Correspondence
Correction
Drug-Induced Hepatotoxicity
N Engl J Med 1996; 334:863-864March 28, 1996
- Article
To the Editor:
In Dr. Lee's excellent review of drug-induced hepatotoxicity (Oct. 26 issue),1 he recommends a 48-hour course of oral N-acetylcysteine for patients who have ingested acetaminophen at an unknown time before coming to the hospital or in whom the dose ingested appears excessive. This statement deserves clarification. If the regimen Lee proposes is implemented, many patients will be treated and hospitalized unnecessarily, and the most critically ill patients may be undertreated. When either the dose or the time of ingestion is unclear, determining both the serum acetaminophen level and the aspartate aminotransferase level may be helpful in making treatment decisions. If the time of ingestion is unknown and either the serum acetaminophen level or the aspartate aminotransferase level is elevated, the patient may benefit from N-acetylcysteine therapy. Currently, a 72-hour oral course of N-acetylcysteine is the recommended and accepted regimen for patients with acetaminophen intoxication. Some experts have recommended variable durations of N-acetylcysteine therapy depending on the individual response to treatment,2 and although 48 hours may be sufficient for some patients, this oral dosing regimen has not been adequately studied. If, however, there is neither a detectable acetaminophen level nor any elevation of aspartate aminotransferase, there is little evidence to show a benefit of N-acetylcysteine, and the patient does not require therapy. Similar logic should be applied when the dose is unknown or appears excessive.
Alternatively, the patients most critically poisoned with acetaminophen often do not present within 24 hours after ingestion, the period in which the Rumack–Matthew nomogram can be used.3 Late treatment with N-acetylcysteine has been clearly shown to decrease morbidity and mortality in patients with fulminant hepatic failure caused by acetaminophen when the mean time to therapy was 53 hours after ingestion.4 This benefit requires that the treatment be continued indefinitely until the encephalopathy resolves or the patient dies. The mechanism by which delayed and prolonged therapy with N-acetylcysteine is efficacious is unclear, although evidence suggests that it improves hepatic delivery and consumption of oxygen.5
Although these data pertain solely to patients with fulminant hepatic failure, it seems reasonable to give late N-acetylcysteine therapy with an indefinite duration to all patients with clinically important hepatic injury. Until further clinical research examines specific regimens of N-acetylcysteine and clarifies which patients will benefit from therapy, it seems prudent to individualize the regimens. The approach suggested by Dr. Lee — giving 48 hours of therapy to any patient in whom the time of ingestion or the dose is unclear — may lead to both undertreatment and overtreatment and should be modified.
5 ReferencesFrancis J. De Roos, M.D.
Hospital of the University of Pennsylvania, Philadelphia, PA 19104-4283Robert S. Hoffman, M.D.
New York City Poison Control Center, New York, NY 100161
Lee WM . Drug-induced hepatotoxicity. N Engl J Med 1995;333:1118-1127
Full Text | Web of Science | Medline2
Woo OF ,Anderson IB ,Kim SY ,Mueller P ,Keller K ,Olson KR . Shorter duration of N-acetylcysteine (NAC) for acute acetaminophen poisoning. J Toxicol Clin Toxicol 1995;33:508-508 abstract.3
Rumack BH ,Matthew H . Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-876
Web of Science | Medline4
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
CrossRef | Web of Science | Medline5
Harrison PM ,Wendon JA ,Gimson AES ,Alexander GJM ,Williams R . Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991;324:1852-1857
Full Text | Web of Science | Medline
To the Editor:
Lee states that halothane is a “seldom-used anesthetic agent that was very popular for a number of years.” This is untrue. Halothane, one of the least noxious of the inhalational anesthetics, is the anesthetic of choice for inhalational use. It is because of this property that halothane is used frequently for induction in the pediatric population. Moreover, the mechanism of halothane-related hepatotoxicity has not been as clearly elucidated as the review states. It is true that one theory of the cause of halothane-induced hepatotoxicity is that it involves an immune-mediated allergic reaction. Clinical evidence supporting this theory includes the rarity of the response (1 in 35,000 cases)1 and the occurrence of eosinophilia and accelerated liver dysfunction on repeated exposure. However, toxic metabolites produced by the reductive metabolism of halothane could bind irreversibly to intracellular structures, causing their destruction. In addition, there are other theories that invoke a genetic susceptibility of the liver to toxic metabolites of halothane.2
2 ReferencesGreg T. Palleschi, M.D.
4 Longfellow Pl., Boston, MA 021141
National Academy of Sciences, National Research Council
CrossRef | Web of Science2
Hoft RH ,Bunker JP ,Goodman HI ,Gregory PB . Halothane hepatitis in three pairs of closely related women. N Engl J Med 1981;304:1023-1024
Full Text | Web of Science | Medline
To the Editor:
The “dapsone syndrome,” also known as the sulfone syndrome, is a rare hypersensitivity reaction to dapsone.1-4 First described in 1949, the syndrome consists of fever, hepatitis, exfoliative dermatitis, generalized lymphadenopathy, and mononucleosis occurring within the first six weeks of treatment. It usually occurs with doses of up to 300 mg per day. Low-dose dapsone, combined with pyrimethamine as maloprim (dapsone, 100 mg; pyrimethamine, 12.5 mg) is used as antimalarial prophylaxis and has been reported to cause the dapsone syndrome.
