Preventing the medical sequelae of alcohol abuse
Robert G . Batey
Staff Specialist, Gastroenterology Unit, Department of Medicine, John Hunter Hospital, Newcastle, NS W
Abstract: Excessive alcohol use is responsible for a significant amount of medical harm in the Australian community. It is not appropriate to suggest that alcohol use should be eliminated but it is important that we take steps to minimise harm produced by intake of inappropriate amounts of this drug. Many alcohol related problems are irreversible once established and thus it is imperative that information be made available to the public and to health care workers to help minimise problems before they become permanently established. It is suggested that harm niay be minimised by a number of strategies that include measures to: 1. Prevent the desire or need to drink excessively. 2. Prevent the ingestion of excessive amounts of alcohol. 3. Prevent the effects of excessive intake by protecting susceptible tissues. 4. Treating tissue damage early to prevent progressive injury. Early detection and intervention must play an increasing role in any attempt to minimise alcohol related problems. (Aust NZ J Med 1992; 22: 214-219.) Key words: Prevention, education, substitution therapy, cytoprotection, aversion therapy.
INTRODUCTION n an era in which the health care budget is stretched it is essential to examine ways in which preventable disorders might actually be prevented. While the last decade has seen a major change in the attention given to alcohol as a cause of illness, more effort is needed to decrease the medical sequelae of alcohol abuse. The fact that this epidemic affects almost, if not all, communities suggests to the naive that this problem might be high on the list of research priorities worldwide. This is not the case however, and there are many and complex reasons for the disparity. Solutions to the problem in Australia, for example, may not be practical or acceptable in other countries. I will focus on the needs in Australia, hoping that these thoughts can be translated to other communities. Before identifying areas for action in the campaign to reduce adverse consequences of alcohol excess it is appropriate to document the medical complications. They are many and various and the link between them and alcohol abuse ranges from clear to tenuous. Further study of some of these associations is required.
I
214
ALCOHOL ABUSE The Medical Sequelae of Alcohol Abuse Trauma to any part of the body from alcohol related accidents. An increase in the rate of malignancies in a variety of organs, including: - oro-pharynx - oesophagus - colon - breast - liver Cardiovascular disorders, including: - hypertension - coronary artery disease - cardiomyopathy - acute heart failure due to thiamine deficiency Gastrointestinal disease, including: - oesophagitis - gastritis - small bowel dysfunction resulting in diarrhoea and malabsorption - pancreatitis - liver disease from fatty liver to cirrhosis, portal hypertension and liver failure
Aust NZ J Med 1992; 22
BATEY
Haematological disorders - blood loss anaemia - folate deficiency
- thrombocytopenia
world. Each of the strategies listed has been employed in some settings with varying degrees of effectiveness and each will now be discussed in detail.
- acute and chronic haemolytic states
Neurological disease:
- central nervous system disorders both acute and chronic - peripheral neuropathy Endocrine disturbances: - Pseudo-Cushing’s syndrome - altered sex steroid metabolism (often secondary to liver disease). Immunological disturbances evidenced by: - increased susceptibility to infections - altered antibody production - impaired T cell function Foetal Alcohol syndrome. An examination of this list can only produce a sense of despair as the toxic effects of alcohol are so far-reaching. Many papers have reported on the frequency with which alcohol can be blamed for the disorders leading to admission to hospitals in this country.’.2 Many more patients suffer their medical conditions, at home but still cost the health care system significant sums of money. Some of the complications of alcohol abuse can be attributed directly to the effect of the drug on the CNS (e.g. accidents), others may be due to vitamin deficiency caused by an alcoholic life-style (e.g. Wernicke’s encephalopathy and beri-beri). Some conditions reflect direct ethanol toxicity (e.g. gastritis), while others reflect a combination of ethanol toxicity, nutritional factors and perhaps other influences (e.g. alcoholic hepatitis and cirrhosis). Preventing these various problems may require different strategies. Reducing alcohol consumption by the community as a whole will lead to a reduction in alcohol related morbidity3 but this approach may not be the most acceptable one for many. How might this problem be approached? Four major approaches may be identified: 0 Preventing the desire or need to drink excessively. Preventing the ingestion of excessive amounts of alcohol. fl Preventing the effects of excessive alcohol usage by protecting tissues from the drug or its metabolites. Treating the diseases produced by the drug to prevent progression of the disease process and the development of further complications. These approaches may be seen in terms of the standard primary, secondary and tertiary forms of prevention but they raise certain possibilities that are not yet in current practice in most parts of the MEDICAL SEQUELAE OF ALCOHOL ABUSE
PREVENTION STRATEGIES Preventing the Desire or Need to Drink Excessively It is easy, and usual, to gloss over this area of prevention strategy when discussing the medical consequences of alcohol abuse. It is often more satisfying to discuss the biochemical mechanisms of tissue injury and to consider ways of limiting this damage. Some judge that alcohol abuse is a problem for people who fail to control their urges and the issue of decreasing the desire to drink is a matter of ‘personal strength or weakness’. This attitude is unhelpful. It is imperative that more attention be directed to the processes underlying the ‘uncontrolled’ drinking patterns of those who are regarded as alcohol abusers. To many working clinically it seems as though the most dependent drinkers are quite unable to control their desire to consume alcohol. T o be able to define and then modify the factors controlling alcohol abuse would represent a huge step forward in our management of alcohol related medical disease. If all alcohol drinkers drank no more than the recommended safe levels4 we would find the medical consequences of alcohol usage markedly reduced. We would have, by definition, no alcohol abuse either. It is a reasonable goal and it does not derive from a desire to stop people from enjoying themselves but rather from a desire to understand human behaviour, particularly as it relates to the use of addictive substances, more clearly. How might this objective be achieved? B y continuing the studies that are &signed to identifr biochemical and neurophysiological reasons for a tendency to consume harmful quantities of alcohol.
