Relationships Among Alcohol Consumption, Facial Flushing Response, and Metabolic Syndrome in Healthy Men

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1 Relationships Among Alcohol Consumption, Facial Flushing Response, and Metabolic Syndrome in Healthy Men JIN-GYU JUNG, MD, PHD, JONG-SUNG KIM, MD, PHD, SEOK-JOON YOON, MD, AND MI-KYEONG OH, MD, PHD PURPOSE: It is believed that alcohol has an intimate connection with metabolic syndrome (MS). However, the role of facial flushing after alcohol consumption in this relationship has not yet been well known. We explored the relationship between weekly alcohol consumption, risk of MS, and the flushing response. METHODS: The subjects were 1823 Korean adult males (305 nondrinkers, 540 flushers, 978 nonflushers) who had undergone a comprehensive medical check-up at Chungnam National University Hospital. We excluded the cases with the history of hypertension, diabetes, dyslipidemia, or who had taken medication in the previous month. After controlling for age, body mass index, exercise status, and smoking history, we used a logistic regression analysis to calculate the risk of MS with drinks per week in flushers and nonflushers as compared with nondrinkers. RESULTS: The risk of MS in flushers was significantly increased with alcohol consumption O4 drinks (4 16 drinks: odds ratio [OR] 1.93; O16 drinks: OR 2.20). However, in nonflushers, the risk of MS was increased in those consuming O16 drinks (OR 2.02). CONCLUSIONS: Our results suggest that the threshold for MS from alcohol consumption is lower in flushers than in nonflushers. Ann Epidemiol 2012;22: Ó 2012 Elsevier Inc. All rights reserved. KEY WORDS: Drinking, Flushing Response, Metabolic Syndrome. INTRODUCTION Metabolic syndrome is characterized by central obesity, dyslipidemia, hypertension, and insulin resistance (1). The most important clinical implications of metabolic syndrome are an increased risk of cardiovascular disorders and type II diabetes (2). Moderate alcohol consumption increases high-density lipoprotein (HDL) cholesterol and is thought to confer protection against cardiovascular disease and type II diabetes (3). However, excessive drinking increases triglycerides (TG), stimulates hypertension (4), and may increase the risk of type II diabetes (5). Therefore, alcohol and metabolic syndrome appear to be intimately connected. Acetaldehyde, a toxic metabolite of alcohol, is oxidized in the mitochondria by aldehyde dehydrogenase (ALDH2). A point mutation in the ALDH2 gene causes glutamine to be replaced by a lysine residue at the active site, thus inactivating ALDH2 enzyme activity and From the Department of Family Medicine (J.-G.J., J.-S.K., S.-J.Y.), Research Institute for Medical Sciences, Chungnam National University College of Medicine; and Department of Family Medicine (M.-K.O.), Gangneung Asan Hospital, Ulsan University College of Medicine, Korea. Address correspondence to: Jong-Sung Kim, MD, PhD, Department of Family Medicine, Chungnam National University Hospital, 640 Daesa- Dong, Jung-Gu, Daejeon , South Korea. Tel.: þ ; Fax: þ josephkim@cnu.ac.kr. Received December 28, Accepted April 15, Published online May 9, inhibiting alcohol metabolism in affected individuals (6). ALDH2 inactivity can cause unpleasant disulfiram-like reactions after drinking, such as facial flushing, tachycardia, headache, perspiration, and nausea. Facial flushing may therefore be a noninvasive method for evaluating an individual s ALDH2 activity and vulnerability to the harmful effects of alcohol. This mutation has been reported to occur in up to 50% of Asians (7). There are no data on the prevalence of alcohol consumption among people who have ALDH polymorphism associated with flushing syndrome in Korea. The fact that the rate of drinkers among Korean men ages 19 years or older is 86% (8) suggests that many flushers are drinkers despite the potential hazards from drinking. From a physician s point of view, this is an important issue in Korea. Individuals with a flushing response (flushers), and thus inactive ALDH2, are known to have a lower prevalence of alcohol abuse and dependence because of the unpleasant experience of drinking as compared with those without the flushing response (nonflushers) (9). However, this population is more susceptible to liver damage and esophageal cancer from excessive drinking (10). Our previous study has also reported that those with a flushing response were more susceptible to developing insulin resistance at lower alcohol intake levels than those without a flushing response and that moderate drinking does not appear to be protective against insulin resistance in flushers, unlike nonflushers Ó 2012 Elsevier Inc. All rights reserved /$ - see front matter 360 Park Avenue South, New York, NY doi: /j.annepidem

