AUSTRALIAN ALCOItOL/DRUG REVIEW, VOL.2, NO. 2, JULY lge3, 48-52

WHY DO WOMEN APPEAR TO DEVELOP ALCOHOLIC LIVER DISEASE MORE READILY THAN MEN?

*Robyn Norton **Robert Batey

ABSTRACT

In the last 20 years evidence has accumulated which suggests that women develop alcoholic liver disease more readily than do men. A number of factors have been hypothesized as contributing to their increased susceptib- ility. Differences in nutritional intake were initially thought to play a large role in the development of alcoholic fiver disease. However, more recently, a number of constitutional and other environmental factors have been investigated.

It is suggested that there is much to be gained from studies which consider factors in combination rather than in isolation. It is possible that more than one factor contributes to the differing suscceptibility in males and females. In addition, it is likely that some of the proposed factors are not independent of one another. The relative importance of each factor in explaining the difference between sexes, and their degree of independence can only be assessed in multi- variate studies.

INTRODUCTION

Over the past 20 years, a number of studies have been published suggesting that women develop alcoholic liver disease more readily than do men. 1-25 These have been supplemented by two recent review articles? 6,27 critically assessing some of these papers, and concluding that there is evidence to support the greater susceptibility of women to the hepatotoxic effects of alcohol.

The reported increase of alcohol consumption by women, both in Australia 28 and overseas ~,3°, and the suggestion that women may be at greater risk of developing alcohol- related liver damage, gives rise to concern about a possible increase in the numbers of women with such damage. Knowledge as to why women may be more susceptible than men has implications for clinical practice and, more importantly, for 6ducation and prevention.

This paper presents an overview of those reports which suggest that women develop alcoholic liver disease more readily than men, and examines the literature concerning the factors implicated in this difference in susceptibility to alcoholic liver damage.

EVIDENCE SUGGESTING WOMEN DEVELOP ALCOHOUC LIVER DISEASE MORE READILY THAN MEN

The first study suggesting that women may be more susceptible to the hepatotoxic effects of alcohol than are men was that reported by Spain in 1945.31 He noted, from autopsy findings in a sample of patients suffering from portal cirrhosis associated with heavy drinking, that women were over- represented compared with men. Since then, a number of other mortality studies have shown that the prevalence of

alcohol-related disease in women is higher than would be expected from the ratio of women to men alcoholics in the population. 1-7

Morbidity studies have likewise shown a higher prevalence of women with alcohol-related liver damage than would be expected from the numbers of women alcoholics in the population, s-18 In addition, a number of other studies have reported that women tend to have more severe forms of liver disease than do their male counterparts. 19,2° Other studies have suggested that the prognosis for women with alcohol- related liver disease is worse for them than for men. s,9,17,31 However, the evidence concerning severity and prognosis is conflicting 19,32-35 and suggests the need for further investi- gation.

A number of researchers have not reported a greater-than- expocted prevalence of disease, or more severe forms of disease, but have found that the women studied have drunk for a shorter period of time, and have drunk smaller daily amounts of alcohol, than the men.10,15,17,18, 21 Both findings support the view that women may develop alcoholic liver disease more readily than men.

Workers in France have suggested that the level of alcohol consumption required to increase the risk of development of liver disease in women is considerably less than that for men. 23-25 In particular, they believe that the risk of developing cirrhosis of the liver in women increases signifi- cantly at levels greater than 20 mg of alcohol daily, whereas for men, they suggest that it increases at levels greater than 60 gm of alcohol daily.

FACTORS THAT MAY CONTRIBUTE TO THE IN- CREASED SUSCEPTIBILITY OF WOMEN

Knowledge about factors that may account for the increased susceptibility of women to alcohol-related liver disease, has come from three typos of studies. Firstly, work undertaken to investigate factors which determine individual susceptibility to the development of alcohol-related liver disease has provided some information about factors that may account for the greater susceptibility of women. Secondly, a number of studies have specifically investigated sex-related differences among patients with alcoholic liver disease and have suggested factors that may account for the greater susceptibility of women. Finally, the effects of alcohol on women have been studied by researchers whose interest has been to investigate the role played by constitutional and environmental factors that affect women only.