4 ReferencesAnn Noble, M.B., B.Ch.
City General Hospital, Stoke-on-Trent ST4 7QG, United KingdomAlistair MacDonald, B.A.
University of Washington School of Medicine, Seattle, WA 981951
Hutchinson DB ,Whiteman PD ,Farquhar JA . Agranulocytosis associated with maloprim: review of cases. Hum Toxicol 1986;5:221-227
CrossRef | Medline2
Grayson ML ,Yung AP ,Doherty RR . Severe dapsone syndrome due to weekly maloprim. Lancet 1988;1:531-531
CrossRef | Web of Science | Medline3
Phillips-Howard PA ,Buckler JW . Idiosyncratic reaction resembling toxic epidermal necrolysis caused by chloroquine and maloprim. BMJ 1988;296:1605-1605
CrossRef | Web of Science | Medline4
Johnson DA ,Cattau EL Jr ,Kuritsky JN ,Zimmerman HJ . Liver involvement in the sulfone syndrome. Arch Intern Med 1986;146:875-877
CrossRef | Web of Science | Medline
To the Editor:
In his discussion of cholestatic reactions, Dr. Lee did not mention two important drugs that can also cause this problem — azathioprine and cyclosporine. Azathioprine can induce episodes of intrahepatic cholestasis associated with moderate increases in liver enzymes in patients with renal transplants. In most patients the clinical outcome is good when the drug is diminished or stopped. Nevertheless, in some patients progressive and irreversible cholestasis can appear despite the discontinuation of azathioprine, and liver failure results a few weeks later.1 Cyclosporine induces an acute, dose-dependent, reversible cholestatic syndrome of hyperbilirubinemia characterized by the mild elevation of alkaline phosphatase and aminotransferase levels, with no clinical importance.2 It is usually accompanied by high blood cyclosporine levels.
2 ReferencesJose M. Morales, M.D.
Hospital 12 de Octubre, 28041 Madrid, SpainTo the Editor:
Contrary to Lee's assertion,1 quinidine is not metabolized by P450 2D6.2 Quinidine inhibits P450 2D6 (potentially slowing the metabolism of phenothiazines, polycyclic antidepressants, and many other drugs), but the oxidation of quinidine itself is due to P450 3A4, a reaction in which quinidine competes with such other substrates as dihydropyridines and imidazole antifungal agents.
2 ReferencesRobert R. Fenichel, Ph.D., M.D.
Food and Drug Administration, Rockville, MD 208571
Lee WM . Drug-induced hepatotoxicity. N Engl J Med 1995;333:1118-1127
Full Text | Web of Science | Medline2
Brosen K . Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet 1990;18:220-239
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Lee replies:
To the Editor: De Roos and Hoffman correctly point out that the accepted regimen for the duration of treatment with N-acetylcysteine in acetaminophen overdose is 72, not 48 hours, as I stated. It may well be that shorter courses are effective, but this should not be assumed to be the case until further study is undertaken. If N-acetylcysteine were available in this country in the intravenous form, it would present a more acceptable alternative antidote. I am still concerned that physicians' reliance on the acetaminophen nomogram may give a false sense of security. The nomogram does not apply after 24 hours have passed, and one should not assume, because the alanine aminotransferase level is normal and the acetaminophen level low or undetectable, that the situation is invariably safe. Cases of combined intoxication with alcohol and acetaminophen may show these exact features and involve substantial toxicity later on. One should err on the side of treatment here, since N-acetylcysteine is both effective and safe. Studies clearly show that toxicity is minimal, and survival greatest, when N-acetylcysteine is given in a timely fashion.1
Palleschi correctly reports that halothane is still used to induce anesthesia in children, but it is frequently not the sole agent, or is not used during the entire operation, since other agents (or a combined approach) are available. Whether children can have halothane-induced hepatitis is unclear. In children, the dose of halothane is likely to be less because operations are generally relatively short or the drug is used only for induction, and it is usually the child's first exposure to the agent. In addition, children may be less prone overall to the development of severe drug reactions.
Fenichel is correct in pointing out that the principal oxidative pathway for quinidine is P450 3A4, although since quinidine “inhibits” P450 2D6, this may represent a slower alternative metabolic pathway.
Morales and Noble and MacDonald simply demonstrate that it is impossible to include every single drug reaction in a review of this limited length, and I appreciate their additions.
1 ReferencesWilliam M. Lee, M.D.
University of Texas Southwestern Medical School, Dallas, TX 75235-88871
Makin AJ ,Wendon J ,Williams R . A 7-year experience with severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995;109:1907-1916
CrossRef | Web of Science | Medline
