—Ä^ TNO Nutrition and Food Research Biomedical and social aspects of alcohol use: a review of the literature

Dirk G. van der Heij & Gertjan Schaafsma (Editors) TNONutrition andFood Research, Zeist, Netherlands

Pudoc Wageningen 199 CIP-data Koninklijke Bibliotheek, Den Haag

Biomedical

Biomedical and social aspects of alcohol use: a review of the literature / Dirk G. van der Heij and Gertjan Schaafsma (eds.). - Wageningen : Pudoc [etc.]. - III. Met reg. ISBN 90-220-1051-I geb. NUGI 735 Trefw. alcoholgebruik.

BIBLIOTHEEK r^oBOUWUNIVERS: WAGENINGEN ISBN 90-220-1051-1 NUGI 735

© Centre for Agricultural Publishing and Documentation (Pudoc), Wageningen, Netherlands, 1991.

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Printed in the Netherlands. Preface

The useo f alcohol-containing beverages hasbee n connectedwit hbot h positive and negativesocia l and health consequences. From timeimmemorial , wine andbee r have belonged to the everyday menu in many countries and cultures. The use of distilled beverages isa comparativel y recent phenomenon. In many cultures, the appreciation for alcohol hasbee n high for centuries, and many artists and scientists still find support in alcoholicbeverage s as asourc e of inspiration. Therol eo f alcoholic beveragesi n gastronomy isundisputed . Besides, many medicinal properties have been ascribed to thesebeverages . However, positive asth e effects of alcohol consumption maybe , iti sundeniabl y true that somepeopl emisus ealcohol . Thisma y explain, at least in part, the ambivalence in the attitude towards alcohol usei n present-day society. On the onehand , this attitude ispositiv ebecaus eo f the sensory and aesthetic properties of alcoholicbeverage s and their highlyvalue d rolei n awid e rangeo f cultural expressions. On the other hand, society's attitude isnegativ e because of the risks of misuseinheren t in the useo f any product. Somegovernment s havetrie d to influence thebalanc ebetwee n positive and negative effects of alcohol use in the communityb yformulatin g alcohol control policies. These relate to price and excisemeasures , to restrictions imposed on advertising and availability, and to education and information. Thesepolicie s are largelybase d on research data obtained byinvestigatin g thereason s for and consequences of excessivealcoho l use. Byfa r the majority - probably even asmuc h as99 %- of scientific literaturepertain s to alcohol abuse and alcoholism. As early as 1980, theDutc h alcohol industry and alcohol tradejudge d it desirable tohav e available an overview of scientific literature on moderate alcohol use and its social andbiomedica l implications and assigned theTN O Toxicology and Nutrition Institute at Zeist to carry out thiswork . This literature survey, entitled 'Biomedical and social aspects ofth eus eo f alcoholicbeverages' ,wa swritte nb yM sI rW.G . Vrij- Standhardt and Ms Ir E.L. Rasmussen-Conrad. Itwa scomplete d in 1981 und updated in 1984. This state-of-the-art report prompted alcohol production and trade companies to embark on various activitiesi n thefield s ofpubli c education, training and education of staff in alcohol production and trade, starting an alcohol documentation centre and acurren t awareness newsletter 'Alcohol Selectief'. The report also provided the scientific basisfo r discussionswit hbot h the Dutch government andE C authorities on alcohol control measures. Finally, itresulte di n theidentificatio n of the topic 'alcohol and cardiovascular diseaseprotection ' asa n area for experimental researchwhic hha sprove d tob ever y fruitful. From thever ystar t in 1980, allthes eactivitie shav ebee n based at the TNO Toxicology and Nutrition Institute, under theguidanc eo f the SAR ('Stuurgroep Alcohol Research', SteeringGrou p for Alcohol Research). The SAR comprises representatives of theDutc h wine, spirits andbee r industry and trade. Its present composition is: Mr H. Bergsma, chairman; Mr R.J.B. Wallast Groenewoud, secretary; Mr Th.G.Chr. Hooij, DrsN.J . Gratama, DrsJ.J.M . Verhoek and Mr H.E. Jonker Roelants, members. The citical and constructive attitude of all SÂR participants towards the subject matter hasmad e the cooperation with SAR amos t fruitful one. In recent years, manyne w research data havebecom eavailable . That iswh ybot h the SAR and TNO felt it necessary to update the 1984literatur e survey. We feel pleasure and satisfaction inpresentin g thisbook , which isa n updated and thoroughly revised edition of the 1984 report.

We aremos t grateful to the authors, MsI r W.G. Vrij-Standhardt, MsDr s E. te Wierik and Dr J. Veenstra, whohav espen t agrea t deal of time and attention to writing the chapters. We alsomention with gratitude the contributions madeb yth e staff ofth eAlcoho l Documention Centre, MsM . van Ruyven and MsE . Vermeulen- Hermans. Many of the drawings and schemesi n thisboo k havebee n aptfully designed and lettered byM rM . van der Vaart. Weacknowledg ewit h appreciation the SAR for generously providing thefund s for thisproject . Wear eindebte d to the publisher, Pudoc, for pleasant cooperation in producing thisvaluabl ereview . The project hasbee n coordinated byD r G. Schaafsma. Finally, wewis h to thank Mr D.G. van der Heij and Dr G. Schaafsma for undertaking thepainstakin gwor k involvedi n editing this book.

It isou r hope that 'Biomedical and social aspects of alcohol use'wil lprovid eal l those interested in thevariou s aspects of alcohol consumption with the scientific facts underlying theimplication s of alcohol use. We alsohop e that abette r understanding of allaspect s of moderate alcohol usewil lhel p to formulate effective policies to prevent excessiveus eo f alcohol.

Zeist, June 1991 Professor Dr R.J .J . Hermus, Director TNO Toxicology and Nutrition Institute Contents

Abbreviations 1

Introduction 3 1. Moderate and excessive drinking, problem drinking and alcoholism/ Definitions IE. teWierik 5 2. Thebiokinetic s of alcohol/ W.G. Vrij-Standhardt 14 3. Alcoholmetabolis m/ W.G. Vrij-Standhardt 32 4. Alcohol and hormone metabolism /W. G. Vrij-Standhardt 47 5. Effects of alcohol on themetabolis m ofmacronutrient s /W. G. Vrij- Standhardt 62 6. Effects of alcohol onvitami n metabolism /E. teWierik and W.G. Vrij- Standhardt 72 7. Effects of alcohol onwate r and mineral balanceIE. teWierik and W.G. Vrij-Standhardt 83 8. Effects of alcohol on thelive rI W.G. Vrij-Standhardt 90 9. Effect of alcohol on thebrai n and thenervou s system/ W.G. Vrij- Standhardt 116 10.Effect s of alcohol on the cardiovascular system/ J. Veenstra 130 11.Effects of alcohol on various organs and tissuesIE. teWierik and W.G. Vrij-Standhardt 157 12.Alcoho l and cancer/ E. teWierik and W. G. Vrij-Standhardt 169 13.Alcoho l and pregnancy/ E. teWierik 180 14.Differences between alcoholicbeverage s/ W.G. Vrij-Standhardt 190 15.Factor s influencing behaviour in relation to alcohol/ E. teWierik 204 16.Alcoho l and traffic /E. teWierik 228 17.Prevention of alcohol abuse:model s of control/ E. teWierik 238 18.Measurest o control alcohol abuse/ E. teWierik 252

Subject index 263 Abbreviations

AA Alcoholics Anonymous HBV hepatitis Bviru s AAD alcohol amnestic disorder HDL high-density lipoprotein AC adenylate cyclase HLA human lymphocyte antigen ACTH adrenocorticotropic hormone, HPA hypothalamic-pituitary axis corticotropin IARC International Agency for Research on ADH alcohol dehydrogenase Cancer ALA 6-aminolaevulinicaci d IBS intermediate brain syndrome ALAT alanine aminotransferase IQ intelligence quotient AMP adenosine monophosphate LD50 median lethal dose AP alkaline phosphatase LDL low-density lipoprotein Apo apolipoprotein LH luteinizing hormone ASAT aspartate aminotransferase LHRH luteinizing hormone-releasing AST aspartate aminotransferase hormone ATPase adenosine triphosphatase MAO monoamine oxidase AUC area under the (blood alcohol) curve mAST mitochondrial aspartate AUDIT Alcohol Use Disorders Identification aminotransferase Test (of the WHO) MCV mean corpuscular volume AVP arginine vasopressin MEOS microsomal ethanol-oxidizing system BAC blood alcohol concentration MLPA minimum legal purchase age cAMP cyclic adenosine monophosphate NAD nicotinamide adenine dinucleotide CDAT carbohydrate-deficient transferrin NADH reduced form of NAD CHD coronary heart disease NADP nicotinamide adenine dinucleotide CNS central nervous system phosphate CoA coenzyme A NADPH reduced form of NADP CRF corticotropin-releasing factor PAI-1 plasminogen activator inhibitor 1 CT computerized tomography PGE1 prostaglandin El CVD cardiovascular disease PLP pyridoxal-5' -phosphat e DGLA dihomogammalinolenic acid PSU portal-systemic encephalopathy DSMIII Diagnostic and Statistical Manual of PTU propylthiouracil Mental Disorders PUFA polyunsaturated fatty acids DWI driving while intoxicated RBP retinol-binding protein EEG electro-encephalogram RR relative risk ERP event-related potential SCE sister chromatid exchange FAE ' foetal alcohol effects SES socio-economic status FAS foetal alcohol syndrome SHBG sexhormone-bindin g globulin FEV forced expiratory volume t-PA tissue pasminogen activator FSH follicle-stimulating hormone THBC tetrahydrobetacarboline GABA y-aminobutyric acid TIQ tetrahydroisoquinoline GGT y-glutamyltransferase TPP thiamin pyrophosphate GH growth hormone TRH thyrotropin-releasing hormone GHRH growth hormone-releasing hormone TSH thyroid-stimulating hormone GOT glutamic-oxaloacetic transaminase UK-PA urokinase-plasminogen activator (aspartate transaminase, ASAT) VLDL verylow-densit y lipoprotein GPT glutamic-pyruvic transaminase WHO World Health Organization (alanine aminotransferase, ALAT) WKS Wernicke-Korsakoff s syndrome GSH glutathione Introduction

Thisboo k primarily offers asurve yo f literaturerelatin g tobiomedica l and social aspects of the consumption of alcoholicbeverages . Theinformatio n contained in thisboo k isaime d at thosewh o are concernedwit h alcohol research, alcohol policies or theproductio n of alcoholicbeverages . Moreover, theboo k isintende d to bea usefu l sourceo finformatio n for health educationers and advisers, staff of alcohol and drugscentres , food scientists and nutritionists. Relevant recent literature hasbee n searched for in theAlcoho l Documentation Centre of theTN O Toxicology and Nutrition Institute at Zeist, Netherlands. This Centre has the disposal ofman yjournals , books and other publications dealingwit h the social andbiomedica l aspects of alcohol usean d abuse. ,

Chapter 1 presents thevariou s definitions of terms related to alcoholism, problem drinking and moderate and excessivealcoho l consumption. It isfollowe d by overviews of the biokinetics of alcohol (Chapter 2) and alcohol metabolism (Chapter 3). The subsequent eight chapters (Chapters 4-11) review theliteratur e on the biomedical consequences of alcohol consumption and the effects of ethanol on various systems and organs. Studiesint o the relationship between the consumption of alcoholicbeverage s and the development of cancer are discussed in Chapter 12. The consequences of the consumption of alcoholicbeverage s during pregnancy are treated in Chapter 13.Difference s between thethre e main categories of alcoholic beverages- beer, winean d spirits- arementione d in Chapter 14. Thelas tfou r chapters are devoted to the social aspects of the useo f alcohol. These chapters focus on factors that influence behaviour inrelatio n to alcohol consumption (Chapter 15), alcohol and traffic (Chapter 16),preventio n of alcohol abuse (Chapter 17) and measures to control abuse of alcoholicbeverages .

Sinceth e previous edition much progress hasbee n madei nman yfield s discussedi n thisbook . Some of thesewil lb ementione dbriefl y below. Various studies havelargel y revealed the effects of alcohol on thebrai n and the wayalcoho l affects neurotransmission. A recent discoveryi sth epresenc e of alcohol- metabolizing enzymes in the stomach which are claimed to metabolizea significant proportion of the alcohol ingested. The significance of thisfindin g isno t clearyet , but it could explain thefac t that somealcoho li s 'missing'whe n BACcurve s are calculated. Research into thehepatotoxicit y of alcohol has elucidated details on various mechanisms (with free-radical production being themos t recent one)whic h could explain alcoholic liverinjury . There isn o such thing asa competition from one mechanism oncewil lcom e out asthe mechanism . Instead, various mechanisms acti n concert to result in liver injury. Another field inwhic h much progress hasbee n madei n recent years ismolecula r biology and genetics. Identification of lociwhic h codefo r enzymes has revealedwid e genetically determined variation in enzymeactivity . This mayb ewh ysom epeopl e are morevulnerabl e to the adverse effects of alcohol abusetha n others. Besides hereditary factors, other factors that influence behaviour in relation to alcohol use havebee n studied extensively. Interaction studies havebee n carried out to study several factors in onemodel . A chapter on alcohol use in relation to traffic participation isne wt o this edition. Sinceman y traffic accidents arerelate d to alcohol use, many studiesint o the motives for drinkingprio r to drivinghav ebee n performed and prevention strategies have been developed. Various strategies havebee n designed to dissuadepeopl efro m using alcohol excessively. The useo f massmedi a for alcohol abusepreventio n programmes isa novel phenomenon.

Byreviewin g the vast body of literature on thebiomedica l and social aspects of alcohol useth e authors of thisboo k havetrie d to givea n outline of the present knowledge in this fascinating multidisciplinary field. CHAPTER 1 Moderate and excessive drinking, problem drinking and alcoholism. Definitions

E. te Wierik

Thewor d 'alcohol' stems from Arabic (al= the ;kuhl= 'spirit' or 'refined'). Originally it referred to afin e powder used to darken the area around the eyes,i .e . eyeblack, and isrelate d to theHebre w kahol,a substance outlining the eyes (5, 10). In Latin pharmacology theter m wasuse d toindicat efin e powdery substances or concentrations of distilled liquids. Paracelsus (1493-1541) used the term for thebes t or the spirit ofwine . The only alcohol suitablefo r consumption is ethyl alcohol, or ethanoj. Ethanol is a clear, colourless liquid, generated bycarbohydrat e fermentation orb y chemical synthesis, and constitutes the intoxication element of alcoholicbeverages . In itspur e form ethanol mayb euse d for severalpurposes , for example asa solvent, or- in a70 %solutio n - asa bactericide . When administered as amedicine , alcohol mayhav ea stimulatin g aswel l asa sedative, anaesthetic or narcotic effect. Its effectiveness depends on the concentration in the organism (13). The effects of alcohol mayrang efro m euphoria to intoxication and are responsible for the tremendous popularity of alcoholic beverages. In fermented beverages the alcoholic concentration variesfro m 2t o 17%. In distilled drinks it mayb e considerably higher. Irrespective of the typeo f drink a standard drink (glass) contains about 10g ethanol . Research on drinking habits attempts toprovid einsigh t into patterns of alcohol consumption and in its consequences. Other motives are: - to gain insight into the development of problem drinking and alcoholism by studying drinking habits, - to collect data in order to establish aimsfo r preventive action, - to provide abasi sfo r the development of theories regarding drinking habits, - to laya foundatio n for future research sotha t changesi n drinking habits can be investigated in the long term. Not onlyth emotive s of alcohol research vary, but also thewa yi nwhic h these drinkingpattern s are classified. Consequently, the results of these studies can be compared onlyt o alimite d extent. The quantities of alcohol drunk during normal and excessivealcoho l consumption andi n cases of alcoholism expressed in, for instance, grammes of pure alcohol per dayvar ywidely .Ther e are also differences in interpretation of terms 'alcoholism' and 'alcoholic'. Research on alcohol has developed into 'alcohology' in the courseo f time. Asan y science, alcohol research ischaracterize d bya distinct terminology of its own. To define ase t of concepts Keller et al. (10) havecompile d aDictionar y ofword sabou t alcohol.

In thisreview , however, covering theliteratur e up to 1991,term s are adopted from the original sources. Sinceth emeanin g attached to terms mayvar yamon g authors, anumbe r of frequently used terms, such asmoderat e drinking, excessive drinking, problem drinking and alcoholism, willb e elucidated below.

1.1. Moderate and excessive drinking

It isb yn o means easyt o givea straightforward answer to the question what quantities of alcohol shouldb e considered moderate, reasonable or acceptable, nor to definewha t quantities represent light, moderate, safe, heavy and excessive drinking or alcoholism. There are several reasons whylimit sfo r 'safe'' drinking are hard to give. First, it isno t feasible to perform .experimentswit h humans to investigate the chronicinjurie s incurred after different patterns of alcohol consumption. Second, somealcohol-relate d diseases occur rarely. Third, it is difficult to detect 'true' alcohol consumption byinterviewin g (12). Moreover, iti s difficult to fix limits sincether e isa broa d variation in sensitivity to alcohol. After the same amount of alcohol, women willhav ea highe rbloo d alcohol concentration than men becauseo f the differences inbod y composition. Besides, there isa n intra-individual variation related to someone's state of health. Pregnancy, for example, goeswit ha much lower limit of safe drinking. In addition, under certain conditions (traffic, use of medicine) safe drinking levelsar ehar d togive . Although moderate alcohol consumption ishar d to define many scientists have tried to do so. McDonald defines two drinks per dayfo r the averagewoma n and three drinks per dayfo r the averagema n asmoderat e (14). Up to 13 drinkspe rwee k bywome n and up to 20 drinkspe rwee kb yme n isregarde d ashealth y drinking in another study (1). The Royal College of Physicians suggest 17 drinks per week for men and 11drink spe rwee kfo r women tob emoderat e (2). Keller (10) defines the terms 'moderate drinking' and 'moderate drinker' as, respectively, arat eo f alcohol consumption or someonewhos ealcoho l consumption is: - moderate in amount (i)i n terms of dailycalori cvalu eo f alcoholintake , and (ii)i n terms of temporary effect (i.e. , never or rarely involvingintoxication;'an d - moderatei nlong-ter m effects, i.e. therei sn o question ofnegativ e effects bearing onhealth , job, family or relatives, socialliv eo r community welfare. According to Forrest (8), 'moderate drinkers' or 'social drinkers' may consume one or two alcoholicbeverage s per drinking occasion. Suchindividual s may drink once or twicea wee k or perhaps evenfa r lessfrequently . A social drinker may consume onlythre e or four alcoholicbeverage s each year, on specific festive occasions, but the definition alsohold sfo r apatter n of dailyconsumptio n that is limited to lesstha n two drinks per day. Perhaps theke ycharacteristic s of social/moderate drinkers isthei r capacity to control their use of ethanol and the absence ofbehavioural , social, legal and medical problems associated with drinking. Keller (10) describes an excessivedrinke r assomeon ewhos e alcohol consumptionis : - excessivei n amount (i)i nterm s of dailycalori cvalu eo f alcohol intake, and (ii)i n terms of reversible effects, i.e., causing intoxication; or - excessivei n the course of time, accompanied with shorter or longer periodso f intoxication; or - excessivewit h regard to effects, e.g. in the eyeso f peoplei n the individual's social environment; or - excessivewit h regard to aetiological (e.g. cultural, physical or psychological) factors. Forrest (8) classifies heavy drinkers asthos ewh o consume three of four alcoholic beverages or more per drinking occasion and drink on three or more occasionsa week. Thesepeople , likesocia l drinkers, may drink to thepoin t of intoxication on an infrequent basis. /

1.2. Problem drinking

Rinaldi et al. (19) tried to reach aconsensu s on alcohol-related terms. They askeda multidisciplinary group of experts to cooperate. After four rounds of data gatheringa list of 50 substance abuse termswa sproduced ; thegrou p reached consensus on most of these. In this listproble m drinking has two definitions: - a drinking pattern that has resulted in serious disturbances of health, work, social adjustment, or other areas of functioning, and - apatter n of alcohol consumption that does not satisfy allth e criteria of alcoholism, but that ischaracterize d bya sufficiently largeintak e to havegenerate d problems ofhealt h or social functioning. A definition of aproble m drinker isals opresente d byKelle r (10): 'One whose heavy, deviant or implicative drinking causes private or public harm andwh o issee n to causeproblem s for himself andfo r others. The category includes the alcoholics.' Problem drinking isdefine d byForres t (8) aspeopl ewh o drink excessively, frequently drink to thepoin t of intoxication, and experiencefamily , interpersonal, legal, medical or economicproblem s as adirec t result of their alcohol consumption.

1.3. Alcoholism

The term 'alcoholismus' wasfirs t coinedb yth ephysicia n Magnus Huss in 1849 (10). Over theyear svariou s attempts havebee n madet o givegenera l and universal definitions of the terms 'alcoholism' and 'alcoholic'. In his 'The disease concept of alcoholism', Jellinek proposed adefinitio n of alcoholism as 'any useo f alcoholicbeverage s that causes damaget o theindividua l or society orboth ' (9). After theproposa l of theDiseas e Concept, alcoholism was redefined according tovariou sprofessiona l (medical, social, psychological) interests. At least ten definitions arecommonl y used. Boyd et al. (4) tested the following ten definitions of alcoholism used in theUnite d States and Europe.

1.Alcoho l abuse as defined byth e Diagnostic and Statistical Manual of Mental Disorder, 3rd edition (DSM-III). The diagnostic criteria are: - pattern of pathological alcohol use - impairment in social or occupational functioning due to alcohol - the disorder existsfo r at least onemont h (11, 21).

2. Alcohol dependence as defined byDSM-III : - pattern of pathological alcohol use - impairment in social or occupational functioning duet o alcohol - the disorder existsfo r at least one month - tolerance -withdrawal symptoms (11,21) .

3. Alcoholism as defined byth e Research Diagnostic Criteria (RDC). This category isfo r subjects who havesymptom s in at least three out of thefollowin g five groups for at least onemont h (20): Group 1 - tremors, delirium tremens or ahistor y of cirrhosis - impotence associated with drinking - alcoholicblack-out s - alcoholicbinge s or benders Group 2 - drinking everyda y - exceeding the equivalent, in terms of alcohol content, of lVilitre s ofwhisk ype r week - being unablet o answer questions concerning frequency or quantity of drinking Group 3 - the subject had notbee n ablet o stop drinkingwhe n hewante d to - the subject tried to control drinkingb yallowin ghimsel f to drink onlyunde r certain circumstances - drinkingbefor e breakfast - drinking non-beverageform s of alcohol Group 4 - arrestsfo r drinking - traffic difficulties associated with drinking - trouble atwor k owingt o drinking - fighting associated with drinking Group 5 - the subject felt he drank too much - hisfamil y objected tohi s drinking - other people objected to his drinking - he lostfriend s because of his drinking - he felt guilty about his drinking

4. Alcoholism as defined byth eFeighne r criteria (6). A 'definite' diagnosis is made when symptoms occuri n at least three of thefou r following groups. A 'probable' diagnosis ismad ewhe n symptoms occur in onlytw ogroups . Group 1 - anymanifestatio n of alcohol withdrawal such astremulousness , delirium tremens, convulsions or hallucinations - history of medical complications - alcoholic black-outs - alcoholicbinge s or benders Group 2 - the subject had not been ablet o stop drinkingwhe n hewante d to ' - the subject tried to control drinkingb yallowin ghimsel f to drink onlyunde r certain circumstances - drinkingbefor e breakfast - drinking non-beverage forms of alcohol Group 3 - arrests for drinking - traffic difficulties associated with drinking - trouble atwor k owingt o drinking - fighting associated with drinking Group 4 - the subject thinks he drinks too much - hisfamil y objected to his drinking - other people objected to his drinking - he lostfriend s because of his drinking - hefel t guilty about his drinking.

5. Alcoholism as defined byth eNationa l Council on Alcoholism. 'Alcoholism isa chronic, progressive andpotentiall yfata l disease. It ischaracterize d by: tolerance, physical dependency and/or pathological organ changes allo fwhic h areth e direct or indirect consequences of the alcohol ingested' (3).

6. Jellinek's definition of alpha, beta, and gamma alcoholism (9): -Alpha alcoholism isa purel y psychological, continuous dependence on the capacity of alcohol to alleviatephysica l or emotional pain. Although thistyp eo f drinking exceeds conventional norms andha s social consequences for the drinker and his relatives, it does not lead to uncontrolled drinking, nor doesi t causea n inability to abstain from drinking. Alpha alcoholism maydevelo p into gamma alcoholism (see below), i.e .i t mayb e a stagedevelopment . On the other hand, there areperson swh o have maintained the drinking pattern characteristic of alpha alcoholism for thirty or forty yearswithou t showing anychange s or progressive development. - Beta alcoholism isth etyp eo f alcoholism inwhic hphysica l complications occur such aspolyneuropathy , gastritis or cirrhosis of theliver , but inwhic h no physical or psychological dependence on alcohol ispresent . According to Jellinek, this typeo f drinkingi sfoun d in atyp eo f social setting inwhic h nutritional déficiences are rife and excessive drinking ishabitual . - Gamma alcoholism represents a seriousfor m of drinking. An increase in tissue tolerance to alcohol, adaptation of cellmetabolism , physical dependence, withdrawal symptoms, and loss of control over drinking mayb e observed. In gamma alcoholism there isa definite progression from psychological to physical dependence. The gamma alcoholic usuallyha s alternating periods of intoxication and sobriety, andi s not ablet o abstain from drinking for more than one or two days. Intra- and interpersonal changes in this typeo f drinking areconsiderable . Generalhealth damage and harmful effect on social standing aremor emanifestl y present than other types of alcoholism.

7. Thealcoho l dependence syndrome as defined byth e 9th Revision of the International Classification of Diseases (ICD-9): 'A state, psychican d usually also physical, resulting from taking alcohol, characterized bybehaviora l and other responses that alwaysinclud ea compulsio n to take alcohol on a continuous or periodicbasi si n order to experience itspsychi c effects and sometimes to avoid the discomfort of absence;toleranc e mayo r mayno t bepresent ' (15, 23).

8.Alcoholis m as defined byth e Present State Examination (PSE) (22) holds ifan y item of thefollowin g check-list applies. • 'During thepas t month, haveyou : - had family problemsbecaus eo f drinking? - missedwor kbecaus e drinking? - had morning shakes or other withdrawal symptoms? - had blackouts for several hours? - heard voices or seenvisions? '

9. Thefou r different stages of alcoholism defined byth e Iowa Alcoholism Stages Index (16). This diagnostic test contains four scalesbase d on thefou r major typeso f signstha t mark problem drinkers or alcoholics: - trouble due to drinking - drinkingfo r personal effects - preoccupied drinking - uncontrolled drinking A subject who qualifies on anyon eo f the scalesi sclassifie d asbein g in an early stage (stageI ) of theprocess ;i fh e qualifies on twoscale sh ei si n stageII , and soon . 10 10. Alcoholism as defined byth eMichiga n Alcohol Screening Test (MAST). Thisi s a self-judgement scalecomprisin g 25items . Everyite m hasit sow nweighe d score. A score of 4i ssai d tob eprobabl y problematic and a scoregreate r than 4i sindicativ e of alcohol dependence. Someo f theseitem swit h their weighted scores are (11):

Item Question Score

yes no 4. Is it possible for you to stop drinking after one or twoglasse s without difficulties? 2 16. Doy o drink before the afternoon? 1 19. Have you ever asked help for your use of alcoholicbeverages ? 5 23. Haveyo u everbee n arrested for drunkenness? 2 Bytestin g these ten definitions on 23alcoholi cpatient s Boyd et al. (4) observed that allpatient swer e defined as alcoholicb yseve n of thete n definitions (Nos. 1, 2, 3,5 , 6, 10), and at least 78% o f thepatient swer e diagnosed asalcoholi cb yth e other three definitions. The authors havedevelope d theAlcoho l Poly-Diagnostic Interview which isderive d from thete n definitions mentioned. This interview wasfoun d to be sensitivefo r treated alcoholics, but has not yet been tested on untreated alcoholics (11). In an experiment designed to find the lexicalmeaning s of the term 'alcoholic' the conditions defined byDSM-II Iwer einvestigated . Thehypothesi s that the presence of pathological alcohol use, impairment in social or occupational functioning, tolerance to alcohol, andwithdrawa l symptomswoul d each evoke 'alcoholic' with agreate r frequency than the absenceo fthes efactor s was corroborated. Noneo f thesefactor s wasfoun d tob e analogous to a necessary definitional condition sinceth e absence of any one didno t result in azer o frequency. Thesevariable swer efoun d tob e supplementary (17). Rinaldi et al. (19) tried to reach aconsensu s on alcohol-related terms. As described above, amultidisciplinar y group of expertswa s asked to cooperate. Among the 50 definitions agreed upon are: - alcoholic: aperso n who has experienced physical, psychological, social or occupational impairment asa consequenc e of habitual, excessiveconsumptio n of alcohol; - alcoholism: a chronic, progressive and potentially fatal biogenetic and psychosocial disease characterized bytoleranc e and physical dependence manifested bya los s of control, aswel la s diversepersonalit y changes and social consequences; - alcoholdependence: chroniclos so f control over the consumption of alcoholic beverages, despite obviouspsychologica l or physical harm to the person. Increasing amounts arerequire d over time, and abrupt discontinuance may precipitate awithdrawa l syndrome. Following abstinence, relapsei s frequent. Although the resultsme twit h somecriticism , this attempt to arrive ata consensus hasbee n receivedfavourabl y (7, 18).

11 Summary

A sharp distinction expressed in terms of amount of pure alcohol per daybetwee n moderate and excessive, orbetwee n excessivedrinkin g and alcoholism, ishar d to establish. Observations havebee n madewit h regard to physical, social and psychological damage. One issuppose d tob e amoderat e drinker when onei sabl et o control hisus eo f ethanol andwhe n there aren obehavioural , social, legal and medical problems associatedwit h drinking. Excessive/heavy drinking isassociate d with intoxication, whereas a problem drinker ischaracterize d ason ewho' s repeated heavy drinkingha s resulted in problems of health or social functioning. This category includes alcoholics. More­ over, in most definitions alcoholics are supposed tob e physically dependent on alcohol. Many definitions concerned with 'alcoholism' and other alcohol-related terms are commonly used, but an attempt to arrivea t consensus hasbee n made.

References

1. Anderson P. What isa safe level of alcohol consumption? Stress Medicine 1986;2: 99-101. 2. Anonymus. Alcohol and health. Lancet 1987;I: 876. 3. Babor TF, Kranzler HR, Kadden RM. Issues inth e definition and,diagnosi s of alcoholism: implications for a reformulation. Prog Neuro- Psychopharmacol Biol Psychiat 1986;10 : 113-28. 4. BoydJH , Derr K, Grossman Be t al. Different definitions on alcoholism. II. Apilo t study on 10 definitions in a treatment setting. AmJ Psychiatry 1983;140: 1314-17. 5. Caenegem RC et al. Grote Winkler Prins Encyclopedie. Amsterdam/Brussels: Elsevier Argus, 1980:491. 6. Feigner JB et al. Diagnostic criteria for use inpsychiatri e research. Arch Gen Psychiatry 1972;26: 57-63. 7. Fleischhacker WW, Barnas C. Substance use terminology. JAMA 1988;260:478 . 8. Forrest GG. Guidelines for responsible drinking. Springfield, MA: Charles C. Thomas, 1989. 9. Jellinek EM. The disease concept of alcoholism. New Häven, CN: Hillhouse Press, 1960. 10. Keller M, McCormick M, Efron V. A dictionary of words about alcohol. NewBrunswick , NJ: Rutgers Center of Alcohol Studies Publication Division, 1982. 11. van Limbeek J, Walburg JA. De vroege signalering van alcoholproblematiek. Lisse: Swetz& Zeitlinger, 1987. 12. De Lint J. Alkoholtrinken und gesundheitliche Schädigung:zu r Diskussion über Sicherheitsgrenzen und Risikograde. Drogalkohol 1986;10: 39-51. 13. Majchrowitz E. The role ofbloo d in alcohol intoxication and addiction. In: Lisansky Gomberg E, Raskin White H, Carpenter JA, eds. Alcohol science aridsociet y revisited. Ann Arbor, MI: The University of Michigan Press, 1982; 171-85. 14. McDonald J. Moderate amounts of alcoholicbeverage s and clinical nutrition. J Nutr Educ 1982;14: 58-60. 15. Meyer RE. What characterized addiction? Alcohol Health Res World 1989;13:316-20 . 16. Mulford HA. Stages in the alcoholic process: toward a cumulative, nonsequential index. J Stud Alcohol 1977;38:563-83 . 17. Ö'Donohue. Experimental semantics:th e lexical definitions of 'prejudice' and 'alcoholic'. J Mind Behav 1989;10: 21-36. 18. Reder Sm. Substance use terminology. JAMA 1988;260:477-8 .

12 r

19. Rinaldi RC, Steindler EM, Wilford BB, Goodwin D. Clarification and standardisation of substance abuse terminology. JAMA 1988;259: 555-7. 20. Spitzer RL, Endicott J, RobinsE . Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-82 . 21. Williams GD, Grant BF, harford TC, NobleJ . Population projections using DSM-III criteria, alcohol use and dependence 1990-2000. Alcohol Health ResWorl d 1989;13:366-70 . 22. WingJC , Cooper JE, Sartorius N. Measurements and classification of psychiatricsymptoms . NewYork : Cambridge University Press, 1974. 23. World Health Organization. Ninth revision of the international classification of diseases. Geneva: World Health Organization, 1979.

13 CHAPTER 2 Biokinetics of alcohol

W.G. Vrij-Standhardt

Biokinetics mayb e defined asth e processing of substances byth ebody . In this chapter the absorption, distribution and elimination of alcohol willb e discussed successively. The metabolism of alcohol (biotransformation) willb e dealt withi n Chapter 3.

2.1. Absorption

Alcohol isabsorbe d over almost the entire length of the digestive tract. Absorption from themout h and oesophagus isminimal . Asignifican t proportion of alcoholi s absorbed from the stomach (ca. 20%) (37). Most of the alcohol isabsorbe d from the duodenum and smallintestine . Someabsorptio n mayals o occur in the large intestine. The alcohol ingested ishighl y dilutedb yth eadmixtur e of saliva and digestive juices. After administration of 40g alcohol , diluted to 10 arid 20%, Israel (32) found a maximum concentration in thejejunu m of 2.5 and 3-%, respectively. The administration of 0.8 galcoho l per kgbod yweigh t (diluted to 25%) resulted ina maximum concentration of 1-5% in thejejunum . Its concentration in theileu mwa s equal to that in serum (0.2%).Afte r twohour s the alcohol concentrations in the entire digestivetrac t almost equalled the leveli n the serum (21). When alcohol (45 to 60 g, diluted to 20%)wa sadministere d directly to the stomach, peak concen­ trations of 6-10% and 5-7%wer eobserve d in the duodenum and the jejunum, respectively (53). The alcohol molecules are absorbed through the intestinal wallb ya proces so f passive diffusion (7);th e quantity of alcohol absorbed per unit of timei s directly proportional to the concentration gradient between intestinal lumen, epithelial cells, capillaries and the portal vein (4). This implies that alcohol absorption follows first- order kinetics. The presence of food in the stomach delaysgastri c emptying and consequently postpones themomen t the alcohol isabsorbe d inth eintestine . Considering thehig h rate of absorption in theintestina l tract, gastric erhptyingi sa rate-limiting factor, thus affecting the rate of absorption and the overall absorption period. Various models havebee n proposed to describe theprocesse s of alcohol input and absorption (29, 67, 101). Pieters et al. (67) have developed themos t extensive modelwit h 6parameters . Iti sa 3-compartmen t model with feed-back control of stomach emptying depending of actual stomach alcohol concentration. 14 It maytak e sixhour s or evenlonge r until the stomach is entirely void of alcohol. Of the total amount ingested, however, 90%wil lb e absorbed within 1t o 3 hours depending on various factors such asth equantit y and concentration of alcohol as wella sth e amount and typeo f food present in the stomach (21). In normal circumstances amaximu m blood alcohol concentration (BAC) willb e reached 45 minutes after the consumption of asingl edos e (1).

2.1.1. Effects offood onalcohol absorption

Various experiments havebee n performed to establish the effect of thepresenc eo f food on the absorption rate of alcohol. Asa rule, theinfluenc e of the consumption of food on the BAC or on the serum alcohol level wasinvestigated . The BAC, however, isno t only determined byth eabsorptio n of alcohol, but alsob yth e distribution in the body and byth e elimination rate. The results of these experiments are hard to comparebecaus e of differences in experimental design. Thetype s and quantitieso f food ingested, the intervalsbetwee n food intake and alcohol consumption, and the quantities of alcohol all tend tovar ya swel la s thewa yo f determining alcohol levels (in venous or capillary blood, serum or breath). Based on the results ofman y experiments thefollowin g conclusions mayb e drawn. The delay of gastric emptying caused byth e presence of food results ina lowe r BAC peak: the alcohol willb e absorbed into the blood over alonge r period of timewhil e elimination has already

BAC (g/l) 1.0-,

2 3 4 5 6 7 Timeafte r consumption (h)

Fig. 2.1. BAC curvesafte r the consumption ofvariou s kinds of spirits, wine and beer. Each of these beverages contained 0.6 g of alcohol per kgbod y weight. Types ofbeverage : 1,gin , vodka; 2,whisky ; 3, dessert wine;4 , table wine; 5, beer; 6, table winewit h meal; 7, beer with meal. After: Leake& Silverman (42).

15 set in. The effects of alcohol consumption are thusweakene db yth eintak e of food. A larger amount offoo d results in alowe r BACpea k (44). The effect of food consumption ismaxima lwhe n alcohol isconsume d with themea l or lesstha n two hours after themea l (30, 79). Haggard et al. (21) have devoted agrea t deal of research to the rate of alcohol absorption. Aligh t meal, taken just before the consumption of 22-44 go f alcohol (whisky or martini-based cocktails) lowered the BACpea k by 50-80%. The BAC peak resulting from the consumption of 600-1200 mlbee r washardl y affected by taking meals. Maximum BACs upon the consumption ofbeer , whether or not preceded bya meal , were comparablewit h amaximu m BACinduce d by the consumption ofwhisk y or cocktails after ameal . Others (42), however, found asmal l decreasei n BACinduce d bybee r when amea l had been taken (seeFig . 2.1). Food, particularly food rich in fats and carbohydrates, delaysgastri c emptying, and thusmake s alcohol reach theintestin emor e slowly. This explains the effect of the presence of food on the absorption rate of alcohol. Themajo r factor accounting for the delayi n absorption bysoli dfoo d seems tob e aslowe r delivery ef alcohol to the smallintestine , wherei t israpidl y absorbed, rather than thepresenc e of solid

BAC (g/l) l.U

ƒ \ A 0.8

0.6 B

*\k

0.4 «

f

0.2

1

1 1 l I 1 >4 '^_J 12 3 4 5 6 7 Time after consumption (h)

Fig. 2.2. Blood alcohol curves. Simulated data generated according to the one-compartment open model with first-order absorption and Michaelis-Menten elimination kinetics. For curve A, the absorption rate constant wasassigne d avalu e of 8/h, and for curve Bth e absorption rate constant was 1/h.After : Sedman et al. (78).

16 food acting asa mechanica l barrier to the absorptive epithelium (30). It is assumed that thelowe r BACpea k in thepresenc e of food ismerel y attributable to delayed absorption, not to areductio n of thetota l amount of alcohol absorbed. In experiments on dogs Harger et al. (23) and Southgate (82) found that 90%o f the alcohol ingested isabsorbed , irrespective ofwhethe r the stomach contains food. Welling et al. (99) based their assumption that less alcohol isabsorbe d iffoo d is present in the stomach on the smaller area under the BACcurv e (AUC). Sedman et al. (56), however, found that a delayi n absorption per seresulte d in asmalle r AUC although the total amount of alcohol ingested remained equal (seeFig . 2.2). The maximum BACi sreduce d more successfully byfoo d rich in carbohydrates thanb y food with ahig h protein content. Fats haveofte n been considered to exert a stronger effect than carbohydrates because of the stronger inhibitory effect of fat on gastric motility. In some experiments, however, fats werefoun d tob eles s effective than carbohydrates (99), or roughlya s effective asprotei n (78). In general, thevariou s macronutrientsma yb esai d to delayabsorptio n in thefollowin g order: carbohydrates > fats > proteins. Clark et al. (12) distinguished various types of carbohydrate. They compared the effects offructose , sorbitol and galactose. The administration of sorbitol resultedi n thelowes t BAC, withfructos e as aclos esecond , while even galactose still lowered theBAC . They explained the delaying action of thesemonosaccharide s on alcohol absorption asfollows . Sorbitol isabsorbe d extremely slowly, solarg equantitie so f water willb e retained in theintestine due to its osmotic effect. Notjus twater , but also the alcohol dissolved init , isretaine d in the intestinefo r alonge r period of time byth e osmotic effect of sorbitol. Fructose isabsorbe d morerapidl y than sorbitol, and galactosea t stilla faste r rate. Aquantit y of sorbitol (125g ) aslarg ea stha t administered in these trials causes fermentative diarrhoea because most of it eventually reaches thelarg eintestine and isfermente d byth e microflora. A quantity of 40g a dayi sth emaximu m amount deemed permissible (2). A similar quantityo f fructose (125 g) alsoprove d effective whereas half of this amount proved to have hardly any effect. Fructose not only affects the absorption of alcohol, but also accelerates its elimination from thebloo d (cf. Chapter 3). Consequently, fructose mayals oinduc ea lowe r BAC. Largequantitie s of glucosea swel la so f amixtur eo f glucose and fructose lowered theBA Cthroug h inhibition of gastric emptying (17, 78, 85). Broitman et al. (10), on the other hand, found ahighe r alcohol absorption ratei n ratswhe n glucose or other carbohydrates werepresen t in theintestine . This held truewhe n alcohol concentrations werelo w (0.23%) and carbohydrate contents were small (50 mmol/1). Thisphenomeno n mayb e explainedb y an increased absorption of water. Somemil kan d dairyproduct s areconsidere d tob eparticularl y effective in loweringth e BAC (5, 54);however , thisha sno t been confirmed byothe r groups (33). Presumably, milktake n on an empty stomach has some effect by delaying gastricmotilit y and diluting the alcohol. When the stomach isfilled , milkha s no additional BAC-loweringeffect . In experimentswit h rats, caffeine proved tohav ea delaying effect on gastric emptyingowin gt o relaxation of thegastri c musculature 17 L resulting in alowe r BAC, particularly when caffeine had been administered a quarter of an hour before alcoholwa singeste d (80).

2.1.2. Differences inabsorption amongalcoholic beverages

The quantity and typeo f alcoholicbeverage s consumed also affect alcohol absorption (68). Theproces s isinfluence d byth e alcohol concentration andb y the occurrence of other substances in thebeverag ei n question. Alcohol is absorbed relatively slowlyfro m low-alcohol beverages, presumably asa resul t of dilution (the absorption rate in theintestin e isdirectl yproportiona l to thealcoho l concentration present in the lumen). Largequantitie s ofhigh-alcoho l beverages, however, mayslo w down gastricmotilit y and cause erosion of gastricmucos a (38). Pylorospasm, often followed byvomiting , mayals o occur. When alcohol consumption has become habitual, thiswil l occur lessfrequentl y (21). Owingt o these effects highly concentrated doses of alcoholwil l alsob e absorbed at aslowe rrat etha n doseswit h 15-30%alcohol . Alcohol from beer isabsorbe d rather slowlyan d results in alowe r BACtha n an equal quantity of alcohol from spirits (seeFig . 2.1). Alcohol from wine isals o absorbed more slowlytha n alcoholfro m spirits (56). The difference in absorption ratebetwee n thesebeverage s isdetermine d not only by differences in alcohol concentration but alsob yth epresenc e of other components. The carbohydrate content ofbee r and sweetwin e decreases gastric motility likemeal s do. Consequently, alcohol absorption from beer isdelaye d hardly anyfurthe r bymeal s (21). Potential delaying effects on alcohol absorption haveals o been attributed to other qualities of alcoholicbeverage s (acidity,buffe r capacity, alkaloid content) (41). ,

2.1.3. Otherfactors influencing absorption

Everyphysiologica l or pharmacological factor affecting gastricmotilit y or circulation maybasicall ymodif y alcohol absorption. An efficient blood circulation maintains the concentration gradient throughout theintestina l mucosa byrapidl y removing the alcohol absorbed. Kalant (38) and Holford (29) havereviewe d thefactor s affecting absorption. Alcohol absorption mayb e delayed not onlyb yfoo d ingestion, dilution of the alcohol and the presence of congeners, but mayals o result from a drop inbod y temperature, deep mental concentration or physical exercise. Aspirin, aminopyrine and anticholinergic drugs also slow down absorption whereas cholinergic drugs, insulin-induced hypoglycemia and arais ei nbod ytemperatur e increase the absorption rate slightly. Variation inhormona l status (e.g. stageo f themenstrua l cycle) affects ethanol absorption (36). The absorption rate showsa diurnal rhythmicity (45). Alcohol absorption seems also tob eunde r genetic control (71).

18 2.2. Distribution

Once alcohol hasbee n absorbed into thebloodstrea m iti srapidl y transported throughout thebod y and distributed over thebod yfluids . The small electrically neutral alcoholmolecule s can diffuse easilythroug h membranes. During absorption the arterial BACtend s tob ehighe r than thevenou s BAC,peakin g at ahighe r level and requiring lesstim et o reach thepeak , until an arterio-venous concentration equilibrium isreached , whereafter thevenou s BACremain s aboveth e arterial BAC (51). About 1.0-1V ih after drinking an equilibrium isreache d (63). Thiswil l take place sooner in organs highlyperfuse d withbloo d (brain, lungs, kidneys, liver) than in other organs (96). Itwil ltak e arelativel y long timefo r this equilibrium to be reached ininactiv eskeleta lmuscula r tissuebecaus eo f thepoo r perfusion of this tissue. Onceth e equilibrium hasbee n reached theamoun t of alcohol inth e organs willb eproportiona l to theorgans 'wate r content (63,72) . Determination of alcoholi n otherbod yfluid s asa n alternative tobloo d alcohol determination hasbee n proposedb ysevera l authors (20, 46, 76, 92). Blood sampling hasvariou s medical and legal drawbacks, whereas saliva, tear fluid en urine are easilyobtainable . When thewate r content isconsidered , therei sa close correlation between alcohol concentrations ofbloo d and salivai n the elimination phase (from twohour s after drinking) (20, 76). Thetear/bloo d alcohol ratiowa s found tob e 1.14, independently of BAC. Thetear/bloo dwate r content ratio is1.16 , soth e distribution of alcohol in tears follows closely itswate r content (46). The recent development of a simplean d cheap dipstick based on alcohol oxidasehold s promisefo r immediate determination of alcohol concentrations in saliva or other bodyfluid s (27). Thorough studies to test theaccurac y of these dipstick methods are tob e recommended. Sometimes urine isuse dfo r alcohol determinations (55),bu t these calculations often lack accuracy becauseth e timeo f urineformatio n isusuall y unknown. In mutilated orpartl y decomposed bodiesflui d of the eye, internal ear orbrai n can be used for forensic alcohol determination (92). Hypothetically, physical exercisema ylowe r thepea k ofth e BACcurve . As the muscular tissuewil lb emor e richlyperfused , the alcohol equilibrium between blood and muscular fluid mayb ereache d sooner. Consideringth elarg eamoun t of muscular tissue (some 18kg ) and itshig h fluid content (79%) (81) thepea k of the BACcurv emigh tb eflattene d appreciably. Experiments byPikaa r et al. (69) didno t proveBAC-lowerin g effects of physical exercise(cycling) , although alowe r breath alcohol content wasfound , presumablybecaus ea n equilibrium in thelung s had not been reached duet o panting. Bodyfa t and skeletal mass absorb hardly anyalcohol .

2.2.1. Breath alcoholanalysis

The application of equipment tomeasur e the alcohol content ofbreat h from which the alcohol content of thebloo d mayb e deduced subsequently, servesvariou s aims

19 today. Theprincipl ei sbase d onth efact s that part ofth e alcohol present in thebloo d is excreted viath elung san dtha t thealcoho l concentration in exhaled breathi s proportional toth eBAC . Thepartitio n coefficient between breath andbloo dha s been estimated at 1:2100t o 1:2300 (57,70) ,i.e . 2100-2300 mlo fbreat h containsa s much alcohol as 1 mlo fbloo d oncea nequilibriu m between blood andbreat h inth e lungsha sbee n reached. Determination ofth e alcohol content of expiredbreat hha s advantages aswel la sdrawback s ascompare dwit h determination ofth e alcohol content directly inth eblood . Theadvantage s liemainl yi nth espee d andeas e of determination andi nth efac t that themetho d isnon-invasive . Oneo fth e drawbacks istha t thespecime n cannot bestore d for repeat analyses. Another problem is the lack ofprecision . Thedeterminatio n ofbreat h alcohol content isa nindirec t way of determining the(arterial ) BAC. Iti sonl yvali dwhe n arespirator y equilibriumha s been established (34). Breathing techniques, temperature, humidity andothe r factors mayinterfer e with thedeterminations. Gullberg (19) showed that variationi n human breath byfa r exceeds theinaccurac y ofbreat h alcohol analysis equipment. Thefirs t 7t o2 0minute s after alcohol consumption thealcoho l stilllingerin gi nth e mouth yieldsvalue s that areto ohigh , even after drasticrinsin g andgarglin gwit h water (25,83) . In thefirs t Wi hour high values tend tob efoun d withbreat h tests ascompare d withbloo d tests. It shouldb enote d thatbloo d testsusuall yar eperforme d invenou s blood. Thebreat h alcohol concentration, however, closelyfollow s thepatter no f arterial BAC duringabsorption. This discrepancy isi naccor dwit h thefindin g that the alcohol concentration inarteria l blood ishighe r than that invenou sbloo d during the first 1-1Vi hour. Because alcohol ishighl ysolubl ei nwate r iti seasil y transported via capillaries from thearterie s toth etissues ;later , it diffuses from thetissue s toth e veinswit h areverse d diffusion gradient (65). , The alcohol concentration inth ebrai n also depends onth ealcoho l concentration in arterial blood. During elimination there isa clos erelationshi p between alcohol concentrations inbreath , arterialbloo d andvenou sbloo dwherea s during absorption breath alcohol concentration isa muc h better predictor ofarteria l BAC (51).

2.2.2. Sexdifferences in distribution

Men andwome n differ inbodil y constitution. Onaverage ,wome n haveles sbod y water perk gbod yweigh t than males (500an d60 0ml/kg , respectively) (81). A certain quantity ofalcoho l perk gbod yweigh twil linduc e ahighe r BAC (considered asth edegre e ofintoxication ) inwome n than inme n(36) . Becauseth eaverag ebod y weight ofwome n islower , evenlarge r mean differences inBA Cbetwee n men and women willoccu r upon theconsumptio n ofth e samequantit y ofalcohol .Th e 'reference man' weighs7 0kg , 60%o fwhic h isbod ywate r (42litres) ,wherea sth e 'reference woman' weighs 58kg , 50%o fwhic h isbod ywate r (29litres) . So,o n average, theamoun t ofbod ywate r overwhic hth ealcoho l canb edistribute di s appreciably larger inme ntha n inwome n (81). Kohlenberg (40)foun d alcohol

20 distribution volumes of 51an d 38litres , respectively, calculated withMichaelis - Menten kineticsfro m the BACs ofme n and women.

2.3. Elimination

Theter m 'elimination' isuse d in twomeaning s in theliteratur e on alcohol. Sometimes it stands for themer e excretion of unconverted alcohol, sometimes for the elimination of alcohol from thebod y including the transformation of alcohol in the liver. In this paper the term willb e used in thelatte r sense. Alcohol metabolism is discussed in Chapter 3. Practically all alcohol isoxidize d to CO2an d H2O. Asmal lproportio n of the alcohol is excreted as such with urine, breath, sweat and tears. At alltime s the excretion of alcohol isa functio n of the actual BAC, so thetota l amount of excreted alcohol can besee n asa functio n of the area under theBAC-tim e curve (AUC). There isa non-linea r relationship between oral ethanol dose and AUC (101). An oral dose of 40 galcoho l for aperso n of 70k gresult s in an AUC of about 3g • h/1 . Assuming abreath/bloo d partition coefficient of 1:2100an d alun g ventilation rate (in rest) of 81/min ,72 0m go f alcohol- i.e . 2%o f the dose of 40g A i s expired. Elimination viath elung s depends onbreat h volume. Alcohol isno t concentrated in urine (57). Theblood/urin e alcohol concentration ratio isaroun d 1(0.5-1. 0 in the absorption phase, 1.2-2.0 in the elimination phase (75). With an average urine production of 1.5 1/h 0.5%o f a dose of 40g alcoho l is estimated tob e excreted via thekidneys . The amount of alcohol extreted in sweat isnegligibl e except in caseo f excessive perspiration owing to extremephysica l exertion (0.5% at most (50)). In theliteratur e (albeit, as arule , not in primary sources) varyingpercentage s are givenfo r thevariou s elimination routes (12, 14, 29, 50, 57, 63,72 , 96). Generally speaking, 90-98%ma yb e said tob e oxidized, 1-5% is excreted via the lungs, and 1-5% isexcrete dvi aothe r routes (urine, sweat).

2.3.1. The bloodalcohol curve

Theheigh t of aBA C at anygive nmomen t will depend on the amount of alcohol absorbed at that particular moment, its distribution over thebody , and the amount of alcohol already converted and excreted. Agrea t deal of research hasbee n devoted to the course of the BACcurve . Wilkinson (101) hasproduce d quite an adequate state- of-the-art report in this field. The BACcurv efirs t showsa steep increase, followed - sometimes after maintaining aplatea u - bya slo w decrease (seeFigs . 2.1an d 2.2). Theincreas ei s often called the 'absorption phase' and the decrease the 'elimination phase'. A descending curve, however, onlyindicate s that elimination exceeds absorption. It doesno t mean that absorption hasfinishe d yet. Absorption may take sixhour s or more, whereas theBA C curvepeak s much earlier. Holford

21 (29) found alinea r relationship between oral alcohol dosean d BACpeak, which can be expressed byC vea^(mg/l) = 20 xdos e (g/70kg) . Views on thewa yth e curve descends havechange d through theyears . Around 1934, Widmark stated that elimination follows zero-order kinetics, that ist o say, the amount of alcohol eliminated isno t related to BACvalues . Expressed asa grap h this corresponds with a straight line:

C =C Q-ßt inwhic h Crepresent s the concentration found at agive nmomen tt, CQth e initial concentration, and ßth e slope. Thetheoretica l initial concentration CQ isfoun d by extrapolating the linear phaseo f the BACcurv et o theordinat e according to Widmark. Multiplying CQ with thevolum ei nwhic h alcohol isdistribute d resultsi n the (theoretical) initial quantity of alcohol rM^CQ , inwhic hM ^i sth ebod y mass andr isth eWidmar k factor, which reduces thebod ymas st o the alcohol distribution mass. This quantity proves tob e smaller than the quantity of alcohol consumed, especially in caseo f delayed absorption due to food in the stomach. This discrepancyi scalle d the 'alcohol deficiency' problem which hasbee n the subject of many hypotheses (26, 50). According to Heifer (26) the difference is, at least to some extent, the result of an unallowed procedure of linear extrapolation. Therei sn oproo f for a chemical reaction (esterification withfatt y acids or amino acids from food, as suggestedb yWidmark) . Possibly therecentl y found 'first-pass metabolism' of alcohol in the stomach (16) can explain the 'alcohol deficiency'. According to Widmark, thelive ralcoho l dehydrogenase (ADH) leveli s saturated even if alcohol concentrations are low. If this istrue , the slope of the straight line(ß) must not berelate d to the amount of alcohol. However this assumption often turns out tob eincorrect : frequently higher values of the slopear efoun d when initial BAC values arehighe r (15, 101). Presumably it isno t ADH but the amount of NAD that reduces the speed of this reaction (43). The Michaelis-Menten equation iscurrentl y preferred asa representatio n of the descent of the BAC (47, 95):

C0-C + KMlnC0/C = Vmt inwhic hKy^ stands for the Michaelis constant and ^mfor themaximu m velocity (all other symbols represent the same elements asi n theWidmar k equation). TheMichaelis-Mente n equation expresses the experimentally obtained courseo f the curvemor e adequately than Widmark's straight linedoes , particularly the tailo f the curve (Fig. 2.2). At concentrations much greater than theÜT- ^th e elimination rate approaches Kmand elimination isapproximatel y of azer o order, i.e. elimination is independent of alcohol concentration. At lowconcentration s elimination is concentration-dependent. Ueno (93) found I^mto be significantly correlated to /3^Q although theforme r valuewa sslightl yhigher . When BACvalue s exceed 0.1t o 0.2 g/1 virtually all experimentally obtained curvesar e (pseudo)linear. Recentlyne w models

22 havebee n developed, which account for Michaelis-Menten elimination kineticso f alcohol aswel l askinetic s of acetaldehyde and acetate, which are defined by first- order processes (39). Although an approach based on the Michaelis-Menten equation ismor e correct, it remains feasible to approach elimination of alcoholfro m thebloo db yWidmark' s straight line. Either approach mayb e used, dependent on the specific casei ti st o be applied to. Thezero-orde r kinetics approach issimple , but lessprecis e sincei t can be applied onlyt o BACs exceeding 0.2 g/1.Whe n applied to oral consumption of alcohol, when absorption and distribution are often disturbing factors, this method usually issufficientl y accurate. TheMichaelis-Mente n equation covers thewhol eo f the elimination phase, evenwhe n concentrations arelow . Its application, however, requires more complicated calculations.

2.3.2. Elimination rate

Both Wallgrenn &Berr y (96) and Piendl (66) provide asurve y of the literature on therat e of elimination of alcohol from theblood . The elimination rate corresponds to the slope of the decrease of aBA C curve (ß). Sincethi s slopei srarel ylinea r in experimentally established curves (not evenwhe n the BACi s0. 2g/ 1 or higher) the elimination ratei sno t constant in time. Consequently iti sno t correct to speak about theeliminatio n rate. The average elimination ratei s 100mg/k gbod yweigh t per hour. Individual differences, however, mayb elarge , due to differences in genetic constitution, bodyweigh t and habitual alcohol consumption. Depending on individual elimination rate andbod yweight , an amount of 4.5-12 galcoho l per pour (an averageo f 7g/h )ma yb emetabolized , calculated on thebasi s of the slopeo f the descending BAC curve (ß). Back extrapolation ofvenou sbloo d alcohol levels, based on asingl eknow n concentration, asa mean s of determining theBA Ca t thetim eo f the accident, islegall yvali d inman y countries, but canlea d to estimates bordering on wildguesse s (51, 91). A significant difference, both inßg g andV m, issee nbetwee n personswit h normal aldehyde dehydrogenase and personswit h the deficient typeo f it (93). Piendl (66) and Kohlenberg (39) found no consistent differences in elimination ratebetwee n men andwome n assuggeste d byJone s &Jone s (36) and Sutker (88). Regarding the decline of theBAC , Jones &Jone s found that alcohol ismetabolize d more slowlyb y women using oral contraceptives than bymen . Women who do not useora l contraceptives show ahighe r elimination rate than men (expressed inm gk g h ). According to Sutker (88) the elimination rate depends on thephas e of the menstrual cycle,wit h thehighes t elimination rate during themid-lutea lphas e (days 20-25). The elimination ratei sno t the onlyfacto r in determining the duration of alcohol intoxication. The maximum BACvalu eals oplay sa role. For oneparticula r amount of alcohol consumed, thisvalu ei susall yhighe r inwome n than inme n (cf. Section 2.2.2).

23 Theindividua l differences reported byPiend l (66) andb yWallgre n &Berr y (96) mayb e ascribed to differences in study design (quantity of alcohol, method of calculation), differences inbod y composition, metabolic differences between light and heavy drinkers (see Chapter 3), and the time of day atwhic h experiments are performed. A circadian rhythm in alcohol metabolism hasbee n found (55, 86). Around 18.00th e elimination showsa dip (about 10%les sthe n the 24-hour mean) (55).

The rateo f elimination of alcohol from thebloo d isinfluence d bya numbe r of factors. The effect of food components (vitamins, sugars, caffeine, oxygenated water), dietarypatterns , thyroidhormones , physical exercisean d specific sobering agentswil lb e discussed consecutively.

Vitamins Supplementation over aperio d of 5-10 dayswit h amixtur e of vitamins, at a dose several-fold higher than recommended, didno t havea significant effect on the elimination rate of aquantit y of alcohol amounting to 0.5 per kgbod yweigh t (3-4 glasses) (60, 63). According to Susick (87), ascorbic acid enhances alcohol metabolism. Possibly the alcohol metabolism isslowe d downb yseriou s vitamin deficiency. On the other hand, supplementation ofvitamin s to subjects with anorma l dietary pattern appears pointless.

Sugar The sugarsmos t frequently tested aregalactose , xylose, glucosean d fructose. Galactose andxylos e dono t affect the elimination rate,bu t glucoseha s a small effect on alcohol elimination (52). Fructose clearly affects alcohol elimination (11, 13, 35, 60, 62, 63, 84, 94, 100). Iti sno t easyt o arrivea t definite conclusions on the dose- effect relationwhic h largely depends on thewa yalcoho l andfructos e are administered (orally or intravenous) and on the amount of alcohol administered. The effect of fructose also showsa larg eindividua l variation. So,i t isno t supprising that in some experiments fructose wasfoun d to haven o effect at all (24). The effect of fructose isprobabl ybase d on areductio n of theNADH/NA D ratiob yon e or more reactions offructos e or one ofit smetabolite s for which NADHi srequired . Fructose consequently affects both absorption (seeSectio n 2.1.1) and elimination of alcohol.

Caffeine The ingestion of twocup s of strongcoffe e supplementedwit h 50m go f caffeine has no influence on the elimination rate of alcohol (62). On the other harid, large, quantities of caffeine doinfluenc e the effect of alcohol on thecentra lnervou s system (in animal experiments), but this effect appears tob efortifyin g rather than otherwise (9, 59).

24 Oxygenateddrinking water Oxygenated water speeds up alcohol elimination inmonkey sb y60 %(31) . However, in acomparabl e experiment withhuma n subjects, no significant resultswer e found (41).

Dietary composition Carbohydrate-rich (73) and protein-rich (102) diets enhance the alcohol elimination rate. Pawan (61) found that both a 4.2 MJ diet inwhic h fat accounted for 90% of energyintak e and a diet containing onlywate r and vitamins, over aperio d of one week, reduced the alcohol elimination rate. Thisma yb e causedb yminera l deficiencies and other co-factors.

Thyroidhormones The administration of thyroid hormones which speed up the entire metabolism does not affect the rate of alcoholmetabolis m (63).

Soberingagents Quite anumbe r of sobering agents are availablenow , especially in Germany where drug registration policies and prescription are rather lessstrict . Research, however, has demonstrated that these agents dono t havean y effect (8,9) .

Physicalexercise Physical exercise seems unlikely to influence the elimination rate of alcohol. Most scientists found no effects (3,41 ,48 , 62, 64, 69, 74),wherea s some others observed an increasei n the rate of elimination (77).

Body temperature Thealcoho l elimination ratedecrease swit h decreasingbod ytemperature . On the other hand, alarg e dose of alcohol (3.6 g/kgbod yweight ) impairs thermoregulation. Alcohol-intoxicated miceplace d in cold environments areno t capable of maintaining normal body temperature (6).

2.4. An overview of factors influencing the BAC

In theprecedin g sections on absorption, distribution and elimination several factors affecting theseprocesse shav ebee n mentioned. All theseprocesse s taken together define the course of the BAC curve. In Table 2.1a n overview ispresente d of the factors affecting theBA C curveb ythei r effects on absorption, distribution and elimination. Some of thesefactor s are under self-control (quantity and typeo f beverage, meals), whereas other ones canb emodifie d onlyi n the long run (body weight, nutritional deficiencies) or not at all (sex, stature). A distinction should also be madebetwee n direct (e.g. gastricmotility ) and indirect factors (e.g. presenceo f

25 Table 2.1. Overview offactor s possibly influencing the concentration of alcohol inth e blood through their effects on absorption, distribution and elimination. Numbers indicate references.

Factor Absorption Distribution Elimination

Easilyaffected by self-control Amount of alcohol 21,38 Alcohol concentration 21,38 Type of beverage (congener levels) 42,56 Drinking rate 38 Gastric motility 21 Physical activity 38 69,77 Presence of food in the stomach 30,44 99 Dietary pattern 78,99 61,73, 102 Fructose 12 13, 35, 52, 63,9 4 Various drugs 38 38 43,97 Clofibrate 103 Caffeine 80

Affected byself-control only indirectly or in the long term MEOS induction 43; 63 Circulation 38 96 Body temperature 38 6 Oral contraceptives 37 Body weight 63,71 97 Orcadian rhythm 45 55,86 Menstrual cycle 36 88,97 Nutritional deficiencies 18 97 Alcoholism 97 Liver damage 97

Not affectedby self-control Race ' 97 Sex 36 88,89 Stature (%bod y water) 63

food in the stomach). Popular and pseudo-scientific literature uset o publish nomograms, graphs and tablesb ymean s ofwhic h BACvalue s mayb e determined after the consumption of anygive nquantit y of alcohol. Asa rule , thesevalue s are means. Thevariabilit y of BACs, however, iss olarg etha t the application of these nomograms and the likei smos t deceptive and maygiv eris et ohug e over- and underestimates (58). Even in controlled experiments, inwhic h asman yfactor s as possiblewer emaintaine d at aconstan t level, theirrter -an dintra-individua l variance found waslarg e (58,98) .

Summary

A small quantity of the alcohol consumed isabsorbe d from the stomach, whereas most of iti sabsorbe d from the smallintestin efollowin g first-order kinetics. Of the

26 total amount of alcohol consumed 90%i sabsorbe d within 1t o 3hours , depending on the type and quantity of the alcoholicbeverage , and thepresenc e offoo d in the stomach. A delayed gastric emptying extends the overall absorption period. Themaximu m blood alcohol concentration resulting from the consumption of wineo r spirits isconsequentl y reduced byth eintak eo f asoli d meal immediately preceding or during alcohol consumption. Although there are slight differences in effectiveness among thevariou s nutrients and foodstuffs in this respect, no substance canb e said to havea particularl y strong effect, exept possibly fructose. Carbohydrates present in alcoholicbeverage s (beer, wine, sweetliqueur ) also slow down gastric emptying to some extent. The absorption of alcohol in the intestine is directlyproportiona l to the actual alcohol concentration gradient. This causes alcohol from weak alcoholicbeverage s to be absorbed more slowlytha n alcohol from more highlyconcentrate d drinks (dilution effect). The consumption of largequantitie s of high-alcohol beverages may causepylorospasm , thus delaying absorption. Once the alcohol hasbee n absorbed into thebloodstrea m it istransporte d all through thebod y and distributed over the total amount ofbod yfluid . The small alcohol molecules, solublei nwater , easily diffuse through membranes. An equilibrium isreache d about 1-1V i hour after drinking, depending on the degree ofbloo d perfusion of the organs. Bodyfa t and skeletal mass hardly absorb anyalcohol . Men andwome n differ inbod y constitution. Women haveles sbod ywate r per kg bodyweigh t than men (500 and 600ml/k g respectively). An identical quantityo f alcohol per kgbod yweigh twil linduc e ahighe r BAC (measure of intoxication) in women than inmen . Becausewome n usually also havea lowe rbod yweigh t than men, the differences in BACbetwee n the 'reference woman' and the 'reference man' willb e evengreate r after ingestion of an identical amount of alcohol. The amount of bodywate r of thereferenc e women (58 kg)i sonl y69 %o f that of the reference man (70kg) . The alcohol concentration inbloo d can alsob e determined in an indirect manner bymean s of breath analysis. Oncea respirator y equilibrium hasbee n established, the alcohol concentration in exhaled breath willb e proportional to the (arterial) BAC; consequently, thebloo d alcohol concentration canb e calculated from the breath value. Thebreat h test isno t invasive, isbot h easy and fast, but isles sprecis etha n the direct determination ofBACs . Of the alcohol absorbed 90— 98 %i soxidized , 1-5% is excreted in an unaltered state in urine, and another 1-5% is expired via thelungs . Two mathematical functions arewidel yuse dt o describeth e elimination of alcohol from theblood :a straight line (zero-order kinetics according to Widmark), and the Michaelis-Menten equation. The Michaelis-Menten equation expresses more adequately the experimentally obtained course of the curvetha n Widmark's straight line approach does. Particularly the tail of the curvefit s theMichaelis-Mente n equation. Yeti t remains feasible to approach the elimination of alcohol from thebloo d bymean s ofa straight line, depending on the specific application required (balancing precision and ease). Themea n elimination ratefro m blood is 100mg/k gbodyweigh t per hour

27 (range 88-132 mg/kgpe r hour. Depending on individual elimination ratean dbod y weight, an amount varyingbetwee n 4.5 gan d asmuc h as 12g alcoho l may be processed per hour (average 7g/h) . There are no marked differences in elimination rates (expressed in mg/kgpe r hour) between men and women. Differences in elimination rates relate to, among other factors, habituation, the use of large quantities of fructose, the time of the dayand , for women, the use of oral contraceptives.

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31 L CHAPTER 3 Alcohol metabolism

W.G. Vrij-Standhardt

3.1. Introduction

Many reviewshav ebee n devoted to alcoholmetabolis m (e.g. 4, 36, 39-41, 68,92) . Of thealcoho l absorbed 90-98%i smetabolized , the remainder is excreted assuc h (cf. Chapter 2). Most of the alcoholi soxidize d completely to C02 and H20. A small proportion isfirs t converted into acetate and then incorporated inbod y tissuesa s carbohydrates, proteins orlipid s (seeFig . 3.1). If completely convertedvi ath eAD H pathway, alcoholyield s3 0kJ/ g energy. In caseo fhabituatio n to large quantities of alcohol, ityield s less energy owing toa different metabolic mechanisms. In comparison, the energyyiel d ofbot h carbo­ hydrates andprotein s is 17kJ/g , and offat s 38kJ/g . Thisprovide s a direct answer to the questionwhethe r alcohol isa nutrient. Nutrients are defined asth e chemical elements constituting afoo d (any consumable product) which canb e used for growth, maintenance and/or functions of the human body, irrespective ofwhethe r these elements canb e synthesized byth ebod y toa sufficient extent. Ethanol fits inwit h this definition although it shouldb enote d that it isals o apsychotropi c substance. Alcoholicbeverage s mayb e considered as food­ stuffs which areneithe r useful nor indispensable to the anabolism of the human body. The samehold sfo r sugar, but, unlikesugar , alcoholha s psychotropic properties in addition toit snutritiona lvalue . Alcoholi soxidize di n several steps;i ti soxidize dfirs t to acetaldehyde, whichi s

URINE BREATH

3^- ALCOHOL ¥

Fig. 3.1.Th e alcohol pathway.

32 subsequently converted into acetate. Thesereaction s takeplac eprimaril y in thelive r (38, 68, 94). During oxidation to acetate ca. 30%o f thetota l energy produced through the combustion of alcoholwil lb ereleased . When ADH activity ismaximal , thiswil lb e sufficient to provide70-100 %o f the energy needed for thebasa l metabolism of the liver (92).Th e remaining energywil lb erelease d during extra- hepatic oxidation of acetate. Although thesefundamenta l pathwaysfo r alcohol metabolism are common toal l human beings, the enzymes involved can take different forms - so-called isoenzymes or isozymes- which result from the substitution of oneo r more amino acids in the polypeptide chain. Theisozyme s havedifferen t catalyticcharacteristic s which accounts for individual variation in rate of alcohol metabolism. In the following sectionswil lb e discussed: the conversion of alcohol into acetaldehyde (first step); theintermediat e product acetaldehyde; conversion of acetaldehyde into acetate (second step);furthe r reactions of acetate (third step). Finally, the possibilities of influencing alcohol metabolism willb e discussed.

CHRONICAlCOHO lCONSUMPTIO NAN DMETABOLIS M

A. CHjCHjOH + NAD* » CH3CHO+ KADH + H + ADH

B. CHJCHJOH • NAOPH• H*• » O2 *CH3CHO• NADP*• IHjO MEOS

NAOPH • H*• Oj »NADP* • HJOJ NADPH r OxMtM + 1—H.O.H2Oj •+ CH 3CH2OH •ÎHjO • CH3CHO Catalaa«

D. ,_ HYPOXANTHtNE+H20• O2 •XANTHÎNK • HJOJ Xanthine r OxldaM +

H2O2• CH3CH2OH MH2O • CH3CHO L Catalaa*

Fig. 3.2. Three enzyme systems converting ethanol into acetaldehyde. Ethanol is oxidized in the liver by: A, alcohol dehydrogenase (ADH), the oxidized form of nicotinamide adenine dinucleotide, NAD (NAD+ ) and the reduced form of NAD (NADH); B, the microsomal ethanol-oxidizing system (MEOS), the reduced form of nicotinamide adenine dinucleotide phosphate, NADP (NADPH) and the oxidized form of NADP (NADP+ ); C, a combination of NADPH oxidase and catalase; or D, xanthine oxidase and catalase. After: Lieber et al. (40).

33 3.2. First step:conversio n of ethanol into acetaldehyde

Three enzyme systems areno wknow n to catalyseth econversio n of ethanol into acetaldehyde (seeFig . 3.2). Themai n reaction isth eon ei nwhic h ADH functions as the enzyme.Th eothe r twosystems , i.e. theNADPH-dependen t reaction catalysed byMEO S (microsomal ethanol-oxidizing system) and thereactio n influenced by catalases, do not play an important part, although itha s notbee n established towha t extent they exactlycontribut e toth eproces si n question. Thepresenc e of three independent alcohol-metabolizing systems has been demonstrated convincingly (33, 40, 56, 83).The y differ in intracellular localization, pH optimum, K-value, co-ferments and specific inhibitors.

3.2.1. ADH-dependentreaction

For the oxidation of alcohol to acetaldehydeb yalcoho l dehydrogenase (ADH), oxodized nicotinamide adenine dinucleotide (NAD ), ahydroge n receptor, is needed. The chemical equation is:

ADH N x CH3CH2OH + NAD+ v ^ CH3CHO + NADH + H+ (ethanol) (acetaldehyde) The NADH thusproduce d willb ereoxidize d to NAD through various shuttle systems in themitochondria . It canb e calculated that the activity of rat liver ADH is limited to only 50-60%o f itsmaximu m velocity. Regeneration of NAD is considered the rate-limiting factor. Which stepi n this regeneration process exactlyi srate - limiting, depends on the experimental design (species used, starved or fed animals). The dissociation of theADH-NAD H complex, the rate ofwhic h iscontrolle d byth e amino acid on position 47 ofADH , issee n asth erate-limitin gfacto r (22). Re- oxidation of NADH to NAD+ isno t rate-limiting-in man (54, 57).Th e importance of the respiratory chain activity and the transfer rateo f reducing equivalents from the cytosol to themitochondri a byshuttl esystem si sno t clear (28,36) . ADH isno t induced bychroni c alcohol consumption (6). Norman et al. (59) even found a decrease inAD H activity inbaboon s fed alcohol for alon g time. Ina minority of people there isa swif t and transient increasei n alcohol metabolism (SIAM) of more than 40%whe n asecon d doseo f alcoholi sgive n afe w hours after thefirs t dose. SIAM most likelyinvolve s theincrease d reoxidation of NADH, asa result of activation ofmitochondria l electron transport by enhanced adenosine diphosphate (ADP) supply (85). The zinc-containing ADH has alo wsubstrat e specificity: it converts not only ethanol, but also other alcohols (69). There are severalform s of ADH (isozymes), with different specific activities. The existenceo ffiv egenes , codingfo r different variants of ADH, hasbee n demonstrated. Three of thesegene s codefo r isozymes which areimportan t for ethanol metabolism (class I enzymes). The other two genes

34 codefo r other isozymes (class II and III enzymes) with aver ylo w affinity for ethanol (22). Newtechnique s haveallowe d to demonstrate ahig h degreeo f sequence homologybetwee n the 3clas s IAD H genes and enabled the definition of ADH variants at the DNA sequence level (4a). On chromosome 4a n ADH genecluste ri s described. All class IAD H genes are mapped in this specific region of chromosome 4 (9). Individual variation in alcohol metabolism and tolerance can bepartl y explained bybiochemica l and molecular differences between the class I enzymes. Large individual differences in quantitative distribution of isozymes, and hencei n ADH activity, havebee n demonstrated (93). Racial differences havebee n noted aswel l(2 , 18, 19).Almos t all Caucasians haveth eADH ^ enzymei n addition to some other isozymes, whereas ca. 90%o f theJapanes e havea n ADH isozymewit h an activity at physiological pH values that isabou t ahundre d times greater than theADH ^ activity (101). ADH occurs mainly in the cytoplasm of the liver, but several other tissues contain ADH isozymes aswel l (7, 67, 76). Local metabolism of alcohol in gastrointestinal tissueb yAD H (called 'first-pass metabolism') has been reported. Calculated from the differences inAU C ('area under thebloo d alcohol curve') between intra­ venously and orally administered alcohol, first-pass metabolism could account for about 20%o f alcohol oxidation (20). Inwomen , first-pass metabolism, defined by AUC difference, isonl y 25% of theleve l in men (20). This could explain the higher blood alcohol concentration (BAC) inwome n after the same dosis of alcohol per kg bodyweight . In alcoholics gastricalcoho l metabolism isonl yhal f that of non- alcoholics. However, the use ofAU C differences for accurately determining the bioavailability of alcohol isno t appropriate according to others (90). The gastric ADH activity inwome n hasbee n found tob e 70%o f that in men. Ageing and, in particular, alcoholism affect gastricAD H activity (14).

