〔日農 医 誌 40巻4号 917～929頁 1991.11〕

Original:

Alcoholic Tolerance, Drinking Behavior, and - related Health Disorders among the Japanese

Tsuyoshi IMURA*, Akiyoshi BANDOH*, Norimi NISHIMURA*, Mikio ASAI*, Akiyoshi KAKUTANI*, Toshihiro ISHII*, Shigeki ISHIHARA*, Kazuhiro KAWANO* and Shigehito HAYASHI*

In Japan there are many people who are intolerant to alcohol. Known as flushers, they do not

genetically have low Km dehydrogenase (AlDH2). Flushers are judged easily and accu-

rately by the alcohol patch test. An patch test carried out on agricultural and fishing popula-

tions in Japan showed that approx. 40% were deficient in AlDH2. A questionnaire survey of the

drinking behavior of many people showed significant differences between the normal AlDH2 and

AlDH2-deficient groups. The normal group drinks positively and actively, while the deficient group

drinks negatively and passively. As a result, there were significant differences in subjective and

objective symptoms that result from drinking between the two groups: More frequent ,

abnormal physical conditions and higher KAST scores were seen in the normal group, and health

examination showed higher values in liver function tests, including ƒÁ-GTP, and higher levels of blood

pressure, HDL-cholesterol (HDL-C), etc., in the normal AlDH2group.

It may be very useful for prevention of alcohol-related health disorders to help Mongoloid peoples,

such as the Japanese, recognize whether their AlDH2 is normal or deficient, which is as determined by

the ethanol patch test.

(1) AlDH2deficiency (2) Ethanol patch test (3) Epidemiology of drinking (4) KAST (Kurihama Screening Test) (5) Health disorders by alcohol intake

presence or absence of alcoholic tolerance, deter- Introduction mined by this test, is greatly related to Japanese In the Mongoloid group of mankind, which drinking behavior, and in turn closely related to the includes the Japanese, there are many people who results of health examinations. exhibit facial flushing upon ingestion of even small Subjects and Methods amounts of alcohol and who do not have alcoholic tolerance. The so called Oriental flushing is consid- The subjects consisted mainly of agricultural ered due to defficiency in low Km acetaldehyde and fishing people undergoing our physical exami- dehydrogenase (AlDH2) as reported by Mizoi1) and nation, and part of the staff of the head offices of Harada et al2). It is not easy to determine the agricultural cooperatives and our hospital. Drinking presence or absence of AlDH2 in mass groups. behavior was investigated by a questionnaire includ- However, the ethanol patch test developed by Higu- ing such inquires as frequency of drinking (grades 4 chi et al3,4,5) made the determination possible for -7) , alcohol intake (grades 4-7), drinking behavior, epidemiological research. We report here that the disorders due to drinking and manner of drinking.

* Tokushima-Ken-Koseiren Oe-Kyodoh-Hospital, 252 Kamojima Kamojima-cho Oe-gun Tokushima-prefecture, 776, Japan 918

The Kurihama alcoholism screening test (KAST) 2. Drinking behavior in patch test-positive and- was also performed. The details of the question- negative groups naire differed somewhat with the individual subject, (1) Number of drinkers in blood relatives purpose, etc., at the time, and were reported previ- AlDH2 deficiency is believed to be an inherited ously. condition. The results of the questionnaire on blood Table 1 shows the procedure for the ethanol relatives of both groups are shown in Table 3. There patch test. In principle, it followed the method of Higuchi et al3)., except for the use of a finn chamber Table 1. Procedure for the ethanol patch test for the plaster. A finn chamber appears to be more 1) Materials suitable for mass screening because it is empirically Finn chamber, filter paper for plaster (8 mm in nonspecifically less irritative and samples were liq- diameter), 70% ethanol, control liquid: distilled uid ethanol. water. Hematochemistry in health examination was 2) Soak a piece of test filter paper in ethanol or done with autoanalyzers. distilled water. Wipe the plaster paper with clean gauze, etc., Results so that the paper has the proper amount of moisture. 1. Ethanol patch test-positive rate 3) Apply the plaster paper with the finn chamber Table 2 shows the positive rate in the test, to the inner surface of the upper arm (for 7 performed on inhabitants in 7 areas of Japan, fol- min). lowing the procedure given in Table 1, which have 4) Make a judgement 15 min after the plaster is been reported previously7) by our research group. removed. As seen in earlier reports, approx. 40% of the sub- 5) Judgement: Judge erythema on the patched jects were found positive for the ethanol patch test area to be (+). and regarded as deficient in AlDH2 and intolerant to alcohol. Note: Slightly modified method of Higuchi et al.2)

