To the Editor: In Dr. Lee's excellent review of drug-inducedhepatotoxicity (Oct. 26 issue),1 he recommends a 48-hour courseof oral N-acetylcysteine for patients who have ingested acetaminophenat an unknown time before coming to the hospital or in whomthe dose ingested appears excessive. This statement deservesclarification. If the regimen Lee proposes is implemented, manypatients will be treated and hospitalized unnecessarily, andthe most critically ill patients may be undertreated. When eitherthe dose or the time of ingestion is unclear, determining boththe serum acetaminophen level and the aspartate aminotransferaselevel may be helpful in making treatment decisions. If the timeof ingestion is unknown and either the serum acetaminophen levelor the aspartate aminotransferase level is elevated, the patientmay benefit from N-acetylcysteine therapy. Currently, a 72-houroral course of N-acetylcysteine is the recommended and acceptedregimen for patients with acetaminophen intoxication. Some expertshave recommended variable durations of N-acetylcysteine therapydepending on the individual response to treatment,2 and although48 hours may be sufficient for some patients, this oral dosingregimen has not been adequately studied. If, however, thereis neither a detectable acetaminophen level nor any elevationof aspartate aminotransferase, there is little evidence to showa benefit of N-acetylcysteine, and the patient does not requiretherapy. Similar logic should be applied when the dose is unknownor appears excessive.
Alternatively, the patients most critically poisoned with acetaminophenoften do not present within 24 hours after ingestion, the periodin which the Rumack–Matthew nomogram can be used.3 Latetreatment with N-acetylcysteine has been clearly shown to decreasemorbidity and mortality in patients with fulminant hepatic failurecaused by acetaminophen when the mean time to therapy was 53hours after ingestion.4 This benefit requires that the treatmentbe continued indefinitely until the encephalopathy resolvesor the patient dies. The mechanism by which delayed and prolongedtherapy with N-acetylcysteine is efficacious is unclear, althoughevidence suggests that it improves hepatic delivery and consumptionof oxygen.5
Although these data pertain solely to patients with fulminanthepatic failure, it seems reasonable to give late N-acetylcysteinetherapy with an indefinite duration to all patients with clinicallyimportant hepatic injury. Until further clinical research examinesspecific regimens of N-acetylcysteine and clarifies which patientswill benefit from therapy, it seems prudent to individualizethe regimens. The approach suggested by Dr. Lee — giving48 hours of therapy to any patient in whom the time of ingestionor the dose is unclear — may lead to both undertreatmentand overtreatment and should be modified.
Francis J. De Roos, M.D. Hospital of the University of Pennsylvania Philadelphia,PA 19104-4283
Robert S. Hoffman, M.D. New York City Poison Control Center NewYork, NY 10016
References
Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995;333:1118-1127. [Free Full Text]
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
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:871-876. [Free Full Text]
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.
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. [Abstract]
To the Editor: Lee states that halothane is a "seldom-used anestheticagent that was very popular for a number of years." This isuntrue. Halothane, one of the least noxious of the inhalationalanesthetics, is the anesthetic of choice for inhalational use.It is because of this property that halothane is used frequentlyfor induction in the pediatric population. Moreover, the mechanismof halothane-related hepatotoxicity has not been as clearlyelucidated as the review states. It is true that one theoryof the cause of halothane-induced hepatotoxicity is that itinvolves an immune-mediated allergic reaction. Clinical evidencesupporting this theory includes the rarity of the response (1in 35,000 cases)1 and the occurrence of eosinophilia and acceleratedliver dysfunction on repeated exposure. However, toxic metabolitesproduced by the reductive metabolism of halothane could bindirreversibly to intracellular structures, causing their destruction.In addition, there are other theories that invoke a geneticsusceptibility of the liver to toxic metabolites of halothane.2
Greg T. Palleschi, M.D. 4 Longfellow Pl. Boston, MA 02114
References
National Academy of Sciences, National Research Council. Summary of the National Halothane Study. JAMA 1966;197:775-788. [Free Full Text]
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. [Medline]
To the Editor: The "dapsone syndrome," also known as the sulfonesyndrome, is a rare hypersensitivity reaction to dapsone.1,2,3,4First described in 1949, the syndrome consists of fever, hepatitis,exfoliative dermatitis, generalized lymphadenopathy, and mononucleosisoccurring within the first six weeks of treatment. It usuallyoccurs 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 reportedto cause the dapsone syndrome.
Ann Noble, M.B., B.Ch. City General Hospital Stoke-on-Trent ST47QG, United Kingdom
Alistair MacDonald, B.A. University of Washington School ofMedicine Seattle, WA 98195
References
Hutchinson DB, Whiteman PD, Farquhar JA. Agranulocytosis associated with maloprim: review of cases. Hum Toxicol 1986;5:221-227. [CrossRef][Medline]
Grayson ML, Yung AP, Doherty RR. Severe dapsone syndrome due to weekly maloprim. Lancet 1988;1:531-531.