2 AEP Vol. 22, No. 7 July 2012: Jung et al. FACIAL FLUSHING, ALCOHOL CONSUMPTION, AND METABOLIC SYNDROME 481 Selected Abbreviations and Acronyms: ALDH Z aldehyde dehydrogenase BMI Z body mass index HDL Z high-density lipoprotein NIAAA Z National Institute on Alcohol Abuse and Alcoholism TG Z triglyceride (11). In addition, Itoh et al. (12) have demonstrated that those with a flushing response are more vulnerable to hypertension as compared with nonflushers from drinking. The aforementioned studies suggest that there is a relationship between alcohol and the diagnostic elements of metabolic syndrome, and a drinking-related flushing response may indicate an increased vulnerability to alcohol. These findings further support the importance of evaluating the association between alcohol and metabolic syndrome in Asian populations, given the high prevalence of impaired ALDH2 activity. This study examined the link between metabolic syndrome and alcohol consumption in a Korean population. METHODS Study Subjects The sample in this retrospective cross-sectional study consisted of 1823 apparently-healthy adult men who received comprehensive medical examinations for health promotion at Chungnam National University Hospital between February and October Subjects were characterized as nondrinking controls (nondrinkers; n Z 305), those who experienced facial flushing with alcohol consumption (flushers; n Z 540), and those who did not experience the flushing response (nonflushers; n Z 978). All subjects were native Koreans. The exclusion criteria eliminated subjects with the history of diabetes, hypertension, dyslipidemia, or who had taken medication in the previous month. This study was approved by the Institutional Review Board of Chungnam National University Hospital (Institutional Review Board Number: ). Data Collection Data were obtained from the research subjects medical records. We gathered sociodemographic characteristics for all subjects, such as age, smoking, and exercise status. Smoking status was subdivided into smoker, ex-smoker, and nonsmoker. Exercise status was divided into no exercise, those who exercised fewer than three times per week (irregular exercise group), and those who exercised three times or more per week for at least 30 minutes per session (regular exercise group). We defined 14 g of alcohol as a standard drink, according to the guidelines issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (13). Weekly drinking quantity was calculated on the basis of drinking frequency per week and drinks per drinking day. Laboratory data were obtained on aspartate aminotransferase (AST), alanine aminotransferase, gamma-glutamyl transferase, total cholesterol, TG, HDL cholesterol, and low-density lipoprotein cholesterol. To evaluate central obesity, we used waist circumference measured between the lowest rib and the iliac crest while the subject was in an standing position, as recommended by the World Health Organization (14). Body mass index (BMI) was calculated by the Quetelet Index (kg/m 2 ) (15). We used the International Diabetes Federation guidelines, which are preferable for those in Asian populations, who have small bodies compared with Western ones, because they reflect the difference among populations in waist circumference. According to the Guidelines, metabolic syndrome is defined as a waist circumference >90 cm in men (central obesity) plus any two of the following: HDL cholesterol!40 mg/dl (1.04 mmol/l); TG > 150 mg/dl (>1.7 mmol/l); systolic blood pressure >130 mmhg or diastolic blood pressure >85 mmhg; and fasting glucose > 100 mg/dl (5.5 mmol/l) (16). We used a questionnaire developed by Yokoyama et al. (17) to determine facial flushing that occurs in people with inactive ALDH2. The flushing questions were as follows: (1) Do you flush in the face immediately after drinking a glass of beer: always, sometimes, or never? (2) Did you flush in the face immediately after drinking a glass of beer: always, sometimes, or never? When all three categories of flushing (current always, former always, and sometimes) were collapsed into one, the questionnaire s sensitivity and specificity for identifying inactive ALDH2 were 96.1% and 79.0%. These results suggest the utility of this simple flushing questionnaire