Table 2. Positive rate in the ethanol patch test (1987-1988)

(There was no difference in positive rate between the sexes.)

Table 3. Degree of drinking among blood relatives -Difference between the ethanol patch test (+) and (-) groups-

(*P<0.005) 919 were more drinkers in blood relatives of the (-) Table 6 shows the ages when the subjects who group than the (+) group. underwent health examination began drinking. (2) Frequency of drinking Although minors are prohibited from drinking alco- Table 4 shows the frequency of drinking. In the hol, 12.1% in the (-) group, who have alcoholic (-) group, 84% of the subjects drink once or more tolerance, began drinking in their teens, compared a week and 16% do not drink at all while in the (+) with 3.8% in the (+) group. group, approx. 45% have no habit of drinking. Table 7 shows the degree of drinking of the (3) Alcohol intake staff members of agricultural cooperatives when Naturally, there was a significant difference in they were in college. Apparently, the (-) group alcohol intake between the groups; 46% of the drank more often and the (+) group showed a subjects in the (-) group drink 60 ml/day or more negative drinking behavior. alcohol, while 51% in the (+) group drink less than (6) Places of drinking, etc. 30 ml/day (Table 5). The places, frequency of drinking, expenditure (4) Age at the start of drinking and degree of on drinks, etc., are presented in Table 8. The (-) drinking in adulthood group drinks frequently both at home and outdide.

Table 4. Frequency of drinking of the patch test (+) and (-) groups

Table 5. Alcohol intake of the patch test (+) and (-) groups

Table 6. Age at the start of drinking 920

The (+) group drinks more often outside than at compared with the results of the abcohol patch test. home, which suggests that they drink unavoidably The differences were significant; the (-) group as a social duty. Naturally, in the (-) group the (tolerant to alcohol) tended more strongly toward expenditure on drinks was significantly higher . alcohol dependency than the (+) group. (7) Psychological behavior, etc. 4. Differences in health conditions between the Table 9 summarizes the relationship between patch test-positive and-negative groups drinking and psychological behavior, such as the (1) Subjective symptoms necessity of drinking, mental attitude toward drink- is the most common subjective symp- ing, and feeling during drinking . The (-) group tom of disorders due to drinking. The (-) group positively supported the necessity of drinking while suffered from the aftereffect significantly more the (+) group negatively supported it . The reasons often (Table 11). Among the subjects aware of for drinking showed a similar trend . The contrast physically poor conditions at that time, there were between positiveness and negativeness was clear more subjects who had alcohol-associated physical also in the mental attitude toward drinking . Com- symptoms in the (-) group. mission of errors to due drinking was also more (2) Health examination frequent in the (-) group. As described above, the differences in drinking 3. and KAST score (Table 10) behavior due to the presence or absence of alcoholic The scores in KAST, which was developed with tolerance, wchch is ascribed to an inherited disposi- the aim of screening for , were tion, were expressed as a difference in subjective

Table 7. Drinking in adulthood-Difference between the patch test (+) and (-) groups-

(*P<0.005)

Table 8. Differences in the range of drinking behavior , etc., between the patch test (+) and (-) groups [Place of drinking]

[Frequency of drinking outside the home]

P<0.05 921

symptoms under ill physical conditions, and may be of drinking, 40IU/l or more were defined as abnor- expressed as a difference in indexes of various mal, and the percentage of abnormal subjects is health examinations. shown in Table 13. It was high in the (-) group;