For many years, malnutrition was thought to play a large role in the development of alcoholic liver disease, z3,31,36 However, more recent studies have questioned this role, and have shown that excessive alcohol consumption may produce alcoholic liver disease regardless of the nutritional

48

*R.N. Norton, Research Fellow, Commonweatth Institute of Health, University of Sydney, Sydney, NSW 2006; **R. G. Batey, Director, Drug and Alcohol Services, Wes~'nead Centre, Sydney, NSW 2146

state of the person. 37,38 Despite this, some researchers have indicated that patients who maintain an adequate diet following diagnosis have a much better prognosis than those who do not. 39,4° This finding would indicate that nutritional intake may play a role in determining individual susceptibility in the development of alcohol-related liver disease. Those studies that have attempted to assess the nutritional adequacy of diets taken by alcoholics with and without alcoholic liver disease, and those taken by male and female alcoholics with liver disease, have, however, failed to find any significant differences. ~0,4~ Nevertheless, it is interesting to note that the incidence of anaemia in alcoholics is reported to be higher in females than in males ~s, and the incidence of alcohol-related brain damage is reported to be higher in females than would be expected from the number of female alcoholics in the population. The latter finding has been attributed to the nutritionally less adequate diets taken by female alcoholics, compared with male alcoholics. 42,43

One of the main directions of research in the investigation of both individual and female susceptibility to alcoholic liver disease has been the role played by constitutional factors. Differences in metabolism, hormonal factors, immunological responses, genetic factors, body composition and body size, have all been considered as possible modifying factors in the relationship between alcohol consumption and the develop- ment of alcoholic liver disease.

Of these factors, the one that has received the least attention to date is differences in metabolism. Relatively little work has been done in this area, and that which has, has showed no differences between men and women. 22,44,4s

Differences in hormonal factors have been thought to play a significant role in the greater susceptibility of women. It has been noted that alcoholism develops in females shortly before menopause, at a time when hormonal imbalance might predispose the liver to the toxic effects of ethanol 12 It has also been noted that blood alcohol levels differ at different stages of the menstrual cycle, with the peak blood alcohol level occurring during the pre-menstrual stage. ~,47 Among women taking oral contraceptives, alcohol metabolism was much slower, but more regular and predict- able. 4s,47 The implications of these findings with respect to the role played by hormonal factors in the development of alcoholic liver disease is, however, still unclear.

In recent years, a large body of research has focussed on differences in immunological responses between men and women. In particular, it has been suggested that immuno- logical reactions directed against host liver cells may be more severe in women than in men. General support for this idea has come from those workers who have noted that auto- immune reactions are more common in women than in men. 17,4s,49 More specific support has come from a number of recently published studies which have found serum auto- antibodies to be more common among female alcoholics than among male ~7, and higher among cirrhotic women than cirrhotic men. 49 Some of the evidence is contradictory 19, suggesting that further research is needed before any definitive statements can be made.

Individual susceptibility to alcoholic liver disease may be in part related to genetic factors. Associations between alcoholic liver disease and genes related to the GM and HLA loci have been found by some researchers, who suggest that the presence of such factors may predispose to the development of disease. 5°-52 Again, the evidence for these findings is not conclusive, nor has there been any reported investigation of differences between males and females in the presence of these factors. 53,s4

Identical doses of ethanol per kilogram body weight have been shown to produce higher blood alcohol levels in females, at a faster rate. '~,47 Differences in body composition between males and females have been suggested as accounting for this behaviour. Specifically, it has been noted that alcohol has a smaller volume of distribution in women because adipose tissue, into which alcohol diffuses slowly because of the poor blood supply, forms a greater proportion of total body weight in females than in males. 2s,4s Converse- ly, a significantly lower proportion of total body weight in women is water, compared with men, again accounting for the smaller volume of distribution of alcohol in women, s5 In general, females have a lower body weight than males,68 a factor that could in part account for the greater susceptibility of women to the development of alcoholic liver disease.

Environmental factors may also play a role in determining susceptibility to alcoholic liver disease. As has already been discussed, nutritional intake, and hence nutritional status, may be of some importance. Other environmental factors that may play a significant role include previous liver damage and previous use of hepatotoxic drugs.

Recent studies have investigated the presence of serological markers indicating previous exposure to hepatitis A and hepatitis B in persons with alcohol-related liver disease. 19.22,s°,sT,sa At present, most reports have found a higher prevalence of such markers in persons with alcoholic liver disease compared with the general population. ̀~,5°.'~7 Unfortunately, the numbers of females in the studies have been very small, and so it is difficult to know whether previous exposure to hepatitis A or B could be an important determinant in the increased susceptibility of women. The significance of persons having had other forms of liver disease has not been reported, although previous damage could feasibly modify the effects of alcohol to increase the risk of further disease.

