaluated. The present study examined the impact of several severity indices of alcohol dependence on the drinking course after inpatient treatment. METHODS: This prospective study was conducted over a 12-month period following alcohol treatment at a specialized hospital. A total of 712 consecutively admitted alcohol-dependent patients were targeted for enrollment at the time of their hospitalization, with 637 patients registered and followed. The characteristics and severity of the subjects were assessed using multiple methods at admission, with their course after discharge followed continuously using mailed questionnaires that queried them regarding their drinking behavior. RESULTS: Greater severity of dependence, assessed using the number of ICD-10 diagnostic criteria met, was associated with a lower rate of abstinence during the study period (p = 0.035). The rate of abstinence also decreased significantly as the baseline blood gamma-glutamyl transferase value and Alcohol Dependence Scale (ADS) score increased (p = 0.031 and p = 0.0002, respectively). In multivariate Cox proportional hazards analyses, the group with the most severe ADS scores had a significantly greater risk of relapse to drinking than the group with the least severe scores (HR = 2.67, p = 0.001). Dependence severity also associated with the drinking pattern; participants in both the controlled drinking group and the abstinence group had lower ADS scores at admission and a later age at first drinking (p = 0.001 and p < 0.001, respectively) than those with poorer drinking outcomes. CONCLUSIONS: The present study showed that more severe alcohol dependence predicts a poorer course after alcohol treatment, as reflected by findings on multiple measures. These results suggest that assessing the dependence severity at the outset of treatment could be useful both in predicting treatment outcome and targeting interventions to alcohol-dependent individuals who need additional support in their recovery.

Impacts of interactions between ADH1B and ALDH2 genotypes on alcohol flushing, alcohol reeking on the day after drinking, and age distribution in Japanese alcohol-dependent men.

OBJECTIVE: This study sought to evaluate the impacts of interactions between the alcohol dehydrogenase-1B (rs1229984) genotype and the aldehyde dehydrogenase-2 (rs671) genotype on alcohol flushing, alcohol reeking on the day after drinking, and the age distribution in alcohol-dependent patients. METHODS: The study subjects were 4107 Japanese alcohol-dependent men who underwent alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotyping: 4051 patients were asked about their current or former tendency to experience facial flushing after drinking a glass of beer, and 969 patients were asked about whether they had ever been told that they reeked of alcohol more than 12 hours after they had stopped drinking. RESULTS: Current, former, and never flushing were reported in 3.5, 14.9, and 81.5%, respectively, of the subject, and alcohol reeking after more than 12 hours in 36.1% of the subjects. The fast-metabolizing ADH1B*2(+) genotype (*1/*2 or *2/*2) and the inactive ALDH2*2(+) genotype (*1/*2 or *2/*2) affected the multivariate odds ratios for current or former flushing [odds ratio, 95% confidence interval = 2.27 (1.79-2.86) and 23.0 (18.6-28.5), respectively, vs. *2(-) genotype] and for alcohol reeking [0.39 (0.29-0.52) and 1.56 (1.09-2.25), respectively, vs. *2(-) genotype]. An age-dependent decrease in the ADH1B*2(-) and ALDH2*2(-) combination from 32.3% in the 30-39-year age group to 12.5% in the 70-79-year age group and an age-dependent increase in the ADH1B*2(+) and ALDH2*2(-) combination from 52.5% in the 30-39-year age group to 70.5% in the 70-79-year age group were observed (P < 0.0001 for trend). The frequencies of the ADH1B*2(-) and ALDH2*2(+) combination (4.7-6.2%) and the ADH1B*2(+) and ALDH2*2(+) combination (8.9-12.0%) did not change markedly with increasing age. CONCLUSION: Interactions between the alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 genotypes modified alcohol flushing, alcohol reeking on the day after drinking, and the age distribution. These findings support the protective roles of the ADH1B*2(+) and ALDH2*2(+) genotypes against the development of alcohol dependence.

Influence of Comorbid Psychiatric Disorders on the Risk of Development of Alcohol Dependence by Genetic Variations of ALDH2 and ADH1B.

