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Aim: To elucidate associations among liver disease, lipid profile, body mass index (BMI), ketonuria, and meal skipping under the influence of alcohol dehydrogenase‐1B (ADH1B; rs1229984) and aldehyde dehydrogenase‐2 (ALDH2; rs671) genotypes in men with alcohol dependence. Methods: We investigated the associations among these variables in 1768 Japanese men with alcohol dependence. Serum lipid levels were followed up after abstinence. Results: The slow‐metabolizing ADH1B Arg/Arg genotype and inactive ALDH2 Glu/Lys genotype increased the age‐ and drinking‐adjusted odds ratio or regression coefficient for fatty liver, ketonuria, and serum high‐density‐lipoprotein cholesterol levels (HDL‐C), and decreased these for cirrhosis and serum triglyceride levels (TG). The ADH1B Arg/Arg genotype increased the adjusted regression coefficient for BMI and non‐HDL‐C. In addition to the positive interlinkage among fatty liver, BMI, and atherogenic dyslipidemia, positive associations were observed of fatty liver with ketonuria and meal skipping, of cirrhosis with the BMI, and of ketonuria with non‐HDL‐C. Negative associations were observed of cirrhosis with fatty liver, TG, non‐HDL‐C, and HDL‐C, and of ketonuria with BMI and TG. Overall, after admission for 4 or 6 weeks, the TG and HDL‐C decreased, and the serum low‐density lipoprotein cholesterol levels increased. However, there was no change of the serum low‐density lipoprotein in the patients with cirrhosis or of the serum TG in those with fatty liver. Conclusions: These associations and the alterations in lipid profile after abstinence serve as useful information for a better understanding of the clinical features of men with alcohol dependence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background The presence of the less-active form of alcohol dehydrogenase- 1B encoded by ADH1B *1/*1 (vs. *2 allele) and active form of aldehyde dehydrogenase-2 (ALDH2) encoded by ALDH2 *1/*1 (vs. *2 allele) increases the risk of alcoholism in East Asians. Methods The subjects in this cross-sectional survey were 1,902 Japanese alcoholic men (≥40 years) who underwent ADH1B/ ALDH2 genotyping. Results Age-adjusted daily alcohol consumption did not differ according to the ADH1B/ ALDH2 genotypes. The age-adjusted odds ratios ( AORs; 95% confidence interval) for liver cirrhosis ( LC; n = 359, 1.58 [1.19 to 2.09]), chronic calcific pancreatitis ( CP; n = 80, 2.24 [1.20 to 4.20]), and diabetes mellitus ( DM; n = 383, 1.51 [1.15 to 1.99]) were higher in the ADH1B *2 allele carriers than in the ADH1B *1/*1 carriers. The AORs for LC (1.43 [1.01 to 2.02]), CP (1.68 [0.80 to 3.53]), DM (1.63 [1.15 to 2.30]), and hypertension ( HT; n = 495, 1.52 [1.11 to 2.07]) were higher in the ALDH2 *1/*1 carriers than in the ALDH2 *1/*2 carriers. The ADH1B *2-associated AOR for LC was 2.08 (1.46 to 2.94) among those aged 40 to 59 years, but 0.89 (0.56 to 1.43) among those aged 60 years or over, and the interaction between ADH1B genotype and age on the LC risk was significant ( p = 0.009). When the group with non- LC and no/mild fibrosis was used as controls, the ADH1B *2-associated AORs increased according to the severity of their liver disease: 1.67 (1.32 to 2.11) for the group with non- LC and serum type IV collagen values ≥200 ng/ml, 1.81 (1.24 to 2.63) for the group of Child- Pugh class A LC, and 3.17 (1.98 to 5.07) for the group with Child- Pugh class B/ C LC. Anti-hepatitis C virus ( HCV) antibody was positive in 103 patients, and the groups with a high anti- HCV antibody titer and either the ADH1B *2/*2 genotype or the ALDH2 *1/*1 genotype had the highest AORs (8.83 and 4.90, respectively). The population attributable fraction ( PAF) due to the ADH1B *2 allele was 29% for LC, 47% for CP, and 27% for DM, and the PAF due to the ALDH2 *1/*1 genotype was 26% for LC, 34% for DM, and 30% for HT. Conclusions The ADH1B *2 allele increased the AORs for LC, CP, and DM of the alcoholics, and the ALDH2 *1/*1 genotype increased their AORs for LC, DM, and HT. HCV infection and genetic susceptibility had a synergistic effect on the AOR for LC. [ABSTRACT FROM AUTHOR]