An area of research that has received very little attention, but one which could be of importance, is previous or ongoing use of hepatotoxic drugs. Some widely prescribed medications are known to have hepatotoxic effects, e.g. some anti-hypertensive medications. With respect to the latter it has been noted that, in general, women are more likely to be using anti-hypertensive medication than are men, despite the higher incidence of the disease in men.Sg,s° Over- the-counter preparations, such as paracetamol and aspirin, which are also known to be more widely used by women than by men 61, have been implicated in certain forms of liver damage, although their exact relationship is not yet clear. 62- 64 Similarly, a number of illicit drugs are known to be hepatotoxic, a factor which is of particular relevance when it is considered that a greater percentage of women than men abuse both alcohol and other drugs.iS Finally, the use of oral contraceptives by women may place them at greater risk of developing alcoholic liver disease. Specifically it is believed that estrogens can impair liver function even in the absence of alcohol consumption and may worsen liver damage that is already present, s5

A final consideration in assessing the factors that may contribute to the increased susceptibility of alcoholic liver disease in women is alcohol usage itself. For some years type of beverage consumed was thought to be significant. In particular, it was suggested that wine consumption was associated with a greater incidence of liver disease than were other forms of alcohol, ss,s7 However, few researchers have confirmed such a relationship and, as a consequence, the type of beverage is not considered to be of significance. 41'68 Patterns of drinking though, have been investigated, and a

49

positive association between continuous as opposed to binge, or intermittent, drinking and the development of alcoholic liver disease has been postulated. 1°,13 Examination of the drinking patterns of males and females has not provided any consistent evidence, with some studies suggesting a tendency for women to be continuous drinkers lO,69 and other studies suggesting the opposite, s9

METHODOLOGICAL ISSUES Most of the studies of factors that may contribute to the

increased susceptibility of women to liver disease have looked at factors in isolation, rather than in combination, even though most authors have suggested that a number of factors may play a role in determining the greater suscepti- bility of women. Without exception, all the studies have shown that the factor under investigation can only be seen in a small percentage of the women studied, which would suggest that more than one factor may be of importance. In view of both these points, it would seem appropriate that research consider all the factors indicated in combination.

It is highly likely that some of these factors may not be independent of each other, e.g. hepatotoxic drug usage may interfere with alcohol metabolism. In order to determine the independence of factors, studies investigating a number of factors in combination would seem necessary. Ideally, studies need to be undertaken in which all the factors that could plausibly account for the increased susceptibility of women are measured. Multiple regression analysis could then be undertaken to determine the extent to which each factor independently contributed to the prevalence of alcohol-related liver disease. The significance of any interactions with sex, for each of the factors under consideration, could then be assessed.

CONCLUSIONS Much of the evidence accumulated over the last 20 years

suggests that women develop alcoholic liver disease more readily than men. Although some of the evidence is conflicting, in general, the studies support the view that women are more susceptible to the effects of alcohol.

A number of factors may account for this increased susceptibility. Research into many of these factors has been undertaken. Studies aimed at investigating all these factors in combination, rather than in isolation, are recommended.

Knowledge of the factors that may account for the greater susceptibility in women has implications for both clinical practice and education, particularly the latter. Arming beth medical personnel and the community with information about the amount and patterns of alcohol, and the factors that may interact with alcohol to produce alcoholic liver disease, may help prevent the occurrence of such problems in the future.

ACKNOWLEDGEMENT The material presented in this paper was prepared with the

support of a grant from the New South Wales Drug and Alcohol Authority.

REFERENCES 1. Hallan, J. & Krook, H. (1963), Acta Medica

Scandinavica, 173, 479, 'Follow-up studies on unselected ten-year material of 360 patients with liver cirrhosis in one community'.

2. Taskiro, M. & Lipscomb, W.R. (1963), Quarterly Journal of Studies of Alcohol, 24, 203-212, 'Mortality

50

experiences of alcoholics'. 3. Viel, B.S., Donos, D., Salcedo & Varela, A. (1968),

Journal of Chronic Diseases, 21, 157-166, 'Alcoholic drinking habits and hepatic damage'.

4. Kramer, K., Kuller, L & Fisher, R. (1968), Annals of Internal Medicine, 69, 273-282, 'The increasing mortality attributed to cirrhosis in Baltimore (1957- 1966)'.

