How much alcohol does the liver tolerate?

1. How much alcohol does the liver tolerate? Einar S Björnsson Professor, Chief of GI Landspitali University Hospital Reykjavik Iceland

2. ”Social indulgence in alcohol, whether in the form of a fine Bordeaux,or a New Zealand Sauvignon Blanc, a pint of English beer or a bottle of Swedish vodka, is a fundamental and important part of Western European culture” Nick Sheron MD 2000

3. Liver diseases according to the general population are due to: a) Alcohol b) cancer

4. History • The link between alcohol intake and liver disease was known to ancient Greeks and Ayervedic physicians of India • Alcoholic cirrhosis was described by Matthew Bailllie 1793 • Alcohol induced fatty liver by Addison in 1836 and by Rokitansky 1849

5. Scepticism • However.........the link between alcohol and liver disease was lost to Western medicine until relatively late in the 20th century with the prevailing view that liver damage was due to dietary deficiency

6. Scepticism • ”The evidence for toxic effects of alcohol on liver cells is no more than by toxic effects of sugar” Charles Best 1949

7. Alcohol as a hepatotoxin • In textbooks 25-30 years ago, alcohol as a hepatotoxin was put into question • Malnutrition among alcoholics? Vitamin deficiency etc? • Studies on alcohol drinking babians who were fed with a perfect diet demonstrated fibrosis and cirrhosis development

8. Charles Lieber 1931-2009

9. Lieber C et al. Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells. Gastroenterology 1984, Lieber et al. Biochemical and morphological alterations of baboon hepatic mitochondria after chronic ethanol consumption. Hepatology 1984

10. Alkoholic liver disease (ALD) • General aspects on ALD • Risks for the development of alcoholic cirrhosis • Epidemiology • The prevalence and incidence of liver cirrhosis in Iceland • Transplantation for ALD

11. Alcohol consumption and mortality from cirrhosis in France 1940-1980

12. General aspects of alcohol liver disease • Only 15-20% of heavy consumers of alcohol develop liver cirrhosis • Why only a minority of those who consume large amounts of alcohol develop cirrhosis is unclear • Patients with ALD probably differ from patients with other alcohol related damage

13. Autopsy studies • Approximately 15-20% of patients with chronic alcoholism have liver cirrhosis

14. What is an over consumtion of alcohol-in terms of risk for liver injury? • Numerous studies indicate that threshold values for men to be approximately 40 gr alcohol per day • Threshold values for women is approximately 20 gr alcohol per day

15. Types of alcohol • 330 ml of 5% beer = 9 gr alcohol • 90 ml (9cl) 12% wine = 9 gr alcohol • 30 ml (3cl) 36% spirit = 9 gr alcohol

16. Quantity of alcohol in a standard drink

17. Risk for liver injury by alcohol • Crossectional, case control and prospective cohort studies show that the risk for liver injury increase with: • 20-40 g/day (Pequignot et al.Int J Epidemiol 1978) • 30 g/day (Bellentani et al. Gut 2003) • 12-24 g/day-women (Becker et al. Hepatology 1996) • 24-36 g/dag-men (Becker et al. Hepatology 1996) • 40 g/day (Norton et al.BMJ 1987) • 40-80 g/day (Savolainen et al. Alc Clin Exp Res 1993)

18. Clinical studies • Men with ALD reported alcohol intake between 140-210 gr per day and women between 80-160 gr per day (Saunders et al. BMJ 1981; 282: 1140) • Duration of over consumption was a mean 16 years in men och 10 years among women (Saunders et al. BMJ 1981; 282: 1140)

19. Liver disease among heavy consumers of alcohol

20. Liver disease among heavy consumers of alcohol • Among patients with highest cumulative intake, 52% had liver cirrhosis (Saunders et al. Br J Add 1985) • A total of 91% av cirrhotics drank large amounts of alcohol 6-7 days/week • Drinking pattern (week by week) was a stronger predictor of the severity of liver injury than the mean daily alcohol intake (Saunders et al. Br J Add 1985)

21. Is there a dose-response relationship? • In an autopsy study from Finland, relatives were interviewed on the alcohol history (Savolainen et al. Alc Clin Exp Res 1993) • Occurrence of fatty liver increased with 40-80 gr/day and the risk for cirrhosis increased by ≥80 gr alcohol/day • With more than 80 gr alcohol/day there was no dose-response relationship

22. Autopsy study from Finland • The incidence of both bridging fibrosis and liver cirrhosis increased significantly (RR = 8.8) only when daily intake exceeded 80 g. Amounts of ethanol exceeding 80 g did not relate to further increases in incidence of bridging fibrosis or liver cirrhosis. • In males, daily ingestion of ethanol below 40 g for a period of 25 years does not increase the risk of alcohol-related liver disease

23. Is there a dose-response relationship? • A follow-up of 258 alcohol misusers for 10-13 years, showed the risk for liver injury to be independent of a daily dose of ≥50 gr (Sørensen et al. Lancet 1984) • Cirrhosis developed among 38 (15%) 2% per year developed cirrhosis • The no dose-dependent effects but instead a threshold value was confirmed in a study from Switzerland (Marbet J Hepatol 1987)

24. No-dose dependent effects associated with high intake of alcohol • Several studies indicate that over consumption of alcohol has a”permissive” role, than a dose dependent role (Savolainen 1993, Sörensen 1984 och 1989, Marbet 1987, Kamper-Jørgensen J Hepatology 2004)