By considering alternative agents that might take the place of alcohol in those subjects who are unable to reduce their intake of alcohol to safe levels (at least at this point in time). This option is not acceptable to all, as it might appear to be a mere switching of one problem for another. This line of attack may be no different however, from supplying clean needles to drug users to prevent the spread of infections via dirty needles. Benzodiazepines, or other depressants, may have a real and as yet poorly defined role in the prevention of the medical sequelae of alcohol abuse. Some credibility has been given to this concept by the studies of children of alcoholic parents. Evoked potentials in children who have not previously consumed alcohol have Aust NZ J Med 1992; 22
215
been shown to be abnormal in some instances. These abnormalities have been reversed by the administration of benzodiazepines. It is clear that such data are preliminary, but are not to be ignored.5
By using drugs to reduce alcohol intake. The serotonin uptake inhibitors ( e g zimelidine) reduce alcohol intake in humans and experimental animals. While the percentage reduction in daily intake is only in the order of 20% it is still exciting to consider the significance of this effect on what many have believed is a voluntary process. Using a drug to treat a drug dependence may be worrying but in trying to reduce the huge problem of alcohol related tissue injury, all possibilities must be discussed. It is to be hoped that further research in this field will provide a clearer understanding of the processes behind uncontrolled drug intake in dependent By educating the public of the adverse consequences of excessive alcohol intake. The evidence that education can influence alcohol intake is conflicting8 but this should not act as a barrier in attempts to provide the public with information that will aid in making decisions on alcohol use. A consideration of what has been achieved in changing community attitudes to tobacco use suggests that information can be used to alter drug use. Perhaps the inability to show a convincing influence of education on alcohol consumption may only reflect the fact that studies have been too short to identify an effect. It may take another decade for effects to be measurable. It seems difficult to believe that anyone in the Australian community could be ignorant of the damaging effects of heavy alcohol intake but countless clinical encounters have stressed that information that health care workers have is just not reaching the consciousness of most regular heavy drinkers (I have chosen those words carefully). Community ignorance may be chosen but it is real. The change in attitudes to tobacco use has been achieved, in part, by the provision of convincing data relating smoking to lung disease, peripheral vascular disease, hypertension and malignancy. We can hope to alter drinking patterns if we can closely link drinking to disease. Our own work relating the risk of cirrhosis to levels of alcohol intake in A ~ s t r a l i a n shas ~ . ~been ~ published in part and it shows in an increasing risk once daily consumption exceeds 40 glday in males and females. Similar studies linking intake to the development of pancreatitis, oesophagitis and other disease are urgently needed. The public as a whole has become cynical of generalisations and needs facts to convince them of a need to change. 216 Aust NZ J Mc:d
A brief comment on the issue of alcohol improving health is appropriate here. The suggestion that the consumption of 20 g/day of alcohol reduces mortality from cardiac disease has received considerable attention in the past five year^.'^,'^ The most recent publication raises the issue of carefully choosing the non-drinking population. It appears that a significant number of the nondrinkers in previous studies have been past heavy drinkers and it is these who have contributed to the high mortality figures in the non-drinking p0pu1ation.l~The message from this publication is quite clear. We must not cloud the issues of alcohol use with poorly conducted research designed not so much to advance knowledge but to support preconceived ideas. The drug and alcohol field has suffered too long from a lack of clear, accurate scientific data. Reducing the desire, or need to drink excessively may be achievable. It would reduce medical sequelae of alcohol abuse significantly. Considerable effort is needed in this area if change is to be achieved in the next decade.
Preventing the Ingestion of Excessive Amounts of Alcohol Strategies that apply here include: 0 Legislating to decrease intake to ‘safe’ levels 0 Establishing systems that discourage excessive intake Pricing alcoholic beverages so that economic pressures result in a reduced intake 0 Using drugs that inhibit alcohol use. There is good evidence that legislation in the form of drink-driving laws can influence alcohol intake and thus the consequences of drunken drivingg5 The Australian community has accepted this form of behaviour modification positively and it seems appropriate to recommend that all communities utilise this approach to minimising alcohol related injury and death. Industry has also recognised the importance of alcohol as a contributor to industrial trauma and has endeavoured to implement drug screening in the workplace. Introducing such strategies has been more difficult but if done with appropriate concern and educational input these approaches can ~ o r k . ~ ~ . ~ ’ The data relating alcohol consumption to the price of alcoholic beverages are also convincing. It is a little more difficult however to move from fact to action here as no government is keen to be seen as taxing the working person’s beverage to the point that helshe cannot afford it! The recommendations made to the Federal Government regarding pricing of beverages were considerably modified in the final version of the National Policy on Alcohol.18 1992; 22
BATEY
