Abstract
Background: The possible role of alcohol in the development of hepatotoxicity associated with therapeutic doses of paracetamol (acetaminophen) is currently debated. Case Report: We describe 2 patients who were regular consumers of alcohol and who developed liver failure within 3–5 days after hospitalization and stopping alcohol consumption while being treated with 4 g paracetamol/day. A paracetamol serum level obtained in one of these patients was not in the toxic range. Possible risk factors for the development of hepatotoxicity in patients treated with therapeutic doses of paracetamol are discussed. Conclusion: In patients with risk factors, e.g. regular consumption of alcohol, liver failure is possible when therapeutic doses are ingested. We propose that the paracetamol dose should not exceed 2 g/day in such patients and that their liver function should be monitored closely while being treated with paracetamol.
Journal Section:
Case Report
References
1.
Garcia Rodriguez LA, Hernandez-Diaz S: Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001;12:570–576.
[PubMed]
2.
Lewis SC, Langman MJ, Laporte JR, Matthews JN, Rawlins MD, Wiholm BE: Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: A meta-analysis based on individual patient data. Br J Clin Pharmacol 2002;54:320–326.
[PubMed]
3.
Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 1994;331:1675–1679.
[PubMed]
4.
Graham GG, Scott KF, Day RO: Tolerability of paracetamol. Drugs 2003;63(Spec No 2): 43–46.
[PubMed]
5.
Temple AR, Benson GD, Zinsenheim JR, Schweinle JE: Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6–12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther 2006;28:222–235.
[PubMed]
6.
Prescott LF: Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983;25:290–314.
[PubMed]
7.
Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM: Acetaminophen-induced acute liver failure: Results of a united states multicenter, prospective study. Hepatology 2005;42:1364–1372.
[PubMed]
8.
Zimmerman HJ, Maddrey WC: Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22:767–773.
[PubMed]
9.
Bonkovsky HL, Kane RE, Jones DP, Galinsky RE, Banner B: Acute hepatic and renal toxicity from low doses of acetaminophen in the absence of alcohol abuse or malnutrition: evidence for increased susceptibility to drug toxicity due to cardiopulmonary and renal insufficiency. Hepatology 1994;19:1141–1148.
[PubMed]
10.
Crippin JS: Acetaminophen hepatotoxicity: potentiation by isoniazid. Am J Gastroenterol 1993;88:590–592.
[PubMed]
11.
Denison H, Kaczynski J, Wallerstedt S: Paracetamol medication and alcohol abuse: A dangerous combination for the liver and the kidney. Scand J Gastroenterol 1987;22:701–704.
[PubMed]
12.
Kaysen GA, Pond SM, Roper MH, Menke DJ, Marrama MA: Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen. Arch Intern Med 1985;145:2019–2023.
[PubMed]
13.
Kronenberg A, Krähenbühl S, Zimmermann A, Streuli R: Severe hepatocellular damage after administration of paracetamol and chlorzoxazone in therapeutic dosage (in German). Schweiz Rundsch Med Prax 1998;87:1356–1360.
[PubMed]
14.
Kurtovic J, Riordan SM: Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med 2003;253:240–243.
[PubMed]
15.
Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB: Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986;104:399–404.
[PubMed]
16.
Suchin SM, Wolf DC, Lee Y, Ramaswamy G, Sheiner PA, Facciuto M, Marvin MR, Kim-Schluger L, Lebovics E: Potentiation of acetaminophen hepatotoxicity by phenytoin, leading to liver transplantation. Dig Dis Sci 2005;50:1836–1838.
[PubMed]
17.
Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994;272:1845–1850.
[PubMed]
18.
Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC: Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized controlled trial. JAMA 2006;296:87–93.
[PubMed]
19.
de Morais SM, Uetrecht JP, Wells PG: Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology 1992;102:577–586.
[PubMed]
20.
Prescott LF: Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000;49:291–301.
[PubMed]
21.
Rumack BH: Acetaminophen misconceptions. Hepatology 2004;40:10–15.
[PubMed]
22.
Girre C, Lucas D, Hispard E, Menez C, Dally S, Menez JF: Assessment of cytochrome p4502e1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem Pharmacol 1994;47:1503–1508.
[PubMed]
23.
Oneta CM, Lieber CS, Li J, Ruttimann S, Schmid B, Lattmann J, Rosman AS, Seitz HK: Dynamics of cytochrome p4502e1 activity in man: Induction by ethanol and disappearance during withdrawal phase. J Hepatol 2002;36:47–52.
[PubMed]
24.
Perrot N, Nalpas B, Yang CS, Beaune PH: Modulation of cytochrome p450 isozymes in human liver, by ethanol and drug intake. Eur J Clin Invest 1989;19:549–555.
[PubMed]
25.
Dahlin DC, Miwa GT, Lu AY, Nelson SD: N-acetyl-p-benzoquinone imine: a cytochrome p-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 1984;81:1327–1331.
[PubMed]
26.
Esterline RL, Ray SD, Ji S: Reversible and irreversible inhibition of hepatic mitochondrial respiration by acetaminophen and its toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). Biochem Pharmacol 1989;38:2387–2390.
[PubMed]
27.
Ramsay RR, Rashed MS, Nelson SD: In vitro effects of acetaminophen metabolites and analogs on the respiration of mouse liver mitochondria. Arch Biochem Biophys 1989;273:449–457.
[PubMed]
28.
Jaeschke H: How relevant are neutrophils for acetaminophen hepatotoxicity? Hepatology 2006;43:1191–1194.
[PubMed]
29.
Kon K, Kim JS, Jaeschke H, Lemasters JJ: Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 2004;40:1170–1179.
[PubMed]
30.
Lawson JA, Farhood A, Hopper RD, Bajt ML, Jaeschke H: The hepatic inflammatory response after acetaminophen overdose: role of neutrophils. Toxicol Sci 2000;54:509–516.
[PubMed]
31.
Liu ZX, Han D, Gunawan B, Kaplowitz N: Neutrophil depletion protects against murine acetaminophen hepatotoxicity. Hepatology 2006;43:1220–1230.
[PubMed]
32.
Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002;418:191–195.
[PubMed]
33.
Wolf KK, Wood SG, Allard JL, Hunt JA, Gorman N, Walton-Strong BW, Szakacs JG, Duan SX, Hao Q, Court MH, von Moltke LL, Greenblatt DJ, Kostrubsky V, Jeffery EH, Wrighton SA, Gonzalez FJ, Sinclair PR, Sinclair JF: Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: Comparison of wild-type and Cyp2e1(–/–) mice. Drug Metab Dispos 2007;35:1223–1231.
[PubMed]
34.
Slattery JT, Wilson JM, Kalhorn TF, Nelson SD: Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther 1987;41:413–418.
[PubMed]
35.
Price VF, Jollow DJ: Mechanism of decreased acetaminophen glucuronidation in the fasted rat. Biochem Pharmacol 1988;37:1067–1075.
[PubMed]
36.
Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI: Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 2001;299:998–1006.
[PubMed]
37.
Roberts BJ, Song BJ, Soh Y, Park SS, Shoaf SE: Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1. J Biol Chem 1995;270:29632–29635.
[PubMed]
38.
Caro AA, Cederbaum AI: Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 2004;44:27–42.
[PubMed]
39.
Lauterburg BH, Velez ME: Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988;29:1153–1157.
[PubMed]
40.
Slattery JT, Nelson SD, Thummel KE: The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 1996;60:241–246.
[PubMed]
41.
Thummel KE, Slattery JT, Nelson SD: Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen. J Pharmacol Exp Ther 1988;245:129–136.
[PubMed]
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