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Acetaminophen Hepatotoxicity

Acetaminophen Hepatotoxicity. Barry H. Rumack, M.D. May 28, 2002. Acetaminophen Metabolic Pathways. N-acetyl-p-benzoquinone imine (NAPQI) is the reactive metabolite. Original Nomogram - 1975.

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Acetaminophen Hepatotoxicity

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  1. Acetaminophen Hepatotoxicity Barry H. Rumack, M.D. May 28, 2002

  2. BHR 5/28/2002 Acetaminophen Metabolic Pathways N-acetyl-p-benzoquinone imine (NAPQI) is the reactive metabolite

  3. BHR 5/28/2002 Original Nomogram - 1975 • Data from 30 cases previously published plus 34 additional cases from Ward 3, Royal Infirmary of Edinburgh • Line constructed to discriminate between peak toxic and non-toxic cases (AST > 1,000 IU/L) • NOT originally calculated as a 4 hour half-life line but slope is T ½ 4 hours • Initial plasma level only after >4 hours due to concerns about absorption

  4. BHR 5/28/2002 1975 Original Nomogram Acetaminophen Plasma level, mcg/ml Hours since ingestion Rumack BH and Matthew H, Acetaminophen Poisoning and Toxicity, Pediatrics 1975, 55:871-876

  5. BHR 5/28/2002 APAP and GSH depletion • Hepatic necrosis observed (animals) at approximately 70% depletion • Normal liver GSH approximately 4mmoles/L • Human extrapolation • 4mmoles/L X 1.5L liver = 6 mmoles • 6mmoles X 70% = 4.2 mmoles • If NAPQI is 4% of the dose then: • 4.2 mmoles = 4% X toxic dose • Dose = 4.2mmoles X 151 mg/mmole / 4% =15.9 gm Adapted from: Mitchell et.al., Acetaminophen-Induced Hepatic Necrosis. IV. Protective Role of Glutathione Journal of Pharmacology and Experimental Therapeutics 1973;187:211-217 and published in Rumack, BH, Peterson RG, Acetaminophen Overdose: Incidence, Diagnosis and Management in 416 patients. Pediatrics, 1978 62:898 – 903 (supplement)

  6. BHR 5/28/2002 Multi-center open NAC protocol • Not controlled since prohibited from withholding treatment • Concern re: absorption of APAP delayed due to quantity or drugs which reduced GI motility (e.g. propoxyphene) • T ½ in toxic patients 4 – 12 hours with some to 60 hours therefore FDA wanted a safety margin = 72 hours course • 140mg/Kg loading dose; 70mg/Kg q4h 17 doses • APAP levels 0, 30 min, 1, 2, 4, 8, 24, 32 hours minimum • Lab SGOT, SGPT, Alk, phos, bili, gluc, Cr, BUN 0, 8, 16, 24, 32, 48 hours minimum • Lab pro time and other labs 0, 24, 48 hours minimum • Constructional dyspraxia evaluated

  7. BHR 5/28/2002 Study Design Nomogram - 1976 • Safety line 25% below original line added at the request of the FDA • High risk line 100% above original line added to define risk but did not affect treatment decisions

  8. BHR 5/28/2002 1976 Study design nomogram Acetaminophen Plasma Level, mcg/ml Hours since ingestion Rumack, BH, Peterson, RC, Koch, GG, Amara IA, Acetaminophen Overdose: 662 Cases with Evaluation of Oral Acetylcysteine Treatment, Arch. Intern. Med. 1981, 141:380-385

  9. BHR 5/28/2002 Risk Nomogram - 1988 • Original line, safety line and high-risk line 50% above original line. • Original line relabeled probable-risk • Utilized to analyze data from 2,023 cases meeting protocol requirements

  10. BHR 5/28/2002 1988 Risk Nomogram Acetaminophen Plasma Level Hours since ingestion Smilkstein, MJ. Knapp, GL. Kulig, KW. Rumack, BH. Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose, NEJM 1988, 319:1557 - 1562

  11. BHR 5/28/2002 Outcome nomogram • Included 517 additional patients not included in the 1988 NEJM paper • These patients did not meet protocol criteria but received the full course of NAC • initial plasma levels were below the safety line, or • seen after 24 hours • These patients completed the protocol because their initial plasma levels were not available until after completion of therapy • They were intended to serve as safety controls for NAC however, some developed hepatotoxicity

