Japanese Alcoholic Men Research Articles

Polymorphisms of Alcohol Dehydrogenase‐1B and Aldehyde Dehydrogenase‐2 and the Blood and Salivary Ethanol and Acetaldehyde Concentrations of Japanese Alcoholic Men

The effects of genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2) on alcohol metabolism are striking in nonalcoholics, and the effects of genetic polymorphism of alcohol dehydrogenase-1B (ADH1B) are modest at most, whereas genetic polymorphisms of both strongly affect the susceptibility to alcoholism and upper aerodigestive tract (UADT) cancer of drinkers. We evaluated associations between ADH1B/ADH1C/ALDH2 genotypes and the blood and salivary ethanol and acetaldehyde levels of 168 Japanese alcoholic men who came to our hospital for the first time in the morning and had been drinking until the day before. The ethanol levels in their blood and saliva were similar, but the acetaldehyde levels in their saliva were much higher than in their blood, probably because of acetaldehyde production by oral bacteria. Blood and salivary ethanol and acetaldehyde levels were both significantly higher in the subjects with the less active ADH1B*1/*1 genotype than in the ADH1B*2 carriers, but none of the levels differed according to ALDH2 genotype. Significant linkage disequilibrium was detected between the ADH1B and ADH1C genotypes, but ADH1C genotype did not affect the blood or salivary ethanol or acetaldehyde levels. High blood acetaldehyde levels were found even in the active ALDH2*1/*1 alcoholics, which were comparable with the levels of the inactive heterozygous ALDH2*1/*2 alcoholics with less active ADH1B*1/*1. The slope of the increase in blood acetaldehyde level as the blood ethanol level increased was significantly steeper in alcoholics with inactive heterozygous ALDH2*1/*2 plus ADH1B*2 allele than with any other genotype combinations, but the slopes of the increase in salivary acetaldehyde level as the salivary ethanol level increased did not differ between the groups of subjects with any combinations of ALDH2 and ADH1B genotypes. The ADH1B/ALDH2 genotype affected the blood and salivary ethanol and acetaldehyde levels of nonabstinent alcoholics in a different manner from nonalcoholics, and clear effects of ADH1B genotype and less clear effects of ALDH2 were observed in the alcoholics. Alterations in alcohol metabolism as a result of alcoholism may modify the gene effects, and these findings provide some clues in regard to associations between the genotypes and the risks of alcoholism and UADT cancer.

Chronic Atrophic Gastritis and Metachronous Gastric Cancer in Japanese Alcoholic Men With Esophageal Squamous Cell Carcinoma

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. 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. 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. Accelerated development of severe CAG at least partially explained the very high frequency of development of metachronous gastric cancer in this population.

Risk of metachronous squamous cell carcinoma in the upper aerodigestive tract of Japanese alcoholic men with esophageal squamous cell carcinoma: a long‐term endoscopic follow‐up study

East Asian case-control studies have shown a strong relationship between alcohol consumption combined with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) and the development of squamous cell carcinoma (SCC), especially multiple SCC, of the upper aerodigestive tract (UADT). This study aimed to identify determinants of the development of metachronous SCC in the UADT in alcoholics with esophageal SCC. Follow-up endoscopic examinations were carried out 4-160 months (median, 41 months) after initial diagnosis in 110 Japanese alcoholic men with esophageal SCC diagnosed by screening using endoscopy combined with oropharyngolaryngeal inspection and esophageal iodine staining. ALDH2*1/*2 was significantly associated with the presence of multiple primary intraesophageal SCC at the time of initial diagnosis. Metachronous primary SCC of the esophagus was diagnosed in 29 of the 81 patients whose initial esophageal SCC was treated by endoscopic mucosal resection alone, and metachronous primary SCC of the oropharyngolarynx was diagnosed in 23 of the 99 patients without synchronous primary SCC of the oropharyngolarynx at the time of initial diagnosis. The risks of metachronous esophageal SCC and oropharyngolaryngeal SCC were significantly higher in ALDH2*1/*2 heterozygotes than in ALDH2*1/*1 homozygotes (age-adjusted and alcohol-adjusted hazard ratio = 3.38 [95% confidence interval: 1.45-7.85] and 4.27 [1.42-12.89], respectively), and in patients with multiple intraesophageal SCC at the time of initial diagnosis than in patients with a solitary intraesophageal SCC (3.09 [1.41-6.78] and 3.25 [1.41-7.47], respectively). ALDH2*1/*2 and multiple synchronous intraesophageal SCC were found to be predictors of metachronous SCC in the UADT in this population.