3.2.2. MEOS

In 1965,Orme-Johnso n &Ziegle r (64) reported that ethanol may alsob e oxidized bya n NADPH- and oxygen-dependent enzymesyste m in themicrosome s of theliver , the so-called microsomal ethanol-oxidizing system (MEOS). Thisfindin g hasbee n confirmed byother s (45, 70). Its chemical equationis :

MEOS + CH3CH2OH + NADPH + H + 02v > CHgCHO + 2H20 + NADP+ There isconvincin g evidencefo r theinvolvemen t of cytochrome P-450 in MEOS activity (83). The ethanol-oxidizing capacity isconstructe d invitr ob ymean s of cytochrome P-450, lecithin (phospholipids) and NADPH-cytochromeP-45 0 reductase. Part of the P-450 system isinducibl eb y ethanol. Theseisozyme s are called P450IIE1. Sinceothe r cytochrome isozymes can also contribute to ethanol oxidation, the term MEOS isuse d asa generi c term for the overall capacityo f

35 microsomes to oxidize ethanol rather than for the capacity of the P450IIE1 fraction (42). Many xenobiotics are metabolized by the cytochrome P-450 system. P450IIE1 has a high capacity of metabolizing not only ethanol, but also other aliphatic alcohols as well as other exogenous compounds. It can be induced by various compounds such as acetone, pyrazole and benzene (83). Under normal conditions MEOS plays a minor role (less than 10% according to Wallgren & Berry (92), 20-25%accordin g to Lieber (43), depending on the alcohol concentration). Chronic alcohol consumption results in enzyme induction and thus in an increased alcohol metabolism (43, 59, 66). Some suggest that MEOS, in combination with the catalase system, which will be discussed later, may be respon­ sible for the catabolism of over 50% of the amount of alcohol consumed (5, 83). The increased alcohol elimination in chronic alcohol consumption may be partly caused by a secondary increase in oxidation via ADH. The ADH pathway requires NAD +, whereas NADPH is converted into NADP + via the MEOS pathway. The NADPH/NADP + and NADH/NAD + systems are linked by several shuttle systems. New NAD may thus be generated by the MEOS reaction. In accordance with this hypothesis is the finding that acute administration of alcohol to rats that have become adapted to alcohol results in a smaller'shift to the reduced state in the liver compared with the shift observed in unadapted control animals. In well-fed baboons to which alcohol was administered chronically, the elimination of alcohol from the blood increased progressively while the associated redox change decreased. The conversion of alcohol into acetaldehyde by MEOS requires energy, whereas the formation of acetaldehyde by ADH (during which process NAD is reduced) yields energy. If the first step proceeds via the MEOS pathway only 10 instead of 16 mol ATP per mol ethanol is formed during the complete conversiqn of alcohol. The MEOS pathway operates at subnormal efficiency (23%instea d of 37%), producing less energy and more heat than the ADH pathway. Since the latter energy will not count, only 18.5 kJ becomes available per g alcohol instead of the 29.8 kJ/g usually believed to be the combustion energy of alcohol. The consumption of 180 g of pure alcohol per day (not uncommon in alcoholics) yields ca. (180x29.8 = ) 5400 kJ/day via the ADH pathway; if half of it is converted via the MEOS pathway, the same quantity of alcohol yields only (90x29.8 + 90x18.5 = ) 4400 kJ/day (6). It is, however, hard to explain why subjects who, over a period of one month, have received daily 8.4 MJ of energy derived from alcohol (282 g x 29.8 J/g) in addition to a basic diet supplying 9.2 MJ, gain hardly any weight, whereas an additional daily supply of 8.4 MJ in the form of chocolate results in a significant weight gain (44). Even if half of this huge dose of alcohol is metabolized via the MEOS pathway it should yield (141x29.8 J + 141x18.5 J =)6.8MJ. A study of Reinus (72) suggests an alternative explanation for the absence of an effect of alcohol on body weight. Alcoholics receiving 60% of their energy supply in the form of alcohol administered nasogastrically lost weight as compared with the control period with an isoenergetic supply of carbohydrate (glucose). The results of the energy balance measurements indicated that this weight loss could not be attributed to a negative energy balance caused by excessive heat loss. Alcohol

36 supplied only 5%les s energy, relative to carbohydrate. This difference isprimaril y causedb yrespirator y and urinary losses of unmetabolized alcohol. A small and insignificant component of this difference was due to ahighe r heat release during ethanol feeding relativet o carbohydrate infusion. Weight losswa s due to a negative effect of alcohol on theN balance . Urinary analysis suggested that skeletal muscle breakdown contributed to thelos so fN .

3.2.3. Catalase andother pathways

The thirdwa yvi awhic h alcohol mayb e converted into acetaldehyde isb ymean so f catalase enzymes, which arepresen t in peroxisomes of theliver . As early as 1936, Keilin and co-workers (see 88)pointe d out that under certain conditions peroxidation of ethanol maytak eplace , according to thefollowin g equation:

H202 + CH3CH2OH ^==^2^0 + CH3CHO The peroxide needed isgenerate d byNADP H or hypoxanthine oxidation under the influence of oxidases (39), orb y/3-oxidatio n of fatty acids (23, 85). Theformatio n of H2O2 isconsidere d tob e the rate-limiting factor (40). Towha t extent the catalase system contributes to alcohol conversion isope n to controversy. Most workers (10, 41, 44, 55) consider catalase tob e of littlesignificance , others mention values of up to 25%fo r the extent towhic h catalase accounts for alcohol conversion (23,33) . According to Thurman &Handle r (85), MEOS isth e combination of cytochromeP - 450 (especially isozymeP450IIE1 ) and catalase, whereas cytochrome P450IIE1 plays amino r role in ethanol elimination invivo . Earlier experiments designed to understand pathways of ethanol metabolism didno t include fatty acids;therefor e the role of catalase in alcohol metabolism hasbee n underestimated. Thurman & Handler's recent experiments suggest that catalaseplay s an important rolei n ethanol oxidation in the presence of fatty acids inviv o (in rats). To arrivea t that conclusion they suppose that methanol isno t oxidized byAD H in the rat and that methanol oxidation occurs predominantly via catalase-^C^. However, methanol is metabolized bybot h ADH and MEOS (83). Several minor pathways of ethanol metabolism havebee n described (36). Anon - oxidative pathway for alcohol metabolism isknown , which results in theformatio n of fatty acid ethyl estersfro m ethanol and fatty acids. This reaction iscatalyse db y fatty acid ester synthase, which isfoun d primarily inbrain , pancreas and heart (34,35 , 52). Other reactions are conjugation reactions to form ethyl sulphate and ethyl glucoronide. Thesereaction s appear to be quantitatively insignificant under normal conditions.

3.3. Acetaldehyde

Thefirs t intermediate product in alcohol conversion isacetaldehyd e (CH3CHO). Iti s a toxic substance held tob e partly responsible for theharmfu l effects of excessive

37 alcohol consumption (71,95) . Disulfiram, an antidipsotropic drug, inhibits acetaldehyde conversion, resulting in high concentrations of this substance. In patients taking disulfiram alcohol consumption actually has the effect of acute acetaldehydepoisoning . Acetaldehyde issuppose d to play arol ei n hepatocellular injury (cf. Chapter 8o f thisbook ) and in alcohol dependence, and possiblyi n intoxication and withdrawal symptoms. The cause of emotional and behavioural disturbances as aconsequenc e of alcohol consumption ispresumabl y the generation of morphine-like substances and/or 'false' neurotransmitters (12, 62, 71) - substances formed bycondensatio n reactions of acetaldehyde and influencing the nervous system. According to others (50), these disturbances arecause db y ethanol itself, which brings about amodificatio n of the synapticmembrane s (seeals o Chapter 9). Following an intravenously administered doseo f alcohol, alcoholics arefoun d to havemor e acetaldehydei n theirbreat h andbloo d than social drinkers (32, 46). There are several interpretations of this phenomenon (49). Oneinterpretatio n istha t theincrease d acetaldehydeleve li sa consequenc e of alcoholism; chrcfnic alcohol consumption mayhav einfluence d metabolism/to such an extent, either temporarily or permanently, that more acetaldehydei sformed . Thetyp eo f transformation involvedi sno t clear. It mayb e either a decrease in aldehyde dehydrogenase activity, owingt o acetaldehyde-induced damageo fth emitochondria , a decreaseo f theNA D - regenerating potential, or an accelerated alcohol oxidation (MEOS induction) (47, 96). Others consider the increased acetaldehyde level as acaus eo f alcoholism: even before their addiction hasbecom e established, alcoholics would havea deviant metabolism, producing more acetaldehyde. Thiswoul db e in accordancewit h Schuckit's finding (77) that first-degree relatives of alcoholics havea highe r blood acetaldehydelevel . The reliability of the determination of acetaldehyde concentrations has been subject for debate (16, 47, 51). Itha s recently become evident that acetaldehyde concentrations determined byolde r methods are often artefacts brought about by the acetaldehyde generated during analysis.

3.4. Second step: conversion of acetaldehyde into acetate

During the second step in the oxidation process theacetaldehyd e generated iscon ­ verted into acetateb yth e NAD-dependent enzymcaldehyde dehydrogenase (A1DH). Of the acetaldehyde 90-95%i sconverte d in thelive r (97).Almos t all other tissues also contain AlDH;however , its extrahepatic activity islo w(17) . Human AlDH isa tetrameri c enzymewit ha molecula r weight of ca. 230 000. In the liver at least four different isozymes exist,whic h differ in structural and functional properties such asprimar y structure, molecular weight, electrophoretic migration, isoelectricpoint , catalyticconstant s and subcellular distribution. AIDH2ha s the

38 highest affinity to alcohol (a lowMichaeli s constant, ^m). AIDH2i slocate d in the mitochondria, the other A1DHisozyme s in the cytosol. CytosolicA1D Hi smor e susceptible to inhibition by disulfiram (3). There appear tob e interspecific differences in subcellular distribution and amounts of high- and \ov/-Kmform s in the liver. Whites havetw opredominan t A1DHisozymes :AlDH i and AIDH2. Many Asians dono t haveth e activeAIDH 2isozyme , but an inactivefor m (21). Because one of the 500 amino acids differs (substitution of lysinefo r glutamine (80)), that form of AIDH2i sinactive . Thisvarian t isfoun d in about 50%o f Japanese, 35% of Chinese and 40%o f Vietnamese and Indonesians. Thelac k of the activefor m of thisA1D H isozyme, causing an increased acetaldehyde level upon alcohol consumption, is considered the main causeo f theflushin g syndrome (1, 2, 24, 101)- a hypersensitivity to alcohol frequently seen in peoplebelongin g to the mongoloid race, manifesting itself in cardiac arrhytmia and flushing. These phenomena are comparablewit h the disulfiram reaction. They areconsidere d to result from acute acetaldehyde intoxication. The atypical ADH isozyme demonstrable in ca. 90%o fal l orientals (2, 73) isno w considered of littleimportanc e asa cause of flushing (47, 101). The unpleasant reactions (flushing, cardiac arrhytmia) due to accumulation of toxicacetaldehyd e discourage alcohol use and abuse. Almost allEas t Asian alcoholics (91%) haveth e activeAIDH 2for m and areno t flushers (37). Lack of the generesponsibl e for activeAIDH 2productio n isconsidere d ageneti c protection against alcoholism (79). So, a clear relation issee n between thegeneti cvarian t ofa n enzymean d drinkinghabits . Someside-reaction s of acetaldehyde takeplac ei n addition to its conversion to acetate, such as reactions with pyruvate, alpha-ketoglutaric acid (92), and various proteins (13). Condensation reactions between acetaldehyde and anumbe r of neurotransmitters, such acatecholamines , dopamine and serotonine, duringwhic h morphine-like substances areformed , mayals o occur. These reactions are quantitatively unimportant in acetaldehyde conversion. The compounds formed, however, may exert an essential, but asye t not entirely elucidated, influence on the nervous system (15, 51,87) .

3.5. Third step: the conversion of acetate

All acetate reactions proceed via theactivate d form, acetyl-coenzyme A (acetyl- CoA), which isa metabolit e central to thewhol emetabolism . It isals o formed during catabolism of carbohydrates, fats and anumbe r of amino acids. It isno t clear whether in thelive rfre e acetate or acetyl-CoAi sgenerate d from alcohol (92). The acetate (or acetyl-CoA) formed in thelive ri shardl y oxidized during the citricaci d cyclebecaus eo f an NAD shortage in the liver causedb y previous oxidation of alcohol and acetaldehyde (92, 94). Most of the acetatei s released into the circulation and oxidized extrahepatically to CO2 and H^O through

39 acetyl-CoAi n the citricaci d cycle. In sometissue s such asth eheart , acetate servesa s thepreferre d substrate overglucos e and fatty acids. A smallproportio n of the acetate generated from alcohol isincorporate d in tissue components by anabolic reactions. The endogenous acetatelevel s arerathe r low (0.1-0.3mM) . During alcohol oxidation blood acetate concentration risesi nhal f an hour to about 0.5-1.2 mM and reaches aplatea uwhic h ismaintaine d aslon ga salcoho l ispresen t in the blood. In alcoholicswit h an elevatedrat eo f alcohol elimination, the acetate concentration inbot h the hepaticvei n andperiphera l veinsi shighe r than in controls. Therei sa hig h correlation between therat eo f alcohol elimination andth ebloo d acetate concentration. It issuggeste d that an increased level ofbloo d acetate during ethanol oxidation mayb euse d asa nindicato r of enhanced ethanol oxidation (61). Thehighe r blood acetatelevel si n alcoholics mayhav econsequence s for the heart and theliver , because acetate can havemetaboli c effects on themyocardiu m (30) and interferes withlipi dmetabolis m (78, 81). Extrahepic dissimilation of acetateyield s about twothird s of thetota l combustion energy producedb yalcohol . Theremainin g energy isrelease d duringlhe generation of acetatei n the liver.

prolonged action reduced half-time (drugintolerance ) (drugtolerance ) hapatotoxicity

enhancedactivatio n oftoxi c J metabolites liveri na situatio n alcoholic liver ofsimultaneou s ofa nabstainin g alcoholoxidatio n patient

alcohol

Fig. 3.3. Paradoxical interaction between alcohol and drugs. When liver cellscom e into contact with alcohol, drug metabolism willb e inhibited competitively or non-competitively. This'result s in an extended effect of the drug inth e organism (drug intolerance) (left-hand sideo fth efigure) . On the other hand, when the liver cell does not contain alcohol, but shows aproliferate d smooth endoplasmatic reticulum (SER) due to chronic alcoholism (right-hand side of the figure), the organism mayb e either detoxified more rapidly (drug tolerance) or the drug mayb e converted to larger quantities of toxicmetabolite s and thus enhance liver intoxication. After: Hasumura & Takeuchi (25).

40 3.6. Interaction between alcohol and drugs

Severalxenobiotic s (for instance drugs) are converted through the cytochrome P-450 system. Thispartl y explains the effect of alcohol on the metabolism of drugs, andvic e versa. In alcoholism MEOS isinduce d and thus capable of metabolizing larger quantities. In sober alcoholics, drugs and other xenobiotics are converted more rapidly. Thesesubstance s areconsequentl y less effective, but the concentration of metabolites, which arequit e often hepatotoxic, increases (41,89) . Following alcohol consumption, the system isblocke d by ethanol, which causes a delay in elimination and an increased activity of drugs (25, 43,75 ) (seeFig . 3.3). MEOS induction mayals o result from the useo f certain types of drugs such as barbiturates. Pre-treatment with these drugs mayactivat e ethanol metabolism whereas the presence of drugs mayhav ea inhibitor y effect. Although acute and chronicform s of alcohol consumption have astron g effect on drug metabolism, the reverse effect ismuc h smaller (41). The interaction between alcohol and drugs iscomple x and does not takeplac evi a theMEO S pathway only (42). Some antimicrobial drugsinhibi t A1DH, resultingi n disulfiram-like reactionswhe n combined with alcohol. The effect of drugs that are converted byADH , such as digitalis, canb e influenced byalcoho l through direct competition. GastricAD H isinhibite d byH2-recepto r antagonists such as Cimetidine, resulting in higher blood alcohol levels (8). Alcohol consumption might alter drug absorption byincreasin g solubility (48) orb yinterferin g with gastric emptying. Liverinjur y isusuall y accompanied with a delayi nbiotransformatio n (31). Alcoholic cirrhosis causes reduced plasma binding of some drugs, resulting in toxic effects, even at therapeutic plasma concentrations. Themetaboli c rate of drugs metabolized through acetylation isincrease d byalcoho l (63) due to enhanced acetyl- CoA production during alcohol metabolism. Theoretically, alcohol can interact with drugsvi a thehepati cbloo d flow and hepatic uptake, but there isn o convincing evidencefo r this. All effects mentioned sofa r fall under the heading of pharmacokinetic interactions (inhibition or stimulation of metabolism). No mention hasbee n made as yet of pharmacodynamic interactions, inwhic h the effects on the central nervous system areintensified . Noordhoek (60) has lucidly reviewed the interactions between drugs and alcohol.

3.7. Modification of alcohol metabolism

Theoretically, anumbe r of nutrients mayhav eth epotentia l of influencing alcohol metabolism. Niacin and riboflavin, being part of thehydrogen-acceptin g co-factors NAD and FAD, mayincreas e themetaboli c rate, sinceunreduce d NAD is often considered therate-limitin g factor inmetabolis m (53). Vitamins Can d E aswel la s

41 fructose might also affect metabolism through their effect on redoxreaction s (65). It isals opossibl e toincreas eth e metabolic rateo f ethanol byinductio n of theMEOS . Actually, however, alcohol metabolism proves asgoo d asinsusceptibl e to the influence of external agents. Pre-treatment with some drugsha sbee n found tohav e some effect (via the MEOS pathway). Fructose (1-2 g/kgbod yweight ) accelerates alcohol metabolism (11, 27, 98). The effect of glucose (54) ismuc h smaller than the effect offructos e (27). A carbohydrate-rich diet (with carbohydrates including fructose accounting for 90%o f energyintake ; 74) or aprotein-ric h diet (99) isonl y slighly effective in thisrespect . These effects offructose , glucosean d other carbohydrates are often seen without aconcomitan t decrease of the alcohol-induced increasei n lactate/pyruvate ratio (98), soth emechanis m of action isno t clear. Alsoa megadose of vitamin C (5 gdail yove r aperio d of twoweeks ) enhances alcohol metabolism without affecting thelactate/pyruvat e ratio (82). Other possiblereaction s havebee n discussedi n Sections 2.3.2 and 2.4.

Summary

Ethanol mayb e considered both apsychotropi c substance and anutrient . Alcohol oxidation proceeds along severalpathways . Thefirs t pathway causesacetaldehyd e to begenerated , which issubsequentl y converted into acetate. About 90%o f these reactions take placei n the liver. Theacetat e isfo r thegreate r part released into the circulation and may undergo several more reactions. Three enzymesystem s areno wknow n to increase theconversio n of alcohol into acetaldehyde. The most important reaction isth e NAD-dependent onewit h ADH as an enzyme. There arelarg eindividua l and racial differences in ADH activity (due to differences in quantitative and qualitative distribution of theisozymes) . The other two systems, i.e. the NADPH-dependent MEOS reaction and the catalase-linked reaction, playn o important roleunde r normal conditions. Chronic alcohol consumption induces the cytochrome P-450, which isresponsibl e for the MEOS activity (especiallyisozym eP450IIE1) . So, morealcoho li sconverte dvi ath e MEOS pathway, but towha t extent exactlythi sfacto r contributes to theproces s isno t clear. Several other xenobiotics (such asdrugs ) are also converted via cytochrome P-450. This maypartl y explain the effect of alcohol on drugs and viceversa . In the second oxidation step theacetaldehyd e formed isconverte d into acetateb y theNAD-dependen t enzymeA1DH . Thefac t that one of theisozyme si sinactiv ei n ca. 50%o f alloriental s isresponsibl e for the occurrence of theflushin g syndrome (acute acetaldehyde poisoning upon alcohol consumption). A smallpar t of the acetateforme d isincorporate d in issuethroug h anabolic reactions, theremainde r is broken down to CO2an dH2 O extrahepatically. Theoretically, many nutritional components might affect alcohol metabolism. Actually, a substantial enhancement of therat eo f alcohol metabolism has onlybee n proved for fructose.

42 References

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46 CHAPTER 4 Alcohol and hormone metabolism

W.G. Vrij-Standhardt

In this chapter the effect of alcohol consumption on thevariou s hormones and hormone systemswil lb e considered. Attention willals ob epai d to theinfluenc e of somehormone s on alcohol metabolism.

4.1. Vasopressin, renin and aldosterone

Extracellular water and sodium concentrations are regulated bytw o hormone systems. Vasopressin (antidiuretic hormone), secreted byth eposterio r lobe of the pituitary gland, stimulates water reabsorption in thekidney . Vasopressini s secreted upon stimulation of the osmoreceptors inth e hypothalamus. The second hormone system isth e renin-aldosterone axis. Under the influence of baroreceptors and sodium receptors in thejuxtaglomerula r apparatus in thekidne y the secretion of renin isstimulated , thus causing areleas e of aldosterone byth e angiotensin generated in theliver . Aldosterone issecrete d byth e adrenal cortex and is responsible for the renal reabsorption of sodium and chlorideb y stimulating the Na- Kpump . Besides the endocrinological action of thewhol evasopressi n molecule, therei s evidencetha t certain fragments ofvasopressi n function asneuropeptide s (99). These neuropeptides affect and modulatebrai n processes. One of these central actionsi s modulation of memory processes. Vasopressin represses themil d amnesia causedb y a moderate dose of alcohol (2 mlwodk a per kgbod yweight) . Also in a sober state vasopressin improves human short-term memory processes (and interferes negatively with later learning)(71). This suggests that there isn o interaction between vasopressin and alcohol asfa r asmemor y processes are concerned. There issom e evidencetha t vasopressin plays arol e infunctiona l tolerance (46, 47)b y affecting neurotransmission. Vasopressin attenuates the reinforcing action of some drugs (99). One of the endocrinological effects of alcohol discovered earliest isit s inhibitory effect on release ofvasopressi n (24). Consequently, theconsumptio n of a single dose of alcohol causes diuresis. In caseo f repeated, orally administered doses of alcohol the diuretic response decreases to zero (98) in spiteo f agraduall y increasing blood alcohol concentration (BAC). Themechanis m involved in this diminished response to repeated doses of alcohol canb e explainedb y aresettin g of the osmoreceptorsb y alcohol. Alcoholics in thebeginnin g ofwithdrawa l showa n increased vasopressin level,whic h decreases to normal during detoxification (27, 79). An increased

47 Vasopressin levellead s to an antidiuretic state, and overhydration of thebrai n can occur (54, 63). Itha sbee n hypothesized that overhydration of thebrai n causes some of the neurological symptoms observed duringwithdrawa l aswel la ssom e of the neuropathological abnormalities seen in alcoholics (54). From several studies it hasbecom e apparent that alcohol also affects the renin- aldosterone axis (29, 30, 33, 38, 56). Theresults , however, are contradictory: unchanged, increased aswel l as decreased aldosterone levelshav ebee n found. Presumably the aldosteronerespons e to alcohol consumption depends on the actual doses of alcohol consumed, the timeafte r consumption (determined when the BAC either increases or decreases, or during aperio d ofwithdrawa l orhangover) , the individual involved (alcoholic or non-alcoholic), and thepresenc e of liver disease. In patientswit h cirrhosis therat eo f removal of aldosteronefro m theplasm a is decelerated (18). Although it has not been proved asyet , it seemslikel ytha t thereleas e of renin which hasbee n observed during alcohol intoxication and hangover, should be considered anorma l response to ethanol-induced diuresis. A non-specific stress reaction and a direct influence of alcohol on aldosterone or renin synthesis or release have alsobee n mentioned aspossibl e causes. .

4.2. Parathyroid hormone and calcitonin

The calcium concentration ofbloo d isregulate db yparathyroi d hormone and calcitonin. Parathyroid hormone, secreted byth e parathyroid gland, increases the blood calcium levelb ystimulatin gbon e reabsorption (calcium and phosphate release), decreasing calcium secretion and increasing phosphate excretion in the kidney, and increasing calcium uptakei n theintestine . Calcitonin isproduce d in the C-cellso f the thyroid gland, and decreases thebloo d calcium concentration. Vitamin D regulates calcium absorption and calcium transport to and from thebone , administration of alcohol increases the rate of excretion of calcium and magnesium. Alcohol has a direct stimulating effect on calcitonin release (22, 104). In hospitalized alcoholics hypocalcaemia isfrequentl y observed (10, 12, 28, 67);i tofte n disappears spontaneously upon alcohol withdrawal and adherence to an adequate diet. In alcoholics suffering from both hypocalcaemia and hypomagnesaemia, the administration ofparathyroi d extractprove d tob e aninsufficien t remedy; hypocalcaemia didno t disappear until magnesium had alsobee n administered (28, 67). Hypocalcaemia probably occursprimaril y asa resul t of hypomagnesaemia, since itha sbee n suggested that magnesium isnecessar y for the action of parathyroid hormone in response to hypocalcaemia. So, hypomagnesaemia mayresul t in parathyroid hormone resistance (28). Bjorneboe (10) and Chappard (12) report serum parathyroid levelsi n alcoholicswithi n normal ranges. Consumption of 0.89g alcohol per kgbod yweigh t hasn o significant effect on serum parathyroid hormone level (57).

48 In cirrhotic alcoholics the osteoblastic activity (boneformation ) ratei s reduced and extensive skeletal osteoporosis isfoun d (12). It ispossibl e that the activitieso f enzymes crucial in cholecalciferol (vitamin D-3) metabolism mayb e altered in alcoholics (10).

4.3. Thyroxine

Thyroid activityi sregulate d byth e thyroid-stimulating hormone thyrotropin (TSH) secreted byth e anterior pituitary. TSH isrelease d under theinfluenc e of thyrotropin- releasing hormone (TRH) from thehypothalamus . The thyroid secretes mainly thyroxine (tetra-iodothyronine, T4), and in addition sometri-iodothyronin e (T3). T4 isconverte d into the more activeT 3i n the liver. Thyroid hormones have numerous effects on the organism, such as anincreas e of basal metabolism, and an increased transmission of impulses in theperiphera l nervous system. In general, the thyrotropic axiswil lb e hardly affected byalcohol , provided no liver injury ispresent . No deviant TSH levelswer efoun d innorma l subjects after consumption of alcohol. Thepituitar yrespons e to exogenousTR H wasals owithi n normal limits (55). The results concerning serum T3, T4 and TSH levelsi n alcoholics are conflicting. Normal levels of T3, T4 andTS H havebee n reported (73), but also decreased T3 levels and raised T4 levelshav ebee n found (1, 73, 83, 87). It hasbee n suggested that T4i slowere d in alcoholics, while duringwithdrawa l the T4leve l rapidly increases to normal or above(59) . The hypothalamic pituitary axisha sbee n reported not tob e influenced byalcoho l (1), whileother s found an abnormal TSH response to exogenous TRH in alcoholics (58). Both alcohol per sean d alcoholiclive r injury affect thyroxinelevels . Thelive r playsa majo r rolei n peripheral metabolism of thyroxine. The conversion of T4 into T3 in thelive ri s diminishedi n caseo f liver injury. But also a direct toxic effect of alcohol on thethyroi d gland, independent of the degreeo flive r damage, hasbee n reported (45). Themechanis m of the abnormal TSH response toTR H in alcoholics with liver disease, and also in someothe r alcoholics, isunknown . Among the possible mechanisms suggested (73) are: - a direct effect of alcohol on the hypothalamus; - an increased concentration of circulating oestrogens observed in patients, since hyperoestrogenaemia leads to the sameabnorma l response ofTS H to TRH (20); - hepatic encephalopathy, associated with dopamine depletion, might facilitate TSH release (87); - reduced liverfunctio n (7, 84). Considering the prevalence of the abnormal response, acaus e associatedwit h liver injury appears most likely.

49 4.4. Growth hormone (somatotropin)

Growth hormone (GH) issecrete d episodicallyb yth epituitar y anterior lobewit h the highest peakvalue s occurring shortly after sleep onset. Itplay sa centra l rolei n the regulation of growth. Further, itha s an anabolic effect, itinhibit s theinsulin - mediated uptake of glucose, it delaysth e synthesis offa t from carbohydrates andi t stimulates lipolysis. The regulation of itssecretio n iscomplex . Secretion is stimulated byth egrowt h hormone-releasing hormone (GHRH) from thehypothalamu s andi s presumably also influenced bystress , hypoglycaemia, adrenergic stimuli, and non- esterified fatty acids. Secretion isinhibite d bya release-inhibitin g factor from the hypothalamus (somatostatin). Feedbackb ysomatomedin s alsoplay sa rol ei n this process. Both inhealth y subjects and in alcoholicswit h andwithou t liver injury, the influence of alcohol on plasma growth hormone concentration and on thegrowt h hormone response to hypoglycaemia hasbee n investigated (see 52, 73fo r reviews). Although the results are contradictory most results favour the conclusion that alcohol inhibits GH secretion. Owingt o thepulsatil esecretio n of GH, drawing firm conclusions on the effects of alcohol on serum'GH levels demands sampling overa longperiod . From thefe w studiesbase d on such astrateg y it isconclude d that ethanol, even insmal l doses, abolishesbot h sleep- andnon-sleep-associate d peakso f GH secretion (55, 80, 93,96) . It hasbee n suggested that thisi sno t theresul t of inhibition at thehypophysea l level (97). In cirrhoticalcoholic sprofoun d changesi n GH metabolism arefound . Basal GH levels are elevated owingt obot h increased GH secretion and reduced catabolism in the liver (96). However, Agner et al. (1) suggest that theincrease d growth hormone levelsar e duet o decreased somatomedin levels.

4.5. Insulin and glucagon

Insulin issecrete d byth eß-cell so f the islets of Langerhans in thepancreas . It decreases thebloo d sugar levelb yincreasin g glycogen synthesis, decreasing gluconeogenesis, increasing theglucos e permeability of the cellwall , and decreasing the degradation offat . Insulin secretion isstimulate d by hyperglycaemia. Glucagon, secreted byth e a-cellso f theislet s of Langerhans, isa n insulin antagonist. Itincrease s thebloo d sugarleve lthroug h thebreakdow n of hepatic glycogen, stimulation ofgluconeogenesi s and thebreakdow n of fat. Iti srelease d in caseo f hypoglycaemia. In most investigations alcohol proved not to affect thebasa l plasma insulin level (8, 75). In onlyon e study an increaseha sbee n found (89), in others a decreaseha s been observed (49). Thelatte r mayhav ebee n arespons e to thelowere d blood glucoseleve linduce d byalcohol . When administered tonorma l subjects, both orally and intravenously, alcohol increases theplasm a insulin response to aglucos eloa d (73,75).Th e mechanism

50 involved isunknown , although it hasbee n suggested tob e the result of a direct effect of alcohol on the/3-cell s(73) . In chronic liver disease, whether or not causedb yalcohol , carbohydrate intolerance, usuallywithou t clinical symptoms, isfrequentl y observed (73). Increase ofplasm a insulin levelsi scause db ydiminishe d insulinbreakdow n inth e livera sa result of hepatocellular failure (50). A direct effect of alcohol on glucagon could not be demonstrated (77), but glucagon releasema y result from alcohol-induced hypoglycaemia. Changes inplasm a levelso finsuli n and glucagon, which mayb e common to alcoholics but mayals ob e acute asa respons e to alcohol consumption, have no clinical consequences as arule . Alcohol-induced reactivehypoglycaemi a mayb e partly caused bya changei ninsuli n response. According to Morgan (73), however, neither hormone plays an important part in the pathogenesis of alcohol-related hypo- or hyperglycaemia (see Chapter 5).

4.6. Glucocorticoids

Glucocorticoids, the most important ofwhic h isCortisol , are secreted byth e adrenal cortex under the influence of ACTH (adrenocorticotropic hormone, corticotropin) released from the anterior pituitary. ACTH releasei sregulate d byth e corticotropin- releasing factor (CRF) in thehypothalamus . CRFrelease , and possibly ACTH release aswell , mayb e influenced byth e plasma Cortisol concentration (negative feedback), andb yth e diurnal sleep-wake cycle. Plasma Cortisoli spartl yboun d toa cortisol-binding protein. The unbound fraction isbiologicall y active. Cortisol is metabolized in the liver. It predominantly affects carbohydrate metabolism, thus increasing thebloo d sugar level, and has many other activities such as an anti­ inflammatory effect. The administration of intoxicating doses of alcohol to subjects usually resultsi n an increasei n plasma Cortisol level. Both normal, increased and decreased values have been found in alcoholics (17, 73). Plasma ACTH iselevate d in drinking chronic alcoholics. It hasbee n suggested that chronic alcohol consumption might havea direct stimulatory effect on the adrenal cortex, leading to disorganization of the hypothalamic-pituitary axis (HPA) (61). The plasma Cortisol response depends on the doseo f alcohol (quantity, chronic or acute), thepresenc e of liver disease and the timeo f measurement (during intoxication or after withdrawal). There areindication s that theincreas ei nplasm a Cortisol levelsfollowin g acute alcohol consumption in non-alcoholics isinduce d via thehypothalamic-pituitar y axis (HPA) aswel l asb ya direct effect on the adrenal cortex. It hasbee n suggested that thelatte r effect ismediate d byacetaldehyd e (17). Theindirec t stimulation via the HPAma yb eth e result of stress (77). Theincreas e ofplasm a Cortisol levelsfoun d in alcoholics - decreasing again after amoderat e doseo f alcohol had been administered (69, 70) - supports the stress hypothesis. Thisi sals o thecas efo r theincreas ei n plasma Cortisollevel s of subjects upon large doses of alcohol being associatedwit h

51 gastrointestinal illness (52). A third causeo f an increased plasma Cortisol levelma y be a diminished Cortisol catabolism causedb yhepati c dysfunction. In viewo f the sometimes conflicting experimental findings more definitive conclusions concerning aetiology can not be drawn. In somecase s alcohol-induced hypercortisolaemia givesris e to the pseudo- Cushing syndrome, which isreversibl ei n contrast to the genuine Cushing syndrome (an overproduction of glucocorticoids duet o dysfunction of thepituitar y or the adrenal cortex) (73). Its symptoms arefacia l mooning, truncal obesity, and proximal musclewasting . It isno t clear asye twha t causesth e development of thepseudo - Cushing syndrome.

4.7. Adrenaline and noradrenaline

Adrenaline (epinephrine) and noradrenaline (norepinephrine) areproduce d in the adrenal medulla. Theyals ofunctio n asneurotransmitter s of the sympathetic nervous system. The secretion of (nor)adrenaline iscontrolle d byth enervous'syste m bypassingth epituitary . The adrenal medullar hormones playa nimportan t rolei n stress and arepowerfu l vasopressors. (Nor)adrenaline breakdown follows both an oxidative and areductiv e pathway. Although some investigations produced contradictory results, it mayb e said that administration of alcohol to normal subjects aswel l ast o alcoholics increases circulatory levels and urinary output of catecholamines (a collectiveter m comprising adrenaline, noradrenaline and dopamine). Kakihana and Butte (52) and Paille etal . (77) havereviewe d research in this field. Acute alcohol consumption stimulates central noradrenergic functioning; however, in thelon gterm , chronicintoxicatio n induces noradrenergic hypofunctioning (76). Noradrenergic hypofunction ison e of thefactor s involvedi n craving (3, 76). Other neurotransmitter systems (dopamine, opioidpeptides ) areals o saidt o play arol e (76). There isa grea t deal of controversywit h regard to the relative importance ofth e diverseneurotransmitte r systemsi n reward and reinforcement, resulting in craving (3). Withdrawal isaccompanie d with sudden noradrenergic hyperactivity (76). According to Paille et al. (77) the decreased levelsi n chronic alcoholics mayb e causedb y deficiencies offolat e and vitamin B-6, which arenecessar y for (nor)adrenaline synthesis. In Pohorecky's view (78) catacholamine turnover is increased in alcoholics. Theincrease d plasma (nor)adrenalinelevel safte r acute alcohol consumption are saidt ob ecause db yreductio n ofit s circulatory clearance rather than by an increased release (25). One of theAD H isoenzymes hasa physiological rolei n the degradation of circulating adrenaline and noradrenaline (64). Becauseo f the excesso fNAD H duringalcoho l metabolism, reductivebreakdow n of catecholamines increases at thecos t of oxidativebreakdown . Upon condensation

52 reactions with acetaldehyde the substances generated during this process (such as tetrahydropapaverolin) maypla ya par t in alcohol dependence (77).

4.8. Male sexhormone s

Twofunction s mayb e attributed to the testes: - spermatogenesis under theinfluenc e of FSH (follicle-stimulating hormone) from the anterior pituitary, the androgens playing a 'permissive' role; - production of androgens in theinterstitia l cells of Leydig under the influence of LH (luteinizing hormone) from the anterior pituitary. The androgens, themos t important ofwhic h istestosterone , cause the development of the secondary sexual characteristics and havea stron g metabolic effect. The release ofLH , and presumably also ofFSH , isstimulate d byLHR H (LH- releasing hormone), released from the hypothalamus and inhibited bynegativ e feedback of the androgens (LH) and of inhibin (FSH). Thehypothalamic-pituitary-gonada l axisi sheavil y affected byalcohol , which may lead to regularly occurring clinical consequences. Mandell et al. (62) repprted at least onefor m of sexual dysfunction in 84%o f 44 alcoholics interviewed (erection disorders 59%, ejaculatory incompetence 48%). Further, hypogonadism (manifesting itself as testicular atrophy, impotence and diminished fertility) and hyperoestrogenism (manifested bygynaecomasti a and losso fbod yhair ) havebee n observed in alcoholics (34, 74). These symptoms havebee n observed both in alcoholics with and alcoholics without liverdisease , but alsooccasionall yi n non-alcoholic cirrhotics (74). Upon abstaining, improvement hasbee n seen in alcoholics (35, 102, 103). Many alcoholics are affected bydiminishe d fertility, the semen often showing decreased spermatozoal motility, asmalle r number of spermatozoa per volume of semen, and abnormally shaped spermatozoa (74). The semen qualityo f moderate drinkers didno t differ from that of abstainers (63). Invitr o studies showed acrosomal lossi n human spermatozoa incubated in alcohol (2). Part of theacrosom ei snecessar y for egg penetration. The symptoms seen in alcoholics suggest an imbalance of sexual hormones. In alcoholics often lowlevel so f testosterone arefoun d (43, 48, 74), although normal levelshav eals o been observed (40, 65). According to somestudie s (see 41) acute alcohol administration doesno t affect plasma testosterone concentration, in other studies increased or decreased levelswer efoun d (14, 26, 31,95 ,96) . Most plasma testosterone isboun d to albumin (55%) or sex hormone-binding globulin (SHBG) (40%). Only 2%circulate s freely. SHBG-bound testosteronei sles s biologically active. Gluud et al. (40) found in cirrhotic alcoholics anorma l total testosterone concentration, whereas theconcentration s of the subfractions had changed (less non-SHBG-bound testosterone). Oestrogen concentrations in alcoholics are elevated or normal (40, 41).

53 Themechanism s of decreased testosterone and increased oestrogen levelsar e not completely understood. Someconside r thelive r diseaseofte n seeni n alcoholics tob e the major factor, but othersblam e alcoholitself . According to Bannister et al. (6) liver diseasepe r seappear s to cause sexual dysfunction and sexhormon e changes, but these changes areamplifie d byethanol . Gluud (41) concludes that decreasing liverfunction , but not ethanol consumption, isresponsibl efo r thelo wlevel so f testosterone in alcoholic cirrhotics. There areindication s that alcohol exertsmultipl e effects on thehypothalamic - pituitary-gonadal axis(13 , 15, 16, 102). Towha t extent eacho f these possibilities contribute to sexual disturbances isno t known asyet . Some suggest an effect of alcohol on LH releasefro m thepituitar y (86, 100),bu t according to other studies this sitei sunaffecte d byalcoho l (26). Affection of theLHR H releasefro m the hypothalamus (19) or LH receptors inth etesticula r membrane (9) areals o suggested. Animal studies support theide a that alcohol or acetaldehyde has a direct inhibitory effect on testosterone synthesisi n the testis (14, 35, 85,96) .A n increased metabolic clearancerat eo f testosterone, duet o liverinjury , mayals ocontribut et o thelo wtestosteron e levelsfoun d in alcoholics (92). In addition to direct effects of alcohol, increased adrenal secretion of Cortisol, whichi sknow n to inhibit testosterone synthesis, maycontribut et o the decreasei n serum testosterone (95). Presumably alcoholha s a direct influence on spermatogenesis aswell . Retinal, generated from retinolvi ath e alcoholhydrogenas e (ADH) enzyme,i snecessar y in spermatogenesis. ADH activityha sbee n demonstrated inth eteste s (11). Competitive inhibition byalcoho l results in retinal deficiency and decreased levelso f testosterone inth e testes, thus diminishing spermatogenesis (49). . There aresevera lmechanism s that can explain feminization asa resul t of hyperoestrogenism in chronicalcoholics . Oestrogenic activity canb eincrease db y enhanced conversion of testosterone into estrogen due to alcohol-induced increment of hepatic aromatase activity (42), orb yconversio n of the less active oestrogen oestroneint o the activeoestradio l duet o thehepati credo xreactio n during alcohol metabolism (4). Oestrogen breakdown canb e decreased in caseo flive r damage. Others consider an increase in oestrogen receptors, induced and maintained bylo w serum testosteronelevel s (23). Thiscoul d explainfeminizatio n despite normal oestrogen levels. Recently, phyto-oestrogenic compoundshav ebee n identified in bourbon (82). Thesenaturall y occurring plant metabolites inbourbo n possesswea k oestrogenic activities, which can contribute tofeminizatio n inbourbon-drinkin g alcoholics (37). Itha sbee n shown that sexhormone s mayi ntur n influence alcohol metabolism (90, 91). In female ratshighe r ADH activity andlowe r microsomal ethanol-oxidizing system (MEOS) and catalaseactivit yhav ebee n demonstrated ascompare dwit h male rats. When malerat shav ebee n castrated, orwhe n oestradiol hasbee n administered to them, ADH activityincrease s andMEO S activity decreases. The effects of castration aretotall y annulledb yadministratio n of testosterone. In female rats testosterone decreasesAD H activityan d increases MEOS activity and catalase.

54 Administration of oestradiol and ovariectomy doesno t affect ADH activity in female rats. Whether these observations also apply tohuma n beings andwha t consequences theyma yhave , needs further investigation. Therapywit h testosterone or other anabolic-androgenic steroidsi sapplie di n the treatment of alcohol liver disease (39, 60). This therapy isbase d on the presumption that these anabolichormone s accelerate resolution of alcoholicfatt y liver. Case- control studies suggest testosterone therapy tob e ineffective, whereaswit h some other anabolic-androgenic steroids positive results are obtained (60).

4.9. Female sexhormone s

4.9.1. Progesterone andoestrogen

Themos t important female sexhormone s areprogesteron e and oestradiol. Progesterone issecrete d byth e corpus luteum under theinfluenc e of LH and, in pregnancy, byth e placenta. Oestradiol isproduce d in the ovarian follicles under the influence of FSHfro m thepituitary . Thesehormone s show amonthl y cycledu et o an intricate pattern ofinhibition , stimulation andfeedback , which complicates research on effects of alcohol. Little research has been done asye t on the effect of alcohol on female sex hormones, possiblybecaus e alcoholism causes less striking sexual dysfunction in women than in men. Female alcoholics are often subject to menstrual disturbances such asirregula r menses, menorrhagia and amenorrhoea (74). Ovulation is affected, resulting in diminished fertility. A decreasei ngonada l massha sbee n observed due to the absence of corpora lutea (101). In alcoholicwome n with liver diseaseplasm a concentrations of oestradiol and progesterone aswel la surinar y oestrogen excretion are reduced to roughly the sameleve l asi npost-menopausa lwomen . Thelevel s are significantly lower than thoseo f age-matched menstruating women. Plasma gonadotropin levels are not elevated and their response to stimulation byLHR H is not enhanced. It hasbee n suggested that disturbed regulation of gonadotropin secretion isa n important factor in thegenesi s of oestrogen deficiency and amenorrhoea in chronic alcoholicwome n with liver disease, although ovarian function may alsob e directly impaired (94). In pregnant alcoholicswh oha d deliveredbabie swit h thefoeta l alcohol syndrome oestrogen concentrationsha d decreased throughout pregnancy, whereas alcoholics whoha d delivered healthybabie s maintained normal levels (44). In healthywome n acute alcohol consumption (1.2 galcoho l per kgbod yweight ) hardly affects plasma gonadal hormone concentrations (26, 93).

4.9.2. Prolactin

Prolactin, secreted byth e anterior lobe of the pituitary, activates thecorpu s luteum and promotes lactation. Thebasa l plasma prolactin levelha sbee n found tob e either

55 unaffected (21, 88, 105) or reduced (93) after acutealcoho l intake, whereas the prolactin level after beer (but not after alcohol) was elevated (21). The responseo f prolactin tonaloxon e (an opioid antagonist) andTR H stimulation is exaggerated (1, 68, 105). Suckling-induced prolactin release and milk consumption byth epup s were found tob e strongly inhibited byalcoho l in thera t (88). Bycontras t to alcoholic men, hyperprolactinaemia isno t among the hormonal abnormalities of chronicalcoholi cwome n (94). Nothing isknow n about possible consequences, although some suggestions have been made, such asfeminizatio n inme n (16),breas t cancer inwome n (16) and depression (72).

4.9.3.Oxytocin

Oxytocin issecrete d byth eposterio r lobeo f thepituitary . Oxytocin triggers the 'let down' reflex during lactation and stimulates uterine contractions in delivery. In animal experiments oxytocin release, determined from uterinemotility , proved to be decreased by alcohol. When theBA Cha s reached values of ca. 2g/ 1 theintensit yo f labour decreases and delivery isdelaye d (52).Thi sinhibitio n byoxytoci n release has been clinically tested. BACs of ca. 1.2 g/1 proved topreven t premature labour to some extent (33). However, considering its effect on the unborn child (see Chapter 13), this application of alcohol is debatable.

Summary

The nervous and endocrine systems coordinate and integrateà variet yo f physiological processes. From anumbe r of glands hormones are released into the circulation, which transports them to thetarge t organs. Manyhormone s are secreted under the influence of releasing hormones originating from thepituitary , whichi n their turn arerelease d bycommand s from the hypothalamus. Alcohol consumption and alcoholism affect thebloo d concentration of almost all hormones. Its aetiologyha snot , or notyet , been elucidated entirely. Anumbe r of more or lessplausibl ehypothese s havebee n brought forward. The aetiologyo f growth hormones, insulin and female sexhormon e changes isstil l entirely obscure. The direct and indirect effects of alcohol consumption on hormone metabolism may be manifested within awid erang e of sites: - the effect of alcohol on thehypothalamu s and/orpituitar y (thyroxine, Cortisol, male sexhormones , oxytocin), - the effect of alcohol onhormon e production in or releasefro m the gland (renin, male sexhormones) , - the effects on receptor level (malese xhormones) , - the effects of alcohol metabolites acetaldehyde and hydrogen (e.g. NADH) (Cortisol, male sexhormones) , - the effects oflive r injury (thyroxine, insulin, Cortisol, male sexhormones) ,

56 - effects due to nutritional deficiencies accompanying alcoholism (parathyroid hormone, adrenaline), - effects of stress reactions in alcoholism, or after an acute large doseo f alcohol (renin, Cortisol, adrenaline), - effects caused bychange s of other hormone concentrations asa reactio n to alcohol (renin, thyroxine, glucagon).

The clinical consequences are often unknown. However, the diuretic effect of alcohol viavasopressi n and theincrease d excretion of magnesium and calcium in alcoholism havebee n explained. Twohormon e axes (HPA- and HPG-axes) areknow n to be strongly affected by alcohol, leading to serious consequences. In alcoholics a disturbance of the Cortisol metabolism can cause the pseudo-Cushing syndrome. Both upon asingl e doseo f alcohol and in alcoholics disturbance of the hypothalamic-pituitary-gonadal axisha s been observed in men. Most alcoholics haveon e or more symptoms of sexual dysfunctioning, due tohypogonadis m and/or hyperoestrogenism. An acute doseo f alcohol has apresumabl y reversible effect on spermatogenesis.

References

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61 CHAPTER 5 Effects of alcohol on the metabolismo f macronutrients

W.G. Vrij-Standhardt

5.1. Introduction

The consumption of alcohol hasvariou s effects on the organism. These can be classified into: - the effects of alcohol - the effects of acetaldehyde - the effect of the increasei n NADH/NAD ratiol in theliver . The shifts in metabolism following alcohol consumption aremainl y causedb yth e increasei nNADH/NA D ratio asa resul t of alcoholmetabolization , whereas the effects of alcohol and acetaldehyde rather causeorga n damage. Theincreas eo f NADH/NAD ratio resulting from ADH and ALDH reactions has several con­ sequences (seeFig . 5.1). Basically, allreaction s that need NAD - or another oxidizing equivalent - areinhibited , whereas reactions inwhic h NAD is generated arestimulated . Theincrease d NADH/NAD ratio thusfavour s the conversiono f pyruvate into lactate, fructose into sorbitol, acetoacetate into /3-hydroxybutyrate, and oxaloacetateint o malate. The activity of the citric acid cycle, the/3-oxidatio no f fatty acids andth e activation of acetate to acetyl-coenzymeA (acetyl-CoA) are inhibited. Glycolysisyield spyruvate , which isnormall y oxidated in the citric acidcycle . During alcohol metabolism the citricaci dcycl e(whic h produces hydrogen aswell )i s inhibited because of the increasei n NADH/NAD ratio. Pyruvatewil lthe n be converted into lactate- for which process NADH isnecessar y - resulting in an increased lactate/pyruvate ratio (28, 38, 39). The extent ofth e shift inlactate/ - pyruvate ratio canb einfluence d byth e diet. After a 5-daypre-treatmen t with alow - carbohydrate high-fat diet thelactate/pyruvat e ratio during alcohol metabolism was significant higher than on ahigh-carbohydrat e low-fat diet (39).Ther ewa sn o effect on alcohol metabolism rate. Persons consuming alow-carbohydrat e high-fat diet are morevulnerabl et onegativ emetaboli c effects of alcohol (such asincrease d fat synthesis and decreased fat catabolism, gluconeogenesis inhibition, decreased lactate clearance after exercise).

1NAD , nicotinamide adenine dinucleotide; NAD+ , oxidized form of NAD; NADH, reduced form of NAD.

62 As arule , the increasei nbloo d lactateconcentratio n (hyperlactacidaemia)i s moderate and the acidosisi smild . Severelacti cacidosi s isuncommo n in otherwise healthy intoxicated emergency patients (10). Usuallyclinica l consequences are obviated byth ebuffe r capacity of theblood . Occasionally, however, this buffer capacity mayb e exceeded, thus causing lactic acidosis, which mayb efatal . Thisma y particularly occurwhe n there are already largeamount s of lactatepresen t in the blood, for example duet o liverinjur y (resulting from alcoholism), or oxygen deficits attendant on pulmonary disease. Fructose isknow n toinduc elacti cacidosi s and should therefore be avoided in caseso f alcohol intoxication (32). Theoverproductio n of lactatema ycaus ea n increased level ofuri caci di n the blood (hyperuricaemia). This maylea d to attacks of gout, wellknow n in excessive drinkers. Hyperuricaemia isa consequence of decreased urinary excretion of uric acid secondary to hyperlactacidaemia owing to competitive inhibition of renal clearanceb ylactat e (3,25 , 47), or to increased urate synthesis duet o enhanced turnover of adeninenucleotide s (8).Alcohol-induce d ketosis (an abnormally elevated concentration of ketone bodies) mayals o promote hyperuricaemia (23). Alcoholicketosi s isa syndrome occurring predominantly inchronic alcohol abuserswh o haveha d arecen t binge, which isfollowe d bysever e abdominal pain and vomiting (duet o gastritis, hepatitis or pancreatitis). Thislead s tointerruptio n of food and alcohol consumption, causing dehydration, starvation and ketosis. However, according to Lefevre (23), ketonaemia can be induced bychroni c alcohol administration in combination with calorically adequate diets. Thepathophysiolog y of alcoholicketosi s isreasonabl ewel l understood. In fact theter m 'alcoholicketoacidosis ' isincorrec t (60).Alcoho l inhibits ketogenesis (41), probably due to theincrease d NADH/NAD + ratio. In response to starvation fat stores aremobilized , thus leadingt o amarke d elevation of serum free fatty acids. When alcohol ingestion isstopped , due to abdominal complaints, thebloc k in ketogenesisi s released and the rapid conversion offre e fatty acids leads to substantial production of ketone bodies in theliver . The normal peripheral metabolism of ketonebodie s tend to decreasebecaus elevel so f insulin - necessary for ketonebod ymetabolis m - areofte n lowi n thissyndrome . In alcohol-associated ketosis the/3-hydroxybutyrate/-acetoacetat erati o increases. This accounts for the often minimallypositiv eseru m ketones found in dipstick tests: thisprocedur eonl y measures acetoacetate, not/3-hydroxybutyrate . Many, but not all, patients withlacti cacidosi s orketoacidosi s havea lo wbloo d pH (acidaemia). Acidaemia can be (over)compensated byhyperventilatio n or can occur together with metabolic alkalosis, causedb ygastriti s orpancreatitis , the final pH depending on whether acidosiso r alkalosispredominate s (11). Another possible effect of hyperlactacidaemia isth e stimulation of collagen production through increased activityo fprolin ehydroxylase . In addition to hyperlactacidaemia, changes in theNADH/NA D+ ratio mayals o cause changesi n carbohydrate, fat and protein metabolism.

63 -^NKMKtGI HAU ^^ PROTEINS PROTEINSVji \ /^Äll \^N*^V- DIETARY PROTEINS •-AMINO ACIDS

•- UREA ACETATE

HjO METABOLITES

*-KETOSIS

PROCOLLAGEN-» • HYPOGLYCEMIA ., PYRUVATE HYPERLIPEMIA ^=*-COLLAGEN HYPERURICEMIA « * «IIYPERLACTACIDEMI A "»OPEPTCES ^ HYDROXYPROLIN E

Fig. 5.1.Oxidatio n of alcohol inth e hepatocyte and link of the twoproduct s (acetaldehyde and H) to disturbances in intermediary metabolism (fatty liver, hyperlipaemia, hyperuricaemia, hyperlactacidaemia, ketosis). NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP;MEOS , microsomal ethanol-oxidizing system; ADH, alcohol dehydrogenase. The broken lines indicatepathway s that are depressed by alcohol. The symbol— [ denotes interference or binding. Arrowed lines denote stimulation or activation. After: Lieber (31).

5.2. Effects of alcoholo ncarbohydrat e metabolism

Carbohydrate metabolism isa comple xproces si nwhic h atleas t fivehormone s are involved. Bloodglucos eleve li smaintaine dwithi n certain limits (ca. 1 g/1) bythes e hormones. Dietary carbohydrates are digested and convertedint o glucose. Excess glucosei sconverte d intoglycogen ,whic h isstore di n the liver. Another sourceo f glucosei ssynthesi s from sources other than carbohydrates such asprotei n or fat (gluconeogenesis). Alcohol affects carbohydrate metabolism byvariou s mechanisms most ofwhic h are asye tno t entirely understood. Onepossibl econsequenc e of alcohol consumption isa decreaseo fbloo d glucoseconcentratio n (hypoglycaemia), which may even cause sudden death (25, 37, 38, 43).Th edro pi nbloo dglucos e concentration mayb es o drastictha tbrai n damageresults . Brain damagei n

64 alcoholics must possiblyb e attributed to hypoglycaemia, rather than toalcoho l itself (37, 38). The classicclinica lfeature s of hypoglycaemia aretachycardia , sweating, tremulousness, confusion, irritability and headache. Mildhypothermi a may occur as well. Hypoglycaemia isbrough t about bysevera l mechanisms. The typeo f hypoglycaemia that isbot h thebes t known and the most serious form isalcohol-induce d fasting hypoglycaemia. Asa resul t of an increased NADH/NAD + ratio and an increased lactate/pyruvate ratio, gluconeogenesis in thelive ri s inhibited. Inwell-fe d persons glucosei sthe n released from theglycoge n stores. When glycogen stores are depleted, normal blood glucoselevel s cannot bemaintaine d and hypoglycaemia occurs. In starved alcoholics, but alsoi n people consuming low- carbohydrate diets and fasting people (missing amea l or twowhil e drinking), glycogen stores are depleted. Children areparticularl y susceptible, even without fasting, asthei r glycogen stores are readily depleted (51). Although alcohol-induced fasting hypoglycaemia isuncommon , iti simportan t that iti s diagnosed and treated early, because the outcome can belethal . Another typeo f hypoglycaemia isalcohol-induce d reactive hypoglycaemia (37, 38). Following acarbohydrate-ric h meal, anatura l risei nbloo d glucose concentration takes place, resulting in an increased insulin release untika lower blood glucose level isreached . Alcohol seems to potentiate theinsuli n response to elevated blood glucoselevels , resulting in reactivehypoglycaemia , about 2-3 hours after eating (44, 51). The exact mechanism isno t known; possibly intracellular cyclic adenosine monophosphate (cyclicAMP , or cAMP) plays apar t in it. Clinical tests haveindicate d that about 30 galcoho l plus 80g carbohydrat e are sufficient to induce reactivehypoglycaemia . The rapid declinei nbloo d glucose often triggers astres s response (adrenaline release). In alcoholics themechanis m of alcohol-induced reactivehypoglycaemi a seems tob e different from that described for non-alcoholics, possibly due to disturbed hormonal processes (51). In non-fasting animals and humans acute alcohol consumption has been found to result in glucose intolerance (prolonged elevated blood glucose level after glucose load) or hyperglycaemia (7, 35). However, other studies haveno t confirmed these effects (56, 57). Considerable variation existsi n the reported results of glucose tolerance tests in alcoholics (48). Hyperglycaemia in relation to alcoholism has at timesbee n observed, but itsmechanis m isno t clear. Alcohol-related pancreatitis or adrenergic stimulation of glycogenosis byacetaldehyd e maypla y arol eher e (25, 43, 47). Pezzarossa et al. (49) suggest that glucose intolerance in alcoholicsi s primarily causedb ya n unadequate diet. Oxidation of galactosei smarkedl y inhibited byth e increased redox state in the liver upon alcohol ingestion, but this has no clinically relevant consequences (18).

5.3. Effects of alcohol onfa t metabolism

In the liverfa t issynthesize d from «-glycerophosphate and fatty acids originating from nutritional fats, adipose tissueo r endogenous synthesis. Thefa t thus formed

65 mayb e stored in the liver or released again into thebloodstrea m asver ylow-densit y lipoprotein (VLDL). Furthermore, fatty acids areuse d asa sourceo f energyi n the liver, through conversion into CO2 andH2 O inth ecitri caci dcycl eafte r breakdown to 2-Cfragments . There isa stron gvariatio n in either of thesepathway sprevailin g at anygive n time. This isdetermine d byth e amount andtyp eo f nutrients amea l contains, theperio d of time elapsed sinceth emea l hasbee n taken, but alsob y hormonal factors and stress. Alcohol also affects thesemechanism s in various stages (seeFig . 5.2). The increasei n NADH/NAD + ratio causes more«-glycerophosphat e tob eformed . It also leads tofatt y acid synthesisfro m acetyl-CoA (partly derived from alcohol metabolism) (15)bein gpromote d becausehydroge n equivalents (NADPH) are consumed during the process. The oxidation offatt y acidsi sdecrease d (NAD - dependent reaction). Consequently, themitochondri a consumeth e H equivalents formed during alcoholmetabolism , rather than theH sobtaine db yth eoxidatio n of2 - Cfragment s of fatty acids in the citricaci d cycle. Mitochondrial injury duet o chronic alcohol consumption also disturbs the citricaci dcycle , evenwhe n actually no alcohol ismetabolized . All thesefactor s promoteth ehepati cformatio n of triglycerides causing fatty degeneration of thelive r (25-27, 52). So, thefa t present in afatt y liver isno t generated from alcohol alone, asi ssometime s thought. A direct effect of alcohol on adipose tissue hasno t been established (9, 61).

Fig. 5.2. Possible mechanisms of alcohol-induced fatty liver formation. Unbroken arrows: stimulation by alcohol; interrupted arrows: inhibition by alcohol. After: Lieber et al. (27).

66 The triglyceride concentration inbloo d isconsidere d asa measur e of the transport of lipidsfro m the livert o theperipher y (20). Evenwhe nbloo d alcohol concentrations arelow , in thelive r morefa t isforme d and lessi sbroke n down than without alcohol. This fat ispartl yrelease d into thebloodstrea m aslipoprotein , as appears from an increase of the triglycerideleve l in theblood . In some investigations no changei n the triglycerideleve l upon alcohol consumption was observed (14, 19). In most experiments, however, the triglycerideleve l proved toincrease , mainlyi n the VLDLfractio n (1,4 , 6, 12, 20, 21,36 , 46, 58). Lipoprotein release decreases ata n alcohol concentration exceeding 2g/1 , possibly due to a disturbance of protein metabolism (21) or liver membranes. This leads to alowe r plasma triglycerideleve l and an accumulation of fat in theliver . Thisfatt y degeneration of thelive rwil l disappear sometim e after alcohol hasbee n eliminated from thebody , ifther ei sa timela gsufficien t for recovery. (Fatty degeneration isdiscusse d extensivelyi n Chapter 8.) Notjus t the total amount of triglycerides in theblood , but also the composition of thebloo d lipoproteins change during alcohol consumption. (These changes of the variouslipoprotei n fractions (HDL, VDL, VLDL), aswel la scholestero l changes, are discussed in Chapter 10.) Alcohol changes polyunsaturated fatty acid (PUFA) distribution (stimulation of eicosanoid formation, reduction of arachidonic acid). Results of most studies suggest that alcohol abuse leads to aPUF A deficiency in several tissues, affecting membrane fluidity. Dietary intervention mayb e effective, but recommendations for dietary supplementation cannot begive nye t (53). Evidencei saccumulatin g that part of the actions of alcohol ismediate d by essential fatty acids and prostaglandins (13, 17). Alcohol affects essential fatty acid and prostagladin metabolism. Theacut e effect of alcohol isa n increased production of prostaglandin El from dihomogammalinolenic acid (DGLA). Becease alcohol inhibits theproductio n of DGLAfro m dietary linoleic acid, chronic alcohol consumption causes depletion of DGLA and henceo f prostaglandin El (PGE1). Withdrawal willlea d to asudde n drop of PGE1. PGE1i s known to haveprofoun d effects on the nervous system and behaviour. Horrobin (16, 17) suggests that disturbances in PGE1 and essential fatty acidmetabolis m mediate (via membrane changes) some of the acutebehavioura l effects of alcohol and some chronic effects of alcohol (alcoholicfibrosis , cardiomyopathy, pancreatitis, FAS and other alcohol-related disorders).

5.4. Effects of alcoholo nprotei n metabolism

Until the 1980s,th e changes in theamoun t of hepatic proteins in alcoholics used to be attributed to an indequate diet (alcoholicbeverage s may supply alo t of energy, but hardly anyprotein s or other essential nutrients), and to decreased protein absorption due tointestina l epithelial damagecause db y excessive alcohol consumption. Alcohol proves, however, to havesom e effect on liver protein metabolism aswell . The acetaldehyde formed, and the excesso f NADH in

67 particular, cause these effects. Lieber and co-workers areimportan t investigators in thisfiel d (2, 5, 28, 33,55) . Chronic alcoholfeedin g results inincrease d urinary excretion ofnitroge n in rats and humans (40, 50). Theincrease d excretion ofnitroge n in man isassociate dwit ha negativenitroge n balance andweigh t loss. Chronic alcohol administration in rats decreases whole-body protein synthesis, due to a reduced efficiency in recycling nitrogen for protein synthesis (42). Itseem s cleartha t alcohol inhibits cardiacprotei n synthesis,b ei tb y an asye t unidentified mechanism. Therelationshi p between alterations in cardiacprotei n metabolism and the clinical and morphological consequences of excessivealcoho l intakefo r the heart remains elusive(59) . The liver produces proteins which transport various compounds inth e blood (transferrin, albumin, lipoproteins). Most (with the exception of albumin) are released into thebloodstrea m asglycoproteins . In vitro, alcohol decreases protein synthesis,bu t in vivoth e acute effects of alcohol areles sconsisten t (29). The release of liver proteins into thebloo di sinhibite db yalcohol , inwhic h process acetaldehyde- induced impairment ofmicrotubula rprotei n secretion or inhibition of.th econversio n of proteins and glucosamides into glycoproteins.ma ypla ya par t (2, 15,33) . Hepatomegaly (liver enlargement) duet o alcoholi sattribute d to accumulation of fat for onehalf , and to an increasei n proteins for the other (33). Alcohol may, either directly or indirectly, influence both the synthesis and breakdown (catabolic reactions) of protein in theliver , aswel la ssecretio n of protein from the liver. So,bot h accumulation and adecreas ei n concentration of some amino acids and proteins maytak eplac ei n theliver , as ane t result. Plasma concentrations can be elevated or decreased too. Plasma branched amino acidlevel s areincrease d bychroni c alcqhol consumption, but decreased by an inadequate diet and cirrhosis (34). In alcoholics increased plasma concentrations of the aromatic amino acidstyrosin e and phenylalanine ando f a-aminobutyricaci d havebee n found (5, 55). Tryptophan isdecrease d inbloo d of alcoholicswit h lesssever elive rinjury , and increased in patientswit h severelive r injury andportal-systemi c encephalopathy (PSE). Besidesbein g acomponen t ofproteins , tryptophan isth eprecurso r of the neurotransmitter serotonin and ispossibl y involved inth e aetiology of PSE. Methionine- asulphur-containin g amino acid- isa precurso r of glutathione, a tripeptide protecting cellsagains t oxidative andperoxidativ e damage. Chronic alcohol consumption isassociate d with a decreasei nmitochondria l glutathione and increased peroxidation (24, 34). Thisma y explain thepartia l protective effect of large amounts of methionine, which thelive r can uset o synthesizemor e glutathione (54). In fibrosis liver cellsproliferat e andproduc e increased amounts of collagen. Lactate mayb e afacto r in fibrogenesis bypromotin g collagen synthesisfro m proline. It isno t clearwhethe r increased collagen in fibrotic cellsca nb e attributed to increased synthesis (demonstrable from theincrease d activityo f proline hydroxylase) or decreased breakdown (22, 30, 32,45) .

68 From ahypothetica l point of view, thesemodification s of protein metabolism may havefar-reachin g consequences for several organs (e.g. thebrain ) and body functions (such as the transport of iron and lipidsb yth eblood) . Hardly anything, however, isknow n about the clinical consequences.

Summary

Due to alcohol metabolism various changes in themetabolis m of macronutrients (carbohydrates, proteins, fat) takeplace . Theincreas ei n NADH/NAD + ratio in the liver resulting from alcohol oxidation may havesevera l consequences. Basically, all reactions for which NAD, or another oxidizing equivalent, isnecessar y willb e inhibited, whereas reactions in which NAD isforme d are stimulated. One of the first consequences isa n increasei n the level of lactic acidi n the blood (hyperlactacidaemia). As arule , theincrease d lactateleve l doesno t havean y consequences because of thebuffe r capacity of theblood . If thebuffe r capacityi s exceeded, lactate acidosiswil lfollow . An increased level of uricaci d in the blood (hyperuricaemia) mayresul t from hyperlactacidaemia. Thisma ycaus e attackso f gout, wellknow n in excessive drinkers. The exact mechanism isno t known. Alcohol- induced ketosis can bebrough t about byfastin g after abinge . The change in NADH/NAD ratio does not onlycaus e hyperlactacidaemia, but also changes in carbohydrate, protein and fat metabolism. Acute alcohol consumption may cause fasting and reactivehypoglycaemia , whereas in chronic alcoholics hyperglycemia and glucoseintoleranc e are found. Hyperlipidaemia and accumulation of fat in thelive rar e induced bya complexo f factors. Both an increased production of fat in the liver and an increased supply of fat to theliver , aswel l asa decreased fatty acid oxidation, play arol e here. At ahig h blood alcohol concentration theinhibitio n oflipoprotei n releasereinforce s these effects. The decreased oxidation of fatty acids isa resul t of thelive r using alcohol as an 'alternative fuel'. Theinfluenc e of alcohol on protein metabolism isa n extremely complex matter, which asye t has hardlybee n clarified. Alcohol metabolism affects both protein synthesis andbreakdown , aswel l asprotei n secretion from the liver.

References

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70 38. Marks V. Biochemical and metabolicbasi s of alcohol toxicity. In: Mendlowicz J, van Praag HM, eds. Alcoholism: A multidisciplinary approach, vol 3. Basel: Karger, 1979:88-96 . 39. Mascord D, Rogers J, Smith J, Starmer GA, Whitfield JB. Effect of diet on [lactate]/[pyruvate] ratios during alcohol metabolism in man. Alcohol Alcoholism 1989;24: 189-191. 40. McDonald JT, Margen S. Wine versus ethanol in human nutrition. 1. Nitrogen and calorie balance. Am J. Clin Nutr 1976;29: 1093-1103. 41. McGarry JD, Foster DW. The regulation of ketogenesis from oleicaci d and the influence of antiketogenic agents. J Biol Chem 1971;246:6247-53 . 42. Mezey E. Metabolic effects of alcohol. Fedn Proc 1985;44: 134-8. 43. Morgan MY. Alcohol and the endocrine system. BrMe d Bull 1982;38(1): 35-42. 44. O'Keefe SJD, Marks V. Lunchtime gin and tonic:A cause of reactive hypoglycaemia. Lancet 1977;i: 1286-8. 45. Oratz M. Alcohol and protein synthesis. In: Biomedical processes and consequences of alcohol use. Rockville, MD: NIAAA, 1982: 31-49. (Alcohol and health monograph 2.) 46. Ostrander LD, et al. Relationship of serum lipid concentrations to alcohol consumption. Arch Internal Med 1974;134: 451-6. 47. Paille F, Baille N, Barrucand D. Principales conséquences biologiques de l'alcoolisation (première partie). Revue Alcoolisme 1982;28: 129-61. 48. Patel DG. Effects of ethanol on carbohydrate metabolism and implications for the aging alcoholic. Alcohol Health ResWorl d 1989;13 : 240-6. 49. Pezzarossa A, Cervigni C, Ghinelli, F, Molina E, Gnudi A. Glucose tolerance in chronic alcoholics after alcohol withdrawal: effect of accompanying diet. Metabolism 19^86;35:984-8 . 50. ReinusJF , Heymsfield SB,Wiskin d R, Casper K, Galambos JT. Ethanol: relative fuel value and metabolic effects in vivo. Metabolism 1989;38: 125-35 51. Ryan K. Alcohol and blood sugar disorders: an overview. Alcohol Health ResWorl d 1983;8:3 - 7, 15. 52. Sabesin SM. Effects of alcohol on liver and blood lipids and lipoproteins. In: Biomedical processes and consequences of alcohol use. Rockville, MD: NIAAA, 1982: 131-70. (Alcohol and health monograph 2.) 53. Salem N. Alcohol, fatty acids, and diet. Alcohol Health ResWorl d 1989;13:211-8 . 54. Shaw S,Jayatillek e E, RossWA , Gordon ER, Lieber CS. Ethanol-induced lipid peroxidation: potentiation bylong-ter m alcohol feeding and attenuation bymethionine . J Lab Clin Med 1981;98:417-24. 55. Shaw S, Lieber CS. Plasma amino acids in the alcoholic: nutritional aspects. Alcoholism Clin Exp Res 1983;7:22-7. 56. Singh SP, Kumar Y, Snyder AK, Ellyin FE, Gilden JL. Effect of alcohol on glucose tolerance in normal and noninsulin-dependent diabeticsubjects . Alcohol Clin Exp Res 1988;12: 727-30. 57. ShelmetJJ , Reichard GA, Skutches CL, Hoeldtke RD, Owen OE, Boden G. Ethanol causes acute inhibition of carbohydrate, fat, and protein oxidation and insulin resistance. J Clin Invest 1988;81: 1137-45. 58. Verdy M, Gattereau A. Ethanol, lipase activity and serum lipid level. AmJ Clin Nutr 1967;20: 997-1003. 59. Ward LC. Ethanol and protein and amino acid metabolism in the rat. Int J Biochem 1987;19 : 887-97. 60. Williams HE. Alcoholic hypoglycemia and ketoacidosis. Med Clin NA m 1984;68: 33-38. 61. World MJ, Ryle PR, Jones D, Shaw GK, Thomson AD. Differential effect of chronic alcohol intake and poor nutrition on bodyweigh t and fat stores. Alcohol Alcoholism 1984;19: 281-90.

71 CHAPTER 6 Effects of alcohol onvitami n metabolism

E. teWierik and W.G. Vrij-Standhardt

Almost allresearc h devoted to the effects of alcohol consumption on vitamin metabolism (and viceversa ) hasbee n donewit h alcoholics and animals. The effects ofmoderat e alcohol consumption onvitami nmetabolism , however, havehardl y ever been investigated. In aserie s of papers Bonjour (10-16) describes the relation betweenvitamin s and alcoholism. Inthi schapte rvariou svitamin swil lb ediscusse d in relation to alcohol use.