Finally, in this approach to reducing alcohol intake there is the use of drugs such as disulfiram to cut down intake in excessive and dependent drinkers. The data supporting the use of disulfiram are sparse and the passage of time has done little to strengthen the argument in favour of its role in the management of a l ~ ~ h o l i cNevertheless, ~ . ' ~ ~ ~ ~ it is important to continue examining ways of altering the intake of alcohol, particularly in those who have already experienced adverse consequences of their drinking yet find it hard to cut down or give up drinking. Preventing the Effects of Excessive Alcohol Usage by Tissue Protection While most would prefer to address the problem by reducing drinking, it is not easy to achieve this goal in the short term. This leaves no other option than to minimise the damage that might be done by heavy drinking. Preventing or minimising tissue injury might be achieved by several strategies, some of which remain theoretical possibilities at the present time. They include: 0 Preventing alcohol (or its metabolites) from gaining access to susceptible tissues 0 Protecting susceptible tissues from the direct toxic effects of alcohol Blocking alcohol metabolism so that toxic products of metabolism are not produced 0 Immobilising toxic products of metabolism so that more distant effects of these chemicals are avoided. 0 Protecting tissues from the toxic effects of alcohol metabolites 0 Raising the level of resistance of tissues to the events that follow on from the ingestion of excessive amounts of alcohol. (This includes attempts to modify the changes that occur in the immune system etc. in the heavy drinker.) Considerable data exist in this fascinating area of research endeavour. At present it is not possible to prevent alcohol from reaching specific tissues. Research into the effects of alcohol on cell membranes may, however lead to means of excluding the drug from specific tissues under certain conditions. More is known about means of protecting cells from the direct toxic effects of alcohol. The debate about ethanol toxicity and nutritional deficiencies leading to tissue damage in alcoholics has raged for It is clear that the two factors are both important. Alcohol does damage cells directly and steps can be taken to reduce this direct toxic effect. The use of prostaglandins or even h ~ n e y ~ ' can * ' ~ protect the gastric mucosa from the direct damaging effects of alcohol on the gastric mucosa. Other tissues may MEDICAL SEQUELAE OF ALCOHOL ABUSE
be able to be similarly protected. Avoiding the use of agents that increase the toxicity of alcohol e.g. paracetamol and alcohol hepatotoxicityz5represents another important preventive measure. Much of the effect of alcohol on the liver and perhaps other tissues is linked to its metabolism and the production of acetaldehyde and reactive free radicals. Blocking alcohol metabolism with a drug such as methpyrazole can limit the production of these metabolites but this does not prevent the direct toxicity of ethanol from appearing in these experimental situations.26 Xanthine oxidase inhibitors such as allopurinol have a theoretical role to play in the protection of cells from the damaging effects of free radicals, by preventing their release in cells actively metabolising Some evidence suggests that lipid peroxidation of cell membranes is responsible for the damage produced by alcohol metabolism and membrane stabilising agents such as Vitamin E and fish-oil products have been studied in models of alcoholic liver disease and ~ a n c e r .No ~ ~practical , ~ ~ application of these data has yet been identified for use in humans. Other approaches to this problem have included the use of thiamin to prevent or minimise central nervous system injury and the provision of zinc to heavy drinkers to decrease the risk of zinc deficiency contributing to susceptibility to tissue injury. It is now recognised that glutathione plays a major role in protecting cells from injury in alcoholics and attention is being directed to defining ways of maintaining normal levels of this compound in hepatocytes of heavy drinker^.^' An excellent summary of the metabolic consequences of alcohol metabolism as it relates to the liver and to liver disease has been provided by Lieber who has pioneered the study of alcoholic liver Efforts to alter the response of the body to other sequelae of heavy alcohol intake are only now being investigated. It is known, for example, that heavy alcohol intake is associated with an endotoxinaemia consequent on the release of endotoxin from gut organisms. Normal clearance of the endotoxin by hepatic Kupffer cells is impaired in the alcoholic and thus this material enters the systemic circulation and leads to the release of a range of other inflammatory mediators including interleukins 1 and 6 and tumour necrosis factor and transforming growth f a c t ~ r . ~ ' These - j ~ proteins are able to induce the acute phase response and to lead to tissue necrosis. Immunising the patient against endotoxin has been proposed as one way of reducing the harmful effects of excessive alcohol intake.35Other approaches to this complex problem might include: 0 Using steroids to minimise inflammatory responses to circulating cytokines Aust NZ J Med 1992; 22
217
0 Depressing
antigen-antibody reactions (acetaldehyde-adductP and antibodies) with steroids 0 Decreasing fibrosis by using drugs such as colchicine.
Treating the Diseases Produced by the Drug to Prevent Disease Progression The principle here is quite simply that of preventing more serious consequences of already established diseases. Prophylactic use of thiamin in regular drinkers has been advocated to prevent any, or further neurological damage in those who continue to drink.37 Propranolol has now been shown to decrease the risk of bleeding from oesophageal varices and portal hypertensive gastropathy in patients with cirrhosis and portal hyperten~ion.~' Propylthiouracil appears to improve the survival of alcoholics with liver disease and colchicine decreases the severity of fibrosis in cirrhotics with alcoholic liver disease.39 Much more attention needs to be given to effective management of the medical state of alcoholics. Too many of these patients are regarded as hopeless and follow-up strategies are often poorly planned. It is often the implementation of a caring, systematic medical programme that leads even hardcore alcoholics to change their drinking patterns. Even prevention at this tertiary level has considerable benefits for the individual and for the community. It is clear that prevention has been an area of increasing activity in the past six years in Australia. It is apparent that drinking patterns have changed in this country as a result of numerous factors. Random breath testing has altered drink-driving habits in a measurable manner. An understanding of the cytotoxicity of alcohol will enable new therapies to be defined to decrease the severity of diseases related to heavy alcohol intake. While all this new information exists it is still difficult to implement major change in this field of activity as Elvy has recently pointed Multiple factors lead to a tendency for us all to draw back from those actions that are most likely to lead to a reduction in alcohol related morbidity.
CONCLUSION In concluding it is important that the subject of early detection and intervention not be ignored. A growing body of literature attests to the importance of identifying problem drinkers early so that intervention might occur at a time when damage is minimal and at a time when it may be more effective. It is sufficient here to acknowledge the importance of all health workers taking an adequate 218 Aust NZ J Med