BACKGROUND: Inactive aldehyde dehydrogenase-2 (ALDH2) is a well-known deterrent to the development of alcohol use disorder (AUD), and however, some individuals with inactive ALDH2 do go on to develop AUD. These alcoholics are likely to have strong risk factors for the development of this disorder. Using a model of alcoholics with inactive ALDH2 (the AIA model), we investigated the unique characteristics of alcoholics with inactive ALDH2 in an attempt to identify the risk factors for AUD. In this study, we focused on comorbid psychiatric and personality disorders as potential risk factors for AUD. METHODS: The subjects were 103 male alcoholics with inactive ALDH2 (AIAs), 87 age- and ADH1B genotype-matched alcoholics with active ALDH2 (AAAs) and 200 age-matched healthy men. The alcoholics were divided into 4 subgroups according to their ALDH2 and ADH1B genotypes (inactive ALDH2 vs. active ALDH2, usual ADH1B vs. superactive ADH1B). To assess the participants' comorbid psychiatric disorders, we conducted semi-structured interviews using the Japanese translation of SSAGA version 2. We compared the prevalence of comorbid psychiatric and personality disorders among groups with different combinations of the ALDH2 and ADH1B genotypes. RESULTS: The prevalence of attention-deficit/hyperactivity disorder (ADHD) was significantly higher in the AIAs with usual ADH1B than in the other 3 subgroups of alcoholics. In contrast, the prevalence rates of agoraphobia and panic disorder were significantly lower in the AIAs with superactive ADH1B than in the other 3 subgroups of alcoholics. CONCLUSIONS: This study suggested that (i) ADHD is a risk factor for AUD, consistent with previous reports; (ii) agoraphobia and panic disorder may have deterrent effects against the development of AUD in individuals with inactive ALDH2, probably attributable to the similarity between the symptoms of agoraphobia and panic disorder and the adverse reactions to consumption of alcohol in subjects with inactive ALDH2.

Unguided Chatbot-Delivered Cognitive Behavioural Intervention for Problem Gamblers Through Messaging App: A Randomised Controlled Trial.

Internet-delivered intervention may be an acceptable alternative for the more than 90% of problem gamblers who are reluctant to seek face-to-face support. Thus, we aimed to (1) develop a low-dropout unguided intervention named GAMBOT integrated with a messaging app; and (2) investigate its effect. The present study was a randomised, quadruple-blind, controlled trial. We set pre-to-post change in the Problem Gambling Severity Index (PGSI) as the primary outcome and pre-to-post change in the Gambling Symptom Assessment Scale (G-SAS) as a secondary outcome. Daily monitoring, personalised feedback, and private messages based on cognitive behavioural theory were offered to participants in the intervention group through a messaging app for 28 days (GAMBOT). Participants in the control group received biweekly messages only for assessments for 28 days (assessments only). A total of 197 problem gamblers were included in the primary analysis. We failed to demonstrate a significant between-group difference in the primary outcome (PGSI - 1.14, 95% CI - 2.75 to 0.47, p = 0.162) but in the secondary outcome (G-SAS - 3.14, 95% CI - 0.24 to - 6.04, p = 0.03). Only 6.7% of the participants dropped out during follow-up and 77% of the GAMBOT group participants (74/96) continued to participate in the intervention throughout the 28-day period. Integrating intervention into a chatbot feature on a frequently used messaging app shows promise in helping to overcome the high dropout rate of unguided internet-delivered interventions. More effective and sophisticated contents delivered by a chatbot should be sought to engage over 90% of problem gamblers who are reluctant to seek face-to-face support.

Changes in smoking behavior among victims after the great East Japan earthquake and tsunami.

BACKGROUND: In areas affected by the tsunami of the great East Japan Earthquake, smoking behavior may have deteriorated due to high stress and drastic changes in living environment. Surveys were conducted to reveal changes in smoking behaviors among victims. METHODS: A population-based random-sample home-visit interview survey of victims in Iwate and Miyagi Prefectures affected by the tsunami disaster was conducted in 2012 (n = 1978), while a population-based nationwide survey was conducted in 2013 (n = 1082). A panel survey in 2014 was conducted with respondents of the 2012 survey (n = 930). Multiple logistic regression analysis was performed to reveal factors related to smoking status after the disaster. RESULTS: There was high smoking prevalence of both sexes in the tsunami disaster area (current smoking rate in coastal area, 50.0% for male, 21.4% for female; inland area, 34.7% for male, 7.6% for female). Low prevalence of male quitters was observed (quitter rate in coastal area, 20.8% for male, 8.0% for female; inland area, 23.4% for male, 5.5% for female). The prevalence of nicotine-dependent people assessed by FTND (Fagerström Test for Nicotine Dependence) in the coastal area was also higher than in the inland area or other areas of Japan. Smoking behavior among victims worsened after the disaster and did not improve 3 years from the disaster. Post-disaster factors related to smoking were living in coastal area, complete destruction of house, and living in temporary housing. CONCLUSIONS: Smoking prevalence and the level of nicotine dependence of tsunami victims were still high even 3 years after the disaster. It is important to emphasize measures for smoking control in the disaster areas for an extended time period.

