- Email: [email protected]
Ethanol metabolism in patients with liver cirrhosis
Journal of Clinical Forensic Medicine (2000) 7, 48–51 © APS/Harcourt Publishers Ltd 2000
COMMENTARY
Ethanol metabolism in patients with liver cirrhosis A. W. Jones Department of Forensic Toxicology, University Hospital, SE-581 85 Linköping, Sweden SUMMARY. Aspects of human metabolism of ethanol are reviewed with the main focus on the rate of ethanol clearance from blood in patients suffering from liver cirrhosis. Studies in humans and experimental animals do not support the notion of a slower rate of ethanol metabolism in patients with liver cirrhosis compared with those with normal liver function. The rate of ethanol disappearance from blood in healthy non-alcoholic subjects falls within the range 9–20 mg/dL/h and there is no compelling evidence to suggest that this should be much different in cirrhotic patients. Journal of Clinical Forensic Medicine (2000) 7, 48–51
dose of ethanol ingested is oxidized (95–98%) and the remainder (2–5%) is excreted unchanged in breath, urine and sweat.3,4 The oxidation of ethanol occurs primarily in the liver, first to acetaldehyde and then to acetate. The acetate produced becomes oxidized into carbon dioxide and water principally in the extrahepatic muscle tissues. The class I isozymes of alcohol dehydrogenase (ADH) are primarily responsible for the hepatic oxidation of ethanol and the Km of human ADH is about 5–10 mg/dL, which means that the enzyme quickly becomes saturated even after 1–2 drinks. The elimination kinetics of ethanol therefore exhibit a pseudolinear disappearance phase (zero order kinetics).4,5 After drinking larger amounts of alcohol, the microsomal enzyme denoted P4502E1, which has a Km of 60–80 mg/dL, becomes engaged in the oxidation of ethanol.6,7 Moreover, the ability of P4502EI to oxidize ethanol increases after chronic daily drinking as often seen in alcoholics.8 Some alcoholics are capable of eliminating ethanol 2–3 times faster than moderate drinkers owing to the phenomenon of enzyme induction.9 However, this accelerated rate of ethanol disposal disappears after a few days of abstinence owing to rapid turnover of the P4502E1 enzyme.8 Evidence that catalase plays a role in hepatic oxidation of ethanol in vivo is not very convincing because of the lack of hydrogen peroxide needed for the reaction to occur.6,7 Although ADH is mainly located in the liver, enzyme activity also exists in other tissue such as gastric mucosa, colon, lung, and kidney.5,7 Hepatic ADH activity is little different in healthy subjects and patients with advanced liver cirrhosis as shown by
INTRODUCTION DiMartini and Rao1 described a patient suffering from end-stage liver disease who allegedly attained a blood-alcohol concentration (BAC) of 57 mg/dL after drinking a number of ‘non-alcoholic’ beers containing 0.5% v/v ethanol or less. This moderately high BAC was attributed to the patient’s inability to metabolize the minute amount of ethanol contained in the beer, owing to advanced stages of liver cirrhosis. However, only a single blood sample was obtained so no valid conclusion can be made about the rate of ethanol disposal in this patient. Moreover, the scientific literature dealing with disposition and metabolism of alcohol in cirrhotic patients was not well covered and the papers cited were hardly relevant to the main gist of the article. My intention here is to provide references dealing with the metabolism of ethanol in individuals suffering from liver cirrhosis and offer a more credible explanation for the patient’s BAC being 57 mg/dL.
METABOLISM AND DISPOSITION OF ETHANOL After drinking alcoholic beverages, the ethanol they contain after absorption into the blood becomes diluted with the total body water.2 The bulk of the
Professor A. W. Jones PhD, DSc, Department of Forensic Toxicology, University Hospital, SE-581 85 Linköping, Sweden. Tel: +46 13 120426; Fax: +46 13 104875; E-mail: [email protected] 48
Ethanol metabolism in patients with liver cillhosis obtaining biopsy specimens.10–12 The impact of gastric ADH has been much discussed in recent years in connection with alleged first-pass metabolism of ethanol, which is more pronounced when low (<0.2 g/kg) doses of alcohol are ingested and particularly when taken after a meal.13–16 Studies have shown that extrahepatic oxidation of ethanol might amount to 20% of the total.17 This means that even with severe liver dysfunction people are capable of disposing of ethanol albeit at a slower rate. The efficacy of the first-pass metabolism of ethanol via gastric ADH depends on many factors such as the dose administered, the emptying time of the stomach, age, gender, drinking habits, and dilution of the alcoholic beverage.15,16 Some evidence exists suggesting that first-pass metabolism is more pronounced after drinking very weak alcoholic beverages such as ‘alcohol-free’ beer.18,19 MEASURING THE RATE OF ETHANOL DISAPPEARANCE FROM BLOOD The most direct and easiest way to evaluate the rate of ethanol metabolism in humans is to administer a moderate dose (0.5–0.8 g/kg) and to take a series of venous blood samples at 15–30 min intervals for quantitative determination of ethanol. From a plot of the concentration vs time curve in the post-absorptive state, the rate of ethanol disappearance from blood is determined by methods described many years ago by Widmark.2,20,21 Figure 1 shows an example of a proper study of the disappearance rate of ethanol from blood in one healthy subject for whom the rate of alcohol elimination was 14.3 mg/dL/h. Indeed, the population average rate of ethanol elimination from venous blood in moderate drinkers is about 15 mg/dL/h but in the individual case this