in daily practice. Statistical Analysis We compared general characteristics, anthropometric data, and laboratory results for nonflushers and flushers with those of nondrinkers. A c 2 -test was used for categorical variables, and a t-test was used to analyze continuous variables. Drinkers were divided into the following categories: 4 drinks or fewer, between 4 and 16 drinks, and more than 16 drinks. Although NIAAA sets O14 drinks per week for men as hazardous drinking, we used the aforementioned categories to find out the appropriate cut-points applicable to Korean men considering their low mean body weight compared with white men. In addition, these cut-points are easy to use in Korean clinical practice because one bottle of Soju, favorite popular type of alcohol in Korea, contains 4 standard drinks, when one considers 14 g of alcohol as a standard drink as suggested by the NIAAA (13). The percentage of patients with metabolic syndrome was compared with

3 482 Jung et al. AEP Vol. 22, No. 7 FACIAL FLUSHING, ALCOHOL CONSUMPTION, AND METABOLIC SYNDROME July 2012: nondrinkers by use of a c 2 -test. The relationship between alcohol consumption and metabolic syndrome based on the flushing response was assessed with a logistic regression analysis after adjusting for age, BMI, exercise status, and smoking status. SPSS version 13.0 (SPSS Inc., Chicago, IL) was used for all analyses, and the statistical level of significance was set below RESULTS Subject Characteristics The mean (G SD) age was 50.0 (G 11.7) years in nondrinkers, 48.4 (G 11.3) years in flushers, and 47.0 (G 10.6) years in nonflushers. There was no significant difference in age between flushers and nondrinkers, but the age of nonflushers was significantly lower (p!.001) than that of nondrinkers. BMI and waist circumference in flushers (p!.001) and nonflushers (p!.05) were significantly greater as compared with nondrinkers. The smoking status of nonflushers differed significantly (p!.05) from that of nondrinkers. There was no significant difference in exercise status between any of the groups. When the components of metabolic syndrome were compared, systolic blood pressure and fasting glucose did not show significant differences as compared with nondrinkers; however, flushers showed significantly (p!.01) lower DBP than nondrinkers. For HDL-cholesterol and TG, flushers (p!.01) and nonflushers (p!.001) showed significantly greater levels as compared with nondrinkers. No significant differences were observed for total cholesterol. However, low-density lipoprotein cholesterol of nonflushers was significantly (p!.05) lower than that of nondrinkers. AST and gamma-glutamyl transferase levels of flushers (p!.001, p!.001) and nonflushers (p!.01, p!.001) were significantly greater than nondrinkers. Alanine aminotransferase in nonflushers was significantly (p!.01) greater than that of nondrinkers. Mean (GSD) weekly alcohol intake was 7.6 (G10.7) drinks for flushers and 12.8 (G13.3) drinks for nonflushers. There was no difference in alcohol consumption of each drinker category of flushers and nonflushers except the category of TABLE 1. Characteristics of the subjects Mean G SD or n (%) Variables Nondrinkers (n Z 305) Flushing group (n Z 540) Nonflushing group (n Z 978) Age, years 50.0 G G G 10.6 z Body mass index, kg/m G G 2.9 z 24.9 G 3.1* Waist circumference, cm 84.8 G G 8.1 z 86.0 G 8.4* Smoking Nonsmoker 104 (34.0) 151 (27.6) 225 (22.8)* Ex-smoker 112 (36.8) 176 (32.1) 320 (32.4) Smoker 89 (29.2) 221 (40.2) 444 (44.9) Exercise None 144 (47.2) 238 (43.5) 353 (35.7) Irregular 49 (16.0) 151 (27.6) 258 (26.1) Regular 112 (36.8) 159 (28.9) 378 (38.2) Systolic blood pressure, mmhg G G G 13.3 Diastolic blood pressure, mmhg 72.1 G G 18.7 y 73.6 G 17.0 Total cholesterol, mg/dl G G G 39.1 HDL, mg/dl 45.2 G G 8.4 y 48.4 G 8.3 z LDL, mg/dl G G G 31.2* Triglyceride, mg/dl G G 89.7 y G 92.7 z Fasting blood sugar, mg/dl 93.4 G G G 24.3 AST, IU/L 57.1 G G z 71.4 G y ALT, IU/L 30.7 G G G 27.1 y GGT, mg/dl 28.0 G G 60.9 z 45.0 G 70.7 z Drinks/week G 10.7 z 12.8 G 13.3 z Alcohol consumption of drinker category (drinks/week) &4 1.6 G G 1.3 x 4!, & G G ! 28.2 G G 14.6 Metabolic syndrome 60 (19.7) 124 (23.0) 197 (20.1) ALT Z alanine amino- transferase; AST Z aspartate aminotransferase; GGT Z gamma glutamyl transferase; HDL Z high-density lipoprotein cholesterol; LDL Z low-density lipoprotein cholesterol. *p!.05. y p!.01. z p!.001 by t-test or c 2 test comparing with non-drinkers. x p!.001 by t-test comparing flushing group with nonflushing group.

