Correspondence
Acetaminophen Poisoning and Liver Function
N Engl J Med 1994; 331:1310-1312November 10, 1994
- Article
To the Editor:
The suggestion by Cheung et al. (June 30 issue)1 that an acetaminophen overdose in an alcoholic should be treated with acetylcysteine regardless of the serum acetaminophen concentration is unfounded and contrary to the available evidence. The literature includes well over 10,000 cases of acetaminophen overdose,2,3 and the accumulated experience worldwide must involve well over 100,000 cases. Despite this extensive experience, we are unaware of any other bona fide examples of the phenomenon described by Cheung and colleagues, who reported a case of fatal acetaminophen-induced hepatic failure in an alcoholic patient despite a “nontoxic” serum acetaminophen concentration.
One must first question the accuracy of the history in this case, particularly with regard to the time of ingestion of acetaminophen and the possibility of repeated ingestion. It is inconceivable that the ingestion of 25 g of acetaminophen would result in a concentration of only 124 μg per milliliter four hours after ingestion, suggesting that either the amount or the time is inaccurate. Such an error is further suggested by the occurrence of severe hepatic failure with an undetectable serum acetaminophen concentration within 50 hours after ingestion. In patients with such fulminant toxic effects, the metabolism of acetaminophen quickly becomes negligible, resulting in the persistence of low levels of circulating acetaminophen.
Remarkable cases do occur, however, and consideration must also be given to the implications of this case if the information provided is correct. We agree that both studies in animals and reports of long-term ingestion of acetaminophen suggest that alcoholics are at increased risk for hepatotoxic effects of the drug. Why, then, are such effects not reported more frequently in alcoholics with acetaminophen overdoses?2 The use of a conservative nomogram (25 percent lower than the original data-based version)2 and liberal doses of acetylcysteine (1330 mg per kilogram of body weight over a three-day period) are likely explanations and appear to overcome any disadvantage associated with alcoholism or other conditions.
Long-term use of alcohol appears to be relevant to the discussion of the management of long-term overingestion of acetaminophen. Experience suggests that alcoholics, patients receiving therapy that causes the induction of cytochrome P-450 enzymes,4 and infants with febrile illnesses5 are at substantially higher risk for hepatotoxic effects. Such effects are essentially unheard of in patients without these risk factors.
Given the high prevalence of both alcohol abuse and acute acetaminophen overdose, any change in treatment recommendations would have a substantial effect. Particularly with the current emphasis on cost effectiveness, a change in treatment recommendations on the basis of this or any other remarkable case would be a big step backward.
5 ReferencesMartin J. Smilkstein, M.D.
Daniel R. Douglas, M.D.
Mohamud R. Daya, M.D.
Oregon Health Sciences University, Portland, OR 972011
Cheung L ,Potts RG ,Meyer KC . Acetaminophen treatment nomogram. N Engl J Med 1994;330:1907-1908
Full Text | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
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 | Medline4
Bray GP ,Harrison PM ,O'Grady JG ,Tredger JM ,Williams R . Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol 1992;11:265-270
CrossRef | Web of Science | Medline5
Henretig FM ,Selbst SM ,Forrest C , et al. Repeated acetaminophen overdosing: causing hepatotoxicity in children. Clin Pediatr (Bologna) 1989;28:525-528
CrossRef
To the Editor:
I am sure I will not be the only British reader who feels moved to reply to the letter by Cheung et al. The acetaminophen treatment nomogram is indeed widely used as a guideline for treatment in patients with acetaminophen overdoses,1 here as in the United States. However, in this country, if not in the United States, it is already widely recognized that ethanol, as well as many other hepatic cytochromal enzyme-inducing drugs, may confound this approach. For this reason, it is considered routine practice to halve the level at which treatment is considered, as proposed in the current issue of the British National Formulary.2
If Cheung et al. had taken this into account, the acetaminophen level of 124 μg per milliliter at four hours (which is less than 200 μg per milliliter, the cutoff point in the nomogram, but more than 100 μg per milliliter, half the cutoff point) would have dictated treatment with acetylcysteine, not nontreatment. A decline that became irrevocable might have been prevented. As Cheung et al. point out, there should be a low threshold for treatment with acetylcysteine, since the hazards of such treatment are negligible.3
3 ReferencesAndrew Davie, M.B., Ch.B.
Falkirk and District Royal Infirmary, Falkirk FK1 5QE, United Kingdom1
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
CrossRef | Web of Science | Medline2
British National Formulary. No. 27. March 1994. London: British Medical Association, 1994:20-1.