might range from about 9–20 mg/dL/h.20 Taking only a single specimen of blood makes it impossible to evaluate a person’s ability to eliminate ethanol. Even taking two blood samples one hour apart is not a good way to measure the elimination rate of alcohol because it cannot be certain that the post-absorptive phase of ethanol kinetics existed at the time of blood sampling.22 Dogs tend to eliminate alcohol from blood at roughly the same rate as humans, that is, 15 mg/dL/h and even in animals having undergone a total hepatectomy, the rate of ethanol elimination was 7 mg/dL/h.23 Extrahepatic metabolic pathways and excretion of alcohol in urine, breath and sweat probably accounts for the elimination of ethanol despite having removed the liver. When the class 1 isoenzymes of ADH were inhibited by giving rats 4-methyl pyrazole, the elimination rate of ethanol was reduced by
49
Fig. 1 Blood-ethanol concentration-time profile in one healthy male subject who drank 0.63 g ethanol per kg body weight as neat whisky in 20 min after an overnight fast. The rate of disappearance of ethanol from blood was 14.3 mg/dL/h and was derived according to Widmark; C0/min0 and seven measurements of BAC were included in calculating the slope of the linear elimination phase.
70% compared with a saline-control treatment.24 In a strain of deer-mice genetically lacking hepatic ADH, the animals were still capable of eliminating ethanol from the blood which once again points to extrahepatic sources of ADH or involvement of other alcohol metabolising enzyme.6,25 In a thesis devoted to metabolism of ethanol under pathophysiological conditions, Jokipii26 allowed patients with cirrhosis to drink 0.5 g ethanol per kg body weight on an empty stomach after they had fasted overnight. In cirrhotic patients (n=6), the mean rate of ethanol elimination from blood was 11 mg/dL/h (range 9–13) compared with a mean of 13 mg/dL/h (range 10–17) in a control group (n=42) of healthy subjects receiving the same dose of ethanol.2,26 The existence of extrahepatic pathways of ethanol oxidation, estimated to account for 20% of the dose administered, and excretion through lungs and kidney means that alcohol can be cleared from the blood also in cirrhotic patients with end-stage liver disease.17,27,28 In several older studies of ethanol metabolism in patients with cirrhosis, investigators found no clearcut differences from normal control subjects.29,30 However, in those suffering from cirrhosis and jaundice, a somewhat slower elimination rate of ethanol was observed.30 In a patient with diminished hepatic blood flow owing to cirrhosis and portocaval shunt, the rate of ethanol metabolism as reflected in the blood-alcohol clearance rate was appreciably slower. However, the authors warn that liver blood flow per se might have been a more important factor than the liver cirrhosis.31,32
50
Journal of Clinical Forensic Medicine
CONCLUSION It is not possible to draw any valid conclusions about a person’s ability to metabolize ethanol on the basis of a single blood-alcohol analysis.1 The older literature cited above involving both human and animal experiments points to a marginally slower rate of ethanol elimination in alcoholics suffering from liver cirrhosis. However, this finding might be confounded by malnutrition, delayed stomach emptying rate, ascites, reduced hepatic blood flow or other problems associated with chronic alcohol abuse and alcoholism.33–36 Accordingly, there is no strong evidence to indicate that the alcohol burn-off rate is appreciably less in patients with liver cirrhosis compared with healthy subjects. Furthermore, the calculation of expected BAC presented by DiMartini and Rao seems questionable because they assumed bolus intake and 100% bioavailability of the entire dose of alcohol.1 These assumptions are not valid when very weak alcoholic beverages such as 0.5 vol% beer are consumed over a lengthy time period.18,19 The question of whether alcohol was analyzed in whole blood or serum was not made perfectly clear because hospital laboratories in USA generally analyse serum. This becomes important when Widmark’s factors are used to estimate alcohol in the blood from a given intake.21 Obtaining ethical permission to make a proper study of the rate of ethanol metabolism in abstinent alcoholic patients suffering from liver cirrhosis is probably not feasible nowadays. Nevertheless, long experience in dealing with alcohol abusers and drunk drivers has taught me that they are seldom truthful about their drinking practices. The amounts consumed are often grossly underestimated. Accordingly, the most plausible explanation for the patient’s BAC being 57 mg/dL is through the consumption of conventional alcoholic drinks, such as a couple of normal strength beers (4–5 vol%) a short time before the medical examination or a considerably larger amount of alcohol the evening before. REFERENCES 1. DiMartini AF, Rao KN. Elevated blood ethanol levels caused by ‘non-alcoholic’ beer. J Clin Forens Med 1999; 6: 106–108. 2. Jones AW. Biochemistry and physiology of alcohol: applications to forensic science and toxicology. In Garriott JC (ed) Medicolegal aspects of alcohol, Lawyers & Judges Publishing Co., Tucson, 1996: 85–136. 3. Jones AW. Excretion of alcohol in urine and diuresis in healthy men as a function of their age and the dose administered. Forens Sci Int 1990; 45: 217–224. 4. Jones AW. Forensic science aspects of ethanol metabolism. Forensic Science Progress, Springer-Verlag, Berlin-Heidelberg, 1991, pp 32–89. 5. Crabb DW, Dipple KM, Thomasson HR. Alcohol sensitivity, alcohol metabolism, risk of alcoholism, and the role of alcohol and aldehyde dehydrogenases. J Lab Clin Med 1993; 122: 234–40.