Contribution of the alcohol dehydrogenase‐1B genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men

The less-active homozygous alcohol dehydrogenase-1B (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level (<DL) (<DL-6.4), p = 0.0003]. The ethanol levels in blood and saliva were similar, but the acetaldehyde levels in saliva were strikingly higher than in the blood, and were higher in ADH1B*1/*1 carriers than in ADH1B*2 allele carriers [47.4 muM (22.2-87.6) vs. 1.60 (<DL-26.3) in the saliva, p = 0.009]. The salivary acetaldehyde levels were correlated with salivary acetaldehyde production (r = 0.34, p = 0.002). The oral bacteria and yeast counts were correlated with salivary acetaldehyde production. Both the microorganisms counts and acetaldehyde production decreased after 3 weeks of abstinence, and the decreases were correlated (r = 0.35, p = 0.042). No effect of inactive ALDH2 (n = 12) on ethanol lingering the next morning was observed. In conclusion, the high salivary acetaldehyde levels in the alcoholics were partly attributable to prolonged ethanol exposure because of the less-active ADH1B and increased salivary acetaldehyde production as a result of oral microorganism overgrowth, and may explain their high risk for UADTC.

Helicobacter pylori, chronic atrophic gastritis, inactive aldehyde dehydrogenase‐2, macrocytosis and multiple upper aerodigestive tract cancers and the risk for gastric cancer in alcoholic Japanese men

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] > or = 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. 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. 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 > or =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 (OR(s) = 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 > or =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 (OR(s) = 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). 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.

Risk of Squamous Cell Carcinoma of the Upper Aerodigestive Tract in Cancer-Free Alcoholic Japanese Men: An Endoscopic Follow-up Study

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.

Melanosis and squamous cell neoplasms of the upper aerodigestive tract in Japanese alcoholic men

Melanosis is frequently observed in the upper aerodigestive tract of Japanese alcoholic men, and the prevalences of squamous cell dysplasia and SCC in the upper aerodigestive tract of Japanese alcoholic men are high. This study evaluated associations between melanosis and both neoplasms of the upper aerodigestive tract and factors contributing to the development of melanosis in Japanese alcoholic men. Endoscopic screening of 643 Japanese alcoholic men (aged 50-79 years) was combined with oropharyngolaryngeal inspection and esophageal iodine staining, and ALDH2 genotyping was carried out in 425 of them. Melanosis was frequently (20.8%) observed in the upper aerodigestive tract. The palate was the most common site of melanosis (11.2%), followed by the pharynx (9.5%), and by the esophagus (7.0%). The incidence of melanosis was higher in those with esophageal dysplasia (31/126, 24.6%), esophageal SCC (19/42, 45.2%), and oropharyngolaryngeal SCC (8/14, 54.1%) than in cancer- and dysplasia-free controls (69/437, 15.8%). The presence of melanosis was associated with a higher risk of esophageal dysplasia, esophageal SCC, and oropharyngolaryngeal SCC (OR 1.69, 4.03, and 6.61, respectively). Multivariate analysis showed that older age, heavier smoking, and heterozygosity for inactive ALDH2 were positively associated with the presence of melanosis. The presence of melanosis indicates a high risk for neoplasms in the upper aerodigestive tract of Japanese alcoholic men. Melanosis and neoplasms have the same causes, including older age, heavy smoking, and high acetaldehyde exposure.

P53 protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma

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.

Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men.

Early esophageal squamous cell carcinoma detected by esophageal iodine staining can be easily treated by endoscopic mucosectomy, and identifying its predictors is important in better selecting candidates to screen for this high-mortality cancer. The common etiologies of elevated mean corpuscular volume (MCV) and esophageal cancer, including folate deficiency, smoking, drinking and high acetaldehyde exposure, suggest testing MCV as such a predictor. Japanese alcoholic men with (n = 65) and without (n = 206) esophageal squamous cell carcinomas, excluding those with liver cirrhosis, were assessed for MCV within 7 days of their last drink, alone or in combination with findings from either the alcohol flushing questionnaire or genotyping to identify inactive aldehyde dehydrogenase-2 (ALDH2*1/2*2) and the less-active form of alcohol dehydrogenase-2 (ADH2*1/2*1), which pose risks for esophageal squamous cell carcinoma. MCV was higher in cancer patients than in the control group. MCV was higher in both groups in those who were heavier smokers, had lower body mass index (BMI), experienced alcohol flushing, and had ALDH2*1/2*2. After adjusting for age, drinking and smoking habits, BMI and ALDH2/ADH2 genotypes, macrocytosis of MCV > or =106 fl was associated with increased risk for esophageal cancer (OR = 2.75). Men with both MCV > or =106 fl and alcohol flushing had an even higher cancer risk (OR = 5.51). The combinations of MCV > or =106 fl with ALDH2*1/2*2 or ADH2*1/2*1 alone, and both ALDH2*1/2*2 and ADH2*1/2*1 (ORs = 11.44, 21.22 and 319.7, respectively) showed consistently higher risk than the corresponding group with MCV <106 fl (ORs = 7.24, 4.71 and 27.01, respectively). In conclusion, MCV measurement, alone or in combination with the markers of alcohol sensitivity, provides a new means of predicting risk for esophageal squamous cell carcinoma in Japanese alcoholic men.

Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics.

Alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) gene polymorphisms play roles in ethanol metabolism, drinking behavior and esophageal carcinogenesis in Japanese; however, the combined influence of ADH2 and ALDH2 genotypes on other aerodigestive tract cancers have not been investigated. ADH2/ALDH2 genotyping was performed on lymphocyte DNA samples from Japanese alcoholic men (526 cancer-free; 159 with solitary or multiple aerodigestive tract cancers, including 33 oropharyngolaryngeal, 112 esophageal, 38 stomach and 22 multiple primary cancers in two or three organs). After adjustment for age, drinking and smoking habits, and ADH2/ALDH2 genotypes, the presence of either ADH2*1/2*1 or ALDH2*1/2*2 significantly increased the risk for oropharyngolaryngeal cancer [odds ratios (ORs), 6.68 with ADH2*1/2*1 and 18.52 with ALDH2*1/2*2] and esophageal cancer (ORs, 2.64 and 13.50, respectively). For patients with both ADH2*1/2*1 and ALDH2*1/2*2, the risks for oropharyngolaryngeal and esophageal cancers were enhanced in a multiplicative fashion (OR = 121.77 and 40.40, respectively). A positive association with ALDH2*1/2*2 alone was observed for stomach cancer patients who also had oropharyngolaryngeal and/or esophageal cancer (OR = 110.58), but it was not observed for those with stomach cancer alone. Furthermore, in the presence of ALDH2*1/2*2, the risks for multiple intra-esophageal cancers (OR = 3.43) and for esophageal cancer with oropharyngolaryngeal and/or stomach cancer (OR = 3.95) were higher than the risks for solitary intra-esophageal cancer and for esophageal cancer alone, but these tendencies were not observed for ADH2*1/2*1 genotype. Alcoholics' population attributable risks due to ADH2/ALDH2 polymorphisms were estimated to be 82.0% for oropharyngolaryngeal cancer and 63.9% for esophageal cancer.

Alcohol and Aldehyde Dehydrogenase Gene Polymorphisms Influence Susceptibility to Esophageal Cancer in Japanese Alcoholics

Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.

Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics.

Aldehyde dehydrogenase-2 (ALDH2) eliminates most of the acetaldehyde produced during alcohol metabolism. In some drinkers, a mutant ALDH2 allele contributes to diminished activity of the enzyme, dramatically increasing the risk for esophageal cancer. This study was designed to evaluate the ALDH2 gene polymorphism as a predictor of the development of cancers prevalent in Japanese alcoholics. We performed ALDH2 genotyping on lymphocyte DNA samples from Japanese alcoholic men (487 cancer-free; 237 with cancer, including 34 oropharyngolaryngeal, 87 esophageal, 58 stomach, 46 colon, 18 liver, 7 lung, 9 other sites, and 19 multiple primary cancers in two or three organs). The frequencies of the mutant ALDH2*2 allele were significantly higher in alcoholics with oropharyngolaryngeal (52.9%), esophageal (52.9%), stomach (22.4%), colon (21.7%) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (78.6%), than in cancer-free alcoholics (9.0%). After adjustment for age, daily alcohol consumption and amount of cigarette smoking, significantly increased risks (odds ratios) in the presence of the ALDH2 *2 allele were found for oropharyngolaryngeal (11.14), esophageal (12.50), stomach (3.49), colon (3.35), lung (8.20) and esophageal cancer concomitant with oropharyngolaryngeal and/or stomach cancer (54.20) but not for liver or other cancers. These results suggest a general role of acetaldehyde, a recognized animal carcinogen, in the development of human cancers.