alcohol history when working with patients/clients. All individuals consuming more than the recommended safe levels should be given advice on the long term consequences of heavy alcohol intake. This approach to preventing alcohol related damage will have beneficial effects for a significant percentage of patients. Beyond the process of history taking a further level of early detection strategies exists-screening procedures. A number of serum assays have been studied in the endeavour to find a sensitive and specific marker of excessive alcohol intake. Those that have received most attention include: Gamma glutamyl transpeptidase (GGT) Mean corpuscular volume (MCV) Serum urate Mitochondria1 AST (mAST) Carbohydrate deficient transferrin (CDT). Each of these tests is abnormal in a significant percentage of heavy drinkers. The specificity of some of these tests is less than satisfactory (GGT, MCV, urate). More recently described tests (mAST, CDT) are much more specific and highly sensitive. It is suggested that these tests be used as screening tests in hospitals and health check centres. Those with abnormal tests would be advised of the results and counselled about excess alcohol intake. References 1. Williams AT, Burns FH, Morey S. Prevalence of alcoholism in a Sydney teaching hospital. Med J Aust 1978; 2: 608-1 1. 2. Moen R, Batey RG. Alcohol related disease in hospital patients - revisited. Med J Aust 1986; 144: 515-9. 3. HenryEdwards S, Pols R. Responses to drug problems in Australia. National Campaign Against Drug Abuse. Monograph series No. 16, AGPS, Canberra. 4. National Health and Medical Research Council 1987. Is there a safe level of daily consumption of alcohol for men and women? Recommendations regarding responsible drinking behaviour. AGPS, Canberra. 5. Schuckitt MA, Gold EO, Croot K, Finn P, Polich J. P300 latency after ethanol ingestion in sons of alcoholics and in controls. Biol Psychiatry 1988; 24: 310-15. 6. Naranjo CA, Sellers EM, Roach CA, Woodley DV, SanchezCraig M . Zimelidine-induced variations in alcohol intake in non-depressed heavy drinkers. Clin Pharmacol Ther 1984; 35: 374-81. 7. Naranjo CA, Kadlee KE, Sanhueza P, Woodley Remus D, Sellars EM. Fluoxetine differentially alters alcohol intake and other consumatory behaviours in problem drinkers. Clin Pharmacol Ther 1990; 47: 490-8. 8. Imlah N. In: Addiction. Substance abuse and dependency. Wilmslow, U.K:Sigma Press, 1989. 9. Norton R, Batey RG, Dwyer T, McMahon S. Alcohol consumption and the risk of alcohol related cirrhosis in women. Br Med J 1987; 295: 80-2. 10. Batey RG, Burns T, Benson RJ, Byth K. Alcohol consumption and the risk of cirrhosis in Australian men and women. Med J Aust (in press). 11. Yano K, Rhoads GG, Kagan A. Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii. N Engl J Med 1977; 297: 405-9. 1992; 22
BATEY
12. Marmot MG, Shipley MJ, Rose G, Thomas BJ. Alcohol and mortality: a U-shaped curve. Lancet 1981; i: 580-3. 13. Jackson R, Scragg R, Beaglehole R. Alcohol consumption and risk of coronary heart disease. Br Med J 1991; 303: 211-6. 14. Lazarus NB, Kaplan GA, Cohen RD, Leu Diing-Jiu. Change in alcohol consumption and risk of death from all causes and from ischaemic heart disease. Br Med J 1991; 303: 553-6. 15. Binns CW, Knowles SS, Blaze-Temple D. Is education enough? The drinking and driving practices of 17-30 year old males. Aust Drug Alc Rev 1987; 6: 253-64. 16. Smith R. Workplace drug testing-an overview. Clin Biochem 1991; 1-3. 17. Terrell A. Workplace drug testing- a management view. Clin Biochem 1991; 9-11. 18. Hawks DV. The watering down of Australia’s health policy on alcohol. Drug Alcohol Rev 1990; 9: 91-5. 19. Peachey JE, Naranjo CA. The use of Disulfiram and other alcohol-sensitizing drugs in the treatment of alcoholism. In: Research advances in alcohol and drug problems, Vol. 7. Smart RG, Glaser FB, Israel Y, Kalant H, Popham RE, Schmidt W (Eds). NY: Plenum Press 1987, 397-432. 20. McNichol RW, Sowell JM, Logsdon SA, Delgrado MH, McNichol J. Disulfiram: a guide to clinical use in alcoholism treatment. Am Fam Physician 1991; 44: 481-4. 21. Morgan MY. Alcohol and nutrition. Br Med Bull 1982; 38: 21-9. 22. Chick J. Epidemiology of alcohol use and its hazards. Br Med Bull 1982; 38: 3-8. 23. Sewell RB. Prostaglandins- role in gastric mucosal cytoprotection. Med J Aust 1985; 142: S10-S12. 24. Ali AT. Prevention of ethanol induced gastric lesions in rats by natural honey, and its possible mechanism of action. Scand J Gastroenterol 1991; 26: 281-8. 25. Black M. Acetaminophen hepatotoxicity. Ann Rev Med 1984; 35: 577-93. 26. Goldberg L, Rydberg U. Inhibition of ethanol metabolism in vivo by administration of pyrazole. Biochem Pharmacol 1969; 18: 1749-62.
MEDICAL SEQUELAE OF ALCOHOL ABUSE
27. Houze P, Rouach H, Gentil M, Orfanelli MT, Nordman R. Effect of allopurinol on the hepatic and cerebellar iron, selenium, zinc and copper status following acute ethanol administration to rats. Free Radic Res Commun 1991; 12-13: 663-8. 28. Schepp W, Peskar BM, Trautmann M et al. Fish oil reduces ethanol-induced damage of the duodenal mucosa in humans. Eur J Clin Invest 1991; 21: 230-7. 29. Mufti SI, Eskelson CD. Alcohol related cancers may be inhibited by Vitamin E. Ann N Y Acad Sci 1991; 625: 824-6. 30. Morton S, Mitchell MC. Effects of chronic ethanol feeding on glutathione in the rat. Biochem Pharmacol 1985; 34: 1559-63. 31. Lieber CS. Metabolism of ethanol and associated hepatotoxicity. Drug Alcohol Rev 1991; 10: 175-202. 32. Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI. Circulating tumour necrosis factor, interleukin 1 and interleukin 6 concentrations in chronic alcoholic patients. Hepatology 1991; 13: 267-76. 33. Bird GLA, Sheron N, Goka AJK, Alexander GJ, Williams RS. Increased plasma tumour necrosis factor in severe alcoholic hepatitis. Ann Int Med 1990; 112: 917-20. 34. Jones A, Selby PJ, Viner C, Hobbs S, Gore ME, McElwain TJ. Tumour necrosis factor, cholestatic jaundice and chronic liver disease. Gut 1990; 31: 938-9. 35. Nolan JP. Intestinal endotoxins as mediators of hepatic injury-an idea whose time has come; again. Hepatology 1989; 10: 887-91. 36. Ishak KG, Zimmerman HJ, Ray MB. Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. Alcoholism: Clin Exptl Res 1991; 15: 45-66. 37. Price J, Hicks M, Dunne M. Alcoholic beverage consumption prior t o t h e onset of Wernicke’s encephalopathy. Drug Alcohol Rev 1991; 10: 115-20. 38. Perez-Ayuso RM, Pique JM, Bosch J et al. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991; 337: 1431-4. 39. Orrego H, Blake JE, Blendis LM, Compton KV, Israel Y. Long-term treatment of alcoholic liver disease with propylthiouracil. N Engl J Med 1987; 317: 1421-7. 40. Elvy G. Barriers to the prevention of alcohol problems. Drug Alcohol Rev 1991; 10: 3-6.