6. Takagi T, Alderman J, Lieber CS. In-vivo roles of alcohol dehydrogenase (ADH) catalase and the microsomal ethanoloxidizing system (MEOS) in deermice. Alcohol 1985; 2: 9–12. 7. Lieber CS. Ethanol metabolism, cirrhosis and alcoholism. Clin Chim Acta 1997; 257: 59–84. 8. Keiding S, Christensen NJ, Damgaard SE et al. Ethanol metabolism in heavy drinkers after massive and moderate alcohol intake. Biochem Pharmacol 1983; 32: 3097–3102. 9. Jones AW, Sternebring B. Kinetics of ethanol and methanol in alcoholic sduring detoxification. Alc Alcohol 1992; 27: 641–47. 10. Mezey E, Tobon F. Rates of ethanol clearance and activities of the ethanol-oxidizing enzymes in chronic alcoholic patients. Gastroenterology 1971; 61: 707–715. 11. Nuutinen HU. Activities of ethanol-metabolizing enzymes in liver disease. Scand J Gastroenterol 1986; 21: 678–684. 12. Vidal F, Perez J, Morancho J, Pinto B, Richart C. Hepatic Alcohol Dehydrogenase Activity in Alcoholic Subjects with and Without Liver Disease. Gut 1990; 31: 707–711. 13. Oneta CM, Simanowski UA, Martinez M et al. First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying. Gut 1998; 43: 612–19. 14. Seitz HK, Egerer G, Simanowski UA et al. Human gastric alcohol dehydrogenase activity: effect of age, sex, and alcoholism. Gut 1993; 34: 1433–1437. 15. Seitz HK and Oneta CM. Gastrointestinal alcohol dehydrogenase. Nutr Rev 1998; 56: 52–60. 16. Sato N, Kitamura T. First-pass metabolism of ethanol; An overview. Gastrenterology 1996; 111: 1143–1150. 17. Larsen JA, Tygstrup JA, Winkler. The significance of the extrahepatic elimination of ethanol in determination of hepatic blood flow by means of ethanol. Scand J Clin Lab Invest 1961; 13: 116–121. 18. Jones AW, Ulwan, O. Low-alcohol drinks and risk of high blood-alcohol in children. J Tox Clin Tox 1996; 34: 349–350. 19. Holford NH. Complex PK/PD models – an alcoholic experience. Int J Clin Pharmacol Ther 1997; 35: 465–468. 20. Jones AW. Disappearance rate of ethanol from blood in human subjects; Implications in forensic toxicology. J Forens Sci 1993; 38: 104–118. 21. Widmark, EMP. Die theoretischen Grundlagen und die praktische Verwendbarkeit der gerichtlich-medizinischen Alkoholbestimmung. Urban und Schwarzenberg, Berlin, 1932, pp 1–140. 22. Jones AW, Andersson L. Influence of age, gender and bloodalcohol concentration on the disappearance rate of alcohol from blood in drinking drivers. J Forens Sci 1996; 41: 922–926. 23. Clark BB, Morrissey RW, Fazekas JF and Welch CS. The role of insulin and the liver in alcohol metabolism. J Stud Alcohol 1941; 2: 663–683. 24. Rydberg U, Neri A. 4-methyl pyrazole as an inhibitor of ethanol metabolism; Differential metabolic and central nervous effect. Acta Pharmacol Toxicol 1972; 31: 421–432. 25. Norsten C, Cronholm T, Ekström G, Handler JA, Thurman RG, Ingelman-Sundberg M. Dehydrogenase-dependent ethanol metabolism in deer mice (Percomyscus maniculatus) lacking cytosolic alcohol dehydrogenase. J Biol Chem 1989; 264: 5593–5597. 26. Jokipii SG. Experimental studies on blood alcohol in healthy subjects and in some diseases, Helsinki: Thesis, University of Helsinki, 1951: 1–99. 27. Utne HE, Winkler K. Hepatic and extrahepatic elimination of ethanol in cirrhosis. Scand J Gastroent 1989; 15: 297–304. 28. Winkler K, Lundquist F, Tygstrup N. The hepatic metabolism of ethanol in patients with cirrhosis of the liver. Scand J Clin Lab Invest 1969; 23: 59–69. 29. Lieberman FL. The effect of liver disease on the rate of ethanol metabolism in man. Gastroenterology 1963; 44: 261–266. 30. Asada M, Galambos JT. Liver disease, hepatic alcohol dehydrogenase activity and alcohol metabolism in the human. Gastroenterology 1963; 45: 67–72.