  12. BHR 5/28/2002 Treatment Outcome Nomogram Acetaminophen Plasma Level, mcg/ml Hours since ingestion Rumack, BH unpublished data from 2540 cases

  13. BHR 5/28/2002 Cases Toxic % vs. Treatment Delay * p<0.05 Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH, Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose. NEJM, 1988;24:1557-1562

  14. BHR 5/28/2002 Mean Peak AST vs. Treatment Delay * p<0.05 Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH, Efficacy of Oral N-Acetylcysteine in the Treatment of Acetaminophen Overdose. NEJM, 1988;24:1557-1562

  15. BHR 5/28/2002 Time Course of APAP Overdose Solid line = UntreatedDotted line = NAC treatedDot – Dash line = Severe untreated Rumack, BH, Peterson, RC, Koch, GG, Amara IA, Acetaminophen Overdose: 662 Cases with Evaluation of Oral Acetylcysteine Treatment, Arch. Intern. Med. 1981, 141:380-385

  16. BHR 5/28/2002 Common Misinterpretations • Initial acetaminophen level is not consistent with the history • What is the body burden? • (plasma mcg/ml)(body weight)(VD ~1L) = body burden • Half-life is not consistent with the history • Three levels best but two will allow estimate • If it is initially greater than 4 reconsider time of ingestion • AST is not consistent with the history • Peak occurs at ~ 72 hours • If the peak is on admission reconsider the time course

  17. BHR 5/28/2002 Nomenclature of CYP Enzymes • We now abbreviate them as CYP enzymes taken from the first two letters of the word cytochrome and adding the letter p for protein. • There are more than 500 CYP enzymes and about the same number of genes classified into 74 families of which 14 exist in mammals. • Families are designated by CYP followed by an Arabic number such as CYP1, CYP2, etc. • Subfamilies of enzymes are designated by capital letters such as CYP1A and CYP1B, etc. • Individual enzymes are then classified by adding another Arabic number in the order in which they are identified such as CYP1A1, CYP1A2, etc

  18. BHR 5/28/2002 Function of CYP Enzymes • ~ 20 enzymes, which are known to be involved in the metabolism of xenobiotics in humans. Families CYP1 through CYP4 • There are other CYP enzymes in humans which either are involved in the synthesis or metabolism of normally occurring endogenous substances such as cholesterol, Vitamin D, etc. Examples are CYP5, CYP7, CYP8, etc. • Of the four we are most interested in that deal with xenobiotics the highest concentrations are usually in the liver but some smaller amounts may be located in lung, kidney, etc. • It is now possible to look at individual enzymes and see what they do in intact humans through various marker substances. • We now understand that just because one individual enzyme is induced does not mean that other individual enzymes will be induced.

  19. BHR 5/28/2002 CYP2E1 • 493 amino acids • MW 56,820 • One gene on chromosome 10 with 11,413 base pairs • Metabolizes more than 75 compounds • Unique among CYP producing reactive oxygen radicals through reduction of dioxygen • Unique among CYP in being strongly induced by ethanol • Intra-cellularly in the endoplasmic reticulum with small amounts in the cell membrane and lysosomal vesicles • CYP2E1 primarily located in the rows of 5 cells around the central venules • Originally called “microsomal ethanol oxidizing system”

  20. BHR 5/28/2002 Mechanisms of Zonal Injury Casarett and Doull’s Toxicology, Sixth Edition, 2001 Page 479

  21. BHR 5/28/2002 Hepatic Structure Haschek, WM, Rousseaux, CG, Handbook of Toxicologic Pathology, Academic Press 1991

  22. Normal Hepatic Histology BHR 5/28/2002

  23. Normal Hepatic Histology High Power BHR 5/28/2002

  24. Hepatotoxicity BHR 5/28/2002

  25. Hepatotoxicity High Power BHR 5/28/2002

  26. BHR 5/28/2002 CYP2E1 – Induction & Inhibition I • Induction and inhibition occur at • Transcriptional • Pre-translational • Translational • Post-translational • Post-translational protein stabilization due to ligand binding appears to be the most important mechanism • Acetone extends CYP2E1 degradation half-life from 7 to 35 hours by ligand stabilization • Ethanol, acetone and isoniazid increase CYP2E1 concentration in zone 3 after induction - no recruitment • Hypophysectomy produces recruitment in zone 2 showing transcriptional activity on the apoprotein and demonstrating repression of CYP2E1 expression by growth hormone