Platelet Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men.

BACKGROUND: Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3 weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics. METHODS: We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period. RESULTS: Thrombocytopenia (<15 × 104 /µl) was observed in 25.9% of the subjects upon admission. The platelet counts increased from 21.4 ± 0.3 × 104 /µl (mean ± SE) to 27.6 ± 0.3 × 104 /µl, and a rebound platelet increase of  ≥10 × 104 /µl was observed in 28.6% of the patients during the first 2 weeks after admission. By 4 weeks, the mean platelet counts had returned to intermediate levels and remained stable thereafter. The reversible suppression and rebound increase in the platelet counts were more prominent in the slow-metabolizing ADH1B*1/*1 group than in the fast-metabolizing ADH1B*2 group. Throughout the 8 weeks, the mean platelet counts of the active ALDH2*1/*1 group were consistently lower than those in the inactive ALDH2*1/*2 group. Cirrhosis was a strong determinant of a lower platelet count. After adjustments for nongenetic factors including cirrhosis, multiple linear regression analyses showed that the ADH1B*1/*1 genotype was associated with a lower platelet count (partial regression coefficient = -1.3 × 104 /µl) on the admission day, but subsequently had a positive effect on the platelet count at 1 and 2 weeks after admission (+1.5 and +3.8 × 104 /µl, respectively). The ALDH2*1/*1 genotype was associated with a lower platelet count (-2.1 to -3.9 × 104 /µl) consistently throughout the 8 weeks. Multiple logistic regression analyses showed that the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission (odds ratio [95% confidence interval] = 1.61 [1.14 to 2.27]) and of a rebound platelet increase during the first 2 weeks (3.86 [2.79 to 5.34]). The ALDH2*1/*1 genotype increased the risk of thrombocytopenia upon admission (1.73 [1.06 to 2.82]). CONCLUSIONS: In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2 weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay.

Review: Use of Asian samples in genetic research of alcohol use disorders: Genetic variation of alcohol metabolizing enzymes and the effects of acetaldehyde.

BACKGROUND AND OBJECTIVES: Epidemiological studies consistently find that Asian populations report lower rates of alcohol use disorders (AUD) compared with other racial groups. These differences result from a variety of biological, genetic, and environmental influences, some of which are related to the metabolism of alcohol. We will review several studies of these metabolic factors, including several alcohol clamping studies conducted in our laboratory, that provide further insight into the role of the alcohol metabolizing genes and drinking behavior among Japanese drinkers. METHODS: This manuscript reviewed studies investigating genetic variations of alcohol metabolizing enzymes among Asians and several mechanisms by which these genes are thought to give rise to differences in rates of alcohol dependence. RESULTS: The inactive aldehyde dehydrogenase 2 (ALDH2) and highly active alcohol dehydrogenase-1B (ADH1B) genes are protective factors for the development of AUD. The inactive ALDH2 provides its protective effect through the accumulation of acetaldehyde after consuming alcohol, resulting in unpleasant effects, and heightened sensitivity to alcohol. However, the suppressive effects of inactive ALDH2 and highly active ADH1B for AUDs are only partial and interact with other factors, such as personality traits, psychiatric comorbidities, and environmental factors. DISCUSSION AND CONCLUSIONS: While Asians are excellent models for the study of certain genetic effects on the development and consequences of AUD, few clinical studies of this population have been conducted. Further exploration of the interactions between various genetic, individual, and environmental factors influencing drinking behavior and, thus affecting the risk of AUD, would enhance our understanding of how alcohol-related problems develop. SCIENTIFIC SIGNIFICANCE: The heterozygous ALDH2*1/*2 genotype has only partial effects on limiting drinking behavior, suggesting the potential interaction with other factors. Therefore AUD patients with inactive ALDH2 may be a useful model to identify and to test a variety of other risk factors of AUD. (Am J Addict 2017;26:469-476).