3
Miller LF ,Rumack BH . Clinical safety of high oral doses of acetylcysteine. Semin Oncol 1983;10:Suppl 1:76-85
Web of Science | Medline
To the Editor:
Cheung et al. describe their experience with a 25-year-old woman who had consumed 25 g of acetaminophen in a suicide attempt but was not treated with acetylcysteine because she was not considered to be a risk on the basis of the acetaminophen treatment nomogram. Fulminant hepatic failure subsequently developed, and she died. The reason, the authors conclude, is that she had consumed large amounts of ethanol for a long period. Long-term use of ethanol was thought to have altered the metabolism of acetaminophen sufficiently to invalidate the predictive value of the acetaminophen treatment nomogram for determining hepatotoxicity. Thus, the authors conclude that a careful history of alcohol use should be taken for every patient with an acetaminophen overdose.
There are several serious problems with the authors' presuppositions and conclusions in this case. First, 25 g of acetaminophen (which is more than six times the maximal recommended daily dose) is clearly in the toxic range.1 Second, although the acetaminophen treatment nomogram is useful for population studies, it should never be used to withhold a benign and potentially lifesaving treatment in the case of a known overdose. Third, the magnitude by which alcohol enhances the toxic effects of acetaminophen has never been established in humans. The induction of cytochrome P-450 2E1 enzyme activity by alcohol is only twofold to threefold and returns to normal within five days,2 suggesting that recent alcohol use is more important than long-term use. Furthermore, the reduction in serum glutathione levels in alcoholics is only modest,3 and the reduction in hepatic glutathione levels during ethanol consumption, when controlled for fasting, has not been demonstrated in humans. Finally, other factors that may increase the toxic effects of acetaminophen, such as a genetic predisposition or fasting,4 may be even more important than a history of alcohol consumption. Thus, the case by Cheung et al. provides an argument for the treatment of patients with acetaminophen overdoses regardless of the serum acetaminophen level but fails to prove that the toxic effects of acetaminophen are increased by alcohol consumption.
I would suggest the following approach. Treat every acetaminophen overdose (> 4 g per deciliter) with acetylcysteine. Use the acetaminophen treatment nomogram to inform the patient or family that in large populations an acetaminophen level similar to that in the patient usually results in hepatic toxic effects or minimal toxic effects, depending on the level.
4 ReferencesDavid C. Whitcomb, M.D., Ph.D.
University of Pittsburgh School of Medicine, Pittsburgh, PA 152131
Prescott LF ,Roscoe P ,Wright N ,Brown SS . Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971;1:519-522
CrossRef | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
Lauterburg BH ,Velez ME . Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988;29:1153-1157
CrossRef | Web of Science | Medline4
Whitcomb DC, Block GD. Enhanced susceptibility to acetaminophen hepatotoxicity: the effects of fasting and ethanol use. JAMA (in press).