  27. BHR 5/28/2002 CYP2E1 - Induction & Inhibition II • Inducer and substrate: Acetone, Ethanol, Pyrazole, Isoniazid • Substrate but not an inducer: Acetaminophen, chlorzoxazone, carbon tetrachloride • Inducer but not a substrate: Imidazole • CYP2E1 is increased in diabetes, obesity and other nutritional states that produce acetone • Acetone may be an indirect inducer although effects of growth hormone (repression) and glucagon and epinephrine (accelerated degradation) may be part of the process

  28. BHR 5/28/2002 Differential induction and inhibition used to evaluate other enzymes re: NAPQI • In vitro NAPQI produced by CYP1A2, CYP2E1 and CYP3A4 • In vivo NAPQI produced primarily by CYP2E1 in humans • Techniques used to isolate effects: • Omperazole (Prilosec), a potent inducer of CYP1A2, pre-treatment in volunteers did not enhance NAPQI production from acetaminophen • Rifampin, an inducer of CYP2C9, CYP2C19, CYP1A2 and CYP3A4, pre-treatment of volunteers did not enhance NAPQI production from acetaminophen • Disulfiram, a potent inhibitor of CYP2E1, pre-treatment in volunteers reduced NAPQI production by 69% • Substantial differences between in vitro human and in vivo human data as well as differences with animal data Manyike,P.T. Kharasch,E.D. Kalhorn,T.F. Slattery,J.T., Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation, Clin. Pharmacol. Ther., 2000, 67:275 - 282

  29. BHR 5/28/2002 Glutathione Metabolic Pathways White, et.al. Glutathione deficiency in human disease, J. Nutr. Biochem., 1994;5:218-226

  30. BHR 5/28/2002 N-Acetylcysteine (NAC)

  31. BHR 5/28/2002 Hepatic Disease Glutathione Levels 1 – Poulsen, et. al., Scand J Clinical Lab Invest 1981;41:573-576 2 – Siegers, et. al. Pharmacology Research Communications, 1982;14:61-72

  32. BHR 5/28/2002 Hepatic Disease P-450 Levels 1 – Schoene, et. al., Eur. J. Clin Pharm. 1972;4:65-73 2 – Gabrielle, et. al., Gastro. Clin. Biol. 1977;1:775-782

  33. BHR 5/28/2002 Carbon Tetrachloride as an Example of Metabolic Conversion Garner,R.C.; McLean,A.E., Increased susceptibility to carbon tetrachloride poisoning in the rat after pretreatment with oral phenobarbitone, Biochemical Pharmacology 1969, 18:645-650

  34. BHR 5/28/2002 Phenobarbital: a pleiotropic inducer • Phenobarbital induces both Phase I (functionalization usually on the endoplasmic reticulum such as CYP) and Phase II (biosynthetic usually cytosolic such as glutathione S-transferase) reactions • Induces CYP2B, CYP2C and others • Does NOT induce CYP2E1 • Induces UDP-glucuronosyltransferase, aldehyde dehydrogenase, glutathione S-transferase and others • Early work looking at total P-450 or total metabolism suggested PB increased APAP risk – now not correct

  35. BHR 5/28/2002 Phenytoin: an example of development of knowledge • 1979 Multiple anti-epileptics but found that free and conjugated acetaminophen excretion showed no difference when compared with a control group1 • 1981 Were surprised to find no difference in excretion of mercapturic acid conjugates between those taking anti-epileptics or rifampin and controls2 • The same study showed a significant increase in glucuronide conjugates in those taking anti-epileptics and rifampin compared to controls. 1 - Perucca,E.; Richens,A. Paracetamol disposition in normal subjects and in patients treated with antiepileptic drugs Br. J. Clin. Pharm 1979, 7:201-206 2 - Prescott,L.F.; Critchley,J.A.; Balali-Mood,M.; Pentland,B. Effects of microsomal enzyme induction on paracetamol metabolism in man Br. J. Clin. Pharm 1981, 12:149-153