Blood Leukocyte Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men.

BACKGROUND: Roughly 40% of East Asians have inactive aldehyde dehydrogenase-2 (ALDH2) encoded by the ALDH2*2 allele, and 90% have highly active alcohol dehydrogenase-1B (ADH1B) encoded by the ADH1B*2 allele. Macrocytosis and macrocytic anemia in alcoholics have been associated with ADH1B and ALDH2 gene variants which increase acetaldehyde (AcH) levels. METHODS: We investigated the relationship between ADH1B*2, ALDH2*2, and leukocyte counts of Japanese alcoholic men (N = 1,661). RESULTS: After adjusting for age, drinking habits, smoking habits, body mass index, presence of liver cirrhosis, and serum levels of C-reactive protein, we found that total and differential leukocyte counts were lower in the presence of the ALDH2*1/*2 genotype (vs. ALDH2*1/*1 genotype). ALDH2*2/*2 carriers were not found in our study population. Leukocyte, granulocyte, and monocyte counts were also lower in the presence of ADH1B*2 (vs. ADH1B*1/*1 genotype), but the lymphocyte count was higher. The ALDH2*1/*2 genotype was associated with leukocytopenia (<4,000/µl; adjusted odds ratio [95% confidence interval] = 1.89 [1.27 to 2.80]), granulocytopenia (<2,000/µl; 1.86 [1.22 to 2.82]), monocytopenia (<250/µl; 2.22 [1.49 to 3.29]), and lymphocytopenia (<1,000/µl; 1.93 [1.32 to 2.83]). In contrast, the ADH1B*2 had the opposite effect on lymphocytopenia (0.65 [0.46 to 0.93]). Considering genotype effects under conditions of immune stimulation, we observed suppressive effects of ADH1B*2 allele on leukocytosis (≥9,000/µl; 0.69 [0.50 to 0.97]), granulocytosis (≥6,500/µl; 0.66 [0.47 to 0.93]), and monocytosis (≥750/µl; 0.56 [0.39 to 0.79]). The ADH1B*2 plus ALDH2*1/*2 combination had the greatest suppressive effects on the leukocyte, granulocyte, and monocyte counts. CONCLUSIONS: The total and differential blood leukocyte counts of Japanese alcoholics were strongly affected by their ADH1B and ALDH2 gene variants. High AcH exposure levels probably play a critical role in the suppression of blood leukocyte counts in alcoholics.

Alcohol Dehydrogenase-1B (rs1229984) and Aldehyde Dehydrogenase-2 (rs671) Genotypes and Alcoholic Ketosis Are Associated with the Serum Uric Acid Level in Japanese Alcoholic Men.

AIMS: To identify determinants of hyperuricemia in alcoholics. METHODS: The serum uric acid (UA) levels of 1759 Japanese alcoholic men (≥40 years) were measured on their first visit or within 3 days after admission; ADH1B and ALDH2 genotyping on blood DNA samples were performed. Dipstick urinalyses for ketonuria and serum UA measurements were simultaneously performed for 621 men on their first visit. RESULTS: Serum UA levels of >416 µmol/l (7.0 mg/dl) and ≥535 µmol/l (9.0 mg/dl) were observed in 30.4 and 7.8% of the subjects, respectively. Ketonuria was positive in 35.9% of the subjects, and a multivariate analysis revealed that the ketosis level was positively associated with the UA level. The presence of the ADH1B*2 allele and the ALDH2*1/*1 genotype increased the odds ratio (OR; 95% confidence interval) among subjects with a high UA level of >416 µmol/l (vs. ≤416 µmol/l; 2.04 [1.58-2.65] and 1.48 [1.09-2.01], respectively) and those with a high UA level of ≥535 µmol/l (vs. ≤416 µmol/l; 2.29 [1.42-3.71] and 3.03 [1.51-6.08], respectively). The ADH1B*2 plus ALDH2*1/*1 combination yielded the highest ORs (2.86 [1.61-5.10] and 6.21 [1.49-25.88] for a UA level of >416 µmol/l and ≥535 µmol/l, respectively), compared with the ADH1B*1/*1 plus ALDH2*1/*2 combination. The presence of diabetes and the consumption of Japanese sake rather than beer were negatively associated with the UA levels. CONCLUSIONS: The faster metabolism of ethanol and acetaldehyde by the ADH1B*2 allele and ALDH2*1/*1 genotype and higher ketosis levels were associated with higher UA levels in alcoholics, while diabetes and the consumption of sake were negative determinants.