5. Kuller, L.H., Kramer, K. & Fisher, R. (1969), American Journal of Public Health, 59, 1124--11:33, 'Changing trends in cirrhosis and fatty liver mortality'.

6. Schmidt, W. & de Lint, J. (1969), Quarterly Journal of Studies on Alcohol, 30, 112-118, 'Mortality experiences of male and female alcoholic patients'.

7. Nicholls, P., Edwards, G. & Kyle E. (1974), Journal of Studies on Alcohol, 35, 841-855, 'Alcoholics admitted to four hospitals in England: General and cause-specific mortality'.

8. Phillips, G.B. & Davidson, C.S. (1954), Archives of Internal Medicine, 94, 585-603, 'Acute hepatic insufficiency of the chronic alcoholic: Clinical and pathological study'.

9. Mikkelson, W.P., Turrill, F.L. & Kern, W.H. (1968), American Journal of Surgery, 116, 266-272, 'Acute hyaline necrosis of the liver: A surgical trap'.

10. Wilkinson, P., Santamaria, J.N & Rankin, J.G. (1969), Australian Annals of Medicine, 18, 222-226, 'Epidemiology of alcoholic cirrhosis'.

11. Lischner, M.W., Alexander, J.F., Galambos, J.T. (1974), American Journal of Digestive Diseases, 16, 481-494, 'Natural history of alcoholic hepatitis: 1. The acute disease'.

12. Wilkinson, P., Kornczewski, A., Rankin, J.G., Santamaria, J.N. (1971 ), Medical Journal of Australia, 1, 1217-1225, 'Physical disease in alcoholism: Initial survey of I 000 patients'.

13. Brunt, P.W., Kew, MC., Scheuer, P.J. & Sherlock S. (1974), Gut, 15, 52-58, 'Studies in alcoholic liver disease in Britain. 1. Clinical and pathological patterns related to natural history'.

14. Bhathal, P.S., Wilkinson, P., Clifton, S., Rankin, J.G. & Santamaria, N. (1975), Australian and New Zealand Journal of Medicine, 5, 49-57, 'The spectrum of liver disease in alcoholism'.

15. Ashley, M.J., Olin, J.S., Le Riche, W.H., Komczewski, A., Schmidt, W. & Rankin, J.G. (1977), Archives of Internal Medicine, 137,883-887, 'Morbitity in alcoholics: Evidence for accelerated development of physical disease in women'.

16. Morgan, M.Y. & Sherlock, S. (1977), British Medical Journal, 1, 939-941, 'Sex-related differences among 100 patients with aJcoholic liver disease'.

17. Krasner, N., Davis, M., Portmann, B. & Williams, R. (1977), British Medical Journal, 1, 1497-1500, 'Changing patterns of alcoholic liver disease in Great Britain: Relation to sex and signs of auto-immunity'.

18. Williams, R & Davis, M. (1976), 'Alcoholic liver disease - - Basic pathology and clinical variants', 157-178, in: Edwards, G. & Grant, M. (eds), Alcoholism: New Knowledge and New Responses, University Park Press, Baltimore.

19. Basile, A. (1977), British Medical Journal, 2, 319, 'Alcoholic liver disease' (letter).

20. Nakamura, S., Takazawa, Y., Sato, T., Kera, K. & Maeda, T. (1979), Tohoku Journal of Experimental Medicine, 129, 351-355, 'Alcoholic liver disease in women'.

21. Levi, A.J. & Chalmers, D.M. (1978), Gut, 19, 521-525, 'Recognition of Alcoholic liver disease in a district hospital'.

22. Chalmers, D.M., Chanarin, I., MacDermott, S. & Levi, A.J. (1980), Journal of Clinical Pathology, 33, 3-7, 'Sex- related differences in the haematological effects of excessive alcohol consumption'.

23. Caroli, J. & Pequignot, G. (1958), Proceedings of a World Congress on Gastroenterology, 1, 661-665, 'Enquete sur les circonstances dietedues de la cirrhose alcoolique en France'.

24. Pequignot, G., Chabert, C., Eydoux, H. & Courcoul, M.A. (1974), Revue D'Alcoellsme, 28, 191-202, 'Augmentation du risque de cirrhose en fonction de la ration d'alcool'.

25. Pequignot, G. & Tuyns, A. (1975), INSERM/MRC, 54, 23-40, 'Rations d'alcool consommees "declarees" et risques pathologiques'.