25. Self-reported alcohol intake • Has been questioned.......... • However, self-reported current alcohol intake was a good predictor of future risk of alcohol-induced liver disease (Becker U, et al. Hepatology 1996)

26. The hepatotoxicity of alcohol • Fatty liver is common among heavy consumers of alcohol • 90% of those who drink > 60 gr/day have liver steatosis (fatty liver) (Crabb DW 1999) • 10-35% develop alcoholic hepatitis • 10-20% develop cirrhosis (Grant et al. NIH report 1991; Ishak et al. Alc Clin Exp Res 1991)

27. Conflicting data exist concerning a possible lower risk in wine drinkers • Becker U et al. Lower risk for alcohol induced cirrhosis in wine drinkers. Hepatology 2002; 35: 868-875 • Pelletier S et al. Wine consumption is not associated with decreased risk of alcoholic cirrhosis in heavy drinkers. Alcohol Acohol 2002; 37: 618-621.

28. Are patients with alcoholic liver disease (ALD) different from other heavy consumers? • Many patients med ALD have not experienced psychosocial consequences of alcohol over consumtion or been referred for treatment of alcoholic problems (Saunders et al. Br J Add 1985) • Among 160 patients with ALD referred for liver transplantation in Pittsburgh 21% did not fulfill criteria for alcohol dependency (Dimartini A et al. Liver Transplantation 2006)

29. Stokkeland et al. Different drinking patterns for women and men with alcoholic dependency with and without alcoholic cirrhosis. Alcohol Alcohol 2008 • 50 patients with AC, 50 with AD and 40 with NAC completed Lifetime Drinking History questionnaire • Women with AC reported 14,009 drinks of alcohol consumed during their lifetime compared to 45,658 drinks consumed by men with AC (P < 0.0001).

30. Stokkeland et al. Different drinking patterns for women and men with alcoholic dependency with and without alcoholic cirrhosis. Alcohol Alcohol 2008 • Both women and men with AC had significantly fewer DDD compared to men and women with AD without cirrhosis, 4.4 drinks for women (P = 0.046) and 6.2 for men (P = 0.048) with AC • Women with AC reported 9,198 drinks as binge drinking compared to 25,890 drinks for women with AD without liver cirrhosis (P < 0.05)

32. Normal liver histology

33. Liver steatosis

34. Effects of chronic alcohol use (Belfrage et al. Thesis Lund 1973) • 8 healthy medical students were asked to drink 63 g alcohol per day (45 cl 4 bottles of ”mellanöl”=3.5%) • A total of 10 liver biopsies! • Slightly increased GGT but totally normal values of AST and AlT • Doubling of fat in the liver the first 2 weeks, but after that decreased

35. The liver is a forgiving organ!

36. Alcoholic hepatitis

37. Alcoholic hepatitis

38. Liver cirrhosis

39. Liver cirrhosis-microscopically

40. Effects of excessive alcohol use on the liver

41. Why do only some heavy consumers develop alcohol induced liver injury? • Biological variation in ”response to alcohol” • Genetic susceptibility (twin studies) • Synergism with other factors: hepatitis C, hemochromatosis, alpha-1-antitrypsin deficiency etc. • Nutritional factors

42. Why do only some heavy consumers develop alcohol induced liver injury? A twin study has suggested a genetic basis for the variable predisposition to alcoholic liver disease (Hrubec 1981) Monozygotic twins significantly higher prevalence than dizygotic (Reed 1996) Variation in TNF-alpha polymorfism and cytokine gene polymorphism-II-6, Il-10 (Gleeson et al 2008)

43. Genetic and environmental risk factors of ALD • No combination of environmental risk factors-(hep B or C, diet, alcohol ) leads to 100% incidence of ALD • No genetic variation identified so far leads to 100% incidence • BMI is an independent risk factor for ALD (Raynard Hepatology 2002)

44. Drinking pattern • In Disease of the Liver and Biliary system 1993. Sheila Sherlock: page 371: ”Continued daily imbibing is more dangerous than intermittent consumption when the liver is given a chance to recover. For at least two days in the week a person should not drink alcohol”

45. Higher risk for alcoholic liver disease in women • Several studies have shown differing blood alcohol levels in women vs. men after consumption of equal amounts of alcohol (Baraona et al 2001) • Difference in first-pass metabolism of alcohol (gastric alcohol dehydrogenase) • Difference in volume distribution • Probably not nutrient intake (Wagnerberger 2008)

47. Sweden Norway Iceland Greenland Finland Denmark

48. Alcohol use in Iceland1973-2003

49. Alcohol consumption is equaling out in Europe • In south of Europe the alcohol consumption in France, Greece, Italy, Portugal and Spain decreased from 14 L/year 1974 to 10.4 L 1992. Wine consumption has decreased with 42% but beer consumption increased with 36% • In France alcohol consumtion was 18 L /year per capita 1963 but 11.5 in 1993 (Gual & Colom Addiction 1997)

50. Alcohol liver disease-Epidemiology • Liver cirrhosis is the 9th most common cause of death in USA • Alcoholic cirrhosis was 44% of 26 000 who died of liver cirrhosis in USA 1973-1988 • 5 years survival of cirrhosis 23-50% in USA • 10 000 die in France every year from alcoholic cirrhosis