6.1. Vitamin A

In caseo f alcohol-induced cirrhosis of the liver symptoms ofvitami n A deficiency mayb eobserved , such asnigh tblindnes s and testicular atrophy associatedwit h decreased spermatogenesis (15, 61). The term 'vitamina A' isth e generic descriptor for retinoids exhibiting qualitatively thebiologica l activity of retinol. Likeethano l retinol isa n alcohol. Azinc-containin g enzyme, alcohol dehydrogenase (ADH), isnecessar y to convert retinol into retinal, which playsa n important rolei nvisio n and in spermatogenesis. Bypartl y occupyingth erecepto r site of retinol on the enzyme, ethanol maycaus e competitive inhibition of this conversion. Testicular atrophy isprobabl y theresul t of enhanced peroxidation of testicular lipidstha t occursupo n ethanol exposure. Vitamin A stabilizes testicular membranes byactin g as an antioxidant (62). Decreased blood concentrations ofvitami n A, retinol-binding protein (RBP), and often zinc, arefrequentl y observed in alcoholics. Thisma yb e duet o malnutrition sincepoo r food dietary patterns haveofte n been observed in alcoholics. Other causes ofvitami n A deficiency mayb emalabsorptio n and a decreased storageo fvitami n A in theinjure d liver (63). Verylo whepati cvitami n Alevel shav ebee n found inpatient swit hmoderat elive r diseasesuc h asfatt y liveri n thepresenc eo f normal«eru mconcentration s of vitamin A and RBP (35). Thereductio n ofhepati cvitami n A correlateswit h the degreeo f alcoholiclive r injury in humans andi nbaboon s (38). A causeo f thelo wvitami nA concentration is enhanced breakdown ofvitami n A in thelive rvi a cytochrome P-450, which isinduce d byalcoho l consumption (65). Increased vitamin Ametabolis m asa consequenc eo f chronic ethanol consumption probably results in theproductio n of toxicvitami n Ametabolite swhic h may contribute tolive r damage (35, 36, 37, 40). Therefore, although the alcoholic suffers from vitamin A deficiency, supplementation of thevitami n seems detrimental since

72 vitaminA in excess caninitiat ehepati cinjury . Furthermore, somepatient s do not respond tovitami n Awhe n no supplementary zinci sadministere d aswell .

6.2 Thiamin (formerly designatedvitami n B-l)

Thiamin deficiency isfrequentl y observed in chronic alcoholics; thisma yb e attributed to (6, 17, 28, 56, 60, 69): - inadequate thiamin intake, - impairment of thiamin absorption due to an ethanol related nutritional deficiency state, - decreased activation of thiamin to thiamin pyrophosphate (TPP) in the brain. Theinadequat e dietaryintak ei nman yalcoholics , in particular a decreased thiamin absorption in thegastrointestina l tract, due to damage caused byalcoho l and/or folate deficiency (23,49) , arepresumabl y largely responsiblefo r thiamin defiency in alcoholics. An altered thiamin requirement accompanying alcohol consumption hasno t been established. Asa rule , thiamin requirement isrelate d to energyintak esinc ethiami n playsa rol ei n catabolism, in particular inth e conversion of pyruvateint o acetyl-Coenzyme A (acetyl-CoA) and in the citricaci dcycle . The breakdown ofalcoho l leadst oth eformatio n ofacetyl-Co Aacetaldehyd ewithou t pyruvate as an intermediate product. Consequently, no thiamin isnecessary . The acetyl-CoA formed willb efurthe r broken downvi a thecitri caci d cycle,whic h process can actually dowithou t thiamin. It shouldb epointe d out, however, that alcohol consumption mayincreas e daily energy intake, and thus thiamin requirement. Threeimportan t enzymesystems , allo fwhic h areinvolve d in cerebral glucoseutilization , arethiami n pyrophosphate (TPP)-dependent (17). Itha sbee n noted that neurological disturbances causedb ythiami n deficiency are enhanced byth e consumption of ethanol in rats (74). In some drinkers thiamin deficiency leads toWernicke-Korsakoff' s syndrome (WKS), cardiacberiber i and possiblypolyneuropathy , which areno t always distinguishable from the direct toxiceffect s of alcohol (6). Some90 %o f allWK Spatient s are alcoholics (18). Frequently stupor or comai s the dominant trait of WKS. Without treatment, mortality isestimate d at 100%(54) , but thiamin treatment can reducethi s dramaticfigur e to 17%(18) . Korsakoff's psychosisi sgenerall ybelieve d tob eth efina l stageo f Wernicke's encephalopathy. It ischaracterize d bysever eimpairmen t of the cognitivefunctio n (i.e .los so f past memories, inability to learn or form newmemories , minor impairment of perceptual and conceptual functions, confabulation, and an apathetic loss of insight and initiative (30). Serious amnesia willoccur , and presumably alsoirreversibl ebrai n damage, thus rendering thiamin treatment ineffective. Thepathogenesi s of the diseasei sstil l unknown. Apossibl emechanis m ispropose d byButterwort h (17) (Fig. 6.1).

73 decreased dietary direct toxic effects thiamin intake of ethanol i decreased thiamin decreased thiamin absorption phosphorylation (Gltract ) inth e brain i decreased TPP levels X I decreased activities decreased - of alpha-ketogluterate activities of dehydrogenase (alpha-KGDH) transketolase I decreased pyruvate oxidation

decreased neuro­ decreased increased transmitter oxidation ATP synthesis lactate levels X X biochemical lesions cell death

Fig. 6.1.Possibl e mechanism of thiamin deficiency andbrai n damage.

There isconsiderabl evariatio n not onlyi npathologica l changes asa respons e to thiamin deficiency, but also in susceptibility of thevariou s organs. In some of the responders thebrai n isth e target organ, in others iti sth ehear t and in still othersi t mayb ebot h brain andheart . Cardiacberiber iwa sdiscovere d atth e start of the century in the Orient whereman ypeopl e subsisted:largel y on a diet ofpolishe d rice with itsnegligibl ethiami n but high carbohydrate contents. Theoccidenta l form of cardiacberiber i isusuall y associatedwit h excessivealcoho l intake, but ismuc h rarer than WKS. Oedema mayb e a dominant feature andpulmonar y congestion and dyspnoea issometime s present aswel l(48 ,72) . Therecommende d dailyintak eo f thiamin is0.1 2mg/MJ . Alcoholicbeverage s do not contain thiamin (68) or onlytrace s ofi t (7). Supplementation of thiamin to alcoholicbeverage s hasbee n suggested. From acos't-benefi t analysis of current conditions in theUSA , Centerwall (18) concludes that the cost of supplementation is only 4-25%o f the cost of (often lifelong) treatment of Korsakoff's psychosis. It would also decreaseth enumbe r of cases of alcoholicpolyneuropath y and cardiac beriberi (both causedb ythiami n deficiency). Before embarking on thiamin supplementation, agrea t deal of research willhav et ob e done on several aspects related to it. The addition of thiamin tobee r does not entail technicalproblem s (47).

74 However, fortification with apotentiall yharmfu l substance poses serious problems for health educators. Labellingo f alcoholic beverages as 'vitamin- enriched' could result in changesi n thecommunity' s attitude towards alcohol and hencei nincrease d alcohol consumption. Besides, thenecessit y of modifying the often age-old procedures followed inproductio n of thesebeverage s would doubtlessly meet with resistance. It must alsob e questioned whether iti sjustifiabl e to add asubstanc e to aproduc t consumed byman yi n order to prevent theincidenc eo f a serious disorder incurred byonl yfe w owing to abuse. Society's negative attitude towards fluoridation of drinkingwater , for instance, indicates that the possible effectuation of suppletion maywel l evokepolitica l and social problems.

6.3. Riboflavin (formerly designatedvitami n B-2)

Riboflavin isnecessar yfo r the electron transport system, which playsa par t in alcohol metabolism. There are, however, no indications of an increased riboflavin requirement in alcoholics. A decreased riboflavin status in alcoholics presumably originates from a dietary deficiency tob eattribute d mainlyt o alo wintak eo fmil k and other dairyproducts . Ethanol does not affect the absorption of thisvitami n (14). The riboflavin status of ratswhic hha dbee n administered alcohol in addition toa riboflavin-containing diet didno t differ from that of controls (53). However, Kim& Roe (32) observed that chronic alcohol feeding can induce abiochemica l riboflavin deficiency in hamsters fed a dietlo wi nriboflavi n ascompare d to hamsters fed the sameriboflavin-poo r dietwithou t alcohol. Hietanen (27) has carried out experiments on the effect of riboflavin deficiency in ratsconsumin g alcohol. Hardly any difference in liver function between deficient and non-deficient groups was found.

6.4. VitaminB- 6

Vitamin B-6 isth e generic descriptor for compounds exhibiting qualitatively the biological activityo fpyridoxine . Pyridoxinei stransforme d inth ebod ymainl y to pyridoxal-5'-phosphate (PLP) and isinvolve d in amino acid metabolism, energy production, fat metabolism, centralnervou s system activity, and haemoglobin synthesis. On average, alcoholics havea decreased blood vitamin B-6 level. In about 50%o f allcase s some deficiency mayb e saidt o exist (i.e. PLPlevel sbelo w thelowe r limit ofth e normal range) (12). In thosewit h liver disease, theprevalenc e of reduced plasma PLP concentrations mayb ehighe r (34). Severalpossibl ecause s havebee n suggested (12, 26, 29, 39,49) . - Ethanol and/or acetaldehyde presumably havea direct influence on liver storage andvitami n B-6 metabolism, in particular the conversion ofpyridoxin eint oit s activeform , PLP. - Liver injury duet o excessivealcoho l useals o causes areductio n of PLP, thus deteriorating thevitami n B-6 status even further. - A decreased pyridoxineinput , caused bya n inadequate diet, mayals o playa role. 75 I L In contrast, chronic ethanol administration doesno t changeintestina l pyridoxine absorption (51). - Ethanol and/or alcoholiclive rinjur y couldpromot evitami n B-6deficienc y by accelerating its degradation pathway. Noclea r clinical symptoms ofvitami n B-6 deficiency havebee n observed in alcoholics. Yet alcoholics arefrequentl y treated with pyridoxine or PLPt o re­ establish the normal level. Recently, Löwik et al. (42) havestudie d the effects of moderate alcohol consumption onvitamin eB- 6 indicators. No significant effect ofmoderat e alcohol use on PLPleve lwa sobserved , but therewa sa slight positive relationship between alcohol intakean d PLP concentration. Theauthor s suggest that that alcoholic beverages maycontai n much morevitami n B-6 than isindicate d byfoo d composition tables.

6.5. Folate

Folate isth emos t commonly deficient vitamini n malnourished alcoholics (4). Since beer contains considerably morefoli c acid (360 |xg/l)tha n other alcoholic beverages (0-4 |JLg/l),highe r serum folic acid concentrations arefoun d in alcoholics drinking beer than those drinkingpredominantl y spirits or wine (11). Folate deficiency may causemegaloblasti c anaemia (41). It also causes malabsorption of thiamin and vitamin B-12a swel l aso f folate itself (23). Deficiency frequently occurs, also amongnon-drinkers , but moreofte n in alcoholics, particularly in combination with aninadequat e diet (25) and liver disease (2). Alcoholics tend to havelowe r averagebloo d folate levelstha n non-alcoholics (11, 24, 33). Megaloblastic anaemia isonl yfoun d in individuals withbot h a small folate pool and a diet lowi n folate. If thebod y has an adequatefolat e pool, anaemiawil l usuallyno t occur at oncei f thedie t islackin gfolate , not even in combination with alcohol use. However, aprolonged inadequate dietma y depletefolat e stores. In primates chronic alcohol consumption impairsfolat e coenzymes, increases haematological indices of megaloblastic anaemia, and maycaus e malabsorption of enterohepatically circulating folate infolat e deficiency evenwhe n other essential nutrients areprovide d (9). Long-term experimentswit h monkeys showed that after a coupleo fyear so f chronicalcoho lconsumptio n a decreaseo fbloo d folate levelswil l occurwhil eth eplasm a levelwil l (asyet ) remain unchanged (2). A direct toxic effect of alcohol onbon emarrow , thusinitiatin gmegaloblasti canaemia , seems unlikely (11). Theselo wfolat e levelsi n alcoholics partlyresul tfro m primary and secondary malnutrition (poor dietary intake and decreased absorption) (24). Besides, alcohol itself also directly affects folate metabolism. Both inrat s and inman , administration of alcohol causes an acute decrease of the serum folate level,whic h returns to normal soon after termination of thealcoho l administration (19, 55, 59). Alcohol consumption isattende d bya nincrease d urinary excretion of folate (45, 46, 64).

76 Ethanol also seems tobloc k the enterohepatic circulation of folate and to interfere with intracellular folic acidutilizatio n (1, 11, 57,64) .

6.6 Vitamin B-12

Vitamin B-12deficiency , likefolat e deficiency, maycaus emegaloblasti c anaemia. Besidesit srol ei n erythrocyte development, vitamin B-12als o playsa biochemica l role, unrelated to folate, in themaintenanc e of myelin in thenervou s system. In contrast with thevas tbod y of literature on folate, literature on thevitami n B-12 status of alcoholics isscanty . Chronic alcohol consumption inwell-fe d volunteers decreases the absorption of vitamin B-12 (33). Normal bloodvitami n B-12level shav ebee n found in alcoholics with mild liver disease, but thevitami n B-12leve li selevate d in severealcoholi clive r disease (5, 43). Thenorma l or high serumvitami n B-12level sma yresul tfro m the failure of the damaged liver to takeu p several B-12vitamer s from the serum. This situation mayb e aggravated bya releas e of thesecompound s from the damaged liver into the serum (31). Ahig h incidenceo f pathologically deficient levelso fvitami nB - 12i n cerebrospinal fluid, despitenorma l serum B-12levels , hasbee n observed in patients with alcohol-related brain damage (71). Alcoholics rarely showvitami n B-12deficienc y (75); even if present, the deficiency probably reflects interference byalcoho lwit h vitamin B-12absorptio n (34, 66).

6.7 Vitamin C

In many alcoholics a decreased vitamin Cstatu s hasbee n observed (3, 10). Although a negative correlation between alcohol consumption and vitamin Cleve l has been found, there are no indications of a direct toxic effect of alcohol on vitamin C metabolism (10). Lowvitami n Clevel si n alcoholics arepresumabl y causedb y alcohol-induced inhibition of the activetranspor t system ofvitami n Cthroug h the intestinal wall (21), an enhanced vitamin Cexcretio n in theurin e (20, 52), and/or poor dietary intake. Oral or intravenous administration ofvitami n Ct o patients suffering from delirium tremens or from the alcohol withdrawal syndromelead s toa n increase of the ascorbic acidconcentratio n in the serum of these patients (58). Thisi s contradictory to the presumed lowerabsorptio n of vitamin Ci n alcoholics. No clinical symptoms resultingfro m vitamin Cdeficienc y causedb y excessive alcohol consumption havebee n reported.

6.8. Vitamin D

Vitamin Dha s an endocrinefunctio n in calcium homeostasis. Vitamin Dfro m food (cholecalciferol, also calledvitami n D3) andvitami n D originating from the skinvi a

77 ultraviolet irradiation isconverte d inth elive rint o 25-hydroxycholecalciferol (25(OH)D3), whichi ssubsequentl y converted in thekidne y into 1,25- dihydroxycholecalciferol (l,25(OH)2D3). Thelatte r vitamer isth eactiv efor m of vitamin D. It activates intestinal calcium absorption and calciummobilizatio n from thebone . In several investigations decreased serum 25(OH)D3 levelshav ebee n found in alcoholics the causes of which haveno t been completely elucidated. Several factors canpla ya rol e (8, 16, 22): - apoo r diet, - reduced exposuret o sunshine, - malabsorption, especially in caseo ffa t malabsorption, - anincrease d rate ofvitami n D metabolism, - disturbed hydroxylation in theliver , - metabolic changesi nth ekidneys . Opinions diverge ast owhethe r disturbed hydroxylation in theliver , whether or not in conjunction with liverinjury , mayb e acaus eindee d (16, 33). It.hasbee n suggested that the alcohol-induced decrease of,the metabolic effects ofvitami n D mayno t takeplac ei n the liver, but in thekidne y (50), orbot h (44).Th e activityo f the renal enzymeregulatin g hydroxylation of 25(OH)D3 to l,25(OH)2D3 decreases, whileconversio n into thepresumabl y inactive 24,25-(OH)2D3 takesplace . Thisma y be caused byth e effect of alcohol on thepituitar y regulating thehydroxylas e activity of thekidne y (50). Osteoporosis isfrequentl y observed in alcoholics (67). In animalsi tha s been observed that chronic alcohol administration results in disturbed vitamin D metabolism, ane t increasei nbon e resorption and decreased mineralization of bone matrix (70). Changes in calcium and phosphate metabolism, whether or not of an endocrine nature, presumably alsopla ya role.

6.9 Vitamin E

Vitamin E isa majo r lipid-solubleantioxidan t inbiomembranes . Thevitami n E level isdepresse d in alcoholics. Reduced dietary intakeand/o r malabsorption mayb e the cause ofvitami n E deficiency. It has alsobee n suggested that adecrease d serum vitamin E leveli scause db ylive r disordersvi a a depression oflow-densit y lipoprotein (LDL) formation (73). Vitamin E deficiency maypla ya rol ei n Zieve's syndromebecaus e haemolysis and the transient haemolytic anaemia revert tonorma l upon vitamin E treatment. Whether vitamin E treatment maypreven t fatty liveri n alcoholics, asha s appeared from some animal experiments, isstil lt ob efurthe r investigated (16).

78 Summary

Thevitami n deficiencies frequently observed in alcoholics arepresumabl y largely the result of a decreased vitamin supplyt o the organism. This isa consequenc e of the frequently insufficient diet attendant on alcoholism on theon e hand, ando f decreased vitamin absorption resulting from damage to theintestina l epithelial cells causedb y excessivealcoho l consumption and/or vitamin deficiency on the other. Vitamin deficiencies mayb epromote d byalcoholi clive r disease (hepatitis, cirrhosis). Thevitami n pool in thelive rma yb e decreased as aresul t of the decreased capacity of the liver cellst o storevitamins . Liver injury mayals o affect the metabolism of variousvitamins . Moreover, a direct influence of alcohol on the metabolism of some vitamers (retinol, thiamin, pyridoxin, folic acid, cholecalciferol) seems plausible. Several disorders resulting from vitamin deficiency havebee n observed in alcoholics, themos t important ofwhic h are: - night blindness (causedb yalcoho l interacting withvitami n A and zinc deficiencies), - decreased spermatogenesis (samecauses) , - Wernicke-Korsakoff's syndrome (caused bythiami n deficiency), - cardiacberiber i (caused bythiami n deficiency), - various types of anaemia (caused byfolat e and vitamin B-12 deficiency). Interaction between vitamin A and alcohol during drinking cannot be excluded, sinceth e same enzymes participate in metabolism ofbot h substances. Because the most important causes of vitamin deficiency (inadequate nutrition, malabsorption and liver injury) result from excessivealcoho l consumption and accompany moderate drinking, the latter presumably affects vitamin metabolism onlyslightly . However, on thebasi s of our present knowledge, wecanno t determine theintak eleve lbelo w which alcohol does not havean y effect on vitamin metabolism.

References

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80 42. Löwik MRH, van Poppel G, Wedel M, van den Berg H, Schrijver J. Dependence ofvitami n B status assessment of alcohol intake among elderlyme n andwomen . J Nutr 90;120: 1344-51. 43. Majumbar SK, Shaw GK, Thomson AD. Plasma vitamin E status in chronic alcoholicpatients . Drug Alcohol Dependence 1983;.12:269-72 . 44. Mawer EB, Klass HJ, Warnes TW, BerryJL . Metabolism ofvitami n D inpatient s with primary biliary cirrhosis and alcoholic liver disease. Clin Sei 1985;69: 561-70. 45. McMartin KE. Increased urinary folate excretion and decreased plasma folate levelsi n the rat after acute ethanol treatment. Alcoholism Clin Exp Res 1984;8:172-8 . 46. McMartin KE, Shiao CQ, CollinsTD , Redetzki HM. Acute ethanol ingestion byhuman s and subacute treatment of rats increase urinary folate excretion. Alcohol 1985;2:473-7 . 47. Meilgaard MC. Technical aspects of enrichment ofbee r with thiamine. J Stud Ale 1982;43:427 - 33. 48. Meulders Q, Laterre PF, Corbeel MSL. Shoshin beriberi, afulminan t beriberi heart disease. Acta Clin Belg 1988;43: 115-9. 49. Mezey E, Potter JJ, Merchant CR. Effect of ethanol feeding on bone composition in the rat Am J Clin nutr 1979;32: 25-9. 50. Mezey E. Alcohol and renal vitamin Dmetabolism . Gastroenterology 1980;78: 651. 51. Middleton HM, Mills LR, Singh M. Effect of ethanol on the uptake of pyridoxine• HC l in the ratjejunum . Am J Clin Nutr 1984;39: 54-61. 52. Mochizuki S, Yoshida A. Effects of dietary ethanol on ascorbic acid and lipid metabolism, and liver drug-metabolizing enzymes in rats. J Nutr SeiVitamino l 1989;35:431-40 . 53. Monks E, Potter JJ, Merchant CR. Effect of ethanol feeding on bone composition inth e rat. AmJ Clin Nutr 1979;32: 25-9. 54. Muller-Kobold MJP, Endtz LJ. Het syndroom van Wernicke-Korsakoff, een zeldzaam ziektebeeld? Ned Tijdschr Geneesk 1975;119: 991-7. 55. Paine CJ, Eichner ER, Dickson V. Concordance of radioassay and microbiological assay in the study of the ethanol induced fall inseru m folate level. Am J Med Sei 1973;226: 135-8. 56. Paladin F, Perez GR. The haematic thiamine level in the course of alcoholic neuropathy. Eur Neurol 1987;26: 129-33. 57. Parkkinen E, Stowell L, Kohila T, Halkka O, Eriksson K. Synergistic effects of chronic ethanol consumption and folic acid deficient diet in rats, development of leucopenia and lack of effect on sister chromatid exchanges inbon e marrow cells invivo . Subst AleActions/Misus e 1981;1 : 221-31. 58. Piatkowski J, Wiechert P, Ernst K. Ascorbic acid in chronic alcoholics. Int J Vitam Nutr Res 1987;57:421. 59. Pikaar NA, Wedel M, van Dokkum W, van den Berg H, Schrijver J. Binnen- en tussenpersoonsvariabiliteit van de concentraties van melkzuur, vitamine Bl, B2, B6, B12 en foliumzuur in van de y-GT en ALAT-activiteit inbloed/plasm a na consumptie van 3glaze n gesimuleerde wijn; alcoholbelastingsproeven bij 12proefpersonen. Zeist: CIVO-Instituten TNO, 1983. (Rapport V 84.018/120224.) 60. Rindi G. Alcohol and thiamine of the brain. Alcohol Alcoholism 1989;24:493-5 . 61. Roe DA. Drug-induced nutritional deficiencies. Westport: AVI Publ. Comp., 1976. 62. Rosenblum ER, Gavaler JS, vanThie l DH. Lipid peroxidation, amechanis m for alcohol- injured testicular injury. Free Radical Biol Med 1989;7: 569-77. 63. Rüssel RM. Vitamin A and zincmetabolis m in alcoholism. Am J Clin Nutr 1980;33:2741-9. 64. Rüssel RM, Rosenberg IH, Wilson PD. Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. AmJ Clin Nutr 1983;38: 64-70. 65. Sato M, Lieber CS. Increased metabolism of retinoic acid after chronic ethanol consumption in rat liver microsomes. Arch Biochem Biophys 1982;213:557-64 . 66. Sherlock S. Nutrition and the alcoholic. Lancet 1984;i:436-9 . 67. Spencer H, Rubio N, Rubio E, Indreika M, Seitam A. Chronic alcoholism, frequently overlooked causeo f osteoporosis inmen . AmJ Med 1986;80:393-7 . 68. Stichting Nederlands Voedingsstoffenbestand, Voorlichtingsbureau voor de Voeding. NEVO Tabel 1989/1990. The Hague: Stichting NEVO, 1989. 69. Thomson AD,Jeyasingha m MD, Pratt OE, Shaw GK. Nutrition and alcoholic encephalopathies. Acta Med Scand 1987(suppl 717):55-65 .

81 70. Turner RT, Aloila RC, Segel LD, Hannon KS, Bell NH. Chronic alcohol treatment results in disturbed vitamin Dmetabolis m and skeletal abnormalities inrats . Alcoholism Clin Exp Res 1988;12: 159-62. 71. van Tiggelen CJM. Alzheimer disease/alcohol dementia, association with zincdeficienc y and cerebral vitamin B12 deficiency. J Orthomol Psychiat 1983;13:97-104 . 72. Webster MWI, Ikram H. Myocardial function in alcoholic cardiacberiberi . Int J Cardiol 1987;17:213-6. 73. Yoshikawa T, Takemura S, Kondo M. Alpha-tocopherol level inlive r disease. Acta Vitaminol Enzymol 1982;4:311-8 . 74. Zimitat G, KrilJ , Harper CG, Nixon PF. Progression of neurological disease in thiamin- deficient rats isenhance d byethanol . Alcohol 1990;7: 493-501. 75. Zittoun J. Effects of some drugs and alcohol on folate and cobalamin metabolism. In: Zittoun J, Cooper BA, eds. Folates and cobalamins. Berlin: Springer-Verlag, 1989: 137-44.

82 CHAPTER 7 Effects of alcohol onwate r and mineral balance

E. teWierikand W.G. Vrij-Standhardt

7.1. Water balance

The diuretic effect of alcohol consumption iswel lknown . On the other hand, overhydration and ascites (also calledhydroperitoneum ) arefrequentl y observedi n alcoholics (32). Experiments measuring the diuretic effect of acutelarg e doses of alcohol are usuallycarrie d out over a short period of time. In these experiments anincreas ei n urinary production appears tob e caused bya n inhibited vasopressin (antidiuretic hormone, ADH) release (3). Eiser (13), who has reviewed the studies concerning the effects of alcohol on renal function and excretion, concludes that both alcoholics and non-alcoholics retain sodium andwate r after abrie f diuresis. In a study into the effect of ethanol on water balance and plasma vasopressin 75m l alcohol wasgive n to volunteers. Itwa sbee n observed that ethanol inhibited vasopressin releaseb y resetting thehypothalami c osmoreceptors, sotha t therat e of vasopressin releasei s reduced relative to plasma osmolality. The effect of thisi sa hydratio n stateo f increased plasma osmolality and reduced fluid volumewhic hi sinduce d viaa transient diuresis (12). When drinking isdiscontinue d the osmoreceptor sensitivity returns tonormal , vasopressin secretion increases and normal volume is restored. Beard &Knot t (2) studied chronic alcoholics and observed an expansion of the extracellular fluid volume. Moreover, theyfoun d that both total bodywate r volume and calculated intracellular water volumewer e abovenorma l values. During withdrawal totalbod ywate r decreased significantly. In contrast to these findings, Mander et al. (31) observed fluid retention and increased plasma vasopressin levels in alcoholics duringwithdrawal . A decreased water excretion in alcoholic patients duringwithdrawa l has alsobee n observedb yEmsle y et al. (14). It iswel lknow n that plasma volumema yb e expanded in alcoholics with alive r or cardiac disease. In alcohol-associated cardiomyopathy, with left ventricular dysfunction, plasma volume expandsbecaus elo wcardia c output leads toflui d and salt retention. In caseso f liver cirrhosis volume expansion may occur because increased distal run-off (A-V shunting) decreases the effective (although not actual) plasma volume. Ascitesma y also occuri n this setting (9).

83 7.2. Mineralbalanc e

A closerelationshi p existsbetwee nbod ywate rvolum ean dminera l concentrations. The results of the various investigations into changes of mineral concentrations causedb yacut e or chronic alcohol consumption are difficult tointerpret . With some minerals the effects during the ascending phase differ from those observed during the descending phase of the alcohol curve. Moreover, the differences in experimental designhampe r aprope r comparison. The effects of acuteo r chronicalcoho l consumptionwil lb e discussed only for sodium, potassium, chloride, calcium, phosphate, magnesium, iron andzinc .

7.2.1. Sodium

Sodium, together with potassium, assists in the maintenance of thebody' s electrolyte andwate rbalance . In addition, sodium and potassium playa nimportan t rolei n neural conduction, musclecontractio n and the transport of substances across membranes. Some authors haveobserve d an acute decrease of urinary sodium excretion after the consumption of alcohol (20, 43), whereas others haveno t found such an effect (26, 40). The decreasei n sodium excretion isprobabl y the result of an increasei n elimination of 'free water' (waterwithou t salts)b yth ekidneys , resulting from inhibition of the releaseo fvasopressin . A risei n plasma sodium levelafte r alcohol consumption hasbee n noted aswel l(24 , 41,44 , 46).Thi splasm a sodium increasei s accompanied withwate r retention to compensate for the diuretic effect. Hyponatraemia hasfrequentl y been observed in alcoholics. Several factors may contribute to the diminished concentration of sodium (32): - thekidneys ' ability to eliminate 'free water' is impaired, - an elevatedleve l of antidiuretic hormone enhances thekidneys ' efficiency ofwate r retention, - the diminished total bodypotassiu m content indirectly affects theplasm a sodium concentration, - the use of medication such as diuretics or laxatives causes an increasei n urinary and faecal elimination of sodium andwater , which can result inlo w sodium concentrationswhe n the excretedfluid s arereplace d with sodium-free water. Besidesthes efactor s isha sbee n mentioned thatvaga lneuropath y may contribute toth e lowseru m concentration inpatient swit h cirrhosis. In vagalneuropath y the baroreceptors might contribute to an inappropriate'secretio n of antidiuretic hormone, which might in turn inducehyponatraemi a (11).

7.2.2. Potassium

The effects of alcohol on potassium metabolism areno t unequivocal. A significant increase (19), a decrease (41), aswel l asn o difference (20) inplasm a potassium in

84 r

response to the consumption of alcohol havebee n observed. Urinary potassium excretion seemed to decreasei n some studies (20, 24, 26, 43,44) , and remained equal in other ones (46). Reduced potassium excretion during alcohol ingestion could result from metabolic acidosis. A mildmetaboli c acidosis is frequently observed during alcohol ingestion. An acute acidosis suppresses potassium ecretion in the distal tube (13). Lowseru m concentrations ofpotassiu m arefrequentl y observed in hospitalized alcoholics. They mayreflec t a deficit in total bodypotassiu m or merely ashif t of potassium from the extracellular fluid to the cells (32).

7.2.3. Calcium

Calcium isrequire d for blood clotting, muscle contraction and nerve transmission. Calcium isa majo r constituent of bones and teeth. Alcohol influences the neural calcium channels which mayb e linked to thebehavioura l effects of alcohol (18, 30). Acute alcohol consumption increases urinary excretion of thisminera l (26) and decreases itsplasm a concentration (28). Chronicalcoho l consumption decreases serum calcium concentration (5, 8). Several factors mayaccoun t for theassociatio n between the occurrence of hypocalcaemia and severe alcoholism (6, 32). - Calcium isboun d to albumin, and apoo r diet or liver diseaseresult s in diminished albumin levels (hypoalbuminaemia), thereby limiting the amount of calcium that can remain resolved in the blood. - Hypomagnesaemia decreases the sensitivity of theparathyroi d gland to lowcalciu m levels. - Vitamin D isnecessar yfo r adequate absorption of calciumfro m thegut . Vitamin D malabsorption impairs calcium absorption. - In cases of rhabdomyolysis (destruction or necrosis of skeletal muscle) calcium mayprecipitat e as calcium phosphate or calcium carbonate which leads tohypo ­ calcaemia.

7.2.4. Phosphate

Phosphatei sa constituen t ofbone s and teeth, andi sa nintegra l part of many molecules of thebody . Hypophosphataemia has often been observed in alcoholics. It mayb eprecede d byhyperphosphataemia . Hyperphosphaturia often results from the increased filtered load occurring when muscle releases phosphate (13). Other potential causes of hypophosphataemia in alcoholics are renal loss secondary to toxic injury, a dietary phosphorus deficiency, magnesium deficiency, cellular uptakeo f phosphorus following starvation, respiratory alkalosis, and insulin-stimulated phosphate uptakeb ycell s (6, 32).

85 7.2.5. Magnesium

Magnesium isa n important constituent ofbone s and teeth. It also assists enzymes involvedi n cellular energyproductio n andprotei n digestion, and playsa rol ei n the transmission of impulses innerves . Magnesium deficiency mayaccompan y chronicalcoholism . Decreased magnesium concentrations in serum, lymphocytes andbon ehav ebee n found. Alcohol-associated osteoporosis mayb e related topostmenopausa l and senile osteoporosis (10).A n increasei n urinary excretion ofmagnesiu m after the consumption of alcohol hasbee n observedb yKalbfleisc h et al. (26). In hisrevie w Flink (16) concludestha t alcohol induces excretion ofmagnesium . Besides magnesium lossi n theurine , poor food intake, poor absorption (duet o fat malabsorption), and diarrhoea mayals o resulti nmagnesiu m deficiency. A lowmagnesiu m concentration in thebloo d ismainl yobserve d during withdrawal, when thealcoho lha slos tit s effect andwithdrawa l symptoms occur (22, 24). Thisfal l inmagnesiu m level duringwithdrawa l mayb e attributed to aris ei n free fatty acids. Precipitation of magnesiumwit hfre e fatty acidsca n contributet o the drop inplasm a magnesium level (16).A negativ eassociatio n between serum magnesium concentration and alcohol intakeha sbee n found in drunkenness arrestees. Thisnegativ eassociatio n couldb e expected sinceal l drunkenness arrestees showedwithdrawa l symptoms (27,38) .

7.2.6. Iron

Iron isa nimportan t component ofhaemoglobi n and isinvolve di n avariet yo f enzymesystems . Several disturbances of iron metabolism arefoun d in alcoholics. Serum iron andferriti n levelsma yb eincrease d in somealcoholics ,whil evariou s typeso f anaemia occur in others (29, 39, 48). Thelive riro n content is frequently elevated (7, 39). Iron overload duet o genetichaemochromatosi s (25,37 ) or haemosiderosis (29) mayoccur . Apositiv erelatio n between drinkingfrequenc y and serum iron concentration has been observed inbot h malean dfemal e adolescents. Totaliron-bindin g capacity, transferrin saturation and haemoglobin concentration werepositivel y related to drinkingfrequency . These abnormalities areclaime d tob eprecursor s oflive r iron overload andlive r damage (17). Strain et al. (47) also observed that regular drinking increased someindicator s of the iron status. Nosignifican t correlations between quantity of alcohol consumed andiro n statushav eb*ee nobserve d (17, 47, 27). The relativelylarg equantitie s of easilyabsorbabl eiro n in somealcoholi c beverages (e.g. wine) (21,36 , 45) maycontribut et oth eiro n overload. The effects of ethanol aremoderate d byothe r constituents of alcoholicbeverage s (15). An increasediro n absorption causedb yth epresenc eo f alcohol, a decreased utilization of iron inth ebone s (17), orinteractio n ofiro nwit h other nutrients mediatedb y alcohol (42) may alsopla y apart .

86 Conversely, alcohol-induced diseases such aslive rinjury , pancreatitis, and gastrointestinal tractbleedin g also cause disturbances iniron , ferritin and haemoglobin concentrations that can lead to anaemia (29, 48).

7.2.7. Zinc

Zinc isa n essential trace element required for RNA and DNA synthesis and for the function of many enzymes. It also playsa n important rolei n membrane stabilization. Zinc deficiency causes aprogressiv eincreas ei n membrane fluidity. Zinc deficiency isa frequentl y observed phenomenon in alcoholics both with and without liver disease. A decreased dietary intake, decreased absorption, aswel la s increased urinary excretion (especially inlive rinjury ) playa rol e in this (1, 4, 29, 33). Zinc isa n essential element in anumbe r of enzymes, such asalcoho l dehydrogenase (ADH), sotha t zinc deficiency maymanifes t itself in several disturbances. Disturbances attendant on zincdeficiencie s in alcoholicsinclud e skinlesions , night blindness, hypogonadism, anorexia, diarrhoea, changes in protein metabolism and wound healing, immune dysfunction, carcinogenesis, depressed mental function, and birth defects related to thefoeta l alcohol syndrome (32, 33,34) . / In the caseo f zinci ti sno t clear what the effects of moderate alcohol consumption maybe . A singledos e causes an increased urinary excretion of zinc, but the serum zincconcentratio n remains unchanged after consumption of 98g alcoho l a day overa period of 18day s(29 , 35). Not onlyma yzin c deficiency occurwit h alcoholic liver disease, but there mayals o be an altered zincmetabolism . Alcoholic hepatitis patients appeared to have increased serum levelso f themonokin e interleukin 1,whic h isknow n to decrease the plasma zincleve l and to change theinterna l distribution of zinc. It has therefore been suggested that patients with alcoholiclive r disease arefrequentl y faced with either zincdeficienc y of altered zincmetabolis m (34).

Summary

A direct consequence of the consumption of alcohol isa n increasei n urine production owing to an inhibited releaseo f antidiuretic hormone. Moderate and incidental alcohol consumption causes some, mostlyreversible , changes of thewate r and mineral balance, but does not lead to injury or other problems. Chronic consumption oflarg equantitie s of alcohol maycaus e deficiencies of sodium, potassium, calcium, phosphate, magnesium, iron and zinc either as a result of altered mineral metabolism or consequent toinadequat e intake. The effects of moderate alcohol consumption on mineral metabolism areles s clear. Calcium and phosphate deficiency decreasesbon e density. Magnesium deficiency plays arol ei n delirium tremens. Zinc deficiency maycaus e awid erang eo f disturbances.

87 References

1. Antonson DL, Vanderhoof JA. Effect of chronic ethanol ingestion onzin c absorption in rat small intestine. Dig Dis Sei 1983;28:604-8 . 2. Beard JD, Knott DH. Fluid and electrolytebalanc e during acutewithdrawa l inchroni c alcoholic patients. JAMA 1968;204: 133-7. 3. Beard JD, Sargent WQ. Water and electrolyte metabolism following ethanol intake and during acute withdrawal. In: Majchrowicz E, Noble EP, eds. Biochemistry andpharmacolog y of ethanol, vol. 2. New York: Plenum Press, 1979: 3-16. 4. Beck IT, Dinda PK. Acute exposure of small intestine to ethanol. Dig Dis Sei 1981;26: 817-38. 5. Bj0mboe GEA, Bjernboe A, Johnson J, et al. Calcium status and calcium- regulating hormones in alcoholics. Alcohol Clin Exp Res 1988;12: 229-32. 6. Blachley JD, Knöchel JP. Ethanol and minerals. PharmacThe r 1987;33:435-48 . 7. Chapman RW, Morgan MY, BossAM , et al. Acute ancchroni c effects of alcohol on iron absorption. Dig Dis Sei 1983;28:321-7 . 8. Chappard D, Plantard B, Fraisse H, Palle S,Alexandr e C, Riffat G. Bone changes in alcoholic cirrhosis of theliver . Path Res Pract 1989;184:480-5 . 9. Clark LT. Role of electrolytes in the etiology of alcohol-induced hypertension. Magnesium 1989;8: 124-31. 10. Cohen L, Laor A, Kizes R. Lymphocyte andbon e magnesium inalcohol - associated osteoporosis. Magnesium 1985;4: 148-52. 11. Decaux G, Cauchie P, Soupart A, Kruger M, Dalwiche F. Role ofvaga l neuropathy in the hyponatraemia of alcoholiccirrhosis . BrMe dJ 1986;293:1534-6 . 12. Eisenhofe r G, Johnson RH. Effect of ethanol ingestion on plasma vasopressin and water balance in humans. Am J Physiol 1982;242: R522-R527. 13. Eiser AR. The effects of alcohol on renal function and excretion. Alcohol Clin Exp Res 1987;11: 127-38. 14. Emsley RA, Potgieter A,Taljaar d JJF, Coetzee D,Joubert s G, Gledhill RF. Impaired water excretion inpatient s with alcohol-withdrawal symptoms. QJ Med 1987;64:671-8 . 15. Fairweather-Tait SJ, Southon S, Piper Z. The effect of alcoholicbeverage s on iron and zinc metabolism inth e rat. BrJ Nutr 1988;60:209-15 . 16. Flink EB. Magnesium deficiency in alcoholism. Alcohol Clin Exp Res 1986;10: 590-4. 17. Friedman JM, Kraemer HC, Mendoza FS, Hammer LD. Elevated serum iron concentration in adolescent alcohol users. Am J Dis Child 1988;142: 156-9. 18. Gandhi CR, Ross DH. Influence of ethanol on calcium, inositol phospholipids and intracellular signalling mechanisms. Experientia 1989;45:407-12 . 19. Gill GV, BaylisPH , Flear CTG, Skillen AW, Diggle PH. Acute biochemical responses to moderate beer drinking. BrMe dJ 1982;285: 1770-3! 20. Green RJ, Baron DN. Lack of effect on acute ethanol consumption on active cation fluxes of leucocytes and erythrocytes in healthy humans. Clin Sei 1987;73:387-93 . 21. Hallberg L, Rossander L. Effect of different drinks on the absorption of non-heme iron form composite meals. Hum Nutr Appl Nutr 1982;36A: 116-23. 22. Harris RA. Metabolism of calcium and magnesium during ethanol intoxication and withdrawal. In: Majchrowicz E, Noble EP, eds. Biochemistry and pharmacology of ethanol, vol 2. New York: Plenum Press, 1979: 27-41. 23. Hemmingsen R, Kramp P. Effects of acute ethanol intoxification, chronic intoxication and ethanol withdrawal on magnesium and calcium metabolism in the rat. Psychopharmacology 1980;67:255-9. 24. Howes LG, Reid JL. The effects of alcohol onlocal , neural and humoral cardiovascular regulation. Clin Sei 1986;71: 9-15. 25. Irving MG, Halliday JW, Powell LW. Association between alcoholism and increased hepatic iron stores. Alcohol Clin Exp Res 1988;12:7-13 . 26. Kalbfleisch JM, Lindeman RD, Ginn HE, Smith WO. Effects of ethanol administration on urinary excretion of magnesium and other electrolytes in alcoholic and normal subjects. J Clin Invest 1963:42: 1471-5. 27. Kärkkäinen P, Mussalo-Rauhamaa H, Poikolanen K, Lehto J. Alcohol intake correlated with serum trace elements. Alcohol Alcoholism 1988;23:279-82 . 28. Kischuk RP, Otten MD, Polimeni PI. Effect of acute alcoholic intoxication on myocardial electrolyte and water distributions. J Mol Cell Cardiol 1986;18: 197-205. 29. Kricka LJ, Clark PMS. Biochemistry of alcohol and alcoholism. Chichester: Ellis Horwood, 1979. 30. Leslie SW, Brown LM, DildyJE , SimsJS . Ethanol and neuronal calcium channels. Alcohol 1990;7: 233-6. 31. Mander AJ, Young A, Merrick MV, Morton JJ. Fluid balance, vasopressin and withdrawal symptoms during detoxification from alcohol. Drug Alcohol Depend 1989;24: 233-7. 32. Marsano L, McClain GJ. Effects of alcohol on electrolytes and minerals. Alcohol Health Res World 1989;13:255-60. 33. McClain CJ, Le-Chu S. Zinc deficiency inth e alcoholic, a review. Alcohol Clin Exp Res 1983;7: 5-10. 34. McClain CJ, Antonow DR, Cohen DA, Shedlofsky SI. Zinc metabolism in alcoholiclive r disease. Alcohol Clin Exp Res 1986;10: 582-9. 35. McDonald JT. Wine versus ethanol in human nutrition IV. Zinc balance. AmJ Clin Nutr 1980;33: 1096-102. 36. McDonald JT. Wine and human nutrition. In:Wine , health and society, a symposium. San Francisco: Wine Institute, 1982: 107-18. 37. Muench KH. Hemochromatosis and infection: alcohol and iron, oysters and sepsis. Am J Med 1989;87: 40N-43N. 38. Mussalo-Rauhamaa H, Poikolanen K, Kärkkäinen P, Lehto J. Decreased serum selenium and magnesium levels in drunkenness arrestees. Drug Alcohol Depend 1987;20:95-103 . 39. Paille F, Baille N, Barrucand D. Principales conséquences biologiques de l'alcoolisation, 2ème partie. RevAlcoolism e 1983;29: 65-107. 40. Potter JF, Watson RDS, Skan W, Beevers DG. The pressor and metabolic effects of alcohol in normotensive subjects. Hypertension 1986;81: 625-31. 41. Puddey IB, Vandongen R, Beilin LJ, Rouse IL. Alcohol stimulation of renin release in man, its relation to the hemodynamic, electrolyte, and sympatho-adrenal responses to drinking. J Clin Endocrin Metab 1985;61: 37-42. 42. Roque MC, DaCunha F. Interactions of alcohol and nutrition. Am J Dis Child 1989;143:519 . 43. Rubini ME, Kleeman CR, Lamdin E. Studies on alcohol diuresis. I. The effects of ethyl alcohol ingestion on water, electrolyte and acid-base metabolism. J Clin Invest 1955;34: 439-47. 44. Sargent WQ, Simpson JR, Beard JD. Twenty-four-hour fluid intake and renal handling of electrolytes after various doses of alcohol. Alcohol Clin Exp Res 1980;4: 74-83. 45. Stichting Nederlands Voedingsstoffenbestand, Voorlichtingsbureau voor de Voeding. NEVO Tabel 1989/1990. The Hague: Stichting NEVO, 1989. 46. Stott DJ, Ball SG, Inglis GC, et al. Effects of a single moderate dose of alcohol on blood pressure, heart rate and associated metabolic and endocrine changes. Clin Sei 1987;73:411-6 . 47. Strain JJ, Thompson KA, Barker ME, McKenna PG. Alcohol consumption and measurements of iron status. Proc Nutr Soc 1990;49: 23A. 48. Välimäki M, Härkönen M, Ylikahri R. Serum ferritin and iron levels in chronic male alcoholics before and after ethanol withdrawal. Alcohol Alcoholism 1983;18: 255-60.

89 CHAPTER 8 Effects of alcohol on the liver

W.G. Vrij-Standhardt

The organ most frequently affected by excessivealcoho l consumption isth eliver . Liverinjur y usually comprises one of three successivepathologica l conditions: fatty liver, hepatitis or cirrhosis. Fatty liver, also called steatosis, isa reversibl e disorder, in whichfa t accumulates in thelive rcells . In the caseo fhepatiti smuc h ofth elive r tissuei sdestroye d (necrosis) causing subsequent inflammation. Alcoholiccirrhosis , whichi sfrequentl y equatedwit hLaennec' s cirrhosis, ischaracterize d byhepati c fibrosis. Thenorma l structureo f thelive ran dlive rfunction s areirreversibl y disturbed. The assessment of alcoholiclive r diseasei scomplicate db yth ewel lknow n lacko f correlationbetwee n the clinical syndromean d histopathological abnormalities. Patientswithou t clinical or laboratory evidenceo flive r disease often suffer from histological damagea s evidencedb ybiopsy . This chapter startswit h the clinicalfeature s andpossibl eunderlyin g mechanisms of theselive r diseases, followed byoption sfo r treatment. Subsequenly, threshold limits are dealtwit h aswl la sse xdifference s in theselimits . Next, epidemiological data on cirrhosis mortality and itstempora l and regional relationwit hpe r capita alcohol consumption are discussed. Finally, biochemical markers of alcohol abuse - predominantly liver enzymes- are discussed. '

8.1. Pathology and symptomatology

Fat accumulation in thelive r cellsi sth e earliest andmos t common response to alcohol consumption. Normally, thelive r contains 2-4%(w/w ) of lipidswhic h cannot be discernedb yligh tmicroscopy . Theter m 'fatty liver' isuse dwhe n the lipid content of the liver exceeds theleve l of 5%(w/w) . In this condition, lipid drops can be detected byligh tmicroscopy . Area l fatty liver contains more than 10%(w/w ) lipids, andfa t drops asbi ga sth elive rcel lnucleu s canb eobserve d in more than half ofth elive rcell s (113). Fattylive ri susuall yno t accompaniedwit hclinica l symptoms. Occasionally there arecomplaint s about aheav yfeelin g inth ebelly . Severepain sma yoccu r occasionally, especially after aperio d ofheav y drinkingi nwhic hth elive ri s enlarged veryrapidl y and capsulestretchin g occurs (13). Inlaborator y testshighl y increased serum y-glutamyltransferas e (GGT) valuesar eofte n found incase so ffatt y livera s wella sslightl yincrease d serum aspratate aminotransferase (ASATo r GOT) and serum alanineaminotransferas e (ALATo r GPT)levels .

90 Fatty liveri sno t reversibleimmediately . After some dayso f abstinence fatty degeneration decreases and after 2t o 6week s the disorder usuallyha s disappeared entirely (13, 113). Generally speaking, fatty liveri sfairl y harmless, alsobecaus eit s attendant functional and clinical symptoms arelimited . There are, however, indications that fatty degeneration of the liver mayb e the cause of sudden death, particularly after excessivealcoho l consumption (4, 87). In more than 90%o f alcoholicswit h fatty liverwh o continue to drink, alcoholic hepatitis develops (85). Alcoholic hepatitis isa toxic, degenerative and inflammatory lesion of the liver, characterized bynecrosis , inflammation and, in someinstances , acidophilic hyalin (Mallorybodies) . Alcoholic hepatitis isth emos t difficult alcoholic liver syndrome to diagnose, because of itsinconstan t manifestations - varyingfro m a total asymptomatic process to an acute, life-threatening liverfailur e (108). Usually, however, there are clear symptoms of illness, such asnausea , vomiting, pain in the stomach, losso fweight , anorexia andfever . Theillnes si softe n accompanied with jaundice (13, 33). Classically, alcoholichepatiti s develops overweeks , in contrast to viral hepatitis inwhic h theillnes s evolvesove r days. Necrosis, and later fibrosis, will first beobserve d in theperivenula r zones of the cells. These areth e areas most remote from thevessel swit h oxygen-saturated blood, and thus having the lowest oxygen tension in theliver . Alcoholic cirrhosis represents the end-stagelesio n of alcoholiclive rinjury . The onset can beinsidiou s or mayfollo w acute alcoholichepatitis . The patient mayb e entirely asymptomatic, havenon-specifi c complaints (fatigue, anorexia, weightloss , nausea, abdominal discomfort), or maysuffe r specific syndromes relating to livercel l failure or portal hypertension (108). Cirrhosis isdescribe d as sclerosis of the activelive r tissue and overgrowth caused byfibrou s cellproliferatio n (fibrosis). Thenecrosi s and inflammation in the central lobular zonei n cases of hepatitis stimulateth e development of fibrosis. This results in so-calledhyali n sclerosis (70).Th estrand s offibrou s tissuethu sforme d may expand and eventually cause cirrhosis. Cirrhosis has, however, alsobee n observed following alcohol-induced fibrosis unattended with inflammation (73,77) . Myofibroblasts havebee n recognized in thenorma l liver, and their proliferation was found to accompany and topreced e the earliest signs of fibrosis. In alcohol patients andbaboon s that werefoun d to havethes eperivenula r fibrotic lesions, cirrhosis proved to develop more often than in controls (76, 77). Hepatomegaly appears tob e acommo n clinicalfindin g in alcoholic liver injury. The enlargement of thelive r isprimaril y duet o an increasei n size, not innumber , of hepatocytes. Israel et al. (44, 46) suggest that this cell enlargement is accompanied with areductio n of the extracellular volume resulting in an increased portal pressure. In alcoholics liver enlargement isstrongl y associated with portal hypertension (45). Cirrhosis may entail other complications, such asascite s and hepatic encephalopathy (13, 33).Alcoholi clive r diseasepatient swit h ascitesma yhav ea normal bodyweigh t despitesmalle r skinfold thickness and malnutrition, becauseo f the accumulation of litres of fluid in the abdominal cavity(90) .

91 rü

Liver cancer, which may develop after alcoholiclive r disease, isdiscusse d in Chapter 12.

8.2. Mechanisms of alcoholiclive r disease

8.2.1. Fataccumulation

Alcohol consumption maybrin gabou t an accumulation offa t (triglycerides) in the liver cells. On theon ehand , thisi scause db ydecrease d fat oxidation sinceth elive ri s prompted tous e alcoholinstea d offa t asfuel . On the other hand, the supply of fatty acidst o thelive r and the synthesis oftriglyceride s from fatty acidsar e increased, mainly duet o theincrease d NADH/NAD + ratio during alcoholbreakdow n (seeFig . 8.1an d Chapter 5). The simultaneous administration of alcohol andpyrazole , the latter ofwhic h inhibits metabolichandlin g of alcohol, doesno t resulti nfatt y liver, in contrast to the same doseo f alcoholwithou t pyrazole,whic h induces.fat accumulation (83). Chronic alcohol abuseresult si nfunctiona l and structural changesi nlive rcel l mitochondria (70). Thisi ntur n leadst o a decreasei nlipi doxidatio n and thus promotes accumulation of fat. The influence of alcohol metabolism on protein synthesis inth elive r also adds to fat accumulation, namelyb ya decreased production or decreased releaseo f lipoproteins (56, 72). Liverfattenin g has alsobee n observed in individualswit h diabetes or obesity and as aconsequenc e of pharmacotherapy.

CHOLEST \ FATTY ACID , SYNTHESIS\ SYNTHESIS ? W/CHOLESTEROL + FATTY ACIDS-Jf» C0t I I # =J= / ^/MUSCLE/" TRIGLY- ! i CERIDES Liriua t

; /^LIPOPROTEINS-J|

Fig. 8.1. Influence of alcohol inlipi dmetabolism . After: Lieber et al. (40).

92 8.2.2. Mechanisms ofstructural damage

Susceptibility to the development of alcoholiclive r diseasei shigl yvariable . Only 8-30% of alcohol abusers actually develop structural liver damage (15, 100).I f alcoholwer e directly hepatotoxic, it couldb e expected that liver damage occurs predictably and isdose-related . Thevariabl erespons e to alcohol can be better understood if alcoholiclive rinjur y issee n asa resul t of acomple x offactors , someo f which are alcohol-mediated, and someothe r ones aregeneticall y determined. Several mechanisms underlying the development of hepatitis and cirrhosis seem to be involved: -hypoxia (24, 27, 42, 43, 48, 50, 156); - increased peroxidation (1, 19, 40, 54, 55,59 , 83, 113, 133); - abnormal cellular immunological activityan d disturbed lymphocyte activity (6, 10, 20, 36, 48, 86, 89, 146); - achang ei n collagen production (27, 38, 45, 51,73 ,78 , 99, 152); - mitochondrial injury causedb yalcoho l itself or byon e of its metabolites acetaldehyde orhydroge n (73); , - interference with essential fatty acid and prostaglandin metabolism (32, 38,39 ; seeals o Chapter 5); - an antitubular effect of alcohol or acetaldehyde, causing theformatio n of Mallorybodie s (48). Hypoxia, peroxidation, immunological factors and collagen production willb e extensively discussed below. Asoppose d to somethirt yyear s ago, nutritional deficiencies areno wno t regarded asth eprimar y cause. Alcohol consumption itself, rather than the attendant malnutrition in alcoholics, playsa ke yaetiologica l role in the development oflive r injury (2, 74). There isn o solid evidencetha t dietary deficiency alone resultsi n cirrhosis. Nor has aconsisten t deviating picturebee n found in the nutritional status of alcoholics with andwithou t cirrhosis (15, 135). Both animal experimentswit h baboons and epidemiological investigations haveshow n that cirrhosis mayals o develop in cases of adequate dietaryintak e (in addition to alcohol consumption) (74). However, nutritionalfactor s may exert amodifyin g influence on theincidenc eo f liver injury (73). In rodents, steatosis in relation to agive n alcohol consumption was lessfrequentl y observed when the animalswer efe d low-fat diets than when they received dietswit h anorma l fat content (75). Liversfro m nourished rats mayb e perfused in the absenceo f oxygenfo r up to 2hour swithou t detectable damage, whereas fasted liversar e damaged irreversiblyi n 20-40 minutes (12).A diet lowi n vitamin E seems to enhanceth e effects of lipidperoxidatio n (54).

8.2.3. Hypoxia

Hypoxia (an inadequate supplyo foxyge nt o thecells ) seemst ob ea n important factor in hepatic damage, becausenecrosi s (cell death), andlate r fibrosis (formation 93 of fibrous tissue as areplacemen t for the damaged tissue), willfirs t be observedi n theperivenula r zones of the cells. Thesear eth e areasmos t remotefro m thevessel s with oxygen-saturated blood, which thus haveth elowes t oxygentensio n in thelive r (125). Israel et al. (42, 43) consider necrosis in thesezone s ascause db ya disturbanceo f the equilibrium between theavailabilit y of oxygenan d theliver' soxyge n requirement. Oxygen isindirectl y necessary to metabolize alcohol. Itha s been demonstrated that liver cellshav e an increased oxygen demand during alcohol metabolization (43, 48) aswel la sa n elevatedlobula r oxygen gradient in isolated perfused liversfro m alcohol-treated rats (145). However, in experimentswit h baboons stimulation of oxygen consumption seemed tob efull y offset bya paralle l increasei nbloodflow . Despite the absence ofhypoxia , ethanol increases the lactate/pyruvate ratio 15-fold inhepati cvenou sbloo d and only3-fol di n livertissue . Jauhonen et al. (50) and Baraona et al. (9)propose d an alternativemechanis m for the selectiveperivenular injury, namely, that thelo wpC> 2 at theperivenula r site aggravates the redox-linkedtoxicit y of ethanol. In rat experiments acombinatio n of alcohol consumption andlo woxyge n tension inth eambien t airprove d to causea hig h degreeo flive rnecrosi swherea s the same quantity of alcohol in combination with anorma l oxygentension , or an alcohol-free diet in combination with alo woxyge n tension, didno t causenecrosi s (42, 43). Ani n vitro experiment showedmarke d liver damage due to thecombinatio n of alcohol exposurean d lowbloo d supply, whereas alcohol exposurecombine dwit h normal blood supply resulted in moderate damage (156). Hypoxia maymanifes t itself in alcoholics asa consequenc e of respiratory depression causedb ysever e alcohol intoxication, or asa consequenc eo f pneumonia, an illnesswhic hi scommo n amongalcoholics . Anaemia, whichi sals o frequently observed among alcoholics as aresul t of gastrointestinal haemorrhage, proved to promote the development of necrosis in the experiments of Israel and co-workers. The administration ofpropylthiouraci l (PTU) reduces the oxygen consumption of thelive r and thusprotect s alcohol-fed ratsfro m liverinjur y (42, 43). According to French (24) chronic alcohol ingestion leads tohepatocellula r injury onlyi fmultipl efactor s are operativei n combination to induce centrilobular hypoxia. Possiblefactor s are ashif t inredo xstate , MEOSinduction , ahig hbloo d alcohol concentration (BAC), adie t richi npolyunsaturate d fatty acids (PUFA), and episodic decreased oxygen supplyt o theliver .

8.2.4.Free radicals

Evidencei saccumulatin g for amajo r roleo f free radicals in thepathogenesi so f alcohol-induced liver damage. Freeradical s aremolecule s containing an unpaired electron, which givesth efre e radical ahig h chemicalreactivity . Theyca n damage cellsan d tissues inman y different ways(se eFig . 8.2).

94 DNA damage ^^ Cel1 InJury ^^*^ Mutations

Destruction of Nucleotide coenzyme activities {Change in redox status of NAD(P)H

Disturbance to SH-dependent enzymes (Change in SH/S-S status

Covalent binding to protein and lipid

REACTIVE FREE RADICALS J"™»- Changes in enzyme activities and lipid metabolism

' Damage to proteins, increased protein turnover

1Lipi d peroxidation, changes in membrane structure \and function Secondary products causing disturbances at a distance, such as to the functions of other membranes

Membrane damage to proteins, transport disturbances

Fig. 8.2. Reactions of reactive free radicals. After: Slater (137). The susceptibility of atissu e toperoxidatio n isa functio n of thebalanc e between pro-oxidant and antioxidant systems. Thepro-oxidan t free radicals can originate from lipids, acetaldehyde and even alcoholitself . Iron isa powerfu l catalyst of free radical mechanisms. Glutathione (GSH), ascorbic acid, selenium and «-toco-pherol haveantioxidan t properties. Alcohol seemst oinfluenc e both thepro-oxidan t and the antioxidant systems at various sites. Recently thei nviv oformatio n ofa fre e radicalmetabolit e of alcohol (a-hydroxy- ethylradical ) hasbee n demonstrated (55). Acetaldehyde isals o a substrate of free radical production (113). In vitro peroxidation occurs after the addition of acetaldehyde in thepresenc e ofxanthin e oxidase. In vitro studies of free radical generation with acetaldehydehav ereveale d dependence of and stimulation byiron . Administration of iron to ratspotentiate s hepatic radical production duet o acute alcohol administration. Another source offre e radicalsi slipi dperoxidation . Lipid peroxidation is dependent of cytochrome P-450 reductase activity, particularly thetyp einduce db y chronicalcoho l consumption (MEOS) (40). Chronicalcoho l administration increases microsomal lipid peroxidation in thepresenc e of added iron. Dicker& Cederbaum (19)foun d that chronicalcoho l consumption leads to enhanced generation ofreactiv eoxyge nintermediate s and increased inactivation of enzymes.

95 So,bot h acutealcoho l consumption (direct andvi a acetaldehyde) and chronic alcohol consumption (byinducin g MEOS) promotefre e radicalproduction , which maycontribut et o thehepatotoxi c effects of alcohol. In anumbe r of studiesimpairmen t of the antioxidant systems- which are important inth eprotectio n of cellsagains tfre e radicals- havebee n reported in alcoholics. Hepatic GSHi sdepresse d after chronicalcoho l administration (133). Acute alcohol administration lowers GSHbot h inbaboon s chronicallyfe d alcohol and inbaboon s not pre-treated with alcohol (133). Alcoholics, regardless of whether they suffer from hepatitis, havelowe r liverglutathion elevel stha nnon-alcoholi clive r diseasepatients , and alcoholics (withoutlive r disease)hav elowe r plasma glutathione levels (a reflection oflive r concentration) than healthy controls (59). In cirrhotics decreased selenium concentrations havebee n found (1). In alcoholicswithout , and especiallyi n alcoholicswith , hepaticinjur y decreased vitamin E and seleniumlevel shav ebee n found (142). Alcoholinduce s amarke d alteration ofvitami n Emetabolis m in thelive r(54) . Younes &Strubel t (155) suggest amode lwhic hlink shypoxi a andfree radical production. Hypoxia should convertxanthin edehydrogenas e intoxanthin eoxidase , whichproduce s reactiveoxyge nradical s asa resul to fbot h acetaldehyde conversion and purine degradation. Thereactiv eoxyge n radicals mediateth einhibitio no f glycolysisan d the direct toxiceffect s towards liver cells. Kato etal . (53) present a partly different hypothesis. Theyfin d itunlikel ytha t acetaldehyde can servea sa substratefo r xanthine oxidasei nvivo ,bu t domentio n radicalformatio n resulting from purine degradation.

8.2.5.Immunity ,

Therei sals oincreasin g evidenceo fimmunologicall y mediatedhepati c damage(10 , 20, 36, 86, 146). Itha sbee n suggested that acetaldehydei scapabl eo finducin glive r damageno t onlyb yfre e radical production, but alsob y affecting immunity. However, itsrol ei n alcoholiclive r diseaseremain s speculative(10) . Acetaldehydebind st ofre e amino groups (lysine, valinean d tyrosine) of the proteinsi nth elive rcell , thusformin g protein-acetaldehyde adducts (10, 79). This resultsi n altered surface and structural conformation of theprotei n molecules, changingth eimmunogenicity . Antibodies against theseprotein-acetaldehyd e adducts canb e detected inmic echronicall y fed alcohol (47) and in alcoholics (96). Alcoholicswit hhuma n lymphocyteantige n (HLA) B35 (86) andHL AB 8 (127) develop cirrhosisfaste r and/or after lessalcoho l than other alcoholics, which suggests that ageneticall y determined immunological response to alcohol-induced antigensi s responsible for the difference in susceptibility.

8:2.6. Collagen

Collagens are aheterogeneou s group of proteins. Infibrosi s livercell sproliferat e and produceincrease d amounts of collagen. An increasei n collagen content playsa 96 direct rolei n the pathophysiology of alcoholiclive r diseasethroug h its effect on both hepatic structure and function. It isno t clearwhethe r increased collagen in fibrotic cells canb e attributed to increased synthesis (demonstrable from the increased activity of theprolin e hydroxylase enzyme) or decreased breakdown (27, 38, 45,78) . Lactate, the level ofwhic h increases during alcohol metabolism, promotes collagen synthesisfro m proline. Iti sno t clear whether alcohol itself affects collagen synthesis, in viewo f contradictory results (51, 99). Geneticfactor s mayals o playa rol ei n enhanced collagen production. In cirrhotic alcoholics aspecifi c pattern in oneo f thegene s coding for collagen hasbee n determined (152). This suggests the existence of ageneti c predisposition for hepatic fibrinogenesis .

8.3Treatmen t

In this section the treatment of alcoholic liver diseasewil lb e discussed, rather than the treatment of the underlying drinking problem - which isjus t aswel l essential. An important factor in the treatment of alcoholic liver diseasei sabstinence^Afte r some days of abstinence fat accumulation in fatty liver decreases and after 2t o 6week s the disorder usuallyha s disappeared entirely (13, 114). In hepatitis and cirrhosis abstinence is essential too, but sometimes cirrhosis developsfro m hepatitis despite abstinence. Nutritional support in alcoholiclive r disease therapy isver yimportant . Patients are often malnourished or havesubclinica l nutritional deficiencies. In cirrhosis dietary support has tob egive n carefully, becausea n oversupply of nutrients cangiv e riset o complications, duet o the disturbed metabolism (49). The only effective treatment of end-stagecirrhosi s islive r transplantation (130, 150). This 'start of ane wlife ' seemst o stimulate thepatien t to remain abstinent. However, in some alcoholics there aremedica l objections to liver transplantation, such asmultipl e organ damage or malnourishment. Quitea numbe r of drugs havebee n proposed to modify the diseaseprocess . Sometimes invitr o experimentsyiel dpromisin g results, whereas theresult s of clinical trials are disappointing. Saunders (128) has reviewed the drugsuse d in alcoholiclive r diseasetherapy . The thyroid inhibitor propylthiouracil (PTU) appears nowt ob e the most promising treatment availablefo r treating thebasi c diseaseprocess . PTU reduces the oxygen consumption of thelive r and should thus protect against liver injury (42, 43). Saunders (128) states that corticosteroids shouldb eregarde d ashavin g no rolei n thetreatmen t of alcoholiclive r disease. The effect of anabolic steroids should be examined further. Colchicineinhibit s collagen synthesis and increases collagenase activity. It has also anti-inflammatory properties. Itstherapeuti c potential seems to be considerable, but hasno t yetbee n established unequivocally. Propanolol, a ß- adrenergic blocking drug, reduces portal venous pressure, thus preventing bleeding of oesophageal varices (128).

97 8.4. Thresholdvalue sfo r alcoholconsumptio n relativet olive r injury

A vastbod y of literature on thresholdvalue sfo r alcoholiclive r diseasesha sbee n published in the 1970s (seeTabl e 8.1). The opinion has taken root sincetha t alarg e number of factors, both of an environmental and ageneti cnature , modify the association between alcoholconsumptio n and alcoholiclive r disease, so threshold valuesar eno t aver yactua l topicnow . The advances in modern molecular biologyhav ereveale d that everyindividua l metabolism isa uniqu e concert of enzymes, inwhic h the activity of each enzymei s (partly) genetically determined. Processes canb emor e orles spromote d or inhibited, resultingi nindividua l differences invulnerabilit y for injury. Immunityprobabl yi s involvedi n the development of alcoholiclive rinjury . In alcoholics different genes coding for some antigens arefound , suggesting genetically determined vulnerability. These can be seen asinterna lfactor s modifying the relation between alcohol and injury. Life-style and eating and drinking habits couldb e seen as externat, environmental modifying factors. After aperio d inwhic h malnutrition wassee n asth e most important aetiological factor in alcoholiclive rinjury , followed bya perio d inwhic h dietary factors wereneglected , iti sassume d nowtha t the dietca n havea modifying effect. Excess of fat promotes fatty liver (110), vitamin E deficiency enhances free radical injury (54) and the dietary composition of polyunsaturated fatty acids affects thePUF A composition inth ebody , possiblyattenuatin g alcoholicinjur y (123). However, alcohol iso f courseindispensabl e for the development of alcoholiclive r

Table 8.1.Threshol d valuesfo r alcohol consumption according tovariou sauthors . After: Piendl (106, 107).

Ref. Alcohol use Results (g/day)

61-67 a) < 160 patients suffering from the consequences of excessive alcohol consumption were not found tohav e incurred cirrhosis b) >160 after 12year s of alcohol abuse 25%o f the patientswer e found to have incurred cirrhosis, and after 20year s50 % 95 > 66 up to >110 danger limitfo r the onset of liver cirrhosis (88 on average) 41 160-200 over danger zone for the pathogenesis of liver cirrhosis > 10year s 22 > 125 over increased riskfo r alcoholiclive r cirrhosis 102, 104 a) <80 limit of harmlessness b) 80-160 dangerzon e ('Gefährdungsbereich' ) c) > 160 increased risk of developing liver cirrhosis 7 100 critical limit 5 a) <80 alcohol consumption generally harmless b) > 100 danger limit c)160 critical limit

98 disease. Interviewswit hpatient s suffering from alcoholichepatiti s or cirrhosis (or their relatives) about the quantity and duration of alcohol consumption provide global information about threshold values, and so do animal experiments. In the subsequent sections theselimit swit hrespec t tofatt y liver, hepatitis and cirrhosiswil l be discussed successively. Thelimit s presented, however, shouldb einterprete d with caution. Increasing alcohol consumption increases the riskfo r injury gradually. 'Safe' limits cannot begive nbecaus eo f thelarg evariatio n in individual vulnerability.

8.4.1. Fatty liver

Glouberman (33) mentions (without referring to aparticula r source) an alcohol intake accountingfo r 20%o f total energyintak e (20 en%) asa conceivablelimi t belowwhic h fatty liverwil lno t develop. This level corresponds with ca. 70g alcoho l (7glasses ) per daya t a daily energy intakeo f 10MJ . In the samepape r Glouberman indicated that the accumulation offa t in thelive rstart s as soon as twoday safte r the consumption of alcohol. In an experiment with human subjects Lieber etal . (69)foun d that axt an alcohol consumption level of 300 g/dayfatt y degeneration couldb e observed microscopically after 8days ;whe n 150 g(1 5 drinks) wasconsumed , thiswa sno t observed until after 21 days. Fatty degeneration wasreverse d upon termination of alcohol consumption. According to Rao (110), who criticizes Lieber's experiments, nutritional factors areimportan t for the development offatt y liveri nnon-alcoholics . With adequate diets 260 galcoho l did not produce fatty liver, whereas 130g alcoho l (46 en%) in combination with a diet of 36%fat , 2%carbohydrate s and 16%protei n resultedi n fatty liver.

8.4.2. Hepatitis

Both the quantity of alcohol consumed per dayan d the duration of (excessive) alcohol consumption appear tob e significant in theonse t of hepatitis, but the individual differences found are large. However, frequently either onlyth e periodo f alcohol use or the quantity of alcohol isreported . Brandt &Bronkhors t (13) stateda period of excessivealcoho l consumption extending from one tofiv eyears . Glouberman (33) indicated that hepatitiswa s observedbot h amongindividual swh o had been drinking for three months only and amongperson swh o had done so for 36years . In the samepape r Glouberman mentioned that hepatitis rarely developsi f dailyalcoho l consumption isles s than 80g . Mezey &Santor a (88) found that thefiv e patients suffering from hepatitis (among 55 alcoholics they examined) alluse dt o drinkmor etha n 200g/day . However, also among alcoholicswh o reported to drink lesstha n 80g/da ylive r injury wasfoun d (fibrosis with fatty infiltration). Both in rodents and inprimate s an alcohol consumption corresponding with 36 en%resulte d infatt y liver, but not in hepatitis or cirrhosis. At 50 en%hepatiti s and cirrhosis developed in half of theprimates , 99 however (71-73). Although theseresult sma yno t immediately applyt o human beings, theyprov et o agreereasonabl ywel lwit h theresult sfoun d for man (at adail y energyintak e of 10MJ , 36 and 50 en%correspon d to 120 and 170g alcoho lpe r day respectively).

8.4.3. Cirrhosis

Piendl (106) indicatedwha t quantities areregarde d asinjurious . Table8. 1i sa condensed representation of hissurvey . From these data it mayb e concluded that consumption of moretha n 100-160 galcohol/da y over aperio d of 10-20 yearsi s necessary for the development of liver cirrhosis, but occasionally cirrhosis proves to bebrough t about by smaller quantities.

8.4.4. Sexdifferences inliver disease vulnerability

Many different groups havereporte d sex-related differences in alcohol-induced liver disease (27, 82, 90, 98, 149, 151). In general, female cirrhotic alcoholics drinkles s and for a shorter period of timetha n their male counterparts. The results obtainedb yPéquigno t and co-workers (104, 105)- inwhic h they present threshold valuesfo r liver cirrhosisfo r men andwome n separately- are frequently quoted: ashar p increasei nth eris ko f cirrhosiswoul d occurwhe n daily consumption exceeds 60 gfo r men and 20g fo r women. In their survey Péquignot et al. compare the reported alcohol consumption of male andfemal e cirrhotic patients with that of arando m sample taken from thetota l population. In another investigation they found the slopeo f the increasei n relative riskt ob e steeper for women than for men (147). Inneithe r investigation theyindicate dwhethe r the differences werestatisticall y significant. Norton (98)foun d inAustralia n women anincrease d and dose-dependent risko f alcohol-related cirrhosis from 41g alcoho lpe r day. Whereas 1%o f the female Australian population drink 4o r moreglasse s per day, 90%o fAustralia n cirrhotic women drink that much. In most investigations alcohol consumption expressedi n grammes per dayha s been examined. Chapter 2o f thisrevie wpoint s out thatwome n reach ahighe r BAC than men after the consumption of agive nquantit y of alcoholbecaus e of their smaller averagebod ymas s and their lower averagepercentag e ofbod ywater . This maypartl y account for the differences in susceptibility observed. Another explanation mayb eth e distortion of actualconsumptio n causedb yth e usualmetho d of inquiry among theindividual s tested. From several surveys the notion has emerged that excessiveuser sten dt o underreport their consumption (14, 21,118), especiallywome n (26). It isquit elikel ytha twome nhav ea greater tendency to underreport since, according togenerall y received norms, a woman shouldno t drink much (129). Besides thesepossibl e explanations, abiologicall y determined susceptibility may exist. Sexhormone s influence ADH and MEOS activity, andhenc e acetaldehyde 100 production and lipidperoxidation . Possibly thisplay sa rol ei n the increased susceptibility ofwome n to alcoholiclive r disease. Hormonal differences and differences inimmun e reactivity to alcoholhav ebee n suggested (27, 34, 126). Further research in thisfiel d isdesirable .

8.4.5.Differences between beverages

In somepublication s it hasbee n suggested that there are differences in cirrhogenic activitybetwee n thevariou s types ofbeverage s (70, 102, 107, 143, 153). A higher cirrhogenic activityha sbee n attributed towin ei n particular. In these studies attention hasbee n drawn to thefac t that there isa close r relationship between the consumption ofwin ean d cirrhosis than between theconsumptio n of spirits or beer and cirrhosis. In four investigations cirrhosis mortality and per capita alcohol consumption, differentiated according to typeo fbeverage , arecompare d for a number of countries. When cirrhosismortalit yi srelate d to the consumption of alcohol, both taken together and split up intobeer , winean d spirits, astron g positive correlation between total alcohol consumption and cirrhosis mortality andbetwee nAvin e consumption and cirrhosis mortality isfound , whereas no correlation is found between cirrhosis mortality and the consumption of spirits or beer. These results appear to indicate that cirrhosis mortality islargel y causedb ywin e consumption. However, a critical examination of these associations showsclearl y that the results do not really contradict thehypothesi s that allthre e types ofbeverage s may cause cirrhosis to (almost) the same extent. Differences between countries in actual intake of alcohol prove to be determined mainlyb yvariatio n inwin econsumptio n and less sob yvariatio n in consumption ofbee r and spirits. In other words, from these investigations it can neither be concluded that allalcoholi cbeverage s are (almost) equally cirrhogenic nor that winei smor e cirrhogenic. An important point isth efac t that in theseinvestigation s iti sno t the alcohol consumption (quantity and typeo fbeverage ) bythos ewh o had died of cirrhosis that was examined. Instead, the averageo f the total population over 15wa stake n asa measure. Another methodological drawback of this typeo f investigation arises from the fact that the diagnosis of alcoholiclive r cirrhosis mayvar yfro m one country to another. Moreover, countries (or states) haveno t only different drinking habits, but also different cultures and different eatinghabit s and wayso flife . These mayals o account for the observed variances in cirrhosis mortality. Ahig h correlation coefficient does not necessarily point at causality. Péquignot, too, pointed out that morewin ei sdrun k in France and cirrhosis mortality in France ishighe r than in other countries (102), thus advancing the same statistically invalid argument. Thesam eapplie s to another argument usedb y Péquignot, namelytha t 80-90%o f thealcoho l consumedb ycirrhoti cpatient si n France is drunk aswine : at thetim eo f hisinvestigatio n (1955) ca. 80%o f all alcohol consumed in Francewa s drunk aswin e(3) . 101 Therelatio n between cirrhosis and alcoholicbeverage sha s alsobee n investigated byLelbac h (60). Of the 526 alcoholics he examinedwit h respect tolive rinjur y and alcohol consumption, thebee r drinkers proved tohav eindee d lesslive rinjur y than the spirit drinkers, but thebee r drinkers drank less excessivelyan d for shorter periods. As Lelbach rightlypoint s out, this doesno tjustif y the conclusion that spirits aremor e injurious to the liver than beer. DiLuzi o (83) and Mezey &Santor a (88) didno t find differences among the various types of alcoholicbeverage s asregard s liver injury. Alli n all, there isn o conclusive evidencet ojustif y the statement that a particular typeo fbeverag ewoul db e more cirrhogenictha n another type.