Table 12 shows the results of health examina- one-fourth of the group was abnormal. Alcohol tions. ƒÁ-GTP, HDL-C, and blood pressure levels intake was graded into 4 grades according to the were significantly higher in the (-) group than the amount of ethanol per week, and the correlation

(+) group, indicating the influence of drinking. between alcohol intake and ƒÁ-GTP was examined

(3) Liver functions, such as ƒÁ-GTP (Fig. 1). ƒÁ-GTP levels rose in proportion to alcohol

For ƒÁ-GTP, known as the most sensitive index intake in both the (+) and (-) groups. The same

Table 9. Differences in psychological behavior during drinking between the patch test (+) and (-) groups (1) Reasons for drinking (Three options were chosen out of 10 possibilities. Onlyitems with a significant difference are shown.) (No. of subjects)

(2) Mental attitude toward drinking (Three options were chosen out of 10 possibilities. Only items with a significant difference are shown.) (No. of subjects)

(3) Necessity of drinking

(4) Commission of errors

Table 10. Differences in KAST scores between the patch test (+) and (-) groups (No. of subjects)

P<0.001 922

Table 11. Defferences in development of subjective symptoms between the patch test (+) and (-) groups [Experience of hangovers]

P<0.05

[Relationship between drinking and physical condition abnormality]

P<0.05

Table 12. Relationship between the ethanol patch test and various average values in health examination

*P<0 .05

subjects examined for ƒÁ-GTP in the (+) group Table 13. Difference in abnormal ƒÁ-GTP rates between the two groups showed normal GOT levels (Fig. 2). GPT showed similar behavior. Since alcohol intake might be less than what was self-reported in the (+) group, these results may suggest greater intake of alcohol than in the (-) group in the same grade.

(4) Mean corpuscular volume (MCV), blood pres-

sure, and high density lipo-protein cholesterol

(HDL-C)

The same analysis was done on the MCV, blood pressure, and HDL-C in the same subjects (Fig 3, 4, P<0.05 (Normal:ƒÁ-GTP_39)

5). The MCV increased with increases in alcohol 923

Fig. 1. Relationship between alcohol intake and γ-GTP in the two ethanol patch test Fig. 2. Relationship between alcohol intake and groups. GOT in the two ethanol patch test groups.

intake. Blood pressure showed a similar trend, and it is interesting that the blood pressure of light drinkers in the (+) group was low. HDL-C of the (-) group increased as the alcohol intake increased, while that of the (+) group showed different behav- ior, perhaps because the number of (+) subjects was insufficient and further investigation is needed.

Discussion

Ingested ethyl alcohol is absorbed partly in the stomach and mainly in the intestine, and is distribut- ed all over the body. The majority is degraded in the liver. Oxygenase enzyme systems in the liver include the (ADH) pathway, the microsomal ethanol-oxidizing system (MEOS), and the catalase system. In normal healthy people, the alcohol dehydrogenase pathway is responsible for 80% of the degradation of alcohol. The primary degradation product of alcohol is acetaldehyde Fig. 3. Relationship between MCV and alcohol (Ach) in both the ADH pathway and MEOS. Ach is intake in the two ethanol patch test degraded by mitcondrial AlDH in the liver. Of the 2 groups. types of AlDH, only AlDH2 with low Km is involved 924

Fig. 4. Relationship between alcohol intake and blood pressure in the two ethanol patch test groups. (Same subjects as in Fig. 1.)