26. Saunders, J.B., Davis, M. & Williams, R. (1981), British Medical Journal, 282, 1140-1143, 'Do women develop alcoholic liver disease more readily than men?'.

27. Gavaler, J.S. (1982), Alcoholism: Clinical and Experi- mental Research, 6, 2:186-196, 'Sex-related differences in ethanol-induced liver disease: artifactual or real?'

28. Drew, L.R.H. (1981), Statistical Association Between Alcohol Consumption and Alcohol-related Problems: Implications for Prevention, Commonwealth Department of Health, Canberra.

29. Shaw, S. (1980), 'The causes of increasing drinking problems amongst women: A general etiological theory', 1-40, in Women and Alcohol, Camberwell Council on Alcoholism, Tavistock Publ., London.

30. Weschler, H. (1978), 'Epidemiology of male/female drinking over the last half century', in Alcohol and Women Research Monograph No 1, US Department of Health, Education and Welfare/NIAAA, Maryland.

31. Spain, D.M. (1945), American Journal of Clinical Pathology, 15, 215-218, 'Portal cirrhosis of the liver, a review of 250 necropsies with references to sex differences'.

32. Garceau, A.J. & the Boston Inter-Hospital Group (1964), New England Journal of Medicine, 271, 1173-1179, 'The natural history of cirrhosis: 11. The influence of alcohol and prior hepatitis on pathology and prognosis'.

33. Hardison, W.G. & Lee, F.I. (1966), New England Joumal of Medicine, 275, 61-85, 'Prognosis in acute liver disease of the alcoholic patient'.

34. Powell, W.J. & Klatskin, G. (1968), American Journal of Medicine, 44, 406-429, 'Survival of patients with Laennec's cirrhosis: Influence of alcohol withdrawal and possible effects of recent changes in general management of the disease'.

35. Rankin, J.G., Wilkinson, P., Santamaria, J.N. (1970), Australian Annals of Medicine, 19, 232-239, 'Factors influencing the prognosis of the alcoholic patient with cirrhosis'.

36. Himsworth, H.P. (1950), in Lectures on the liver and its diseases, 37, Blackwell Scientific Publications, Oxford.

37. Rubin, E. & Lieber, C.S. (1968), New England Joumalof Medicine, 278, 869, 'Alcohol-induced hepatic injury in non-alcoholic volunteers'.

38. Wilkinson, P., O'Day, D.M., Breen, K.J. & Rankin, J.G. (1968), Gut, 9, 707, 'Bromosulphthalein metabolism in acute alcoholic liver disease'.

39. Lieber, C.S. (1966), Gastroenterology, 50, 119, 'Hepatic and metabolic effects of alcohol'.

40. Lieber, C.S., Spritz, N. & De Cadi, L.M. (1969), Joumalof Lipid Research, 10,283, 'Fatty liver produced by dietary deficiencies: its pathogenesis and potentiation by ethanol'.

41. Letbach, W.K. (1975), Annals of the New York Academy of Sciences, 252, 85-105, 'Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse'.

42. Victor, M. & Adams, R.D. (1961), American Journal of Clinical Nutrition, 9, 379-397, 'On the aetiology of alcoholic neurologic diseases with special reference to the role of nutrition'.

43. Horvath, T.B. (1975), 'Clinical spectrum and epidemiological features of alcoholic dementia', in Alcohol, Drugs and Brain Damage, Proceedings of a Symposium: Effects of Chronic use of Alcohol and Other Psychotropic Drugs on Cerebral Function, Rankin, J.G. (ed), Addiction Research Foundation, Toronto.

44. Reed, T.E., Kalant, H., Gibbins, R.J., Kapur, BM. & Rankin, J.G. (1976), Canadian Medical Association Journal, 115, 851-855, 'Alcohol and acetaldehyde metabolism in Caucasians, Chinese and Amerinds'.

45. Mello, NK. (1981), 'Some behavioural and biological aspects of alcohol problems in women', in Kalant, O.J. et al, (eds), Alcohol and Drug Problems in Women, Plenum Press, New York.

46. Jones, B.M. & Jones, M.K. (1976), Annals of the New York Academy of Sciences, 273, 567-587, 'Alcohol effects in women during the menstrual cycle'.

47. Jones, B.M. & Jones, M.K. (1976), 'Women and alcohol: Intoxication, metabolism and the menstrual cycle', 103- 136, in Greenblatt, M. & Schuckit, M.A. (eds), Alcoholism Problems in Women and Children, Grune and Stratton. New York.