Aust NZ J Med 1992; 22
2 19
Robert G . Batey
Staff Specialist, Gastroenterology Unit, Department of Medicine, John Hunter Hospital, Newcastle, NS W
Abstract: Excessive alcohol use is responsible for a significant amount of medical harm in the Australian community. It is not appropriate to suggest that alcohol use should be eliminated but it is important that we take steps to minimise harm produced by intake of inappropriate amounts of this drug. Many alcohol related problems are irreversible once established and thus it is imperative that information be made available to the public and to health care workers to help minimise problems before they become permanently established. It is suggested that harm niay be minimised by a number of strategies that include measures to: 1. Prevent the desire or need to drink excessively. 2. Prevent the ingestion of excessive amounts of alcohol. 3. Prevent the effects of excessive intake by protecting susceptible tissues. 4. Treating tissue damage early to prevent progressive injury. Early detection and intervention must play an increasing role in any attempt to minimise alcohol related problems. (Aust NZ J Med 1992; 22: 214-219.) Key words: Prevention, education, substitution therapy, cytoprotection, aversion therapy.
INTRODUCTION n an era in which the health care budget is stretched it is essential to examine ways in which preventable disorders might actually be prevented. While the last decade has seen a major change in the attention given to alcohol as a cause of illness, more effort is needed to decrease the medical sequelae of alcohol abuse. The fact that this epidemic affects almost, if not all, communities suggests to the naive that this problem might be high on the list of research priorities worldwide. This is not the case however, and there are many and complex reasons for the disparity. Solutions to the problem in Australia, for example, may not be practical or acceptable in other countries. I will focus on the needs in Australia, hoping that these thoughts can be translated to other communities. Before identifying areas for action in the campaign to reduce adverse consequences of alcohol excess it is appropriate to document the medical complications. They are many and various and the link between them and alcohol abuse ranges from clear to tenuous. Further study of some of these associations is required.
I
214
ALCOHOL ABUSE The Medical Sequelae of Alcohol Abuse Trauma to any part of the body from alcohol related accidents. An increase in the rate of malignancies in a variety of organs, including: - oro-pharynx - oesophagus - colon - breast - liver Cardiovascular disorders, including: - hypertension - coronary artery disease - cardiomyopathy - acute heart failure due to thiamine deficiency Gastrointestinal disease, including: - oesophagitis - gastritis - small bowel dysfunction resulting in diarrhoea and malabsorption - pancreatitis - liver disease from fatty liver to cirrhosis, portal hypertension and liver failure
Aust NZ J Med 1992; 22
BATEY
Haematological disorders - blood loss anaemia - folate deficiency
- thrombocytopenia
world. Each of the strategies listed has been employed in some settings with varying degrees of effectiveness and each will now be discussed in detail.
- acute and chronic haemolytic states
Neurological disease:
- central nervous system disorders both acute and chronic - peripheral neuropathy Endocrine disturbances: - Pseudo-Cushing’s syndrome - altered sex steroid metabolism (often secondary to liver disease). Immunological disturbances evidenced by: - increased susceptibility to infections - altered antibody production - impaired T cell function Foetal Alcohol syndrome. An examination of this list can only produce a sense of despair as the toxic effects of alcohol are so far-reaching. Many papers have reported on the frequency with which alcohol can be blamed for the disorders leading to admission to hospitals in this country.’.2 Many more patients suffer their medical conditions, at home but still cost the health care system significant sums of money. Some of the complications of alcohol abuse can be attributed directly to the effect of the drug on the CNS (e.g. accidents), others may be due to vitamin deficiency caused by an alcoholic life-style (e.g. Wernicke’s encephalopathy and beri-beri). Some conditions reflect direct ethanol toxicity (e.g. gastritis), while others reflect a combination of ethanol toxicity, nutritional factors and perhaps other influences (e.g. alcoholic hepatitis and cirrhosis). Preventing these various problems may require different strategies. Reducing alcohol consumption by the community as a whole will lead to a reduction in alcohol related morbidity3 but this approach may not be the most acceptable one for many. How might this problem be approached? Four major approaches may be identified: 0 Preventing the desire or need to drink excessively. Preventing the ingestion of excessive amounts of alcohol. fl Preventing the effects of excessive alcohol usage by protecting tissues from the drug or its metabolites. Treating the diseases produced by the drug to prevent progression of the disease process and the development of further complications. These approaches may be seen in terms of the standard primary, secondary and tertiary forms of prevention but they raise certain possibilities that are not yet in current practice in most parts of the MEDICAL SEQUELAE OF ALCOHOL ABUSE
PREVENTION STRATEGIES Preventing the Desire or Need to Drink Excessively It is easy, and usual, to gloss over this area of prevention strategy when discussing the medical consequences of alcohol abuse. It is often more satisfying to discuss the biochemical mechanisms of tissue injury and to consider ways of limiting this damage. Some judge that alcohol abuse is a problem for people who fail to control their urges and the issue of decreasing the desire to drink is a matter of ‘personal strength or weakness’. This attitude is unhelpful. It is imperative that more attention be directed to the processes underlying the ‘uncontrolled’ drinking patterns of those who are regarded as alcohol abusers. To many working clinically it seems as though the most dependent drinkers are quite unable to control their desire to consume alcohol. T o be able to define and then modify the factors controlling alcohol abuse would represent a huge step forward in our management of alcohol related medical disease. If all alcohol drinkers drank no more than the recommended safe levels4 we would find the medical consequences of alcohol usage markedly reduced. We would have, by definition, no alcohol abuse either. It is a reasonable goal and it does not derive from a desire to stop people from enjoying themselves but rather from a desire to understand human behaviour, particularly as it relates to the use of addictive substances, more clearly. How might this objective be achieved? B y continuing the studies that are &signed to identifr biochemical and neurophysiological reasons for a tendency to consume harmful quantities of alcohol.