belong, has people intolerant to alcohol. Alcohol intolerance is scarsely found in the Caucasian and Negroid races. They have facial flushing after in- gestion of even small amounts of alcohol and are called flushers. Mizoi demonstrated that flushing is caused by the retention in the body of Ach, a degra- dation product of alcohol1). Harada et al. reported that the flushers do not genetically possess low Km AlDH22). Recent advances in DNA analysis of low Km AlDH (AlDH-I), designated as AlDH2, have made it possible to prove that in genotypes, a homozygote, AlH-12/AlDH2 has the potential to degrade Ach8). This method of detecting AlDH2 deficiency is not suitable for mass screening, since hair roots are used as samples and high technology and much labor are needed. Higuchi et al. found that an ethanol skin patch test was useful, and made it available for mass screening. The reliability of the Fig. 5. Relationship between HDL-C and alcohol test is reportedly above 95%5). intake in the two ethanol patch test We modified the Higuchi et al. method by use groups. of a finn chamber as the plaster, because it is easy in the degradation of Ach in the body. to handle for mass screening, and there is empiri- The Mongoloid race, to with the Japanese cally little cutaneous erythema with water used as 925

the control liquid, compared with the plaster (Torii and it was shown that the presence or absence of

Co.) initially used by Higuchi. alcoholic tolerance influenced health conditions.

The mechanism of developing erythema in the Table 2 gives the positive rates, broken down

ethanol patch test is the same as that of flushing by by sex. Harada et al. initially pointed out that

drinking. Flushers do not have AlDH2 on the skin. approx. 40% of Japanese are deficient in low Km

They cannot cope with Ach degraded from alcohol. AlDH2, and the percentage varies somewhat from

The irritation from Ach probably causes erythema area to area17). Our study also showed a variation,

on the patched area. from 30% to 50%. It is considered that the average

As described above, the negative group in the is 40%; 50% in the highest area and 30% in the

ethanol patch test can be regarded as non-flushers, lowest area. Considering DNA analysis showing the AlDH2 normal people, the positive group, can be existence of AlDH2 carriers of the normal genotype

regarded as flushers, people deficient in AlDH2. with 58.6% homozygosity, it can be said that AlDH

Japanese flushers are an interesting subject of on the skin is this type and the presence or absence

epidemiological study on drrinking, and many of the AlDH2 is responsible for the positive or

reports have recently been published4•`15). However, negateve response to the patch test.

most of them concern the differences in drinking This inherited disposition may be reflected in

behavior between flushers and non-flushers, who the questonnaire. The drinking status in blood rela-

were classified by response to drinking, itself. There tives, given in Table 3, suggests that the presence or has been only one published article on the basis of absence of alcoholic tolerance is due to genetic the presence or absence of AlDH2 or the ethanol predisposition.

patch test, by Shigemori16). The frequency of drinking is given in Table 4;

In our study, an ethanol patch test was conduct- alcohol intake, a basic item in drinking behavior, in

ed on many healthy adults on a nationwide scale, Table 5; the age at the start of drinking, in Table 6;

and the differences in drinking behavior between degree of drinking in adulthood, in Table 7; drink-

the positive and negative groups were investigated. ing behavior including social problems, in Table 8; The properties of Japanese drinking behavior were psychological condition related to drinking, in clarified from the aspect of inherited disposition, Table 9; and the results of the Kurihama alcoholism

Table 14. Summary of differences in drinking behavior between the patch test (+) and (-) groups 926

screening test, in Table 10. Table 14 summarizes the Table 15. Results of multiple regression analysis (121 male subjects) results of Tables 4-10. Because of alcoholic intoler- ance, the frequency of drinking and alcohol intake (1) ƒÁ-GTP was less in the (-)group (AlDH2 deficient), of subjects who are negative and passive to drinking socially. Such differences can be seen in their views of drinking habits and KAST scores, and agree with the fact that 95% of alcoholics have normal AlDH2.

The differences in drinking behavior between the two groups were also significantly reflected in their physical conditions. Subjective symptoms and indexes of various health examinations were compared between the two groups in Table. 11 and

12. The authors previously reported that many of these indexes increase the risk factor for adult diseases7,18,19). Similar results were seen by compari- (2) KAST son of the (+) and (-) groups: In the (-) group, with the exception of the favorable increase of

HDL-C, the indexes, including liver function tests such as ƒÁ-GTP, blood pressure, MCV, UA, and neutral fat, were significantly higher or somewhat higher. These findings are undesirable from the standpoint of health control and prevention of adult diseases. There have been a large number of reports26•`36) on liver disorder, high blood pressure, (3) Maximum blood pressure and changes in lipid metabolism caused by alcohol.