We investigated the development of esophageal neoplasia in biopsy specimens of the distinct iodine-unstained lesions (DIULs) ≥5 mm detected in 280 of 2,115 Japanese alcoholic men who underwent screening by esophageal iodine staining. Low-grade intraepithelial neoplasia (LGIN) was diagnosed in 155 of them, high-grade intraepithelial neoplasia (HGIN) in 57, and invasive SCC in 35. The size of the DIULs increased with the degree of neoplasia. Most LGINs were flat and were missed before iodine staining. Some DIULs became a light pink color (PC) about 2 min after staining, and 2.6, 56.1 and 96.0% of the LGIN, HGIN and invasive SCC lesions, respectively, were PC-sign-positive. Multiple DIULs of any size markedly increased the risk of LGIN [adjusted OR (95%CI) = 10.1 (7.12-14.5)], HGIN [27.9 (14.6-53.4)] and invasive SCC [21.6 (10.1-46.4)], and were strongly associated with the presence vs. absence of DIULs ≥ 5 mm [13.3 (9.21-19.1)], inactive heterozygous aldehyde dehydrogenase-2 ( ALDH2*1/*2) vs. ALDH2*1/*1 [2.60 (1.79-3.78)], and less-active alcohol dehydrogenase-1B ( ADH1B*1/*1) vs. ADH1B*2 allele [2.61 (1.87-3.64)]. The combination of ALDH2*1/*2 and ADH1B*1/*1 synergistically increased the risk of LGIN [4.53 (2.17-9.47)], HGIN [10.4 (4.34-24.7)] and invasive SCC [21.7 (7.96-59.3)]. Esophageal neoplasia developed at earlier ages in those with ALDH2*1/*2. Biopsy-proven HGIN was diagnosed as invasive SCC in 15 (39.5%) of 38 patients after endoscopic mucosectomy or surgery. In conclusion, large size, non-flat appearance, positive PC sign and multiplicity of DIULs and ALDH2*1/*2 and ADH1B*1/*1 were associated with development of esophageal neoplasia in Japanese alcoholics. Biopsy-proven HGIN should be totally resected for both diagnostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Background: The risk of metachronous gastric cancer is high in Japanese with esophageal squamous cell carcinoma (SCC), especially in alcoholic men, suggesting a common background underlying the gastric and esophageal cancers. Methods: Endoscopic follow-up ranging from 7 to 160 months (median, 47 months) after the initial diagnosis was performed in 99 Japanese gastric-cancer-free alcoholic men (56.8 ± 6.4 years) with esophageal SCC detected by an endoscopic screening examination. Chronic atrophic gastritis (CAG) assessed by the serum pepsinogen test and Helicobacter pylori status was compared between 90 of the 99 esophageal SCC cases and 180 age-matched Japanese gastric- and esophageal-cancer-free alcoholic men. Results: The serum pepsinogen test showed a higher seroprevalence of severe CAG among the cases than among the age-matched controls (35.4% vs. 14.2% for H. pylori-seropositive, 71.4% vs. 7.7% for H. pylori-indeterminate, and 17.1% vs. 9.8% for H. pylori-negative, respectively; H. pylori status-adjusted p = 0.0008), whereas their H. pylori status was similar. The accelerated progression of severe CAG observed in the Japanese alcoholic men with esophageal SCC suggests the existence of common mechanisms by which both esophageal SCC and H. pylori-related severe CAG develop in this