8.5. Epidemiology

Most epidemiological data concerning liverinjur y refer to cirrhosis mortality. There are regional aswel la stempora l relations tob e observedbetwee n mortality duet o cirrhosis and per capita alcohol consumption. These data arebase d on either the entirepopulatio n or the population of 'drinking age', i.e. from the ageso f 14, 15o r 20year son . Sincemos t cases of cirrhosis occur among alcoholics, Jellinek has developed a method to estimate the number of alcoholics of apopulatio n on thebasi s of cirrhosis mortality (in addition to someothe r data):th e 'Jellinek estimation formula'.

8.5.1. Temporalrelations between cirrhosis mortalityand per capita alcohol consumption * A positive temporal correlation between cirrhosis mortality and per capita alcohol consumption hasbee n observed invariou s studies (25, 29, 30, 58, 124), whereas othershav eno t found such acorrelatio n (138). Because cirrhosis tendst o develop only after asman y as 15t o 20year so f excessivealcoho l consumption, it couldb e expected thatbrie f fluctuations in alcohol consumption willno t be reflected in cirrhosismortalit y and that apermanen t change in consumption willno tb efollowe d immediatelyb ya chang ei n cirrhosis mortality (timelag ) (136). Therefore, iti sremarkabl e that Sales (124) found changes in per capita consumption immediately reflected in changed cirrhosismortalit yi n theUK . Longer periods of decreased alcohol consumption areusuall yfollowe d bya decreasei n cirrhosismortality . Prohibition in theUS Afro m 1916 to 1932 (109), the periodbetwee n both World Warsi n theNetherland s (28) andth e scarcityo fwin ei n Paris duringth e secondWorl d War (102) are examples of this. However, a decrease in cirrhosis mortality rate during awa r cannotb e attributed solelyt o a decreaseo f alcohol consumption, considering the changei ntota l and specific mortality: someone suffering from cirrhosiswh o dieso fwartim eactivitie swil lno tb einclude d in the cirrhosis mortality rate!

102 The relation between disorders frequently attributed to alcohol consumption and national statistics on alcohol consumption proves less strong than has often been assumed. Thefac t that alcohol consumption in theNetherland s has quadrupled

Liver cirrhose deaths per 10000 0 35

Wine countries

0 4.55 9.10 13.65 18.20 Absolute alcohol consumption (litres/year)

Fig. 8.3. Relation between per capita alcohol consumption and mortalityfro m liver cirrhosisfo r 29 countries in 1967. A, Austria; AUS, Australia; B,Belgium ; BG, Bulgaria; CDN, Canada; CH, Switzerland; CS, Czechoslovakia; D, Germany; DK, Danmark; E, Spain; F, France; GB, Great Britain; GR, Greece; H, Hungary; I, Italy; IL, Israel; IRL, Ireland; J, Japan; L, Luxembourg; N, Norway; NL, Netherlands; NZ, NewZealand ; P, Poland; PL, Portugal; R, Rumania; S, Sweden; SF, Finland; USA, United States; YU, Yugoslavia. After: Piendl (106, 107) and Smith et al. (139).

103 between 1950 and 1975ha s asye tno t been followed bya comparabl eincreas ei n mortalityfro m illnesses (partly) causedb yalcoho l (cancer of the oesophagus, r cirrhosis) (81).

8.5.2. Regionalvariation inthe relation between cirrhosismortality and per capita alcoholconsumption

Several correlation studies havereveale d aclea r statistical relation between per capita alcohol consumption and cirrhosis mortality comparing the data for various countries or regions (16, 37, 107, 153). Piendl (106, 107) compared per capita alcohol consumption andlive rcirrhosi smortalit y in 29 countries, on thebasi so f 1967 statistics (cf. Fig. 8.3). Hoogendoorn (37) has doneth e samefo r 21countrie s using alcohol consumption statistics over theperio d 1970-1972 and cirrhosis mortality statistics for 1974 (cf. Table 8.2). Franceha d both the highest cirrhosis mortality and thehighes t per capita alcohol consumption. Other countrieswit h ahig h cirrhosis.mortality anda high alcohol consumption wereAustria , Italy, Portugal, West Germany and Spain. In

Table 8.2. Per capita alcohol consumption (average of the period 1970—1972) and cirrhosis mortality (1974 data) in European and non-European countries. After: Hoogendoorn (37).

Country Annual per capita Liver cirrhosis alcohol consumption (1) mortality per 100 000 Europe France 16.0 32.8 Italy 13.7 31.9 Portugal 13.0 31.3 Austria 12.2 32.7 Spain 11.0 22.5 West Germany 10.9 26.9 Switzerland 10.7 14.8 Belgium 9.1 14.4 Denmark 7.3 10.4 England and Wales 6.7 3.6 Netherlands 5.9 4.5 Sweden 5.7 10.5 Ireland 5.7 3.7 Finland 4.7 5.5 Norway 3.7 4.1

Otherregions .. Australia 8.3 8.3 New Zealand 7.9 5.4 Canada 7.1 11.6 USA 6.5 15.8 Japan 5.4 13.4 Israel 1.7 6.2

104 the Netherlands cirrhosis mortality per 100 000 inhabitants wasles s than one seventh of that in France. In Sweden aremarkabl y high cirrhosis mortality isfoun d in spiteo f a lowalcoho l consumption. This could reflect a discrepancybetwee n official and actual consumption data, owing toilliga l alcohol production.

8.5.3.Alcoholics

Several surveys among groups of alcoholics have shown that, on average, alcoholics diesom e 12year s earlier than non-alcoholics. Total mortality is 2t o 4time s higher (14, 80) and the alcoholics' risk of dying of liver cirrhosis is 15-20 times higher than among non-alcoholics (81). Cirrhosis account for 5-15%o f total mortality among alcoholics (14).

8.5.4. Cirrhosis mortalityas an indicatorof the prevalence of alcoholism

Jellinek has developed aformul a which mayb euse d to estimate theprevalenc eo f alcoholism in apopulatio n on thebasi so f cirrhosis mortality - the 'Jellinek estimation formula'. Other methods to estimateth eprevalenc e of alcoholism are the extrapolation of survey results, the Ledermann formula (on thebasi s of per capita consumption), and estimates founded on total mortality or mortality due to suicide. TheJelline k estimation formula and theLederman n formula areth ebes t known and most extensively used methods. For the application of theJelline k formula thefollowin g data areneede d in addition to the total annual number of deaths from cirrhosis. - The ratio between alcohol-induced cirrhosis mortality and total cirrhosis mortality. Initially, this ratio hasbee n estimated from the changei n cirrhosis mortality brought about byalcoho l prohibition in theUSA . Later, this estimation hasbee n adapted several times. Therati o ispresumabl y not constant, but depends on themortalit y due to alcohol-induced cirrhosis and on thenationa l health system of acountr y asa whole . - Themortalit y due to liver cirrhosis among alcoholics showing complications. - The ratiobetwee n alcoholics showing complications and allalcoholics . Thevalu e assigned to this relation depends on which definition of alcoholism isused . There iss omuc h insecurity in thesevariable s that estimationsbase d on the Jellinek formula must beinterprete d with reserve.

8.6. Biochemical identification of alcohol abuse and alcoholism

Alcohol consumption, especially chronic alcohol abuse, affects many metabolic processes. Itsmajo r influence is exerted on processes in theliver . Bythi s mechanism the enzymecontent s of thelive rchange , whichi n turn isreflecte d in changed plasma levelso f liver enzymes. Plasma levelso f liver enzymes, aswel la sothe r blood

105 parameters, are often used asmarker sfo r alcohol abuse. The most commonly used parameters are: - y-glutamyltransferase (GGT) - alkalinephosphatas e (AP) - erythrocyte mean corpuscular volume (MCV) - alanineaminotransferase , or glutamic-pyruvic transaminase (ALAT, GPT) - aspartate aminotransferase, or glutamic-oxaloacetic transaminase (ASAT, GOT) - carbohydrate-deficient transferrin (CDT). Other parameters havebee n used aswell , such asurate , lactate, triglycerides, high-density lipoprotein (HDL) cholesterol, platelet count (91), 6-aminolaevulinic acid (ALA) dehydratase (58), a-amino-N-butyricacid/leucin erati o (132), and even chest radiography (112). Repeatedly new markers areproposed . Recent markers are urinary dolichol (115, 116), methanol (117), acetate (57), /3-hexosaminidase(52) , and reduced erythrocyte aldorase activity (35). On apopulatio n level significant differences in thevalue s of theseparameter s are usually obtainedbetwee n usersan dnon-user s ascontrols . Compared-tocontrols , the values for alcoholics commonly lieoutsid eth enorma l ranges. Plasma GGT leveli s regarded to reflect alcoholism most reliably (8; 119)althoug h thene wmarke r CDT hasbee n claimed tob e more sensitive (11, 31). Yet, thelac k of sensitivity and specificity of theseparameter s hampers their use for individual cases. Sensitivity isdefine d asth epercentag e of alcoholicswit ha positive test and specificity isdescribe d asth e percentagenon-alcoholic s witha negative test. Increased levels of GGT arefoun d in approximately 50%o f alcoholics (18, 23) aswel l asi n most non-alcoholics withlive r cell damage. A combination of results of several testsma yimprov esensitivit yan d specificity (17, 18, 120, 121). Rybacketal. (120) identified correctly 94-100%o f alcoholics (inpatients and outpatients) and 100%o f non-alcoholics byusin g acombinatio n of 25tests . Theusefulnes s of distinctivetest s depends on thewa ythe y areinfluence d by alcohol. Sometest s react readily to asingl ealcoho l dosage (MCV),whil eothe r ones onlyrespon d after hepatocellular damageo r alcohol addiction. GGT seems to react tobot h liver injury (whether or not alcohol-related) and regular alcohol consumption (97, 101, 144). GGTi scorrelate d onlymoderatel ywit h the extent of alcohol use (94). Probably aminimu m amount of alcohol isnecessar y to increaseth e GGT level. Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) levels areno t affected byalcoho l consumption, but are areflectio n of organ damage. An increased ASAT/ALAT ratio isindicativ e of alcoholiclive rinjur y (122). MCVincrease s rapidly after alcohol intakean d drops uponwithdrawa l (154). The simple and cheap MCV test provides an indicator for recent alcohol consumption. Even moderate alcohol drinkers canhav ea n increased MCVleve l (148). ALA dehydratase isals o regarded asa n indicator for recent alcohol consumption. In non-alcoholics ALA dehydratase declinest onorma l valuesonl ywhe n BACha s

106 been decreased to zero (92), whereas in alcoholics it takes several daysbefor e the valuereache s the normal range (58). Opinions on the roleo f a-amino-N-butyricaci d diverge. It isregarde d asa non- sensitiveinde xfo r hepatocellular dysfunction byMorga n et al. (93) and as an indicator for alcoholism bySha w et al. (131). CDTi sa promisin g new marker (11, 31). It hasprove d to be amor e sensitive and specific marker than the eight markers commonly used including GGT. In people drinking 3glasse s or lesspe r dayn o elevated levelswer efound , whereas from 4 glasses per daya n elevated levelwa s demonstrated in 68% of the subjects. In alcoholics 81% had an elevated CDTlevel . The relationship with alcohol consumption seems to bevali dirrespectiv e of alcoholic liverdisease . It has been suggested that acetaldehyde mediates inhibition of enzymesinvolve d in the synthesis of thetrisaccharid e component of transferrin, thus resulting in carbohydrate- deficient transferrin (141). The choice of parameters depends on the aimwhic h ispursue d (e.g. screening, establishing alcoholism in suspected persons, controlling drop-outs in an alcohol treatment programme) and on the simplicity of testing (sometest s are easily automated whileother s are time-consuming and expensive). '

Summary

Prolonged consumption of large quantities of alcohol maycaus efatt y degeneration of theliver , hepatitis and liver cirrhosis. If alcohol ispresen t in thelive r the latter prefers alcohol to fat as afuel . Because of the decreased oxidation of fat, and also because of an increased fat supply and synthesis, areversibl e accumulation of fat in the liverwil l occur. When normal liver metabolism isdisturbe d over alonge r period of timelive rcell s mayb e destroyed and inflammation mayoccu r (hepatitis). Aslive rinjur y becomes progressive, thefibrou s tissuewil lbegi n to proliferate resulting in cirrhosis. Susceptibility to the development of alcoholiclive r diseasevarie swidely . Only 8-30% of alcohol abusers actually develop structural liver damage. The variable response to alcohol makes sense ifalcoholi c liverinjur y issee n asa result ofa complexo f factors, part ofwhic h arealcohol-mediated , and part ofwhic h are genetically determined. A combination of someo f thefollowin g processes presumably isinvolve d in the onset of hepatitis and cirrhosis:hypoxia , increased peroxidation, mitochondrial injury, abnormal cellular immunological activity, changes in collagen production, disturbance of lymphocyteactivit y or antitubular activity of alcohol. Hypoxia (an inadequate supply of oxygen to thecells ) seems tob e an important factor inhepati c damage, becausenecrosi s (cell death), and later fibrosis (formation of fibrous tissuea s areplacemen t of the damaged tissue), isobserve d first in the perivenular zones of thecells .

107 Evidencei saccumulatin g for amajo r rolefo r free radicalsi nth epathogenesi so f alcohol-induced liver damage. The susceptibility of atissu e toperoxidatio n isa function of thebalanc ebetwee n pro-oxidant and antioxidant systems. Thepro - oxidant free radicals can originatefro m lipids, acetaldehyde and evenalcoho litself . Iron isa powerfu l catalyst of free radical mechanisms. Glutathione (GSH), ascorbic acid, selenium and a-tocopherolhav eantioxidan t properties. Alcohol seems to influence both pro-oxidant and antioxidant systems atvariou ssites . It hasbee n suggested that acetaldehydei scapabl eo finducin glive r damageno t onlyb yfre e radical production, but alsob y affecting immunity. However, itsrol ei n alcoholiclive r diseaseremain s speculative. Acetaldehydebind s tofre e aminogroups , forming protein-acetaldehyde adductswit h altered immunogenicity. Itha sbee n suggested that genetically determined immunological response to alcohol-induced antigens arepartl y responsible for the difference in susceptibility to alcoholiclive r injury. An increasei n collagen content playsa direct rolei nth epathophysiolog y of alcoholiclive r disease. It isno t clearwhethe r increased collagen infibroti c cells shouldb eattribute d toincrease d synthesis or to decreasedbreakdown . Genetic factors may also play arol e in enhanced collagen production. The opinion istakin g foot that acomplexit y ofbot h environmental and genetic factors modify the association between alcohol consumption and alcoholiclive r disease. So, threshold limits shouldb einterprete d with caution. Life-style and eating and drinking habits could be seen as external, environmental modifying factors. After a period inwhic h malnutrition wassee n asth emos t important aetiological factor in alcoholiclive rinjury , followed bya perio d inwhic h dietaryfactor s wereneglected , the diet isno w assumed to havea modifyin g effect. There aren o differences betweenbeer , winean d spiritswit h respect to theris ko flive r injury. The quantity of alcohol and the duration of excessiveconsumptio n appear to influence the onset offatt y degeneration ofth eliver . Even short-term excessive alcohol consumption may cause areversibl e accumulation of fat in theliver . Fatty liver does not develop below a dailyalcoho l consumption of ca. 70 g. Hepatitis appears to develop onlyrarel ywhe nles stha n 80g alcoho l isconsume d daily overa period not exceeding 1-5 yearsi sconsumed . When dailyalcoho l consumption of over 100-160 g/dayi sprolonge d for 10-20year sther ewil lb e anincrease d risko f developing cirrhosis. Occasionally, however, cirrhosis provest o developwhe n smaller quantities areconsumed . Itmus tb e strongly emphasized that thevalue s mentioned above aren o more than rough indications. Women appear tob emor e prone to developingfiver cirrhosi s than men. Their lower averagebod yweigh t and smaller averagebod ywate r volumecan 'onl ypartl y explain this. Possiblyhormona l effects play arol e aswell . Both temporally (inth e courseo f time) and regionally (between countries), per capita alcohol consumption appears tob e associated with cirrhosis mortality. Plasma levelso flive r enzymesa swel l asothe r parameters areofte n used to determine the extent of alcohol (ab)use. On apopulatio n level significant differences areusuall y obtained. Asyet , thelac ko f sensitivity and specificity ofth e parameters 108 hamper their applicability to individual cases. However, a combination of various tests mayimprov e sensitivity and specificity drastically.

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115 CHAPTER 9 Effects of alcohol on thebrai n and the nervous system

W.G. Vrij-Standhardt

Alcohol iswidel yknow n to affect functioning of thebrai n and of thenervou s system. The changes of mood andbehaviou r brought about byth e consumption of afe w drinks are the most common and theleas t drastic. On the other hand, irreversibele mental disorders are observed in somealcoholics . A distinction canb emad ebetwee n the effects of acute and chronic alcohol consumption. In this chapter the effects of acute and chronic alcohol consumption and possible mechanisms of the action of alcohol on thebrai n and the nervous system willb e discussed. Attention ispai d to the aetiology and mechanisms of tolerance, physical dependence andwithdrawal .

9.1. Effects of acute alcohol consumption

The effect of alcohol isgreates t during theincreasin g stageo f thebloo d alcohol concentration (BAC). In broad outline, therei sa relatio n between theheigh t of the BACan d the changes observed inmood , behaviour and physical condition (tipsiness, intoxication) (23, 34). When theBA Cha s returned to (almost) normal values, hangover symptoms may appear.

9.1.1. Effectsof increasing BAC

When someone's BACha s reached avalu eo f 0.2 g/1,h ewil lfee l relaxed, pleasantly mellow and talkative. In these quantities alcohol has a 'lubricant' effect on social contacts. At 0.3-0.5g/ 1 an euphoric condition comes about (an increased senseo f well-being, accompanied with unfounded optimism). Powerso f concentration decrease and reaction timeincreases . Subjects whoseBA Crange sbetwee n 0.3 and 0.8 g/1 perform concentration and reaction tests, an9als o driving tests, less successfully than in asobe r state,wherea s most of them areconvince d of the opposite (27, 49, 51). Also, at aBA Co f ca. 0.3 g/1 sport achievements provet o be diminished, mainly asa resul t ofpoo r co-ordination and reflex control (9). A BACo f ca. 0.5 g/1 isth e safety limit for participating in traffic in theNetherlands . In other countries thislimi t hasbee n set at 0.8 g/1 (France, Great Britain) or 1.0 g/1 (USA). At ca. 1g/ 1 intoxication willb e distinctly observed, with itsattendan t symptoms such as slurred speech, unsteady gait and antisocial, possibly aggressive, behaviour. 116 A BACo f 2-3 g/1 maycaus e unconsciousness or ablack-ou t (loss of memory without loss of consciousness). During ablack-out , which maylas t aslon g as4 8hours , onei s unablet o add anyperceptio n to hislong-ter m memory (92). The short-term memory isno t affected, neither isth e ability to recall from thelong-ter m memory. So, the individual in question does not behave differently during blackout drinking as compared to drinkingwithou t amnesia. A BAC of 5g/ 1 mayb e considered asth e LD^g dose. Death isusuall y causedb y respiratory embarrassment (80). From post-mortem investigations the average lethal BAC, calculated retrospectively, hasbee n estimated at 4-4.5 g/1 (76). It ranges between 1.5 and 6.7 g/1,bu t there are peoplewh o have survived BACs of up to 11 g/1 (68, 76, 80). In deaths resulting from acombinatio n of alcohol and drugs lower BACs havebee n found (average ca. 3g/1 , range 1.4-6.2 g/1). There are largeintra - and inter-individual differences not onlyi nletha l dose, but in allreaction s to anyBA C (23, 34). The character of aparticula r person, the mood inwhic h hebegin s to drink, hisrat eo f drinking andhi ssurrounding s allhav e influence on thewa yh ewil l react to alcohol. Alcoholicswh o have developed tolerance to alcohol showles s changes in thecentra l nervous system induced byhig h BACs than others (21). Differences in cognitivean d mood changesbetwee n men andwome n upon alcohol consumption havebee n observed (38, 55, 82).Th e phase of themenstrua l cyclema yals o influence thefemal e reaction to alcohol (58, 91). Moreover, caffein, which in itself does not affect reaction time, proves to reinforce the effect of alcohol on reaction time(72) .

9.1.2. Mechanisms ofaction

Thebloo d circulating in thebrai n isseparate d from the remaining blood bysevera l functional and structural barriers. Anumbe r of substances cannot reach the brain becausethes ebarrier s areimpermeable to them. Ethanol, aswel la sothe r fat-soluble small-molecular substances, crosses thesebarrier s by diffusion, however (16). The alcohol concentration in thebrai n depends on theplasm a concentration. Iti s uncertain whether alcohol can bemetabolize d in thebrain . Somealcoho l dehydrogenase (ADH) activity (27) and possibly also somekatalas e activity (17) havebee n demonstrated. Presumably acetaldehyde, which isgenerate d from ethanol in the liver andwhic h maypas s thebrai n barrier, canb emetabolize d in thebrain , considering the presence of aldehyde dehydrogenase (ALDH) in (rat) brain (89). There issubstantia l evidencetha t at least the acute effects of alcohol on thebrai n are causedb yalcoho l per se (56). The specific mechanisms of acute alcohol action are stilluncertain , albeit several mechanisms seem tob einvolved . Alcohol increases thefluidit y of neuronal membranes by disturbing the composition of thebilipi d layer. This results in a diminished ability to elevateintraneurona l calcium ion concentrations, which could explain the acuteintoxicationa l effects of alcohol (22). Inhibition of glutamate (a neurotransmitter) receptors in thehippocampu s byalcoho l hasbee n observed (64). It has recently been suggested that impairment of memory during alcohol intoxication ismediate d bydeficienc y of the neurotransmitter 117 serotonin, and can bereverse d bydietar y tryptophan (a precursor of serotonin)(103).

9.1.3Hangover

A hangover - the aftereffects of alcohol use- can appear at about thetim ewhe n the ethanol concentration in thebloo d approaches zero and often lastsfo r several hours. Ahangove r isassociate dwit hunpleasan t mood changes, drowsiness, thirst, headache, sleep disturbances and sweating. The occurrence of ahangove r is often related to the quantity offuse l alcohols consumed (75, 83). jSinceth e higher alcohols are absorbed and metabolized more slowlytha n ethanol, theforme r arelonge r detectable in thebloo d (78). Thesepharmacologicall y activehighe r alcohols, such as n-propanol, n-butanol, and iso-amyl alcohol, are present in larger quantities in beverages likewhisky , rum andbrand y than in, for instance, vodka. Murphree (68, 69) found bourbon (American whisky)t ohav emor e effect on theEE G (electro­ encephalogram) than vodka and also to induce astat e ofgreate r stupefaction. Another survey (75) reports for various alcohohcbeverage s arelatio n between hangover symptoms and the congener contento f thebeverag e after the consumption of 15m lalcoho l per kgbod yweight . Yet ahangove r isno t causedb ycongener s only. Pure alcohol may also causea hangover. A decrease of thebloo d sugar concentration and an increase inlactate , triglyceride, ketonebodies , andfre e fatty acidconcentration s causedb yalcoho l consumption may allpla y apar t in this, although no clear relations with the extento f hangover symptoms havebee n found (106). A disturbance of thewate rbalance , causedb yth e influence of alcohol on hormones regulating thewate r balance, may also (partly) account for hangover symptoms (57). Infusion of prostaglandins mayproduc e symptoms that havemuc h in common with hangover (24). Alcohol mayincreas e theformatio n of prostaglandins (18), whereas inhibitors of theprostaglandi n synthesis, such asaspiri n andtolfenami c acid, alleviate somehangove r symptoms (45). Someconside r ahangove r tob e an early withdrawal symptom, also because taking an alcoholic drink during a hangover may alleviateit ssymptom s (25). The occurrence and the extent of ahangove r dono t only depend on the quantity of alcohol and congeners consumed, but are also influenced bypersonality , behaviour, social and environmental factors, smoking and tiredness. Hangover symptoms are difficult to reproducei nlaborator y experiments (46).

9.2. Effects of chronic alcohol consumption

9.2.1. Brain damage

Research on the effect of chronic alcoholism on thebrai n canb e classified into psychometric research related tobrai n function, and research into structural changes

118 inth ebrain . Sincecomputerize d tomography (CTscanning , anon-invasiv ebrain - scanning X-ray technique) cameup , our knowledge of the structural changes in the alcoholicbrai n has substantially increased. The abundance of data wasintiall y confusing, but hasgaine d structureb ynow , and theories and hypotheses have emerged (60, 105). More than half of the abstinent alcoholics in treatment programmes have some detectable cognitive dysfunction. The disorders areusuall ymil d andwoul d not be detected in routine clinical examinations. Most patients improveafte r weekst oyear s of abstinence (30, 105). This common mildfor m of cerebral dysfunction in alcoholicsi scalle dintermediat ebrai n syndrome (IBS). Deficits revealedb ytest s evaluating visuospatial capacity, memory, abstracting ability, learning, problem- solving, perceptual-motor functions, analogic reasoning, and planning havebee n reported frequently (30, 42, 65, 94, 95). Occasionally disturbed motor activityi s observed (23). Both the left and therigh t hemisphere seem tob e affected (11). Some test results suggest that the picturei swors ei n alcoholics with alonge r drinking history (11). Although somehav efoun d arelatio n between alcohol consumption and psychometric tests, onlya ver ysmal lpar t of thevariatio n in test results can be explained byalcoho l consumption. Bowden (13) concludes in hisrevie w that therei s no concern for brain impairment in social drinkers. Cognitive impairment caused byalcoho l abusema yb e compared with the pattern goingwit h ageing. The association between alcohol and ageingi sno t clear. There are three hypotheses: the premature ageing hypothesis (alcohol speeds up the ageing process), the agesensitivit yhypothesi s (elderlypeopl e aremor e sensitivet o thebrain - toxicating effects of alcohol) and theindependent-decrement s hypothesis. The results of investigations are controversial (15, 74, 81,85) . Themos t pronouncing - but relatively rare- effect of alcoholism on thebrai n is Korsakoff's psychosis,wit h impairment ofbot h long-term and short-term memory. Korsakoff's psychosis, also called alcohol amnestic disorder (AAD) or Wernicke- Korsakoff's syndrome, develops mostlyi n survivors of Wernicke's encephalopathy, which iscause db ythiami n deficiency. AADwithou t aclea rhistor y of Wernicke's encephalopathy hasbee n suggested to result from subclinical episodes of Wernicke's encephalopathy (60, 105). Wernicke's encephalopathy canb e effectively treated with thiamin, whereas Korsakoff's psychosis isirreversible . Thememor y islocate d in the deeper, subcortical parts of thebrain . In Korsakoff patientsbot h cortical and subcortical lesions arefoun d (60, 94). There issom e evidence that memory impairment isdu e to repeated periods of alcohol withdrawal, rather than to continuous alcohol consumption (102). About 4%o f all dementia patients havea histor y of alcoholism. This typeo f dementia iscalle d alcoholic dementia and hasprobabl y another aetiologytha n the primary progressive dementia (Alzheimer's disease)(59). Willenbring (105) suggests that alcoholic dementia isa combinatio n of ISBan dAAD . Alcoholism affects both thecortica l and the subcortical regions of thebrain . At autopsy, but alsowit h CTscanning , brain shrinkagei sfoun d (36, 60). Cortical 119 atrophy, sulcalwidenin g and ventricular enlargement issee n (33, 60, 65, 105). The cortex of alcoholics contains lessneuron s than thecorte xo f controls, especially the frontal cortex. A selectivelos so f thelarge rneuron s - which areals omor e vulnerable inbot h Alzheimer's disease and thenorma l ageingproces s - hasbee n demonstrated (35). The dendritic arborization in thefronta l cortex has decreased (36). Also at an alcohol consumption ofles stha n 120g/da ycerebra l atrophy is observed, whichprove s to have decreased after sixmonth s of abstinence (14). Even in heavy alcoholicsbrai n damagei sno t entirely irreversible. Abstinence is followed byimprovemen t (6, 36, 84, 98). Therei sn o clear relation between CT-scan results and severity and length of drinking history (60). Several investigations havereveale d amoderat ebu t significant relation between brain atrophy and impairment of cognitive abilities (33, 65, 104),bu t other investigations have not (60). Thewea k correlation between morphological brain damage and cognitive impairment isunderstandabl e if cognitiveimpairmen t is regarded asresultin gfro m dysfunctioning of nervecells . Not until much later this dysfunctioning isreflecte d in detectable morphological changes. It isno t known exactlyho wbrai n damagecause db ychroni c alcohol consumption isbrough t about, butbot h the direct toxicity o'falcoho l- or of itsmuc h more injurious metabolite acetaldehyde- and thiamin depletion seem tob einvolved . One of the effects of alcohol couldb e cerebral oedema, causedb ya n inappropriate secretion ofvasopressi n in alcoholics (50). The synthesiso f argininevasopressi n (AVP), afragmen t ofvasopressin , isaltere db ychroni c alcohol ingestion (40). AVP controls brain functions and modulates memory processes (39, 100). The toxic substanceswhic h accumulate abnormally in hepaticfailur e may also causebrai n damage (hepatic encephalopathy)(86). The alcoholics examinedb yLe e (52) showed a greater incidence ofbrai n degeneration than oflive r injury, sofiver injur y per sei s not the only causeo fbrai n damage. There seem to be different aetiologies underlying different types ofbrai n damage among alcoholics. Anumbe r of these disorders, Wernicke's encephalopathy in particular, result from malnutrition and vitamin deficiency. Glucoseutilizatio n is thiamin-dependent and islikel yt ob e amajo r factor in thiamin-deficient brain damage (96). Other disorders appear tob e causedb yth e toxicity of alcohol (41) or of acetaldehyde (27). Lishman (60) hypothesizes that alcoholneurotoxicit y affects both the cortex and subcortical structures, whereas thiamin depletion has amarke d effect on subcortical regions only. Thepersona l biochemical vulnerability toneurotoxicit y and/or thiamin depletion determines thetyp ean d severity ofbrai wdamag ei nalcoholics .

9.2.2. Tolerance, dependenceand withdrawal

Chronicalcoho l consumption leadst ohabituation ; morean d morealcoho li sneede d tobrin g about a specific mental effect, duet o an acquired resistancet o the physiological andbehavioura l effects of alcohol. Thisphenomeno n iscalle d tolerance, a distinction beingmad ebetwee n metabolic andfunctiona l tolerance (34). 120 i blood alcohol level •••••••••••• (lethal level) ••••••••••••••••+•••••••••••

Influx of alcohol Ll...... |I||I1|( pharmacological per unito ftim e effects ' A c metabolic ll effects Time (years)

Fig. 9.1. Changes in tolerance during prolonged alcohol consumption. A, range of normal rateo f metabolism; B, increased rate due to adaptation; C, decreased rate due to malnutrition or other factors. After: Lelbach (53).

The term 'metabolic' or 'pharmacokinetic' tolerance refers to the fact that a certain quantity of alcohol consumed leads to alowe r BACowin g to an increased metabolic rate in the liver, partly due to MEOS induction (see Chapter 2). / Metabolic tolerance disappears within threeweek s of abstinence (67). When liver injury and/or malnutrition occursi n caseo f continuing alcohol abuse metabolic tolerance decreases again. In this casealcoho l metabolizes more slowly than before tolerance developed becauseo f a disturbance of alcohol metabolism (seeFig . 9.1). In caseo f functional (also called cellular or pharmacodynamic) tolerance the organism has changed in such awa ytha t it can adapt to thepresenc e of alcohol. A particular BACthu s has less effect on theorganis m than before (34). Alcoholicswit h a BAC of 3g/ 1 aremostl y sleepy or less affected (21). It has been shown that the development of alcohol tolerance canb e influenced genetically and environmentally, soindividual s mayb eparticularl y vulnerable to the reinforcing effects of alcohol. Tabakoff (93) distinguishes an environment- independent and an environment-dependent form of tolerance. The latter isa kin d of Pavlovian conditioning model of tolerance, an adaptive response of the central nervous system to stimuli, produced byth e ritual of drinking. A different phenomenon isacut etolerance ; the effects of anygive n BAC areles s during the decreasing stagetha n during theincreasin g stage (56, 77). Functional tolerance ispresumabl y aprerequisit e of the development of physical dependence (61, 62). Initially thebod y iscapabl e of adapting rapidly again to the absence of alcohol. Later on this adaptive capacity decreases and physical dependence on alcoholwil lb e observed. Adaptation to alcohol has then developed in thebod y (presumably in the central nervous system) necessitating thepresenc eo f alcohol to maintain homeostasis (34). During chronic alcohol consumption some underlying biologic necessity of alcohol develops in thepsychologicall y dependent individual, resulting in aneed , craving, for alcohol. In the absence of alcohol the body cannot function 'normally' anylonge r and abstinence orwithdrawa l symptoms

121 willoccur , such as disturbances of consciousness, nausea, hallucinations, depressions, tremor and anxiety (34). One of themos t criticalwithdrawa l symptoms isdeliriu m tremens (101). Symptoms arementa l clouding (hallucinations, misperceptions, disorientation), tachycardia, hypertension, termors and psychomotor agitation (19, 26). Delirium tremens isbes t managed, and possibly canb eprevented , before it hasbecom e fully manifest. In most patients the deliriahav esubside d after someday so r aweek . Treatment of delirium tremens includes general measures (replacement of fluids, glucose, vitamins, magnesium orphosphates ) aswel la s specific therapyfo r alcohol withdrawal (benzodiazepines, chlormethiazoleo r other CNSdrug s (19, 37). The symptoms appear tob e related tomagnesiu m deficiency in theblood . The administration of magnesium proves an effective therapy in anumbe r of cases (83). What causethes e decreased magnesium values to occurjus t during thewithdrawa l phasei sunknown , albeit there are specific indicators for higher mortality (spirit drinking, overweight, old age, treatment with phenothiazines). In thewidel y used Diagnostic and Statistical Manual of Mental Disorders (DSMIII), the term 'delirium tremens' hasbee n replaced with 'alcohol withdrawal delirium'.

9.2.3. Mechanisms ofaction

There isconsensu s with regard to thenotio n that achang e inneurotransmissio n isa n important factor in the development offunctiona l alcohol tolerance and physical alcohol dependence. Thebiochemica l mechanism bywhic h chronic alcohol consumption causes thisadaptio n has notbee n elucidated sufficiently yet. There are several research lines. It hasbee n suggested that alcohol dependence is actually acetaldehyde dependence. Miceca nb emad e dependent on acetâldehyde; abstinence causes the samewithdrawa l symptoms asfo r alcohol (62). In thebrai n acetaldehyde can form condensation products withbiogeni c amines, i.e. tetrahydroisoquinolines (TIQs) and tetrahydrobetacarbolines (THBC). Both classes of aldehyde adducts can exert specific actions on neurons in different regions of thebrai n (71), acting as false neurotransmitters. Itha sbee n hypothesized that themetabolit e of methanol, formaldehyde, has a stronger affinity to neurotransmitter aminestha n acetaldehyde tofor m TIQs and THBCs, and that methanol contributes partly to the effects of alcoholism. All alcoholicbeverage s contain methanol (5-5000 mg/l)(90). So, the changes inneurotransmissio n canb e caused directlyb yalcohol ,b y acetaldehyde, or bycondensatio n products of acetaldehyde and formaldehyde. These substances can affect neurotransmission on varioussites . One of thesite so f action is the synapticmembrane , whichi saffecte d byalcohol . Other research isdirecte d at the influence of alcohol or acetaldehyde on opioidpeptide s (endorphins, enkephalins) and other neuropeptides (argininevasopressin) . Permanent changes in neurotransmission duet o chronic alcohol consumption havebee n described byHun t (41). The activity ofpre - and postsynaptic receptors - selectivebindin g sites- influence neurotransmission. Effects of alcohol on the

122 functions of theneurotransmitter s noradrenaline (norepinephrine)(58), y- aminobutyric acid (GABA)(97), serotonin (87) and dopamine (3, 5) havebee n found (73). On amolecula r level Linnoila (58) found that chronic alcohol consumption results in a down-regulation of one of the presynaptic receptors of the sympathetic (noradrenergic) nervous system. These alterations mayaccoun t for the mood changeswhic h follow upon alcohol consumption and, later on, during withdrawal. Part bypar t theneurobiologica l mechanisms havebee n elucidated, which leads to the development of drugs that may eventually beuse d to treat alcohol intoxication andwithdrawa l symptoms (58, 87). Alcohol hasbee n found to increase neuronal membrane fluidity, thus altering almost allmembran e functions, i.e. neurotransmitter release, function of membrane- bound enzymes (ATPases), ion conductance channels, and calcium-binding sites(1 , 8, 32, 56, 61,62 , 88). This can result in inhibition of transmembrane signalling (i.e. the translation of extracellular receptor activation to intracellular response)(2). It has

membrane protein phospholipid head groups fatty acid chains

Normal membrane

ethanol administration

'??Sr Membrane adapted by \\i\ incorporation offewe r - polyunsaturated fatty acids

Fig. 9.2. Membrane changes induced byalcoho l consumption. The postulated mechanism for development of tolerance to ethanol at the level of the synaptic membrane isshown . When ethanol enters the phospholipid bilayer it causes some disruption of the lipids asth e head groups are separated and causes slight expansion of the membrane. The cell responds by increasing the proportion of saturated fatty acids in the membrane phospholipids rendering ethanol less effective inthi s respect. After: Locke et al. (63).

123 been suggested that prostaglandins, which areforme d when membranes are disturbed, mediate the effects of alcohol on noradrenaline- and calcium-depending processes (7). Functional alcohol tolerancema y consist inincorporatin g more saturated fatty acidsan d cholesterol in order to compensate for the increased membrane fluidity (cf. Fig. 9.2). Likeothe r addictions and obesitas, alcoholism isno w associatedwit h the endogenous opiate system. There arethre e known families of endogenous opioid peptides: endorphins, enkephalins and dynorphins. The existence of different types of opioid peptides isassociate d with the existence ofmultipl e types of opiate-binding sites, which are classified depending on their affinity to specific opiatetypes . These binding sites- receptors - canb efoun d in the synapses of specific opioid neurons. An important function of endogenous opioids ist o regulate the responses to physical and physiological stress. In non-physiological doses endogenous opioids havea n analgesic effect, just likemorphine . After repeated administration tolerance and physical dependence develop asi sth e casefo r morphine (100). Both acute and chronic alcohol treatment influence the activity of-the endogenous opioid system, but there isconsiderabl e conflict ast o theprecis e effects (31). Alcohol mayinterac t with the endogenous opiate system byproducin g ethanol metabolites - TIQs- whichbin d to opiatereceptor s (20),b yalterin gth ebindin g properties of opiate receptors (4, 54), andb yalterin g the synthesisan d releaseo f endogenous opioid peptides (31). In relation to alcohol, /3-endorphin isth emos t intensively studied endogenous opiate. Beta-endorphin and ACTH shareth e sameprecurso r and are co-released from the pituitary gland under anumbe r of physiological conditions such asstress . Alcohol isknow n to stimulate the releaseo fACTH , but the effects on /3-endorphin releasei sno t clearyet . Naloxonei sa morphin e antagonist which ousts endorphin (and morphine) from the receptors and thus counteracts the effects of (non-physiological doses of) endorphin. Injection of naloxoneprove s to decreaseth e effects of alcohol (decreased reactivity, nystagmus) slightly (42, 43, 66). The endorphin concentration in cerebrospinal fluid isaffecte d during intoxication andwithdrawa l (12). An individual's plasma endorphin concentration andhi smoo d appear tob e related, but theplasm a endorphin concentration doesno t correlatewit h theBA C (47, 48). Evidencei saccumulatin g that vasopressin, oxytocin and some of their fragments, called neuropeptides, modulate neurotransmission. They decrease under certain conditions addictivebehaviou r of experimental animals and man and seem to be involvedi n rewardprocesses , tolerance and dependence (39, 40, 99).

Summary

Theconsumptio n of oneo rmor e glasses of alcoholicbeverag ebring s about a temporary, reversiblechang eo f mood andbehaviour . Thespecifi c mechanismso f

124 acute alcohol action arestil l uncertain. Theyma yconsis t inincreasin g thefluidit y of neuronal membranes oranothe r disturbance of neurotransmission. A hangover canoccu r when there ishardl y any alcohol left inth eblood . Iti s partly caused byth eeffect s ofcongeners , partlyb yth emetabolic , hormonal and central nervous system changes duet oalcoho l itself. During chronicalcoho l consumption tolerance develops. Twodifferen t effects mayb edistinguishe d inthi sprocess , namelymetaboli can dfunctiona l (cellular) tolerance. Metabolic tolerance impliesa nincrease d rate ofalcoho l metabolism, resulting from MEOS induction. Infunctiona l toleranceth ebod y- particularlyth e central nervous system- maybecom e adapted toth epresenc e ofalcoho l inth e organism, thus causing aspecifi c BACt ohav eles s effect than itha dbefore . Physical dependence onalcoho l isestablishe di fth epresenc eo falcoho l hasbecom e necessary for maintaining homeostasis ofth ebody , andabstinenc ei sfollowe d bywithdrawa l symptoms. Recent research hasshe d considerable light onth eintracellula r andmolecula r processes that play arol ei ncellula r tolerance andphysica l dependence. Neurotransmission inan dnea r thesynapse s isaffecte d owingt o alcohol, acetaldehyde orcondensatio n productsfro m aldehydes andneurotransmitte r amines. Chronicalcoho l consumption causes diffuse cortical andcerebella r atrophy. Local degenerative changes also occur inth ecentra l brain structures. Cortical atrophy consists in death ofneuron s and/or degeneration ofth e dendritic arborization. Psychometric testing ofchroni c alcoholics have displayed avariet yo f forms ofimpairment , rangingfro m hardly measurable reversible changes to severe irreversible mental damage (i.e. Wernicke-Korsakoff's psychosis). Thevariou s types ofbrai n damagear epartiall y caused byalcoho l itself, andpartiall yb y thiamin depletion.

References

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125 ^m

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129 T

CHAPTER 10 Effects of alcohol on the cardiovascular system

J. Veenstra

Most of the earlypublication s on the effects of alcohol on the cardiovascular system emphasize the detrimental effects of alcohol abuse on the heart, causing such diseases ascardiomyopath y and cardiacberiberi . Sinceth elat e 1970s, however, an overwhelming majority of epidemiological studiesindicat ethat , although excessive alcohol consumption isassociate d with increased risk of cardiovascular diseases, moderate alcohol consumption isassociate d with areduce d risk ascompare d to non- drinkers, especially of coronary heart disease/These epidemiological studies have initiated avas t number of epidemiological aswel la s experimental studies into the possiblemechanis m of thisprotectiv e effect. In thischapte r the effects of both moderate and excessivealcoho l consumption willb e reviewed.

10.1. Blood lipids and lipoproteins

In epidemiological studies thelevel so f blood lipids and lipoproteins are clearly associated with theris k of cardiovascular diseases (CVD) ofwhic h themos t common form iscoronar y heart disease (CHD). Thelevel so f total cholesterol, low-density lipoprotein (LDL)-cholesterol and apolipoprotein-B (Apo-B) arefoun d to be positively associated with atherosclerosis and CHD, whereas thelevel so f high- density lipoprotein (HDL)-cholesterol and the apolipoproteins Apo-Al and Apo-A2 shownegativ e associations. Successive experimental studieshav eshow n that several dietary factors mayinfluenc e blood lipid and lipoprotein concentrations and consequently probably alsoinfluenc e theris ko fCVD . A largenumbe r of epidemiological studies (3,5 , 16, 19, 21,28 , 33, 34, 44,53 , 54, 61,75 , 83, 103, 104, 108, 112, 134, 135, 185, 196, 209-211) allove r theworl d haveconsistentl y shown apositiv e association between alcohol consumption and HDL-cholesterollevels . Fig. 10.1show ssom eresult s of theTroms 0 Heart Study (28). Significant positive associations werefoun d for allthre e typeso f alcoholic beverage. Evenlo walcoho l consumption wasassociate dwit hincrease d HDL- cholesterol levels. HDL, inwhic hApo-A l and Apo-A2 areth emajo r proteins, is considered tob e an essential factor in thebody' s defence against accumulation of cholesterol in tissues, in aproces s called 'reverse cholesterol transport'. Theinitia l excitement evoked bythi s apparent explanation for theobserve d lower risk of CHD inmoderat e alcohol consumerswa stempere dwhe ni twa sfoun d thati twa smainl y 130 HDL-oholesterol level (mmol/1) 2.0 T

1.9-

1.8 -

1.7-

1.É

1.5 -I

1.4 P1 =0.014

Pe= 0.000 P1= 0.000 =0.000 Pe=0.000 P1=0.00 0 1.3 -A r -1—i—r I 1 T 1 1 1 1 2 3 4+5 1 2 3 4 5 Category 1 2 3 4 Beer Wine Spirits

Fig. 10.1. Relationship between HDL-cholesterol and alcohol consumption. Pe, P vali/e for test of equal group means; Pj, P value for test of similar trend. Values adjusted for time since the last meal. the HDL3 subfraction of HDL-cholesterol that wasassociate d with alcohol consumption, whereasi t wasth eHDL 2 subfraction that showed the strongest association with CHD (151). In more recent studies, however, itwa sfoun d that HDL3-cholesterol wasals o associated with lower risk of CHD (180, 188). In addition, Miller et al. (150), in thefirs t large-scale study (4860 men) on the effects of alcohol consumption on HDL-cholesterol subfraction levels, found comparable positive associations for HDL2- and HDL3-cholesterol. In arelativel y small number of epidemiological studies attention hasbee n paid to the relationship between alcohol consumption and the apolipoprotein concentrations. The levels ofApo-A l and Apo-A2 mayb e evenbette r predictorso f a lowCH D risk than HDL-cholesterol. Phillips et al. (161) havefoun d apositiv e association between alcohol usean d Apo-Al in agrou p of 289 Californian men and women, but havenot measured Apo-A2. Haffner etal . (86) and Williams etal . (211) report positive correlations for both Apo-Al and Apo-A2 in smaller groups (77 men and 50me n andwomen , respectively). Therelationship s between alcohol consumption and HDL-cholesterol and the apolipoproteins Al andA2 , observed in epidemiological studies, havebee n confirmed in anumbe r of experimental studies. The experimental studies, however, varied widelyi n study designwit h respect to thelengt h of the experimental period, thebeverag e typeused , the amount of alcohol consumed and thevariable s measured. Table 10.1give s an overview of thevariatio n in study design. In most of the long-term studies (22, 30, 39, 42, 45, 69, 90-92, 146, 162, 197)a risei n HDL- or HDL-cholesterol wasobserve d within afe wweeks . In onlytw o

131 Table 10.1. Survey of studies intoth e effects of alcohol consumption onbloo d lipidsan d lipoproteins.

Alcohol dose Type ofbeverag e Duration of Reference (g/day) study (weeks)

28 beer 3 90 39 white wine 6 197 31 (average) optional 6 92 31 red wine 5 42 18.4 (average) optional 4 30 24 beer 6 146 23o r 46 red wine 5 162 75 alcohol or beer 5 22' 75 redwin e 5 39 90 diluted alcohol 4 45 34 or 53 wodka 2 73 12.6 beer 8 152 40 beer 6 69 12.5o r 25 beer 3 91

studies (42,43) no effects werefound . In one of these studies (42), however, the experimental periodwa srathe r short, and in the other one (152) the doseo f alcohol wasver ylow . In thelatte r study, despiteth e absenceo f an effect on HDL, a significant increasei n Apo-Al wasobserve d after consumption of only oneglas so f beer (12.6 go f alcohol) per dayfo r 8weeks . In thelong-ter m studiesbloo d lipidshav ebee n examinedi n thefastin g state, usually after an overnight fast. In afe w studies (66, 74, 204) the acute effects of alcohol onbloo d lipidsi n thepostprandia l statehav ebee n investigated. Goldberg et al. (74) and Franceschini et al. (66) have studied the effects of a single dose of 120 mlwhisk y (40 galcohol) , using comparable experimental designs. The alcoholwa s drunk at 09.00 after a 14-hour fast. In the study ofFranceschin i et al. whiskywa s consumed mixedwit h aflui d meal of 100 gmayonnais e and 25g bread . In both studies itwa sassume d that the alcohol hadbee n fully metabolized after 4hours , and measurements wereperforme d 4, 6, 8, 10an d 12hour s after consumption. Goldberg etal . found significantly higherlevel so f HDL-cholesterol after alcohol consumption as compared to the control treatment. In addition, a67 %decreas ewa sobserve d for activity ofhepati clipase , animportan t enzymei n the reverse cholesterol transport. Bycontrast , Franceschini et al. found alowe r HDL-cholesterol level after consumption of alcohol, mayonnaise andbrea d relativet o the treatment without alcohol. Only one studyha sbee n reported (204)i nwhic h the effects of alcohol on blood lipidswer e studied shortly after consumption, when the alcohol isstil li n the circulation. In that study, Veenstra et al. tried to approximaterealit y asclosel ya s possiblei n acarefull y controlled experiment. Sixteen malevolunteer s (8 aged 20-30 and 8age d 45-55) consumed 30g o f alcohol aspor t andwin edurin ga normal evening dinner. For comparison, they drank similar amounts ofminera lwate r instead

132 on another day. One hour after dinner, when thebloo d alcohol levelsreache d a maximum (mean 0.175g/L , SD 0.055), significantly higher levels of HDL- cholesterol, Apo-A2 and triglycerides werefoun d for the alcohol treatment than for the mineralwate r treatment. The HDL-cholesterol-enhancing effect was more prominent in themiddle-age d men andwa smos t evident for the HDL2-cholesterol fraction. In anumbe r of studies (23, 47, 48, 50, 109, 195, 200) HDL-cholesterol levels havebee n studied in alcoholics during aperio d of abstention. Most alcoholics have increased HDL-cholesterol levels,whic h rapidly decline assoo n as alcohol consumption isstopped . The changes upon abstention in alcoholics aremainl y found in theHDL 2 subfraction, whereas most epidemiological studies suggest a relationship between alcohol and the HDL3 subfraction. This controversy prompted Välimäki et al. (56) to compare the effects of moderate (30g/day ) and heavy (60 g/day) alcohol consumption. Theconsumptio n levels differed in their effect on the HDL-subfraction. Heavy alcohol consumption increased HDL2 levelswithi n two daysan d gradually increased HDL3 levelslate r on, whereas moderate alcohol consumption affected HDL3 levelsonly . The epidemiological and experimental studies mentioned above clearly showa relationship between alcohol consumption and levels ofbloo d lipidswhic h is the most frequently cited explanation for abeneficia l effect of moderate alcohol consumption on risk of CHD. However, whether these changes arebeneficia l indeed depends strongly on the exact mechanism causing theincreas ei n HDL-cholesterol, which mayb eindicativ e of an increased reverse cholesterol transport, but couldjus t aswel lb e due to a decreased clearance of HDL-cholesterol. More detailed studies into theprecis emechanis m areneeded . In this respect, the possibility that the observed changes originate from acute effects of alcohol on blood lipids as observed byVeenstr a et al. aswel la sth e differences between moderate and heavy alcohol consumption observed byVälimäk i et al. deservefurthe r attention.

10.2. Haemostasis

Haemostasis isth ebalanc ebetwee n theformatio n of blood clots, inwhic h blood platelets (thrombocytes) areinvolved , and fibrinolysis, the dissolution of such clots. In most cases of myocardial infarction acoronar y artery isblocke d bya clo t primarily consisting of thrombocytes (51). In normal physiological conditions clottingo f thrombocytes, called platelet aggregation, most probably takesplac e constantly to some extent. Thefibrinolyti c system, on the other hand, plays apar t in continually dissolving the newlyforme d clots. An effect of alcohol on this complex and delicate haemostatic balancewould , of course, also havea n effect on the risk of CVD. Measurement of platelet aggregation iscomplicate d and labour-intensive; So far, onlyon e epidemiological studyha sbee n devoted to the relationship between alcohol consumption and platelet aggregation. Meade et al. (148) found an inverse association in apopulatio n of 685 British men and 273 Britishwome n (Northwick

133 Park Heart Study). In the samestud yMead e et al. (147) found theleve l of alcohol consumption tob e associated with a decreased plasma fibrinogen level and an increased fibrinolytic activity. Theselatte r resultswer econfirme d in several other studies (13, 27, 174, 217). However, no correlation between alcohol consumption andfibrinoge n wasobserve db yBalleise n et al. (14) in 2880 men and 1306wome n in the Munster Arteriosclerosis Study. The experimental studies into the effects of alcohol consumption on platelet aggregation and other platelet function tests (52, 55, 60, 63,71 ,95 , 96, 99, 113, 131, 136, 149, 154, 162, 206) are characterized bya larg e diversity in experimental design (Table 10.2). First, the amount of alcohol consumedvarie dwidel ybetwee n 15g an d ad libitum consumption. In sixstudies , the amount of alcohol consumed in asingl ebing ewa s 100 go r more (1 drink contains approximately 10g) . Furthermore, the studies varied considerably in typeo f alcoholicbeverage . In almost all studies the alcohol was consumed on an empty stomach, mostly in themorning . Theresult s are conflicting: no effects (55, 71,99 , 154, 206) inhibitory effects (60, 63/-149) aswel l as stimulating effects (95, 96) on platelet aggregation havebee n observed. The data on thromboxane production are also conflicting, with some studies showing an increase (95, 96) and other ones showing no effect (71, 99, 154),wherea s one study showed a decrease (149) in platelet thromboxane production. Consequently, no definite conclusions canb e drawn from the experimental studies. In theonl y study reported on thelonger-ter m effects ofmoderat e alcohol consumption on platelet

Table 10.2. Survey of studies into the effects of alcohol use on platelet function. ,

Alcohol Term Number of Platelet Year of Reference 1 2 dose (g) volunteers function publication Ad libitum acute 20 0 1981 55 50 acute 12 0 1982 52 120 acute 12 — 1982 113 120 acute 8 — 1982 131 64 acute 7 — 1983 149 51 acute 10 — 1984 60 32 acute 6 — 1984 136 100 acute 15 — 1984 63 32 acute 4 0 1984 71 120 acute 8 + 1985 96 120 acute 10 + • f985 95 88 acute 12 0 1987 99 20 acute 6 0 1987 154 23 and 46 5 weeks 12 — 1987 162 40 acute 8 0 1990 206

'The alcohol dose, irrespective ofth e volunteer's bodyweight , has been converted for a hypothetical 80-kgsubjec t for comparison sake. 2Platele t function: + increased; 0n o effect; — decreased.

134 aggregation (162), a decreasei n platelet aggregation was observed in agreement with the epidemiological findings of Meade et al. (148). In the onlystud y published on the acute effects (206), in which the alcohol wasconsume d at acustomar y timeo f the day and under habitual conditions (during dinner instead of earlyi n the morning and on an empty stomach) no acute effects of alcohol on platelet aggregation could be found.

Table 10.3. Surveyo f studies into the acute effects of alcohol on fibrinolysis.

Parameter Amount of Type of Effect1 Year of Reference alcohol beverage publ.

Blood clot lysistim e 20-40 g beer/cider/ + 1960 62 whitewin e Blood clot lysistim e 20-40 g gin/whisky/ 0 1960 62 alcohol Fibrinolytic acticity 25-100 g beer/wine - 1961 155 Fibrinolytic activity 25-100 g alcohol 0 1961 155 Euglobulin lysis time 90 g cider + 1983 4 Fibrinolytic activity 1.5 g/kg alcohol — 1983 ' 97,98 Euglobulin lysis time 1.5 g/kg alcohol + 1983 97,98 Fibrin degr. products 1.5 g/kg alcohol 0 1983 97,98 Factor VIII: Cactivit y 1.5 g/kg alcohol + 1983 97,98 Factor VIII: antigen 1.5 g/kg alcohol + 1983 97,98 Factor VIII: R cofactor 1.5 g/kg alcohol + 1983 97,98 Antithrombin III 1.5 g/kg alcohol 0 1983 97,98 Factor VIII 0.8g/k g whisky 0 1984 59 Fibrin degr. products 0.8g/k g whisky 0 1984 59 Plasminogen 0.8 g/kg whisky 0 1984 59 Fibrinogen 0.8g/k g whisky 0 1984 59 Fibrinolytic activity 0.8g/k g whisky 0 1984 59 Euglobulin lysis time 0.8 g/kg whisky 0 1984 59 Antithrombin III 0.8 g/kg whisky 0 1984 59 Blood clotlysi stim e 0.5-1.0g/ 1 ethanol + 1987 156 Euglobulin lysistim e 24-47 g shochu/ — 1988 193 sake/beer Fibrin degr. products 24-47 g shochu/ 0 1988 193 sake/beer Fibrinolytic activity 24-47 g shochu/ + 1988 193 sake/beer t-PA activity 30 g red wine/port - 1990 203 PAI activity 30g red wine/port + 1990 203 PAI activity 40 g red wine/gin + 1990 202 PAI antigen 40 g red wine/gin 0 1990 202 t-PA activity 40g red wine/gin — 1990 202 t-PA antigen 40 g red wine/gin + 1990 202 Total UK-PA antigen 40g red wine/gin 0 1990 202 Pro-UK-PA antigen 40 g red wine/gin 0 1990 202 UK-PA inhibitor complex 40g red wine/gin 0 1990 202

1Effect : + increased; 0 no effect; — decreased.

135 Besides platelet aggregation, Pikaar et al. investigated in the same study (162) the long-term effects of moderate alcohol consumption on anumbe r of fibrinolytic factors. No effects on fibrinogen couldb e observed after 5week so f moderate alcohol consumption (23 or 46 g/day)o r after 5week s of binge drinking (14 glasses ofwin epe r week consumed on the threeweeken d days). The levelso f plasminogen and tissue-plasminogen activator (t-PA) activity, however, appeared tob e clearly affected bywin econsumption . Plasminogen levelsmoderatel y increased with an increasing dose ofwine . The t-PAactivity , on the other hand, showed alarg e and dose-dependent decrease. Therewa sn o effect onbleedin g time. In additional analyses (128), the levels of plasminogen activator inhibitor 1(PAI-1 ) were measured, and significantly higher levelswer eobserve d after 5week so f moderate alcohol consumption than in the control treatment. Sincehig h PAI-1 levels inhibit fibrinolytic activity theseresult s are in contrast with the epidemiological findings of Meade et al. (148). In anumbe r of studies (4, 59, 62, 97, 98, 155, 156, 193,202 , 203) over a period of 30years , the acute effects of alcohol on fibrinolytic parameters havebeen investigated (Table 10.3). In the earlier studies, overall fibrinolytic activity of plasma orwhol ebloo dwa s measured in global assays. Thesemeasurement s arever yaspecifi c because fibrinolytic activityi sinfluence d byman yvariable s and the results obtained hence strongly depend on the experimental conditions used. Thisprobabl y explains someo f the contradictions showni n Table 10.3. In recentyears , however, new analytical techniques havemad epossibl e themeasuremen t of more specific fibrinolytic factors. A strong and consistent decreasei n t-PA activity and an increasei n PAI activity have been observed in twostudie s (202, 203), in agreement with thelong-ter m studyo f Pikaar et al. (162). Thelevel s of t-PA antigen, on the other hand, increased whereas no effects on the urokinase-plasminogen activator (UK-PA) system could be observed. In conclusion, the results of studies on alcohol and fibrinolysis are contradictory. Alcohol consumption is epidemiologically associatedwit h increased fibrinolytic activity, whereas decreases infibrinolyti c activity and t-PA activity andincrease si n PAI activity and t-PA antigen havebee n observed in experimental studies. Further research isneede d to explain this contradiction and to investigateth e mechanisms and consequences of these effects of alcohol. Somerecen t epidemiological studies suggest arelationshi p between lipidmetabolis m andfibrinolysis . This possible relationship alsoneed sfurthe r attention. ,

10.3. Blood pressure

Therei sstron g epidemiological evidencetha t regular useo flarg equantitie so f alcohol isrelate d to higherbloo d pressure and agreate r prevalence of hypertension (10, 12, 31,41 ,43 , 56, 58, 65,70 , 77, 85, 88, 89, 116, 123, 138, 153, 159, 163, 190, 198, 207, 213), even after correction for confounding factors such as obesity

136 and excessivesal t intake. In the Kaiser Permanente study, theprevalenc eo f hypertension wastwic ea shig h among peoplewh o had 6o r more drinks per daya s amongpeopl ewh o had 2o r lessdrink spe r day(123) . It seemspruden t for health practitioners to advicehypertensiv e patients who are used to take three or more drinksa dayt o reduce their alcohol use. Potter &Beever s (166) and Malhotra etal . (143) havereporte d significant favourable responses to areductio n of alcohol intake within afe w days (4 and 5days , respectively). Puddy et al. (169), in astud y among 44 hypertensive men with an average alcohol consumption of 6t o 7glasse s per day, demonstrated asignifican t reduction in blood pressure after aswitc h from regular beer (5%v/ valcohol ) to low-alcohol beer (0.9%v/ valcohol) . In the study of Puddy et al. not onlybloo d pressure, but alsobod yweigh t fell significantly in theperio d oflow - alcoholbee r consumption. Thisbod yweigh t reduction hasundoubtedl y contributed to alowerin g ofbloo d pressure. Unfortunately, no studies among hypertensives have been conducted yet inwhic h the independent effect of alcohol, i.e . the energy from alcohol versus non-alcohol energy, hasbee n investigated. There ismuc h lessconsensu s with regard to the effects of moderate alcohol consumption. Some studies havefoun d a continuous increasei nbloo d pressure from abstainers to heavy alcohol users (10, 31, 41, 198). Other studies (43, 123, 213) have established athreshol d abovewhic h alcohol wasfoun d tob e positively associated withbloo d pressure. In still other studies (85, 88, 89, 116) a J-shaped relationship between alcohol consumption and blood pressurewa s found. In an epidemiological study, Periti et al. (159) classified 1190 Italian men and women into twogroups . In one group thepeopl ewer e asked to abstain for 3day s from alcohol before theirbloo d pressurewa smeasured , the others continued their normal alcohol consumption habits until the day ofbloo d pressure measurement. In themen , but not thewomen , ofth elatte r group, systolicbloo d pressure increased significantly with increasing alcohol use, regardless of age, body weight, smoking or coffee consumption. The systolicbloo dpressur eincrease d by4. 6 mmHg per 100g o f alcohol per day. No significant relationship between alcohol consumption and diastolicbloo d pressure could be observed. In thegrou p that wasaske d to abstain from alcohol for 3 days,n o relation between alcohol consumption and blood pressurewa sfound . These results are consistent with earlier findings showing an association ofincrease dbloo d pressurewit h excessivealcoho l consumption and also indicate that this increase disappears after afe w dayso f abstention. The effects of a singledos eo f alcohol havebee n investigated in anumbe r of studies (105, 106, 168, 191,J Veenstra &E . teWierik , in preparation). Potter etal . (168) havestudie d the effect of a single doseo f alcohol on blood pressure in 16 young male students. Blood pressure wasmeasure d over a 5-hour period after the ingestion of either 600 mlnon-alcoholi c beer or 600 mlnon-alcoholi c beer spiked with alcohol (0.75 gpe r kgbod yweight) . Allvolunteer s were subjected to both treatments in across-ove r design. Theperio d between the treatments wasa t least one week. Thebloo d pressure courseroughl yparallele d thebloo d alcohol level:afte r a rapid increaseb yca . 7mmH gwithi n onehour , blood pressure gradually decreased. Similar acute effects havebee n observedb yIrelan d et al. (105, 106). 137 In arecen t studyb yJ . Veenstra &E . teWieri k (inpreparation ) the effects ofa moderate doseo fbeer , winean d spirits (40g alcohol ) and mineralwate r were studied in a randomized cross-over design. The drinkswer e consumed duringa normal evening dinner, thevolunteer sbein g 8health y middle-aged men aged 45-5 5 years. In contrast toth e studiesmentione d above, alowe rbloo d pressurewa s observed after alcohol consumption ascompare d to theminera l water treatment. Therewer en o significant differences among the alcoholicbeverages , albeit the effect wasno t as strong for beer asfo r wineo r spirits, possibly due to thelarge r volumeo f thebeer . The contradiction with the earlier studies can possiblyb e explained byth e lower alcohol dose, the combination with ameal , theag eo f thevolunteer s or the time of the day. In the study of Veenstra &t eWieri k the aimwa st o study the effects of alcohol under conditions mimicking normal life asclosel y aspossible . Therefore, normal alcoholicbeverage swer euse d in combination with anorma lbu t standardized evening dinner in anon-laborator y environment. The acute studies mentioned sofa r haveth e drawback that thetreatment s areno t isocaloric, i.e . the caloricvalu e of the alcohol isno t compensated for in the control treatment. This energy effect wastake n into account in a studyb yStot t et al. (191). In that study, the design ofwhic hwa scomparabl e with that of Potter et al., an isocaloric amount of glucosewa sadde d to the non-alcoholic drink. In agreement with the results of Potter et al., asligh t increaseo fbloo d pressurewa sobserve d one hour after alcohol ingestion, followed bya decrease. However, asimila r increase and subsequent decrease inbloo d pressurewa sobserve d after the consumption of the glucose-enriched non-alcoholic drink. From thisstud yi twa sconclude d that the increase ofbloo d pressure after the consumption of a singlemoderat e doseo f alcohol does not differ from theincreas e after theingestio n of an isocaloric amount of glucose. Kelbaek et al. (117, 118)recentl y studied the effect of a singlealcoho l dose (0.9g per kgbod yweight ) on thehear t function of 20mal eCH D and cardiopathy patients. Ten controls with asimila r clinical picture received an equal amount of an isocaloric non-alcoholic drink. A slightbu t significant decrease (-6%) of the systemic arterial bloodpressur ewa sfoun d after alcohol ingestion. Alcoholwa sfoun d to haven o effect on central venous pressure, pulmonary artery pressure, cardiac output, stroke volume or globalperiphera l resistance. Kelbaek etal . concluded that ingestion ofa moderate dose of alcohol byCH D patients isunlikel y to evoke diseasesymptoms . In some studies (101, 105, 167, 170) anincreas ei nplasm a adrenaline and noradrenaline after alcohol consumption hasbee n connectedwit h aris ei n blood pressure. In the carefully controlled studyo f Stott et al., however, no effects of alcohol consumption on plasma catecholamine levelswer e observed. An alternative explanation for the relation between alcohol consumption andbloo dpressur e istha t alcohol induces changes in electrolyte excretion (36). J Veenstra &E . teWieri k (in preparation) observed largechange si n mineral excretion in theurin ean d a strong diuretic effect of alcohol, which couldpossibl y explain the acute decreaseo f blood pressure observed in their study. Finally, theresult so f a studyb yFinc h et al. (64) suggest that an increasei nperiphera l blood flow and subsequently in skin 138 temperaturema yb e responsiblefo r a decreasei nbloo d pressure after a moderate doseo f alcohol.

10.4. Atherosclerosis

In several studies the relationship between level of alcohol consumption and degree of atherosclerosis hasbee n investigated. The degreeo f atherosclerosis has been established byautops y (72, 100, 139) or inviv ob ymean s of arteriography (15, 17, 18, 20, 67, 82, 87, 158, 183). As early as 1904, itwa s concluded from an autopsy study that atherosclerosis is uncommon in alcoholics. However, judgingb ypresen t standards, this studywa s poorly designed, lacking controls. Later, in 1965,Hirs t et al. (100) observed no differences in degree of occlusion between non-cirrhotic alcoholics and controls. In cirrhotic alcoholics, however, hefoun d fewer occlusions, which made him conclude that cirrhosis mayhav ea protectiv e effect against atherosclerosis, possiblyb ya changei n oestrogen metabolism orbloo d coagulation. Some studies have confirmed this association between cirrhosis and atherosclerosis, others did not find any effect (11,72). In afe w studies among non-alcoholics the extent of occlusion of coronary arteries in CHD cases hasbee n related to the level of alcohol consumption (17, 18, 67,82 , 158). Barboriak et al. (17) havestudie d the effects of smoking and of alcohol consumption on coronary artery occlusion in agrou p of 2989 men. Fig. 10.2 summarizes the results ofthat study. Smokingwa sfoun d tohav e a dose-dependent

160 <444)T

(678)

(211)"- 140 (654) H •>• heavy smokers ± _ (153) X I 71) s>f light smokers (256) I

Ï 120 non-smokers o O 1 100 -

0L j_ JL ? <30 30-180 >180 Alcohol dose (ml/week) Fig. 10.2. Interrelationships between the extent of coronary occlusion, alcohol intake and smoking (17). Number ofpatient s in parenthesis. Vertical bars: SEM. 139 occlusive effect, whereas the effect of alcoholwa sassociate d withlowe r occlusion scoresi n non-smokers, light smokers aswel l asheav ysmokers . Within the samestud yframewor k Gruchow et al. (82) investigated the effect of alcohol consumption patterns byclassifyin g the subjects into non-drinkers, occasional drinkers, regular drinkers adhering to amor eo r lessfixe d dose, and regular drinkers varying the amounts consumed. Regular users of moderate doseso f alcoholwer efoun d tob e at significantly lowerris k of occlusion of coronary arteries. Irregular drinkerswer e at higher riskirrespectiv e of theleve l of alcohol consumption. In aver yrecen t studyb yHand a et al. (87), the relation between alcohol consumption and severityo f coronary atherosclerosiswa s examinedi n 212 men undergoing coronary angiography. Inaddition , abloo d samplewa stake n to measure blood lipids. The men were categorized asfollows : non-drinkers, light drinkers (1-100 ml alcoholweekly) , moderate drinkers (101-300 mlweekly ) and heavy drinkers (> 30 0 mlweekly) . HDL-cholesterollevel sincrease d and total cholesterol levels decreased with increasing alcohol consumption. After adjustment for age, smoking, hypertension, HDL-cholesterol, total cholesterol and triglycérides the relative risk of coronary stenosis for moderate drinkerswa sonl y0.2 9(95 % confidence interval 0.13-0.63). Therelativ e risk ofligh t and ofheav y drinkers did not differ significantly from that of non-drinkers. Alsoth e severity of coronary atherosclerosis wassignificantl y lessi n the moderate drinkers category (about 8-24 glassesweekly) . Fried et al. (67) studied in agrou p of 31me nwit h coronary arteries of normal diameter the effects of smokingan d of alcohol consumption on the diameter of three main coronary arteries. Smoking and alcohol use appeared to affect these diameters highly significantly and independently. Smokingwa sfoun d to have'a vasoconstrictive effect, whereas alcohol consumption promoted vasodilatation. In contrast with the studies mentioned above, two earlier studies, an autopsy studyb yGen t et al. (72) and an artériographiestud yb ySirtor i et al. (183), have reported apositiv e correlation, i.e. an increase in alcohol consumption associated with alarge r number or more extensiveatheroscleroti c lesions.

10.5. Coronaryhear t disease and mortality

Therelationshi pbetwee n levelo f alcohol consumption and risko f CHD has been investigated in many epidemiological studies. In ecological studies thepe r capita alcohol consumption in various countriesha sbee n correlated with themortalit y rate for CHD (29, 93, 119, 137, 181, 184, 208). St. Leger et al. (184), for example, compared thesevalue sfo r 18countrie s andfoun d aclea rinvers erelatio n between average alcohol consumption and CHD. The observed effect of alcoholwa s not attributable to differences inknow n CHD riskfactor s such as smoking, cholesterol intake, fat intake or total energy intake. Thestronges t association wasobserve d for wineconsumptio n and CHD (Fig. 10.3).

140 II j— FINLAND 10 • USA. • 9 - • -, »AUSTRALIA SCOTLAND •

c 8 O) • CANADA E o E&W o 7 • o • IRELAND a> • NORWAY CL 6 ë" #NETHERLANDS co • DENMARK tr o 5 - • »BELGIUM 2 SWEDEN • «AUSTRIA 4 WEST GERMANY

ITALY 3 • • SWITZERLAND 2 • FRANCE 1 1 1 1 1 1 040 080 120 160 200

Wine consumption (log10 scale)

Fig. 10.3. Relationship between CHD mortality rate inme n aged 55—64an d wine consumption (143).

g 4.8

> cp m

Q. E

3 o 3. SU

Fig. 10.4. Relationship between changes in adult per capita intake of alcohol inbee r (solidline , 1945—1975) and changes intota l age-adjusted heart disease death rates inth e USA (broken line, 1950-1975) (137).