The present research findings suggest clearly that the drinking behavior of healthy individuals toler- ant to alcohol increases the risk factors for adult diseases, in comparison with individuals intolerant to alcohol.

It is necessary to conduct an alcohol patch test and objectively check alcoholic tolerance or intoler- ance in general mass health examinations. Table 15 shows the results of multiple regression analysis on (4) Minimum blood pressure the importance of the patch test among indexes of health examination. Contrary to a positive correla- tion between ƒÁ-GTP or blood pressure and alcohol intake and between KAST score and alcohol intake or frequency of smoking, there was no definitely positive correlation between the patch test and other indexes, although a trend toward a negative correlation was seen. In conclusion, the ethanol patch test may not be very important for an overall grasp of the health condition of mass groups in a general health examination. This conflicts with the 927

previous findings7) obtained by variance analysis of differences in these parameters between the two the relationship between drinking behavior and in- groups, and it was found that drinking patterns in dexes of health examination, where the weight of Japanese are considerably characterized by individ- the patch test was approx. one-fourth that of ƒÁ- uals deficient in AlDH2, comprising 40% of the GTP. population. The presence or absence of a alcoholic toler- References ance is a basic inherited disposition similar to differ- 1) Mizoi Y., Iziri I., Tatsuno T., et al: Relationship between ences between the sexes. This disposition is expres- facial flushing and blood acetaldehyde levels after alco- sed in drinking behavior, and the drinking behavior hol intake. Pharmacol. Biochem. and Behay.,16 303 is expressed in the extent of health. It has, therefore, -311 , 1979

a more profound importance on a wider scale than 2) Harada S., Misawa S., Agarwal D. P. and Goedde H. W.: Liver alcohol dehydrogenase and aldehyd dehydrogenase individual drinking behavior and health indexes. in the Japanese-Isozyme variation and its possible role in From this standpoint, the significance for determin- . Am. J. Hum. Genet., 32: 8-15, 1980 ing the presence or absence of alcohol tolerance 3) Higuchi S., Muramatsu T., Sasao M., Murayama K. and

(normal or deficient AlDH2) by an ethanol patch Kohno K.: Ethanol Patch Test for Low Km aldehyd test is investigated and summarized as follows: dehydrogenase defficiency. Lancet, 8333: 629, 1987 4) Higuchi S., Muramatsu T., Saito M., Shigemori K. et al : (1) Flushers and non-flushers (as they are gener- Elhanol Patch Test (1)-Screening method for low Km ally called) are recognized by responses to drinking A1DH defficiency. Jpn J. Alcohol and Drug Dependence, alcohol. However, the patch test makes the judge- 22 (4 Supp): 218-219, 1987 ment easily without drinking and confirms objec- 5) Muramatsu T., et al: Ethanol Patch Test (2)-Possible tively. Moreover, it's reliability is high. Mechanism-. Jpn. J. Alcohol and Drug Dependence, 22 (4): 220-221, 1987 (2) To give the patch test to youths and educate 6) Group of Studies of Social Pathology in Center of Leisure on alcoholic tolerance and intolerance are useful for Deveropment: Studies of alcohol intake in Japanese prevention of accidents due to alcohol when youths modern society. Center of Leisure Deveropment, Tokyo, begin drinking. 1979