48. Mistilis, S.P. (1968), Australian Annals of Medicine, 17 248-266, 'Liver disease in pregnancy with particular emphasis on the cholestatic syndromes'.

49. Hodgson, H.J.F. & Thompson, R.P.H. (1976), Lancet, 11, 118-121, 'Cirrhosis in South London'.

50. Cunningham, A.L, Gust, I.D., Matthews, J.D., Laymen, N. & Tait, B. (1981), 'Genetic factors, hepatitis virus and alcoholic liver disease', (Unpublished report), Melbourne.

51. Tait, B.D. & Mackay, I.R. (1982), Tissue Antigens, 19, 6-10, 'HLA and alcoholic cirrhosis'.

52. Saunders, J.B., Wodak, A.D., Haines, A., Powell- Jackson, P.R., Portmann, B., Davis, M., Williams, R. (1982), Lancet, 1381-1384, 'Accelerated development of alcoholic cirrhosis in patients with HLA-88'.

53. Gluud, C., Aldershvile, J., Dietdekson, D. et al. (1980), Scandanavian Joumal of Gastroenterology, 15, 337-341, 'Human leucocyte antigens and patients with alcoholic liver cirrhosis'.

54. Melendez, M., Vargas-Tank, L, Fuentes, C. et al. (1979), Gut, 20, 288-290, 'Distribution of HLA histocompatability antigens, ABO blood groups and Rh antigens in alcoholic liver disease'.

55. Bell, C.H., Davidson, J.N. & Scarborough, H. (1968), Text book of Physiology and Biochemistry, Williams and Wilkins, Baltimore.

56. International Committee for Radiological Protection (1975), Report on the Task Group on Reference Man, Press, Oxford. Pergamon.

57. Mills, P.R., Pennington, T.H., Kay, P., MacSween, R.N.M., Watkinson, G. (1979), Joumal of Clinical Pathology, 32, 778-782, 'Hepatitis B antibody in alcoholic cirrhosis'.

58. Gluud, C., Aldershvile, J., Henriksen, J., Kryger, P.,

51

Mathiesen, L. (1982), Journal of Clinical Patho/ogy, 35, 693--697, 'Hepatitis B and A virus antibodies in steatosis and cirrhosis'.

59. Sokolow, M. & Harris, R.E. (1961), 'The natural history of hypertensive disease', 3-19, in Hypertension, Recent Advances, Brest A.N. and Moyer J.H. (eds), Kimpton, London.

60. MacMahon, S.W., Blacket, R.B., Macdonald, G.J. & Hall, W. (1983), 'The effects of body mass and alcohol consumption on blood pressure levels and the prevalence of hypertension in Australian men and women', UNSW (Unpublished manuscript).

61. Celentano, D.P., McQueen, D.V. & Chee, E. (1980), Journal of Chronic Diseases, 33, 383-394, 'Substance abuse by women: a review of the epidemiologic literature'.

62. Bonkowsky, H.L., Mudge, G.H.~ McMurtry, R.J. (1978), Lancet, 1, 1016-1018, 'Chronic hepatic inflammation and fibrosis due to low doses of paracetamol'.

63. Lancet Editorial (1981), 'Aspirin or Paracetamol.' i, 287- 289.

64. Zimmerman, H.J. (1981), Arcnives of Internal Medicine, 141,333-342, 'Effects of aspirin and acetaminophen on the liver'.

65. Galambos, J.T. (1972), 'Alcoholic hepatitis: its therapy and prognosis', 567, in Progress in Liver Diseases, Vo/ IV. Popper, H. & Schaffner, F. (eds), Grune and Stratton, New York.

66. Schmidt, W. & Bronetto, J. (1962), Amedcan Joumalof Public Health, 52, 1473, 'Death from liver cirrhosis and specific alcoholic beverage consumption: an ecological study'.

67. Mackay, I.R. (1966), Medical Journal of Austrafia, 2, 372, 'The effects of alcohol on the gastrointestinal tract'.

68. Lelbach, W.R. (1976), 'Epidemiology of alcoholic liver disease', 494-515, in Progress in Uver Disease, Vol V, Popper, H. & Schaffner, F. (eds), Grune and Stratton, New York.

69. Beckman, L.J. (1975), Journal of Studies on Alcohol, 36, 797-824, 'Women alcoholics: A review of social and psychological studies'.

52