[Relapse prevention program consisting of coping skills training, cue exposure treatment, and letter therapy for Japanese alcoholic men who relapsed after standard cognitive-behavioral therapy].

Coping skills training (CST) and cue exposure treatment (CET) have yielded favorable outcomes when used to treat alcoholics. We conducted 6-week inpatient programs that consisted of 9 CST group sessions (n = 117) during 2005-2009 and 9 CST group sessions plus 4 CET group sessions (n = 49) during 2009-2011 and subsequent 1-year letter therapy for Japanese alcoholic men who had relapsed and been readmitted after standard cognitive-behavioral inpatient therapy. When patients received a letter containing encouraging words every 2 weeks, they were asked to reread their CST and CET records and to respond to the letter by marking drinking days on a calendar and naming the skills on a list of the 9 CST themes and CET that were useful for maintaining abstinence during that 2-week period. The estimated percentages of achievement of 30 or fewer drinking days during the one year of letter therapy were 36.1 - 45.8%. 'Non-smoking', '2nd admission', and 'After age-limit job retirement' were significant factors in achieving good outcomes. The 'usefulness' responses for 'Increasing pleasant activities', 'CET', 'Anger management', ' Managing negative thinking', 'Problem solving', and ' Seemingly irrelevant decisions' as percentages of overall responses to the letters were significantly higher, in order of decreasing percentages, in the achiever group than in the non-achiever group, but the differences between the groups in ' Managing urges to drink', ' Drink refusal skills', ' Planning for emergencies', and ' Receiving criticism about drinking' were not significant. The odds ratios for achievement of 30 or fewer drinking days during the 1-year period increased significantly by 1.15 -1.31 fold per 10% increment in the 'usefulness' ratio for 'Increasing pleasant activities'. The difference in percentage achievement between the group treated by CST alone and the group treated by CST plus CET was not significant. In conclusion, some coping skills were more useful for relapse prevention than others in this study population, and addition of CET to CST and subsequent letter therapy did not improve outcomes.

Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men.

BACKGROUND: Oxidation of ethanol by alcohol dehydrogenase (ADH) generates acetaldehyde (AcH), which is converted to acetate by aldehyde dehydrogenase-2 (ALDH2). Roughly 40% of East Asians are ALDH2-deficient due to an inactive enzyme encoded by the ALDH2*2 allele. ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer from alcohol consumption. METHODS: We investigated the relationship between ALDH2*2, ADH1B*2 (encoding a highly active ADH) and erythrocyte abnormalities, in a population of Japanese alcoholic men (N = 1,238). RESULTS: Macrocytosis (mean corpuscular volume [MCV] ≥100 fl) and macrocytic anemia (MCV ≥100 fl and hemoglobin <13.5 g/dl) were found in 62.4 and 24.1% of the subjects, respectively. Age-adjusted daily alcohol consumption did not differ according to ADH1B and ALDH2 genotypes. However, macrocytosis and macrocytic anemia were strongly associated with the ALDH2*1/*2 genotype multivariate odds ratios (ORs; 95% confidence interval [CI] = 2.85 [1.95 to 4.18] and 3.68 [2.64 to 5.15], respectively, versus ALDH2*1/*1). In comparison with the ADH1B*1/*1 and ALDH2*1/*1 genotype combination, the ADH1B*1/*1 and ALDH2*1/*2 genotype combination and the ADH1B*2 allele and ALDH2*1/*2 genotype combination increased stepwise the ORs (95% CI) for macrocytosis (1.65 [0.92 to 2.94] and 4.07 [2.33 to 7.11], respectively, p for difference in OR = 0.015) and macrocytic anemia (2.80 [1.52 to 5.15] and 5.32 [3.29 to 8.62], respectively, p for difference in OR = 0.045). Genotype effects were more prominent on the risks of the more advanced erythrocyte abnormalities. Older age, cigarette smoking, and low body mass index independently increased the risks of the erythrocyte abnormalities. Consumption of beer, which contains folate, decreased the risks, whereas consumption of alcoholic beverages lacking folate did not. CONCLUSIONS: These results suggest that the erythrocyte abnormalities in alcoholics are attributable to high AcH exposure as well as to nutritional deficiencies and may be prevented by folate.