141 Comparable results havebee n reported byother s (29, 93, 119, 137, 181,208) . Schmidt &Popha m (181) and Werth (208) also reported significant negative correlations between total consumption of alcohol, winean d spirits and CHD mortality in the 50 states of the USA. LaPorte et al. (137) have alsopai d attention to trends in alcohol usean d CHD incidence ratesbetwee n 1945 and 1975 and found significant correlations between these, the strongest for beer. Taking into account a5 - year lagperiod , the correlation coefficient between beer consumption and CHD mortalitywas-0.94 3 (Fig. 10.4). Ecological studies aren o realproo f of afavourabl e effect of alcohol consumption on CHD development. The resultsjus t indicatea relationshi p on apopulatio n level, and differences between countrieswit h regard to culture and living and working conditions areno t taken into account. A second drawback of these studies istha t the alcohol consumption data are derived from alcohol sales data, uncorrected for home production, for salest o visitors from abroad or for consumption abroad. Finally, the hypothetical U-shaped curvebetwee n alcohol consumption and CHD poses an insurmountable problem for ecological studies sinceth eus e of sales statistics does not differentiate between non-drinkers, moderate drinkers and heavy drinkers. In several case-control studies the alcohol consumption of CHD patients hasbee n compared with acontro l group (94, 115, 126, 160, 171, 175, 177, 189).Th e results of thesestudie s fairly consistently point at aninvers erelatio n between moderate alcohol consumption and CHD for both men andwomen . OnlyKaufma n et al. (115) found no effect of moderate alcohol consumption. Hennekens et al. (94) classified their study population into three categories, with an average daily alcohol consumption of 0, 0-3.5 and >3.5 glasses respectively. The relative riskwa sfoun d tob e significantly lowerfo r moderate drinkprstha n for non- drinkers (relativeris k (RR) = 0.4). Therelativ eris kfo r drinkers of more than 3.5 glasses per day, on theothe r hand, wasno t significantly different from that of non- drinkers (RR = 0.7). In contrast, Klatsky et al. (126) found the relativeris k to decreasewit h increasing consumption level,wit h relativerisk s of 1.0, 0.7 and 0.4 for categorieswit h a daily alcohol consumption of <3, " 3-5 and >5 glasse s respectively. Case-control studies,jus t as ecological studies, havea numbe r of drawbacks. Probably the most serious onei stha t alcohol consumption isaske d about after the diseaseha sbee n diagnosed. Thisma yresul t in specific underreporting of alcohol consumption byth epatients . Moreover, thepatient s mayhav egraduall y reduced their alcohol usei n thepreclinica l phase of the disease. The strongest support for aprotectiv e effect of moderate alcohol consumption on CHD risk comes from cohort studies. In cohort studies, also calledprospectiv e or longitudinal studies,larg epopulation s areclassifie d into categoriesvaryin gi n alcohol consumption level. After anumbe r ofyear sth e association between alcohol consumption and CHD incidencei sstudied . In aremarkabl y largenumbe r of these studies performed invariou s parts ofth eworld , areduce d risko f CHDi n moderate drinkers hasbee n found (7-9, 25, 26, 32, 38, 46, 57, 68, 76, 78, 79, 81, 114, 120, 122, 124, 129, 130, 133, 145, 179, 182, 186, 192, 214-216). In twostudie s- onei n Ireland (81), another in California (32)- no effects of alcohol usewer efound . A 142 recent studyi nFinlan d showed, in contrast to allothe r studies, a positiveassociatio n between consumption of alcohol, inparticula r ofspirits , and CHD incidence (192). Iti sals ofro m cohort studiesi n particular that theide a of aU-shape d curveha s arisen, i.e . moderate drinkerswoul d bea tlowe rris ko f CHD than both teetotallers and heavy drinkers. Dyer et al. (57), in 1980, wereth efirs t to suggest such aU - shaped curve on thebasi s ofa study inwhic h theyfollowe d 1899 employees of the Western Electric Company from 1957 to 1974. A decrease in CHD incidencewa s found with increasing alcohol consumption up to adail y dose of 5glasses . At higher dosesCH D incidencewa sfoun d toincreas e again. However theseresult s lost their significance after correction for smokinghabits , serum cholesterol and blood pressure. In 1981,th e existenceo f aU-shape d relationship wasconfirme d intw o independent studies, oneb yKlatsk y et al. (124), the other byMarmo t et al. (145). Later support camefro m astud yo fFriedma n &Kimbal l (68) among 5209 men and women in Framingham during a24-yea r follow-up period. Although thevas t majority of allstudie s have reported a decreased incidenceo f CHD among moderate drinkers as compared to non-drinkers, not allstudie shav e found a U-shaped relationship. Thereis , however, no doubt that heavy alcohol consumption, besides increasingothe r healthrisks, damage s the cardiovascular system (seeals o Sections 10.3an d 10.6-10.8). Possiblyalcoholic san d excessive alcohol users areles slikel yt ob e included in the cohort studies. Thisis ,fo r example, the casei n the Nurses Health Cohort Study byStampfe r et al. (186), inwhic h the alcohol consumption of thecohor t was relativelylow . A serious drawback ofman y cohort studiesi stha t the category of non-drinkers considered in these studies maycompris eforme r heavydrinker s aswel l as people whohav egive n up alcohol on medical adviceowin gto , for example, heart complaints. Thispotentia l biasha srecentl ybee n studied byShape r et al. (182)i na cohort of 7735me n livingi n 24 different townsi n England, Scotland andWales . Theyfoun d a U-shaped relationship between alcohol consumption and total mortality and an inverserelationshi p between alcohol consumption and cardiovascular disease mortality, in fair agreement with the results of earlier studies. At thestar t of thefollow-u p study, when the averageag eo f the subjects was5 0years , 24.2%o f the subjects already had heart complaints. Theassociation s between alcohol use and totalmortalit y andbetwee n alcohol usean d CVDmortalit ywer eals o studied for both sub-cohorts separately (men suffering from and menfre e from heart disorders). In the categoryinitiall yfre e from heart disorders a U-shaped or inverse relationship could no longer befound . Shaper et al. concluded that the U-shaped curvecoul d largelyb e explained from thefac t that people suffering from CVD disorders tend to reduce or even giveu p alcohol consumption sotha t the curvature cannot be attributed to anyfavourabl e effects ofmoderat e alcohol use. An alternative explanation, however, couldb etha tb yexcludin g 24.2%fro m the cohort, thosepeopl ear e removed that aremos t susceptablet o CVD and therefore could benefit most from a potential protective effect of moderatealcoho l consumption. TheLance t paper of Shaper et al. (182)ha s evoked alivel ydiscussio n in that journal ast owhethe r moderate alcohol useprotect s against CHD (7-9). 143

A In anumbe r of studies thenon-drinker s group hasbee n clearly defined. In the Honolulu Heart Study (216), in which thenon-drinker s were classified into lifelong teetotallers and former drinkers, ahighe r CHD incidence ascompare d to drinkers wasfoun d for both categories. Thisfindin g issupporte d byth e results of acase - control study among 513 cases and 918 controls (175) and other studies (122, 129, 130). In the Honolulu Heart Study (184) and in astud yb yKlatsk y et al. (122) no significant differences in CHD riskwer efoun d between lifelong teetotallers and former drinkers. Finally, Stampfer et al. (186), in acohor t of asman y as 87 526 nurses, has recently searched for anychange s in drinking habits over thepas t ten years. Subjects who had givenu p drinking on medical advicecoul db e excluded from the study thisway .Th e CHD riskfo r thenon-drinker s group wasfoun d to be up to 2.5 times ashig h asfo r the drinkers categories. Interestingly, Stampfer et al., in the Nurses Health Cohort Study, also describea decreased risk of ischaemic strokei nligh t and moderate alcohol consumers, which indicates apossibl e common physiological mechanism. The risk of haemorrhagic stroke, on the other hand, showed a dose-dependent increasewit h increasing alcohol consumption. These resultswer e recently confirmed for both men andwome n ina cohort studyb yKlatsk y et al. (121) comprising over 100 000 people. The increased risk ofhaemorrhagi c stroke could partlyb e explainedb yth e effects of alcohol on blood pressure. An important question with respect to thepropose d beneficial effects of moderate alcohol consumption on risk of CHD iswhethe r total mortality rates are alsofavourabl y influenced. Obviously, it isimportan t to showthat , when the risko f CHDi nmoderat e drinkers decreases, theris ko f other death causes does not simultaneously increase. Large-scale epidemiological studies, sucl)a s the Chicago Western Electric Company Study (57), theHonulul u Heart Study (25), the London CivilServan t Study (145), the Kaiser Permanente Study (124), the Framingham Study (78) and - veryrecentl y- thelarg eAmerica n Cancer SocietyProspectiv e Study (26), however, haveshow n that not only CHD risksar elowe r in moderate alcohol consumers, but that therei sals o aU - or J-shaped relationshipbetwee n alcohol consumption and risk of total mortality. Finally, the effects of alcoholconsumptio n onbloo dlipids , haemostasis, blood pressure and atherosclerosis (see sections 10.1-10.4) allhav ebee n put forward to explain the observedbeneficia l effects of moderate alcohol consumption in epidemiological studies. An alternative explanation, however, mightb e that moderate alcohol consumption isassociate dwit h a^healthierlife-style . In afe w studies the relationship between level of alcohol consumption and dietary patterns hasbee n investigated (49, 84, 107, 110, 205). With respect to theintak elevel s for variousnutrient s the results areno tver yconsisten t andma yvar ydu et o cultural differences in dietary habits between thepopulation s studied. Itwa s fairly consistently shown, however, that total energyintak eincrease swit h increasing alcohol consumption. In otherwords , the energyconsume d in thefor m of alcohol is not compensated for byomittin g caloriesfro m other dietary sources. Furthermore, it wasshow n that alcohol consumption, eveni n moderate amounts, is strongly

144 associatedwit h smoking, which isi n agreement withfinding s inman y other epidemiological studies (125, 144, 187). Thesefinding s dono t providea n alternative explanation for the observed decreased risk of CHD inmoderat e drinkers. Therefore, thephysiologica l mechanisms described in sections 10.1-10.4 still form themos t likely explanation.

10.6. Angina pectoris

According to Orlando et al. (157), angina pectoris (pain in the chest during exercise, caused byischaemi a of the coronary arteries), occurs morefrequentl y after alcohol consumption. In earlier studies alcohol wasprove d either tohav en o effect (40) or to attenuate angina pectoris (178). Hrubec et al. (102) found astatistica l relationship between angina pectoris and thenumbe r of timesindividual s areintoxicated , but found no clear relationwit h the quantity of alcohol consumed weekly. Takizawa et al. (194) concluded that alcohol consumption mayprovok e attackso f variant angina, a typeo f angina pectoris which mayoccu r spontaneously in rest. In viewo f the conflicting evidence no definite relationship between alcohol consumption and angina pectoris, either positive or negative, can be said to exist.

10.7. Cardiomyopathy

A singlelarg edos e of alcohol has a deleterious effect on cardiac performance such as myocardial contractility and depression of the left ventricular function. Van Zwieten (218) reported consumption of 80g alcoho l in 2hour s tob eassociate d with this phenomenon. Regan et al. (172) reported this change tooccu r at abloo d alcohol level of 0.75 g/1. Others mention with regard to thissyndrom ebloo d alcohol levelso f 0.1t o 2.85g/ 1 (1, 35). Theconsumptio n ofa singl elarg e doseo falcoho l mayals o causearrhythmi a of thehear t muscle such as atrial fibrillation (132, 140). In astud y byLowenstei n et al. (140), 35% ofth e cases admitted to thehospita l with new-onset atrialfibrillatio n could belinke dwit h excessivealcoho l consumption. In a large prospective studyb yCohe n et al. (37) itwa s shown that arrhythmia in generalwa s 2.3 timesmor e common in heavy drinkers (moretha n 6glasse spe r day) than inligh t drinkers (lesstha n 1 glasspe r day).Th e so-called 'holidayhear t syndrome', whichi s characterized by arrhythmia, isals o associated with acute excessive alcohol consumption (80, 111). Alcoholism maycaus emyocardia l injury (173, 218). This effect of excessive alcohol consumption isno t specific for the heart muscle, but mayaffec t other musclesa swel l (seeChapte r 11). Recently, Urbano-Marquez etal . (199) showed strongcorrelation s between the total lifetime amount of alcohol consumed and the performance ofbot h skeletal and cardiacmuscle , in agrou p of severealcoholics . Therei sno wsufficien t evidence (seeTabl e 10.4)t osuppor t the causal roleo f alcohol and/or acetaldehydei n injury of thehear t muscle (cardiomyopathy) in

145 Table 10.4. Evidence in support of the syndrome called 'alcoholic cardiomyopathy' (from 127).

1. Association of drinking and heart muscle disease noted bynumerou s authorities. 2. High proportion of chronicuser s oflarg e amounts of alcohol among patientswit h congestive cardiomyopathy. 3. Cases that showconvincin g evidence of heart muscle dysfunction in relation to episodic drinking. 4. Acute impairment of heart muscle contractility due to alcohol inma n and animals. 5. Acute rhythm disturbances related to alcohol in man ('holiday heart syndrome'). 6. Impaired heart function in alcoholicswithou t acute alcohol load. 7. Heart muscle metabolic dysfunction inanimal s related to acute alcohol load. 8. Alcohol-produced heart muscle cellular abnormalities in animals. 9. Autopsy evidence ofhear t muscle damage in alcoholicswithou t ahistor y of clinical heart disease. 10. Well-documented acute and chronic skeletal muscle syndromes owing to alcohol. alcoholics (127, 172, 218), also inth e absenceo f thenutritiona l deficiencies often observed in alcoholics (176, 199). Among thepossibl ecause smentione d are: changes inio npermeabilit y of muscle cells (164), inhibition of protein synthesis, inhibition of actin and myosin bindingi n the heart muscle (6), and mitochondrial abnormalities (1). Cardiomyopathy mayals ob ecause db yintoxicatio n due to trace elements, cobalt in particular (1). Alexander (2) found myocardial injury in 27heav y drinkerswh o used to drink oneparticula r brand ofbee r towhic h 1-1.5 mg/1 cobalt had been added to stabilize the froth. Alcohol abusemus t have continued over alon gperio d of timei n order to cause severehear t muscleinjury . Wink (212) mentioned an alcohol limit of 250 g/dayove r 10year sa sth eborderlin e abovewhic h definite cardiacris kwil loccur . Alimi t of 10 years of excessivealcoho l intake isals o indicated elsewhere (1,6). Damage to other organs in thebod yi susuall y observed prior to cardiomyopathy (6, 218).

10.8. Cardiac beriberi

Beriberi isa nutritiona l disorder causedb y deficiency of thiamin (vitamin B-l). The disease hasbee n widespread in poor communities in East Asia, with ricea sth e staple food and an otherwisever ypoo r diet. However, in rich countries thiamin deficiency may also occur in peoplewhos emai n source of energyi salcohol . Thiamin deficiency maylea d to theWernicke-Korsakof f syndrome (seeChapte r 9) in somealcoholics , or cause cardiacfailur e with generalized oedema, pulmonary congestion and breathing difficulties in others (28, 142, 165). These diseases can occur together in one patient, but thisi suncommon . Therei sn o explanation ast owh yi n somepatient s the heart isaffecte d byth ethiami n deficiency and inother s thebrain . In beriberi among alcoholics lactacidosisi sregularl y observed (141),whic h isno t the casefo r beriberi in non-alcoholics. In its earlystage s the diseaseca n alsob etreate dwit h thiamin, but recovery of severecase si sslo wan dofte n incomplete (127). Supplementation with

146 thiamin isa ver ysuccessfu l and cost-effective wayo f preventing the disease. Doctors and socialworker s should therefore payattentio n toth e alcoholic's diet and be awareo f the risks of thiamin deficiency.

10.9. Final considerations

In thischapte r the effect of alcohol on thecardiovascula r system is described. Excessivealcoho l use has obviously detrimental effects on thevascula r system,b y increasing blood pressure, and on the heart muscleitself . Moderate alcohol use, on the other hand, hasbee n shown tohav e aprotectiv e effect on CHD. The exact mechanism of thiseffec t isno tye tfull y known, but anumbe r of plausible mechanisms havebee n put forward. Theseresult s underline the senseo f prudent drinking limits. On theon ehand , they should not be used to promote alcohol consumption among non-drinkers. It shouldb e realized that thelowe r risk of CHDi s mainlyobserve d in population studiesan d isno t necessarily applicable to each single individual. On the other hand, theseresult s mayb euse d to persuade excessive drinkers to moderate their alcohol use.

Summary

Consumption of alcohol has an influence on several processes that play an important rolei n the development of diseases of the cardiovascular system. - Alcohol consumption ispositivel y correlated with HDL-cholesteroli n epidemiological studies. In experimental studies alcohol increases the HDL- cholesterol levelwithi n someweeks . - Studies on the acute effects of alcohol on platelet aggregation have revealed conflicting results. Epidemiological and long-term experimental evidence shows that alcohol consumption probablyreduce splatele t aggregation. - Alcohol consumption, even at moderate doses, strongly affects the components of thefibrinolyti c system, acutely and in thelon g term. PAI activity and the levelo f t-PA antigen isincreased , whereas theleve l of t-PA activityi s strongly decreased. - Excessivealcoho l consumption isclearl yassociate dwit h anincrease d blood pressure. The effects of moderate alcohol use areles s evident. Some epidemio­ logical studies have shown acontinua l dose-dependent increase, other ones have shown anincreas e abovea certain level, andi n some studies a U-shaped relationship between alcohol andbloo d pressureha sbee n found. - Studies amonghypertensiv e excessivealcoho l consumers have clearly shown a marked reduction inbloo d pressurewithi n days after reducing alcohol intake. - A number of studieshav e shown that moderate alcohol usei s associated withlowe r scoresfo r occlusion ofth ecoronar y arteries. In thesestudies , the drinking pattern was shown tob ea n important factor. Binge drinkingwa sassociate d with a higher risk.

147 The relationship between alcohol consumption andcardiovascula r diseases has been the subject of alarg enumbe r of studies. - In anumbe r of ecological studies an inverserelationshi p between alcohol use and theincidenc e of CHD hasbee n found. - Aprotectiv e effect ofmoderat e alcohol consumption against the development of CHD hasbee n confirmed in manypatient-contro l and cohort studies. Total mortality wasals o shown to decrease amongmoderat e drinkers ascompare d to non-drinkers. - Since excessivealcoho l usei sassociate dwit h anincrease d risko f CHD, the relationship between alcohol consumption and CHD issai dt ob e U-shaped. - Moderate alcoholus eha sbee n found tob e associatedwit h alowe r incidenceo f ischaemic stroke. Theris k of haemorrhagic stroke, on the other hand, increases with alcohol consumption. - In anumbe r of studies moderate alcohol consumption wasfoun d not to be associated with ahealthie r life stylea sfa r as dietary patterns and smoking habits are concerned. - Long-term aswel l asacut e excessivealcoho l consumption hasbee n shown to increase the risk of cardiac arrhythmia. - Long-term excessivealcoho l consumption can causecardiomyopathy , even in the absence of nutritional deficiencies. In alcoholics, the total lifelong consumption of alcohol hasbee n shown tob einversel y correlatedwit hbot h cardiac performance and skeletal muscle strength. - In alcoholics, thiamin deficiency mayresul t in cardiacberiberi , whichi n an early stage canb eprevente d easilyan d cost-effectively bythiami n supplementation. # References

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156 CHAPTER 11 Effects of alcohol onvariou stissue s and organs

E. teWierik and W. G. Vrij-Standhardt

In other chapters the effects of alcohol consumption on the liver (Chapter 8), the cardiovascular system (Chapter 10), thebrai n and thenervou s system (Chapter 9) havebee n discussed. In this chapter the effects of alcohol on some other organswil l bebriefl y discussed, inparticula r the effects on the gastrointestinal tract, the pancreas, the eyean d thelung . The effect of alcohol on muscles, blood and bone marrow willals ob e mentioned.

11.1. Thegastrointestina l tract

Alcohol consumption affects thefunctio n and structure of the gastrointestinal tract inman y direct and indirect ways (23, 57, 81).Alcoho l itself affects the mucosao f mouth, oesophagus, stomach and intestines, and modifies the secretion of hormones and enzymes that areinvolve d in digestion and absorption. Changes inth e function of liver, pancreas and gall-bladder resulting from excessivealcoho l consumption also affect digestion. The poor nutritional status of many alcoholics isa consequenc eo f primary malnutrition (decreased or imbalanced dietary intake) on the onehand , and of secondary malnutrition on the other. The latter term refers to a decreased utilization of nutrients, causedb y (among other factors) impaired digestion and absorption. Theresultin g vitamin deficiencies willi n turn cause afurthe r decreaseo f thefunctio n of thegastrointestina l tract, thus causing aviciou s circle. In this section theinfluenc e of alcohol consumption on thegastrointestina l tract willb e discussed, except for therol eo f alcohol in carcinogenesis which is discussed in Chapter 12.

11.1.1. Mouth andoesophagus

Alcohol affects the salivaryglands . Hyperamylasaemia frequently occurs in alcoholics (14), possibly due to to an injurious effect of ethanol on salivary glands or toa decreased renal clearance of amylase (15). Further, chronic alcohol consumption can lead to a reduced salivary secretion rate (16, 46). Sincesaliv a seems tob e able to protect the mucosa against theloca l actions of chemical carcinogens, reduction of the salivary glandfunctio n mightpla ya rol ei n carcinogenesis of theuppe r digestive tract.

157 In the oesphagus chronic alcohol consumption maycaus e oesophagitis or oesophageal motility disturbances (37).

11.1.2. Influence ofalcohol on the integrity ofgastric mucosa

11.1.2.1. Acute effects After once-only excessivealcoho l consumption, both in man and in laboratory animals, distinct lesions of the gastricmucos a (hyperaemia, erosion) are detectable bymean s ofgastroscopy . Theselesion swil lhea l after 1t o 3week s(58) . In most studies inwhic h theharmfu l effects of acute alcohol consumption on gastricmucos a were demonstrated, concentrated ethanol solutions or spiritswer e used (17, 84). Diluted solutions (10%) havehardl y any effect on themucos a (17). According to Davenport (10)th e deleterious effect of alcohol depends on the concentration of the alcohol that comesint o contactwit h the gastricmucosa , rather than on the quantity of concentrated alcohol. Both theconcentratio n and the quantity of alcohol havebee n found topla ya role. Kawashima &Glas s (34, 35) observed inmic etha t a 10%ethano l solution, irrespective ofth e dose, didno t cause mucosal lesions, whereas the administration of 25-50%solution s instilled into the stomach caused mucosal erosion. Thehighe r theconcentratio n and (for concentrations of 25%o r higher) the larger the quantity, themor e extensive and the more severeth elesion s observed. The effects of solutions containing 10-25%alcoho l haveno t been reported in these papers. Further research in this intermediate range willb equit einterestin g invie wo f thebroa dvariet yo f alcoholicbeverage s inthi s range (wine, sherry, port, long drinks). * 11.1.2.2. Chroniceffects In about 66%o f the7 0 alcoholics studiedb yDinos o et al. (13) chronic atrophic gastritisi n the gastric antrum wasfound . Gastritis isa nimportan t cause of gastric haemorrhage in alcoholics (20). Themucos a generallyheal supo n abstinence (78). Gastriclesion s arepresumabl y causedb yth eincrease d permeability of the mucosa inducedb yalcohol . According to Davenport &Arbo r (9), administration of alcohol has abarrier-breakin g effect: thejunction sbetwee n the epithelial cells are loosened. Becauseo f theincrease dpermeability , thecapacit y ofth e epitheliallaye r of thegastri cmucos a toprotec t theunderlyin g tissuefro m thebein g enteredb y hydrogen ionsi slost . Theinvadin ghydroge n ions stimulateothe r mucosalcell s to secretehistamine, which stimulates acid secretion and causesvascula r dilatation. Ina studyi n rats an altered gastricmucosa lpermeabilit y hasbee n observed after the administration of asolutio n containing 25% alcohol. In this study thepresenc eo f alcoholwa saccompanie d with an increased passageo f larger agents across thegastri c mucosa (73). In dog experiments thebarrier-breakin g effect wasfoun d onlyfo r solutionswit h an alcohol content of 14%o r more, and no effect at all«fo rthos econtainin g 8% alcohol or less (8). Acetylsalicylic acid (aspirin) has the same barrier-breaking capacity (10). It istherefor e advisablet orefrai n from taking aspirin incas eo f alcohol 158 T~

intoxication. However, animal studies haveshow n that bland irritating agents (e.g. alcohol solutions) havea protectiv e effect towards later administration of strong irritating agents. In human studiesi t hasbee n observed that the antral injury occurring after a single doseo f aspirin isreduce d when the administration of aspirin hasbee n preceded bya cocktail ofvodk a and tomatojuice . According to Cohen et al. (5) this protective effect mayb emediate d bya n enhanced production of endogenous prostaglandin after the consumption of themildl yirritatin g agent. It hasbee n reported that free radicalsma yb einvolve d in thepathogenesi s of mucosal injury (61, 80),bu t themechanism s of action areno t knownyet .

11.1.3. Influenceof alcohol on gastric motility

Both animal experiments andhuma n studieshav eindicate d that acute alcohol administration decreases gastricmotilit y and delaysgastri c emptying (20, 29, 32, 85). Thisma ycaus enause a andvomitin gi n caseso f alcohol intoxication. Themechanis m underlying theinfluenc e ofalcoho l on gastricmotilit yi sno t clear. It mayfunctio n viait sinfluenc e on oneo rmor e of thegastrointestina l hormones, such asgastri n orcholecystokini n (50), on smooth muscleso r thenervou s system, or on the releaseo f neurotransmitters.

11.1.4. Effectof alcohol on gastric acid secretion

Investigations on apossibl estimulatin g effect of alcohol on gastricaci d secretion haveno t produced unambiguous results. In somestudie s no effect wasfoun d (6,7) , whereas in other studies effects werefoun d after theconsumptio n of low-alcohol solutions, beer orwin e (11, 27, 38, 43,69-71) . Recent investigations haveshow n that particularly red andwhit ewine s and beer causegastri n response and an increased acid secretion. Whiskyan d ethanol, in comparable concentrations, bring about this effect onlyt o alowe r extent or not atal l (43, 68,75) . Stimulation ofgastri caci d secretionb yth eingestio n ofbee r orwin ei s presumably causedb ya n enhanced releaseo f gastrin.Th e mechanism through which alcohol solutionsbelo w 5%stimulat egastri caci dproductio n isno t known yet.

11.1.5. Influenceof alcohol on the intestines

The effects of alcohol on theintestine s havebee n the subject ofman ystudie s and reviews (51, 56, 86).Th e structural and functional changesfoun d in theintestine s of alcoholics and surveyed in these reviewswil lb esummarize d below. Morphology. Acuteingestio n of alcoholcause shaemorrhagi c erosion ofth ejejuna l villi.Amon g the effects ofchroni cconsumptio n of alcohol areshortenin g ofth evill i and a decreaseo f thenumbe r of epithelial cellslinin gth evill i (59). Thisma yb e due to mitoticinhibitio n (40). Thesemorphologi c changes can presumablyb e reversed by alcohol abstinence (74). 159 Permeability. An increased permeability to anumbe r of substances asa consequence of chronic alcohol consumption hasbee n demonstrated. Intact moleculeswit ha molecularweigh t <500 0 can pass theintestina l mucosa of alcoholics (1). The consequences of thisincrease d permeability mayb e that smalltoxic , ordinarily non­ absorbable, compounds mightb e absorbedb yalcoholic s and accelerate extra­ intestinal damage. Otherwise, increased losses of substances from thebloo d to the gutlume n mayoccu r (86). Absorption ofnutrients by thesmall intestine. Malabsorption ofnutrient s in the smallintestin ei sa n important factor inmalnutritio n of alcoholics. Damage to the intestinal mucosa interferes with thephysiologica l absorption ofvitamin s (especially the Bvitamin s andfolate) , minerals, proteins and amino acids (51, 56, 86). Fat malabsorption frequently occursi n alcoholics. This defect disappearswhe n these alcoholics receivea n adequate diet, irrespective ofwhethe r they continue to use alcohol. Alcohol reducesth e absorption of glucoseb yinhibitin g the glucose transport mechanisms (55). Intestinalenzymes. Alcohol consumption resultsi n adecrease dactivity-p f disaccharidases and ATPase activity, andi n increased microsomal enzyme activities (51).

11.2. The pancreas

The pancreas isa glan dwit h both external andinterna l secretion. The external secretion, containing digestive enzymesan dbicarbonate , contributes to the digestion of food in the duodenum. Theinterna l secretion, containing insulin and glucagon among other substances, regulatescarbohydrat e metabolism. *

11.2.1. Harmfuldoses of alcohol in relation topancreas injury

In several studies (66) itwa sfoun d that most patients suffering from pancreatitis consumed over 150-175 galcoho lpe r day. It is, however, not possiblet o establish a lower 'safe' limit; there appears tob e alarg eindividua lvariabilit y in susceptibility to the development ofpancreatitis . The relativeris kincrease s logarithmically with the quantity of alcohol ingested. The duration of theperio d of (excessive) alcohol consumption untilclinica l symptomsbecom eapparen t isestimate d at 3t o 20year s (men 18years ,wome n 11 yearso n average). Themea n total alcohol consumption before diseasebecome s manifest hasbee n calculated tob e 1166 ± 176litre s for men, and 605 ± 195litre sfo r women (79). Although acutedose s of alcoholhav ebee nfoun d toinduc echange si nvolum e and composition of thepancreati c secretion invitr o (31, 76), in animal experiments (3, 83) andi nhuma n studies (12, 18, 44), there aren o indications that moderate quantities of alcohol areharmfu l to thepancreas . Thiswil lstil lhav et ob e confirmed byspecifi c investigations, however.

160 11.2.2. Pancreatitis

Alcoholism isa nimportan t causeo fpancreatitis , inwhic hbot h achronic an d an acuteinflammatio n mayb efound . Moretha n 75%o fpatient swit h chronic pancreatitis havea histor yo f heavyalcoho l consumption (82). Threemajo r hypotheses havebee n posed to explain thepathogenesi s of pancreatitis (72). - Flow/refluxhypothesis Duodenopancreaticreflux. According tothi shypothesis , alcoholreduce s the tone of the sphincter of Oddi, therebyfacilitatin g reflux of duodenal contents into the pancreatic duct. Enterokinase, present in the duodenal contents, activates intraductal pancreatic enzymes that diffuse into thepancreati c interstitium, therebycausin gacut epancreatitis . Biliarypancreatic reflux. Proponents of thistheor ypostulat etha t ethanol causes spasms of the sphincter of Oddi, thereby creating acommo n channel between bile and pancreatic duct. Thispermit s reflux ofbil eint o thepancreati c duct and causes pancreatitis. - Ductal-plughypothesis ' Thishypothesi s proposes that secretion ofpancreati cjuic eric hi nprotein sma y 'plug' the small ductules, leading to obstruction, inflammation and, consequent­ ly, degeneration of the area drained bythes e ductules, thusinducin g chronic pancreatitis. - Toxicmetabolic hypothesis Thishypothesi s suggeststha t ethanol hasa directinjuriou s effect, leading ultimately to pathophysiologic changes culminating in pancreatitis. Becausenon e of the concepts outlined above aremutuall y exclusive, itma yb e true that most or allo f the changespropose db ythes ehypothese s occur at different stages duringprogressio n of ethanol injury to thepancrea s (72). The role ofnutritiona l factors in chronicpancreatiti s isuncertain . Sarles (66) has hypothesized that a diet rich infa t and proteins predisposes alcoholics to pancreatitis. However, Mezey et al. (52), who studied pancreatitis in subjects who consumed more than 50%o fthei r energy asalcohol , concluded that ahig h dietary intakeo f protein andfa t isno t afacto r in the development of chronicpancreatiti si n alcohol-dependent individuals. In Stockholm county theincidence s of hospitalization for chronic and acute pancreatitis have declined during thepas t decades. Moreover, the apparent national and Stockholm prevalence of chronic pancreatitis declined in the sameperiod . A concomitant declinei n the Stockholsale sfigure s of spiritswa sals o observed, whereas the salesfo r winean dbee r increased. From these data Schmidt (67) concludes that the consumption of spirits,bu t not of beer andwine , appears tob ea riskfacto r for pancreatitis. Thisinterpretatio n indicates thepopulatio n athig h risk to beth echronic alcoholics , whoar eknow n toconsum epredominantl y spirits.

161 11.3. The eye

11.3.1. Effectof acute alcoholconsumption onthe eyefunction

The inhibition ofbrai n activity causedb yalcoho l also affects vision. In acute alcohol consumption motor disturbancewil loccur , including reduction ofvelocit y of eye movements, impairment of convergence and induction ofnystagmu s (33,53 ,77) . At abloo d alcohol concentration (BAC) of 0.8g/ 1 accommodation and convergencei s disturbed to such a degreetha t depthvisio ni simpede d (26). Doublevision ,wel l known tob e attendant on alcohol intoxication, mayals o occur. Gramsberg- Danielsen &Lindne r (22) haveinvestigate d the effect of alcohol consumption on vision in relation tojustifiabl e participation in traffic. Vision isaffecte d most before themaximu m BACha sbee n reached.

11.3.2. Effectof chronic alcohol consumption on the eye

Alcoholism mayb e accompanied with disturbances of themoto r activityo f theeye . Chronic consumption of alcohol mayresul t in histological changes or in premature ageingo f thebrai n including theoculomoto r system (39). The 29patient swit ha slowlyprogressin g decrease ofvisio n examinedb yHenke s (26) allreporte d to drink atleas t 150g alcoho l daily. Heavysmokin g and poor dietaryhabit swer eals o observed in most of them. It isno t clearwhethe r alcohol has a direct toxic effect on the opticnerv eo rwhethe r vitamin deficiency (vitamin A (63),vitami nB-1 2(4 , 26)) isa causal factor. Cyanide, present in tobacco smoke andbeer , mayals o causethi s opticoneuropathy, formerly also referred to as alcohol- or tobacco-jnduced amblyopia (4, 26). Local retinol deficiency goingwit h alcohol consumption playsa part in causing nightblindnes s (see Chapter 6). Heavy drinking (moretha n 4glasses/day ) mayb e aris kfacto r for cataract (24). There isa ris ko f confounding between heavy drinking, cigarette smoking, andwor k on amilitar ybase , but analyses haveindicate d that these three riskfactor s are independent (25).

11.4. The lung

Sincealcoho l isexcrete d in significant quantitiesb yth elun g and sincealcoho l istoxi c to several organsi sseem splausibl etha t alcohol affects thelun g aswell . However, sincemos t heavy drinkers are also smokersi t ist ob e expected that their pulmonary function willb e abnormal. Therefore iti s difficult to assessth e effects of alcohol per seo n thelung . No significant difference inpulmonar y function between alcoholics and their matched controlswa s shownb yLyon s et al. (45). The authors conclude that thehig h prevalence of respiratory diseasei n alcoholicsi slargel y attributablet o their smoking habits. No evidenceo f a specific pulmonary toxic effect of alcoholwa sidentified . The

162 relationship between alcohol consumption and respiratory symptoms has also been studied byLebowit z (42). In this studyheav y drinkerswer e stratified bysmokin g status in order to clarify theindependen t effect of alcohol consumption. The author observed that heavy drinkers (> 17glasses/week ) had moreproductiv e cough, wheeze, and reported moreacut erespirator y illness than other drinkers. In this study smokingwa sfoun d tob e afa r moreimportan t contributor torespirator y symptoms, but alcoholi s asignifican t riskfacto r aswell . Norelationshi p wasobserve d between alcohol consumption and lungfunction . In arecen t longitudinal study alcoholwa s found tob e asignifican t independent predictor of declinei nforce d expiratory volume (FEV). The authors of this study alsolooke d after theinteractio n between alcohol consumption and smoking. Alcohol consumption in smokers led to aslowe r decrement in FEV than expected asa resul t of smoking alone (41). These results havebee n confirmed in acase-contro l study (19).

11.5. The muscles

11.5.1. Myopathy ,

During thepas t centurymuscl e dysfunction resultingfro m chronic alcohol abuse accompanied byweaknes s of thelimb swa s described for thefirs t time. Later on, more cases of myopathy in alcoholicswer ereporte d (65). Chronic alcohol consumption causesmorphologica l changeso f theskeleta lmuscle . Atrophy of fibres (especially typeli b fibre), reduction of theprotein/DN A ratio, and reduction of myofibrillary Ca + -ATPaseactivit yhav ebee n observed in alcoholics. According to Martin et al. (47), these results suggest a selectivelos s of typeI I fibre myofibrillary protein. Athrophy of typeI I fibres after alcohol consumption in alcoholics hasbee n observed in several other studies (54, 62)). TypeI Imuscl efibr e atrophy is often reversible and isdirectl y related to alcohol consumption, not to malnutrition, vitamin deficiency or peripheral neuropathy (28, 48,60) . In animal studies it hasbee n found that alcoholfeedin g significantly reduces the RNA content. Thislos s of protein synthetic apparatus mayb e an important eventi nth e development of skeletal muscle myopathy (49). Perkoff (58a) classified alcoholicmyopath y into three forms: asubclinical , an acutean d achroni cform . Thefirs t twoform s arepresumabl y entirely, and thelas t one ispartl y reversible upon abstinence (65).

11.5.2. Harmfulamounts of alcohol in relation to myopathy

Research on alcoholic myopathy has almost exclusivelybee n donewit h alcoholics. Roughly speaking, excessivealcoho l consumption mayb e saidt o gowit h alcoholic myopathy almost without exception. In Rubin's experiment (64) 225-260 g/daywa s consumed, which corresponds with a dailyconsumptio n of 22-26 drinks. These are clearlyn o examples of 'moderate' alcohol consumption!

163 From literature reviewsi tbecome s apparent that the development of reversible selective atrophy of typeli b fibres mayresul t from the consumption of amounts exceeding 100g alcohol/da y for at least threeyear s (30). There aren o indications of moderate alcohol consumption causing muscle damage. On the other hand, no studies reporting harmlessness of alcohol to muscle havecom e to our knowledge either. Alsoi n this field studies on the effects of moderate doses of alcohol areneeded , e.g. in sportsmen.

11.6. Blood and bone marrow

The effects of chronic alcoholism onbon emarrow , erythrocytes and leucocytes have currentlybee n summarizedb yBallar d (2) andb yother s (21,56) . Itha sbee n noted that the occurrence ofvacuolate d pronormoblasts (precursor cellso f erythrocytes)i s the most striking effect of alcohol on marrow cells. Thisvacuolizatio n disappears during thefirs t week of abstinence. Therapi d reversibility ofvacuolatio n is consistent with a direct toxic effect of alcohol. An elevated erythrocytemea n corpuscular volume (MCV) occursfrequentl y in heavy alcohol consumers. Thisma yb e the consequence of membrane damaget o primitivebon emarro w cells. Several forms of anaemia havebee n noted tob e associatedwit h alcoholism, including haemolytic anaemia (increased rate of red cell attrition or destruction). Thrombocytopenia (decreased platelet count) andimpaire d platelet function haveals obee n associated with excessivealcoho l consumption. Littlei sknow n about the effects of alcohol on whitebloo d cells. It has, however, een noted that an ineffective immunesyste m may be aconsequenc e of alcoholism. » 11.7. Other organs

In caseo f severe continuous alcohol abuseth e totalfunctio n of thebod ywil lb e disturbed to such an extent that in addition to the dysfunctions mentioned in other chapters, damagema yb e caused to almost everyothe r organ. This damagewil lno t be a consequence of the directtoxicit y of alcohol asa rule , but of secondary disturbances of the organism. These disturbances arebeyon d the copeo f this literature review andwil lno t be discussed here. The quantity of alcohol causing this damaget o occur depends on individual sensitivity, but generally exceeds or equalsth e quantitywhic hma yinjur e theliver , heart or brain.

Summary

Alcohol consumption affects thefunctio n and structure ofth egastrointestina l tract inman y direct and indirect ways.Alcoho l decreases gastricmotility , delaysgastri c emptying andpossibl y affects the secretion of gastrin and gastricjuic e (indirectly).

164 Acute alcohol consumption maycaus e damage to theoral , oesophageal, gastric and duodenal mucosa ('barrier breaker'). The degree of the damagecause d depends on the alcohol concentration of thesolutio n that comesint o contact with the mucosa, and consequently on the concentration and quantity (with respect to dilution) of the beverage consumed. Alcoholism is one of themai n causes of pancreatitis. In manyinstance s the injury manifests itself as acutepancreatiti s which mayb e considered thefirs t shift of chronic relapsing pancreatitis. Three hypotheseswit h regard to the pathogenesis of pancreatitis inalcoholic s havebee n posed. An acutedos eo falcoho l alters the secretion of pancreaticjuice . Evidenceo fth eharm , ifany , ofth econsumptio n of moderate quantities of alcohol causedt o thepancrea s isno t available. Alcohol causes a reversible disturbance ofvisua lmoto r activity. Chronic excessive alcohol consumption affects theopti cnerv ean d maycaus enigh tblindness . Cataract mayb e aconsequenc e ofheav y drinking. A declinei n forced expiratoryvolum ean d occurrence of respiratory symptoms mayb erelate d to excessiveconsumptio n ofalcohol . However iti sdifficul t to establish the independent role of alcohol consumption sincemos t heavy drinkers are also smokers. ' Prolonged excessivealcoho l consumption maylea d to morphological changeso f the muscles. Atrophy of typeli b fibres hasfrequentl y been observed. This maycaus e subclinical, acute or chronicmyopathy . There isn o evidencetha t moderate alcohol consumption leads to muscle injury. The effects of alcohol on blood are diverse. Abnormalities of erythrocytes, platelets and leucocytes mayoccu r separately or invariou s combinations. Functioning of thebod yi n its entirety mayb edisturbe d bychroni c excessive alcohol consumption to such an extent that indirect damagema yb e caused to almost everyorgan . The quantity of alcoholwhic h maycaus ethi s damagedepend s on the individual's susceptibility, but usuallycorrespond s to thosequantitie swhic h cause injuries of theliver , thehear t or thebrain .

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167 59. Persson J, Berg NO, Sjölund K, Stenling R, Magnusson PH. Morphologic changes in the small intestine after chronic alcohol consumption. ScandJ Gastroenterol 1990;25: 173-84. 60. PetersTJ , Martin F, Ward K. Chronic alcoholicskeleta l myopathy, common and reversible. Alcohol 1985;2:485-9 . 61. Pihan G, Regillo C, Scabo S. Free radicals and lipid peroxidation in ethanol-o r aspirin-induced gastric mucosal injury. DigDi s Sei 1987;32:1395-401 . 62. PreedyVR , Bateman CJ, SalisburyJR , PriceAB , PetersTJ . Ethanol-induced skeletal muscle myopathy:biochemica l and histochemical measurement on type I and type II fibre rich muscles inth eyoun g rat. Alcohol Alcoholism 1989;24:533-9 . 63. Roe DA. Drug-induced nutritional deficiencies. Westport, CT:AVI , 1976. 64. Rubin M, Katz AM, Lieber CS, Stein EP, Puszkin S. Muscle damage produced by chronic alcohol consumption. AmJ Path 1976;83:499-516 . 65. Rubin E. Metabolic and pathological changes in muscle during acute and chronic administration of ethanol. In: Majchrowicz E, Noble EP. Biochemistry andpharmacolog y of ethanol. NewYork : Plenum Press, 1979;1: 623-40. 66. Sarles H. An international survey onnutritio n and pancreatitis. Digestion 1973;9:389-403 . 67. Schmidt DN. Apparent riskfactor s for chronican dacut epancreatiti s in Stockholm county. Int J Pancreatol 1991;8:45-50 . 68. Singer MV, Eysselein V, Goebell H. Beer and winebu t notwhisk y andpur e ethanol do stimulate release ofgastri n in humans. Digestion 1983;26:73-9 . 69. Singer MV, Calden H, Eysselein VE, Leffmann C, Goebell H. Lowconcentration s of ethanol stimulate gastricaci d secretion independent ofgastri n release inhumans . Gastroenterology 1984;86: 1254. 70. Singer MV, Leffmann CJ, Schnober D, Goebell H. Beeran d winebu t not whiskyan d cognac stimulate gastric acid secretion inhumans . Gastroenterology 1986;88:1588. 71. Singer MV, Leffmann C, Eysselein VE, Calden H, Goebell H. Action of ethanol and some alcoholicbeverage s ongastri caci d secretion and release ofgastri n inhumans . Gastroenterology 1987;93:1247-54. 72. Singh M, Simsek H. Alcohol and the pancreas; current status. Gastroenterology 1990;98:1051 - 62. 73. Sjódahl R, Andersson PA, Tagesson C. Alcohol and gastricmucosa spermeabilit y to different- sizedmolecules . ScandJ Gastroenterol 1984;19;75-7 . 74. Sjölund K, Persson J, Bergman L. Canvillou satroph y be induced bychroni c alcohol consumption? J Intern Med 1989;226: 133-5. 75. Snelten H, teWieri k E, Veenstra J, Schaafsma G. De invloed van bier en wijn op de gastrinespiegel. Voeding 1991;52:86-9 . 76. Solomon N, SolomonTE , Jacobson ED, Shanbour LL. Direct effect of alcohol on inviv oan d in vitro exocrine pancreatic secretion and metabolism. Am J Dig Dis 1974;19: 253-60. 77. Stapleton JM, Guthrie S, Linnoila M. Effects of alcohol and other psychotropic drugs on eye movements: relevance to traffic safety. J Stud Alcohol 1986;47:426-32 . 78. Stuyt PMJ, vanTongere n JHM. Alcohol en maagdarmziekten. Ned Tijdschr Geneesk 1979;123: 1255-9. 79. Teichmann W, Zastrow R. Alkohol und Pankreas. Z GesIn n Med 1981;36: 567-71. 80. Terano A, Hiraishi H, Ota S, ShigaJ , SugimotoT . Role of superoxide and hydroxyl radicalsi n ratgastri c mucosal injury induced by ethanol. Gastroenterol Jpn 1989;24:488-93 . 81. Thomson AD, Majumdar SK.Th e influence of ethanol on intestinal absorption and utilization ofnutrients . ClinGastroentero l 1981;10:263-93 . 82. VanThie l DH, Lipsitz HD, Porter LE, Schade RR, Gottlieb GP, Graham Ta Gastrointestinal and hepatic manifestations ofchroni calcoholism . Gastroenterology 1981;81: 594-615. 83. Walton B, Shapiro H, Woodward ER. The effect of alcohol onpancreati c secretion. Surg Forum 1960;11: 365-6. 84. WilliamsAW . Effects of alcoholo ngastri cmucosa . BrMe dJ 1956;1:256-9 . 85. Willson CA, Bushneil D, Keshavarzian A. The effect of acute and chronic ethanol administration ongastri c emptying incats . Dig Dis Sei 1990;35:444-8 . 86. World MJ, RylePR , Thomson AD. Alcoholicmalnutritio n and the small intestine. Alcohol Alcoholism 1985;20: 89-124.

168 CHAPTER 12 Alcohol and cancer

E. teWierik and W.G. Vrij-Standhardt

The results of thevariou s studies on the relation between alcohol and cancer are not unanimous. A largegrou p of experts, invited byth eInternationa l Agency of Research on Cancer, havereviewe dth eliteratur e on this subject and concluded that the occurrence of malignant tumours of the oral cavity, pharynx, larynx, oesophagus and liveri scausall y related to the consumption of alcoholicbeverage s (16). However, this conclusion has met withmuc h criticismbecaus ei t doesno t account for a dose-effect relationship. Therei ssom e evidenceo f arelationshi p between the consumption ofalcoho l and cancer of the lungs, thepancrea s and thebreas t andbetwee n the consumption of beer and intestinal cancer and cancer of the rectum. However, these relationships need not allb e causal.

12.1. Epidemiology

12.1.1. Cancerof the upper digestive tract

In reaction to the monograph issuedb yth e International Agencyfo r Research on Cancer (16) mentioned above, Turner et al. (53) reviewed studiesint o the relationship between moderate drinking and theris ko fcance r ofth e oropharynx, larynx, oesophagus andliver .The yconclude d that therei sn o solidan d consistent scientific evidence that moderate use (< 0. 7 gethano l per kgbod yweigh t per day)o f alcoholicbeverage s isassociate d with an enhanced risk of thesetype s of cancer. Moreover, theynote d that most of the studies reveal cancer ofth e oropharynx and thelaryn xt ob epositivel yassociate dwit hver yheav yalcoho l use, but that similar associationswer e notedbetwee n these typeso f cancer and environmental factors like smoking and other tobacco use, and ingestion ofver yho t drinks. The separate effects of heavy alcohol usean d smoking arehar d to establish unambiguously. A casecontro l study of cancer of the oral cavityan d cancer ofth e oropharynxwa s performed in Torino, Italy. Amongmen , an effect of alcoholwa sobviou s onlyi n those consuming 120g alcoho l or morepe r day. Forwomen , a dose-effect relationship was suggested. In both sexesa n elevated riskwa sfoun d for subjects who drank beer whether or not in combination with other alcoholicbeverages . However, therewa sn o effect of alcohol in non-smokers. Among heavyuser s ofbot h alcohol and tobacco the risko fbot h oral and oropharyngeal cancerwa sver yhigh . This study corroborates the suggestion of a combined effect of alcohol and tobacco on therisk 169 of oral cancer (31). A study of 178 cases of cancer of the oesophagus in NewYor k confirmed thesefindings . Both alcohol and smoking independently increased theris k of oesophageal cancer. In acase-contro l study Tuyns et al. (56) havepai d special attention to the risk ofvariou s sites of the larynxan d hypopharynx. The consumption of more than 80g alcoho l increased the relativeris kfo r cancer of the epilarynxo r hypopharynx by4.3 , and the relative risk for cancer of the endolarynxb y 2.1. These relative riskswer e adjusted for smoking and other factors. The combined relativeris k among heavy drinkers and smokerswa s 135.5 for cancer of the epilarynx/hypo- pharynx and 43.2fo r cancer of the endolarynx.

12.1.2. Livercancer

About 60 to 90%o f allcase so f liver cancer are associated with cirrhosis (55). Epidemiological studies are equivocalwit h regard to the causal relation between alcohol consumption and liver cancer (16, 46).

12.1.3. Breast cancer

Epidemiological data regarding the relation between alcohol consumption and the risk ofbreas t cancer are inconsistent. Ameta-analysi s (a quantitative review) of the available data hasbee n performed byLongnecke r et al. (26). The authors found strong evidencefo r a dose-response relationship inbot h the case-control and follow- up data. Theris k ofbreas t cancer at an dailyalcoho l intake of 24g (abou t 2 drinks) relative to the riskfo r non-drinkers was 1.4 in the case-control and 1.7 in the follow- up data. Although thesefinding s areno t aproo f of causality, they support a strong association between alcohol consumption and risk ofbreas t cancer. Stampfer etal . (49) reviewed studies into the relationship between the consumption of alcoholic beverages and breast cancer. They concluded that epidemiological data demonstrate an association between alcohol intake and the risk ofbreas t cancer. This association appeared to hold for allform s of alcoholicbeverages . Theauthor s also noted a dose- response effect, but wereno t ablet o delineate the shape of the curve. The evidence wasinsufficientl y strong to conclude that the association iso f acausa lnature . Although some studies dono t support the association between alcohol consumption andbreas t cancer (3,43 , 47) other studies do (14, 35, 42). It hasbee n suggested that the risk of breast cancer mayb ehighe r inwome n who havebegu n drinking at alate r age (35). Assessment of theinfluenc e of the agea twhic h alcohol consumption began, the duration of exposure aswel la sth eidentificatio n of plausible mechanisms of actionwoul d clarify the roleo f alcohol consumption inbreas t cancer pathogenesis (20).

12.1.4. Lungcancer

Theobserve d relation between alcohol consumption and lung cancer (39, 40) may largelyb e attributed to thefac t that heavy drinkers often also smokeheavil y (25, 50). 170 Schmidt &Popha m (44) found no difference in lung cancer mortality figures between alcoholics and non-alcoholic veteranswit h similar smokinghabits .A direct influence of alcohol on the genesis of lung cancer isconsidere d tob e unlikely. In another studyi n which patientswit h lung cancer werecompare d to healthy controls thepatient s werefoun d to consume significantly more alcohol (beer in particular) and tob e more likelyt o smoke. When the analysiswa srestricte d to cigarette smokers and adjusted for other variables, beer consumpion remained a significant factor. The authors conclude that the association ofbee r consumption with lung cancer does not appear tob e explained solelyb yconfoundin g bycigarett e smoking (14).

12.1.5. Pancreas cancer

Pancreatitis has often been observed in conjunction with pancreatic cancer. Heavy alcohol consumption isstrongl y associated with pancreatitis. Therefore, itha sbee n suggested that pancreatitis iscausall yrelate d to pancreatic cancer and that alcohol leads topancreati c cancer via pancreatitis. Meanwhile, it hasbee n shown that alcohol mayalte r pancreatic function in various waysno t mediated byalcohol-induce d pancreatitis. A carcinogenic effect seems plausible. An association between alcohol consumption and pancreas cancer could notbee n demonstrated consistently and the available evidencei sinconclusiv e (57). The IARCWorkin g Group concluded that the consumption of alcoholicbeverage si sunlikel yt ob ecausall yrelate d to cancero f thepancrea s (16).

12.1.6. Othertypes ofcancer

Alcohol consumption hasbee n found to beassociate d with stomach cancer (13), rectal cancer (6, 12, 18,50 ) and cancer of the sigmoid colon (12). No relation between prostate cancer (50) and stomach cancer (12, 36, 50) on the one hand and alcohol useo n the other wasobserve d in other studies. The associations between alcohol consumption and rectal cancer observed mayb eattributabl e to an incomplete control for confounding variables such associo-economi c status and dietary practices (18). With regard to theris k of stomach cancer Boeing et al. (2) observed apositiv eassociatio n withbee r consumption and anegativ e association withwin ean d liquor consumption. These associations of alcoholicbeverage swit h stomach cancer mayreflec t aparticula r life-style rather than a causal relationship.

12.2. Differences betweenvariou stype s ofbeverage s

There are several, mainly epidemiological, indications that thevariou s typeso f beverages differ in theirinfluenc e on carcinogenesis. Several epidemiological studies havereveale d arelatio n between theconsumptio n ofbee r and the incidenceo f severalform s of cancer (2, 10, 39,40) ,bu t thisha sno t been confirmed by other investigations (3,36 , 43). In somestudie s cancer of the upper digestive tract has

171 been found tob e associated specifically with the consumption of either spirits or beer. The IARCWorkin g Group concludes that drinking of alcoholicbeverage si s causally related to cancers of the oral cavity, pharynx, larynx, oesophagus andlive r and that therei sn o evidencetha t the effect isdependen t on typeo fbeverage . The IARC Working Group notestha t some epidemiological data aresuggestiv eo fa causal role of alcoholicbeverage s in rectal cancer. Moreover, this role of alcoholic beverages in rectal cancer could often be explainedb ybee r consumption (16). Iti sb y no means certain, however, whether the observed relationship iscausal , i.e . whether beer does actually cause this typeo f cancer. If thisprove s tob e thecase , it should be investigatedwhic h substance present inbee r isresponsibl efo r this effect. The difference between types ofbee r (e.g. dark/light) mayb eo f importance. Thepresenc e of nitrosamines, known tob e carcinogenic, in alcoholicbeverage s willb e discussed in this chapter. Inmaiz ebee r and itsdistillates , aswel la si n calvados,whisk y and somebrand s ofbee r these substances havebee n demonstrated, albeit inmino r quantities. Their presence inwin ean d some distilledbeverage s such asgi n and vodka seems unlikely.

12.3. Mechanisms

Iti sno t clear how the influence of alcoholicbeverage s on thepathogenesi s of cancer of themouth , pharynx, larynx, oesophagus and livermus tb e explained; the beveragesma yb e carcinogenic in themselves, or be active asa cocarcinogen; either ethanol or other additives maycaus e those effects. Indirect effects of alcoholism mayals opla ya part . Regarding carcinogenesisi n sites that are directly exposed to alcoholicbeverages , aloca l effect hasbee n suggested. Thefollowin g mechanisms havebee n mentioned in order to explain the relationship between alcohol consumption and carcinogenesis (8, 24, 46).

12.3.1. Directcarcinogenic effect of alcoholic beverages

One or more of the many congenerswhic h mayb epresen t in alcoholicbeverage si n greater or smaller quantities, mighthav e acarcinogeni c effect. Somesee m to doso , other ones donot . Someo f these substances willb e discussedbelow . -Ethanol. Ethanol itself isunlikel y tob e carcinogenic. Experiments performed to inducecance rwit h ethanol inwell-fe d laboratory animalswithou t liverinjur y have failed sofa r (19). - Fuselalcohols. Fusel alcohols, i.e . the higher alcohols present in all alcoholic beverages invaryin gquantities , contribute to thespecifi c taste and flavour of these beverages. Several animal experiments haveshow n that fusel alcohols (in far greater quantities than usual) arecarcinogeni c (9, 19, 37, 54). - Tannins.O n thebasi s of correlation studies Morton (33) has suggested that the absorption of certain typeso f tannin from sorghum (used inpreparin g kaffir beer) is associated with ahig h incidence of cancer of theoesophagus . The action and activity

172 of different typeso f tannin varywidely . Consequently, itwoul dno t bejustifie d to consider tannins (found in winean d other beverages) ascarcinogenic . - Nitrosamines. Small quantities ofnitrosamines , known tob e carcinogenic, have been found inAfrica n maizebee r and distilledmaiz ebeverage s (29)whil ei n the areaswher e thesebeverage s are consumed, the incidenceo f cancer of the oesophagus ishig h (4, 37). In cider distillates, too, slight quantities of nitrosamines havebee n found. Somesugges t thisa sa possibl e explanation of thefac t that mortalityfro m cancer of theoesophagu s in Francei shighes ti n Normandy and Brittany (54, 55). Whiskyan d sometype so f beer (especially the dark types), contain (as does cigarette smoke (30)) traces of nitrosamines (19, 48, 58)whic h are formed when the malt isroasted . Furthermore, the presence of ethanol seemst o catalyse the production ofnitrosamine s from their constituent compounds, namelynitrite s and secondary amines, under the conditions encountered in the upper gastrointestional tract (38). - Othercongeners or contaminants. Alcoholicbeverage s are extremely complex mixtures inwhic h hundreds of substances mayb epresent . It can byn o means be excluded that one or more of these contribute to carcinogenesis. Mutagenetic investigations have revealed mutagenic activityi n several commercially produced and home-made applebrandie s (27) aswel la si n redwin ean d in red grapejuic e (52). A variety of carcinogens such aspolycycli chydrocarbon s (28) and asbestos fibres (59) havebee n detected in alcoholicbeverages .

12.3.2. Dietarydeficiencies and alcohol abuse

Nutritional deficiencies arever ycommo n in alcoholics. A poor nutritional status seems tob e a riskfacto r for oesophageal cancer (61). Chronic alcohol consumption has striking effects on tissuevitami n A levels (see also Chapter 6). Considering the enhancing effects ofvitami n A deficiency on carcinogenesis, iti sconceivabl etha tpar t ofth e interaction between alcohol and cancer mayb e caused at least indirectlyb yth e alteration ofth evitami n A status induced bychronic alcohol abuse(21) . Deficiencies of some other vitamins (riboflavin, vitaminB-6 , vitaminE ) haveals o been implicated in thepathogenesi s of cancer (24).

12.2.3. HepatitisB virus andhepatocellular carcinoma

Hepatitis Bviru s (HBV) isassociate d with an increased risk of hepatocellular carcinoma (cancer affecting thelive r cells) (22, 41), and alcoholics havea n increased risk of HBVinfectio n (32). HBV-DNAi scapabl e ofintegratin gint o host genomic DNA and thus mayinduc echromosoma l alterations important in hepatic carcinogenesis (11). In addition toth eassociatio n between HBV infection and hepatocellular carcinoma, an association between cirrhosis and hepatocellular carcinoma hasbee n observed (17).

173 | PROCARCINOGEN| 1ETHANOL1 CELL MEMBRANE 1 /fiC TIVATION - INITIATION PROMOTION PROGRESSION / BINDING 1 1 TUMOR ICARC TO DNA.RNA, . CANCER INVASION. \ PROTEINS CELL SPREAD

\ , REPAIR SYSTEM INACTIVATION • SYSTEM "1 | ETHANOL|

ELIMINlATlO N REPAR VTION DESTRUC1riO N |ETHANOL|

Fig. 12.1.Simplifie d scheme of two-step carcinogenesis and possible sites of action of ethanol (46).

12.2.4. Ethanolas a cocarcinogen

There isn o evidencefro m animal studies that ethanol per sei scarcinogeni c (19). However, alcohol mayincreas eth e susceptibility ofvariou stissue s to chemical carcinogens bya variet y of mechanisms (51). Among these are alteration of the metabolism and/or distribution of carcinogens, interfering with the repair of carcinogen-mediated DNA alkylation and theimmun e response, and stimulation of cellular regeneration. Fig. 12.1show s the possible sitesfo r application in carcinogenesis. ' - Alcohol causes changes in thepermeabilit y ofmembrane s ('barrier breaker') (30, 37) which mayincreas eth e diffusion of carcinogenic substances from tobacco smokean d other sources into thecells . - Byactin g asa solven t for carcinogens alcohol mayincreas eit s activity. Poly- cyclicaromati c hydrocarbons, dissolved in alcohol, mayinitiat ecance ri n laboratory animals,wherea s the samequantit y dissolved inwate r doesno t (54). - As apossibl emechanis m MEOS induction hasbee n suggested. Regular alcohol consumption induces themicrosoma l ethanol-oxidizing system (MEOS) in the liver and in theintestin e (seeChapte r 3)whic h isassociate d with anincreas ei n various constituents of proteins of themicrosoma l system, namely phospholipids, cytochromeP-45 0 reductase and cytochromeP-450 « Other substances (such as drugs) are also metabolized via this system. The conversion of procarcinogenic substances into carcinogens in theintestine and/or liverma yals ob e stimulated viainductio n of microsomal enzymes (23,37 , 45). - There aretw o effects of alcohol on DNAmetabolis m that might be associatedwit h cocàrcinogenicactivity , namelyit s effect on sister chromatid exchanges (SCEs) and on DNA repair. Obe &Risto w (37) havereporte d that acetaldehyde, the first metabolite of alcohol, induces an abnormal exchangeo f geneticinformatio n from

174 one sister chromatid to another in cellsgrow n in culture. In addition, they found an elevation of chromosomal aberrations in thelymphocyte s of alcoholics. A second mechanism bywhic h alcohol abusema yincreas e theris ko f developing cancer isb yinhibitin g the capacity of cellst o repair carcinogen-induced DNA damage. Results of animal studies indicate that chronic alcohol consumption inhibits the activity of the DNA repair enzymeO -methylguanine transferase. However, it remains tob e determined whether alcohol alsoinhibit s human O -methylguanine transferase (7). - DNA demethylation mightb e related totumou r development by enhancing gene expression or inhibiting chromatin condensation. Inoue et al. (15) noted that demythylation of exon 2o fth ec-myc gen eo f thehepatocellula r carcinoma is more (albeit not significantly more) frequently encountered in groups ofheav y drinkers. - Sincesevera l studies haveshow n an association between heavy drinking and decreased immune response (34), alcohol-associated immunosuppression has been considered apossibl efacto r contributing to an increased risk of cancer (5). For the most part, however, studies inwhic h decreased immunerespons e has been associated with alcohol abuseinvolve d patients who already had alcoholic liver disease. Therefore, it is difficult to assesswhethe r the immunological defects observed were due directlyt o alcohol or reflected other aspects of the ongoing disease process. There isreaso n to question the significance of immuno­ suppression ingenera l carcinogenesis. Although cancer incidencei shighe r among immunosuppressed patients or animals, the cancers observed aremostl y cancers of theimmun e system itself (1). Nevertheless, theimmun esyste mma ypla ya vital role in the defence against virallyinduce d tumours, particularly in HBV- associated hepatocellular carcinoma (8).

12.3. Safety limits

Considering thefac t that themechanis m through which alcoholicbeverage s promote or initiate carcinogenesis remains largely unknown asyet , asi sth e complexityo f factors which appear toinfluenc e this (e.g. the composition of thebeverag e itself, interaction with tobacco consumption), iti sno t possible to determine a border-line between safe and harmful quantities of alcohol consumption inrelatio n to cancer. Presumably nowel l defined limit canb e established and a continuous increaseo f the riskwit h increasing alcohol consumption appears morelikely , the rateo f increase depending on modifying factors such as typeo fbeverag e and tobacco consumption. Ast o this, everyone shouldweig h enjoyment against risk, asi nman y other mattersi n life. In social alcohol consumption theris khadrl yincreases , or doesno t increasea t all, particularly innon-smokers . Heavy smokerswh o areals oheav y drinkers, particularly drinkers ofspirits , run ahighl yincrease d riskfo r cancer of themouth , throat, larynx and oesophagus. This risk mayb e decreased byrestrictin g either the useo f alcohol, or smokingless ,o r (whichi seve nmor e effective) both.

175 Liver cancer isassociate dwit h liver injury (cirrhosis). Consequently, the quantity of alcohol consumed which initiates cancer of thelive ri s equal to or larger than the quantity that causeslive r injury.

Summary

Therei sa relationshi pbetwee n (excessive) consumption of alcoholicbeverage s and the incidence of cancer of theoral/pharyngea l cavity, the oesophagus, the pharynx and theliver . Therei sprobabl y arelationshi p between alcohol consumption and breast cancer, lungcance r and rectal cancer. Thiscompare swit hth enotio n that not only alcohol, but also other substances (such asthos epresen t in tobacco smoke) play a rolei n thepathogenesi s of cancer of the mouth, throat, oesophagus andlarynx . Theincrease dmortalit y as aconsequenc eo f thesetype so f cancer among alcoholics mayb epartl y attributed to the fact that they often smokeheavily , and possibly also to the fact that they differ from moderate drinkersi n other respects (life-style, (mal)nutrition). Sincemos t caseso flive rcance r occur among cirrhotics;i t appears to be causedb ylive r injury. Theincrease d mortality causedb ylun g cancer among alcoholics mayb e attributed almost entirely to tobacco. Viawha t mechanism the cancer-promoting action of alcoholicbeverage s proceeds isunkown . Presumably there are distinctivemechanism s underlying the pathogenesis of cancer of theliver , and of cancer of the organs and tissueswhic h are in direct contact with alcoholicbeverage s (local effect). Pure ethanol isprobabl y not carcinogenic considering the results obtained in several animal experiments. However, fusel alcohols, nitrosamines and tannins (only certain types) havebee n shown tob ecarcinogenic . Possibly ethanol or another substancepresen t in alcoholic beverages acts as acocarcinogen . Dietary deficiencies, commonly observed in alcoholics, mayals o contribute to carcinogenesis. Infection withhepatiti s Bvirus , impairment, induction ofmicrosoma l enzymestha t activateprocarcinogens , impairment of DNAmetabolism , and immunosuppression mayals o contribute to carcinogenesis. Asye ti tha sno t provedpossibl et o determinelimit sbelo wwhic h alcoholic beverages haven o effect on carcinogenesis. It isals o difficult to differentiate between wine,bee r and spirits, albeitbee r consumption hasbee n associatedwit h the incidenceo f cancer of thecolo n and the rectum. TheIAR CWorkin g Group concludes that drinking of alcoholicbeverage si scausall yrelate d to cancers of the oral cavity, pharynx, larynx, oesophagus and liver and that there isn o evidence that the effect isdependen t on typeo fbeverage . A great deal of research willstil lhav et ob e donet o arrivea tmor e definite conclusions about themechanis m and to develop, on thebasi s of that knowledge, more effective preventivepolicie san d treatment.

176 References

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177 25. de Lint JEE. De invloed van het toenemende alkoholgebruik op het sterftepatroon. Tijdschr Soc Geneeskd 1980;58: 547-51. 26. Longnecker MP, Berlin JA, Orza MJ, ChalmersTC . Ameta-analysi s of alcohol consumption in relation to risk ofbreas t cancer. JAMA 1988;260: 652-6. 27. Loquet C, Toussaint G, LeTalaer JY. Studies on mutagenic consituents of apple brandy and various alcoholicbeverge s collected inWester n France, ahig h incidence area for oesophagal cancer. Mutation Res 1981;88: 155-64. 28. Matsuda Y, Mori K, Hirohata T, Kuratsune M. Carcinogenesis inth e esophagus. III. Polycyclic aramatic hydrocarbons and phenols inwhiskey . Gann 1966;75:549-57 . 29. McGlashan ND. Oesophagal cancer and alcoholic spirits in Central Africa. Gut 1969;10 :643 - 50. 30. McGoy GD, Wynder EL. Etiological and preventive implications in alcohol carcinogenesis. Cancer Res 1979;39: 2844-50. 31. Merletti F, Boffetta P, Cicconne G, Mashberg A, Terracini B. Role of tobacco and alcoholic beverages in the etiology of the oral cavity/oropharynx inTorino , Italy. Cancer Res 1989;49: 4919-24. 32. Mills PR, Pennington TH, Kay P, MacSween RNM, Watkinson G. Hepatitis Bantibod y in alcoholic cirrhosis. J Clin Pathol 1979;32:778-82 . 33. Morton JF. Tentative correlations of plant usage and esophagal cancer zones. Econ Bot 1970;24: 217-26. 34. Mufti SI, Darban HR, Watson RR. Alcohol, cancer and immunomodulation. CRC Crit Rev Oncol/Hematol 1989;9: 243-61. 35. Nasca PC, Baptiste MS, Field NA, et al. An epidemiological case-control study of breast cancer and alcohol consumption. Int J Epidemiol 1990;19 : 532-8. 36. Nomura A, Grove JS, Stemmerman GN, Severson RK. Aprospectiv e study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption. Cancer Res 1990;50: 627-31. 37. Obe G, Ristow H. Mutagenic, carcinogenic and teratogenic effects of alcohol. Mutation Res 1979;65: 229-59. 38. Pignatelli B, Castegnaro M, Walker EA Effects ofgalli c acid and ethanol on formation of nitroso-diethylamine. Lyon: International Agency for Research on Cancer, 1976: 173-8. (IARC Science Publication 14.) 39. Pollack ES, Nomura AMY, Heilbrun LK, Stemmerman GN, Green SB. Prospective study of alcohol consumption and cancer. NEng l J Med 1984;310: 617-21. 40. Potter JD, Sellers TA, Foison A. Beer and lung cancer in older women, the IOWA Women's Health Study. AmJ Epidemiol 1990;132: 784. 41. Qiao ZK, Halliday ML, Rankin JG, Goates RA. Relationship between hepatitis B surface antigen prevalence, per capita alcohol consumption and primary liver cancer death rate in 30 countries. J Clin Epidemiol 1988;41: 787-92. 42. Richardson S, de Vincenzia J, Pujol H, Gerber M. Alcohol consumption in a case-control study ofbreas t cancer in Southern France. Int J Cancer 1989;44: 84-9. 43. Rosenberg L, Palmer JR, Miller DR, Clarke EA, Shapiro S.A case-control study of alcoholic beverage consumption and breast cancer. AmJ Epidemiol 1990;131:6-14 . 44. Schmidt W, Popham RE. The role of drinking and smoking in mortality from cancer and other causes inmal e alcoholics. Cancer 1981;47: 1031-41. 45. Seitz HK, Garro AJ, Lieber CS. Effect of chronic ethanol ingestion on intestinal metabolism and mutagenicity ofbenzo(a)pyrene . Biochem Biophys Res Commun 1978;85:1061-6. 46. Seitz HK, Simanowski UA. Alcohol and carcinogenesis. A

178 51. Swann PF. Effect of ethanol on nitrosamine metabolism and distribution: implications for the role of nitrosamine inhuma n cancer and for the influence of alcohol consumption on cancer incidence. Lyon: International Agency for Research on Cancer, 1984: 501-512.(IARC Science Publications 57.) 52. Tamura G, et al. Fecalase: amode l for activation of dietaryglycoside s to mutagensb y intestinal flora. J Stud Alcohol 1982;42: abstr 307. 53. Turner TB, MacMohan B,Kimbal l AW, Chappel CI. Moderate drinking and the risk of cancer of the oropharynx, larynx, esophagus and liver. Maryland: Alcoholic Beverage Medical Research Foundation, 1989. 54. Tuyns AJ. Cancer and alcoholicbeverages . In: Gastinau CF, Darby WJ, Turner TB, eds. Fermented food beverages in nutrition. NewYork : Academic Press 1979:427-38 . 55. TuynsAJ . Epidemiology of alcohol and cancer. Cancer Res 1979;39:2840-3 . 56. Tuyns AJ, EstèveJ , Raymond L, et al. Cancer of the larynx/hypopharynx, tobacco and alcohol. IARC International case-control study inTuri n and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvadas (France). Int J Cancer 1988;41: 483-91. 57. VelemaJP . Walker AM, Gold EB. Alcohol and pancreatic cancer, insufficient epidemiologic evidence for a causal relationship. Epidemiol Rev 1986;8: 28-41. 58. Webb KS, Gough TA. Human exposure topreforme d environmental N-nitroso compounds in th U.K. J Stud Alcohol 1981;42: abstr 1669. 59. Wehman HJ , Plantholt BA. Astbestos fibrils inbeverage s I. Gin. Bull Envir Contam Toxicol 1974;11:267. 60. Yu MC, Mack T, Hanisch R, Peters RL, Henderson BE, Pike MC. Hepatitis, alcohol consumption, cigarette smoking, and hepatocellular carcinoma in LosAngeles . Cancer Res 1983;43: 6077-8. 61. Ziegler RG, Morris LE, Blot WJ, Pottern LM, Hoover R, Fraumine F. Esophagal cancer amongblac k men inWashingto n DC II. J Natl Cancer Inst 1981;67: 1199-206.

179 ITT

CHAPTER 13 Alcohol and pregnancy

E. te Wierik

Even in antiquity alcohol consumption duringpregnanc y hasbee n associatedwit h the incidence of malformations of the unborn child (45). In ancient Greece the marital couplewa sno t permitted to drink alcohol during theweddin gi n order to prevent abnormal children (44). When spiritswer efirs t introduced in England and alcohol consumption simultaneously increased dramatically (thegi n epidemic, 1720-1750), several types of abnormalities wereobserve d in thechildre n of alcoholics aswel la sincrease d mortality and morbidity (44, 45). An identifiable syndrome observed inbabies.'o f alcoholicmother s was first described 1968. Since 1973 this syndromeha sbee n known asth efoeta l alcohol syndrome (FAS) (28).

13.1. Clinical symptoms

Maternal alcohol consumption duringpregnanc y mayhav ea variet y of effects on the unborn child. Themos t pronounced effect isth efoeta l alcohol syndrome (FAS). To standardize the criteria for FAS theFeta l Alcohol Study Group of the Research Societyo n Alcoholism formulated the criteria for diagnosisi n 1980 asfollow s (5): - pre- and/or postnatal growth retardation (weight, length, and/or head circum­ ference < 10th percentile, when corrected for gestational or postnatal age); - central nervous system involvement (signso f neurologic abnormality, develop­ mental delay or intellectual impairment, e.g. mental retardation); - characteristic facial dysmorphology (at least 2o f 3symptoms) : • microcephaly (head circumference <3r d percentile) • microphthalmia and/or short palpebral fissures • poorly developed philtrum, thin upper lip, and flattening of themaxillar y area. To satisfy a diagnosis of FAS, anindividua l must exhibit an abnormality in eacho f the three categories. In addition to these, abormalities of other organs and systems (cardiovascular, skeletal, genital systems) mayoccu r (56). If onlyon eo r twoo f these characteristics are evident and themothe r issuspecte d of alcohol use during pregnancy, a diagnosis of 'possibleFAS' , 'partial FAS', 'foetal alcohol effects' (FAE) or 'alcohol-related birth defects' mayb emad e (2).

180 13.2. Incidence

In arevie w of 20 relevant epidemiological papers inwhic h atota l of 88 236 births had been evaluated Abel &Soko l (3) observed 164 cases of FAS. Theyconclud e that theworld-wid eincidenc e of theFA Si s 1.9 per 1000births . Incidencerate svar y considerably depending on study site, rangingfro m 0.6 to 2.6 per 1000. Theincidenc e of FASi n children of mothers identified as 'problem drinkers'i s considerably higher. Among alcoholicwome n in theUS Ath eincidenc e ranges from 24t o 42pe r 1000, and in Europe from 66t o 259 per 1000 livebirth s (5).

13.3. Specific foetal alcohol effects

Alcohol use during pregnancy hasbee n associated with anumbe r of specific foetal effects. Since 1973,hundred s of studiesint o the relationship between alcohol and foetal effects havebee n published (1, 30, 47,60) .