Ethanol metabolism in patients with liver cillhosis 31. Leube G, Mallach HJ. Zur Alkoholelimination bei einem Leberkranken mit portocavalem Shunt. Blutalkohol 1980; 17: 15–25. 32. Mallach HJ, Von Oldershausen HF, Springer R. Der Einfluβ oraler Alkoholzufuhr auf den Blutalkoholspiegel von Gewohnheitstrinkern und Leberkranken unter verschiedenen alimentären Bedingungen. Klin Wschr 1972; 50: 732–738. 33. Sonne J. Drug metabolism in liver disease: Implications for therapeutic drug monitoring. Ther Drug Monit 1996; 18: 397–401.
51
34. Isobe H, Sakai H, Satoh M, Sakamoto S, Nawata H. Delayed gastric emptying in patients with liver cirrhosis. Dig Dis Sci 1994; 39: 983–987. 35. Hoyumpa AM, Schenker S. Major drug interactions: Effect of liver disease, alcohol, and malnutrition. Ann Rev Med 1982; 33: 113–149. 36. Bode JC. The metabolism of alcohol: Physiological and pathophysiological aspects. J Roy Coll Physicians 1978; 12: 122–135.
Response from authors We appreciate the thorough explanation of the pharmacokinetics of ethanol metabolism by Dr Jones in response to our case report. This insightful commentary adds a helpful discussion to this issue. The pharmacokinetics in Dr Jones’s commentary are not to be disputed. However, we were not commenting on the rate of ethanol metabolism, rather on the fact that with a sufficient loading dose of ‘non-alcoholic’ beers a patient could achieve a positive blood ethanol level. The fact that the patient has end-stage liver disease with a significant reduction in parenchymal function must impact on ethanol metabolism. We hypothesize that this allowed a higher peak level of blood ethanol, which was obtained as the reported BAL of 57 mg/dL. Our main intent was to elucidate the potential dangers of these types of beverages for both alcoholic patients abstinent from regular alcohol (in whom the presence of blood ethanol could precipitate alcoholic relapse) and also patients with end-stage liver disease (in whom the presence of blood ethanol will continue to do further liver damage). As Dr Jones points out, patients with cirrhosis may have a reduced blood alcohol clearance rate owing to diminished hepatic blood flow. Our patient had portal hypertension with ascites and would have physiologic portal-systemic shunting. In addition the definition of cirrhosis is important. The Childs-Pugh scoring system of cirrhosis gives an estimation of the amount of damage to the liver parenchyma by a scoring system using total bilirubin, synthetic functions, the amount of ascites, and encephalopathy. In our case, the patient’s Childs-Pugh score was C13 (the highest score being a 15) which places him at the most advanced stage of liver disease, thus he had end-stage liver disease. This patient’s metabolism would be expected to be markedly impaired. In some of reports cited by Dr Jones on cirrhotic patients and ethanol metabolism, less accurate
estimations of parenchymal function, such as liver biopsy are used. Biopsy can help to establish the histologic stage, though sampling errors can occur due to the uneven distribution of the pathologic changes.1 In addition, Dr Jones used two citations to support the statement that hepatic alcohol dehydrogenase (ADH) is not significantly different between healthy subjects and patients with advanced liver cirrhosis.2,3 In fact, these citations demonstrated that alcohol dehydrogensase activity was significantly different between normal controls and patients with alcoholic liver disease. In a third citation that Dr Jones cited,4 patients with jaundice or a history or clinical evidence of cirrhosis were excluded, therefore this citation cannot be used as evidence that patients with cirrhosis do not have diminished ADH. Dr Jones identified that it would be unethical to study the pharmacokinetics of blood ethanol metabolism in cirrhotic patients. Therefore, we must rely on these chance encounters which may be less than perfect. Nevertheless, our original contention and recommendations still hold and were formed on the basis of this case. So-called ‘non-alcoholic’ beverages should be eliminated from consumption by patients with liver disease and/or alcoholism. REFERENCES 1. 2. 3. 4.
Van Leeuwen DJ, Wilson L, Crowe DR. Liver biopsy in the mid-1990s: questions and answers. Seminars in Liver Disease 1995; 15: 340–359. Nuutinen HU. Activities of ethanol-metabolizing enzymes in liver diseases. Scand J Gastroenterol 1986; 21: 678–684. Vidal F, Perez J, Morancho J, Pinto B, Richart C. Hepatic Alcohol dehydrogenase activity in alcoholic subjects with and without liver disease. Gut 190; 31: 707–711. Mezey E, Tobon F. Rates of ethanol clearance and activities of the ethanol-oxidizing enzymes in chronic alcoholic patients. Gastroenterology 1971; 61: 707–715.