Acceptance of controlled drinking among treatment specialists of alcohol dependence in Japan.

AIMS: This study evaluated the acceptance of controlled drinking (CD) goals among physicians specializing in the treatment of alcohol dependence (AD) in Japan. METHODS: A mailed questionnaire survey was sent to physician members of the Japanese Society of Alcohol-Related Problems (n = 232) who were specialists in the treatment of AD in Japan. The evaluated items included the acceptance of CD goals, the definition of CD, the reasons for accepting or rejecting CD and the patient factors used to make treatment-goal decisions. RESULTS: CD as an interim goal on the way toward abstinence was accepted by about two-thirds of the specialists, while CD as a final goal was accepted by about one-third of specialists. Specialists supported harm-free drinking and a satisfactory quality of life, rather than alcohol consumption limits, as the definition of CD. Of note, a significantly higher percentage of specialists who rejected CD, compared with those who accepted CD, supported the disease model of AD as grounds for their decision. Specialists who accepted CD relied mostly on factors such as the severity of dependence, attitude toward CD and abstinence, and the level of psychological dependence and social stability, when making treatment-goal decisions. CONCLUSION: CD was accepted as an interim goal by two-thirds and as a final goal by one-third of Japanese physician specialists. Despite differences in drinking cultures and treatment circumstances, great similarities were found between this study and those conducted in Europe and North America with regard to the reasoning of treatment providers and the use of patient characteristics to make treatment-goal decisions.

Blood ethanol levels of nonabstinent Japanese alcoholic men in the morning after drinking and their ADH1B and ALDH2 genotypes.

AIMS: Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) affect ethanol (EtOH) metabolism and susceptibility to alcoholism. METHODS: We evaluated associations between ADH1B/ALDH2 genotypes and the blood EtOH levels of 805 Japanese alcoholic men in the morning after they had drunk within the previous 34 h. RESULTS: Age-adjusted usual alcohol consumption did not differ according to ADH1B/ALDH2 genotypes. Higher blood EtOH levels persisted for longer periods in the ADH1B*1/*1 carriers (n = 246) than in the ADH1B*2 carriers (n = 559). Blood EtOH levels did not differ by ALDH2 genotype. The blood EtOH levels ≥ 0.3 mg/ml (criterion for drunk driving in Japanese law) were observed (40% vs. 14-17%, P < 0.0001) in a higher proportion of the ADH1B*1/*1 carriers than of the ADH1B*2 carriers after a 12.1-to-18-h interval since the last drink. Multivariate analyses showed that the EtOH levels heightened by 0.500 mg/ml in the presence of ADH1B*1*1 and by 0.248 mg/ml in the presence of cirrhosis, and lowered by 0.120 mg/ml per 10-year age increase, by 0.087 mg/ml per 10-kg body-weight increase and by 0.673 mg/ml per 10-h interval since the last drink. The odds ratio (95% confidence interval) for an EtOH level ≥ 0.3 mg/ml was 3.44 (2.34-5.04) in the presence of ADH1B*1/*1, 2.01 (1.28-3.14) in the presence of cirrhosis, 0.59 (0.49-0.71) per 10-year age increase, 0.80 (0.68-0.95) per 10-kg body-weight increase and 0.10 (0.07-0.15) per 10-h interval since the last drink. CONCLUSION: The longer-than-expected EtOH lingering in the blood of the ADH1B*1/*1 alcoholics may exacerbate alcohol-related problems, including drunk driving.

Alcoholic Ketosis: Prevalence, Determinants, and Ketohepatitis in Japanese Alcoholic Men.

