Correspondence
Drug-Induced Hepatotoxicity
N Engl J Med 2003; 349:1974-1976November 13, 2003
- Article
To the Editor:
In his otherwise excellent review of drug-induced liver injury, Lee asserts that N-acetylcysteine reliably prevents liver injury if treatment is begun within 12 to 24 hours after the ingestion of acetaminophen. This is incorrect.
N-acetylcysteine is almost universally effective when given within 8 to 10 hours after an acute overdose of acetaminophen, but its antidotal efficacy decreases substantially thereafter.1,2 Most patients presenting after a delay should still receive the antidote,1,3 but clinicians should remain vigilant for evidence of acute liver failure in such cases.
3 ReferencesDavid N. Juurlink, M.D., Ph.D.
University of Toronto, Toronto, ON M4N 3M5, Canada
david.juurlink@ices. on. ca 1
Smilkstein MJ ,Knapp GL ,Kulig KW ,Rumack BH . Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319:1557-1562
Full Text | Web of Science | Medline2
Prescott LF ,Illingworth RN ,Critchley JA ,Stewart MJ ,Adam RD ,Proudfoot AT . Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979;2:1097-1100
CrossRef | Web of Science | Medline3
Keays R ,Harrison PM ,Wendon JA , et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991;303:1026-1029
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To the Editor:
In his review article about drug-induced hepatotoxicity (July 31 issue),1 Lee states that “each drug has its own pattern of injury.” This contention may lead to a misconception among readers who are unfamiliar with the diagnosis of hepatotoxic reactions. Actually, there are many examples of mixed pictures of injury. Among older drugs, for instance, amoxicillin–clavulanate tends to cause a cholestatic or mixed pattern of injury, although hepatocellular damage has also been reported frequently,2 as has hepatocellular and cholestatic or mixed injury with nimesulide3 or troglitazone. It is important that physicians approach a suspicion of hepatotoxicity with the awareness that a given drug may produce diverse types of injuries. To further stress that a drug “signature” is of little help in assessing causality, neither of the clinical diagnostic scales used for the assessment of hepatotoxic effects4 includes questions pertaining to the pattern of hepatic damage induced by the suspected drug.
4 ReferencesRaul J. Andrade, M.D., Ph.D.
M. Isabel Lucena, M.D., Ph.D.
Hospital Universitario, 29071 Malaga, Spain
andrade@uma.es 1
Lee WM . Drug-induced hepatotoxicity. N Engl J Med 2003;349:474-485
Full Text | Web of Science | Medline2
Brown SJ ,Desmond PV . Hepatotoxicity of antimicrobial agents. Semin Liver Dis 2002;22:157-167
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Andrade RJ ,Lucena MI ,Fernandez MC ,Gonzalez M . Fatal hepatitis associated with nimesulide. J Hepatol 2000;32:174-174
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Lucena MI ,Camargo R ,Andrade RJ ,Perez-Sanchez CJ ,SanchezDe La Cuesta F . Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001;33:123-130
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To the Editor:
In the context of a review of drug-induced hepatotoxicity, it is important to mention Reye's syndrome — acute liver failure that may follow aspirin intake during certain viral infections, particularly in children.1
1 ReferencesEmmanuel Andres, M.D.
Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France1
Glasgow JF ,Middleton B . Reye syndrome -- insights on causation and prognosis. Arch Dis Child 2001;85:351-353
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To the Editor:
Lee does not mention heparin in his review of drug-induced hepatotoxicity. The Physicians' Desk Reference 1 reports that “significant” elevations of aspartate aminotransferase and alanine aminotransferase levels have been found in a high percentage of patients who have received heparin sodium, and this finding was recently confirmed for low-molecular-weight heparin as well.2 Moreover, a search of the literature reveals two reports of reversible cholestatic liver reaction during heparin therapy.3,4 The mechanism of heparin hepatotoxicity is not known, but the temporal association and the course after the discontinuation of treatment with the drug may be suggestive of an idiosyncratic reaction. Heparin should be added to the list of potentially hepatotoxic drugs.
4 ReferencesRoberto Manfredini, M.D.
Benedetta Boari, M.D.
Massimo Gallerani, M.D.