COMMENTARY
Ethanol metabolism in patients with liver cirrhosis A. W. Jones Department of Forensic Toxicology, University Hospital, SE-581 85 Linköping, Sweden SUMMARY. Aspects of human metabolism of ethanol are reviewed with the main focus on the rate of ethanol clearance from blood in patients suffering from liver cirrhosis. Studies in humans and experimental animals do not support the notion of a slower rate of ethanol metabolism in patients with liver cirrhosis compared with those with normal liver function. The rate of ethanol disappearance from blood in healthy non-alcoholic subjects falls within the range 9–20 mg/dL/h and there is no compelling evidence to suggest that this should be much different in cirrhotic patients. Journal of Clinical Forensic Medicine (2000) 7, 48–51
dose of ethanol ingested is oxidized (95–98%) and the remainder (2–5%) is excreted unchanged in breath, urine and sweat.3,4 The oxidation of ethanol occurs primarily in the liver, first to acetaldehyde and then to acetate. The acetate produced becomes oxidized into carbon dioxide and water principally in the extrahepatic muscle tissues. The class I isozymes of alcohol dehydrogenase (ADH) are primarily responsible for the hepatic oxidation of ethanol and the Km of human ADH is about 5–10 mg/dL, which means that the enzyme quickly becomes saturated even after 1–2 drinks. The elimination kinetics of ethanol therefore exhibit a pseudolinear disappearance phase (zero order kinetics).4,5 After drinking larger amounts of alcohol, the microsomal enzyme denoted P4502E1, which has a Km of 60–80 mg/dL, becomes engaged in the oxidation of ethanol.6,7 Moreover, the ability of P4502EI to oxidize ethanol increases after chronic daily drinking as often seen in alcoholics.8 Some alcoholics are capable of eliminating ethanol 2–3 times faster than moderate drinkers owing to the phenomenon of enzyme induction.9 However, this accelerated rate of ethanol disposal disappears after a few days of abstinence owing to rapid turnover of the P4502E1 enzyme.8 Evidence that catalase plays a role in hepatic oxidation of ethanol in vivo is not very convincing because of the lack of hydrogen peroxide needed for the reaction to occur.6,7 Although ADH is mainly located in the liver, enzyme activity also exists in other tissue such as gastric mucosa, colon, lung, and kidney.5,7 Hepatic ADH activity is little different in healthy subjects and patients with advanced liver cirrhosis as shown by
INTRODUCTION DiMartini and Rao1 described a patient suffering from end-stage liver disease who allegedly attained a blood-alcohol concentration (BAC) of 57 mg/dL after drinking a number of ‘non-alcoholic’ beers containing 0.5% v/v ethanol or less. This moderately high BAC was attributed to the patient’s inability to metabolize the minute amount of ethanol contained in the beer, owing to advanced stages of liver cirrhosis. However, only a single blood sample was obtained so no valid conclusion can be made about the rate of ethanol disposal in this patient. Moreover, the scientific literature dealing with disposition and metabolism of alcohol in cirrhotic patients was not well covered and the papers cited were hardly relevant to the main gist of the article. My intention here is to provide references dealing with the metabolism of ethanol in individuals suffering from liver cirrhosis and offer a more credible explanation for the patient’s BAC being 57 mg/dL.
METABOLISM AND DISPOSITION OF ETHANOL After drinking alcoholic beverages, the ethanol they contain after absorption into the blood becomes diluted with the total body water.2 The bulk of the
Professor A. W. Jones PhD, DSc, Department of Forensic Toxicology, University Hospital, SE-581 85 Linköping, Sweden. Tel: +46 13 120426; Fax: +46 13 104875; E-mail: [email protected] 48
Ethanol metabolism in patients with liver cillhosis obtaining biopsy specimens.10–12 The impact of gastric ADH has been much discussed in recent years in connection with alleged first-pass metabolism of ethanol, which is more pronounced when low (<0.2 g/kg) doses of alcohol are ingested and particularly when taken after a meal.13–16 Studies have shown that extrahepatic oxidation of ethanol might amount to 20% of the total.17 This means that even with severe liver dysfunction people are capable of disposing of ethanol albeit at a slower rate. The efficacy of the first-pass metabolism of ethanol via gastric ADH depends on many factors such as the dose administered, the emptying time of the stomach, age, gender, drinking habits, and dilution of the alcoholic beverage.15,16 Some evidence exists suggesting that first-pass metabolism is more pronounced after drinking very weak alcoholic beverages such as ‘alcohol-free’ beer.18,19 MEASURING THE RATE OF ETHANOL DISAPPEARANCE FROM BLOOD The most direct and easiest way to evaluate the rate of ethanol metabolism in humans is to administer a moderate dose (0.5–0.8 g/kg) and to take a series of venous blood samples at 15–30 min intervals for quantitative determination of ethanol. From a plot of the concentration vs time curve in the post-absorptive state, the rate of ethanol disappearance from blood is determined by methods described many years ago by Widmark.2,20,21 Figure 1 shows an example of a proper study of the disappearance rate of ethanol from blood in one healthy subject for whom the rate of alcohol elimination was 14.3 mg/dL/h. Indeed, the population average rate of ethanol elimination from venous blood in moderate drinkers is about 15 mg/dL/h but in the individual case this might range from about 9–20 mg/dL/h.20 Taking only a single specimen of blood makes it impossible to evaluate a person’s ability to eliminate ethanol. Even taking two blood samples one hour apart is not a good way to measure the elimination rate of alcohol because it cannot be certain that the post-absorptive phase of ethanol kinetics existed at the time of blood sampling.22 Dogs tend to eliminate alcohol from blood at roughly the same rate as humans, that is, 15 mg/dL/h and even in animals having undergone a total hepatectomy, the rate of ethanol elimination was 7 mg/dL/h.23 Extrahepatic metabolic pathways and excretion of alcohol in urine, breath and sweat probably accounts for the elimination of ethanol despite having removed the liver. When the class 1 isoenzymes of ADH were inhibited by giving rats 4-methyl pyrazole, the elimination rate of ethanol was reduced by