AIMS: Alcoholic ketosis and ketoacidosis are metabolic abnormalities often diagnosed in alcoholics in emergency departments. We attempted to identify determinants or factors associated with alcoholic ketosis. METHODS: The subjects of this cross-sectional survey were 1588 Japanese alcoholic men (≥40 years) who came to an addiction center within 14 days of their last drink. RESULTS: The results of the dipstick urinalyses revealed a prevalence of ketosis of 34.0% (±, 21.5%; +, 8.9%; and 2+/3+; 3.6%) in the alcoholics. Higher urine ketone levels were associated with higher serum total bilirubin, aspartate transaminase (AST), alanine transaminase and gamma-glutamyl transpeptidase levels. A multivariate analysis by the proportional odds model showed that the odds ratio (95% confidence interval) for an increase in ketosis by one category was 0.94 (0.84-1.06) per 10-year increase in age, 0.93 (0.89-0.97) per 1-day increase in interval since the last drink, 1.78 (1.41-2.26) in the presence of slow-metabolizing alcohol dehydrogenase-1B (ADH1B*1/*1), 1.61 (1.10-2.36) and 1.30 (1.03-1.65) when the beverage of choice was whiskey and shochu, respectively (distilled no-carbohydrate beverages vs. the other beverages), 2.05 (1.27-3.32) in the presence of hypoglycemia <80 mg/dl, 0.91 (0.88-0.94) per 1-kg/m(2) increase in body mass index (BMI), 1.09 (1.00-1.18) per +10 cigarettes smoked, and 2.78 (2.05-3.75) when the serum total bilirubin level was ≥2.0 mg/dl, and 1.97 (1.47-2.66) when the serum AST level was ≥200 IU/l. CONCLUSION: Ketosis was a very common complication and frequently accompanied by alcoholic liver injury in our Japanese male alcoholic population, in which ADH1B*1/*1 genotype, consumption of whiskey or shochu, hypoglycemia, lower BMI and smoking were significant determinants of the development of ketosis.

[Concurrent inpatient smoking cessation and alcohol abstinence programs for alcoholics and their outcomes].

Alcoholics have a high prevalence of nicotine dependence, and smoking is a major contributor to their high mortality. Three weeks after admission to an addiction center in Japan, 193 alcoholic men who were participating in an 11-week concurrent inpatient smoking cessation and alcohol abstinence programs filled out an anonymous self-report questionnaire regarding smoking and drinking, and 6 months after the completion of the programs, 83 patients were asked to respond to a mailed questionnaire about their smoking and drinking status. Of the 193 subjects, 73.3% were current smokers, but many were highly motivated in regard to both smoking cessation and alcohol abstinence. The subjects' scores on a 0 to 10 point scale for rating motivation and confidence in regard to smoking cessation and smoking urge were significantly correlated with each other and with their scores for motivation and confidence in regard to alcohol abstinence and drinking urge. Three weeks after admission, varenicline treatment was well-tolerated, and the varenicline group had a high rate of smoking cessation than the smoker group not treated with varenicline (67.7% vs. 44.6%, p = 0.012). Forty-six (55.4%) of the 83 subjects who were mailed the questionnaire responded, and the drinking category was 'totally abstinent' in 35 subjects (42.2%), and 'mostly abstinent' in another 4 subjects (4.8%). Seventeen (20.5%) of the 83 subjects were non-smokers before treatment, but after treatment, 23 (50.0%) of the 46 responders and 20 (51.3%) of the 'totally or mostly abstinent' 39 responders were total or almost non-smokers. The response rate of 'totally or mostly abstinent' was higher among the 17 non-smokers before treatment than among the 66 smokers before treatment (70.6% vs. 40.9%, p = 0.033), and the age-adjusted odds ratio (95% confidence interval) for the response of 'totally or mostly abstinent' was 3.30 (1.03-10.56) for the non-smokers before treatment (vs. the smokers before treatment). In conclusion, smoking status had a great impact on the drinking status of treatment-seeking alcoholic men, and smoking cessation should be recommended to smoking alcoholics.

[Alcohol-related dementia].

Excessive alcohol use is associated with health problems for the elderly in combination with their chronic conditions. One such complication, alcohol-related dementia (ARD) is brought about by direct or indirect ethanol intoxication, and coexisting nutritional deficiency, liver disease, cerebrovascular disease and traumatic brain injury. The elderly people with ARD have been underestimated and underdiagnosed. In these older alcoholics, atrophic changes, lacunar infarcts and deep white matter lesions of the brain are evident and are associated not only with their cognitive decline, but also with their frailty, leading to high morbidity and mortality ratio. Although lifelong abstinence can recover patients with ARD to temporally lull, aging, the severity of alcohol dependence, and the concomitant nutritional, physical and environmental factors can all impact negatively their outcome. Therefore, a comprehensive approach to lifestyle factors is recommended so that they can minimize preventable risks and maintain health status. Nursing home placement may be an appropriate treatment option for some refractory, long-term patients with ARD.