By considering alternative agents that might take the place of alcohol in those subjects who are unable to reduce their intake of alcohol to safe levels (at least at this point in time). This option is not acceptable to all, as it might appear to be a mere switching of one problem for another. This line of attack may be no different however, from supplying clean needles to drug users to prevent the spread of infections via dirty needles. Benzodiazepines, or other depressants, may have a real and as yet poorly defined role in the prevention of the medical sequelae of alcohol abuse. Some credibility has been given to this concept by the studies of children of alcoholic parents. Evoked potentials in children who have not previously consumed alcohol have Aust NZ J Med 1992; 22
215
been shown to be abnormal in some instances. These abnormalities have been reversed by the administration of benzodiazepines. It is clear that such data are preliminary, but are not to be ignored.5
By using drugs to reduce alcohol intake. The serotonin uptake inhibitors ( e g zimelidine) reduce alcohol intake in humans and experimental animals. While the percentage reduction in daily intake is only in the order of 20% it is still exciting to consider the significance of this effect on what many have believed is a voluntary process. Using a drug to treat a drug dependence may be worrying but in trying to reduce the huge problem of alcohol related tissue injury, all possibilities must be discussed. It is to be hoped that further research in this field will provide a clearer understanding of the processes behind uncontrolled drug intake in dependent By educating the public of the adverse consequences of excessive alcohol intake. The evidence that education can influence alcohol intake is conflicting8 but this should not act as a barrier in attempts to provide the public with information that will aid in making decisions on alcohol use. A consideration of what has been achieved in changing community attitudes to tobacco use suggests that information can be used to alter drug use. Perhaps the inability to show a convincing influence of education on alcohol consumption may only reflect the fact that studies have been too short to identify an effect. It may take another decade for effects to be measurable. It seems difficult to believe that anyone in the Australian community could be ignorant of the damaging effects of heavy alcohol intake but countless clinical encounters have stressed that information that health care workers have is just not reaching the consciousness of most regular heavy drinkers (I have chosen those words carefully). Community ignorance may be chosen but it is real. The change in attitudes to tobacco use has been achieved, in part, by the provision of convincing data relating smoking to lung disease, peripheral vascular disease, hypertension and malignancy. We can hope to alter drinking patterns if we can closely link drinking to disease. Our own work relating the risk of cirrhosis to levels of alcohol intake in A ~ s t r a l i a n shas ~ . ~been ~ published in part and it shows in an increasing risk once daily consumption exceeds 40 glday in males and females. Similar studies linking intake to the development of pancreatitis, oesophagitis and other disease are urgently needed. The public as a whole has become cynical of generalisations and needs facts to convince them of a need to change. 216 Aust NZ J Mc:d
A brief comment on the issue of alcohol improving health is appropriate here. The suggestion that the consumption of 20 g/day of alcohol reduces mortality from cardiac disease has received considerable attention in the past five year^.'^,'^ The most recent publication raises the issue of carefully choosing the non-drinking population. It appears that a significant number of the nondrinkers in previous studies have been past heavy drinkers and it is these who have contributed to the high mortality figures in the non-drinking p0pu1ation.l~The message from this publication is quite clear. We must not cloud the issues of alcohol use with poorly conducted research designed not so much to advance knowledge but to support preconceived ideas. The drug and alcohol field has suffered too long from a lack of clear, accurate scientific data. Reducing the desire, or need to drink excessively may be achievable. It would reduce medical sequelae of alcohol abuse significantly. Considerable effort is needed in this area if change is to be achieved in the next decade.
Preventing the Ingestion of Excessive Amounts of Alcohol Strategies that apply here include: 0 Legislating to decrease intake to ‘safe’ levels 0 Establishing systems that discourage excessive intake Pricing alcoholic beverages so that economic pressures result in a reduced intake 0 Using drugs that inhibit alcohol use. There is good evidence that legislation in the form of drink-driving laws can influence alcohol intake and thus the consequences of drunken drivingg5 The Australian community has accepted this form of behaviour modification positively and it seems appropriate to recommend that all communities utilise this approach to minimising alcohol related injury and death. Industry has also recognised the importance of alcohol as a contributor to industrial trauma and has endeavoured to implement drug screening in the workplace. Introducing such strategies has been more difficult but if done with appropriate concern and educational input these approaches can ~ o r k . ~ ~ . ~ ’ The data relating alcohol consumption to the price of alcoholic beverages are also convincing. It is a little more difficult however to move from fact to action here as no government is keen to be seen as taxing the working person’s beverage to the point that helshe cannot afford it! The recommendations made to the Federal Government regarding pricing of beverages were considerably modified in the final version of the National Policy on Alcohol.18 1992; 22