49
Fig. 1 Blood-ethanol concentration-time profile in one healthy male subject who drank 0.63 g ethanol per kg body weight as neat whisky in 20 min after an overnight fast. The rate of disappearance of ethanol from blood was 14.3 mg/dL/h and was derived according to Widmark; C0/min0 and seven measurements of BAC were included in calculating the slope of the linear elimination phase.
70% compared with a saline-control treatment.24 In a strain of deer-mice genetically lacking hepatic ADH, the animals were still capable of eliminating ethanol from the blood which once again points to extrahepatic sources of ADH or involvement of other alcohol metabolising enzyme.6,25 In a thesis devoted to metabolism of ethanol under pathophysiological conditions, Jokipii26 allowed patients with cirrhosis to drink 0.5 g ethanol per kg body weight on an empty stomach after they had fasted overnight. In cirrhotic patients (n=6), the mean rate of ethanol elimination from blood was 11 mg/dL/h (range 9–13) compared with a mean of 13 mg/dL/h (range 10–17) in a control group (n=42) of healthy subjects receiving the same dose of ethanol.2,26 The existence of extrahepatic pathways of ethanol oxidation, estimated to account for 20% of the dose administered, and excretion through lungs and kidney means that alcohol can be cleared from the blood also in cirrhotic patients with end-stage liver disease.17,27,28 In several older studies of ethanol metabolism in patients with cirrhosis, investigators found no clearcut differences from normal control subjects.29,30 However, in those suffering from cirrhosis and jaundice, a somewhat slower elimination rate of ethanol was observed.30 In a patient with diminished hepatic blood flow owing to cirrhosis and portocaval shunt, the rate of ethanol metabolism as reflected in the blood-alcohol clearance rate was appreciably slower. However, the authors warn that liver blood flow per se might have been a more important factor than the liver cirrhosis.31,32
50
Journal of Clinical Forensic Medicine
CONCLUSION It is not possible to draw any valid conclusions about a person’s ability to metabolize ethanol on the basis of a single blood-alcohol analysis.1 The older literature cited above involving both human and animal experiments points to a marginally slower rate of ethanol elimination in alcoholics suffering from liver cirrhosis. However, this finding might be confounded by malnutrition, delayed stomach emptying rate, ascites, reduced hepatic blood flow or other problems associated with chronic alcohol abuse and alcoholism.33–36 Accordingly, there is no strong evidence to indicate that the alcohol burn-off rate is appreciably less in patients with liver cirrhosis compared with healthy subjects. Furthermore, the calculation of expected BAC presented by DiMartini and Rao seems questionable because they assumed bolus intake and 100% bioavailability of the entire dose of alcohol.1 These assumptions are not valid when very weak alcoholic beverages such as 0.5 vol% beer are consumed over a lengthy time period.18,19 The question of whether alcohol was analyzed in whole blood or serum was not made perfectly clear because hospital laboratories in USA generally analyse serum. This becomes important when Widmark’s factors are used to estimate alcohol in the blood from a given intake.21 Obtaining ethical permission to make a proper study of the rate of ethanol metabolism in abstinent alcoholic patients suffering from liver cirrhosis is probably not feasible nowadays. Nevertheless, long experience in dealing with alcohol abusers and drunk drivers has taught me that they are seldom truthful about their drinking practices. The amounts consumed are often grossly underestimated. Accordingly, the most plausible explanation for the patient’s BAC being 57 mg/dL is through the consumption of conventional alcoholic drinks, such as a couple of normal strength beers (4–5 vol%) a short time before the medical examination or a considerably larger amount of alcohol the evening before. REFERENCES 1. DiMartini AF, Rao KN. Elevated blood ethanol levels caused by ‘non-alcoholic’ beer. J Clin Forens Med 1999; 6: 106–108. 2. Jones AW. Biochemistry and physiology of alcohol: applications to forensic science and toxicology. In Garriott JC (ed) Medicolegal aspects of alcohol, Lawyers & Judges Publishing Co., Tucson, 1996: 85–136. 3. Jones AW. Excretion of alcohol in urine and diuresis in healthy men as a function of their age and the dose administered. Forens Sci Int 1990; 45: 217–224. 4. Jones AW. Forensic science aspects of ethanol metabolism. Forensic Science Progress, Springer-Verlag, Berlin-Heidelberg, 1991, pp 32–89. 5. Crabb DW, Dipple KM, Thomasson HR. Alcohol sensitivity, alcohol metabolism, risk of alcoholism, and the role of alcohol and aldehyde dehydrogenases. J Lab Clin Med 1993; 122: 234–40.