Phillips-Howard PA, Buckler JW. Idiosyncratic reaction resembling toxic epidermal necrolysis caused by chloroquine and maloprim. BMJ 1988;296:1605-1605.
Johnson DA, Cattau EL Jr, Kuritsky JN, Zimmerman HJ. Liver involvement in the sulfone syndrome. Arch Intern Med 1986;146:875-877. [Free Full Text]
To the Editor: In his discussion of cholestatic reactions, Dr.Lee did not mention two important drugs that can also causethis problem — azathioprine and cyclosporine. Azathioprinecan induce episodes of intrahepatic cholestasis associated withmoderate increases in liver enzymes in patients with renal transplants.In most patients the clinical outcome is good when the drugis diminished or stopped. Nevertheless, in some patients progressiveand irreversible cholestasis can appear despite the discontinuationof azathioprine, and liver failure results a few weeks later.1Cyclosporine induces an acute, dose-dependent, reversible cholestaticsyndrome of hyperbilirubinemia characterized by the mild elevationof alkaline phosphatase and aminotransferase levels, with noclinical importance.2 It is usually accompanied by high bloodcyclosporine levels.
Jose M. Morales, M.D. Hospital 12 de Octubre 28041 Madrid, Spain
References
Bruguera M, Pinto JB. Enfermedades hepaticas en los trasplantes renales. Gastroenterol Hepatol 1991;14:129-135.
Rodicio JL, Morales JM. Liver disease in renal transplant patients. In: Massry SG, Glassock RJ, eds. Textbook of nephrology. 3rd ed. Vol. 2. Baltimore: Williams & Wilkins, 1995:1684-9.
To the Editor: Contrary to Lee's assertion,1 quinidine is notmetabolized by P450 2D6.2 Quinidine inhibits P450 2D6 (potentiallyslowing the metabolism of phenothiazines, polycyclic antidepressants,and many other drugs), but the oxidation of quinidine itselfis due to P450 3A4, a reaction in which quinidine competes withsuch other substrates as dihydropyridines and imidazole antifungalagents.
Robert R. Fenichel, Ph.D., M.D. Food and Drug Administration Rockville,MD 20857
References
Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995;333:1118-1127.
Brøsen K. Recent developments in hepatic drug oxidation: implications for clinical pharmacokinetics. Clin Pharmacokinet 1990;18:220-239. [Medline]
Dr. Lee replies:
To the Editor: De Roos and Hoffman correctly point out thatthe accepted regimen for the duration of treatment with N-acetylcysteinein acetaminophen overdose is 72, not 48 hours, as I stated.It may well be that shorter courses are effective, but thisshould not be assumed to be the case until further study isundertaken. If N-acetylcysteine were available in this countryin the intravenous form, it would present a more acceptablealternative antidote. I am still concerned that physicians'reliance on the acetaminophen nomogram may give a false senseof security. The nomogram does not apply after 24 hours havepassed, and one should not assume, because the alanine aminotransferaselevel is normal and the acetaminophen level low or undetectable,that the situation is invariably safe. Cases of combined intoxicationwith alcohol and acetaminophen may show these exact featuresand involve substantial toxicity later on. One should err onthe side of treatment here, since N-acetylcysteine is both effectiveand safe. Studies clearly show that toxicity is minimal, andsurvival greatest, when N-acetylcysteine is given in a timelyfashion.1
Palleschi correctly reports that halothane is still used toinduce anesthesia in children, but it is frequently not thesole agent, or is not used during the entire operation, sinceother agents (or a combined approach) are available. Whetherchildren can have halothane-induced hepatitis is unclear. Inchildren, the dose of halothane is likely to be less becauseoperations are generally relatively short or the drug is usedonly for induction, and it is usually the child's first exposureto the agent. In addition, children may be less prone overallto the development of severe drug reactions.
Fenichel is correct in pointing out that the principal oxidativepathway for quinidine is P450 3A4, although since quinidine"inhibits" P450 2D6, this may represent a slower alternativemetabolic pathway.
Morales and Noble and MacDonald simply demonstrate that it isimpossible to include every single drug reaction in a reviewof this limited length, and I appreciate their additions.
William M. Lee, M.D. University of Texas Southwestern MedicalSchool Dallas, TX 75235-8887
References
Makin AJ, Wendon J, Williams R. A 7-year experience with severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995;109:1907-1916. [CrossRef][Medline]
Wallace, K. P., Center, S. A., Hickford, F. H., Warner, K. L., Smith, S.
(2002). S-Adenosyl-L-Methionine (SAMe) for the Treatment of Acetaminophen Toxicity in a Dog. Journal of the American Animal Hospital Association
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