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Finally, in this approach to reducing alcohol intake there is the use of drugs such as disulfiram to cut down intake in excessive and dependent drinkers. The data supporting the use of disulfiram are sparse and the passage of time has done little to strengthen the argument in favour of its role in the management of a l ~ ~ h o l i cNevertheless, ~ . ' ~ ~ ~ ~ it is important to continue examining ways of altering the intake of alcohol, particularly in those who have already experienced adverse consequences of their drinking yet find it hard to cut down or give up drinking. Preventing the Effects of Excessive Alcohol Usage by Tissue Protection While most would prefer to address the problem by reducing drinking, it is not easy to achieve this goal in the short term. This leaves no other option than to minimise the damage that might be done by heavy drinking. Preventing or minimising tissue injury might be achieved by several strategies, some of which remain theoretical possibilities at the present time. They include: 0 Preventing alcohol (or its metabolites) from gaining access to susceptible tissues 0 Protecting susceptible tissues from the direct toxic effects of alcohol Blocking alcohol metabolism so that toxic products of metabolism are not produced 0 Immobilising toxic products of metabolism so that more distant effects of these chemicals are avoided. 0 Protecting tissues from the toxic effects of alcohol metabolites 0 Raising the level of resistance of tissues to the events that follow on from the ingestion of excessive amounts of alcohol. (This includes attempts to modify the changes that occur in the immune system etc. in the heavy drinker.) Considerable data exist in this fascinating area of research endeavour. At present it is not possible to prevent alcohol from reaching specific tissues. Research into the effects of alcohol on cell membranes may, however lead to means of excluding the drug from specific tissues under certain conditions. More is known about means of protecting cells from the direct toxic effects of alcohol. The debate about ethanol toxicity and nutritional deficiencies leading to tissue damage in alcoholics has raged for It is clear that the two factors are both important. Alcohol does damage cells directly and steps can be taken to reduce this direct toxic effect. The use of prostaglandins or even h ~ n e y ~ ' can * ' ~ protect the gastric mucosa from the direct damaging effects of alcohol on the gastric mucosa. Other tissues may MEDICAL SEQUELAE OF ALCOHOL ABUSE
be able to be similarly protected. Avoiding the use of agents that increase the toxicity of alcohol e.g. paracetamol and alcohol hepatotoxicityz5represents another important preventive measure. Much of the effect of alcohol on the liver and perhaps other tissues is linked to its metabolism and the production of acetaldehyde and reactive free radicals. Blocking alcohol metabolism with a drug such as methpyrazole can limit the production of these metabolites but this does not prevent the direct toxicity of ethanol from appearing in these experimental situations.26 Xanthine oxidase inhibitors such as allopurinol have a theoretical role to play in the protection of cells from the damaging effects of free radicals, by preventing their release in cells actively metabolising Some evidence suggests that lipid peroxidation of cell membranes is responsible for the damage produced by alcohol metabolism and membrane stabilising agents such as Vitamin E and fish-oil products have been studied in models of alcoholic liver disease and ~ a n c e r .No ~ ~practical , ~ ~ application of these data has yet been identified for use in humans. Other approaches to this problem have included the use of thiamin to prevent or minimise central nervous system injury and the provision of zinc to heavy drinkers to decrease the risk of zinc deficiency contributing to susceptibility to tissue injury. It is now recognised that glutathione plays a major role in protecting cells from injury in alcoholics and attention is being directed to defining ways of maintaining normal levels of this compound in hepatocytes of heavy drinker^.^' An excellent summary of the metabolic consequences of alcohol metabolism as it relates to the liver and to liver disease has been provided by Lieber who has pioneered the study of alcoholic liver Efforts to alter the response of the body to other sequelae of heavy alcohol intake are only now being investigated. It is known, for example, that heavy alcohol intake is associated with an endotoxinaemia consequent on the release of endotoxin from gut organisms. Normal clearance of the endotoxin by hepatic Kupffer cells is impaired in the alcoholic and thus this material enters the systemic circulation and leads to the release of a range of other inflammatory mediators including interleukins 1 and 6 and tumour necrosis factor and transforming growth f a c t ~ r . ~ ' These - j ~ proteins are able to induce the acute phase response and to lead to tissue necrosis. Immunising the patient against endotoxin has been proposed as one way of reducing the harmful effects of excessive alcohol intake.35Other approaches to this complex problem might include: 0 Using steroids to minimise inflammatory responses to circulating cytokines Aust NZ J Med 1992; 22
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0 Depressing
antigen-antibody reactions (acetaldehyde-adductP and antibodies) with steroids 0 Decreasing fibrosis by using drugs such as colchicine.
Treating the Diseases Produced by the Drug to Prevent Disease Progression The principle here is quite simply that of preventing more serious consequences of already established diseases. Prophylactic use of thiamin in regular drinkers has been advocated to prevent any, or further neurological damage in those who continue to drink.37 Propranolol has now been shown to decrease the risk of bleeding from oesophageal varices and portal hypertensive gastropathy in patients with cirrhosis and portal hyperten~ion.~' Propylthiouracil appears to improve the survival of alcoholics with liver disease and colchicine decreases the severity of fibrosis in cirrhotics with alcoholic liver disease.39 Much more attention needs to be given to effective management of the medical state of alcoholics. Too many of these patients are regarded as hopeless and follow-up strategies are often poorly planned. It is often the implementation of a caring, systematic medical programme that leads even hardcore alcoholics to change their drinking patterns. Even prevention at this tertiary level has considerable benefits for the individual and for the community. It is clear that prevention has been an area of increasing activity in the past six years in Australia. It is apparent that drinking patterns have changed in this country as a result of numerous factors. Random breath testing has altered drink-driving habits in a measurable manner. An understanding of the cytotoxicity of alcohol will enable new therapies to be defined to decrease the severity of diseases related to heavy alcohol intake. While all this new information exists it is still difficult to implement major change in this field of activity as Elvy has recently pointed Multiple factors lead to a tendency for us all to draw back from those actions that are most likely to lead to a reduction in alcohol related morbidity.
CONCLUSION In concluding it is important that the subject of early detection and intervention not be ignored. A growing body of literature attests to the importance of identifying problem drinkers early so that intervention might occur at a time when damage is minimal and at a time when it may be more effective. It is sufficient here to acknowledge the importance of all health workers taking an adequate 218 Aust NZ J Med