13.3.1. Growth retardation '

Birth weight isa n important factor in future development. Reduced birth weighti s one of themor e reliablyobserve d effects associated withi n utero alcohol exposurei n man and animals. In aprospectiv e study in California, involving 5093mother-infan t pairs, it has been observed that frequent consumption ofbee r (> 2 0beers/month ) isa significant determinant in that it decreases intra-uterinegrowt hb y 100g . This effect on birth weightwa sindependen t of the effects of cigarette smoking and caffeine intake, both ofwhic h also appeared to reduceinfan t birth birth weightindependentl y and interactively (31). Barr et al. (9) noticed that maternal alcohol use during early pregnancy was significantly related toinfan t weight and length both at birth and at the ageo f 8months . Maternal alcohol consumption wassignificantl y related to head circumference atbirt h only. Apositiv erelationshi p between heavy drinking and growth retardation hasbee n observed in several other studies (19, 23,32 , 50). The effect of moderate alcohol consumption onfoeta l growth was studiedb y Little et al. (35). Average dailyconsumptio n of 10g alcoho l in thewee kprio r to recognition of pregnancywa srelate d to a decreasei n infant birth weight of 225g . Thisrelationshi p between alcohol consumption andbirt h weightwa sstronge r in male than infemal e infants. Consumption of moretha n 10g pe r day, in early pregnancy, hasbee n found tob e associated with growth retardation in other studies (23,62) . Fried &O'Connel l (19) reportedbot h birth weight andlengt h atbirt h to be negatively correlated with an average alcohol use exceeding 28g pe r day. Mills etal . (40) have demonstrated that drinking an averageo f onet o two drinks per day reduces infant birth weightb y8 3g . In theNetherland s the effect of moderate alcohol use on intra-uterine growth retardation hasbee n studied. This studyinvolve d 3400 pregnant women (mean

181 w

gestation ca. 18weeks )wh ower equestione d about their alcoholconsumption . This consumption wascategorize d into 0, 1-50, 51-120 and > 120g alcoho l per week. Intra-uterinegrowt h retardation didno t occur morefrequentl y in drinking women than in non-drinking women (58). In aprospectiv e study atBosto n City Hospital (46) no differences ingrowt h werefoun d between offspring ofwome nwh ower erar e drinkers (abstaining or drinking lesstha n once amonth ) and offspring of moderate drinkers (mean consumption 8.6 g/day). Walpole et al. (59) alsofaile d to showa significant relationship between light or moderate (< 2 drinks/day ) maternal alcohol consumption and foetal growth. Thegrowt h retardation in offspring of heavily drinkingmother s mayb e reduced when drinkingha sbee n moderated duringth efirs t trimester (15, 50) In conclusion, there appears to exist anegativ erelationshi p between heavy alcohol consumption during earlypregnanc y and foetal growth. Therema yb e adose - response relationship, but iti sno t clear whether there issuc h athin g assaf e drinking during pregnancy.

13.3.2. Effects onthe central nervous system

Infants exposed to alcohol prenatally, evenwhe nthe y dono t suffer from FAS,ma y be athig h riskfo r many of the negative outcomes typicallyfoun d among children of alcoholics including hyperactivity and other behavioural and learning problems. Smith et al. (50) observed that infants ofwome nwh ouse dt o taketw oo r more drinkspe r daythroughou t pregnancy had significantly lower scores on orientation (i.e . theywer eles sabl et o maintain aquie t alert state and attend to thevisua l and auditory stimulii nthei r environment) than infants ofnon-drinkin g women. Infants of women who continued to drink duringpregnanc y scored significantly lower on autonomic regulation than infants ofmother swh o stopped drinking orwh o abstained. Streissguth et al. (51) observed in afollow-u p study that maternal alcohol usedurin gpregnanc y at aleve lo f about four drinkspe r dayo r aboveha sa n adverse effect onmenta l and motor development in their offspring. In aserie s of studies Coles et al. (15) investigated theincidenc e and persistence of central nervous system (CNS)-related behavioural alterations in three groups of infants (n = 103)bor n to (i)thos ewome nwh oneve r drank inpregnancy , (ii)thos ewome n whoha d an averageo f 5drink spe r day, and (iii) thosewome nwh o drank an equivalent amount initiallybu t stopped doing sob yth e second trimester ofpregnancy . The neonates were examined on three separate days. Thosewh oha dbee n exposed to alcoholwer e found tob eles s optimal inneurobehavioura l responses. Infants whosemother s had continued to drink had significantly lower scores on their orientation towards auditory andvisua l stimuli, motor performance and autonomic regulation than the non-exposed infants. Although a secondstud yfoun d that someo f these effects were related to theneonata l withdrawal syndrome, afollow-u p to 30 dayso f age found that therewer epersisten t behavioural alterations. Over thefirs t month, infants in the 'stopped drinking' group showedmor erecover ytha n thosei nth e 'continued drinking' group in reflexive behaviour and autonomic control. Areassessmen t atsi x

182 months of ageamon g 60 of theinfant s indicated that differences in orientation, motor performance, reflexivebehaviou r and autonomic control atthre e dayso f age werepredictiv e of six-month mental and motor performance in the BaylayScale so f Infant Development. Morerecently , in alongitudina l prospective study Streissguth et al. (52) examined thelong-ter m effects of moderate prenatal alcohol exposure. Consumption of two drinkspe r dayo r moreo n theaverag ewa srelate d to a 7-point decrement in intelligence quotient (IQ) in 7-year-old children. Communication skills in children aged 4V i to 9Viyear swit h diagnosed forms of FASwer e assessedb y Becker et al. (10). As compared to the matched non-FAS controls, FAS children demonstrated abnormalities of thespeec h mechanism articulation abilities inconsistent with mental age. Further, theFA Schildre n demonstrated a reduced capacity to process and storecritica l elements ascompare d with non-FAS children. Ioffe &Chernic k (27) reported that thepowe r of an EEG at birth both during REM (rapid eyemovements ) and quiet sleepi sa sensitiv einde x of alcohol effects on thefoeta l brain and mayb e usedt o predict future motor and mental development.

13.3.3.Malformations

Children of alcoholicmother s appeared tohav ea n increased risko f congenital anomalies (23, 25, 42, 48, 61). These defects includecraniofacial , cardiac, renal and skeletal abnormalities (38). O'Connor et al. (42) noticed that an increased incidenceo f anomalieswa s noted in theinfant s of mothers who reported ahighe r alcohol consumption during pregnancy. The data suggest that motherswh ower e used to drink largequantitie so f alcohol, even af they didi tinfrequently , had infants with agreate r proportion of anomalies. This suggestion isconsisten t with thefindin g that social drinkerswh o 'binged' had infants with increased EEG power compared to infants of chronic alcoholics who drank in amor e continuous pattern (26). In astud y into the relationship between moderate drinking during pregnancy and the risk of malformations Mills et al. (41) collected information from 32 870wome n about thefirs t trimester of pregnancy. The authors observed total malformation rates not tob e significantly higher amongoffsprin g ofwome nwh oha d an averageo fles s than one drink per day (77.3 per 1000) or one or two drinkspe r day (83.2pe r 1000) than among non-drinkers (78.1pe r 1000). However, the prevalence of sexorga n malformations and genito-urinary malformations taken together increased significantly with increasing alcohol consumption.

13.4. Mechanisms of action

Themechanism s of action are stillunknown . Thereare , however, various suggestions of thewa yalcoho l can inducefoeta l abnormalities. Thehypothese s relating to the cause of theFA S and other alcohol-induced abnormalities mayb e classified into three categories (38,39) :

183 - direct and indirect mechanisms of action of alcohol - nutrition-related effects of alcohol exposure - cellular mechanisms of alcohol-induced growth retardation.

13.4.1. Directand indirectmechanisms of action ofalcohol

Both alcohol and itsmajo r metabolite, acetaldehyde, readily crossth eplacent a and havebee n shown tob eteratogeni c (29). Becauseth efoetu s lacksth e enzymes required to degradethes e substances, it isexpose dlon g after these substances have been cleared from thematerna l system (29). Both alcohol and acetaldehyde have shown toimpai r nucleic acidan d protein sythesis directlyi nvitr o (16). In particular, the pharmacological effects of ethanol areth e result of cellmembran enarcosis , leading to general depression of cellfunctio n (29).

13.4.2. Nutrition-relatedeffects ofalcohol exposure

A poor nutritional status of themothe r in addition to the toxic effects'óf alcoholma y be more detrimental to the developing foetus than either factor alone. In addition, impairment of placental transport of amino acidsb yalcoho l mayresul t in transient or chronic deprivation of essential amino acids, resultingi n intra-uterine growth retardation, and amplify anytoxi c effects of ethanol on embryogenesis. Reduced placental transfer of zincan dfolat e (18, 20) and an altered vitaminA metabolism (22) hasbee n demonstrated in animal models of alcohol-induced teratogenesis.

13.4.3. Cellularmechanisms of alcohol-induced growth retardation

According toKenned y (29)al lalcohol-relate d developmental abnormalities result from derangements in protein synthesis occurring during periods of rapid organ growth. Thishypothesi s isbase d on threebasi c observations. - Alcohol-related abnormalities includea cluster ofphysica l malformations involving many organ systems,whic h arehighl yvariabl ei n their frequency and severityo f expression. This suggeststha t alcohol isa non-specifi c teratogen that affects some developmental process common toal lcel ltypes . - Themos t common consistent manifestation of gestational alcohol abusei sintra ­ uterine growth impairment (reductions in head circumference, bodylength , body weight). - Normal growth and development are dependent upon the accumulation and organization of protein. Alcohol directly and indirectly impairs protein synthesisi n foetal and adult tissues through reductions in RNA and DNA, aswel la si n total and subcellular processes that arevita lt o foetal growth (29, 39). The current state of our knowledgeo f the interactions of these eventsi s schematized in Fig. 13.1.

184 Fig. 13.1. Relationship between maternai alcohol intoxication and placental nutrient transport deficiencies, protein synthesis inhibition and malnutrition (39).

maternal alcohol intoxication 4 4 (in)direct inhibition reduced placental of protein synthesis protein synthesis infoeta l organs, e.g. and reduced amino brain and liver acid transport 4 4 decrease of ribosomes nutritional deprivation and enzyme activities of foetus 4 4 decreased organ development J 4 growth retardation

13.5. Breast-feeding

Several physicians prescribe onebee r a day to increase lactation for new mothers who aret obreast-fee d theirbabies . Although some experts arei nfavou r with this prescription (17, 21), others are not (7, 12). After birth maternal consumption patterns maystil lhav edetrimenta l effects on thechil dvi abreast-feeding . The alcohol concentration of themil k equals the mother's thebloo d alcohol concentration (33). In caseo fhig h BACs (< 2 g/1 )th e milkyiel d willb e reduced (14). The inhibitory effect of alcohol on milkyiel dma yb e attributable to disruption of transmission of the suckling stimulus (53). Binckiewicz (11) has reported acas eo f thepseudo-Cushin g syndrome (characterized byretarde d linear growth and increased weight) affecting the baby ofa mother who consumed some 2.5 litres of beer a dayi n addition to other alcoholic beverages. Themother' s milk contained 1 g/1 alcohol. Therelatio n between the mother's alcohol use during breast-feeding and theinfant' s development at an age of oneyea r has alsobee n investigated byLittle et al. (37) in astud y covering 400 infants. After correction for alcohol exposuredurin g gestation, motor development was stillsignificantl y lower in infants exposed regularly (1 drink or morepe r day) to alcohol inbreas t milk. No effects on mental development wereobserved . The authors postulated that other environmental factors could havea greate r effect on motor development, and that any effect of alcohol on the infant would not be permanent. However, Lawton (33) claimed that the strong dilution of the alcohol contained in themil kb yth ebaby' sbod yflui d renders thebaby' s resultant blood alcohol level verylow . For example, if amother' s BACi s 1.19g/ 1 (after 7drinks ) her 6-month-old babyweighin g6. 5k gan d drinking 180m lo fmil kwil lhav ea BA Co f approximately 0.06 g/1 (33). It isuncertai n that exposuret o alcohol ofthat magnitude affects the baby.

185 13.6. Paternal alcoholism

Alcohol consumption impairshuma n sperm (57). Badr &Hussai n found chromosome abnormalities amongmal e alcoholics (8). There are onlyfe w scientific data availableo n thefrequentl y assumed relation between paternal alcohol consumption and abnormalities of the child. In animal experiments alcohol administration toth efathe r before conception gaveris et o aprogen y lesser in number, sizean d brain weight (55). However, the findings areno t consistent, which mayb e aconsequenc e of differences in study design (4, 6, 13). Somepreliminar y reports suggest that prolonged paternal exposure to ethanol can result inbehavioura l effects inyoun g rodent offspring (34, 54). Little &Sin g (36) reported a significant negative association between the father's alcohol usei n themont h before conception and theweigh t of their infants at birth. The authors studied 377 newborns and found that thebirt h weight of children of fathers who used to drink regularly (i.e. atleas t two drinkspe r dayo r 5drink s ona singleoccasio n at least once amonth ) was 137 glowe r than that of children of fathers who drank lesstha n that. This result wasindependen t of the mother's drinking, smoking and marijuana use, and could not be ascribed to other factors such asth eparents ' height orweight . Theinfant' s birth weightwa sles swhe n the father drank regularly evenwhe n he did not smoke. Thisfindin g ishar d to interpret because thebiologica l mechanisms that might underliei t are obscure. Other authors do not support theseresult s (49). To explore therol e of parental alcohol consumption in miscarriage 80wome n who had miscarried wereinterviewe d about their own and their partner's drinking habits. Although this method employed for the assessment of alcohol usei sope n to criticism the authors concluded that light maternal (2 drinks or lesspe r week) orpaterna l (4 drinkspe r week'a tmost ) alcohol consumption does not increaseris ko f miscarriage (24). Parazzini et al. (43) also conclude that light maternal andpaterna l alcohol usei sunlikel y to affect abortion rates.

Summary

Consumption oflarg equantitie s of alcohol duringpregnanc y mayinduc eth e foetal alcohol syndrome (FAS), characterizedb ygrowt h disturbances, mental retardation andfacia l abnormalities. Moderatequantitie s of alcoholma yals ob einjurious ; the consumption of 1drin k per dayappear s to reduce sljghtlybirt h weight and mental and motor development. Therema yb e a dose-response relationship between maternal alcohol usean d foetal alcohol-related effects, but therei sn o such thinga sa safe drinkinglevel . Theincidenc e of FASha sbee n assessed at 1.9 per 1000birth s for the total population, but at 66-259 per 1000birth sfo r alcoholicmothers . Themechanis mo f its action isunknow n although there area fe w likelyhypotheses . Alcohol mydirectl y

186 or indirectly inhibit protein synthesis in foetal organs, or reduceplacenta l protein synthesis and amino acidtranspor t both ofwhic h canlea d togrowt h retardation. After birth, maternal consumption maystil lhav eadvers e effects on the childvi a breast-feeding. The effect ofpaterna l alcoholism isobscure .

References

1. Abel EL. Consumption of alcohol during pregnancy, a reviewo f effects ongrowt h and development of offspring. Human Biol 1982;54:421-53 . 2. Abel EL. Prenatal effects of alcohol. Drug Alcohol Depend 1984;14: 1-10. 3. Abel EL, Sokol RJ. Incidence offeta l alcohol syndrome and economic impact of FAS-related anomalies. Drug Alcohol Depend 1987;19:51-79 . 4. Abel EL. Duration ofpaterna l alcohol consumption doesno t influence offspring growth and development. Growth DevelAgin g 1989;53:195-9 . 5. Abel EL, Sokol RJ. Alcohol consumption during pregnancy, the dangers of moderate drinking. In: Goedde HW, Agarwal DP, eds. Alcoholism, biomedical and genetic aspects. New York: Pergamon Press, 1989: 228-37. 6. Abel EL, Bilitzke P. Paternal alcohol exposure, paradoxical effect in mice and rats. Psychopharmacology 1990;100: 159-164. , 7. Auerbach K, SchreiberJR . Beer andth ebreast-feedin g mom. JAMA 1987;258:2126 . 8. Badr FM, Hussain H. Chromosomal aberrations in chronic male alcoholics. Alcohol Clin Exp Res 1982;6: 122-9. 9. Barr HM, Streissguth AP, Martin DC, Herman CS. Infant size at 8month s of age, relationship to maternal use of alcohol, nicotine, and caffeine during pregnancy. Pediatrics 1984;74: 336-41. 10. Becker M, Warr-Leeper GA, Leeper HA. Fetal alcohol syndrome, a description of oral motor, articulatory, short-term memory, grammatical, and semantic abilities. J Commum Disord 1990;23: 97-124. 11. Binkiewicz A, Robinson MJ, Senior B. Pseudo-Cushing syndrome caused byalcoho l in breast milk. J Pediatr 1978;93:965-7 . 12. Blume S. Beer and the breast-feeding mom. JAMA 1987;258:2126 . 13. Cake H, Lenzer I. On effects ofpaterna l ethanol treatment onfeta l outcome. Psychol Rep 1985;57:51-7 . 14. Cobo E, Quintero CA. Milk-ejecting and antidiuretic activities under neurohypophyseal inhibition with alcohol and water overload. AmJ Obstet Gynecol 1969;105:877-87 . 15. Coles CD, Smith IE, Falek A. Prenatal exposure and infant behavior, immediate effects and implications for later development. In: Bean-Bayog M, Stimmel B, eds. Children of alcoholics. New York: The Haworth Press 1987: 87-104. 16. Dreosti E, Ballard FJ, BellingGB , et al.Th e effect of ethanol and acetaldehyde on DNA synthesis ingrowin g cells and on fetal development inth e rat. Alcohol Clin Exp Res 1981;5: 357-62. 17. Falkner F. Beer and the breast-feeding mom. JAMA 1987;258:2126 . 18. Fisher SE. Ethanol, effect onfeta l brain growth and development. In:Tarte r RE, vanThie l DH, eds. Alcohol and thebrain , chronic effects. NewYork : Plenum Press, 1985: 265-81. 19. Fried PA, O'Connell CM. A comparison of the effects of prenatal exposure to tobacco, alcohol, cannabis and caffeine on birth sizean d subsequent growth. Neurotoxicol Teratol 1987;9:79-85 . 20. Ghishan FK, Patwardhan R, Greene HL. Fetal alcohol syndrome, failure ofzin c supplementation to reverse the effect of ethanol on placental transport ofzinc . Pediatr Res 1983;17:529-31. 21. Grossman ER, Calif B. Beer, breast-feeding, and thewishdo m of oldwives .JAM A 1988;259: 1016. 22. Grummer MA, Zachman RD. The effect of maternal ethanol ingestion on fetal vitamin A in the rat. Pediatr Res 1990;28: 186-9.

187 23. Halmesmäki E. Alcohol counseling of 85pregnan t problem drinkers, effect on drinking and fetal outcome. BrJ Obstet Gynaecol 1988;95: 243-7. 24. Halmesmäki E, VälimäkiM , Roine R, Ylikahri R, Ylikorkala O. Maternal and paternal alcohol consumption and miscarriage. BrJ Obstet Gynaecol 1989;96: 188-91. 25. Hollstedt C, Dahlgren L, Rydberg U. Outcome of pregnancy inwome n treated at an alcohol clinic. Acta Psychiatr Scand 1983;67: 236-48. 26. Ioffe S, Chernick V. Development of the EEG between 30 and 40week s ofgestatio n in normal and alcohol-exposed infants. Dev Med Child Neurol 1988;30: 797-807. 27. Ioffe S, Chernick V. Prediction of subsequent motor and mental retardation innewbor n infants exposed to alcohol inuter o bycomputerize d EEG analysis. Neuropediatrics 1990,21: 11-7. 28. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973;ii:999-1001 . 29. Kennedy LA. The pathogenesis of brain abnormalities inth e fetal alcohol syndrome, an integrating hypothesis. Teratology 1984;29:363-8 . 30. Knipschild P. Is alcohol teratogeen? Epidemiologisch onderzoek naar het verband tussen alcoholgebruik in de zwangerschap en aangeboren afwijkingen bij het kind. Tijdschr Soc Gezondheidsz 1985;63:471-6 . 31. Kuzma JW, Sokol RJ. Maternal drinking behavior and decreased intrauterine growth. Alcohol Clin Exp Res 1982;6: 369-402. 32. Larsson G, Bohlin AB, Tunell R. Prospective study of children exposed to variable amountso f alcohol inutero . Arch Dis Child 1985;60: 316-21. 33. Lawton ME. Alcohol inbreas t milk. Aust N Z J Obstet Gynaecol 1985;25: 71-3. 34. LeeJA , Zajac C, Tracy NM et al. Paternal alcoholintak e and offspring behavior inmice . Alcohol Clin Exp Res 1987;11: 204. 35. Little RE, Asker RL, Sampson PD, Renwick JH. Fetal growth and moderate drinking during pregnancy. Am J Epidemiol 1986;123:270-8 . 36. Little RE, Sing CF. Father's drinking and infant's birth weight, report of an association. Teratology 1987;36: 59-65. 37. Little RE, Anderson KW, Ervin CH, Worthington-Roberts B, Clarren SK. Maternal alcohol use durig breast-feeding and infant mental and motor development at oneyear . N Eng J Med 1989;321:425-30. 38. Luke B. The metabolicbasi s of the fetal alcohol syndrome. Int J Fertil 1990;35:333-7 . 39. Michaelis EK, Fetal alcohol exposure, cellular toxicityan d molecular events involved in toxicity. Alcohol Clin Exp Res 1990;14: 819-26. 40. MillsJL , Graubard BA, Harley EE, Rhoads GG, Berendes HW. Maternal alcohol consumption and birth weight, how much drinking inpregnanc y issafe ? JAMA 1984;252: 1875-9. 41. MillsJL , Graubard BI. Ismoderat e drinking during pregnancy associatedwit h an increased risk for malformations? Pediatrics 1987;80: 309-14. 42. O'Connor MJ, Brill NJ, Sigman M. Alcohol use inprimiparou s women elder than 30year so f age, relation to infant development. Pediatrics 1986;78:444-50 . 43. Parazzini F, Bocciolone L, LaVecchi a C, Negri E, Fedele L. Maternal and paternal moderate daily alcohol consumption and unexplained miscarriages. BrJ Obstet Gynaecol 1990;97:618 - 22. 44. Quelette EM. Alcohol inpregnancy ; and its effect on offspring. In: Gastineau CF, Darby WJ, Turner TB, eds. Fermented food beverages in nutrition. NewYork : Academic Press, 1979:439 - 456. 45. Rosett HL. Clinical pharmacology of the fetal alcohol syndrome. In: Majchrowicz E, Noble EP, eds. Biochemistry and pharmacology of ethanol. NewYork : Plenum Press, 1979;2:485-505 . 46. Rosett HL, Weiner L, Lee A, Zuckermann B,Doolin g E, Oppenheimer E. Patterns of alcohol consumption and fetal development. Obstet Gynecol 1983;61: 539-46. 47. Rosett HL, Weiner L. Alcohol and pregnancy, a clinical perpective. Ann RevMe d 1985;36:73 - 80. 48. Rostand A, Kaminski M, Lelong N et al. Alcohol use inpregnancy , craniofacial features, and fetal growth. J Epidemiol Commun Health 1990;44: 302-6. 49. Rubi DH, Leventhal JM, Krasilnikoff PA, Weile B, Berget A. Father's drinking (and smoking) and infant's birth weight. NEn gJ Med 1986;315:1551 . 50. Smith IE, Coles CD, LancasterJ , Fernhoff PM, FalekA . The effect ofvolum e and duration of prenatal ethanol exposure on neonatal physical and behavioral development. Neurobeh Toxicol Teratol 1986;8: 375-81. 51. Streissguth AP, Barr HM, Martin DC, Herman CS.Effect s of maternal alcohol, nicotine, and caffeine use during pregnancy oninfan t mental and motor development at eight months. Alcohol Clin Exp Res 1980;4: 152-64. 52. Streissguth AP, Barr HM, Sampson PD. Moderate prenatal alcohol exposure, effects on child IQ and learning problems at age IViyears . Alcohol Clin Exp Res 1990;14:662-9 . 53. Subramanian MG, Abel EL. Alcohol inhibits suckling-induced prolactin release and milkyield . Alcohol 1988;5:95-8 . 54. Tan S, Zajac CS, Moore C, Rudel D, Zajac C,Abe l EL. Effects of paternal alcohol consumption on behavior of offspring in rats.Alcoho l Clin Exp Res 1987;11: 193. 55. Tanaka H, Suzuki N, Arima M. Experimental studies on the influence of male alcoholism on fetal development. Brain Devel 1982;4: 1-6. 56. TholenJ , Siero S, Kok GJ. Gevolgenva n alcoholgebruik tijdens zwangerschap. Tijdschr Ale Drugs 1988;14:41-9. 57. Välimäki M, Ylikahri R. The effect of alcohol on male and female sexual function. Alcohol Alcoholism 1983;18:313-20 . 58. Verkerk PH, van Noord-Zaadstra BM, Verloove-Vanhorick SP. Alcohol-consumptie tijdens de zwangerschap en foetale groei. Tijdschr SocGenees k 1990;5:26-7 . 59. Walpole I, Zubrick S, Pontré J. Isther e afeta l effect withlo wt o moderate alcohol usebefor e or during pregnancy? J Epidemiol Community Health 1990;44: 297-301. 60. Waterson EJ, Murray-Lyon IM. Preventing alcohol related birth damage, a review. SocSe iMe d 1990;30: 349-64. 61. WrightJT , Toplis PJ. Alcohol and thefetu s in the westo f Scotland. Br MedJ 1983;287:428 . 62. Wright JT, Waterson EJ, Barrison IG, et al. Alcohol consumption, pregnancy andlo w birthweight. Lancet 1983;i:663-5 .

189 CHAPTER 14 Differences between alcoholicbeverage s

W.G. Vrij-Standhardt

14.1. Introduction

Alcoholicbeverage sma yb e classified into three groups:beer , winean d spirits. Beer isbrewe db yfermentin g malted barley and occasionally other cereals to which hops areofte n added in order to improvetast e andkeepin g qualities. There areman y types ofbeer , themos t popular typei n theNetherland s being thepilsene r type. Wine ismad eb yfermentin g grapejuic e (whitewine ) or crushed grapes (redwin e and roséwine) . Sherry and port belong to the category offortifie d wines, i.e . extra winealcoho l hasbee n added. For thepreparatio n of distilledbeverage s (spirits) various sources of starch or sugarma yb eused : cereals andmolasse s (from sugar-beets) for thepreparatio n of gin and Hollands (Hollands gin, geneva);grape sfo r cognacan dbrandy ; barley, maizefo r bourbon; ryefo r whisky;potatoe s (or sometimes cereals) for vodka and aquavit; cherries for kirsch;plum sfo r slivovitz, and soon . When thesuga r has fermented, theliqui d isdistille d- and sometimes dilluted again - usuallyunti l an ethanol1 content of ca. 40%i sachieved . Somebeverage s are aromatizedwit h herbs during or after distillation: gin and Hollandswit hjuniper-berries , aquavitwit hcaraway . Others getthei rflavou r from the rawmateria l (e.g. cognacan d slivovitch). A special group of distilledbeverage s areth eliqueurs . These are ablen do f neutral distilled ethanol, water, sugar and/or other sweeteners, natural (from herbs and spices) or artificial flavouring and colouring agents, and sometimesfrui t juices, cream, eggs, and so on. The classicalliqueur shav ehig h ethanol contents (ca. 40%). Manymodern , liqueur-likebeverages , however, havea n ethanol concentration below 15%. In theNetherland s area lliqueu r legallymus t contain 20%ethano l at least. In the past decade dealcoholized and low-alcohol beverages have increasingly gainedpopularity . Low-alcohol beershav ebee nproduce d sinceman yyears , but a

1I n contrast to other chapters, inwhic hth e terms 'alcohol' and 'ethanol' are used interchangeably, in thischapte r the term 'ethanol' isuse d to discriminate between ethanol and other alcohols.

190 seriouspubli c demand for thesebeer s isa recen t development. Countries varyi n definitions for low-alcohol and alcohol-free beers. InEnglan d alcohol-free beer must contain no moretha n 0.05%v/ vethanol , in Germanyi tmus t haveles stha n 0.5% w/w(ca . 0.6 %v/v) . In the USA alcohol-free beer doesno t exist:a beverag eha s to contain no alcohol tob ecalle d alcohol-free, and at least 0.5%ethano l tob ecalle d beer (55). There aresevera l methods currently usedt o producebeer swit hlo walcoho l contents, which can beclassifie d into twoprocedures :limite dproductio n of alcohol (weakworts , poorlyfermentabl e sugars, specialyeasts , interruption of fermentation, conditionswhic h dono t allowfermentatio n to occur), and removal of alcohol (by steam distillation, distillation at reduced or normal pressure, dialysis, reverseosmosi s and spray-drying) (55). With regard tophysiologica l effects iti sno t necessary, asa rule , to distinguish between different typeso f alcoholicbeverages . Therefore, thestatemen t 'alcohol is alcohol, irrespectiveo f thebeverag ei ti scontaine d in' maysafel yb e used asa starting point. For someaspects , on theothe r hand, iti sno t onlyth equantit yo f alcohol that matters, but alsoit sconcentration , and in thesecase sa distinction has to bemade . Moreover, alcoholicbeverage s areno tjus t mixtures of ethanol andwater , but maycontai n hundreds of substanceswhic h combinet o constitute the natureo fan y particular beverage. Thesesubstances , present in small to minutequantities , may - individually or in combination - exert specific effects on thebod yo r affect the action of ethanol. Differences in typean d quantity ofthes esubstance s areno t onlyfoun d between thethre eclasse so fbeverages , but alsowithi n thesegroups ,whic h makesi tpossible , for instance, to distinguish between wines of different yearso r from different chateaus, and causeswhisk yt o smell and taste differently from cognac. In this chapter thefollowin g topicswil lb e dealtwit h separately: - ethanol - macronutrients (carbohydrates, proteins and fats) - vitamins - minerals and trace elements -congeners (higher alcohols, methanol, esters, etc.). Anumbe r of references willb emad et opreviou s chapters of thisboo k inwhic h the differences betweenwine ,bee r and spiritsconcernin g the effects ofthes e substances havebee n touched on.

14.2. Ethanol

Thequantit y of alcohol contained in one drink doesno t only depend on the alcohol concentration of thebeverag e (6),bu t also on the capacity of the glass (see Table 14.1). If the capacityo fglasse scommonl yuse d in theNetherland s istake n asa

191 Table 14.1. Average ethanol content ofvariou s alcoholicbeverage s inth e Netherlands.

Beverage Alcohol content Capacity ofa Amount of ethanol standard glass (ml) per glass

%v/v %w/ w ml g Beer (pilsener) 5 4 250 12 10 Wine 12 10 100 12 10 Distilled drinks (gin, cognac) 35 28 35 12 10 Sherry/port 18 14 50 9 7 Liqueurs >22 >18 35 s8 ï6 Whisky 44 35 35 15 12

standard (6), aglas so fbeer , wineo r spiritswil l each contain about 10g alcoho l and a glass of sherry or port ca. 7.5 g. Severalles scurren t beverages such asblackcurran t gin (16%alcohol ) contain lesstha n 10g alcoho l per glass. It should be'noted, however, that at home glassesma ysometime s contain more than astandar d glassa s used inrestaurant s and thelik e(12) . Roughly speaking, however, aglas sma yb e considered to contain 10g (ca . 12ml ) alcohol. Asregard s theinternationa l literature, it shouldb etake n into account that both the ethanol concentration ofbeverage s and the actual capacity of astandar d glass may differ from thevalue smentione d above. In Germany a standard glasso f spiritsi s taken to contain 20ml , and astandar d glasso fwin e20 0ml , so aglas so f 'Schnapps' will contain 6g ethano l and aglas s ofwin ecirc a 20g .America n measures also differ from Dutch ones. Atypica l American drink contains 12g ethanol .Th e resultso f epidemiological studies concerning alcohol consumption arehar d to compare because of these differences in ethanol content of standard glasses or units. It has been suggested to express alcohol consumption data in g/day, to increase compatibility of research results(53) . The ethanol concentration of abeverag eonl yplay s arol einasmuc h it comesi n direct contactwit hth ebody . Thisi sth e casei n theuppe r digestivetrac t (mouth, oesophagus, stomach). Beverages with an ethanol concentration in excesso f ca.25 % may causereversibl e damaget o thegastri cmucos a depending on the quantityo f alcohol and the presence of other substances in the stomach, whereas ethanol in beer, winean dlon g drinksi sdilute dt o such a degreetha t thesebeverage s can hardly causemucosa l damage (see Chapter 11). Therei ssom econtrovers y ast o the question whether spirits areassociate d more stronglywit h carcinogenesis of the upper digestivetrac t than areothe r typeso fbeverages . Sincei t isno t knownwhethe r moderate alcohol consumption alsoplay s apar t in carcinogenesis inth egastrointestina l tract, no distinction canb emad ebetwee nwine , beer and spirits,whe n usedmoderately , in relation to (co)carcinogenicity. The concentration of ethanol iso fimportanc e toit sabsorptio n rate (see Chapter 2).Th elevel s of other substances (particularly sugar and carbohydrates),

192 however, also playa par t sincethe y slightly delay absorption. Thebloo d alcohol curveconsequentl y varieswidel yamon gth e different beverages, particularly when ethanol isconsume d on an emptystomach . When iti sconsumed in combination with food these differences largely disappear.

14.3. Macronutrients

Table 14.2 represents the macronutrient composition of anumbe r of (groups of) alcoholicbeverage s derivedfro m the NEVO table (Dutch nutrient database) (6). The data given in this table do not agree entirelywit h other sources. The famous handbook bySouc i et al. (47), for instance, reports that beer doesno t contain carbohydrates whereas theNEV O table mentions theabsenc e of protein. Obviously, the analytical data cannot beconsidere d tob e exactvalue sbu t rather rough approximations. Values for thevitamin , mineral and congener contents should also be seen in this light. Themos t important cause of these divergences isth efac t that there arelarg e differences in composition between several batches of one particular typeo fbeverage . Thecompositio n ofwhisk ydoe s not exist. Possible differences in methods of analysisma yals opartl yaccount fo r thedivergenc ei n results obtained. Wine and beer dono t contain fat. Nor dospirits , except for eggnog and some cream liqueurs (Table 14.2). Beer and winecontai n minutequantitie s of proteins

Table 14.2. Composition of alcoholicbeverage s (expressed per 100g beverage ) according to the Dutch NEVO table (6).

Beverage type Energy Protein Fat Mono- and Poly- Water Alcohol disacch. sacch. kJ g g g g g g Eggnog 1000 4 3 28 0 55 12 Blackcurrant gin 770 0 0 18 0 65 16 Beer (old brown) 126 0 0 2 2 94 2 Beer (pilsener) 184 0 0 2 1 91 4 Brandy 967 0 0 0 0 65 33 Campari 753 0 0 10 0 70 20 Lemon gin 753 0 0 3 0 73 24 Cognac 954 0 0 0 0 68 32 Hollandsgi n 820 0 0 0 0 70 28 Liqueur 1013 0 0 29 0 48 18 Port 628 0 0 13 0 71 14 Rum 967 0 0 0 0 66 33 Sherry 460 0 0 3 0 81 14 Vermouth (sweet) 619 0 0 16 0 71 12 Whisky 1025 0 0 0 0 65 35 Wine (red) 343 0 0 3 0 87 10 Wine (sweet) 690 0 0 22 0 66 11 Wine (white) 410 0 0 7 0 82 10

193 and amino acids (< 0.5%) ; they arecompletel y absentfro m spirits, again except for eggnog. Carbohydrates arepresen t in somebeverage s asmonosaccharide s and disaccharides (sugars):i nbee r (2%),i nwin e (from practically nili n drywin eu p to 22%i n sweet Spanishwine) , andi nliqueur s and (spiced)bitter s (10-30%). Besides, beer contains 1-2% polysaccharides. Theprotein s and carbohydrates in alcoholicbeverage s delayth e absorption of ethanol. The contribution ofprotein s and carbohydrates from alcoholicbeverage s to dailynutritiona l intakei snegligible .

14.4. Vitamins

During their growthyeas t cellsproduc eB vitamins . Immediately after fermentation beer andwin econsequentl y contain considerablequantitie s ofB vitamins . Mosto f thevitamin s areremove dtogethe rwit h theyeas t cellsb yfiltratio n and clarification, sob yth etim ethes ebeverage s areavailabl efo r consumption theycontai n onlymino r amounts ofvitamin s (8). To cover the dailyrecommende d intakeo f riboflavin, 5 litresbee r areneeded , and to satisfy one's vitamin B-6requiremen t one should take at least 1 litre ofwin ea day (54). However, apositiv ecorrelatio n wasfoun d between alcohol consumption (90%o f thealcoho lwa sconsume d asbeer ) and plasma folate and pyridoxin (B-6) levelsi n moderately drinking men (39). Thevitami n Cpresen t in grapes (10-180 mg/kg)i sfoun d in only negligible quantities in thefina l productwin e (0-20 mg/kg)(8) . Distillation reducesth evitami n level evenfurther . As aresult , most distilled beverages contain hardly anyvitamins , exceptfo r someliqueur-lik ebeverage swhic h maycontai n traces of somevitamins . , Thecontributio n of alcoholicbeverage s to dailyvitami n requirement mayb e neglected. That iswh yalcoholi cbeverage s aresometime s saidt o supply 'empty' calories, i.e. merely energy (from ethanol and carbohydrates) and hardly any 'building' substances and 'protecting' substances such asproteins , vitamins and minerals. In caseo f moderate consumption thisusuall y does not causeproblems . Excessiveconsumption , however, maygiv eris et ovitami n deficiency causedb y substitution effects (seeChapte r 6).Alcoholis m isconsidere d themai n causeo f malnutrition in Western societies (seeChapte r 11an d Thomson &Makumda r (51)).

14.5. Minerals and trace elements

Beer and, inparticular , winecontai n awid erang eo f minerals and trace elements (seeTabl e 14.3). Theminera l content ofwin ema yvar ywidel yan di saffecte d by manyvariable s including soiltype , grapevariety , climaticconditions , harvesting practices andprocessin g conditions (decrease duet o clarification, increase through additives). The useo fpesticide s andfertilizer s aswel la saccidenta l contamination duringprocessin gwil lals ocontribut et oth e content ofmetals .

194 Table 14.3. Average contents of some minerals and trace elements inwin e and their contributions to dietary intake. After: Parr (36).1

Mineral or Concentration Dietary intake Proportion of dietary trace element intake providedb y 250 mlwin e per day mg/1 mg/day %w/ w

Boron 5 1.3 96 Copper 0.6 3.5 4 Fluorine 0.3 1.8 4 Iodine 0.15 0.2 19 Iron 10 16 16 Lead 0.2 0.44 11 Potassium 700 3300 5 Magnesium 60 305 5 Manganese 1.5 3.7 10 Phosphorus 150 1400 3 Silicon 20 3.5 143 Tin 0.5 4 3 Zinc 2 13 4

'The contribution to dietary intake is < 1%fo r aluminium, arsenic, bromine, cadmium; chlorine, chromium, cobalt, lithium, molybdenum, nickel, sodium and vanadium.

Becauseth emineral s precipitatei n theresidu e during distillation the distilled drinks dono t contain minerals unless these are added during processing. Theminera l most abundantly occurring inwin ei spotassium , followed by phosphorus, magnesium and calcium. Thepresenc e of somemineral s mayb e regarded asfavourabl e (potassium, calcium, magnesium, iron, chromium and silicium),wherea s thepresenc e of others shouldb e considered ashazardou s (cobalt, lead). The effects of thevariou smineral swil lno t be discussed extensively here. Some minerals that arementione d explicitly in theliteratur ewil lb ebriefl y dealtwith . Copper and zincoccu rnaturall y ingrapes , in certain enzymecomplexes . Their presence inwin e depends on thetyp ean d the pH of the soil, theripenes s of the grape and the general climatic conditions (11). However, thepresenc e of these metals inwin eca n point at residues of insecticides and fungicides; other possible sources areindustria l complexesnearb y thevineyar d and leadfro m exhaust gaseso f motor vehicles. High concentrations of lead (0.12mg/1) , copper (7.21 mg/1), and zinc (16.10 mg/1)hav ebee n found in Spanish 'Oloroso' winesfro m areas nearby highways and acity . In areas more remotefro m these sites concentrations of these metalswer eappreciabl y lower (0.06, 0.65 and 3.40 mg/1,respectively ) (27). Other sources of lead inwin ean dbee r arelead-containin g solder andbronz e and brassfitting s inprocessin g equipment and draught beer installations, aswel la s the leadfoi l caps ofwin ebottle s (29, 45, 46, 52). In aBritis h investigation in 1982/83 into leadi nwin ean dbeer , 90%o fcanne d andbottle dbee r contained 10 |xg/lo rless , whereas almost half the draughtbeer s sampled contained more than 10 u.g/1,an d4 % even moretha n 100 fig/1(mea n 20 u,g/l) (45). As areactio n to theseresults , the lead

195 sources for draught beer wereidentifie d and, wherepracticable , eliminated. A reinvestigation in 1985/86 showed a decreasei nlea d concentration in draught beer (mean 9.8 ug/1) (46). Not a singlebee r contained moretha n 100 ug/1. An investigation ofbottle dwine sshowe d amea n lead concentration of 88u.g/ 1 (range 27-240 u.g/1)(45) . Pouring out lead-capped winewithou t cleaning the necko f thebottl e resulted in amea n valueo f 565 ug/1 (46). In 20%o f the samples the lead concentration exceeded the (British) statutory limitfo r lead inwin e( 1mg/kg) . Thorough cleaning of the neck of lead-capped winebottles , especially ifcorrosio n is visible, decreases thelea d content ofpoure dwin e (29). Smart etal . (46) estimated that consumption of 1 litre ofwin econtainin g 565 ug/1 resultsi n a6 time s greater uptake oflea dtha n theweekl ylea dintak efro m theremainde r ofth e diet (46). Wine drinkers havehighe r blood lead levelstha n drinkers of other types ofbeverage s (10). As apossibl e explanation of the consumption ofpor t being associated with attacks of gout - as assumed in the 18than d 19th centuries - Gastineau et al. (12) suggest lead contamination of thisbeverag ecause db yth elead-containin g soldero f processing equipment. Contamination causedb yth elea d capsules sealing thebottle s mayals o account for this. Daynes (9), on the other hand, supposed - based on his own experience- that agout y attack afflicting individuals susceptiblet oi t mayb e induced byoxidatio n products which are supposed tob egenerate d inpor t exposed to the air for alon gtime . Thepresenc e of silicium and/or chromium inwin ei ssometime s regarded asa possible explanation of the decreased risk of coronary heart diseasei n caseo fwin e consumption, found in several studies (see Chapter 10). Deficiencies of these minerals are associated with theincidenc e of cardiovascular disease. According to Parr (36), 250 mlwin esupplie s ca. 1.5 times the daily silicium intake (see Table 14.3). Beerha spracticall y the samesiliciu m content (10-20 mg/1)(36) . Jennings &Howar d (20) found an average chromium level of 450 ug/1 inwine , 300 u/1i nbeer , and 135 ug/1 in spirits, whileth e dailyrequiremen t hasbee n estimated at 20-500 ug. Parr (36) reports that 250m lwin eaccount s for less than 1% of the mean dailyintak e of chromium. The cardiomyopathy found amongbee r drinkers in Canada wascause db ycobal t salts added to thebee r asa head-retainin g agent (2, 23). Arsenicpoisoning , caused bycontaminatio n of rawmaterials , hasbee n reported byKlatsk y (23).

14.6. Congeners

The rawmaterial s of alcoholicbeverage s (grapes, barley, etc.) are complexmixtures . During thefermentatio n process of alcoholicbeverage s small quantities of anumbe r of compounds aregenerate d in addition to ethanol. Allthes ecompound s - such as methanol, higher alcohols (alcohols with alonge r hydrocarbon chain than ethanol whichcontain s two Catoms) , aldehydes, ketones, phenols, esters, hydrocarbons, lactones, and nitrogenous and sulphurous compounds - are designated as congeners in theEnglis h literature. The German literature uses the term 'Begleitstoffe".

196 Congeners are also referred to as 'Fuselöl', which doesno t alwaysinclud e methanol becausei ti smor evolatil e than ethanol. 'Fuselöl' isindicate d as amixtur eo f substances produced during the distillingprocess , distinguishing itself from the ethanol/water system, which mayinclud ealiphati c alcohols, acids, esters, aldehydes and acetals of higher molecular weightwhic h areforme d during the metabolism of yeast aswel l as thevolatil esubstance s from the rawmaterial s (24). In the latter category fall terpenes and furfural inth e first place. Generally, onlyth e higher alcohols are regarded asfuse l alcohols (German: 'Fuselalkohole'), although the term Fuselöl' isoccasionall y also used in this more restricted sense (24). Sinceth e analysis of minute quantities of substances becamepossibl e through the introduction of gas-liquid chromatography, aprofusio n of literature on the analysis of congeners in alcoholicbeverage s has appeared (1, 40, 42, 44). Several surveys havebee n devoted to this subject (21, 28, 38). Thevariatio n inlevel s of congeners reported in the literature isstriking . Schreier et al. (44), for example, has found marked differences inlevel s of congeners in oneparticula r kind ofwin e (Pinot Noir burgundy) over anumbe r ofyears . Obviously, it does not make much sense to speak ofthe congene r level, or of themethano l level, ofwine . On the other hahd, there are specific differences between types ofbeverage s on thebasi s ofwhic h the genuineness and thepurit y of abeverag ema yb e checked (40). Iti salmos t impossible to examineth e effects of allo f the approximately 400 congeners identified in alcoholicbeverage s (21). Of some substances, particularly ethanol and thefuse l alcohols, somepharmacologica l effects areknow n (15, 19,34 , 35, 41). Congeners are saidt o playa rol ei nhangove r (41), carcinogenesis (33) and allergicreaction s to alcoholicbeverage s (16).

14.6.1. Methanol

All alcoholicbeverage s contain methanol (48), varyingi n concentration from negligible quantities (4-50 mg/1 inbeer ) to sometimes even 14g/ 1 in distilled beverages prepared from fruit such as 'Obstler', 'Williams', 'Kirsch' and 'Zwetschenwasser' (38, 40). Most methanol originates from pectins towhic h iti s bound as an ester; it isrelease d during maceration andfermentatio n of the grapes and fruits. Most other alcoholicbeverage s have ethanol levelsno t exceeding 400mg/ 1 (38, 48). Theletha l dose ofmethano l for someoneweighin g 70k gha sbee n estimated at 30-70 g(4 , 17). The quantity ofmethano l consumed in caseo f moderate alcohol consumption ispresumabl y harmless;whe n pectin-containing fruits and vegetables are digested in thegastrointestina l tract methanol bound to pectin as an esteri s released, which doesno t cause anyproblem s either (17). Methanol poisoning ismainl y characterized by- often fatal - metabolic acidosis and optic nerve damage endingi nblindness . Iti sno t themethano l itself, but its metabolites formaldehyde and formate, which causeth e symptoms of poisoning (48). Theformatio n of thesemetabolite s isinhibite d byth epresenc e of ethanol (applied in 197 the treatment of methanol poisoning), because alcohol dehydrogenase prefers ethanol to methanol. Alcoholics, however, areabl e to oxidizemethano l despitehig h ethanol levels (7). Theformaldehyd e formed ishighl yreactive , forming condensation products with endogenous amines. These condensation products might partly be responsible for addiction and long-term toxicity (7, 48). Methanol poisoning only occurs after the consumption of non-beverage methanol solutions orbeverage swhic h contain largequantitie s of methanol, either owing to mistakes or ignorance or ifillicitl y distilled ethanol hasbee n mixedwit h methanol. Until 1978,methano l poisoningwa sno t uncommon among Swedish alcoholics, who spikedthei r regular drinkswit h cleansing solutions containing up to 80% methanol. Since 1978, onlycleansin g solutions with amaximu m metanol concentration of 5%ar e allowed in Sweden. These solutions are quite popular among alcoholics. No acidosiso r other signso fmethano l poisoning havebee n found in alcoholics who had used these solutions excessively(30) .

14.6.2. Fuselalcohols

Table 14.4 showsth e averagelevel so f higher alcohols andmethano l reported in the literature, expressed as amount of congener (mg)pe r 80g ethano l (about 8glasses) . Not onlyth e occurrence of fusel alcohols in alcoholicbeverage s hasbee n investigated, but also thebiologica l and toxic action of fusel alcohols. Sincethes etw o types of investigations havebee n carried out independently, aconclusio n regarding the effect of fusel alcohols consumed during moderate alcohol consumption can only be drawnwit hgrea t caution. In common alcoholicbeverage s thefuse l alcohol content isharcjl y one tentho f the toxicdose . There are onlyver yfe w useful data availableo n reliable comparative studies relating to the toxicity and side-effects ofbeverage s and theinfluenc e of fusel alcohols on human physiological functions. There isn o substantial difference in pharmacological action between ethanol and the higher alcohols. Differences between various types offuse l alcohols and differences between fusel alcohols and ethanol aremainl y found in the degree and duration of their action (17, 24). According to Prokop (41) fusel alcohols areknow n tob ehighl ytoxi c substances with aspecifi c effect on thenervou s system, which affect abroa d variety of biological functions. Theyhav ea distinct narcotic effect and causeman y objectively and subjectively negativechanges . Compared with ethanol, thenarcoti c effect of n- propanol is3. 9 times greater, n-butanol 14.3,isobutano l 11.7, secondary amyl alcohol 28, and isoamyl alcohol 52times . Fuselalcohols , which arepresen t in quantitiesvaryin gbetwee n 0.1an d 2.0g/ 1- depending on thebas emateria l of the beveragei n question - mayb e associated with thewel lknow nfac t that the effect of ethanol in specific beverages mayoccasionall yincreas eo r change, and unpleasant after-effects willb ebrough t about, usually referred to asa hangover. Thehighe r alcohols areusuall y absorbed and metabolized more slowlyb y alcohol

198 Table 14.4. Some congeners in alcoholicbeverage s (in mgpe r 80g ethanol). After: Piendl et al. (38).

Beverage type Congener1

1 2 3 4 5 6 7 8 9

Pilsener beer 6 21 18 22 72 30 18 0? 37 White wine 54 30 72 34 122 30 52 122 65 Red wine 74 26 58 38 166 41 40 194 110 Obstler 798 204 59 61 141 3 10 40 107 Plum brandy 922 118 70 38 116 2 14 46 166 Gin 16 1 1 0 0 0 1 0 1 Hollands gin 12 6 19 13 25 1 3 0? 2 Brandy 54 38 82 48 237 2 18 12 60 Scotch whisky 9 38 93 29 129 3 7 1 42 Rum 8 53 22 18 135 1 11 0? 41 Vodka 38 0 0 0 0 0? 2 0? 1

'Congeners: 1,methanol ; 2, n-propanol; 3, isobutanol; 4, 2-methylbutanol-l; 5, 3-methylbutanol-l; 6, 2-phenylethanol; 7, acetaldehyde; 8, ethyl lactate; 9, ethyl acetate.

dehydrogenase (ADH) than ethanol because theyar e lesswater-solubl e and more fat- soluble. They are still detectable in thebloo d 14hour s after intake (41). Fusel alcohols are associated with hangovers, delayed reactions, nystagmus (jerky eye movement) and sleepiness (24, 41). It isa sgoo d asunknow n what mechanism underlies thesephenomen a and after what quantities they occur.

14.6.3. Othercongeners

In addition to the 37 alcohols identified invariou salcoholi cbeverages , Kahn (21) reports theoccurrenc eo f 80acids , 118esters , 41carbony l compounds, 17acetals , 41phenols , 11hydrocarbons , and 50 other compounds. Relatively littlei sknow n about the effects of these substances, particularly when they are consumed asa mixture of minute quantities, asi sth e casei n moderate alcohol consumption. A discussion of all thecomponent s of alcoholicbeverage s isbeyon d the scopeo f thisliteratur ereview ;onl y someo fthes ewil lb e discussed. Thehistamine si n somewine sma yaccoun t for somehangove r symptoms (22). Grab (17) mentions that the narcotic effect of esters ishighl y dependent on their fat solubility. As regards the reported changes inbehaviou r and mood following the consumption ofvariou s alcoholicbeverage s (50) it shouldb einvestigate d which substancesbrin g them about. Bourbon contains at least one biologically activephyto-oestroge n (plant-derived oestrogen-like substance) (13, 14, 43).I t hasbee n suggested that the effects of the consumption of alcoholicbeverages , particularly asthe yrelat et o endocrine systems (e.g. feminization), areno t resulting solelyfro m ethanol. Somepeopl e suffer from migraine attacks after consumption of some types of red wine.Althoug h tyraminei sknow nt o causemigraine , the migraine-provoking winei n

199 Littlewood's experiment contained only2 mg/ ltyramin e (26). He suggests phenolic flavanoidsa sresponsibl e substances. Giesemann (16) suggests that migrainemus t be seen asa n allergicreactio n to fungi ('Schimmelpilzen', related to the ones usedi n the production ofbee r andwine . Tannins (tannic acids),belongin g to the group of phenols, arepresen t in (mainly red) winea swel l asi n such products aste a and cocoa. Sometannin s have exhibited measurable inhibitory activity towardsvariou spathogeni c organisms (3,31) . Some scientists (e.g. 18) regard thetannin s from sorghum (used inth e preparation of kaffir beer) ascarcinogeni c (see Chapter 12). However, iti sno tjustifie d to regard the tanninsi nwin ean d tea asbein gcarcinogeni ctoo . Tannin isa collectiv eter m for agrou p of substances each ofwhic h has an entirely different effect. Hydrolysable tannins areno t only distinguished from condensed tannins nowadays, but the (most frequently occurring) condensed tannins differ from each other asregard s activity. Sometannin s provet ob eharmful , other ones are almost or entirely harmless. Condensed tannins from grapepip sprove d not to be toxicwhe n administered up to a doseo f 2%i n thefoo d oflaborator y animals (25). Further investigations into thismatte r areneeded , alsoi nvie wo f the confusing nomenclature in older literature. TheFrenchma n Masquelier (32) reports on hisinvestigation s intoprocyanidin s in wine. Procyanidins are condensation products of 2t o 5flavane-3-ol s (catechins). With moretha n 5flavane-3-ol s themolecul ei sconsidere d to be a tannin. Procyanidins inwin ear esai d tohav equit e somepositiv ephysiologica l effects (e.g. antiviral effects, effects on collagens, cholesterol, free radicals, histamine), acting as an antidote of ethanol. Tom yknowledge , Masquelier's findings haveno t been confirmed byothe r studies into therol e of procyanidins. , Congeners originating from thera wmateria l or thefermentatio n process are not theonl ysubstance s in alcoholicbeverages . In thepresent-da yproductio n of most alcoholicbeverage s various additives areused . Many additives are of a cosmetic nature, used toimprov e the colour orbod y of thebeverage , or are applied to retain the head inbeer . There are at least 60additive s for beer and 20fo r wines (37). Occasionally, additives giveris et o accidents or affairs, liketh e caseo f ethyleneglyco l in Austrian winei n 1984, and thecas eo f cobalt saltsi n Canadian beer in the 1960s. Another group of congeners areth e contaminants: substances which enter the beverages unintentionally during growth orharves t of thefruit s and cereals or during processing. Traces ofpesticides , asbestos, mycotoxins (such asaflatoxin) , arsenic- containing insecticides andfungicide s allhav ebee n demonstrated in alcoholic beverages, particularly inwin e(5a) .

Summary

Alcoholicbeverage s mayb e classified into three main groups:beer , wine (including fortified wine), and distilled drinks (includingliqueur-lik ebeverages) . A recent development isth epopularit y of dealcoholized and low-alcoholwin ean dbeer . In the

200 Netherlands standard glasses ofwine ,bee r and spirits contain ca. 10g ethano l each, except for glasses of sherry and port and someles scurren t beverageswhic h contain a littleles salcohol . The ethanol concentration of abeverag ei so f importancei n relation to damaget o thegastrointestina l mucosa. Besides ethanol andwate r (and sugari n sweetbeverages) , alcoholicbeverage s maycontai n hundreds of other substances which together characterize the beverage in question. These substances canb e classified into macronutrients (carbohydrates and proteins), vitamins, minerals and trace elements, and congeners. Small quantities of carbohydrates, proteins, vitamins and minerals mayb e present in alcoholicbeverages , particularly inwin ean dbeer . They do not contribute significantly to dailynutritiona l intake, possiblywit h the exception of some trace elements (e.g. silicium). However, even thesignificanc e of thecontributio n of solicium remains questinable. Consumption ofwin ean d draught beer can result ina significant intake oflea d (originating from lead capuleso n winebottle s and leadi n processing and tap installations). Congeners can originatefro m the rawmateria l orb eproduce d during fermentation (methanol, higher alcohols, phenols, acids). Other congeners are contaminants (pesticides, asbestos, mycotoxins) or additives (e.g. head-ietaining agents,flavourin g agents, preservatives). Thehighe r alcoholswhic h mayb epresen t in alcoholicbeverages , albeit in minute quantities, havea n effect comparable to that of ethanol, but the intensiveness and the duration of the effects aremor emarked . Higher alcohols haveals o been associated with hangover symptoms. Methanol ispresen t in small quantities inal l alcoholicbeverages , especially in distilled beverages madefro m fruit. In caseo f moderate consumption methanol intake doesno t causeintoxication . Methanol metabolites maypla ya rol ei n the development of addiction. Hardly anything isknow n about the physical effects of the other congeners, least of allo f thosecause db yth emixtur eo fminut equantitie s ofthes esubstance s present in alcoholicbeverages . An integrated approach bychemists , toxicologists and biomedical expertswil lb e needed tob e ableto reach solid conclusions as to the biological activity of congeners in alcoholicbeverages .

References

1. Adam L. Gaschromatographische Bestimmung flüchtiger Inhalsstoffe in alkoholischen Getränken. Dissertation, Technische Universität, München, 1973. 2. Alexander CS. Cobalt-beer cardiomyopathy. Circulation 1970;128(Suppl III):470 . 3. Anonymous. Wine and medical practice: asummary . San Francisco, CA:Win e Institute, 1979. 4. Anonymous. Methanol poisoning. Lancet 1983;i:910-2 . 5. Anonymous. Composition of foods: beverages (raw, processed, prepared). Washington DC: USDA, 1986. (Agriculture Handbook 8-14.) 5a. Anonymous. Chemical composition of alcoholicbeverages , additivesan d contaminants. In: Berrino F, et al. Alcohol drinking. Lyon:WH O International Agencyfo r Research on Cancer, 1988: 71-99. (IARC monographs on the evaluation of carcinogenic riskst o humans 44.)

201 6. Anonymous. NEVO tabel: Nederlands voedingsstoffenbestand 1989/90. The Hague, Netherlands: Voorlichtingsbureau voor de Voeding/Zeist, Netherlands: NEVO Foundation, 1989. 7. Bonte W, Sprung R, Lesch OM. Ethanol-independent elimination of methanol in chronic alcoholics. In: Kuriyama K, Takada A, Ishii H, eds. Biomedical and social aspects of alcohol and alcoholism: proceedings of the Fourth Congress of the International Society for Biomedical Research inAlcoholis m (ISBRA), Kyoto, Japan, 26 June—2Jul y 1988. Amsterdam: Elsevier Science Publishers, 1988:637-40 . 8. Darby WJ. The nutrient contributions of fermented beverages. In: Gastineau CF, Darby WJ, Turner TB, eds. Fermented food beverages in nutrition. NewYork : Academic Press, 1979; 61- 82. 9. Daynes G. Gout and port. Br Med J 1979:669 . 10. Elinder CG, Lind B, Nilsson B, Oskarsson A. Wine: an important source oflea d exposure. Food Addit Contam 1988;5:641-4 . 11. Fernandez C, Martin A. Contenido en elementos metalicos devino s espanoles. Alimentaria 1987;180:75-83. 12. Gastineau CF, Darby WJ, Turner TB, eds. Fermented food beverages innutrition . New York, Academic Press, 1979. 13. Gavaler JS, Rosenblum ER, Thiel DH, et al. Biologically active phytoestrogens are present in bourbon. Alcohol Clin Exp Res 1987;11: 399-406. 14. Gavaler JS, Imhoff AF, Pohl CR, Rosenblum ER, Van Thiel DH. Alcoholicbeverages :a source of estrogenic substances? In: Lindros KO, Ylikahri R, Kiianmaa K, eds. Advances in biomedical alcohol research: third congress of the International Societyfo r Biomedical Research on Alcoholism (ISBRA), Helsinki, Finland, 8—13Jun e 1986. Oxford: Pergamon Press, 1987: 545-9. 15. GibelW , Lohs K, Wildner GP. Experimentelle Untersuchungen zur kanzerogenen Wirkung von Lösungsmitteln am Beispiel von Propanol-1,2-Methylpropanol-1 und 3-Methylbutanol-l. Arch Geschwulstforsch 1975;45: 19-24. 16. Giesemann G. Migräne nach Rotwein. Dt Med Wochenschr 1988;113:1941 . 17. Grab W. Pharmakologische Probleme bei Wein und Spirituosen. Arzneimittelforschung 1961;11:73-79. 18. Heath A. Methanol poisoning. Lancet 1983;i: 1339-40. , 19. Hillbom ME, Franssila K, Forsander OA. Effects of chronic ingestion of some lower aliphatic alcohols in rats. Res Commun Chem Path Pharmacol 1974;9: 177-80. 20. Jennings ME, Howard JMH. Chromium, wine, and ischaemic heart disease. Lancet 1080;ii: 90- 1. 21. Kahn JH. Compounds identified inwhisky , wine, and beer: a tabulation. In: Gastineau CF, Darby WJ, Turner TB, eds. Fermented food beverages innutrition . NewYork : Academic Press, 1979: 505-17. 22. Kalish GH, Kaufman H. Headaches after red wine. Lancet 1981;i: 1263. 23. Klatsky AL. Effects of alcohol on the cardiovascular system. In: Gastineau CF, Darby WJ, Turner TB, eds. Fermented food beverages innutrition . NewYork : Academic Press, 1979: 317- 41. 24. Klausa A. Vorkommen und biologische Wirkung von Fuselöl in alkoholischen Getränken. Giessen, FRG: Institut für Ernährungswissenschaft, 1974. 25. Lang K. Biochemie der Ernährung. Darmstadt, FRG: Dietrich Steinkopf Verlag, 1974. 26. Littlewood JT, Glover V, Davies PTG, Gibb C, SandlerM, Rose FC. Red winea sa cause of migraine. Lancet 1988;i: 558-9. 27. Lopez-Artiguez M, GriloA , Soria L, Castro M, Repetto M. Levels ofzinc , copper, and lead in winesfro m the area south of Seville. Bull Environm Contam Toxicol 1990;45:711-7 . 28. Maarse H, Visscher CA. Volatile compounds infood : Alcoholicbeverages . Qualitative and quantitative data. Zeist, Netherlands:TN O Nutrition and Food Research, 1989. 29. Marks V,Taylo r A. Lead foil onwin ebottles . Lancet 1987;ii: 1473-4. 30. Martensson E, Olofsson U, Heath A. Clinical and metabolic features of ethanol-methanol poisoning in chronic alcoholics. Lancet 1988;i:327-8 . 31. Masquelier J. Vin et santé. Bull Office Int Vin 1979;52:1025-35.

202 32. Masquelier J. Effets physiologiques duvin :s apar t dansl'alcoolisme . Bull Office Int Vin 1988;61:554-78. 33. Morton JF. Tentative correlations ofplan t usage and esophageal cancer zones. Econ Bot 1970;24: 217-26. 34. Murphree HB, Price LM. Cumpter time-series analysis ofth e EEG effects of alcoholic beverages. Fedn Proc 1966;25:503 . 35. Murphree HB, Greenberg LA, Carroll RB. Neuropharmacological effects of substances other than ethanol in alcoholicbeverages . Fedn Proc 1967;26:1468-73 . 36. Parr RM. Silicon, wine and the heart. Lancet 1980;i: 1087. 37. Parratt T. Nameyou r poison!A guid e to additives in drinks. London: Robert Hale, 1990. 38. Piendl A, Geiger E, Hoffmann H. Über das Vorkommen vonÄthano l und alkoholischen Begleitstoffen in Bier, Wein und Spirituosen. Brauwissenschaft 1977;30:33-45 . 39. van Poppel G, Schrijver J, Löwik MRH, Wedel M. Alcoholgebruik envitaminestatu s bij35 - jarige mannen. Voeding 1989;50: 118. 40. Postel W, Drawert F, Adam L. Aromastoffen inBranntweinen . In: Geruch- und Geschmackstoffe. Nürnberg, FRG: Verlag Hans Carl, 1975: 99-111. 41. Prokop L, Machata G. Höhere Alkohole und Äthanolwirkung beim Menschen. Blutalkohol 1974;11:80-7. 42. Reinhard C. Über gaschromatographische Untersuchungen an Brennweinen. Branntweinwirtschaft 1970;110 :334-9 . 43. Rosenblum ER, Van Thiel DH, Campbell IM, Eagon PK, Gavaler JS. Separation and identification ofphytoestrogeni c compounds isolated from bourbon. In: LindrosKO , Ylikahri R, Kiianmaa K, eds. Advances inbiomedica l alcohol research: third congress of the International Societyfo r Biomedical Research on Alcoholism (ISBRA), Helsinki, Finland, 8-13 June 1986. Oxford: Pergamon Press, 1987:551-5 . 44. Schreier P, Drawert F, Abraham KO. Identification and determination ofvolatil e constituents inBurgund y Pinot Noir wines. Lebensmittelwiss u. -technol 1980;13:318-21 . 45. Sherlock JC, Pickford CJ, White GF. Lead in alcoholicbeverages . Food Addit Contam 1986;3: 347-54. 46. Smart GA, Pickford CJ, Sherlock JC. Lead in alcoholicbeverages : a second survey. Food Addit Contam 1990;7:93-9 . 47. Souci SW, Fachmann W, Kraut H. Food composition and nutrition tables 1986/87, 3rd ed. Stuttgart, FRG: Wissenschaftliche Verlagsgesellschaft, 1986. 48. Sprung R, Bonte W, Lesch OM. Methanol: einbishe r verkannter Bestandteil aller alkoholischen Getränke: eine neuebiochemisch e Annäherung an das Problem des chronischen Alkoholismus. Wien KlinWochensch r 1988;100:282-5 . 49. Standhardt WG. Bier, wijn engedestilleerd : verschillen ingebruik , bereiding, samenstelling en lichamelijke effecten. Tijdschr Alcohol Drugs 1983;9: 119-27. 50. Takala M, Pihkanen TA, Markkanen T. The effects of distilled and brewed beverages:A physiological, neurological and psychological study. Helsinki:Finnis h Foundation for Alcohol Studies, 1957. 51. Thomson AD, Makumdar SK The influence of methanol on intestinal absorption and utilization of nutrients. Clin Gastroenterol 1981;10:263-93 . 52. Todhunter EN. A historical perspective onfermentatio n biochemistry and nutrition. In: Gastineau CF, DarbyWJ , Turner TB, eds. Fermented food beveragesi n nutrition. NewYork : Academic Press, 1979:83-98 . 53. Turner C. Howmuc h alcohol isi n a 'standard drink'?:a n analysis of 125studies . BrJ Addict 1990;85: 1171-75. 54. Vrij-Standhardt WG. Alcohol en nutriëntenvoorziening. In: Voeding en alcohol. Alphen aan den Rijn: Samsom Stafleu, 1986: 56-67. (Voeding engezondhei d 7.) 55. Wainwright T. The lowalcoho l revolution. Brew Guardian 1987;116: 16-8.

203 CHAPTER 15 Factors influencing behaviour in relation to alcohol

E. te Wierik

A great deal of attention hasbee n paid to the aetiology of alcoholism. The real causes are stillunknown . It must evenb e questioned whether a specific causewil l everb efound . Various studies havetrie d to provideinsigh t into the factors determining individual behaviour in relation to alcohol. The specific properties of alcohol aswel la sth e individual's physical condition and personality play an important role. Factors influencing behaviour in'relation to alcohol havebee n studied from the viewpoint of various disciplines. Thefollowin g classification can be made (38): - hereditary or constitutional studies, - trait studies, also called 'psychological studies': investigations of the specific character features of the alcoholics, - psychoanalytic studies, reconstructions of the alcoholic's development, - learning theories, - sociocultural studies, . - studies focusing on an interaction model,

15.1. Hereditary or constitutional studies

15.1.1. Familystudies

Thefac t that alcoholism runs infamilie s hasbee n known for centuries. Aristotle, Plutarch ('Ebrii gignunt ebrios', Drunkards beget drunkards), old testament writers, doctors and preachers havecommented on thefamilia l nature of alcoholism. Alcoholism appears to occur morefrequentl y among first-degree relativeso f alcholics (161). Research on this subject hasbee n carried outb yman y (2, 11,114 , 119). It hasbee n estimated that about 40%o f alcoholics havea n alcoholic parent (70). Cotton (33) reviewed 39famil ystudie s doneove r the preceding 40year s that involved atota l of 6251 relatives of alcoholics and 4083 relatives of non-alcoholics. He concluded that an alcoholici smor e likelytha n anon-alcoholi c tohav ea mother, father or more distant relativewh oi sa n alcoholic. More recent studies continued to demonstrate familial aggregation in alcoholism. Guze et al. (59) observed that male relatives of alcoholics had higher rates of alcoholism than had female relatives. On

204 the other hand, the sexo f the proband didno t influence theris ki n hisrelatives . The observed transmission of liability to alcoholism does not fit thepatter n onewoul d expectwhe n itwa st ob eattribute d to a singleautosoma l or sex-linked gene(4) . Penick et al. (117) observed in alarg emulti-centr e study comprising 568 male alcoholics that alcoholics with apositiv efamil y history (65%) had (1) an earlier onset of alcoholism, (2)greate r alcoholic severity, (3) moremedica l and legalproblems , (4) abroade r range of treatments, (5) an increased life-time prevalence of additional psychiatric disorders and (6) agreate r diversity of psychiatric disturbances among biological relatives. In their search for riskfactor s for alcoholism Nagoshi et al. (107) studied 35 subjects who reported to havea n alcoholicparen t or sibling (family history positive (FHP)) andwh ower ematche d with 35 controls (family history negative (FHN)). Theyfoun d significant FHP decrements in cognitive performance prior toingestio n of alcohol. FHP subjects didno t differ from FHN subjects in sensitivity and acute tolerance to alcohol or in perceived intoxication. Despite the fact that family studies support thehypothesi s that alcoholism is transmitted viakinshi p it cannot be established towha t extent genetic or environmental factors contribute to thisphenomenon . Studies among twins and adoptees havebee n carried out in attempts to distinguish between theseaspects .

15.1.2. Twinstudies

Monozygotic twins share all their geneswherea s dizygotictwin s share about 50% of their genes. Over 100year s ago, Francis Galton pointed out that twins provide natural experimental material enabling aseparatio n tob emad ebetwee n the effects of nature and nurture. Thefirs t study of alcoholism among twinswa sreporte d in 1960b yKa y (78). In that study alcoholism in monozygotic twinswa sfoun d to occur twicea sfrequentl y as among dizygotictwin s- afact , according to Kay, clearly pointing to a genetic influence. Twoothe r studies comparing thesimilarit y in monozygotictwin swit h the similarity in dizygotictwin s (58, 67) arrived at opposite conclusions ast o the roleo f genetic factors in alcoholism. Theinfluenc e of heredity of normal drinking habits among non-alcoholic twins hasbee n investigated byPartane n (115), Johnson &Nilso n (74), Loehlin (88), Pederson (116), Kaprio (77) and others. Themajorit y of studies agreetha t there isa substantial genetic effect on many aspects of normal drinking and that environmental influences increasewit h age. The similarityi n drinkingpatter n of monozygotic twins mayb e related to thefrequenc y ofth emutua l social contacts theyhave . To separate the effects of socialinteractio n between monozygotic twinsfro m their genetic similarity, Kaprio et al. (77)performe d astepwis emultipl eregressio n analysis,whic h showed that thegreate r social interaction between identical twinscanno t account for their greater similarity in drinking pattern. The authors concludetha t genetic variancesignificantl y contributes topopulatio n variancei nfrequency , quantity and density of social drinking.

205 15.1.3. Adoption studies

One possibility of separating genetic and environmental factors ist o study children who havebee n adopted bynon-relative s immediately after birth. Adoption studies began with Roe (134)wh o studied children whoha d been placed in institutions before the ageo f 10. No differences in drinking behaviour were found between children with and children without parental history of drinking problems. Roe concluded that alcoholism ispresumabl y not hereditable. The incidence of alcoholism among children of alcoholics hencemus t result from environmental factors. The results of this study havebee n criticizedbecaus e of the limited sizean d agerang e of thegrou p of children studied. The resurgence of the idea that inherited factors mayb eimportan t determinants of alcohol abusestem slargel yfro m studiesperforme d by Goodwin and co-workers in the early 1970s in Denmark (52, 53,54 , 55). Theyinvestigate d alcoholism and drinkingpattern s among adopted children with atleas t oneparen t who had been an alcoholic. Theprevalenc e of alcoholism wasfoun d tob e almost four tim.esa shig h among adopteeswit h an alcoholicnatura l parent asi n the control group of adoptees whosenatura l parents were non-alcoholics (52)..'Furthermore, thelikelihoo d of the sons being alcoholicwa srelate d to theseverit y of parental alcoholism. No environmental factors predisposing to alcohol abusewer eidentifie d in this study. Theincrease d susceptibility to alcoholism in sons raisedb ythei r alcoholic biological parents wasabou t similar to that in their brothers whoha d been raisedb ynon ­ alcoholicfoste r parents (53). For the daughters of alcoholicparent s the findings were quite different (52, 54). Therewa sn o increasei n prevalence of alcoholism compared with adopted-away daughters of non-alcoholic parents. The sisters of the adopted-away daughters of alcoholicswh o remained with their natural parents, however, had ahighe r incidence of depression, emphasizing the unfavourable effects of their remaining at homewit h an alcoholicparen t (54, 55). These results seem, at first glance, to providemos t convincing evidencetha t alcoholism has an important geneticbasi s in men, but not inwomen . The author¬etha t some evidence indicates thatwome n develop alcoholism at alate r agetha n domen , and possibly not allo f thesewome n in their thirties had entered theag eo f riskfo r alcoholism. Support for Goodwin's conclusions camefro m a Swedish study conductedb y Bohman (14) who compared the alcoholism rate among 50mal eadoptee s who had an alcoholicfathe r with that in asimila r group of adopteeswhos efather s had no history of alcoholism. Registrations for alcoholism werethree-fol d higher among the group with alcoholic fathers. When asimila r analysiswa smad e for female adoptees no difference wasfoun d between thosewh oha d an alcoholicbiologica l parent and thosewh o had not. Another adoption studywa sperforme d byCadore t et al. (20) who studied agrou p of 127 male and 87femal e adoptees. Antisocial personality and alcohol abusewer erelate d tobiologica lbackgroun d and to environmental factors. In theme n alcohol abuseincrease d bya backgroun d of problem drinkingamon g first- degreebiologica l relatives andb ydrinkin gproblem s in theadoptiv ehome . An antisocial personality prevailed morefrequentl y in menwhos efirst-degre e biological

206 relatives had antisocial behaviour problems. Among thewome n theprevalenc eo f alcohol abusewa s elevatedwhe n first-degree biological relatives had a drinking problem.

15.1.4. Thesearch for a biological marker

The evidence that alcoholism occursmor efrequentl y amongfirst-degre e relativeso f alcoholics, evenwhe n theserelative s are adopted out ofbirth , and that the concordance ratei shighe r amongmonozygoti c than among dizygotictwins , has prompted asearc h to identify possible genetically influenced factors that might contribute to the riskfo r alcoholism.

15.1.4.1. Electrophysiologicalmarkers of alcoholism Ethanol ingestion has an effect upon the central nervous system (CNS). Two measures of CNSfunctio n are spontaneous brain activitymeasure d bya n electroencephalogram (EEG) and elicited activityvi a evoked potential (EP) orvi a event-related potential (ERP). TheEE G patterns areknow n tob eheritabl e and involveslow-wav e(o r alpha) activity (127). Male alcoholics and their sonshav e shown evidence of significantly decreased slow-waveactivit yo n EEGs (48, 123, 126, 155). Begleiter and hisco-worker s have documented aphenomeno n involvinga positivepolarit y brain wavesee n 300 milliseconds after an external stimulus hasbee n applied. Among alcoholics and their sonsthi sbrai nwave , termed P300, is significantly smaller in amplitude than among controls (7, 40, 108, 124). Begleiter notes that the possiblepredictiv evalu eo f electrophysiological deficits in sonso f alcoholics can onlyb e assesedi nlongitudina l studiesi n which individuals athig h risk and lowris k for alcoholism areteste d regularly over several yearsunti l they pass through theperio d ofmaximu m riskfo r alcoholism (8). Other results suggest that therelationshi p between the P300 ERP and theinheritabilit y of alcoholism isno t veryclea r (121,122) .