University of Ferrara, I-44100 Ferrara, Italy
mfr@unife.it 1
Physicians' desk reference. 52nd ed. Montvale, N.J.: Medical Economics, 1998.
2
Carlson MK ,Gleason PP ,Sen S . Elevation of hepatic transaminases after enoxaparin use: case report and review of unfractionated and low-molecular-weight heparin-induced hepatotoxicity. Pharmacotherapy 2001;21:108-113
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Olsson R ,Leonhardt T . Cholestatic liver reaction during heparin therapy. J Intern Med 1991;229:471-473
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Manfredini R ,Boari B ,Regoli F ,Gallerani M . Cholestatic liver reaction and heparin therapy. Arch Intern Med 2000;160:3166-3166
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Author/Editor Response
Drug-induced hepatotoxicity is a complex subject, and any attempt at a comprehensive review can always be improved on. Dr. Juurlink is correct in noting that I suggested that the use of N-acetylcysteine within 12 to 24 hours after the ingestion of acetaminophen prevents injury. It might better be said that the use of N-acetylcysteine within 24 hours prevents severe liver injury but that various degrees of elevations in aminotransferase levels may ensue if the interval between ingestion and the administration of the antidote is longer than 12 hours. However, very few, if any, fatal cases can be attributed to acetaminophen if N-acetylcysteine therapy is begun within 24 hours. In the study cited by Dr. Juurlink, all patients who died in whom measurements had been obtained had elevated aminotransferase levels at the time of the administration of N-acetylcysteine, suggesting that more than 24 hours had passed since the ingestion of acetaminophen, given that aminotransferase levels are not elevated before 24 hours after ingestion.1
Drs. Andrade and Lucena note correctly that although most drugs fit a consistent clinical pattern, some, inexplicably, can cause several different patterns of injury. However, methods for establishing causality have not yet been adequately validated, so referring to them as the gold standard seems risky.
The association of aspirin with Reye's syndrome has been adequately discussed previously. Acetylsalicylic acid was listed under causes of mitochondrial toxicity in Table 1 of my article, but Reye's syndrome is limited to children. Because of the fear of Reye's syndrome, acetaminophen has frequently been substituted for aspirin in recent years, which may not be an improvement, given the current amount of acetaminophen toxicity.
Given the amounts of heparin that are used, toxic effects are exceedingly rare, meriting only two case reports in all the years of use. I was not aware of the apparent toxicity of enoxaparin, but I would caution that this represented an instance of elevations in aminotransferase levels and not necessarily severe hepatocyte injury.
1 ReferencesWilliam M. Lee, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75390-9151
william.lee@utsouthwestern. edu 1
Smilkstein MJ ,Knapp GL ,Kulig KW ,Rumack BH . Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose: analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988;319:1557-1562
Full Text | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
María Isabel Lucena, Henry Cohen, Nelia Hernández, Fernando Bessone, Cristina Dacoll, Camilla Stephens, Yolanda Borraz, Eugenia Ulzurrun, Miguel Bruguera, Raúl J. Andrade. (2011) Hepatotoxicidad, un problema global con especificidades locales: hacia la creación de una Red Hispano Latinoamericana de Hepatotoxicidad. Gastroenterología y Hepatología 34:5, 361-368
CrossRef2
Raúl J. Andrade, M. Isabel Lucena, M. Carmen Fernández, Gloria Pelaez, Ketevan Pachkoria, Elena García-Ruiz, Beatriz García-Muñoz, Rocio González-Grande, Angeles Pizarro, José Antonio Durán, Manuel Jiménez, Luis Rodrigo, Manuel Romero-Gomez, José María Navarro, Ramón Planas, Joan Costa, Africa Borras, Aina Soler, Javier Salmerón, Rafael Martin-Vivaldi. (2005) Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period. Gastroenterology 129:2, 512-521
CrossRef3
Amit S. Kalgutkar, Kirk R. Henne, Mary E. Lame, Alfin D.N. Vaz, Claire Collin, John R. Soglia, Sabrina X. Zhao, Cornelis E.C.A. Hop. (2005) Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. Chemico-Biological Interactions 155:1-2, 10-20
CrossRef