alcohol history when working with patients/clients. All individuals consuming more than the recommended safe levels should be given advice on the long term consequences of heavy alcohol intake. This approach to preventing alcohol related damage will have beneficial effects for a significant percentage of patients. Beyond the process of history taking a further level of early detection strategies exists-screening procedures. A number of serum assays have been studied in the endeavour to find a sensitive and specific marker of excessive alcohol intake. Those that have received most attention include: Gamma glutamyl transpeptidase (GGT) Mean corpuscular volume (MCV) Serum urate Mitochondria1 AST (mAST) Carbohydrate deficient transferrin (CDT). Each of these tests is abnormal in a significant percentage of heavy drinkers. The specificity of some of these tests is less than satisfactory (GGT, MCV, urate). More recently described tests (mAST, CDT) are much more specific and highly sensitive. It is suggested that these tests be used as screening tests in hospitals and health check centres. Those with abnormal tests would be advised of the results and counselled about excess alcohol intake. References 1. Williams AT, Burns FH, Morey S. Prevalence of alcoholism in a Sydney teaching hospital. Med J Aust 1978; 2: 608-1 1. 2. Moen R, Batey RG. Alcohol related disease in hospital patients - revisited. Med J Aust 1986; 144: 515-9. 3. HenryEdwards S, Pols R. Responses to drug problems in Australia. National Campaign Against Drug Abuse. Monograph series No. 16, AGPS, Canberra. 4. National Health and Medical Research Council 1987. Is there a safe level of daily consumption of alcohol for men and women? Recommendations regarding responsible drinking behaviour. AGPS, Canberra. 5. Schuckitt MA, Gold EO, Croot K, Finn P, Polich J. P300 latency after ethanol ingestion in sons of alcoholics and in controls. Biol Psychiatry 1988; 24: 310-15. 6. Naranjo CA, Sellers EM, Roach CA, Woodley DV, SanchezCraig M . Zimelidine-induced variations in alcohol intake in non-depressed heavy drinkers. Clin Pharmacol Ther 1984; 35: 374-81. 7. Naranjo CA, Kadlee KE, Sanhueza P, Woodley Remus D, Sellars EM. Fluoxetine differentially alters alcohol intake and other consumatory behaviours in problem drinkers. Clin Pharmacol Ther 1990; 47: 490-8. 8. Imlah N. In: Addiction. Substance abuse and dependency. Wilmslow, U.K:Sigma Press, 1989. 9. Norton R, Batey RG, Dwyer T, McMahon S. Alcohol consumption and the risk of alcohol related cirrhosis in women. Br Med J 1987; 295: 80-2. 10. Batey RG, Burns T, Benson RJ, Byth K. Alcohol consumption and the risk of cirrhosis in Australian men and women. Med J Aust (in press). 11. Yano K, Rhoads GG, Kagan A. Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii. N Engl J Med 1977; 297: 405-9. 1992; 22
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12. Marmot MG, Shipley MJ, Rose G, Thomas BJ. Alcohol and mortality: a U-shaped curve. Lancet 1981; i: 580-3. 13. Jackson R, Scragg R, Beaglehole R. Alcohol consumption and risk of coronary heart disease. Br Med J 1991; 303: 211-6. 14. Lazarus NB, Kaplan GA, Cohen RD, Leu Diing-Jiu. Change in alcohol consumption and risk of death from all causes and from ischaemic heart disease. Br Med J 1991; 303: 553-6. 15. Binns CW, Knowles SS, Blaze-Temple D. Is education enough? The drinking and driving practices of 17-30 year old males. Aust Drug Alc Rev 1987; 6: 253-64. 16. Smith R. Workplace drug testing-an overview. Clin Biochem 1991; 1-3. 17. Terrell A. Workplace drug testing- a management view. Clin Biochem 1991; 9-11. 18. Hawks DV. The watering down of Australia’s health policy on alcohol. Drug Alcohol Rev 1990; 9: 91-5. 19. Peachey JE, Naranjo CA. The use of Disulfiram and other alcohol-sensitizing drugs in the treatment of alcoholism. In: Research advances in alcohol and drug problems, Vol. 7. Smart RG, Glaser FB, Israel Y, Kalant H, Popham RE, Schmidt W (Eds). NY: Plenum Press 1987, 397-432. 20. McNichol RW, Sowell JM, Logsdon SA, Delgrado MH, McNichol J. Disulfiram: a guide to clinical use in alcoholism treatment. Am Fam Physician 1991; 44: 481-4. 21. Morgan MY. Alcohol and nutrition. Br Med Bull 1982; 38: 21-9. 22. Chick J. Epidemiology of alcohol use and its hazards. Br Med Bull 1982; 38: 3-8. 23. Sewell RB. Prostaglandins- role in gastric mucosal cytoprotection. Med J Aust 1985; 142: S10-S12. 24. Ali AT. Prevention of ethanol induced gastric lesions in rats by natural honey, and its possible mechanism of action. Scand J Gastroenterol 1991; 26: 281-8. 25. Black M. Acetaminophen hepatotoxicity. Ann Rev Med 1984; 35: 577-93. 26. Goldberg L, Rydberg U. Inhibition of ethanol metabolism in vivo by administration of pyrazole. Biochem Pharmacol 1969; 18: 1749-62.
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27. Houze P, Rouach H, Gentil M, Orfanelli MT, Nordman R. Effect of allopurinol on the hepatic and cerebellar iron, selenium, zinc and copper status following acute ethanol administration to rats. Free Radic Res Commun 1991; 12-13: 663-8. 28. Schepp W, Peskar BM, Trautmann M et al. Fish oil reduces ethanol-induced damage of the duodenal mucosa in humans. Eur J Clin Invest 1991; 21: 230-7. 29. Mufti SI, Eskelson CD. Alcohol related cancers may be inhibited by Vitamin E. Ann N Y Acad Sci 1991; 625: 824-6. 30. Morton S, Mitchell MC. Effects of chronic ethanol feeding on glutathione in the rat. Biochem Pharmacol 1985; 34: 1559-63. 31. Lieber CS. Metabolism of ethanol and associated hepatotoxicity. Drug Alcohol Rev 1991; 10: 175-202. 32. Khoruts A, Stahnke L, McClain CJ, Logan G, Allen JI. Circulating tumour necrosis factor, interleukin 1 and interleukin 6 concentrations in chronic alcoholic patients. Hepatology 1991; 13: 267-76. 33. Bird GLA, Sheron N, Goka AJK, Alexander GJ, Williams RS. Increased plasma tumour necrosis factor in severe alcoholic hepatitis. Ann Int Med 1990; 112: 917-20. 34. Jones A, Selby PJ, Viner C, Hobbs S, Gore ME, McElwain TJ. Tumour necrosis factor, cholestatic jaundice and chronic liver disease. Gut 1990; 31: 938-9. 35. Nolan JP. Intestinal endotoxins as mediators of hepatic injury-an idea whose time has come; again. Hepatology 1989; 10: 887-91. 36. Ishak KG, Zimmerman HJ, Ray MB. Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. Alcoholism: Clin Exptl Res 1991; 15: 45-66. 37. Price J, Hicks M, Dunne M. Alcoholic beverage consumption prior t o t h e onset of Wernicke’s encephalopathy. Drug Alcohol Rev 1991; 10: 115-20. 38. Perez-Ayuso RM, Pique JM, Bosch J et al. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991; 337: 1431-4. 39. Orrego H, Blake JE, Blendis LM, Compton KV, Israel Y. Long-term treatment of alcoholic liver disease with propylthiouracil. N Engl J Med 1987; 317: 1421-7. 40. Elvy G. Barriers to the prevention of alcohol problems. Drug Alcohol Rev 1991; 10: 3-6.
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