6. Takagi T, Alderman J, Lieber CS. In-vivo roles of alcohol dehydrogenase (ADH) catalase and the microsomal ethanoloxidizing system (MEOS) in deermice. Alcohol 1985; 2: 9–12. 7. Lieber CS. Ethanol metabolism, cirrhosis and alcoholism. Clin Chim Acta 1997; 257: 59–84. 8. Keiding S, Christensen NJ, Damgaard SE et al. Ethanol metabolism in heavy drinkers after massive and moderate alcohol intake. Biochem Pharmacol 1983; 32: 3097–3102. 9. Jones AW, Sternebring B. Kinetics of ethanol and methanol in alcoholic sduring detoxification. Alc Alcohol 1992; 27: 641–47. 10. Mezey E, Tobon F. Rates of ethanol clearance and activities of the ethanol-oxidizing enzymes in chronic alcoholic patients. Gastroenterology 1971; 61: 707–715. 11. Nuutinen HU. Activities of ethanol-metabolizing enzymes in liver disease. Scand J Gastroenterol 1986; 21: 678–684. 12. Vidal F, Perez J, Morancho J, Pinto B, Richart C. Hepatic Alcohol Dehydrogenase Activity in Alcoholic Subjects with and Without Liver Disease. Gut 1990; 31: 707–711. 13. Oneta CM, Simanowski UA, Martinez M et al. First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying. Gut 1998; 43: 612–19. 14. Seitz HK, Egerer G, Simanowski UA et al. Human gastric alcohol dehydrogenase activity: effect of age, sex, and alcoholism. Gut 1993; 34: 1433–1437. 15. Seitz HK and Oneta CM. Gastrointestinal alcohol dehydrogenase. Nutr Rev 1998; 56: 52–60. 16. Sato N, Kitamura T. First-pass metabolism of ethanol; An overview. Gastrenterology 1996; 111: 1143–1150. 17. Larsen JA, Tygstrup JA, Winkler. The significance of the extrahepatic elimination of ethanol in determination of hepatic blood flow by means of ethanol. Scand J Clin Lab Invest 1961; 13: 116–121. 18. Jones AW, Ulwan, O. Low-alcohol drinks and risk of high blood-alcohol in children. J Tox Clin Tox 1996; 34: 349–350. 19. Holford NH. Complex PK/PD models – an alcoholic experience. Int J Clin Pharmacol Ther 1997; 35: 465–468. 20. Jones AW. Disappearance rate of ethanol from blood in human subjects; Implications in forensic toxicology. J Forens Sci 1993; 38: 104–118. 21. Widmark, EMP. Die theoretischen Grundlagen und die praktische Verwendbarkeit der gerichtlich-medizinischen Alkoholbestimmung. Urban und Schwarzenberg, Berlin, 1932, pp 1–140. 22. Jones AW, Andersson L. Influence of age, gender and bloodalcohol concentration on the disappearance rate of alcohol from blood in drinking drivers. J Forens Sci 1996; 41: 922–926. 23. Clark BB, Morrissey RW, Fazekas JF and Welch CS. The role of insulin and the liver in alcohol metabolism. J Stud Alcohol 1941; 2: 663–683. 24. Rydberg U, Neri A. 4-methyl pyrazole as an inhibitor of ethanol metabolism; Differential metabolic and central nervous effect. Acta Pharmacol Toxicol 1972; 31: 421–432. 25. Norsten C, Cronholm T, Ekström G, Handler JA, Thurman RG, Ingelman-Sundberg M. Dehydrogenase-dependent ethanol metabolism in deer mice (Percomyscus maniculatus) lacking cytosolic alcohol dehydrogenase. J Biol Chem 1989; 264: 5593–5597. 26. Jokipii SG. Experimental studies on blood alcohol in healthy subjects and in some diseases, Helsinki: Thesis, University of Helsinki, 1951: 1–99. 27. Utne HE, Winkler K. Hepatic and extrahepatic elimination of ethanol in cirrhosis. Scand J Gastroent 1989; 15: 297–304. 28. Winkler K, Lundquist F, Tygstrup N. The hepatic metabolism of ethanol in patients with cirrhosis of the liver. Scand J Clin Lab Invest 1969; 23: 59–69. 29. Lieberman FL. The effect of liver disease on the rate of ethanol metabolism in man. Gastroenterology 1963; 44: 261–266. 30. Asada M, Galambos JT. Liver disease, hepatic alcohol dehydrogenase activity and alcohol metabolism in the human. Gastroenterology 1963; 45: 67–72.