population. Metachronous gastric adenocarcinoma was diagnosed in 11 of the 99 gastric-cancer-free patients, and the cumulative rate of metachronous gastric cancer within 5 years was estimated to be 15% according to the Kaplan–Meier method. The age-adjusted hazard ratios were 7.87 (95% confidence interval: 1.43 to 43.46) and 4.84 (1.16 to 20.21), respectively, in the patients with severe CAG in comparison with those without CAG and those without severe CAG. Inactive heterozygous aldehyde dehydrogenase-2, a very strong risk factor for esophageal SCC in the alcoholics, was not associated with an increased risk of metachronous gastric cancer. Conclusions: Accelerated development of severe CAG at least partially explained the very high frequency of development of metachronous gastric cancer in this population. [ABSTRACT FROM AUTHOR]

Background: Gastric carcinoma occurs at a high rate in alcoholic Japanese men. Inactive heterozygous aldehyde dehydrogenase-2 ( ALDH2* 1/2* 2) and macrocytosis (mean corpuscular volume [MCV] ≥ 106 fl) enhance the risk for esophageal carcinoma, which frequently occurs with gastric carcinoma in this population. Whether alcoholism affects Helicobacter pylori-induced chronic atrophic gastritis (CAG) is unknown. Methods: This study of Japanese alcoholic men with ( n = 45) and without ( n = 281) gastric carcinoma included assessment of H. pylori IgG antibody, serum pepsinogen-confirmed CAG, MCV, and ALDH2 genotype. Results: The gastric carcinoma cases had a significantly higher age-adjusted prevalence of H. pylori-positivity (78% vs 57%), CAG (78% vs 42%), ALDH2* 1/2* 2 (36% vs 14%), MCV ≥106 fl (38% vs 20%), and concurrent esophageal/oropharyngolaryngeal carcinoma (18% vs 5%) than controls. Among gastric cancer-free controls, the prevalence of CAG was higher than generally reported in Japan, regardless of H. pylori status ( H. pylori-positive, 56% vs 35–36% for Japanese general population; H. pylori-negative, 8% vs 1–3%). Alcoholism may accelerate the progression of CAG. Each of these factors increased the risk of gastric carcinoma (O Rs = 3.7 for H. pylori-positive, 2.7 for non-severe CAG, 8.7 for severe CAG, 3.5 for ALDH2* 1/2* 2, 2.5 for MCV ≥106 fl, and 3.7 for concurrent carcinoma). A multivariate analysis showed that CAG and ALDH2* 1/2* 2 were independently related to the risk of gastric carcinoma. Combinations of CAG and ALDH2* 1/2* 2 showed greater risks of gastric carcinoma (O Rs = 4.0 for non-severe CAG alone, 17.6 for severe CAG alone, 9.7 for ALDH2* 1/2* 2 alone, 17.1 for non-severe CAG plus ALDH2* 1/2* 2, and 39.2 for severe CAG plus ALDH2* 1/2* 2). Conclusions: Combining blood tests for H. pylori, CAG, MCV and ALDH2 genotype could offer a new means of predicting risk of gastric carcinoma in Japanese alcoholic men. [ABSTRACT FROM AUTHOR]

Abstract: Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) and less-active alcohol dehydrogenase-1B (ADH1B*1/*1) increase the risk of esophageal cancer in East Asian drinkers, and esophageal cancer multiplicity is strongly associated with ALDH2*1/*2. p53 alterations are key molecular events in multifocal carcinogenesis in the esophagus. We studied 260 esophageal-cancer free Japanese alcoholics with esophageal dysplasia diagnosed by biopsy of distinct iodine-unstained lesions (DIULs) ⩾5mm. The degree of p53 protein accumulation was positively associated with the degree of atypia (p <0.0001) and size (p =0.040) of DIULs and with the presence of multiple DIULs (p=0.070), but not with ALDH2*1/*2 or ADH1B*1/*1. [Copyright &y& Elsevier]

Abstract: Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity. [Copyright &y& Elsevier]