Author/Editor Response
The authors reply:
To the Editor: Whitcomb, citing Prescott et al.,1 states that ingestion of 25 g of acetaminophen clearly falls in the range associated with hepatotoxic effects. However, an absolute relation between an ingested dose of acetaminophen and the plasma level or degree of hepatotoxicity has not been clearly established in humans. According to the acetaminophen treatment nomogram,2 our patient's plasma acetaminophen level (in micrograms per milliliter) was not in the toxic range; the plasma level, not the total ingested amount, is commonly used as a guide to predict toxicity. Whitcomb also states that the induction of cytochrome P-450 enzyme activity is only mildly increased by alcohol and returns to normal within five days, suggesting that recent alcohol use is more important than long-term use. However, the induction of cytochrome P-450 enzyme activity by alcohol can range from two- or threefold to six- or sevenfold because of large variations in genetic and environmental factors; it returns to normal within five days only after abstinence.3 Continued daily use may not allow a return to normal cytochrome P-450 enzyme activity. Although the reduction of glutathione levels in alcoholics may be only modest, a modest decline may be sufficient to increase the toxic effects, if toxic accumulation of acetaminophen metabolites further depletes glutathione stores.
Smilkstein et al. suggest that the combination of hepatotoxic effects with a nontoxic acetaminophen plasma level that we described in a long-term alcohol user is “remarkable” in that a similar case has not been reported in studies involving over 100,000 cases. However, most studies have not been specifically designed to explore the outcome in such patients. For example, among the studies cited by Smilkstein et al., only 5 of the 662 cases in the study reported by Rumack et al. involved nontoxic acetaminophen levels and a history of long-term alcohol use without short-term alcohol ingestion (which alone has been suggested to be protective against the hepatotoxic effects of acetaminophen).2 Furthermore, in the National Multicenter Study reported by Smilkstein et al.,4 patients with a history of alcohol use were uniformly distributed among the study groups in order to decrease confounding variables. Alcohol use was not evaluated as an independent risk factor. An accurate history indicating the amount and time of ingestion is critical for predicting hepatotoxic effects. In our patient, the onset of symptoms and the elevation in the liver-enzyme levels correlated with the expected clinical stages of acetaminophen toxicity, suggesting that the time of ingestion was accurate.5
Davie points out that halving the acetaminophen level at which treatment is considered is routine practice in patients with an alteration in cytochromal enzyme induction. We are not aware of such a routine practice in the United States, but this approach should be considered. We agree with Whitcomb that a potentially lifesaving and benign therapy should not be withheld solely on the basis of the acetaminophen level. The case of our patient demonstrates that reliance on the acetaminophen treatment nomogram as a guide to therapy can have fatal consequences. We do not agree with Smilkstein et al. that a reconsideration of current treatment recommendations would be “a big step backward.”
5 ReferencesLisa Cheung, M.D.
Keith C. Meyer, M.D.
University of Wisconsin Clinical Science Center, Madison, WI 537921
Prescott LF ,Roscoe P ,Wright N ,Brown SS . Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971;1:519-522
CrossRef | Web of Science | Medline2
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
CrossRef | Web of Science | Medline3
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
CrossRef | Web of Science | Medline4
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 | Medline5
Linden CH ,Rumack BH . Acetaminophen overdose. Emerg Med Clin North Am 1984;2:103-119
Medline
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Charles F Seifert, Douglas C Anderson. (2007) Acetaminophen Usage Patterns and Concentrations of Glutathione and γ-Glutamyl Transferase in Alcoholic Subjects. Pharmacotherapy 27:11, 1473-1482
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Laurie F. Prescott. (2000) Paracetamol, alcohol and the liver. British Journal of Clinical Pharmacology 49:4, 291-301
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Gordon MacFarlane, Dan Scheller, Diana Ersfeld, Todd Jensen, Anthony Jevans, Pui-Yeun Wong, Masakazu Kobayashi. (1996) A Simplified Whole Blood Enzyme-linked Immunosorbent Assay (ProTrac II) for Tacrolimus (FK506) Using Proteolytic Extraction in Place of Organic Solvents. Therapeutic Drug Monitoring 18:6, 698-705
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Daniel R. Douglas, James B. Sholal, Martin J. Smilkstein. (1996) A Pharmacokinetic Comparison of Acetaminophen Products (Tylenol Extended Relief vs Regular Tylenol). Academic Emergency Medicine 3:8, 740-744
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Lee, William M., . (1995) Drug-Induced Hepatotoxicity. New England Journal of Medicine 333:17, 1118-1127
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