4 AEP Vol. 22, No. 7 July 2012: Jung et al. FACIAL FLUSHING, ALCOHOL CONSUMPTION, AND METABOLIC SYNDROME drinks or less per week. The distribution of metabolic syndrome was not significantly different between groups, with 60 in nondrinkers (19.7%), 124 in flushers (23.0%), and 197 in nonflushers (20.1%; Table 1). Weekly Drinking Quantity and the Risk of Metabolic Syndrome on the Basis of the Flushing Response The percentage of subjects with metabolic syndrome in each group by weekly drinking amount was compared with nondrinkers. In nonflushers, the percentage of subjects with metabolic syndrome who consumed four drinks or fewer per week was 12.7%, which is significantly (p!.05) lower than that of nondrinkers. However, the percentage of subjects with metabolic syndrome who consumed more than 16 drinks was 29.8%, which is significantly (p!.01) greater than that of nondrinkers. In flushers, a weekly drinking quantity that decreased the risk of metabolic syndrome as compared with nondrinkers was not observed. The rate of metabolic syndrome in flushers, i.e., 35.2% for the 4 to 16 drinks category (p!.001) and 32.9% for more than 16 drinks (p!.01), was significantly greater than that of nondrinkers (Fig. 1). After adjusting for age, BMI, exercise status, and smoking status, we performed a logistic regression analysis by using weekly alcohol consumption as an independent variable and the diagnosis of metabolic syndrome as a dependent variable. In flushers, the risk of metabolic syndrome increased significantly among those drinking more than four drinks per week (4 16 drinks: odds ratio [OR] 1.93, 95% confidence interval [95% CI] 1.04w3.58; more than 16 drinks OR 2.20, 95% CI 1.02w4.74). However, in the nonflushers group, metabolic syndrome risk increased significantly only when exceeding 16 drinks per week (O16 drinks OR 2.02, 95% CI 1.15w3.55). We performed a logistic regression to determine which of the five components of metabolic syndrome were closely FIGURE 1. Metabolic syndrome according to weekly quantity of consumed drinks in nonflushers and flushers. *p!.05, y p!.01, z p!.001 via the c2 as compared with nondrinkers. related to the flushing response. After we adjusted for confounding factors, weekly alcohol consumption was set as an independent variable and each factor of metabolic syndrome was set as a dependent variable. The risk of central obesity was not related to alcohol consumption, but consumption of more than four drinks per week significantly increased the risk of impaired fasting glucose in flushers (OR 1.76, 95% CI 1.02w3.02) and nonflushers (OR 1.87, 95% CI 1.22w2.87) as compared with nondrinkers. The risk of low HDL-cholesterol decreased significantly in flushers when subjects exceeded four drinks per week. However, for nonflushers, the risk decreased even with a small consumption of 4 or fewer drinks. The risk of high blood pressure increased significantly for flushers (OR 1.72, 95% CI 1.07w2.77) and nonflushers (OR 1.56, 95% CI 1.07w2.84) when weekly alcohol consumption exceeded four drinks. The risk of hypertriglyceridemia increased significantly for subjects in group flushers who consumed more than 4 drinks per week (4 16 drinks OR 1.65, 95% CI 1.10w2.47; greater than 16 drinks OR 1.72, 95% CI 1.13w2.60), and the risk increased for nonflushers exceeding 16 drinks per week (OR 1.54, 95% CI 1.06w1.94; Table 2). DISCUSSION Our study shows that the intake threshold for harm from alcohol consumption is lower in flushers than in nonflushers. In flushers, more than four drinks per week (8 g/day) increased the risk of metabolic syndrome, whereas in nonflushers the risk was increased with consumption of more than 16 drinks weekly (32 g/day). Regarding the risk of metabolic syndrome, our finding of 16 drinks in nonflushers was similar to the results of a previous study (18) in which the authors examined the relationship between alcohol consumption and metabolic syndrome in American adults. They showed that metabolic syndrome risk increased with the consumption of two drinks per day (14 drinks