Ethanol metabolism in patients with liver cillhosis 31. Leube G, Mallach HJ. Zur Alkoholelimination bei einem Leberkranken mit portocavalem Shunt. Blutalkohol 1980; 17: 15–25. 32. Mallach HJ, Von Oldershausen HF, Springer R. Der Einfluβ oraler Alkoholzufuhr auf den Blutalkoholspiegel von Gewohnheitstrinkern und Leberkranken unter verschiedenen alimentären Bedingungen. Klin Wschr 1972; 50: 732–738. 33. Sonne J. Drug metabolism in liver disease: Implications for therapeutic drug monitoring. Ther Drug Monit 1996; 18: 397–401.
51
34. Isobe H, Sakai H, Satoh M, Sakamoto S, Nawata H. Delayed gastric emptying in patients with liver cirrhosis. Dig Dis Sci 1994; 39: 983–987. 35. Hoyumpa AM, Schenker S. Major drug interactions: Effect of liver disease, alcohol, and malnutrition. Ann Rev Med 1982; 33: 113–149. 36. Bode JC. The metabolism of alcohol: Physiological and pathophysiological aspects. J Roy Coll Physicians 1978; 12: 122–135.
Response from authors We appreciate the thorough explanation of the pharmacokinetics of ethanol metabolism by Dr Jones in response to our case report. This insightful commentary adds a helpful discussion to this issue. The pharmacokinetics in Dr Jones’s commentary are not to be disputed. However, we were not commenting on the rate of ethanol metabolism, rather on the fact that with a sufficient loading dose of ‘non-alcoholic’ beers a patient could achieve a positive blood ethanol level. The fact that the patient has end-stage liver disease with a significant reduction in parenchymal function must impact on ethanol metabolism. We hypothesize that this allowed a higher peak level of blood ethanol, which was obtained as the reported BAL of 57 mg/dL. Our main intent was to elucidate the potential dangers of these types of beverages for both alcoholic patients abstinent from regular alcohol (in whom the presence of blood ethanol could precipitate alcoholic relapse) and also patients with end-stage liver disease (in whom the presence of blood ethanol will continue to do further liver damage). As Dr Jones points out, patients with cirrhosis may have a reduced blood alcohol clearance rate owing to diminished hepatic blood flow. Our patient had portal hypertension with ascites and would have physiologic portal-systemic shunting. In addition the definition of cirrhosis is important. The Childs-Pugh scoring system of cirrhosis gives an estimation of the amount of damage to the liver parenchyma by a scoring system using total bilirubin, synthetic functions, the amount of ascites, and encephalopathy. In our case, the patient’s Childs-Pugh score was C13 (the highest score being a 15) which places him at the most advanced stage of liver disease, thus he had end-stage liver disease. This patient’s metabolism would be expected to be markedly impaired. In some of reports cited by Dr Jones on cirrhotic patients and ethanol metabolism, less accurate
estimations of parenchymal function, such as liver biopsy are used. Biopsy can help to establish the histologic stage, though sampling errors can occur due to the uneven distribution of the pathologic changes.1 In addition, Dr Jones used two citations to support the statement that hepatic alcohol dehydrogenase (ADH) is not significantly different between healthy subjects and patients with advanced liver cirrhosis.2,3 In fact, these citations demonstrated that alcohol dehydrogensase activity was significantly different between normal controls and patients with alcoholic liver disease. In a third citation that Dr Jones cited,4 patients with jaundice or a history or clinical evidence of cirrhosis were excluded, therefore this citation cannot be used as evidence that patients with cirrhosis do not have diminished ADH. Dr Jones identified that it would be unethical to study the pharmacokinetics of blood ethanol metabolism in cirrhotic patients. Therefore, we must rely on these chance encounters which may be less than perfect. Nevertheless, our original contention and recommendations still hold and were formed on the basis of this case. So-called ‘non-alcoholic’ beverages should be eliminated from consumption by patients with liver disease and/or alcoholism. REFERENCES 1. 2. 3. 4.
Van Leeuwen DJ, Wilson L, Crowe DR. Liver biopsy in the mid-1990s: questions and answers. Seminars in Liver Disease 1995; 15: 340–359. Nuutinen HU. Activities of ethanol-metabolizing enzymes in liver diseases. Scand J Gastroenterol 1986; 21: 678–684. Vidal F, Perez J, Morancho J, Pinto B, Richart C. Hepatic Alcohol dehydrogenase activity in alcoholic subjects with and without liver disease. Gut 190; 31: 707–711. Mezey E, Tobon F. Rates of ethanol clearance and activities of the ethanol-oxidizing enzymes in chronic alcoholic patients. Gastroenterology 1971; 61: 707–715.