(3) The presence of alcoholic intolerance in ap- 7) Bandoh A.: Studies of relationship between alcohol intake and health in agricultural and fishing populations prox. 40% of Mongoloid populations, such as the in Japan. J. J. Rural Med., 39(3): 182-192,, 1990 Japanese, is objectively confirmed by the test. The ibid.: 39(6): 1110-1122, 1991 test will be helpful to let society widely recognize ibid.: Report (1). Jap. Assoc. of Agric. Med. and Rural this fact and the right of people who cannot drink Health, Tokyo, 1988; Report (2), 1989; Report (3), 1990 alcohol not to drink at drinking parties. This may 8) Harada K., Fukunaga T. and Mizoi Y.: Investgation on the genotypes of alcohol and help Japanese to improve manners of drinking at and their metabolisms. Jpn. J. Alcohol and Drug Deenden- drinking parties. dence, 24(4): 236, 1989 (4) To make the general public widely under- 9) Mori M., Fukazawa H., Moriyama T. Ogata M. et al: stand such problems of drinking and health is useful The epidemiological study on flushing reaction in Hoku- kaido (1)-Difference of physical reaction in drinking to prevent the non-flusher's risk of health disorders between Flusher and Non-flusher and genetics of flushing and adult diseases from increasing due to drinking. reaction. Jpn. J. Alcohol and Drug Dependence, 21(2):

Conclusion 121-127, 1986 10) Mori M., Fukazawa H., Maruyama T. Ogata M. et al: By applying the ethanol patch test, the subjects The epidemiological study on flushing reaction in Hoku- who underwent general health examination were kaido (2)-Frequency difference in drinking, amount of drinking, and Problem drinking. Jpn. J. Alkohol and classified into two groups; a (+) group (intolerant Drug Dependence, 22(3): 163-175, 1987 to alcohol, or flusher), and a (-) group (tolerant to 11) Kubochi H, Suwaki H. and Ohara H.: The relationship of alcohol, or non-flusher). When drinking behavior, the intensity of alcohol-induced flushing to drinking KAST scores, and indexes of health examination of patterns in Japanese students. Jpn. J. Alcohol and Dyrug the groups were compared, there were significant Dependence, 22(4): 362-365, 1987 928

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日本人の飲酒耐性 と飲酒行動 ならびに 関連する健康障害について

居 村 剛*,坂 東玲 芳*,西 村典三*,浅 井幹夫*, 角 谷昭佳*,石 井敏博*,石 原 茂樹*,河 野和弘*, 林 重仁*

日本 人 に は 飲 酒 不 耐 性 者 と し てflusherが 存 在 し,こ の 人 達 は先 天 的 にLow Km Acetaldehyde Dehydrogenase(AlDH2)を 有 し な い 。 こ のflusherは,alcohol patchtestに よ り,簡 単 か つ 確 実 に 判 定 で き,日 本 人 農 漁 村 住 民 を対 象 と し て 検 討 し た 結 果,そ の 欠 損 者 は 約40%存 在 し た 。 多 数 の 対 象 者 に 対 す る ア ン ケ ー トに よ りそ の 飲 酒 行 動 を調 査 す る と,AlDH2正 常 保 持 群,欠 損 の 両 群 間 に は,そ の 飲 酒 行 動 に著 明 な 差 が み られ た 。 す な わ ち,正 常 者 群 は積 極 か つ 能 動 的 に 飲 酒 す る が,欠 損 群 の 飲 酒 は 消 極 か つ 受 動 的 で あ る。 この 結 果,両 群 間 に は 飲 酒 に よ る 自他 覚 的 所 見 に 有 意 差 が み られ,正 常 群 に は 二 日酔 や 体 調 異 常 が 多 く,KASTscoreも 高 い 。 ま た,健 診 結 果 で も,γ-GTP等 肝 機 能 等 の 値 や 血 圧,HDL-choles- terol等 にAlDH2正 常 群 が 高 い こ とが 認 め られ る 。 日本 人 な ど モ ン ゴ ロイ ド属人 種 に 属 す る 人 達 に,Ethanol Patch Testに よ っ て知 ら れ るAlDH2 正 常 か 欠 損 か を 周 知 させ る こ と は,そ の 人 達 の飲 酒 に よ る健 康 障 害 の 予 防 上,非 常 に 有 用 で あ ろ う と考 え ら れ る。

(1) AIDH2 Defficiency (2) Ethanol Patch Test (3) Epidemiology of Drinking (4) KAST「 久

里 浜 式 ア ル コ ー ル 症 ス ク リ ー ニ ン グ テ ス ト」(5)Health Disorders by Alcohol Intake

* 徳 島県厚生連麻植協同病院