per week). However, our study suggested that a much smaller number of drinks, even four drinks per week in flushers, was associated with metabolic syndrome. Given these results, we examined which components of metabolic syndrome were important regarding the differences between flushers and nonflushers. In our study, the risk of hypertriglyceridemia increased when alcohol consumption exceeded 16 drinks per week for nonflushers. This finding is similar to those of previous studies, i.e., that >14 drinks per week or >22 g per day is associated with increased triglyceride levels (19, 20). However, our results indicated that in flushers, the risk of hypertriglyceridemia is associated with a much lower level of alcohol consumption, or greater than four drinks per week. Specifically, unlike previous studies, our findings

5 484 Jung et al. AEP Vol. 22, No. 7 FACIAL FLUSHING, ALCOHOL CONSUMPTION, AND METABOLIC SYNDROME July 2012: TABLE 2. Logistic regression analysis on metabolic syndrome and its five components according to weekly drinking amount in flushers and nonflushers Drinks/week OR* (95% CI) Drinks/week flushing group (n Z 540) Nonflushing group (n Z 978) Metabolic syndrome y & (0.44w1.28) 0.59 (0.33w1.06) 4!, & (1.04w3.58) 1.06 (0.60w1.87) 16! 2.20 (1.02w4.74) 2.02 (1.15w3.55) Waist circumference > 90 cm & (0.59w1.71) 0.97 (0.55w1.71) 4!, & (0.81w3.04) 1.71 (0.94w3.10) 16! 1.01 (0.43w2.33) 0.94 (0.50w1.76) Fasting blood sugar >100 mg/dl & (0.67w1.58) 1.07 (0.71w1.65) 4!, & (1.02w3.02) 1.87 (1.22w2.87) 16! 2.31 (1.21w4.40) 2.63 (1.70w4.08) HDL! 40 mg/dl & (0.53w1.15) 0.41 (0.27w0.63) 4!, & (0.24w0.98) 0.34 (0.21w0.55) 16! 0.29 (0.16w0.55) 0.35 (0.21w0.58) SBP >130 mmhg or DBP > 85 mmhg & (0.77w1.55) 1.06 (0.75w1.50) 4!, & (1.07w2.77) 1.56 (1.07w2.84) 16! 2.19 (1.21w3.96) 1.58 (1.06w2.36) Triglyceride > 150 mg/dl & (0.91w1.94) 0.91 (0.61w1.35) 4!, & (1.10w2.47) 0.89 (0.52w1.50) 16! 1.72 (1.13w2.60) 1.54 (1.06w1.94) CI Z confidence interval; DBP Z diastolic blood pressure; HDL Z high-density lipoprotein cholesterol; OR Z odds ratio; SBP Z systolic blood pressure. *Adjusted for age, exercise, smoking state, and body mass index; Reference, nondrinkers (n Z 305). y Defined by the guideline of International Diabetes Federation. show that the incidence of hypertriglyceridemia is greater with a lower alcohol intake in flushers. With respect to the hypothesis that alcohol causes hypertriglyceridemia, inhibiting the activation of lipoprotein lipase has been described as a critical mechanism (21). Another possible mechanism is that increased acetaldehyde in the body of flushers damages the mitochondrial membranes, thus inhibiting the oxidation of fatty acids (22). Our study suggested that the risk of low HDL cholesterol decreased for all drinking categories, even with the consumption of four or fewer drinks in nonflushers. This finding is thought to be consistent with previous studies in which authors found that alcohol intake is strongly associated with HDL cholesterol levels (23, 24). Conversely, our study suggests that this positive effect on HDL cholesterol is uncertain with a small amount of drinking in flushers. In other words, positive effects of drinking on HDL were found with lower alcohol consumption in nonflushers as compared with flushers. There is no clear association between the biochemical mechanism of the flushing reaction and low HDL. However, a study that targeted women with severe flushing showed that the response of vessels after the administration of vasodilators was greater in women who flushed than in those who did not and that the levels of HDLcholesterol were significantly lower in the flushing women as compared with the control women (25). In addition, the result of a cross-sectional study (26) has suggested that ALDH2 deficiency is associated with low HDL cholesterol level in the Japanese sample (n Z 1736). On the other hand, a cross-sectional study (27) that targeted subjects (n Z 225) with type II diabetes mellitus suggested that HDL cholesterol level was significantly increased by heavy