15.1.4.2. Biochemicalmarkers Earlyinvestigation s into the relationship between blood group and alcoholism revealed an association ofbloo d group Awit h alcoholism (9, 109), but subsequent studies could not establish anyrelationshi p between ABO system and alcoholism (19,23,65, 131,150) . Another approach to search for geneticfactor s in alcoholism ist o study human lymphocyte antigens (HLA). Themajorit y of studies, however, haveno t focused on alcoholism itself but on alcoholism-related diseases such aslive r cirrhosis, steatosis and pancreatitis. Twostudie s defined alcoholism asth e trait of interest. Robertson et al. (132) could not determine a difference in occurrence of HLA-A and HLA-B locus antigensbetwee n an alcoholicpopulatio n and acontro l population. In another studyHL A patterns of 30 alcoholicswer ecompare d with thoseo f two control groups. HLAB4 0an d HLADR 4 occurred morefrequently , and HLA DR3 less

207 frequently among inalcoholics . Theauthor s concludetha t thesefinding s arei n agreement with thevie wtha t alcoholism hasa geneti c component (31). One ofth emos t cited markersi nalcoho l association studies isplatele t monoamine oxidase (MAO). This enzymei simportan t inth edegradatio n ofbrai n neurotransmitters andhenc ema ypla ya rol ei nth eregulatio n ofmoo dan d behaviour. Theactivit y levelo fthi s enzymei ssai dt ob elo wi nalcoholic s andi nthei r sons (42,91 ,92 ,93 ,112) . Knorring etal . (80, 81)applie d thetw otype so f alcoholism, TypeI an dTyp eII , classified byth eStockhol m adoption study, toa clinical sample. TypeI (milieu-limited) alcoholism wascharacterize d by early onset and fewsocia l complications. TypeI I (male-limited) alcoholism wascharacterize db y early onset andus ean dabus eno tonl yo falcoho lbu tals oo fothe r drugs. Thesetw o typeso falcoholis m couldb edistuinguishe d onth ebasi so fplatele t MAO activity. Platelet MAO activitywa snorma l inTyp eI alcoholic s ascompare d to healthy normals,bu tsignificantl y loweri nth eTyp eI Ialcoholics . Theseresult sar econsisten t with other findings (149). Ina recen t study, however, significant differences in MAO activitybetwee n alcoholics andcontrol s wereobserved , butth eauthors'-wer e unable to reproduce aplatele t MAOactivit y among alcoholics specific forgende ran d subgroup (163). Anincreas ei nMA O activityha sbee n noted upon alcohol withdrawal andabstinenc e (1, 104).I na recen t study, thei nvitr oinhibitio no f monoamine oxidaseb y ethanol wasfoun d tob esignificantl y higher inth eplatelet so f alcoholics (151). In conclusion, alin kbetwee n MAO activityan dgeneti cpredispositio n to alcoholism remains tob e established unequivocally. Another platelet enzymeinvestigate d inrelatio n toalcoholis m isadenylat e cyclase (AC). Tabakoff (151) andWatanab e (157) studiedth eactivit yo fthi s enzymei n alcoholics andi nnon-alcoholi c controls. Nodifferenc e inbasa l activitywa s found, but platelet ACactivit y after stimulation was significantly loweri nalcoholic s andi n alcoholicswh oha dabstaine d for onet ofou r years. Schuckit andGol d (138)evaluate d multiple aspects ofth e reaction totw odose s of alcohol in3 0son so falcoholic san d3 0matche d controls. Astepwis e discriminant analysis showed that thehormone s prolactin (after alo w dose) andCortiso lan dth e subjective feelings after ahig h doseo falcoho l (discomfort, drug high, floating feelings, etc.)classifie d 83%o fth e controls and70 %o fth eson so falcoholic s correctly. These observations suggest that hormonal changes after ados eo f alcohol may servea sa marker . Ina stud yb yGianoulaki s (49)difference s inbot h thebasa l levelsan dth erespons eo fth eCortiso lan dth e/3-endqrphi n systemt oa n acute ethanol dosewer enote d between subjects atlo wan dthos ea thig h riskfo r alcoholism. The direct toxic effects ofalcoho l andalcohol-relate d physical alterations have been attributed to acetaldehyde rather than toalcoho litself . Acetaldehydei sth e first catabolicproduc t ofalcoho l oxidation andi smuc hmor e toxictha n alcoholitself . It hasbee n suggested that theconcentratio n ofacetaldehyde , after drinking an acute doseo falcohol , inth ebloo d ofrelative s ofalcoholic s risest oa significantl y higher leveltha n incontrols , andthi sha sbee n considered anindicato r ofa possibl eris k

208 factor associated with alcoholism (137). But, asth e authors themselves and others (41) emphasize, themetho d ofbloo d acetaldehyde determination goeswit h many problems that can leadt o erroneous values. Another method for the determination of blood acetaldehyde levels didno tyiel d significant differences between alcoholics and their first-degree relatives (156). Alcohol isbroke n down byalcoho l dehydrogenase (ADH) to acetaldehydewhic h ismetabolize d byaldehyd e dehydrogenase (ALDH). Multipleform s (isoenzymes) of ALDH havebee n found in thelive r (61). Afe w years after theidentificatio n of these isoenzymes itwa sfoun d that ALDH2 wasmissin g inmor e than half ofth e Japanese people, whereas Germans appeared to havemor eisoenzyme s (51). Orientalswh o aremissin g this isoenzyme areles slikel ytha n other orientals to drink heavily and appear to have alowe r rate of alcoholism (62). In the absence of this isoenzyme ethanol oxidation results in significantly higher levelso fbloo d acetaldehyde and consquently in a syndrome of facial flushing, tachycardia, sweating and nausea. Recently, the molecular and geneticbasi s ofALDH 2 hasbee n determined. The ALDH2 enzymeha s two alleles (corresponding genes on the samelocu s of two homologous chromosomes) designatedALDH21 andALDH22. TheALDH21 allele encodes information for the activeform , whereasALDH2 2 encodes information for the inactiveform . The activean d inactiveform s of ALDH2 are different due to point mutation. In many cases, one allele encodes information that is dominant over the corresponding allele. In astud y amongJapanes e subjects itwa s observed that allALDH2-activ e liversha d theALDH21/ALDH21 genotype. The ALDH2-deficient livershadALDH2 1/ALDH22 orALDH2 2/ALDH22 genotypes. From these results iti sconclude d that theALDH2 2 allele, theinactiv e allele,i s dominant (34). Li et al. (87) investigated theALDH 2 genotypes of native Taiwanese and of Chineselivin gi n Taiwan. TheALDH2 2 allelewa sfoun d to occur in 50%o f the Chinese and in only 15%o f thenativ eTaiwanese . Themajorit y of Chinese alcoholics haveth eALDH2 '/ALDH21 genotypefo r the activeALD H enzyme. Only a small number of the Chinese alcoholics possessed the other twogenotype s for the inactiveALD H enzyme. These data are consistent with the results obtained in the Japanese study (140). So, onegeneticall y determined enzymeseem s to influence the chance of developing alcoholism among Orientals, thusprovidin g aprotectiv e factor for heavy drinking.

15.1.4.3. DNA research The aim of genetic analysisi st o detect thelocatio n of the defective genean d to discover the nature of themutatio n in theDN A molecule that hasle d to deviation in itsfunction . Three strategies arecommonl y used to typeth egeneti cmarker s (36). Thefirs t and most attractivei sth ecandidate-gen e approach. Numerous candidate geneshav ebee n mentioned someo fwhic h havebee n discussed asbiochemica l markers. A list of candidate genesi n alcoholism ispresente d in Table 15.1. The second strategy isth e so-called 'shot-gun' method (i.e. usinglarg enumber s of DNA probes to cover theentir e genome). Thethir d strategy isth e useo f hypervariable DNAprobe s to look for a closeassociatio nwit h specified DNA sequences. 209 Table 15.1.Candidat e genes in alcoholism (36).

Candidate gene Chromosome References location

Alcohol dehydrogenase 1 4q21-25 142 Alcohol dehydrogenase 2 4q21-25 142 Alcohol dehydrogenase 3 4q21-25 142,11 3 Alcohol dehydrogenase 4 4q21-25 142 Alcohol dehydrogenase 5 4q21-25 142 Aldehyde dehydrogenase 1 9q21 130 Aldehyde dehydrogenase 2 12q24 142 Aldehyde dehydrogenase 3 17 136 Aldehyde dehydrogenase 4 Formaldehyde dehydrogenase 4q21-25 142 Cytochrome P450IIE1 10 97 Fatty acid ethyl ester synthase 36 Esterase D 13ql4 143 Transketolase 36 2,3-butanediol dehydrogenase 36 Monoamine oxidase A Xpll-21 111 Monoamine oxidase B Xpll-21 Propiomelanocortin 2p23. 43 Adenylate cyclase Phospholipase D 105 Arylsulphatase A 22ql3—qter 69 MNS blood group 4q28-31 95 HLA-A,B,C,DR 6p21 118 Dopamine D2 llq22-23 13

However, the latter twostrategie s areno t very useful. Tanna et al. (152) performed alinkag e studyi nwhic h associations between alcoholism and 30polymorphi c marker lociwer e studied in 42families . The authors suggest that alinkag ema y existbetwee n agen efo r alcoholism and the esterase-D locus on chromosome 13q.

15.2. Psychological studies

Alcoholics are supposed to havea typ eo fpersonalit y predisposing them to turn into alcoholics. In other words, alcoholics areassume d to possess acommo n basiso f personal characteristics. Manyhav estudie d therelationshi p between alcohol consumption and personality. Results of someo f these studies are reviewedbelow . Most studies of personality factors bearing on the development of alcoholism are retrospective. Specific traitsfoun d mayconsequentl y both causealcoholis m and result from it (6). Heavy drinking hasbee n related to: -impulsiveness (64, 76, 39), - tendency towardsbein g easilyupse t (60), - lowself-estee m (18, 64, 71,85 , 102, 133, 162),

210 - poor hostility control and lowtoleranc e towards frustration, anxiety and depressive feelings (64, 73, 102), - lowinterpersona l orientation (25), - higher extraversion scores (39, 85, 133) - higher neurotism scores (85, 133) - higher activity and sociability (39), - bored temperament / longingfo r sensation (72, 100) - low docility (100), and - fear of failure (72). It hasbee n observed that TypeA individual s (47), described as exhibiting impatience and achronic sense of timepressure , enhanced competitiveness, aggressive drivean d (often) sometendenc y towards hostility, drink more frequently than doTyp eB individual swh o lack these traits (44). In another study (50) no relationship between TypeA behaviou r and alcohol consumption wasfound . Mayer (96) studied the relation between alcohol involvement and eighteen personality characteristics. The eight characteristics highlyrelate d to alcohol involvement as shown byregressio n analysiswere , in descendant order: social presence, tolerance, achievement via conformance, socialization, flexibility, responsibility, self-control and sense ofwell-being . In astud y of Forsyth and Hundleby the desire to drink amongyoun g adultswa sgreate r in (a)bot h stressful and convivial situations for thosewh o scored higher on neurotism, (b) convivial situations for thosewh o scored higher on depression, and (c)borin g situations for thosewh o scored higher on sensation seeking (45). There are afe w prospective studieswhic h tried to solveth e cause-effect relation. McCord &McCor d (98) followed thepossibl e development of alcoholism amonga group ofboy sfro m deprived families (n= 225) and acontro l group (n= 225) overa period of 18years . In thesegroup s alcoholism manifested in 29 and 22individuals , respectively. Anumbe r of shared personality traits such as aggressiveness, feelings of inferiority and hyperactivitywer efound . Jones (73) studied agrou p of individuals over a30-yea r period, starting at school age. Theresult s of this studyindicat e that alcohol-related behaviour, to some extent, reflects personality traits that were demonstrable evenbefor e the drinking pattern becamemanifest . Thesefinding s were confirmed in astud yb yTarte r et al. (153). Jones (73) found that eventual problem drinkers differed aschildre n from moderate drinkers and non-drinkers by uncontrolled, impulsive and rebellious behaviour. Cloninger et al. (27) observed that novelty seeking, harm avoidance and reward dependencewer e predictive characteristics of later alcohol abuse. Schulsinger et al. (139) used for their studya Danishbirt h cohort. From thecohor t 134son s of alcoholicfather s (high-risk group) and 70matche d controlswithou t parental alcoholism wereselected . When the subjects were about 19year s old thehigh-ris k group wascharacterize d bypoo r verbal ability and impulsivebehaviour . The authors indicatetha t these characteristics may result from paternal psychopathy rather than from alcoholism per se;a follow-up studyha sbee n planned. In a similar study, Sieber &Angs t (141) questioned abirt h cohort of 1577 men at the ageo f 19an d again atth e ageo f 31. Personality, social

211 background and substance usewer e connected with subsequent consumption of alcohol, tobacco and cannabis. Antisocial attitudes, depressiveness and psychosomatic complaints werefoun d tob enon-specifi c indicators. Specific predictors for the level of alcohol usewer eparenta l consumption and self-description as aggressivean d extraverted. In another prospective study, in descendant order, antisocial personality disorder, gender and familial history of alcoholism were found tob e predictors of alcoholism (144). In conclusion, no singlepersonalit y typei scharacteristi c of allalcoholic s although alcoholics share some common characteristics which mayb ealread y present before drinking starts.

15.3. Psychoanalytic studies

Most of thesestudie s arefounde d on Freudian and neo-Freudian theories. According to Freud (46) the pregenital years areth emos t critical in theformatio n of personality structure. In thefirs t fiveyear s of achild' s life thepregenitaf-'(oral , anal and phallic) stages of development arebelieve d tob e experienced. In Freud's theories alcoholics haveneve r passed beyond the oral phaseo f development inwhic h the mouth maintains contact with theworld . Theora l character istake n to refer toa predilection to smoking, eating, drinking and munching sweets. Asa rule , psychoanalists define alcoholism in terms of dependence on a substance, an actitivy or aperso n believed to provide enjoyment on the onehan d and relief of mental pain on the other (12, 24, 89). This dependence of the addict isth e consequence of afailin g development. In Dominicus' model (37) alcoholism issee n as amixe dbifactoria l neurosis, composed of twopersonalit y characteristics: the neurotic primary disorder and the neurotic alcohol hunger component. Thesetw o neurotic characteristics develop according to athree-stag e scheme (Fig. 15.1). In the first stage, thepremorbidit y stage, the primary disorder ismanifest ; the alcohol hunger component isstil llaten t although a disposition to abusei salread y present, which can berecognize d retrospectivily. In this stageth epremorbidi c personality, i.e. neurotic symptoms, is expressed. During the second stage, thehabituatio n stage,a raising alcohol abusebecome s evident. Normal social drinking isalternate d with problem drinking. In the third stage, the depending stage, thehunge r component dominates theprimar y disorder and alcohol abusei sthere . Thesethre e stages canb e preceded bya preliminar y stagewhic h reaches from birth until puberty. In this preliminary stagequestion s of guilt could arise. Alcoholism isconsidere d asubstitut e for an emotionally adult adaptation to living with conflicts. In thiswa yaddiction s protect theindividua l against more serious consequences of hisfailures , such as suicide, psychosis, and antisocial and criminal behaviour (24). Other authors mention unconscious guilt asa caus e of alcoholism and antisocialbehaviou r (99).

212 Developmentalstag eo fth e neurotic personality

neurotic alcohol hunger component (factor2 )

neuroticprimar y disorder Manifestationzon e (factor1 ) (M)

Latencyzon e (L) age

earlystage : premorbidity habituation dependence latency stage stage stage

Fig. 15.1. Development of two personality characteristics in alcoholics, dependent on age (three-stage scheme) (37).

Some analysts relatebehaviou r with respect toalcoho l to unsolved conflicts associated with the relationship with parents inearl yyouth . Thebehaviou r ofth e adult alcoholic issee n asa reflectio n ofwha t isi n fact apathologica l remembranceo f what/who parents wereo ri sbase d on adistorte d image, impressions from childhood and adolescence (12, 24). Oneproble m inherent in this approach isth efrequenc y at which similar personality syndromes maypredispos e towards many other typeso f deviant behaviour such askleptomania , drug addiction and gambling (12).A critica l treatise on this problem hasbee n written byBlu m (12).

15.4. Learning theories

In terms of learning or'reinforcement ' theories, behaviour isdefine d asa stimulus - response action. Learning isth einteractio n between theindividual , the environment and specific stimulii nthi s environment (120). Thewa yreac t tostimul i (e.g. alcohol) invariou s situations changes continuously. Personality traits areimportan t factors. Part ofth e continuous learning process passes through its association with certain 'things'.A nexampl eregardin g alcohol istha t drinkingbehaviou r mayhav e different effects. Ifth erespons e toa certai n stimulus, such asalcohol , provespositive , this 213 behaviour willb ereinforced . This means that if drinking alcohol isexperience d as enjoyable, itwil lb e continued. If the responsei snegative , thisinclinatio n willb eles s strong. In other words, success leads to repetition and theindividua l is conditioned with respect to alcoholb ya positiv erewar d (relaxing or pleasant experiences), orb ya negative effect (ahangove r or aheadache) . Habituation resultingfro m a constantly repeated experience develops in manypeople . The effects become less strong and interest decreases. This mayb e thewa y excessive drinkers grow out of their drinking habits (120). In terms oflearnin g theories alcoholism isregarde d asa conditioned behavioural responsewhic h canb e unlearned byappropriat e modifications of environmental stimuli and reinforcement situations (148). Bandura (5) developed atwo-stag emode l to account for the causeso f alcoholism. He finds thepositiv evalu eo f alcohol to derivedfirs t from central suppression and the stupefying properties of alcohol. Itspharmacologica l effect does infac t alleviate stress situations. Drinking behaviour willb e stimulated becausei ti s followed bya diminishment of theunpleasan t experience. Repeated diminishment of fear, tension, or other disagreeable stimuliwil lresul t in aprogressiv e reinforcement of drinking habits. Onceth ehabi t hasbecom e established, the excesso f alcohol has adverse effects on theindividua l who intur n creates new stimulus conditions in order to continue drinking. Prolonged excessive drinkingwil l eventually cause physiological changes in thebody , resulting in physiological dependence. The idea that alcohol can decrease anxiety datesbac k to antiquity. Kushner etal . (84) conclude that therelationshi p between alcohol problems and anxiety appears to bevariabl e among the anxiety disorders. In agoraphobia and socialphobia , alcohol problems appear morelikel yt o follow from attempts at self-medication of anxiety symptoms, but panic disorder and generalized anxiety disorders mayb emor elikel y to follow from pathological consumption. The main starting point istha t alcoholics start drinking and continue to drinkwhil efeeling s of anxiety,fear , stress and tension exist (10, 75, 86, 103, 146, 147), orwhe n events like 'loss' and 'danger' are present (56). Twopossibl e explanations for drinking under these circumstances may be that intoxicated personsbecom eles ssensitiv et onegativ esocia lfeedbac k by (1) isolating the emotional components aroused bysuc h feedback from its cognitive content, or (2) isolating cognitive elements from other cognitive elements that in the sober state are connected to each other through association (57). Besides thesefeelings , socialvariable s playa n important rolei n the onset of this behaviour (94, 164).

15.5. Socio-cultural studies

15.5.1 Culturalf actors

An explanation of the development of differences in drinkingbehaviou r issough t in the cultural sphere. In countries whereproscriptio n against alcohol use exists alcoholism ispresumabl y morefrequen t than in countrieswher eprescription s for

214 alcohol use are given. Cultures that teach children to drink responsibly, cultures that haveritualize d when andwher e to drink tend to havelowe r rates of alcohol abuse than do cultures that forbid children to drink. Moreover, howa society socializes drunkenness isa simportan t asho wi t socializes drinking. For example, both France and Italy learn their children responsible drinking practices, but public drunkenness ismor e socially acceptable in France than in Italy. This mayb eth e reasonwh y France experiences ahighe r rate of alcohol abuse. The Irish andAmerica n Indian forbid children and adolescents to drink, but theyprais e the capacity of men to drink largeamount s of alcohol. In theseculture s alcohol dependence occurs more frequently (154). In astud y amongAustralian , American and Papua New Guinean students, the majority ofAustralia n and American students had drunk alcohol whileth e majority of Papua New Guinean young peopleha d never drunk alcoholicbeverages . The latter ones gavehighe r ratings of reasons for drinking and emphasized more than the other students that alcoholwa srelate d tofeeling s ofbein g important and to friendship (158). It hasbee n observed that West Germans consume more alcohol than Americans. This mayb e due to the cultural habit of Germans to support the consumption of alcohol (beer in particular) (30). Average consumption measured in Switzerland, Germany and the Netherlands washighes t in Germany followed by Switzerland (79). Caetano (22) reported that U.S. Hispanics who are more acculturated embark morefrequentl y on social events and drink morefrequentl y ina number of social settings than lessacculturate d Hispanics.

15.5.2. Familyrelationships

Family studies show ahighe r prevalence of alcoholism among parents, brothers and sisters of alcoholics than in the entirepopulation . An explanation mayb e the presence of ageneti cfactor . Another explanation istha t thecommunit y transmits culture through a socialization process, aproces s inwhic h parents and other educators play an important role, specifically through the transmission of drinking behaviour and the approval of drinking (63, 110, 145, 160, 165). Wilks& Calla n (159) presented in their study 32 convivial situations and asked parents and their children inwhic h situations they supported drinking. Daughters differed lessi nview s from their parents than did sons. According to the authors differences between parents and their children aret ob e expected asolde r people reduce their number and variety of situations inwhic h they drink, and older peoplema ytherefor e make judgements according to their current drinking practices. On the other hand, similaritiesbetwee n children and their parents mayreflec t earlier socialization experiences and close contact.

15.5.3. Influence ofthe peer group

Whilea n important part ofwha t islearne d isacquire d at an early age, social learning isa continuou s process. Initially learning isrestricte d to arelativel y small (family) 215 circle. Later on, an individual mayparticipat e simultaneously in several other groups, consisting of schoolmates or members of asport s club. New abilities acquired and new attitudes adopted asa participan t in thesegroup s may differ from thosewhic h the family teaches. Themember s of groups mayinfluenc e each other in various spheres, such as education, clothes, drugus e and also alcohol use. Theinfluenc e of the peer group ishel d to beo f particular importance during adolescence and continues thewhol eo f one's life. From teen ageonward s drinkingwil lmor e and more takeplac e awayfro m home and the importance of theinfluenc e of friends parallels this changing situation. An explanation of social drinking behaviour might be socialpressur e exertedb ypeers . Rabow et al. (128) observed that the obligation to servealcoho l on social occasions influences both thefrequenc y of drinking and the amount consumed. In other studies arelationshi p between drinkingbehaviou r and perceived normative support for drinkingha sbee n found (63, 129, 160).

15.5.4. Personalvariables

15.5.4.1. Sexandage Results of astud yi n the USA (83) showtha t morewome n then men are lifelong abstainers, and that abstainers are older than alcohol consumers. This result showsa historical change sincethes eyoun gnon-abstainer s (18-34years ) cannot be lifelong abstainers when they are old. An increasei n heavy drinkingi n theUS A among people aged 21-34 hasbee n observedbefor e (66). Moreyounge r peopletha n older people drink moderately or heavily and moreme n than women drink moderately or heavily (83). Aso astud yi n NewYor k (3) indicated that more men than women drink moderately at least. In that study itwa s also observed that men reduce drinking when they are 50year so r over and that theyounge r one starts drinking, themor ei s consumed inlate r life. Itha s alsobee n noted in Switzerland, Germany and the Netherlands (79) aswel l asi n other studies (17, 32, 135) that alcohol consumption is higher amongme n than amongwome n andhighe r amongyounge r than among older people.

15.5.4.2. Socio-economicstatus (SES) Education and/or profession and/or incomeo f thebreadwinne r isgenerall y taken as an index of social status. Aprofessio n isofte n associated with status or position of authority and mayals o be an indication of income. The income in turn indicatesho w largeth efinancia l means arewhic h are disposablefo r thepurchas e of alcoholic beverages. That ist o say, it ison eo f thefactor s playing arol ei n the availabilityo f alcohol. In the study ofKnupfe r (83) SESwa sbase d onincom ean d education. He observed in both men andwome n that the lower the SES, the higher the proportion of abstainers. So, there arelarge r proportions ofheav y drinkers in thehighe r SES groups. There weren o differences in SESamon g theme nwh ower e frequently drunk. Apositiv eassociatio n between drinking and SESha sbee n observed in other studies (39, 50, 60, 68). Knibbe &Lemmen s (79) found a difference between the 216 sexes:i n Germany, the Netherlands and Switzerland (albeit in thelatte r country the association wasno t significant) women consumed more alcoholwhe n they had received ahighe r education. With the exception of theNetherlands , men witha higher education consumed lessalcoho l than thosewit h alowe r education. Higher alcohol consumption by educated women but not bythei r male counterparts wasals o observed byBraddo n etal . (17). In a Swedish study (135) itwa sfoun d that mean alcohol consumption was roughlyth e sameamon gvariou s socio-economic and educational categories for both sexes.However , amongyoun gpeopl e the proportion of heavy userswa shighe r inbot h sexesamon gworker s and thosewit h alowe r formal education. On the other hand, among older people theproportio n of heavy userswa s generallyhighe r among thosewit h ahighe rforma l education. In addition, Filipino maleswit h alo wincom ewer emos t likelyt ob eheav y drinkers (90).

15.5.4.3. Maritalstate A relationship between singlestat ean d heavy drinking hasbee n noticed in several studies (32, 73, 135). Knibbe& Lemmen s observed that divorced German and Dutch men andwome n havea highe r alcohol consumption than widowed and unmarried people. Thesefinding s arei n agreement with other studies (35, 39, 50). Power &Estaug h (125) performed astud yint o the roleo f marriage and other partnerships and of theformatio n offamilie s on the development of the drinking behaviour ofyoun g adults. Drinkingwa smos t strongly associated with the family formation variables:marita l state, havingchildre n (moderate drinkers) and experiencing thebreaku p ofa partnership (heavy drinkers). Thisfindin g was consistent for both sexes.

15.5.4.4. Religion Studies relating to the differences in drinkingbehaviou r between religious groups showtha t religion playsa par t in thedevelopmen t of drinkingbehaviour . It appears that Protestants and Catholics consume more alcohol than Jews (3, 101). Protestants aremor elikel yt o abstain while Catholics aremor epermissiv e in their attitudes towards drinking (106). Atheists arefoun d to haveth ehighes t alcohol consumption (35, 90). Cosper et al. (32) found that, among other variables, having a religion other than Protestant wasa predicto r of regularity in tavern visit. Irreligiositywa s one of the other predictors. Cochrane &Ba l (29) observed that Sikhslivin gi n Britain weremos t likelyt ob e regular drinkers, followed bywhit eBriton s and Hindus. The veryfe w Muslim men who drank didno t got o themosqu e everywee k and consumed thehighes t amount of alcohol on average.

15.6. Interaction studies

The aetiology of alcoholism isbes t understood within thecontex t of aframewor k that includes more than one factor: a multifactoral interaction model. Cloninger etal . (26) developed amode l that captures theinteractiv e relationship between the earlier

217 hereditary and environmental findings. Studying samples of adoptees they identified two distinct subtypes of alcoholism that are distinguished in terms of distinct alcohol- related symptoms, personality traits, ageso f onset and patterns of inheritance: - TypeI ('milieu-limited') alcoholism ischaracterize d byanxiou s (passive- dependent) personality traits and rapid development of tolerance and dependence on theanti-anxiet y effects of alcohol. Thislead s to losso f control, difficulty in terminating binges, guilt feelings and liver complications following socially encouraged exposuret o alcohol intake. This subtype demonstrates asignifican t gene- environment interaction. - TypeI I ('male-limited') alcoholism ischaracterize d byantisocia l personality traits and apersisten t longing for alcohol for its euphoriant effects. Thislead s to an early onset of inability to abstain entirely, aswel la sfightin g and arrestswhe n drinking. This subtypetend s tob e highlyheritabl e from father to son across different social backgrounds and isassociate d with earlier onset of alcohol problems and criminality in thebiologica l father. In acompanio n study (15) these authors focused on afemal e sample and found, aspredicted , that daughterswit h typeI backgroun d weremor elikel yt ob e alcohol abusers than were daughters of typeI Ifamilies .-Furthermore , theyfoun d that typeI I daughterswer emor e likelyt o haveprominen t somatic complaints as evidencedb y their excessivephysica l complaints and ahig h level of absenteeism. In other words, given the samegeneti cpredisposition , men usually express typeI I alcoholism and women express somatization. Somatization inwome n and typeI I alcoholism inme n are associatedwit h antisocial personality traits (16, 28). In another study thesetw o types of alcoholism were compared to personality traits (82). TypeI I alcoholics had significantly higher scorestha n typeI alcoholic s on somatic anxiety and verbal aggression scales and significantly lower scores on socialization and'inhibition of aggression scales. Furthermore, on theimpulsiv esensation-seekin g psychopathy factor, typeI I alcoholics had significantly higher values. These results indicate that alcoholism accompanied withantisocia l behaviour shouldb e kept separate from alcoholism unrelated to antisocial behaviour. Iti slikel ytha t typeI I alcoholics are similar to alcoholics with antisocialbehaviou r (82). Another model isshow nb yCadore t etal . (20) (Fig. 15.2). Thismode li sbase d on thefinding s in the Lutheran Social Servicedat a and hasbee n verified bya n adoption study donewit h Iowa Children's and Family Services (ICFS). This model showstha t (1)biologica l family alcohol-related problems predict increased alcohol abusei nth e adoptee, (2) biologicalfamil y antisocialbehaviou r predicts increased antisocial personality diagnosisi n theadoptee , and (5) environmental factors of alcohol-related problems in theadoptiv efamil y predict increased adoptee alcohol abuse. Donovan (38) reviewed and critized studiesint o the aetiology of alcoholism and integrated hereditary, environmental andpsychostructura l riskfactor s into the design presented in Fig. 15.3.H e observedfou r guidelinessfo r future research: - alcoholism ismultifactoria l in cause, and studieso f alcoholic aetiology must be truly multifactoral; 218 Alcohol problem in 1st ­ 4.4* Adoptee with ör2nd-degre e relative alcohol abuse (BIOALC12) (ALC)

1.4 10.3****

Y Antisocial behaviour in Adoptee with anti- 1st-degre e relative -»- social personality (BIOASB1) 3.4* (ASP)

Fig. 15.2. Best-fitting four-factor model for ICFSdat a (solid linessho w relationships found by analysis;broke n lines show relationships forced into modelfo r conditioning).P value offi t 0.42. *P<0.05 ; **P< 0.001; ****p<0.00001 . The model isbase d on a sample of 150 adult men. After: Cadoret et al. (20).

PRIMARY RISK FACTORS MEDIATING CONDITIONS EXPRESSION OF ILLNESS

A. Hereditary or Constitutional Factors D. Psychostructural Deficit

1. Male sex 1. Antisocial personality 2. Positive family history 2. Generalized ego weakness Alcohol Dependence 3. Neuropsychological deficit (splitting)

' Alcohol Abuse * 1. Early onset, rapid B. Psychostructural Deficit (?) E. Environmental Variables progression, severe » consequences Blackouts, increased | 2. Later onset, slower 1. Antisocial personality 1. Social class of an adoptive , tolerance, etc. progression 2. Generalized ego weakness father (splitting) 2. Age of placement, if >3. Other course and symptom adopted picture 3. Family interactional C. SocioculturalFactors patterns that maintain disease 1. Ethnic or subcultural group

Fig. 15.3.A n aetiological model of alcoholism (38).

specific groups of patients shouldb e studied separatelybecaus e onema y suspect that different riskfactor s lead to different forms ofillness ; personality variables must bepresente d in continuous versus categorial forms, irrespective of the design; because themorbidit y ofalcoholis m can distort theperceptio n of premorbid factors, research designs shouldb eprospectiv ewheneve r possible.

219 Summary

The study of factors influencing alcohol-related behaviour has been approached from various disciplines. A classification comprising hereditary, psychological, learning, socio-cultural and interactional studies hasbee n made. Heredity studies, mainlyfamily , twin and adoption studies, emphasize the hypothesis that alcoholism istransmitte d via kinship. Based on this evidence a search for abiologica l marker that might bea riskfacto r for developing alcoholism has arisen. Manypotentia l markers havebee n suggested, but one singleris k factor cannot yetb e established. Psychological studies used tob efounde d on thethesi s that alcoholics have specific personal traits in common whichwer ethough t tob ecruciall y important to the development of alcoholism. Formerly, attempts havebee n made to describe the so-called 'alcoholicpersonality' , in other words, a constellation of characteristics and attitudes which together constitute a specific psychological susceptibility to develop alcoholism. In psychoanalytical studies theories about development of alcoholics are presented. Learning theories arebase d on thetheor y that learning isa n interaction between the individual, the environment and specific stimuli in this environment (such as alcohol). According these theories alcoholics start drinkingbecaus ealcoho l can decreasenegativ e emotions. Socio-cultural investigations into drinkingbehaviou r focus on variousproblems , such as drinking patterns and alcohol consumption, the development of problem drinking and alcoholism among various cultural, ethnic, social and fegional groups. Thesetheorie s refer tofamily , religion and demographicvariable s such as age, sex, social status, marital statean d ethnicity. Finally, interaction studies, which tryt o includemor e than onefacto r in one model - multifactoral interaction models - are described.

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227 CHAPTER 16 Alcohol and traffic

E. te Wierik

Accidents are the third main cause of death in Europe 40%o fwhic h areroa d traffic accidents. One quarter of these deaths and 10%o f theinjurie s are associated with alcohol (55). In 1989, 11.2%o f fatal road traffic accidents and 6.5%o f road accidents leading to injuries in theNetherland s were associatedwit h the useo f alcohol (9). Although alcohol playsa role in many traffic accidents it isno t sureho w many of these accidents would not havehappene d if the driver had not drunk. Drivers can probably be roughly classified into two categories: alarg e group consisting of thosewh o dono t drink, or drink verylittle , before drivingan d a smaller one comprising thosewh o regularly drink no matter whether theyinten d to drive. Theforme r category can dowithou t drinks, the latter onecannot . Various legislative measures with respect to the drinking-drivingproble m havebee n introduced. These measures canb e divided into primary, secondary and tertiary prevention (12). Primarypreventio n strategies targetyoun g driverswit h thegoa l ofpreventin g the initiation of drinking-driving behaviour. Secondary prevention aims at the driving population asa whol e and is founded on principles of general deterrence. Tertiary prevention focuses on convicted DWI (driving whileintoxicated ) offenders with the goal of reducing recidivism.

16.1. Motives for drinkingbefor e driving

Before starting measures to tackle the drinking-driving problem, moreinsigh t into themotive sfo r drinking and driving after drinkingi sneeded . Among the reasons to drink driversma yhav e are: stress, worries, problems, need for comfort in social events and courage for tough situations, 'can't refuse' buddies, andboredom . These reasons for drinkingfor m patterns related to psychological adjustment (46). Beck (5) noted that, as compared tonon-drivin g drinking students, drunk driving students tended lesst o drink alcohol in,their ownhome , but more to drink iti n a dormitory. Themos t important drinking reasons for drunk driving studentswere : to get along better on dates, to get high, toge t drunk, and tog o to sleep. In aDW I offender sample, Snow &Wells-Parke r (45) regressed four drinking reasons on alcohol consumption levelsan dfrequenc y of drinking in seven typeso f locations. 'Escapism' reasons arerelate d to quantity consumed per occasion, but are onlyweakl y associatedwit h specific locations. 'Sociability' reasons are associatedwit h drinking infriends ' home, but areno t related to high consumption levels. Drinking 'for pleasure', 'to meet people of theopposit e sex', and 'to get

228 drunk' reasons are associated withbot h quantity consumed per occasion and away- from-home locations. Thissuggest sa hig h traffic accident risk. The authors noted that opposite sex/drunkenness reasons aremos t important amongyoun g DWI offenders, and declinesharpl yi nimportanc eafte r theag eo f 25. Therefore, the authors recommend age-specific countermeasures rather than global strategies. Rosenberg (38)interviewe d 29person swh ower e drinkingregularl ybu t who reportedly didno t driveunde r theinfluenc e on 75% of drinking occasions and had neverbee n convicted for DWI. Themos t frequently reported typeso f reasons for drivingafte r drinkingwere : - lacko f perceived intoxication, - perceived need or desire to gohom eo r to someothe r location, often despite intoxication, - geographical convenience ('I wasi n themiddle o f nowhere, if Ira n off the road into amaiz efield , nobi gloss') , - confidence in driving ability (e.g. Tfel t most fit to driveo f thegroup') . The most frequently reported strategies to avoid detection/arrest when driving after drinkingwere : - change of drivingbehaviou r (e.g. drivingslower , takingmino r streets,bein g careful of speed limits, keeping an eyei n themirror) , - enhanced concentration and awareness (e.g. keeping alert, payingmor e attention, 'makemysel f conscious ofwha t I'm doing'), - self-talk (e.g. telling oneself 'you havet o shake off the effect'), - playing the radio, opening the carwindow , and talking/singing out loud (38).

16.2. Primary prevention

Young drivers represent apopulatio n at particular risk for accidents. Deaths and injuries due to road-crash involvement area majo r health and safety problem, especially among theyouth . Jonah (23), for example, noted that young people between the ageso f 16an d 24represente d about 17%o f the Canadian population and 21% of the licenced drivers. However, this agegrou p accounted for 52%o fal l driverfatalities , for 31% of alltraffi c fatalities, and for 33% of alltraffi c injuries. Young people who driveafte r drinking havea greate rrisk o f crash involvement than older drinking drivers at allbloo d alcohol concentrations (BACs). One explanation of this finding assumes thatyoun gpeopl e areinexperience d both with drinking and with driving. There isals o evidencei nfavou r of an alternative hypothesis, namely, that the higher crash risk amongyoun g drinking driversi sattributabl e to asubse t of thisgrou p- thosewh o engagei n riskydrivin gbehaviou r andwh o also happen to use alcohol (30). However, young peoplewh o do driveafte r drinking havea higher relative risk of total and fatal accident involvement than older drinking drivers (30). Young male drivers appear to havea highe r risk than adolescent female drivers. Women seem tob emor e realistican d perhaps moreresponsibl e in the assessment of a dangerous drinking-driving situation (15).

229 Given thehig h relativeris k of accidents among theyoun g drivingpopulation , this group hasbecom e thefocu s of primary prevention strategies.

16.2.1. Education

Most educational programmes aimed at tackling the drinking-driving problem are school-based programmes. Theseprogramme s depart from the assumption that an increasei n knowledge of the consequences of drinking and drivingwil lresul t ina reduction of alcohol use, achang eo f drinking-drivingbehaviour , and areductio n of alcohol-related accidents (13) The effectiveness of aTeams-Games-Tournamen t (TGT) alcohol education programmeha sbee n demonstrated byWodarsk i (54). Two-yea r follow-up data indicated apermanen t changeo f attitude towards drinking and drivingafte r the TGT alcohol education programme. In his dissertation Kayser (24) evaluated an education programme offered byDutc h driving schools. Theprogramm einclude d a course book, slides, video tapes and amanual . Theprogramm e appeared to havea positive effect on knowledge, attitude and intended behaviour. With regard to self-reported driving after alcohol consumption no differences were observedbetwee n thetw o groups oneyea r after completion of theprogramme . However, lessca r driversi n the experimental group drovewit h an assessed BAChighe r than the legallimi t of 0.5 g/1. Morepeopl ewh oparticipate d in the experimental group refused tob e drivenb ya person who had consumed alcohol. In the Netherlands apublicit y campaign focused on the combination of drinking and drivingi sconducte d by 'Veilig Verkeer Nederland' (Dutch Road Safety Board). The evaluation of this campaign consistso f the analysis of theresult s of aquestionair e distributed amongyoung.mal e drivers aged 18-25. The results shown o significant differences in number of non-drinking drivers, attitude, intention and normativebelief s towards drinking and driving. However, thenumbe r of glasses drunkbefor e drivingha s decreased after the campaign. The decreasei nBA Ci n driverswh oha d drunk wasalread y observedi n breath analyses (47). Mann et al. (29) havereviewe d school-based programmes aimeda tpreventio n of drinkingi n combination with driving. Themos t consistent finding istha t that such programmes broaden theknowledg e and understanding of alcohol and its effects aswel la sth e riskso f drinking combined with driving. An impact on attitudes concerning thisbehaviou r has alsobee n noted. Virtually no studies have evaluated theimpac t of education programmes on traffic safety measures. In the absence of an assessment of theseva/iable si ti sdifficul t to determine the relative effectiveness ofprogramme s with respect to their.primary goal, namely, theimprovemen t of traffic safety. A public education campaign against drinking-driving directed towards 18-24- year-old Australian men hasbee n evaluatedb yRezni k et al. (37). The authors arrived at the conclusion that thenumbe r of road traffic accidents inWollongon g fell significantly in the three-month period following thecampaig n ascompare d to other regions in New South Wales.

230 16.2.2. Increasingminimum purchaseage

Another method to prevent drinking and drivingamon gyoun g peoplei st o decrease the availability of alcohol bylegislativel y regulating the agea twhic h it can be purchased. Asmentione d in Chapter 17,i n recent times, manyAmerica n states have changed the minimum legal purchase age(MLPA) , with 29 states reducing thelega l agebetwee n 1970 and 1975 (53), 24o fwhic h raised the MPLA again within thenex t decade (7). In 1988,Wyomin gbecam eth elas t statet o repeal aMLP Ao f 18, thus making the MLPA of 21unifor m throughout the country. Thelega l riseo f the MLPAt o theag eo f 21i n theUS Awa sprimaril ybase d on studies relativet o car accidents and fatalities inwhic hyouthfu l driverswer einvolved . Trends indicate that loweringth eMLP Aincrease s alcohol-related accidents and fatalities, whileraisin g thelega l ageaccomplishe s the opposite in the affected agegroup s (4, 27). Reductions in fatal crash involvement asa consequenc e of raisingth e MLPA has been reported in other studies (2, 33,51) . An alternative viewsuggest s that the dangers of drinking and driving^are increased not bya driver's youth per se,bu t byth eyoun d driver's lack of experience both with drinking andwit h driving (3). In an examination of the long-term effects of raising theMLP A on fatal crashes itha sbee n concluded that: - aMLP A isassociate d with an increase of 5%o n averagei nfata l crashes involving driversi n their first year after theyreac h thepurchas eage ; - when a stateraise s itsMLPA , therei sa corresponding , and unequal, shift in increased fatal crashes from a lowert o a higher agegroup ; - states that didno t raisethei r MLPA expierenced aslightl y larger decreasei n fatal crashes among drivers under 21a scompare d to those states that did raisethei r MLPA (28). Du Mouchel et al. (33) also determined whether thefirs t year of legal purchase agewa sespeciall y hazardous. The authors observed a 'negligible' effect, viz. a2 % increase of fatal crashes among beginning drinkers. If reductions in alcohol consumption and motor vehicleaccident s amongyoun g people are desired, both aMLP A of 21an d an increasei npric e of alcoholic beverages are suggested (11).

16.2.3. Loweringthe maximum allowableBAC for trafficparticipants

A closerelationshi p appears to existbetwee n theheigh t ofth e BACo n onehan d and drivingperformanc e (16, 32) and theprevalenc e of traffic accidents (42) on the other. Moskowitz &Robinso n (32) havereviewe d 41finding s of alcohol effects on drivingperformance , including 27finding s resultingfro m simulator studies. Results suggest that aBA Ca slo wa s 0.3 g/1 can significantly impair the driver's performance; BACs of 0.8g/ 1 or lesshav eshow n to lower accuracy of steering, braking, speed control, lanetrackin g and gear changing, and alsojudgement s of 231 speed and distance in the driving situation. Smith (42) reported that lowering the legal BACfro m 0.8t o 0.5g/ 1 in New South Walesha d abeneficia l effect on the casualty accident involvement of 17-20-year-old male drivers. Afe wyear s later he reported that areductio n of thelega lBA Ci n several states ofAustrali a had significantly reduced casualty accidents for drivers andmotorcyclist s (43,44) . Although the relationship between alcohol and road safety hasbee n the subject of numerous studies, much remains unknown about mechanisms bywhic h alcohol contributes to traffic accidents. Anumbe r of other factors that can contribute to car accidents mayinterac t with alcohol, possiblyi n acomple xmanner . Tolerance, age, driving experience, medicine, fatigue, stress andweathe r conditions mayb e among thefactor s that play arol ei n addition to alcohol (10). Sinceeve nver ylo wBA C levelsma yimpai r the driver's capabilities, someauthor s recommend that licence holders should not bepermitte d to drivea moto r vehicleafte r the ingestion of alcohol (1,31).

16.3. Secondary prevention: general deterrence

Methods for interveningwit h individuals at riskfo r drinkingi n combination with driving, once the habit has taken root, arebase d on the model of deterrence. This model predicts that the threat of sanctions willpreven t individuals from engagingi na specified behaviour (40).

16.3.1. Increasingrisk of punishment andarrest

A significant inverse relationship between theperceive d chanceo f apprehension and self-reported frequency of drinkingwhe n drivingha sbee n observed inmale s aged 17-30 (6). Increasing theprobabilit y of detecting incompetent drivers can be mediated byalcoho l breath tests. The introduction of random breath testing inNe w South Walesi n 1982wa simmediatel y followed bya drop in road traffic casualties. The obviousness ofpolic epresenc ewa sconsidere d asth e cornerstone (19). Support for thehypothesi s that increases inla w enforcement leading to agreate r probability of sanctions result in alowe r incidenceo f fatal and seriousinjur y accidents hasbee n demonstrated in Scandinavia (50). Somestudie s havereporte d declines in night-time fatal crashes or other measures of alcohol-involved driving that preceded implementation of laws (14, 18, 22, 40). Studies on themer e effects of legislation haveno t uniformly demonstrated sustained declines'innight-tim efata l crashes. A typicalpatter n showsa n immediatepost-la w declinei nnight-tim efatalitie s followed bya return to thepre-la wlevel . This trend hasbee n observed in Great Britain, France and the Netherlands (40), aswe la si n Canada (25), in the stateo f Maine (22), and in Stockton, acit yi n California (49).Whe n thepubli cbecome s awaretha t policeinforcemen t isno t asrigi d asinitiall yperceived , the incidenceo f crashes returns topre-la wlevel s (40).

232 16.3.2. Increasingseverity ofpunishment

Itwoul d be easier and less costly topunis h DWI arrestees more severelytha n to tighten up the enforcement measures. Anincreased severityo fpunishmen t usually translates to moretim ei njail . Evaluations of such measures haveno t produced much support for their effectiveness (36, 39, 48).Th efailur e of countermeasures based on increased severity of punishment liesi n thepossibilit y that the public disregards threats when it percieves anegligibl elikelihoo d of these threats being enforced. Another explanation istha t members of the target population mayno t haveperceive d ajai l asa severepunishment (41). Itha sbee n concluded that countermeasures based on severity of punishment mayb emor e costlytha n initially anticipated and less effective than desired (36,39) .

16.4. Tertiary prevention

Sinceprimar ypreventio n and general deterrence strategies areno t fully effective, individuals willcontinu e to driveafte r drinking. Tertiary prevention focuses on those individualswh o havebee n arrested for DWI. Someo fth e tertiary interventions represent deterrence stategies (fines, jail, licence revocation), other interventions involveeducationa l or therapeutic approaches.

16.4.1. Licencerevocation

Iti sassume d that thelos so f drivingprivilege srepresent s apunishmen t appropriate to theoffenc e and that over thecours e of therevocatio n period the driverwil lhav e learned hislesso n andwil lno t repeat DWI offence (35). Thelos so f one's licencei s viewedb yth e general public as arelativel y severe sanction (26). Licence revocation doesno t lead to a complete elimination of drivingb yth e convicted DWI offender. Between one-third and two-thirds of thosepeopl ewit h licence suspensions or revocations havebee n found to drive duringth e sanction period (52). The resultso f studies that have evaluated the effectiveness of licencerevocatio n have shown that it isth emos t cost-effective countermeasure identified asye t for reducing drivingb y drunken offenders (20, 21). For example, Hagen (20) noted that multiple DWI offenders who had their licencesuspende d hadbette r subsequent records than comparable convicteeswh o had not been punished with suspension. Thebenefit s of licencesuspensio n continued after the suspension period had expired.

16.4.2. Educationaland therapeutic approaches

Therational e underlying atherapeuti c approach istha t aDW I offender signalsa potential drinking problem that likelyextend s into manyarea s of the individual's life (35). The expectation istha t treatment, byattenuatin g or eliminating drinkinghabits , willreduc e thefrequenc y of drivingafte r drinking and thus reduce theprobabilit yo f

233 DWI recidivism. On the other hand, educational approaches provideindividual swit h information about alcohol and its effect onbehaviou r without directly attempting to change drinking patterns. Recently, the Dutch government has evaluated the 'Alcohol Verkeer Project Drenthe' (Drenthe Alcohol in Traffic Project), an education programmei nwhic h DWI offenders couldvolunteer . Thesevolunteer s received amilde r punishment than DWI offenders who choseno t to participatei n thisproject . Theprojec t appeared to be effective; after the project, data showed that participants had ahighe r knowledge of alcohol and its effects onbehaviou r and drivingperformance . Moreover, the project seemed to reduce recidivism by30 %a scompare d to the matched control group (8). Foon (17) reviewed drinking-driving education and treatment programmes reported in the literature. In hisrevie wh enote s that theusefulnes s of educational programmes for drinking-driving offenders isquestionable . While someo f these programmes appear to increaseknowledg e about socially appropriate attitudes towards drinking and driving, others do not. Likewise, someprogramme s appear to reduce thenumbe r of drinking-driving and otheralcohol-relate d traffic offenders, while other ones have anegativ e orindiscernabl e effect. It has alsobee n noted that, aswit h education programmes, therapy programmes haveno t provided definitive evidencefo r their effectiveness. In arevie w Nichols (34) concludes that DWI offenders who haveles ssever e drinking-related problems aremor elikel yt o benefit from an education programme than offenders withmor e severedrinkin gproblems . According to Nichols (34), education and treatment programmes shouldb e viewed as adjuncts, not asalternatives , to deterrent efforts.

Summary

Drinking impairs driving capabilities. Alcohol consumption isinvolve d inman y traffic accidents. Somereason s for drinking and drivingafte r drinking are mentioned. Various legislativemeasure swit h respect to the drinking-driving problem areintroduced . Thesemeasure s canb e classified into primary, secondary and tertiary prevention. Primary prevention strategies targetyoun g driverswit h the goal of preventing the initiation of drinking-driving behaviour. Educational programmes haveshow n to havea wea k positiveinfluenc e on traffic safety problems. Increasing the minimum purchase ageo r loweringth emaximu m allowablebloo* dalcoho l concentration for traffic participants have demonstrated tob emor e effective. Secondary prevention strategies target thegenera l population and arebase d on general deterrence. Increasing theperceive d risk ofpunishment and arrest appears to havea short-lived effect. Increasing severity ofpunishment seems tob e more expensivean dles s effective than desired. Tertiary prevention focus on thoseindividual swh ohav ebee n arrested for DWI (drivingwhil eintoxicated ) in order topreven t recidivism. Licencerevocatio n appears

234 tob e the most cost-effective countermeasure identified for reducing drivingb y drunken offenders. Results of educational and treatment programmes are contradictary. Theseprogramme s mayreduc eDW Ii n less severeproble m drinkers. Overall, it can beconclude d that none of theseapproache s isfull y effective in reducing the drinking-driving problem. Integration ofvariou s ofthes eapproache s is probably the most effective countermeasure.

References

1. Anonymous. Alcohol and the driver: council on scientific affairs. JAMA 1986;255: 522-7. 2. Arnold R. Effect of raising the legal drinking age on driver involvement in fatal crashes, the experience of thirteen states. Washington, DC: National Center for Statistics and Analysis, 1985. 3. Asch P, Levy DT. Does the minimum drinking age affect traffic fatalities? J PolicyAnalysi s& Management 1987;6: 180-92. 4. Ashley MJ, Ranking JG. A public health approach to the prevention of alcohol-related health problems. Ann Rev Public Health 1988;9: 233-71. 5. Beck KH, Summons TG. The social context of drinkign among high-school drinking drivers. AmJ Drug Abuse 1987;13:181-98. / 6. Binns CW, Knowles SS, Blaze-Temple D. Is education enough? The drinking and driving practices of 17-30yea r old males. Austr Drug Alcohol Rev 1987;6: 253-64. 7. Bonnie RJ. Regulating conditions of alcohol availability, possible effects on highway safety, J Stud Alcohol 1985(suppl 10): 129-43. 8. Bovens R. Evaluatie van het alcohol verkeer project Drenthe. The Hague: Staatsuitgeverij, 1987. 9. Centraal Bureau voor de Statistiek (CBS). Statistisch Zakboek. The Hague: Staatsuitgeverij, 1989. 10. Chan AWK. Factors affecting the drinking driver. Drug Alcohol Depend 1987;19:99-119. 11. Coate d, Grossman M. Change in alcoholicbeverag e prices and legal drinking ages, effects on youth alcohol use and motor vehicle mortality. Alcohol Health Res World 1987;12 :22-5 . 12. Donavan DM, Driving while intoxicated, different roads to and from the problem. Criminal Justice Behav 1989;16: 270-298. 13. Douglass RL. Youth, alcohol, and traffic accidents. In: Special population issues, alcohol and health, monograph No. 4. Rockville, MD: National Institute ofAlcoho l Abuse and Alcoholism, 1982. (Department of Health and Human Servicespublicatio n [ADM] 82-1193.) 14. Epperlein T. Initial deterrent effects of the crackdown on drinking drivers in the State of Arizona. Accident Anal Prev 1987;19:285-303 . 15. Farrow JA, Brissing P. Risk for DWI, a newloo k for gender differences in drinking and driving influences, experiences, and attitudes among new adolescent drivers. Health Educ Quarterly 1990;17:213-21. 16. Flanagan NG, Strike PW, Rigby CJ, Lochride GK. The effects of lowdose s of alohol on driving performance. Med SeiLa w 1983;23:203-8 . 17. Foon AE. The effectiveness of drinking-driving treatment programs, a critical review. Int J Addict 1988;23: 151-70. 18. Forcier MW, Kurtz NR, Parent DG, Corrigan MD. deterrence of drunk driving in Massachusetts, criminaljustic e system impacts. Int J Addict 1986;21: 1197-220. 19. Gloag D. Drinking and driving, discretionary or random testing? BMJ 1988;297: 440-41. 20. Hagen RE. The efficiacy of licensing controls asa countermeasure for multiple DUI offenders. J Safety Res 1978;10: 115-22. 21. Hagen RE, Rickey LW, McConnel EJ. The traffic safety impact of alcohol abuse treatment as an alternative to mandatory licensing controls. Accident Anal Prev 1979;11: 275-91. 22. Hingson RW, Heeren T, Kovenock D, et al. Effects of Maine's 1981 and Massachusett's 1982 driving-under-influence legislation. AmJ PublHealt h 1987;77:593-7 .

235 23. Jonah BA. Accident risk and risk-taking behaviour amongyoun g drivers. Accident Anal Prev 1986;18:255-71. 24. Kayser RE. Rijden onder invloed, effectiviteit van eenvoorlichtingsprogramma , een wetenschapppelijke proeve op het gebied van de socialewetenschappen . Kampen: Mondiss, 1990. 25. Liben CB, Vingilis ER, Blefgen H. The Canadian drinking-driving countermeasure experience. Accident Anal Prev 1987;19: 159-81. 26. Little JW. Atheor y and emperical study ofwha t eters drinking drivers, if, when, andwhy . Admin Law Rev 1971;23:169-93 . 27. Lotterhos JF, Glover ED, Holbert D, Barnes RC. Intentionality of college students regarding North Carolina's 21-year drinking age law. Int J Addict 1988;23:629-647 . 28. Males MA. The minimum purchase age for alcohol and young-driver fatal crashes: a long-term review. J Legal Stud 1986;15: 181-209. 29. Mann RE, Vingilis ER, Leigh G, Anglin L, Blefgen G. School based programmes for the prevention of drinking and driving, issues and results. Accident Anal Prev 1986;18:325-37 . 30. Mayhew DR, Donelson AC, Beirness DJ, Simpson HM. Youth, alcohol and relative risko f crash involvement. Accident Anal Prev 1986;18: 273-87. 31. McDermott FT, HughesESR . Driver casualties inVictoria . Med J Aust 1983;1: 609-11. 32. Moskowitz H. Robinson CD. Effects of lowdose s of alcohol driving-related skills: a reviewo f the evidence. Alexandria: SRA Technologies, 1988. 33. duMouchel W, Williams AF, Zador P. Raising the alcohol purchase age, its effects on fatal motor vehicle crashes in twenty-six states. J Legal Stud 1987;16: 249-66. 34. Nichols JL. Treatment versus deterrence. Alcohol Health ResWorl d 1990;14: 44-51. 35. Peck RC, Sadler DD, Perrine MW. The comparative effectiveness of alcohol rehabilitation and licensing control actions for drunk driving offenders, a review of the literature. Alcohol Drugs Driving 1985;1: 15-39. 36. Reed DS. Reducing the costs of drinking and driving. In: Moore MH, Gerstein DR, eds. Alcohol and public policy, beyond the shadow of prohibition. Washington, DC: National Academy of Science, 1981. 37. Reznik R, Morey S, Best JB. Evaluation of the Australian Medical Association drink-driving campaign inWollongong . Med J Aust 1984;8: 818-21. 38. Rosenberg H. Coping strategies, reasons for driving, and the effect of self-monitoring in drinking-driving situations. Addict Behav 1988;13:97-100 . 39. Ross HL. Deterring drunken driving, an analysis of current efforts. J Stud Alcohol 1985(suppl 10): 122-8. 40. Ross HL. Deterring the drinking driver, legal policy and social control. Lexington, MA: Lexington Books, 1982. 41. Ross HL, McCleary R, LaFree G. Can mandatoryjai l lawsdete r drunk driving? The Arizona case. J Criminal Law& Criminolog y 1990;81: 156-70. 42. Smith DI. 0.05%o r 0.08%? MedJ Aust 1984;4: 176-7. 43. Smith DI. Effect of lowproscribe d blood alcohol levels (BALs) on traffic accidents among newly-licensed drivers. Med SeiLa w 1986;26: 144-8. 44. Smith DI. Effect on traffic safety of introducing a 0.05%bloo d alcohol level in Queensland, Australia. Med SeiLa w 1988;28: 165-70. 45. Snow RW, Wells-Parker E. Drinking reasons, alcohol consumption levels, and drinking locations among drunken drivers. Int J Addict 1986;21: 671-89. 46. Snowden RL, Campbell DR. Reasons for drinking among problem drinker-drivers, client and counselor reports during treatment. Addict Behav 1984;9:391-4 . 47. SöderJCM , de Bruin RA. 'Alcohol en verkeer, dat kunj e niet maken', evaluatie onderzoek V.V.N.-campagne Alcohol inhe tverkeer , 1988-1989. Haren: Verkeerskundig Studiecentrum, Rijksuniversiteit Groningen, 1989. 48. Voas RB. Evaluation ofjai l asa penalt yfo r drunk driving. Alcohol DrugsDrivin g 1986;2:47 - 70. 49. Voas RB, Hause JM. Deterring the drinking driver, the Stockton experience. Accident Anal Prev 1987:19: 81-90.

236 50. Voley HL. Recent evidence from Scandinavia on deterring alcohol impaired driving. Accident Anal Prev 1984;16: 123-38. 51. Wagenaar AC. Preventing highway crashes byraisin g the legal minimum age for drinking: the Michigan experience sixyear s later. J Safety Res 1986;17: 101-9. 52. Waller PF. Licensing and other controls of the drinking driver. J Stud Alcohol 1985(suppl 10): 150-60. 53. Wechsler H, Sands ES. Minimum age lawsan d youthful drinking, an introduction. In: Wechslet H, ed. Minimum-drinking-age laws, an evaluation. Lexington, MA: Lexington Books, 1980: 1- 10. 54. Wodarski JS. Teaching adolescents about alcohol and driving, a twoyea r follow-up. J Drug Educ 1987;17: 327-44. 55. World Health Organization, Regional office for Europe, Copenhagen: Working group on alcohol and accidents, ICP/APR 117/2, 1987.

237 CHAPTER 17 Prevention of alcohol abuse

E. te Wierik

Someauthor s assume aclos erelationshi p between average alcohol consumption and theprevalenc e of excessive drinking in apopulatio n to exist (9, 34, 59). Excessive drinking playsa distinct rolei n the development of allkind s of deviant behaviour and the pathogenesis of several syndromes. Alcohol-related problems are expected to increasewit h an increasei n average alcohol consumption. Onewa yo f tacklingthi sproble m mayb eth e development ofpreventiv epolicies . Dekker (12) considers prevention to encompass allmeasure s and activities directed at preventing the occurrence of mental and physical diseasean d atpromotin g public health in general. Wema y distinguish primary, secondaryan d tertiary prevention. Primary prevention stands for thepreventio n of newcases . Asregard s alcohol- related problems this implies an effective governmental policywit h regard to alcohol consumption, including promotion of activities likehealt h education, and changing habits, norms and values so that another drinking pattern willb e encouraged. Secondary prevention includes the earlyidentificatio n of prodromal or developing cases, their treatment and rehabilitation, in order topreven t the development of chronic cases- in other words, an intervention in the 'pathological process' at the earliest possiblemoment . Tertiary prevention isth etreatmen t of prdblem drinkersb y means of various methods in drying-out clinics or centres (72). This chapterwil l discuss primary prevention strategies. Secondary and tertiary prevention willb e discussedi n Chapter 18.

17.1. Models of control

The aimso f tertiary prevention, and themeasure s tob etaken , arerelativel y the least troublesome. The question is,however , what measures shouldb e considered in primary and secondary prevention. The essential difference between thesei stha t primary prevention concentrates on alcohol-related problems evenbefor e they have arisen. Anumbe r of prevention modelshav ebee n described (31). Themost popular model isth e 'single distribution' model. Three modelsbase d on different starting pointswil lb e elucidated below.

238 17.1.1. TheLedermann or 'singledistribution ' model

The singledistributio n model isbase d on research doneb yth e Frenchman Ledermann (34). Several aspects ofLedermann' s theory have evolved and been modified in the course of time (59). The current model hasbee n described bysevera l authors (9, 31, 41,54 , 56, 62, 64). Epidemiological research has shown that the per capita consumption of alcohol and theprevalenc e of excessivealcoho l consumption are associated: the larger the averagequantit y of alcohol consumed by the population, thehighe r thenumbe r of excessivedrinker s (9). Theoretical speculations and empirical evidenceindicat e that a substantial increasei n averageconsumptio n is almost alwaysaccompanie d with an increasei nnumbe r of excessive drinkers. When thepe r capita consumption increases, therewil lb e concomitant increase of alcohol- related problems, such asmortalit y due to excessive drinking, cirrhosis of theliver , drunken driving, and hospitalization of alcoholics. Ledermann's model (34) indicates themathematica l relation between mean alcohol consumption and theproportio n of excessivedrinker s in a homogeneous population. Ledermann classified allalcoho l consumers in agive n population according to the quantities of alcohol consumed during aparticula r period. Subsequently, hewa sabl et o study the distribution pattern in detail. Hefoun d that thefrequenc y distribution of alcohol consumers asregard s their individual

Consumers (%)

20 r modal level median level mean level 15

10

40 60 80 100 120 140 Consumption (inlitre so f purealcoho l peryear ) Fig. 17.1. Log-normal distribution of alcohol consumption among 30 million adults in France according to Ledermann (34).

239 consumption showsa highl ypositiv e skewed pattern. The distribution given inFig . 17.1show sa log-norma l pattern. Thisi susuall y described bytw oparameters , namely the mean and the standard deviation (measure of dispersion). Themea n in this case corresponds to the annual per capita consumption whileth e standard deviationwa s established byresearch . Thelatte r mayb e afairl y constant valuei n various populations, sotha t the distribution mayb e described byapplyin g only one parameter, viz. themea n alcohol consumption of a population. Ledermann's model implies that, when thepe r capita consumption increases, the frequency of drinkerswil lalway sb e distributed in accordancewit h a specific distributional pattern causingpredictabl e proportions of drinkers tob e classified ina higher consumption category and viceversa . It hasbee n questioned, however, whether the skewed distribution of alcohol consumption does really correspond with thefixe d distribution Ledermann suggests and whether themea n consumption asa soleparamete r indeed reflects the prevalence of excessivedrinkers . Theinterpretatio n of Ledermann's distribution curveha sbee n discussedb y Duffy (13, 14, 16), Duffy &Cohe n (15) and Skog (64, 65, 66). Duffy &Cohe n as wella s Skogconclud e that populations may deviatefro m thelog-norma l model. The hypothesis concerning thefixe d relationship between mean alcohol consumption and the prevalence of excessivealcoho l usei sno t tenable. Empirical investigations into the regularities in the distribution of alcohol consumption have experienced some disabilities that complicate attempts to draw precise, unequivocal conclusions. The most important disabilities met are: the underestimation of alcohol consumption in surveys, the small number of longitudinal studies (especially studies describinga decreasei n mean alcohol consumption) and statistical problems related to sample size. Moreover, the theoretical foundations of Ledermann's model developedb y Ledermann andb y others are scanty, brief and incomplete (35). Therei sonl y one investigator, Skog (67),wh o has developed atheor y about the distribution of alcohol consumption and whoha s tested thehypothese s drawn. Hishypothesis , 'Theus eo f alcohol byindividual s ist o such a degree acollectiv ephenomeno n that an increasei n mean consumption isindicativ e of an increasei n level of consumption for all drinkers (light and heavy)' is endorsed byLemmen s et al. (35). Fluctuations inmea n alcohol consumption levels can thusb einterprete d asbein gindicativ e of changesi n consumption levels of allalcoho l consumers. The description 'indicativeo f changes' means that iti sno t possible togiv ea n exact, numerical prediction concerning the distribution of alcohol consumption.

17.1.2. Thesocio-cultural model

The socio-cultural modeli scharacterize d byth e emphasis on social standards and on appreciation of the use of alcoholicbeverages . Cultures mayb e classified according to their drinkingpattern s and attitudes. Pittman (53) madeth e following classification.

240 -Abstinent cultures. In an abstinent culture alcohol consumption isprohibite d and drinking alcohol provokes strong negativefeelings . Abstinence from alcohol is inherent in thelife-styl e in this cultures. Members of theseabstinen t groupswh o start to drink have agreate r risk of turning into an alcoholicbecaus e theyhav eneve r learnt drinking. Examples of abstinent cultures areMormones , Islamics and some Protestant groups. -Ambivalent cultures. In an ambivalent cultureth e attitudes towards alcohol are contradictory in that there are two directly opposed value systemswit h regard to alcohol use. When there aren o integrated control systemsi n a culture, the individual isi n an ambivalent position whichma ylea d to alcoholism. Examples of such ambivalent cultures are Ireland and Scotland. -Permissivecultures. Apermissiv eculture i sdefine d as acultur ei nwhic h attitudes towards alcohol consumption arefavourable , but inwhic h strong social sanctions exist regarding excessivedrinkin g and intoxication or other types of deviant drinking behaviour. Thenumbe r of alcoholicswil lb e smallwhe n in agrou p or a community mutual consent exists on established habits, values, sanctions and attitudes towards alcohol use, and ifthes e are compatiblewit h the other norms in that culture. The Jewish and Italian cultures are often mentioned asbein g permissive. ' - Overpermissive cultures. In an overpermissive culture attitudes towards alcohol use arefavourabl e and types of deviant behaviour during drinking or resulting from drinking isaccepted . This attitudei sfound , for instance, in France. Somemeasure s to prevent alcohol abuse in thismode l are: - stimulation of the development and maintenance of prohibitivenorms , - encouragement of the useo f alcoholi npermissiv esituation s and discouragement of situations inwhic h alcohol drinking isth emai n activity, - abolishment of the legal drinking ages otha t premises are open to families, and encouragement of consumption of alcohol in domestic situations. The socio-cultural model mayb e open to criticism. Themos t pronounced criticism is expressed byMäkel ä (41) and Frankel &Whitehea d (19). Mäkelä (41) has shown that information on differences in alcohol abuse among different cultures had not been interpreted correctly. Theprevalenc e of alcohol abusei n the abstinent culture of Mormones, for example, islowe r than in any of the other cultures defined above. Frankel &Whitehea d (19) noted that factors such aspermissio n of alcohol consumption and aprescriptiv e norm increase alcohol consumption and thus induce a higher prevalence of alcohol-related problems. They concluded that mean alcohol consumption most strongly affects the rateo f negative consequences of alcohol consumption.

17.1.3. The mental-health model

Alcoholicbeverage s reduce stress. Peoplewh o often havet ofac e stressful situations aremor eincline d to drink tob erelieve d from theseanxiou s feelings at least temporarily (55). Psychological studies support thishypothesi s (seeChapte r 15). However, causean d effect arehar d to unravel:lead sunemploymen t to alcoholuse , 241 or isi tjus t the other wayround ? The 'mental-health model' assumes that social or psychological deprivation leads to excessiveus e of alcohol. The aim of prevention of alcohol abusei st o strengthen mental health. Plaut (55) mentioned, among other things, improvement of the quality of domesticlife , advancement of the understanding of emotions and relations, reduction of poverty, discrimination and alienation, and the care ofbette r housing. One can note that thesemeasure s are characterized byhumanit y and areno t directed at alcohol consumption per se. Garretsen (22) noted that light and moderate drinkers also use alcohol to reduce stress. Moreover, not allproble m drinkers consumealcoho l to reduce anxious feelings. Therefore, prevention inlin ewit h the 'mental-health model' could only prevent acertai n category from drinking excessively.

17.2. Measures to prevent alcohol abuse

Measures to prevent alcohol abusewhic h mayb etake n byth e government include measures aimed at restricting the availability of or influencing the demand for alcohol. Among thesemeasure s arepric econtroLan d aba n on or restrictions ast o advertising.

17.2.1. Price control

One of themos t fundamental economic lawsstate s that increase of pricetend s to lead to a decreasei n quantities bought (9, 33,76) . The elasticyvalue s of price and income arenumerica l expressions of thewa y consumers react to changing prices and incomes. All other factors remaining equal, a price increasewil llea d to a decreasei n consumption whilea n increasei nincom ewil l result in an increased consumption. The elasticyvalue swil lals ob einfluence d by such variables asothe r goods, previous political controlling measures and marketing strategieswhic h condition consumer preference. Moreover, in time elasticity values maychang e considerably in reaction to social, cultural and economic developments (68). Concerning price control thefollowin g observations havebee n made: - alcohol consumption ismor einfluence d byincom e than bypric e (17,33) , - the calculated elasticitiesvar yamon g types of alcoholicbeverages :bee r and wine appear tohav e alowe r elasticity than spirits (17, 58). Price regulation mayb e an effective alcohol policy element capableo f forcing alcohol consumption down. However anumbe r of objections havebee n raised. First, ifth epric eincreas emerel ylead s to aswitc h to alcoholicbeverage swhic h do not increasei n price, at least not to the same extent, then iti sb yn omean s certain that the priceincreas elead st o a declinei n overall alcohol consumption. Se/ond, the econometric calculations in question arebase d on registered alcohol/ales. A decline in registered consumption following upon apric eincreas e canb e counteractedb ya n increasei n unregistered consumption. Third, iti sconceivabl etha t the great majority

242 ofmoderat e drinkers respond topric eincrease sb yreducin g alcohol consumption, whileth e heavy drinkers sustain their old drinking pattern (55).

17.2.2. Restrictionsbearing on the availabilityof alcohol

Somemeasure s of control which are assumed to influence theprevalenc e of alcohol- related problems are: - regulating thewa yalcoho l issold , i.e .whethe r therei sa stat emonopoly , asi n Scandinavian countries and in somestate s ofth eUSA , or salesar ei n thehand so f independent enterprises, - limiting the number of outlets, i.e .th enumbe r of shops and publicplace s where alcohol mayb e sold, - fixing the times atwhic h alcohol mayb e sold, i.e . the opening and closing timeso f bars and shops selling alcohol. Popham et al. (56) were unable to showa significant difference in consumption level or liver cirrhosis mortalitybetwee n US stateswher e alicencin g systemwa si n force and themonopol y states. Similarfinding s arereporte d elsewere (29, 63). According to Loeb (37) statesi nwhic h licences are given out should havea higher consumption than stateswit h astat emonopoly . Hisconclusio n isbase d solely on statistics relating to the consumption ofspirits . The consumption ofwine , beer and mixedbeverage s isno t taken into account, thus resulting in adistorte d picture. Pittman (53) quotes asurve yi nwhic h seven US Statesi nwhic h the alcohol tradei s government-controlled are compared with seven statesi nwhic h alcohol issol db y privatelicencees . Consumption, asfa r ascoul db e determined, was even higher in the stateswit h astat emonopoly . From astud y on statemonopol y systems and alcohol prevention in developing countries arelationshi p appear to emergebetwee n thelevel s of alcohol consumption and Statecontrol : in countrieswit h ahig h levelo f stateinterventio n with regard to the availability of alcohol (Norway, Sweden, Finland, Poland) per capita consumption waslowe r than in countries with alo wleve l of State control (USA, Ontario, FRG)(32). It shouldb enote d that these data refer onlyt o registered alcohol consumption, which maydiffe r from real consumption. A second possibility of limiting the availability of alcohol isrestrictio n of the number of outlets. Iti sgenerall y assumed that themor e outlets of alcoholic beverages there are, themor ewil lb e drunk and themor eofte n drunkennesswil l occur (56). Parker et al. (51)foun d that stateswit h ahig h densityo fliquo r outlets havehighe r levelso fpe r capita consumption. Harford et al. (27) examined the effects of thenumbe r of on-premise outlets (i.e .wher ealcoholi cbeverage s can be purchased for consumption on thepremises ) per 100,000 persons on alcoholism ratesi n the USA. Theyfoun d that outlet density and urbanism, when controlled for income and consumption, were significantly related to rates of alcoholism in 38 states and theDistric t of Columbia. In another study, thenumbe r of on-premise outlets per million population wasfoun d tob ecorrelate d significantly with and beer consumption (11). A studyint o the effects of allowingliquor-by-the-drin k (LBD) (i.e .providin g alcohol outlets the option to sellindividua l drinksfo r on-premise

243 consumption), suggests a 6-7%increas ei nliquo r sales attributable to LBD implementation. More recently, an association between alcohol availability (density of liquor outlets) and mortality hasbee n demonstrated. The association was evident for heart disease, cancer, alcohol-related deaths and overall mortality. On the other hand, Smart (70) wasno t ablet o detect a significant correlation between availability and average consumption in astud y covering 50 states. Itwa sconclude d that personal incomema yb e abette r predictor of variations in consumption than is availability. MacDonald &Whitehea d (39) reviewed research into the relationship between per capita consumption of alcohol and density of alcohol retail outlets within acommunity . They concludetha t a substantial increasei n off-premise consumption isaccompanie d with anincreas ei n consumption. Most of the studies reviewed canb einterprete d alternatively. For example, thenumbe r of outletswithi n a community isaffecte d byman yfactor s including socio-demographic composition, disposable income and tourism aswel la s regulations controlling thenumbe r of outlets. A change of any one of thesefactor s maylea d to an increasei nbot h the number of alcohol outlets and alcohol consumption. Although there seems tob e an association between number of outlets andlevel so f alcohol consumption and alcohol- related diseases, the decision to restrict availabilitywil lno t necessarily lead to lower alcohol consumption or less alcohol-related problems. This canb e exemplified byth e Polish experience. In October 1980, thePolis h government decided to reduce the number of outlets purveying spirits andwin eb yon ethird . However, thePolis h spirits salesi nth elas t threemonth s of thatyea rwer eth ehighes t everrecorded . This development wasinfluenced , amongst other things,b ya collaps ei n themarket s for other products, agrowt h in national income and rumours of aplanne d increaseo f the price of alcohol. The closure of many outlets stimulated customers tobu y 'just in case' whenever theypasse d asho p selling spirits. This example demonstrates that stable economic and political conditions are aprerequisit e if control measures are to reduce consumption (32). Limiting the hours duringwhic h alcohol isavailabl ewoul db emor e effective than restricting thenumbe r of outlets (9). An attempt to reducemoto r vehicleaccident s associated with the early closing timefo r hotels (18.00)wa smad ei nAustralia . Extension of the opening time to 22.00 on thepremis ewa sbelieve d to reduceth e urget o drink. Thenumbe r of accidentswa sno t reduced, but thepea k accident timewa s shifted from 18.00-19.00 to 22.00-23.00 (57). The effects of closureo fwin ean d spirits shops on Saturday havebee n measured in Norway. Both thenumbe r of reports of, and thenumbe r of incarcerations for, drunkenness, and thenumbe r of cases of domestic disturbance showed areductio n in thetown s coveredb yth e study relativet o thecontro l towns, particularly on Saturdays and Saturdaynights , asmigh tb e expected. However, the number of reports ofviolenc eincrease d in the experimental townsrelativ et o the control towns, especially on Fridaynight s (46). Insofar asthe y allow comparison, studies inFinlan d (30, 61) and Sweden (49)yiel d similar results. Frankel & Whitehead suggested that thehour s duringwhic h alcohol couldb esol d determined

244 where andwhe n alcoholwa s consumed, but not theconsumptio n rateo r the total amount of alcohol consumed (19). Asregard s themeasure s of control mentioned itma yb epointe d out that: - seen in thewide r context of apreventiv epolicy , littlei st ob e expected from changes in thelegalizatio n of alcohol sales, - itha s not been demonstrated convincingly that restriction of thenumbe r of outlets willresul t in lowersales , - restrictions posed on opening and closingtime sma ybrin g about side-effects, i.e . morema yb e drunk in theperiod sth e shopi sopen .