  36. BHR 5/28/2002 Phenytoin and Acetaminophen • Overdoses in patients with mixed anti-epileptics of acetaminophen ranged from 7.5 grams to 75 grams in the nine patients.“Patients on anticonvulsant drugs should be warned not to exceed recommended doses of paracetamol, i.e. 4g/day, even if they have severe pain.”1 • A later report from the same group showed a changed view with either anti-convulsants or ethanol producing similar mortality rates of 33% and 37%.2 • Another series with phenytoin alone compared to a control group showed a decrease in mercapturic acid but an increase in glucuronide concluding no increased risk.3 1-Bray, et. al. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure, Hum Exp Toxicology 1992;11:265-270. 2-Makin,A.J. et al. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993) Gastroenterology 1995,109:1907-1916 3-Tomlinson,B. et al. Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics 1996 Eur. J. Clin. Pharm. 50:411-415

  37. BHR 5/28/2002 Phenytoin and Acetaminophen 2 • Phenytoin is primarily metabolized to p-HPPH* facilitated by CYP2C9 and CYP2C19 which phenytoin induces • P-HPPH is conjugated by glucuronide and excreted and phenytoin is a potent inducer of glucuronosyltransferase • The metabolism of phenytoin to its glucuronide increased due to increased activity of CYP2C9/2C19 but the metabolism of acetaminophen through the toxic pathway to mercapturic acid did NOT increase because phenytoin does NOT induce CYP2E1. • Prior phenytoin treatment is hepato-protective in acetaminophen overdose rather than being a risk factor *5-(4-hydroxyphenyl)-5-phenyhydantoin

  38. BHR 5/28/2002 Isoniazid Induction of CYP2E1 • Isoniazid stabilizes CYP2E1 • Acetaminophen and isoniazid consumed together resulted in a 63% inhibition of NAPQI • When isoniazid was stopped and APAP continued the formation of NAPQI was enhanced 24 hours after the last isoniazid dose but the effect is not likely to be critical. Zand et.al., Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clinical Pharmacology Therapeutics 1993;54:142-9

  39. BHR 5/28/2002 Ethanol and APAP Overdose • An overdosage of acetaminophen in an alcoholic results in the same pattern of hepatotoxicity as in a non-alcoholic • Degree of hepatotoxicity is not affected by alcoholism • Severe alcoholics also take a larger dose of acetaminophen Makin,A.J. et al. A 7-year experience of severe acetaminophen-induced hepatotoxicity (1987-1993) Gastroenterology 1995,109:1907-1916

  40. BHR 5/28/2002 Ethanol Induction of CYP2E1 • Stabilization of mRNA at higher doses of ethanol (>250mg/dL) • Enhanced de novo synthesis • Stabilization of the CYP2E1 protein at lower doses of ethanol (< 250mg/dL) • Ligand stabilization is ligand concentration dependent by binding to the active site • The net result is simultaneous inhibition (during ethanol consumption) and induction of CYP2E1 by increased concentration

  41. BHR 5/28/2002 Induction and Inhibition of CYP2E1 by Ethanol: A COMPUTER SIMULATION I = Inhibitor, Ki = Inhibitory Constant, Cl(t)/Cl0 = Ratio after to before infusion Slattery et. al. Clinical Pharmacology and Therapeutics 1996;60:241-246

  42. BHR 5/28/2002 Ethanol Induction of CYP2E1 • CYP2E1 was increased two-fold in human alcoholics who were drinking1 • After 5 –10 days of abstinence from ethanol the effect disappeared • APAP consumed during ethanol infusion reduced NAPQI 72% but NAPQI increased 24% 8 hours after the infusion stopped2 • Induction leads to a maximum 2 fold increase of NAPQI 1 - Perrot, et.al., Modulation of cytochrome P450 isozymes in human liver by ethanol and drug intake. European Journal Clinical Investigation 1989;19:549-555 2 - Thummel,K.E.; Slattery,J.T.; Ro,H.; Chien,J.Y.; Nelson,S.D.; Lown,K.E.; Watkins,P.B. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults, Clin. Pharmacol. Ther. 2000, 67:591-599