drinking in flushers. Therefore, the relationship between alcohol intake and HDL cholesterol in flushers requires clarification. However, because studies on the relationship of alcohol flushing with HDL cholesterol are limited, further investigations, including prospective studies are in need to confirm the relationship. Studies examining alcohol consumption and obesity have produced discordant results. Although in some studies investigators have found that alcohol intake is related to central obesity (28), our results are similar to other studies in which authors did not find this association (29, 30). The lack of consistent findings demonstrates the need for forward-looking studies. We found that regardless of the flushing response, the risk of impaired fasting glucose increased when weekly alcohol consumption exceeded four drinks. This result is consistent with studies in which authors found that high alcohol consumption was associated with an increased risk of diabetes combined with impaired fasting glucose (31, 32). However, our current results differ from our previous study (11), in which we showed that the amount of alcohol consumption necessary to increase insulin resistance was smaller in flushers than nonflushers. In our previous study we measured fasting glucose and serum insulin (11), whereas we measured fasting glucose only once in the current study. We found that the weekly alcohol consumption associated with increased blood pressure was more than four drinks in flushers and nonflushers. This result agrees with previous studies that light-to-moderate alcohol consumption increased the risk of hypertension in American men and drinking was also independently associated with incident hypertension in Chinese adults (33, 34). However, when we compared ORs for the same alcohol consumption levels, the likelihood of increased blood pressure was greater in flushers. The flushing response in those who do not effectively remove acetaldehyde is associated with peripheral vasodilation, which would decrease visceral blood flow. It seems reasonable to hypothesize that noradrenaline release

6 AEP Vol. 22, No. 7 July 2012: Jung et al. FACIAL FLUSHING, ALCOHOL CONSUMPTION, AND METABOLIC SYNDROME 485 from sympathetic nerves to compensate for this reduction is responsible for the increased blood pressure (35). In conclusion, TG and HDL are the two components of metabolic syndrome that appear to be most sensitive to differences in alcohol intake in flushers. Our results showing that alcohol had a less positive effect on HDL and a more negative effect on TG in flushers suggest that additional work should investigate the relationship between acetaldehyde and lipids. Although it has not been clear that the mechanism accounts for whether acetaldehyde has a negative influence on lipid levels in flushers, oxidative stress and/or acetaldehyde adducts induced by acetaldehyde may be suggested on the endoplasmic reticulum stress and mitochondrial dysfunction, which cause metabolic unbalance. Acetaldehyde may decrease fatty acid oxidation and increase fatty acid synthesis by mitochondrial dysfunction (36) and may cause oxidative stress on the endoplasmic reticulum which is an essential organelle for biosynthesis of lipids (37). In addition, the results (38) that oxidative stress is associated with low HDL cholesterol support our findings. Our study highlights the need for future studies exploring the flushing response and quantity of alcohol intake associated with health hazards in Asians. As a short-term, cross-sectional study of observed drinking behaviors, the limitations of this work highlight the need for longitudinal research to evaluate the relationship between drinking and metabolic syndrome in those exhibiting reduced ALDH2 activity. In addition, there was no difference between the two groups (4 16 and O16 drinks) in the flushing group. Therefore, it becomes difficult to say that a level of quantity and frequency is uniquely associated with metabolic syndrome. 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