17.2.3. Changingthe minimum drinkingage

In most countries saleo f alcoholicbeverage s to persons under a specified minimum agei sprohibited . In theNetherlands , for instance, the agesa twhic h thepurchas eo f weak and of strong alcoholicbeverage s ispermitte d differ, namely 16an d 18year s respectively. In recent times, many states havechange d theminimu m legalpurchas e age (MLPA) for alcohol, with 29 states reducing that agebetwee n 1970 and 1975 (76) and 24 of these samestate s raising it again within thenex t decade (8). The decision in the USA to set theMLP A on 21wa sprimaril y founded on studies into car accidents and fatalities amongyouthfu l drivers. Afe w authors have summarized previous studies on theimpac t of raising and lowering the MLPA on consumption, accidents and fatalities. Although results are somewhat conflicting, trends indicate that lowering the MLPA tends toincreas eth e incidence of alcohol-related accidents and fatalities, whereas raising that ageha s the opposite effect in the affected age groups (5,38) . Somestudie s have examined the effects of reductions in MLPA on consumption. Wagenaar (74) observed ashort-ter m increasei n draft beer sales after Michigan had reduced the MLPA in 1972,wherea s package and total beer andwin esale s remained unchanged. Barsby &Marshal l (7) investigated liquor sales in 25 states oneyea r before and oneyea r after these stateslowere d their MLPA. Their analysis did not yield reliable evidencetha t liquor salesincreased . However, the authors did not examineliquo r consumption in theag egrou p affected byth ene wlaw ,bu t in the total market. Smart (70) examined per capita consumption for each beverage type separately in 25state s that had lowered their MLPA. Over a3-yea rperiod , each statewa scompare d with aneighbourin g state that had not changed that age. Overall, beer and liquor salesincrease d inth estate s that had loweredth e MLPA;win esale s remained stable. Other studies have examined the effects of an increase of MLPA on consumption. Wagenaar (74) reported a decreasei n package and totalbee r sales after the MLPA hadbee n raised in Michigan, but draft beer salesincrease d aswell . Thisincreas ewa s attributed to the simultaneous raisei n thepric eo f packagebeer . A short-term aswel l asa long-ter m reduction infrequenc y and quantity of drinking among age groups affected bya chang e of law(increas e of MLPA) havebee n mentioned (78,79) . 245 Several negative effects of raising theMLP Afo r alcohol consumption havebee n mentioned. Studentswh o areunde r agewhe n thene w drinkingla wi soperativ e tend to changethei r location of alcohol use, tend to use other drugsmore , tryt o obtain alcohol from theirfriend s or tend to use afals e orborrowe d identification, but do not inclinet o teetotalism (24, 28,38) . Several studieshav eshow ntha t mostyoun g people drinkbefor e reaching thelega lminimu m age. Usually this concerns drinking athom e (18), sometimespermitte db ythei rparents . Drinkingwithou t legal sanctions being applicablewoul d promote the development of social ambivalence. Suppression ofjuvenil ealcoho lus ean d abusei saccomplishe dbes twit hbot h an increasei n legal drinking agean d anincreas ei nprice s of alcoholicbeverage s (10).

17.2.4. Mass media

Prevention of the abuse of alcoholicbeverage s canb emediate d bymas smedi a (i)b y restricting or evenprohibitin g advertising of alcohol, and (ii)b ymedi a campaigns against alcohol abuse. Restricting or prohibiting advertising of alcohol, asha shappene d in the Scandinavian countries, isregarde d asa measur e.whic hmigh t causea decreasei n alcohol-related problems. Smart &Cutle r (69) studied the effect of aba n on advertising of alcohol over 14month si n British Columbia (Canada) in the early 1970s. Thisba n had no significant effect on the sales ofbeer , winean dspirits . Ogborne &Smar t (48) investigated the effects ofprohibitio n of advertising of beer through the press and thebroadcastin g media in Manitoba (Canada). This survey demonstrated, on the-basiso f astead yincreas ei n themonthl y per capita beer consumption statistics over theperio d 1974-1978, that theprohibitio n order had no effect whatsoever. A similar increasei n alcohol consumption wasobserve di n the control provinceAlberta . Another part of Ogborne &Smart' s survey concerned the various restrictions applying to the advertising of alcoholicbeverage s in thepres si n several states of the USA. Here, too, no relation wasfoun d between the extent of official restrictions on theon ehan d and thepe r capita consumption ofbeer , wine and spirits on the other. Most research assesses the effects of marginal changes in advertising expenditure on total consumption. Reviewers ofthi sliteratur e (20, 73, 77) concludetha t the inability to find an effect on consumption suggeststha t the effect isunlikel y to be substantial (45). TheDutc h liquor trade applies afairl y strict self-censorship regarding advertising of alcohol. It has, on itsow ninitiative , adopted the German beer advertising code which hasbanne d advertisements showingillustration s associating alcohol usewit h sportsmen, adolescents, cars, aprofession , and soon . Thecomplet e codei s essentiallybase d on thefac t that advertising should not stimulate alcohol consumption per sean d should certainly not promote excessiveconsumptio n (4). A restriction of alcohol advertising isbein g considered: advertising mayb e prohibited on television in thefuture . Thismeasur eha sbee n critizedbecaus e some studies suggest that advertising hashardl y anyeffec t on total alcohol consumption. 246 Moreover, themeasur ewoul d impedeth eintroductio n of low-alcoholbeverage s (2, 3). Mass media canb e used to advertise alcoholicbeverages , but also to affect the public's attitude, and hencebehaviour , towards the consumption of alcoholic beverages. The massmedi a areuse dbecaus e (23): - manypeopl e canb e reached thatwa y - massmedi a operate quickly - the use of massmedi a isrelativel y simple - the use of mass media isrelativel y cheap. TheDutc h government uses such slogans as 'Behonest.. . howmuc h doyo u really drink?' and 'Doyo uknow , doyo ucare? ' tomak eth epubli cawar eo f alcohol- related problems and to prevent moderate drinkers from becoming an alcoholic. Preliminary investigations suggest that the results of these campaigns are positive (41). Others dispute thesucces s of media campaigns against drug and alcohol abuse (23). In theUS A a similar campaignbase d on the slogan 'Be smart, don't start! - Just sayno! ' has started (21). It hasbee n argued that personal contact ismor e credible than media contact. Future campaign efforts should exploreway so f making people reflect on and, preferably, discuss their attitude andbahaviou r prior to or perhaps in conjunction with specific drug/alcohol messages (6). Health education mayb e agoo d manner.

17.2.5.Alcohol education

Alcohol education programmes are often carried out in classrooms becausea manageable number ofyoun gpeopl ear e already together there. The alcohol and drug education evaluation literature hasbee n reviewed extensively (25, 43, 45, 60). Thesereview s are unanimous in their opinion that alcohol education significantly improves knowledge, but ishardl y effective in preventing substanceus eo r abuse. Therefore iti sgenerall yfel t that school-based prevention programmes need to reconsider their conceptual bases, their logican d their strategies (26). An explanation for thelac k of effect of theseprogramme s istha t schools do not know how to develop such programmes. Moreover, presenting programmes of this nature requires akin d of training that classroom teachers do not usuallyreceive . Especiallyjunio r and senior highschool teachers whofocu s on presenting a content-orientated curriculum areles sfocuse d than elementary school teachers onjuvenil elearnin g processes (1, 50). School-based programmes mustb e directed at allth emajo r social influences en institutions that shapeth eyouth . Onepossibilit y to changeth e prevention programmes ist o concentrate more on factors such asparent s and peers (42). Perry & Grant (52) noted that peer leadership isa nimportan t component of primary prevention programmes. That iswh ythe yperforme d apilo t study thatwa s designed to elicit comparisons between peer-led and teacher-led instructions. Peer-leaders volunteered orwer eselecte db ythei rteachers . Schoolsi nfou r countries were assigned topeer-led , teacher-led or control (nointervention ) conditions. After

247 intervention, peer-led conditions gaveris et o significantly lower alcohol use scores than teacher-led and control conditions. There weren o significant differences between peer-led and teacher-led programmes in knowledge scores. Students in the peer-led programme had significantly higher knowledge scores after thetes t than students in the control group. These outcomes provide some optimism for the potential of alcohol education.

Summary

Three models upon which prevention canb ebase d are described. None of these models satisfies completely asa basi sfo r alcohol prevention. According to Ledermann, the average alcohol consumption isregarde d asa n indication of the prevalence of excessive drinking and alcohol-related problems. Prevention of alcohol abusei n this model can bemediate d by decreasing per capita consumption. The Ledermann model hasbee n critized sinceth efixe d relationship between mean alcohol consumption and theprevalenc e of excessivealcoho l usei sno ttenable . In the 'sociocultural model' cultures areclassifie d according their drinking patterns and attitudes. In cultures inwhic h alcohol abuse occursfrequentl y measures can be taken to influence behaviour. However, information on differences in alcohol abusei n different cultures seems tob einterprete d incorrectly. The 'mental-health model' assumes social or psychological deprivation to lead to excessiveus eo f alcohol. Theai m ofpreventio n of abuseo f alcohol ist o improve mental health. Nevertheless, it isdifficul t to detect causes and effects: leads unemployment to alcohol use, or the other wayround ? Several measures that can be taken byth e government are described. Effects of the main policies canb e summarized asfollows : - price control may decrease alcohol consumption under certain conditions; - trends indicate that lowering theminimu m legal purchase ageresult s in an increase of alcohol consumption and alcohol-related accidents and fatalities, whileraisin g the MLPAha sth e opposite effect inth e affected agegroups ; - alcohol advertisement on consumption has asmal l effect, ifany , on total alcohol consumption; - media used for campaigns against alcohol abusema ychang e thepublic' s behaviour with regard to alcohol consumption, but firm conclusions cannot be drawn yet; - alcohol education programmes mayb e agoo d policy to change thebehaviou r of the youth, but strategies have tob echange d tob e effective.

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250 56. Popham RE, Schmidt W, de Lint J. The prevention of alcoholism: epidemiological studies on the effects of government control measures. BrJ Addict 1975;70: 125-44. 57. Raymond A. Ten o'clock closing:th e effect of the change in hotel bar closing time on road accidents inth e metropolitan area of Victoria. Aust Road Res 1969;3:3-17 . 58. Ravn I. The control-of-consumption approach to alcohol abuse prevention. II: arevie wo f emperical studies. Int J Addict 1987;22: 957-79. 59. Room R. Social science research and alcohol policy making. Paper given at the Conference on the Utilization of Research in Drug Policy Making, Washington, 1978. 60. Rundall TG, Bruvold WH. A meta-analysis of school-based smoking and alcohol use prevention programs. Health Educ Q 1988;15:317-34 . 61. Säilä SL.Th e experiment of Saturday closing and drunken misbehavior. Alkoholpolitik 1978;41:61-9. 62. Schmidt W, Popham RE. The single distribution of alcohol consumption. J Stud Alcohol 1987;39:400-19 . 63. Simon JL. The economic effects of state monopoly of packed-liquor retailing. J Pol Econ 1966;74: 188-94. 64. SkogOJ . On the distribution of alcohol consumption. Oslo: National Institute for Alcohol Research, 1977. 65. Skog OJ. Isalcoho l consumption lognormally distributed? Oslo: National Institute for Alcohol Research, 1979. 66. Skog OJ. Total alcohol consumption and rates of excessive use: a rejoinder to Duffy and Cohen. BrJ Addict 1980:75:133-45. 67. Skog OJ. The collectivity of drinking cultures: a theory of the distribution of alcohol consumption. BrJ Addict 1985:80: 83-99. ' 68. Skog OJ. An analysis of divergent trends in alcohol consumption and economic development. J Stud Alcohol 1986;47:19-25. 69. Smart RG, Cutler R. The alcohol advertising ban inBritis h Columbia: problems and effects on beverage consumption. BrJ Addict 1976;71: 13-21. 70. Smart RG. The relationship of availability of alcoholicbeverage s to per capita consumption and alcoholism rates.J Stud Alcohol 1977;38: 891-96. 71. Smart RG. Changes in alcoholicbeverag e sale after reductions in the legal drinking age. AmJ Drug Alcohol Abuse 1977;4: 101-8. 72. Smart RG. Priorities minimizing alcohol problems among youth people. In: Blake HT, Chafetz ME, eds. Youth, alcohol and social policy. NewYork : Plenum Press, 1979: 229-62. 73. Smart RG. The impact of prvention measures: an examination of research findings. In: Institute of Medicine: an Inter-American workshop. Washington DC: National Academy Press, 1982: 224-46. (Publication IOM-82-003.) 74. Wagenaar AC. Aggregate beer and wine consumption: effects of changes inth e minimum legal drinking age and a mandatory beverage container deposit in Michigan. J Stud Alcohol 1982;43: 469-88. 75. Walsh BM. Alcoholicbeverage s in Ireland: market forces and government policy. BrJ Addict 1989;84:1163-71. 76. Wechsler H, Sands ES. Minimum age lawsan d youthfull drinking: an introduction. In: Wechsel H, ed. Minimum-drinking-age laws:a n evaluation. Lexington, MA: Lexington Books, 1980: 1- 10. 77. Whitehead P. Is advertising effective? Implication for public health policy. In: Rush B, Ogborne A, eds. Evaluation research inth e Canadian addictions field. Ottawa, Canada: Health and Welfare, 1982. 78. WilliamsTP , LillisRP . Changes in alcohol consumption by 18-year-oldsfollowin g an increase in NewYor k State's purchase aget o 19.J Stud Alcohol 1986;47:290-6 . 79. WilliamsTP , Lillis RP. Long-term changes in reported alcohol purchasing and consumption following an increase inNe wYor k State'spurchass e age to 19. BrJ Addict 1988;83:209-17 .

251 CHAPTER 18 Measures to control alcohol abuse

E. te Wierik

As mentioned in Chapter 17,preventio n of alcohol abuse canb e classified into primary, secondary and tertiary prevention. Primary prevention hasbee n discussedi n Chapter 17. The aim of secondary prevention, i.e. earlyidentificatio n of developing cases, ist o givea n alcoholic access to help now, an alternative to the old strategyo f allowing the alcoholic to 'hitbottom ' before initiating efforts to change drinking behaviour. Tertiary prevention isth etreatmen t of problem drinkersb ymean so f various methods. Secondary and tertiary prevention willb e elaborated below.

18.1. Earlyidentificatio n and treatment •

The process of secondaiypreventio n canb e divided into screening, recruitment and implementation (31).

18.1.1. Screening

Screening isdesigne d to differentiate among apparently healthy people, separating thosewh o probably haveth e condition of interest from thosewh o havenot . One of thefirs t identified idicators of alcohol abusei sth eleve l of serum gamma- glutamyltransferase (GGT). GGT isa live r enzymewhos eleve l iselevate d in caseo f excessivealcoho l use (34). Another objectivebloo d indicator used for screening and diagnosis isth e mean corpuscular volume (MCV). However, thevalue s of thesetw o parameters are also affected bysubstance s other than alcohol, aswel la sb yphysica l conditions unrelated to drinking. Furthermore, they areno t invariably elevatedi n heavy drinkers. Therefore, both GGT and MCV tests are considered as imperfect screening tests (7, 56),bu t for thetim ebein g they are thebes t available. Theleve l of serum ferritin, themajo r storagefor m of iron in thebody , has been found tob e significantly higher in heavy drinkers, but asa screenin g test it did not giveadditiona l information over acombinatio n of GOT and MCV (12). Other new laboratory diagnostic markers havebee n developed, such asseru m mitochondrial aspartate aminotransferase (mAST) activity (46, 47), carbohydrate-deficient transferrin level (58, 67), aldehyde dehydrogenase activity in redbloo d cells(70) , platelet affinity to serotonin (36) and urinary dolichols (60). Further research is needed to confirm their usefulness in routine screening. Besides theselaboratoriu m tests self-report instruments liketh e Michigan Alcoholism Screening Test (55), the CAGE questions (40) and other diagnostic tests 252 mentioned in Chapter 1ar ebein g used. Theseintervie w testsar e rapid and inexpensive. Additionally, theyar egenerall y more sensitive than routine biochemical tests (8,33) . Until the newmarker s of alcohol usementione d haveprove d their usefulness, GGT (perhaps in combination withMC Van dAST ) isstil l thebest , cost-effective biochemical indicator of recent alcohol abuse. Self-administered or interview tests areknow n tohav ea hig h sensitivity and areasonabl e specificity, but are prone to deliberate falsification and subconscious denial. Therefore, GGT combined with one or more self-administered or interview tests andwit h theful l clinical picturei s the method of choicefo r the assessment of alcoholism (26, 38, 48). Two screening procedures havecombine d thebiological , clinical and verbal report methods into one screening procedure. Thesetw o screening approaches areth eWorl d Health Organization's Alcohol UseDisorder s Identification Test (AUDIT) and theAlcoho l Clinical Index (61, 64). Although thesene w screening testshav eno t been studied yet, the use of combined procedures presently holds great promisefo r early identification.

18.1.2.Recruitment

Onceindividual s at riskhav ebee n identified, the question isho w they can be engaged in intervention intended to reduce risk? Thegloba l intensity of this intervention need not be determined byth emeasure s required for themor e damaged patient, which would implytha t scarceclinica l resources would be directed ata unnecessarily largenumbe r ofpeople . Given the distinctivecharacte r - in the eyeso f thepotentia l client- of specialist units dealingprimaril ywit h alcohol-related problems, namely units dealingwit h 'alcoholics', iti sunlikel y that theywil l attract thesepotentia l clients. Thesolutio n to this dilemma, therefore, ist o conduct the intervention in general hospitals, general practice, industry and the like(59) . Clinical studieshav eshow n that problem drinkers consult their doctors more frequently than do others (10). So, health professionals in primary care and communityhealt h settings (e.g.famil y doctors, publichealt h nurses) are often ina good position to identify individualswh o drink excessivelybu t dono t consider themselves as 'alcoholics'. The results ofa stud yi n Sweden are encouraging (34):i n a screening programme among middle-aged men, 585proble m drinkers were identified on thebasi s of elevated liver enzyme (GGT) level. These caseswer e randomly assigned to either brief advicean d continuingfollow-u p consultations with a physician, or to acontro l group advisedb ylette r torestric t their alcohol consumption. During a4-6-yea rfollow-up , theinterventio n group, ascompare d to thecontro lgroup , gavea 80%reductio n of absenteeism, a 60%reductio n of hospital daysan d a 59%reductio n ofmortality . Thisstud yclearl y demonstrates the potential impact of physician's advicet o problem drinkers. Theauthor s conclude that screeningfo r early-stageproble m drinkerslinke dwit hbrie f adviceo n drinking habits isa n effective strategy that shouldb eroutinel y used in general hospitals.

253 Recent reports suggest that theinformatio n obtained during screening can be used asfeedbac k to motivate anindividual' s engagement inprogramme s aimed ata changeo f habits. Miller et al. (45) report amodes t decrease of alcohol use and increasedhelp-seekin g in apopulatio n ofproble m drinkersfo r a 'drinker's check­ up' that involved feedback regarding personal impairment related to alcoholuse . The drinker's check-up isoffere d toindividua l drinkers asa mean s to discover what negative effects alcohol mayhav ei nthei r livesan d consists of abatter y of measures sensitivet o alcohol's early effects on health andbehaviour . Ojectivefeedbac k from thesemeasure si sgive nt o the drinkerwit h theintentio n toincreas eawarenes so f risk.

18.1.3. Implementation

Evenwhe n effective screening, recruitment and intervention strategieshav ebee n defined, there remain anumbe r of logistical, technical and professional.issue stha t mustb e addressedbefor e promisingfinding s arelikel yt ob e appliedi n'clinica l practice and public health settings. Evidencei smountin g for the success of early intervention strategies for alcohol problems. Despitethi spromisin g prospect, early intervention programmes areno tbein gimplemente d on anysystemati cbasis . The following reasons areoffere d for this apparent lack of action (65): - wide-spread pessimism amongth ephysician s aboutbein gabl et o intervene effectively, - the multidisciplinary nature of alcoholproblem s (social, medical, psychological problems, traffic accidents, crime) givingris et o confusion ast o thequestio n who isresponsibl e for tackling alcohol problems, ' - uncertaintywit h regard to the appropriate target population, - inappropriate treatment programmes and philosophies, - practical skillsan d techniques notbein g taught tohealt h professionals. Given the considerable promisetha t earlyinterventio n strategies hold for reducing alcohol and drug abuse, onemus t address theissu eo fho w early intervention programmes canb eimplemente d in asystemati cwa yb yhealt h professionals. Thefollowin g steps arepropose d (65): - adopt abasi cstrateg yfo r early intervention, - makepractica l techniques and training available, - convinceke ypeopl e toimplemen t the programme. Secondary prevention isa promissor ypath , but therei sstil la lon gwa yt ogo .

18.2. Treatment of alcoholism

Recently area l explosion of studieshav ereporte d results from themultitud eo f disciplines involvedi n the treatment ofalcoho labus e and dependence. Treatment seeks tobrin g about achang ei n theindividual' s useo f alcoholan dothe r drugs and to reduceproblems accociatedwit h that use. Typically, thegoa lo f treatment

254 programmes hasbee n total abstention from alcohol and other drugs. Among the methods of treatment various approaches can be distinguished, such as detoxification, pharmacotherapies, mutual help groups, psychotherapy, hospitalization and relapse prevention.

18.2.1. Detoxification

A necessaryfirs t stepi n the treatment of alcoholism isdetoxification . This procedure isdesigne d to carry the individual safely through theproces s of alcohol withdrawal, minimizing the risks associated with the abstinence syndromefo r thosewh o are severely dependent on alcohol. Detoxification poses special problems for persons who experience an alcoholwithdrawa l syndrome. The cluster of symptoms ranging from tremulation and seizures to delirium tremens maymanifes t when alcohol consumption isdiscontinue d after prolonged heavyconsumption . According to Arnold &Feuerlei n (6) a drug must ensure thefollowin g effects in treatment of delirium: sedation, elevation of thelimi t atwhic h thepatien t decides to stop treatment, suppression of autonomic hyperexcitability, and antipsychotic effects. Busch &Fring s (11) havereviewe d variousfrequentl y used pharmacological concepts. Chlomethiazole and benzodiazepines are established monotherapeutics against delirium. However, their somatic side-effects and, above all, the problemso f dependence on thismedicatio n make itnecessar y to look for alower-ris k medication. In anycase , physicians must look more closely into the possibility of treating the individual alcohol-withdrawal syndromewit h an agent that isles sliabl et o cause addiction. Carbamazipineseem s tob ea n effective substancewithou t dependence potential. It canb e usedfo r the treatment of severealcoho l syndromes. Other treatments are still under investigation, such as diphenylhydantion (3), gamma- hydroxybutyric acid (22) and calcium channelblocker s (37).

18.2.2. Pharmacotherapy

Medication in the treatment of alcohol problems canb e classified into three major strategies. 1.Antidipsotropic medications. Thesemedication s causeadvers e reactionswhe n alcohol isconsumed . Their intended effect ist o suppress drinking. Disulfiram isth e antidipsotropic medicinemos t frequently used. Iti sa n inhibitor of aldehyde dehydrogenase, an enzymetha t catalyses theoxidatio n of acetaldehyde. Ethanol ingestion during disulfiram treatment resultsi n veryunpleasan t symptoms (e.g. flushing, tachycardia, hypotension) which aregenerall ybelieve d tob e consequences of the elevated concentrations of acetaldehyde (29). Disulfiram mayhav ea long - lastingbeneficia l effect for certain subgroups ofpatients , such as elderlypatients , socially stablepatients , and patientswh o arewel lmotivated . Treatment with disulfiram hasn o established effect on thelong-ter m outcome of alcoholism (4,73) . Calcium carbimide, another dipsotropic medication, isavailabl ei n Canada and Europebu t hasno tye tbee n admitted for therapeutic usei nth e USA. Carmibide 255 appears tob eles stoxi can t toyiel dles sside-effect s than disulfiram (53). Well- controlled clinical trialswit h carbimidehav eno tye tbee n reported. 2.Effect-altering medications. Effect-altering medications are designed to reduce the reinforcing properties of ethanolwithou t producing illnessrathe r than to induce aversivereaction s to alcohol. Numerous serotonin uptakeinhibitor s havebee n shownt o decrease alcohol consumption in animalmodels . Inhibition of serotonin, a neurohormonal compound, inducesflushing . Zimelidine, Citalopram, viqualine and fluoxetine appear to increaseabstinen t daysan d to lower thenumbe r of drinks on drinking daysi nmoderatel y dependent drinkers (63). 3. Psychotropics. Psychotropic medication isdesigne d to treat such concomitant disorders as depression, psychosis and anxiety. Their intended effect ist o alleviate psychopathology that mayaccompan y alcohol abuse, thereby diminishing the likelihood ofrelaps e to drinking. Lithium, antidepressant and antipsychotic medications are of known therapeuticvalue .

18.2.3. Mutualhelp groups

Thefellowshi p Alcoholics Anonymous (AA) hasbee n founded in 1935whe n two alcoholics discovered that itwa spossibl e to abstain from alcoholb ymutua l help. The fundamental principles of AAar e embedded init stwelv etradition s which have one purpose: recovering alcoholics. In theideolog y ofAA , alcoholism has tob e regarded as a disease that hast ob e controlled. Themember s ofA Ahav et o learn to be responsiblefo r their ownbehaviour . Their responsibility isno t to drink (27). The effectiveness ofA Aha sbee n discussedwidely . Emrick (15, 16)ha s reviewed evaluation studieswit h regard to data on AA's effectiveness asa treatment . He concludes thatwhe n alcoholicsparticipat ei nA Ai n addition to professional treatment, results areno t worsean dma yb ebette r than for patientswh o do not engagei nAA . AA involvement tends tob e associatedwit h relatively high abstinence ratesbu t with lowtota l improvement rates. Emrick argues that thehig h abstinence rates derivefro m aself-selectio n process inwhic h thoseindividual swh o aremos t likelyt o commit themselves to and achieveabstinenc e areth e onesmos t apt tojoi n AA. According to Emrick, the effectiveness of AAa scompare d to other treatments of alcoholism hasye tt ob e demonstrated. Other authors aremor epositiv etoward s the effectiveness ofA A (2, 30, 39, 57). Geelen (23), inhi srevie w on the effectiveness ofAA , notes thatA Ai sattractiv et owomen , higher-educated people and people aged 35-50. Thisimplicate stha t AAi sself-selective . Geelen stresses that thefinding s of the studies reviewedwer ehar d tointerpre t sincemos t studies contained methodological weaknesses. Despite theseshortcoming s he concluded that theresult swer epromisin g and comparablewit h those of professional treatments.

256 18.2.4. Psychotherapy

Psychotherapy means the treatment of alcoholism bypsychologica l methods. The four basic elements ofpsychotherap y according to Frank (21) are: a confidential relationship between patient and therapist; agoal -an d mind-mediated treatment theory; a demanding and supporting manner; and aconvivia l treatment institute. Several problems regarding thesefou r elements havebee n reported (54). Controlled treatment studiesprio r to 1980faile d toyiel d any evidencefo r the effectiveness of psychotherapy for alcoholics (43). Recent controlled studies have not substantially altered this picture (9, 50). Similarly, Annis &Cha n (5) found no effect of confrontational group therapy in arandom-assignmen t designwit h incarcerated alcohol-related offenders. Individuals lowi n self-esteem suffer detrimental effects from confrontational psychotherapy, whereas thosehighe r inself - esteem experience somebenefit . Swenson &Cla y (69) observed no differences after an eight-month follow-up intervalbetwee n drunk-driving offenders assigned to confrontational group therapy and thosegive n onlya home-stud y course.

18.2.5. Hospitalization

It isa common-sens e assumption that if one kind of treatment islonger , more intensive, offered in ahospita l or more expensivetha n another one, it should also be more effective. Several uncontrolled studieshav ereporte d morefavourabl e outcomes among patients receiving longer treatment in either inpatient (residential) or outpatient (non-residential) settings (19, 42, 66). Others havefoun d no relationship (49, 51) or even anegativ e correlation (25). Miller &Heste r concludetha t 26 controlled trials haveconsistentl y failed to show an overall advantagefo r residential over non­ residential settings, or for moreintensiv eove r lessintensiv eintervention s in treating alcohol abuse. Intensivetreatmen t mayb e differentially beneficial for severely deteriorated and socially unstable (e.g. unemployed or homeless) individuals (44). In a prospective multi-centre studyfo r inpatient treatment of female alcoholics a negative relationship between prognosis and length of treatment hasbee n observed (i.e. thebette r the prognosis, the shorter the treatment). For men, no statistically confirmed correlation between rateo f abstinence and length of treatment could be established (18). Thevalu eo f inpatient treatment hasbee n confirmed byAdelma n & Weis (1) who found somefeature s that appeared tob ehelpfu l in inpatient treatment. Thesefeature s include aresponsiv eintak eprocedure , patient participation in treatment planning, aprofessiona l staff with good interpersonal skills, interdisciplinary assessment, judicious useo f medication, and astron g aftercare programme. Inpatient hospital-based medical treatment appears tob e themos t common form of alcohol detoxification (62). Because of thehig h costs of this treatment studies havebee n performed in order to estimateth e effectiveness of outpatient detoxification. Hayashida et al. (28) concludetha t outpatient medical detoxification 257 isa n effective, safe and cost-effective treatment for patientswit h mildt o moderate symptoms of alcoholwithdrawal . These conclusions are confirmed byColling s etal . (13) who suggest that outpatient detoxification may obviateth enee d for many patients tob e admitted, freeing psychiatricbed s for other uses. Recently, in England an experiment including home detoxification hasbee n started. Alcoholicswh o also participated in aftercare programmes andwh o scored lowi n an alcohol problems inventory, had better changes for afavourabl e progress (68).

18.2.6. Relapseprevention

Relapse prevention includes anyinterventio n that isdesigne d to diminish or forestall relapses after treatment. Programme components referred to as 'aftercare' have been designed to promote this samegoal . Thewor k ofVannicell i (72) and Costello (14) suggests that aftercare attendance isinstrumenta l in fostering maintained abstinence. One obstaclei n evaluating aftercare programmes isth ehig h drop-out rate. Ossip- Klein et al. (52) haveobserve d that distribution of calender prompts and a contract laying down that the patient has agreed to attend aftercare increase attendance and hence theprobabilit y of long-term maintenance of alcohol treatment effects. Gilbert (24) found that meeting the alcoholics at a convenient location improved therapy attendance, but this didno t correspond one-to-onewit h an improved treatment outcome. Approaches of relapse prevention found tob esuccessfu l varyfro m attendanceo f AAmeeting s (32, 71) to antidepressant agents (35) and aftercare services for adolescents rendered byclinician s (aftercare managers) (17). Conflicting results arereporte d byFitzgeral d &Mulfor d (20) who tested frequent telephone contacts in addition to theusua l aftercare treatment and found them ineffective as compared to the usual treatment without the experimental element. McClatch &Lom p (41) also didno t find an advantageo f extended therapy in the treatment of alcoholics. Theywer e not able to observe a difference between mandatory aftercare, voluntary aftercare and no aftercare at allwit h regard to relapse rate, satisfaction withlife-styl e and anxiety symptoms. They recommend a more individual aftercare planning for alcoholics.

Summary

Secondary prevention, i.e . earlyidentificatio n and treatment of developing casesca n be divided into screening, recruitment and implementation. Until now, thebes t method of identifying alcohol abusers isth e combination of the useo f the gamma- glutamyltransferase level asa n alcohol abuseindicato r with one or more self- administered or interview tests andwit h theful l clinicalpicture . Theinterventio n to be given to earlyidentifie d alcohol abusers need not to asintensiv e aswha t might be required for more damaged patients. Promising results emergefro m a studyi n

258 Sweden inwhic h apotentia l impact of the doctor's adviceha sbee n demonstrated. Despite thepromisin g results of earlyidentificatio n there are still several reasonswh y earlyinterventio n programmes haveno t yetbee n implemented on a systematicbasis . Thereason s for thislac k of action and aproposa l for an earlyinterventio n strategy aregiven . The approaches towardstertiary prevention mentioned in this chapter are detoxification, pharmacotherapies, mutual help groups, psychotherapy, hospitalization and relapseprevention. Anecessar yfirs t stepi n the treatment of alcoholism isdetoxification . Chlometiazole andbenzodiazepin e are established therapeutics against delirium, but thesemedication s suffer from side-effects. Carbamazipine seems to bea n effective alternative. The use ofmedicatio n in the treatment of alcoholics can follow three major strategies. Antidipsotropic, effect- altering and psychotropic medication are described. Although theresult s concerning the effectiveness ofmutual-help groups such asAlcoholic s Anonymous (AA) are contradictory, results arepromising . Thehig h abstinence rates inA Ama yb ebase d on a self-selection process. Evidencefo r the effectiveness of psychotherapy isno t convincing to date. Outpatient treatment ofalcoholic s appears tob ea n Effective, safe and cost-effective treatment for moresociall ystabl ean dles s deteriorated individuals. Conflicting results arereporte d concerning relapseprevention. A more individuallyoriente d aftercare planning has been recommended.

References

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261 r'

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262 Subject index

absenteeism 18.1.2 —-induce d ketosis 5.1 absorption —-induce d pancreatitis 12.1.5 —o f alcohol 2.1 - intoxication 8.2.3 —o f nutrients 11.1.5 - liver disease, treatment of 8.3 —phas e 2.3.1 —metabolis m 3 abstinent culture 17.1.2 —metabolism , modification of 3.7 abuse, measures to control 18 —-relate d birth defects 13.1 accumulation of fat 8.2.1 —withdrawal delirium 9.2.2 acetaldehyde 2.3.1, 3.2.1, —withdrawal syndrome 6.7, 18.2.1 3.3, 3.4, 4.6, 5.1, -, fusel 12.3.1 8.2.4, 12.3.4, alcoholic (definition) 1.3 13.4.1 - beverages, differences between 2.1.2, 12.2 —dependenc e 9.2.3 - cardiomyopathy 10.7 —poisoning , acute 3.3 —cirrhosi s 3.6 acetate 2.3.1, 3.4, 3.5, 5.1 —dementi a 9.2.1 —,extrahepati c dissimilation of 3.5 —fibrosi s 5.3 acetoacetate 5.1 —hear t disease 10.7 acetyl-CoA 3.5, 3.6, 5.1, 5.3 —hepatiti s ,8.1 acetylsalicylic acid 11.1.2.2 —ketoacidosi s 5.1 acidaemia 5.1 —ketosi s 5.1 acidophilic hyalin 8.1 —live r disease 8.2 acidosis 5.1 Alcoholics Anonymous 18.2.3 —, lactic 5.1 alcoholism (definition) 1.3 —, metabolic 7.2.2, 14.6.1 -, aetiologyo f 15 adaptation 9.2.2 -, alpha 1.3 adenosine monophosphate, cyclic 5.2 -, beta 1.3 adenylate cyclase 15.1.4.2 -, familial history of 15.1.1 adipose tissue 5.3 -, gamma 1.3 adoption studies 15.1.3 —, paternal 13.7 adrenaline 4.7, 5.2, 10.3 —,treatmen t of 18.2 adrenocorticotropic hormone 4.6 aldehyde dehydrogenase 2.3,2, 3.3, 15.1.4.2 advertising of alcohol 17.2.4 18.2.2 —,self-censorshi p in 17.2.4 —activit y 18.1.1 aetiology of alcoholism 15 aldorase activity, erythrocyte 8.6 aftercare 18.2.6 aldosterone 4.1 age 15.5.4.1 alkaline phosphatase 8.6 aggregation, platelet 10.2 alkalosis agitation, psychomotor 9.2.2 -, metabolic 5.1 alanine aminotransferase 8.6 -, respiratory 7.2.4 albumin 5.4 alpha alcoholism 1.3 alcohol ambivalent culture 17.1.2 - abuse, measures to control 17.2, 18 amblyopia 11.3.2 - abuse, prevention of 17 amenorrhoea 4.9.1 —amnesti c disorder 9.2.1 amino acids —-associate d cardiomyopathy 7.1 —,absorptio n of 11.1.5 - -associated immunosuppression 12.3.4 -, placental transport of 13.4.2 —deficienc y 2.3.1 amino groups, free 8.2.5 - dehydrogenase 3.2,4.8, 6.1, 7.2.7, aminobutyric acid 8.4.4, 15.1.4.2 aminobutyric acid, alpha- 5.4 - dehydrogenase activity 9.1.2 —/leucin eratio , alpha- 8.6 —dependenc e 1.3 —, gamma- 9.2.3 —educatio n 17.2.5 aminolaevulinic acid dehydratase 8.6 —-fre e beer 14.1 aminopyrine 2.1.3 —-induce d fibrosis 8.1 amylase, renal clearance of 11.1.1

263 anabolic steroids 8.3 biokinetics of alcohol 2 anaemia 7.2.6, 8.2.3, 11.6 biologicalmarker s of alcoholism 15.1.4 -, haemolytic 6.9, 11.6 biotransformation 3.6 -, megaloblastic 6.5, 6.6 birth angina - defects, alcohol-related 7.2.7, 13.1 —pectori s 10.6 —weigh t 13.3.1 —, variant 10.6 black-out 9.1.1 angiography, coronary 10.4 bleeding time 10.2 anomalies, congenital 13.3.3 blindness, night 6.1 anorexia 7.2.7, 8.1 blood 11.6 antidipsotropic drugs 3.3, 18.2.2 —alcoho l concentration (BAC), antidiuretic hormone 4.1, 7.1, 7.2.1 maximum allowable 16.2.3 antigen, human lymphocyte 15.1.4.2 —alcoho l curve 2.3.1 antimicrobial drugs 3.6 - lipids 10.1 antioxidant 6.9, 8.2.4 —pressur e 10.3 antitubular effect of alcohol 8.2.2 bodily constitution 2.2.2 antocholinergic drugs 2.1.3 body antral injury 11.1.2.2 —mas s 8.4.4 anxiety 9.2.2 - temperature 2.3.2 apolipoprotein 10.1 —wate r 8.4.4 apprehension, increasing chanceo f 16.3.1 bone marrow -.11.6 arachidonic acid 5.3 bourbon "'4.8, 14.6.3 area under the blood alcohol curve 2.1.1, 3.2.1 brain- 9 arginine vasopressin 9.2.1 - atfophy 9.2.1 aromatic hydrocarbons, polycyclic 12.3.1, 12.3.4 —damag e 5.2, 6.2, 6.6, 9.2. arrest, increasing risko f 16.3.1 brandy 9.1.3 arrhythmia, cardiac 3.4, 10.7 breast arteriography 10.4 —cance r 12.1.3 articulation abilities 13.3.2 - -feeding 13.5 asbestos fibres 12.3.1 breath alcohol analysis 2.2.1 ascites 7.1 ascorbic acid 2.3.2, 8.2.4 caffeine 2.1.1, 2.3.2 aspartate aminotransferase 8.6, 18.1.1 calcitonin 4.2 —, mitochondrial 18.1.1 calcium , 7.2.3 aspirin 2.1.3, 11.1.2.2 —carbimid e 18.2.2 atherosclerosis 10.4 —homeostasi s 6.8 ATPase 11.1.5 calvados 12.2 atrial fibrillation 10.7 campaign, media 17.2.4 atrophic gastritis, chronic 11.1.2.2 cancer 12 atrophy —o f the breast 12.1.3 —o f type lib fibre 11.5.2 — of the digestive tract 12.1.1 —, cerebral/brain 9.2.1 — of the endolarynx 12.1.1 —, testicular 6.1 — of the epilarynx 12.1.1 autonomic regulation (control) 13.3.2 — ofth e hypopharynx 12.1.1 availability of alcohol 17.2.2 - of the larynx 12.1.1 - of the liver 12.1.1, 12.1.2 barrier breaker 11.1.2.2, 12.3.4 - of the lung 12.1.4 beer 8.4.5, 12.1.6, 12.2, — of the oesophagus 12.1.1, 12.3.1 13.5, 14.4, 14.5 — of the oropharynx 12.1.1 behaviour 15 — of the paficreas 12.1.5 —, reflexive 13.3.2 - of the prostate •12.1.6 behavioural problems 13.3.2 - of the rectum 12.1.6, 12.2 benzodiazepines 9.2.2, 18.2.1 - of the sigmoid colon 12.1.6 beriberi, cardiac 6.2, 10.8 - ofth e stomach 12.1.6 beta alcoholism 1.3 carbohydrate 2.1.2, 2.3.2, 14.3 beverages, differences between 2.1.2, 12.2, 14 —intoleranc e 4.5 biliary pancreatic reflux 11.2.2 - metabolism 5.2, 11.2 biochemical markers —-deficien t transferrin 8.6 —fo r alcohol abuse 8.6 carcinogenesis 7.2.7, 12 —o f alcoholism 15.1.4.2 —,mechanism so f 12.3

264 carcinoma, hepatocellular 12.3.3 coma 6.2 cardiac communication skills 13.3.2 - abnormalities 13.3.3 concentration tests 9.1.1 —arrhythmi a 3.4, 10.7 confrontational group therapy 18.2.4 - beriberi 6.2, 10.8 confusion 5.2 cardiomyopathy 5.3 congeners 14.6 -, alcohol-associated 7.1, 10.7 congenital anomalies 13.3.3 cardiopathy 10.3 congestion, pulmonary 6.2 cardiovascular consciousness, disturbances of 9.2.2 —diseas e 10.1 constitution, bodily 2.2.2 —syste m 10 constitutional studies of alcoholism 15.1 - system of the unborn 13.1 control, modelso f 17.1 catabolism 3.2.2 coordination 9.1.1 catalase pathway 3.2.3 coronary cataract 11.3.2 - angiography 10.4 catechin 14.6.3 -heart disease 10.1, 10.5 catecholamine 3.4, 10.3 —stenosi s 10.4 cell membrane narcosis 13.4.1 corpuscular volume, mean 8.5, 11.6, 18.1 cellular corticosteroids 8.3 —mechanism s 13.4.3 Cortisol 4.6, 15.1.4.2 —toleranc e 9.2.2 cough, productive 11.4 central nervous system 2.3.2, 13.1, 13.3.2, craniofacial abnormalities 13.3.3 15.1.4.1 cream liqueur 14.3 centrilobular hypoxia 8.2.3 cultural factors of alcoholism 15.5.1 cerebral culture / —atroph y 9.2.1 —, abstinent 17.1.2 —dysfunctio n 9.2.1 -, ambivalent 17.1.2 —glucos e utilization 6.2 —, overpermissive 17.1.2 —oedem a 9.2.1 —, permissive 17.1.2 check-up, drinker's 18.1.2 Cushing syndrome 4.6 chest radiography 8.6 cyanide 11.3.2 chlormetiazole 9.2.2, 18.2.1 cyclic adenosine monophosphate 5.2 cholecalciferol 6.8 cytochrome P-450 3.2.2, 3.6,6.1, —metabolis m 4.2 12.3.4 cholecystokinin 11.1.3 —reductas e 8.2.4, 12.3.4 cholesterol, HDL 8.6 chromium 14.5 dealcoholized beverages 14.1 chronic alcohol consumption 9.2 deficiency Cimetidine 3.6 -, alcohol 2.3.1 circadian rhythm(icity) 2.3.2 -, dietary 12.3.2 cirrhogenic activity of beverages 8.4.5 definitions of alcoholism 1 cirrhosis 7.1, 8.4.3, 10.4, delirium 12.1.2, 12.3.3, —tremen s 6.7, 9.2.2 12.4, 15.1.4.2 —, alcohol withdrawal 9.2.2 - mortality 8.4.5, 8.5 dementia, alcoholic 9.2.1 —,alcohol-induce d (alcoholic) 3.6, 6.1 dependence, alcohol 1.3, 9.2.2 -, epidemiology of 8.5 depressions 9.2.2 citric acid cycle 5.1, 5.3, 6.2 deterrence, general 16.3 clearance, renal 5.1 detoxification 4.1, 18.2.1 closingtim e of outlets 17.2.2 diarrhoea 7.2.7 clouding, mental 9.2.2 diastolic blood pressure 10.3 cocarcinogen, ethanol asa 12.3.4 dietary deficiency 12.3.2 coenzyme A (CoA), acetyl- 3.5, 3.6 differences cognitive —betwee n beverages 14 - dysfunction 9.2.1 - in cirrhogenic activity 8.4.5 —functio n 6.2 digestive tract 2.1, 11.1.1 colchicine 8.3 —,cance r of the 12.1.1 collagen 5.1, 5.4, 8.2.6 dihomogammalinolenic acid 5.3 - production 8.2.2 dihydroxycholecalciferol, 1,25- 6.8 collagenase 8.3 dilatation, vascular 11.1.2.2

265 dilution effect 2.1.2 enzymes direct carcinogenic effect 12.3.1 -, intestinal 11.1.5 —, pancreatic 11.2.2 disaccharidase 11.1.5 disaccharide 14.3 epidemiology 12.1 disorientation 9.2.2 - of liver cirrhosis 8.5 dissimilation of acetate, extrahepat c3.5 epilarynx, cancer of the 12.1.1 distribution epinephrine, see adrenaline - of alcohol 2.2 equation, Michaelis-Menten 2.3.1 —o f isozymes 3.2.1 erosion —o f gastric mucosa 2.1.2 disulfiram 3.3, 3.4, 3.6, 1 18.2.2 diuresis 4.1, 7.1 —o fjejuna l villi, haemorrhagic 11.1.5 diurnal rhythm(icity) 2.1.3 -, mucosal 11.1.2.1 erythrocyte DNA research 15.1.4.3 11.6 dolichol 8.6, 18.1.1 - aldorase activity 8.6 dopamine 3.4, 4.7, 9.2.3 escapism 16.1 dose-response relationship 13.3.1 esophagus, see oesophagus double vision 11.3.1 essential fatty acid 5.3 drinker's check-up 18.1.2 - metabolism 8.2.2 drivingwhil e intoxicated 16 estrogen etc., see oestrogen etc. drop-out rate 18.2.6 ethanol 1,5.1, 12.3.1, 14.2 drugs —a sa cocarcinogen .'.12.3.4 -, anticholinergic 2.1.3 etiol-, see aetiol- -, antidipsotropic 3.3 excessivedrinking/drinke r 1.1 —, antimicrobial 3.6 exercise, physical 2.2, 2.3.2 -,CNS 9.2.2 expiratory volume, forced (FEV) 11.4 ductal plug 11.2.2 extracellular fluid 7.1 extrahepatic dissimilation of acetate 3.5 duodenopancreatic reflux 11.2.2 eye 11.3 dysfunction, sexual 4.8 dysmorphology, facial 13.1 facial dysmorphology 13.1 dyspnoea 6.2 false neurotransmitters 3.3, 9.2.3 early identification 18.1 familial history of alcoholism 15.1.1 family edema, see oedema education programmes 16.2.1, 16.4.2 - relations ' 15.5.2 —studie s of alcoholism 15.1.1 17.2.5 —, peer-led 17.2.5 fasting hypoglycaemia 5.2 —, teacher-led 17.2.5 fat 2.1.1 educational approach 16.4.2 - accumulation 8.1, 8.2.1 - catabolism effect-altering medication 18.2.2 5.1 - malabsorption 11.1.5 eggnog 14.3 —metabolis m 5.3 eicosanoid formation 5.3 electrolyte —synthesi s 5.1 —balanc e 7.2.1 fatigue 8.1 —excretio n 10.3 fatty acid(s) electron transport 6.3 - ester synthetase 3.2.3 -, mitochondrial 3.2.1 -metabolism, essential 8.2.2 electrophysiological markers 15.1.4.1 —,endogenou s synthesiso f 5.3 —,essentia l 5.3 elimination - of alcohol 2.3 -, polyunsaturated 5.3, 8.2.3 —phas e 2.3.1 fatty liver 6.1, 8.1, 8.4.1 -rate 2.3.2 female - fertility 4.9.1 emprisonment 16.3.2 encephalopathy - sex hormones 4.9 ferritin 7.2.6 —, hepatic 4.3,9.2.1 —, Wernicke's 6.2,9.2.1 fertility endogenous synthesis offatt y acids 5.3 -, female 4.9.1 —, male 4.8 endolarynx, cancer of the 12.1.1 fetal, see foetal endorphin, beta- 15.1.4.2 fever 8.1 enterohepatic circulation 6.5 fibre, type lib 11.5.1 enterokinase 11.2.2

266 fibrillation, atrial 10.7 - absorption 11.1.5 fibrinogen 10.2 —intoleranc e 5.2 fibrinolysis 10.2 - utilization, cerebral 6.2 fibrinolytic activity 10.2 glutamate receptor 9.1.2 fibrosis, alcohol-induced (alcoholic) 8.1 glutamic-oxaloacetic transaminase 8.6 first-order kinetics 2.1 glutamic-pyruvic transaminase 8.6 first-pass metabolism 2.3.1, 3.2.1 glutamyltransferase flavanoids, phenolic 14.6.3 -, alpha- 8.6 flushing syndrome 3.4 -, beta- 18.1.1 foetal glutathione 5.4, 8.2.4 - alcohol effects 13.1 glycerophosphate, alpha- 5.3 —alcoho l effects, specific 13.3 glycogen stores 5.2 - alcohol syndrome 5.3, 7.2.7, 13.1, 13.2 glycogenosis 5.2 folate 6.5, 14.4 glycolysis 5.1 —deficienc y 6.5 glycoproteins 5.4 -, placental transport of 13.4.2 gonadotropin 4.9.1 folic acid 6.5 group therapy, confrontational 18.2.4 follicle-stimulating hormone 4.8 growth fortification of beverages 6.2 —hormon e 4.4 free amino groups 8.2.5 —hormone-releasin g hormone 4.4 free radicals 8.2.4 - retardation 13.1, 13.3.1 free water 7.2.1 —retardation , intra-uterine 13.4.3 frequency distribution of alcohol —,intra-uterin e (foetal) 13.3.1 users 17.1.1 gynaecomastia ' 4.8 fructose 5.1 functional tolerance 9.2.2 habituation 15.4 fusel alcohol 9.1.3, 12.3.1, 14.6, haemochromatosis 7.2.6 14.6.2 haemolysis 6.9 haemolytic anaemia 6,9, 11.6 galactose 2.1.1,2.3.2 haemorrhage gamma alcoholism 1.3 -, gastric 11.1.2.2 gamma-glutamyltransferase 18.1.1 -, gastrointestinal 8.2.3 gastric haemorrhagic —emptyin g 2.1 —erosio n ofjejuna l villi 11.1.5 - emptying, delay of 2.1.1 - stroke 10.5 —haemorrhag e 11.1.2.2 haemosiderosis 7.2.6 -juice 11.1.4 haemostasis 10.1 —lesion s 11.1.2.2 hallucinations 9.2.2 - motility 2.1.1, 2.1.2, 11.1.3 hangover 9.1.3, 14.6.2 —mucos a 11.1.2 headache 5.2 —mucosa , erosion of 2.1.2 heart disease, alcoholic 10.7 —mucosa , permeability of 11.1.2.2 heavydrinking/drinke r 1.1 gastrin 11.1.3, 11.1.4 help groups, mutual 18.2.3 gastritis 5.1 hemo-, see haemo- -, chronic atrophic 11.1.2.2 hepatic gastrointestinal —encephalopath y 4.3, 9.2.1 - haemorrhage 8.2.3 —lipas e 10.1 —hormon e 11.1.3 hepatitis 5.1, 8.2.4 —trac t 11.1 —B viru s 12.3.3 - tract bleeding 7.2.6 -, alcoholic 8.1 genes involved in alcoholism 15.1.4.3 hepatocellular carcinoma 12.3.3 genetic control 2.1.3 hepatocytes 8.1 genital system of the unborn 13.1 hepatomegaly 8.1 genito-urinary malformations 13.3.3 hereditary studies of alcoholism 15.1 globulin, sex hormone-binding 4.8 heredity 15.1 glucagon 4.5, 11.2 hexosaminidase, beta- 8.6 glucocorticoids 4.6 high-density lipoprotein 10.1 gluconeogenesis 5.1 - cholesterol 8.6 glucosamides 5.4 histamine 11.1.2.2 glucose 2.3.2 holiday heart syndrome 10.7

267 homeostasis, calcium 6.8 hypozincaemia 7.2.7 hormonal status 2.1.3 hormone identification, early 18.1 —metabolis m 4 immune dysfunction 7.2.7 —, adrenocorticotropic 4.6 immunity 8.2.5 —, antidiuretic 4.1, 7.1, 7.2.1 immunosuppression, alcohol- -, female sex 4.9 associated 12.3.4 -, follicle-stimulating 4.8 infarction, myocardial 10.2 -, gastrointestinal 11.1.3 inflammation of the liver 8.1 -, growth 4.4 inheritability 15.1 —, growth hormone-releasing 4.4 inpatient treatment 18.2.5 -, luteinizing 4.8 insulin 4.5, 5.1, 5.2, 11.2 -, luteinizing hormone-releasing 4.8 —-induce d hypoglycaemia 2.1.3 —,mal e sex 4.8 intelligence quotient 13.3.2 —, thyroid 2.3.2, 4.3 interaction -, thyroid-stimulating 4.3 - studies 15.6 —, thyrotropin-stimulating 4.3 -, pharmacodynamic 3.6 hospitalization 18.2.5 -, pharmacokinetic 3.6 human lymphocyte antigen 8.2.5, 15.1.4.2 intermediate brain syndrome 9.2.1 hyalin interstitium, pancreatic 11.2.2 —sclerosi s 8.1 intervention •18 —, acidophilic 8.1 —programmes , implementation of 18.1.3 hydrocarbons, polycyclic aromatic 12.3.1, 12.3.4 interview tests 18.1.1 hydroperitoneum 7.1 intestinal hydroxybutyrate 5.1 —enzyme s 11.1.5 hydroxycholecalciferol, 25- 6.8 - mucosa 11.1.5 hyperactivity 13.3.2 intestine 11.1.5 hyperaemia 11.1.2.1 -, small 11.1.5 hyperarnylasaemia 11.1.1 intolerance, carbohydrate 4.5 hypercortisolaemia 4.6 intoxication, alcohol 8.2.3,9.1.1 hyperglycaemia 4.5, 5.2 intra-uterine hyperlactacidaemia 5.1 —growt h 13.3.1 hyperlipaemia 5.1 —growt h retardation 13.4.3 hyperoestrogenaemia 4.3 intracellular water 7.1 hyperoestrogenism 4.8 iron 7.2.6 hyperphosphataemia 7.2.4 irritability 5.2 hyperphosphaturia 7.2.4 ischaemic stroke 10.5 hyperprolactinaemia 4.9.2 isozymes, distribution of 3.2.1 hypertension 9.2.2, 10.3 -, portal 8.1 jejunal villi, haemorrhagic erosion hyperuricaemia 5.1 of 11.1.5 hyperventilation 5.1 Jellinek estimation formula 8.5.4 hypoalbuminaemia 7.2.3 juvenile alcohol use, suppression o! 17.2.3 hypocalcaemia 4.2,7.2.3 hypoglycaemia 4.4, 4.5, 5.2 katalase activity 9.1.2 -, fasting 5.2 ketoacidosis, alcoholic 5.1 -, insulin-induced 2.1.3 ketogenesis 5.1 -, reactive 5.2 ketoglutaric acid, alpha- 3.4 hypogonadism 7.2.7 ketone bodies 5.1 hypomagnesaemia 7.2.3 ketosis, alcohol-induced 5.1 hyponatraemia 7.2.1 kinetics hypopharynx, cancer of the 12.1.1 —, first-order 2.1 hypophosphataemia 7.2.4 —, Michaelis-Menten 2.2.2 hypothalamic —, zero-order 2.3.1 - osmoreceptors 7.1 kirsch 14.6.1 —-pituitar y axis 4.6 Korsakoff spsychosi s 6.2,9.2.1 - -pituitary-gonadal axis 4.8 hypothermia 5.2 lactacidosis 10.8 hypoxia 8.2.2, 8.2.3 lactate 5.1, 5.4, 8.2.6, 8.6 -, centrilobular 8.2.3 - clearance 5.1

268 —/pyruvat e ratio 3.7, 8.2.3 malnutrition 9.2.1 lactic acidosis 5.1 -, primary 11.1 larynx, cancer of the 12.1.1 -, secondary 11.1 LD-50 dose 9.1.1 marital state 15.5.4.3 lead 14.5 markers of alcoholism learning -, electrophysiological 15.1.4.1 - problems 13.3.2 —, biochemical 15.1.4.2 —theorie s 15.4 —,biologica l 15.1.4 Ledermann's theory 8.5.4, 17.1.1 marrow, bone 11.6 leucocytes 11.6 mass media 17.2.4 licence revocation 16.4.1 maximum allowable blood alcohol life-style factors 8.4, 12.1.6 concentration 16.2.3 lipase, hepatic 10.1 mean corpuscular volume 8.5, 11.6, IS !.1.1 lipid 8.1 measures to control alcohol abuse 17.2, 18 - metabolism 8.2.1 mechanisms of carcinogenesis 12.3 - oxidation 8.2.1 media campaigns 17.2.4 —peroxidatio n 8.2.2 medication -, blood 10.1 —, antidipsotropic 3.3, 18.2.2 lipoprotein 5.3, 5.4, 8.2.1 —, detoxification 18.2.1 —, high-density 10.1 -, effect-altering 18.2.2 —, low-density 6.9, 10.1 -, psychotherapeutic 18.2.4 —,ver y low-density 5.3 megaloblastic anaemia 6.5, 6.6 liqueur, cream 14.3 membranes, permeability of ^2.3.4 liquor-by-the-drink 17.2.2 menorrhagia 4.9.1 liver 8 menses, irregular 4.9.1 —cance r 12.1.1, 12.1.2 menstrual cycle 2.3.2 - cell mitochondria 8.2.1 mental - cirrhosis 7.1, 15.1.4.2 - clouding 9.2.2 —cirrhosis , epidemiology of 8.5 —developmen t 13.5 -disease, alcoholic 8.2 —function , depressed 7.2.7 —enlargemen t 8.1 - -health model 17.1.3 -injury 6.4, 7.2.6, 12.4 MEOS 3.2.2, 3.6, 4 lobular oxygen gradient 8.2.3 8.2.4, 8.4.4 low-alcohol - induction 12.3.4 —bee r 14.1 metabolic —beverage s 14.1 —acidosi s 7.2.2, 14.6.1 low-density lipoprotein 6.9, 10.1 —alkalosi s 5.1 lung 11.4 —toleranc e 9.2.2 —cance r 12.1.4 metabolism luteinizing hormone 4.8 —o f macronutrients 5 —-releasin g hormone 4.8 -, alcohol 3 lymphocyte —, carbohydrate 5.2, 11.2 —activit y 8.2.2 -, cholecalciferol 4.2 —antigen , human 15.1.4.2 -, essential fatty acid 5.3, 8.2.2. lysine 8.2.5 -, fat 5.3 —, first-pass 2.3.1, 3.2.1 macronutrients 14.3 —, hormone 4 —,metabolis m of 5 -, lipid 8.2.1 magnesium 7.2.5 —,modificatio n of alcohol 3.7 - deficiency 9.2.2 —, prostaglandin 5.3, 8.2.2 malabsorption, fat 11.1.5 -, protein 5.4, 7.2.7 malate 5.1 -, vitamin 6 male methanol 8.6, 14.6.1 —fertilit y 4.8 methionine 5.4 —se x hormones 4.8 methylgyanine transferase, O - 12.3.4 malformations 13.3.3 Michaelis-Menten kinetics 2.2.2, 2.3.1 - of the unborn child 13 microcephaly 13.1 -, genito-urinary 13.3.3 microphthalmia 13.1 —,se x organ 13.3.3 microsomal ethanol-oxidizing 3.2.2, 3.6, 4 Mallory bodies 8.1, 8.2.2 system 8.2.4

269 microsomes 3.2.2 nervous system 9, 14.6.2 migraine 14.6.3 —, central 15.1.4.1, 13.1 milk 2.1.1 neurobehavioural response 13.3.2 mineral 14.5 neurological disturbances 6.2 - absorption 11.1.5 neuropathy —balanc e 7.2 -, peripheral 11.5.1 minimum -, vagal 7.2.1 - drinking age 17.2.3 neurosis 15.3 —lega l purchase age 16.2.2, 17.2.3 neurotransmission 4.1, 9.2.3 miscarriage 13.7 neurotransmitters 3.4,4.7, 11.1.3 misperceptions 9.2.2 -, 'false' 3.3, 9.2.3 mitochondria 5.3 niacin 3.7 -, liver cell 8.2.1 nicotinamide adenine dinucleotide 3.2 mitochondrial night blindness 6.1, 7.2.7, 11.3.2 —abnormalitie s 10.7 nitrosamines 12.2 —aspartat e aminotransferase 18.1.1 noradrenaline 4.7, 9.2.3, 10.3 —electro n transport 3.2.1 norepinephrine, see noradrenaline —injur y 8.2.2 nucleic acid synthesis 13.4.1 mitotic inhibition 11.1.5 nutrient model of control 17.1 - absorption 11.1.5 —, Ledermann's 17.1.1 —transport , placental 13.4.3 —, mental-health 17.1.3 nutrition-related effects of alcohol —, single-distribution 17.1.1 •exposure 13.4.2 -, socio-cultural 17.1.3 nystagmus 11.3.1, 14.6.2 moderate drinking/drinker 1.1 modification of alcohol metabolism 3.7 occlusion, arterial 10.4 monoamine oxidase, platelet 15.1.4.2 oculomotor system 11.3.2 monokine interleukin 1 7.2.7 Oddi, sphincter of 11.2.2 monosaccharide 14.3 oedema 6.2 mortality 9.2.2 -, cerebral 9.2.1 —, cirrhosis 8.4.5, 8.5 oesophageal motility, oesophageal 11.1.1 - cancer 12.1.1, 12.3.1 motives for drinking before driving 16.1 —motilit y 11.1.1 motor —vari x 8.3 —disturbanc e 11.3.1 oesophagitis 11.1.1 —performanc e 13.3.2 oesophagus 11.1.1 mucosa oestradiol 4.8, 4.9.1 —,erosio n of gastric 2.1.2 oestrogen 4.8,4.9.1 -, gastric 11.1.2 oestrone 4.8 -, intestinal 11.1.5 on-premise consumption 17.2.2 mucosal optic nerve damage 14.6.1 - erosion 11.1.2.1 opticoneuropathy 11.3.2 —lesion s 11.1.2.1 organs 11 muscle 11.5 oropharynx, cancer of the 12.1.1 muscular tissue 2.2 osmolality, plasma 7.1 mutai help groups 18.2.3 osmoreceptors, hypothalamic 7.1 myocardial osmotic effect 2.1.1 —infarctio n 10.2 osteoblastic activity 4.2 -injury 10.7 osteoporosis 6.8, 7.2.5 myofibrillary protein, losso f 11.5.1 —, skeletal 4.2 myofibroblasts 8.1 outlets, restriction of number of 17.2.2 myopathy, alcoholic 11.5.1, 11.5.2 outpatient treatment 18.2.5 overhydration 7.1 NADH 5.4 - ofth e brain 4.1 NADH/NAD ratio 5.1, 5.3 overpermissive culture 17.1.2 narcosis, cell membrane 13.4.1 ovulation 4.9.1 nasogastrical weight loss 3.2.2 oxaloacetate 5.1 nausea 8.1, 9.2.2, 11.1.3 oxygen necrosiso f the liver 8.1 —deman d of liver cells 8.2.3 neonatalwithdrawa l syndrome 13.3.2 -gradient, lobular 8.2.3

270 oxygenated drinking water 2.3.2 potassium 7.2.2 oxytocin 4.9.3 pregnancy 13 prevention pancreas 11.2 —model s 17.1 —cance r 12.1.5 -model, Ledermann's 17.1.1 pancreatic -model, mental-health 17.1.3 -duct 11.2.2 - model, single-distribution 17.1.1 —enzyme s 11.2.2 -model, socio-cultural 17.1.2 —interstitiu m 11.2.2 —o f alcohol (ab)use 17 - reflux, biliary 11.2.2 —, primary 16.2, 17.2.5 pancreatitis 5.1, 5.2, 5.3, 7.2.6, -, relapse 18.2.6 11.2.1, 11.2.2, -, secondary 16.3, 18 12.1.5, 15.1.4.2 -, tertiary 16.4, 18 —, alcohol-induced 12.1.5 price asa control mechanism 17.2.1 —,pathogenesi s of 11.2.2 primary parathyroid hormone 4.2 —malnutritio n 11.1 paternal alcoholism 13.6 -prevention 16.2, 17.2.5 pathogenesis of pancreatitis 11.2.2 pro-oxidants 8.2.4 peer group 15.5.3 problem drinkers/drinking 1.2 peripheral neuropathy 11.5.1 -, screening for 18.1.1 perivenular zoneso f liver cells 8.1, 8.2.3 procyanidin 14.6.3 permeability productive cough 11.4 - of gastric mucosa 11.1.2.2 progesterone 4.9.1 —o f intestinal mucosa 11.1.5 prolactin 4.9.2, 15.1.4.2 —o f membranes 12.3.4 proline 5.4 permissive culture 17.1.2 —hydroxylas e 5.1, 5.4, 8.2.6 peroxidation, lipid 8.2.2 pronormoblasts, vacuolated 11.6 personal variables 15.5.4 propanolol 8.3, personality 15.2 propylthiouracil 8.2.3, 8.3 pharmacodynamic prostaglandin 9.1.3, 11.1.2.2, 5.3 - interactions 3.6 -El 5.3 - tolerance 9.2.2 - metabolism 8.2.2 pharmacokinetic interactions 3.6 prostate cancer 12.1.6 pharmacotherapy 18.2.2 protein 2.1.1, 2.3.2, 14.3 phenolic flavanoids 14.6.3 —metabolis m 5.4, 7.2.7 phenothiazines 9.2.2 —synthesi s 10.7, 13.4.1, 13.4.3 phenylalanine 5.4 pseudo-Cushing syndrome 4.6, 13.5 phosphate 7.2.4 psychoanalytic studies 15.3 phospholipids 12.3.4 psychological studies 15.2 physical exercise 2.2, 2.3.2 psychomotor agitation 9.2.2 phytoestrogen 14.6.3 psychosis, Korsakoff s 6.2 placental transport psychotherapy 18.2.4 - of amino acids 13.4.2 pulmonary - of folate 13.4.2 - congestion 6.2 —o f zinc 13.4.2 —functio n 11.4 plasminogen 10.2 punishment platelet 8.6 —,increasin g risk of 16.3.1 - affinity to serotonin 18.1.1 -, severityo f 16.3.2 —aggregatio n 10.2 purchase age, minimum legal 17.2.3, 17.2.3 - function 11.6 purine degradation 8.2.4 —monoamin e oxidase 15.1.4.2 pylorospasm 2.1.2 poisoning, methanol 14.6.1 pyrazole 8.2.1 polycyclicaromati c hydrocarbons 12.3.1, 12.3.4 pyridoxal-5'-phosphate 6.4 polyneuropathy 6.2 pyridoxine 6.4 polysaccharide 14.3 pyruvate 3.4, 5.1 polyunsaturated fatty acids 5.3, 8.2.3 portal racial differences in distribution —hypertensio n 8.1 of isozymes 3.2.1, 3.4 —-systemi c encephalopathy 5.4 radicals, free 8.2.4 —venou s pressure 8.3 radiography, chest 8.6

271 reaction tests 9.1.1 sexual dusfunction 4.8 reactive hypoglycaemia 5.2 shuttle system 3.2.1 recruitment of clients 18.1.2 sigmoid colon, cancer of the 12.1.6 rectal cancer 12.1.6, 12.2 silicium 14.5 reference man/woman 2.2.2 single-distribution model 17.1.1 reflex control 9.1.1 sister chromatid exchange 12.3.4 reflexive behaviour 13.3.2 skeletal reflux - abnormalities 13.3.3 -, biliary pancreatic 11.2.2 —osteoporosi s 4.2 -, duodenopancreatic 11.2.2 - system of the unborn 13.1 regional variation 8.5.2 skin lesions 7.2.7 relapse prevention 18.2.6 sleepiness 14.6.2 religion 15.5.4.4 small intestine 11.1.5 renal smoking 12.1.1, 11.3.2, - abnormalities 13.3.3 12.1.4 —clearanc e 5.1 sobering agents 2.3.2 renin 4.1 sociability 16.1 respiratory social drinking/drinker 1.1 - alkalosis 7.2.4 socio-cultural - depression 8.2.3 - model 17.1.2 —diseas e 11.4 —studie s 15:5 - equilibrium 2.2.1 socio-economic status 15.5.4.2 restriction of alcohol use 17.2 sodium ' 7.2.1 retardation, growth 13.1, 13.3.1 somatomedin 4.4 retinal 4.8, 6.1 somatotropin 4.4 retinol 4.8, 6.1 sorbitol 2.1.1, 5.1 - -binding protein 6.1 spermatogenesis 4.8, 6.1 reverse cholesterol transport 10.1 spermatozoal motility 4.8 revocation, licence 16.4.1 sphincter of Oddi 11.2.2. rhabdomyolysis 7.2.3 spirit 8.4.5 rhythm(icity) steatosis 8.2.2, 15.1.4.2 —,circadian 2.3.2 stenosis, coronary 10.4 —, diurnal 2.1.3 steroids, anabolic 8.3 riboflavin 3.7, 6.3, 12.3.2, stomach cancer > 12.1.6 14.4 stroke rum 9.1.3 -, haemorrhagic 10.5 -, ischaemic 10.5 safety limits 12.4 studies salicylic acid 11.1.2.2 -, adoption 15.1.3 saliva, determination of alcohol in 2.2 -, constitutional 15.1 salvary glands 11.1.1 -, family 15.1.1 sclerosis, hyalin 8.1 -, hereditary 15.1 screening for problem drinkers 18.1.1 -, interaction 15.6 secondary —, psychoanalytic 15.3 —malnutritio n 11.1 —, psychological 15.2 —preventio n 16.3, 18 —, socio-cultural 15.5 seleniium 8.2.4 —, twin 15.1.2 self-censorship in advertising 17.2.4 stupor 6.2 self-control 2.3.2 sugar 2.3.2, 14.3 serotonin 3.4, 9.1.2,9.2.3 supplementation, vitamin 6.1, 6.2 -, platelet affinity to 18.1.1 suppression ofjuvenil e alcohol use 17.2.3 severity of punishment 16.3.2 sweating 5.2 sex 15.5.4.1 synaptic membranes 3.3 —difference s 2.2.2 syndrome —difference s in liver disease 8.4.4 -, alcohol withdrawal 6.7, 18.2.1 —hormon e 8.4.4 -, Cushing 4.6 —hormone , female 4.9. -, flushing 3.4 —hormone, male 4.8 —,intermediat e brain 9.2.1 —hormone-bindin g globulin 4.8 —,neonata l withdrawal 13.3.2 —orga n malformations 13.3.3 —, pseudo-Cushing 4.6 .

272 -, Wernicke-Korsakoffs 9.2.1, 10.8 vagal neuropathy 7.2.1 —, Zieve's 6.9 valine 8.2.5 synthetase, fatty acid ester 3.2.3 variant angina 10.6 systolic blood pressure 10.3 varix, oesophageal 8.3 vascular dilatation 11.1.2.2 tachycardia 5.2, 9.2.2 vasoconstriction 10.4 tannin 12.3.1, 14.6.3 vasodilatation 10.4 tear fluid, alcohol in 2.2 vasopressin 4.1, 7.1, 9.2.1 temperature, body 2.3.2 venouspressure , portal 8.3 temporal relations 8.5.1 villi, jejunal 11.1.5 teratogenicity 13.4.1 vision 11.3 tertiary prevention 16.4, 18 vitamin(s) 2.3.2, 14.3 testicular atrophy 6.1 -A 6.1, 11.3.2, 12.3.2 testosterone 4.8 - A deficiency 6.1, 11.3.2 therapeutic approach 16.4.2 - absorption 11.1.5 therapy, confrontational group 18.2.4 -B-l, see thiamin thermoregulation 2.3.2 - B-2, see riboflavin thiamin 6.2, 10.8 -B-6 6.4, 12.3.2, 14.4 —deficienc y 6.2, 9.2.1 - B-6 deficiency 6.4 —pyrophosphat e 6.2 -B-12 6.6, 11.3.2 threshold values 8.4 -B-12 deficiency 6.6 thrombocytopenia 11.6 -C 3.7, 6.7, 14.4 thromboxane 10.2 -D 6.8 thyroid -E 3.7, 6.9, 8.2.4, 12.3.2 - activity 4.3 - deficiency 9.2a, 11.3.2 - hormone 2.3.2, 4.3 - metabolism 6 - inhibitor 8.3 - supplementation 6.1, 6.2 —-stimulatin g hormone 4.3 vomiting 8.1 thyrotropin 4.3 —-stimulatin g hormone 4.3 water balance 7.1, 7.2.1 thyroxine 4.3 -, disturbance of 9.1.3 tissue-plasminogen activator 10.2 weight loss 8.1 tobacco use 12.1.1 -, nasogastrical 3.2.2 tocopherol, alpha- 8.2.4 Wernicke-Korsakoff s syndrome 6.2, 9.2.1, 10.8 tolerance Wernicke's encephalopathy 6.2, 9.2.1 —, functional 9.2.2 whisky 9.1.3, 12.2 —, metabolic 9.2.2 wine 8.4.5, 10.5, 12.1.6, trace elements 14.5 14.4, 14.5 traffic 16 withdrawal 4.1, 9.2.2 transferrin 5.4, 7.2.6 -delirium, alcohol 9.2.2 -, carbohydrate-deficient 8.6 —syndrome , alcohol 6.7, 18.2.1 treatment - syndrome, neonatal 13.3.2 —o f alcohol liver disease 8.3 wodka 9.1.3 —o f alcoholism 18.1, 18.2 wound healing 7.2.7 tremor 9.2.2 tremulousness 5.2 xanthine dehydrogenase 8.2.4 triglycerides 5.3, 8.2.1, 8.6 xanthine oxidase 8.2.4 tryptophan 5.4 xenobiotics 3.2.2, 3.6 twin studies 15.1.2 xylose 2.3.2 tyrosine 5.4, 8.2.5 young drivers 16.2 U-shaped relationship 10.5 unborn child, malformations of the 13 zero-order kinetics 2.3.1 unconsciousness 9.1.1 Zieve's syndrome 6.9 underreporting of alcohol use 8.4.4 zinc 7.2.7 urate 8.6 - metabolism 7.2.7 uric acid 5.1 -, placental transport of 13.4.2 urokinase-plasminogen activator 10.2 vacuolation of pronormoblasts 11.6

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