  43. BHR 5/28/2002 APAP Ethanol and Fasting • Study of cases 72% – 94% recent fasting1 • All patients who developed severe hepatotoxicity took more than 4g/day • 70% of patients who developed hepatotoxicity were chronic acetaminophen users consuming 4 to 10 g/day • All patients who developed toxicity while consuming > 10g/day were alcohol users • Study of patients restricted to 500 – 1000 calories per day showed no change in APAP metabolism2 1 - Whitcomb and Block, Association of Acetaminophen Hepatotoxicity with Fasting and Ethanol Use, JAMA 1994;272:1845-1850; 2 - Schenker, S., Speeg, K.V., Perez, A., Finch, J., the effects of food restriction in man on hepatic metabolism of acetaminophen. Clinical Nutrition 200120:145 - 150

  44. BHR 5/28/2002 Acute and Chronic Ethanol and Acetaminophen • Ingestion of ethanol and acetaminophen concomitantly in a non-alcoholic individual results in less exposure to NAPQI than if ethanol was not ingested simultaneously • Long term administration of high dose ethanol followed by brief abstinence is a risk for enhanced toxicity of APAP in overdose but NOT at therapeutic doses.

  45. BHR 5/28/2002 APAP During Ethanol Withdrawal • In 201 patients administration of acetaminophen 4 times per day at 1 gram per dose to withdrawing alcoholics show no difference to a control1 • Evaluation of a large group of patients in an alcohol detoxification program revealed no hepatotoxicity2 1 - Kuffner, et. al. Effect of Maximal Daily Doses of Acetaminophen on the Liver of Alcoholic Patients. Arch Intern Med 2001, 161: 2247 - 2252 2 - Kenny, et. al., Routine screening for acetaminophen (APAP) toxicity of patients requesting alcohol detoxification. Journal Studies Alcohol 1999;60:139-140

  46. BHR 5/28/2002 Alcoholism and high risk versus low risk patients • Toxicity, as defined by AST and ALT was worse in patients categorized in the high risk (above the “300” line) acetaminophen overdose • Toxicity, was no different in low risk (below the “200” line) acetaminophen overdoses whether they were alcoholics or not • Consistent with others who have reported more acetaminophen ingested in alcoholics. Smilkstein MJ Rumack BH, Chronic Ethanol Use and Acute Acetaminophen Overdose Toxicity; Journal of Toxicology Clinical Toxicology 1998;36: 476

  47. BHR 5/28/2002 Ethanol-Acetaminophen Literature example of data issues • 68 cases 1977 - 1993 • 18/68 report 4 g/day or less but, examine the cases: • 9/18 cases – no blood level • 2/18 cases – no blood level and no history of last dose • 4/18 cases – APAP level and timing consistent with overdose • 3/18 cases – APAP level consistent with low dose history

  48. BHR 5/28/2002 Clinical Literature of Ethanol Induction 1 • Paper reports the results of a registry. The cases are very poorly documented and do not demonstrate what they are reported to show. • Many cases are letters with minimal information and it is impossible to look at other aspects of the case • Focus is on a “Therapeutic misadventure” – an expression of molecular intent! Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure Hepatology 1995; 22(3):767-773.

  49. BHR 5/28/2002 Clinical Literature of Ethanol Induction 2 • Paper reviews 25 patients – 19 from the literature, 5 new • Table 1 in this study shows the details for 19 patients. Fifteen of those patients consumed more than 4 grams in 24 hours with a range of 4.5 to 16.5 grams. • Patient 2 reported in this study ingested 12.5 g/d of acetaminophen with a six pack of beer. It is hard to imagine he thought this was therapeutic. • A patient quoted from the literature as 4g of APAP had a level of 63 mcg/ml in the original article on day 3 of hospitalization. This would be a higher body burden than the ingested amount and so was clearly an overdose. Seeff, et. al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986; 104(3):399-404.

  50. BHR 5/28/2002 Clinical Literature of Ethanol Induction 3 Despite the case of 12.5 g/day and the inability to have any idea of the intent from the published cases the authors state, “There seems little doubt that none of the 25 patients deliberately took an overdose of acetaminophen or deliberately distorted the information regarding the amount that they consumed.”

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