Acetaminophen hepatotoxicity

GASTROENTEROLOGY

Acetaminophen

78382-392,

1980

Hepatotoxicity

MARTIN BLACK Department of Medicine, Liver Unit, Temple University School of Medicine, Philadelphia, Pennsylvania

Over the past five or more years, laboratory and clinical investigations aimed at elucidating the pathogenesis of acetaminophen-induced liver-cell necrosis have achieved a striking degree of success in considerably resolving the biochemical mechanisms involved, and they have identified novel therapeutic approaches to the management of the disorder. Fortuitously, these investigations have also served a number of purposes beyond their primary objectives. They have been singularly responsible for opening lines of communication between biomedical scientists whose paths had infrequently crossed previously. General internists, gastroenterologists, clinical hepatologists, pharmacologists, toxicologists, experimental pathologists, chemists, biochemists, pharmacists, and others from allied fields have increasingly sought each other’s counsel as the available information on acetaminophen hepatotoxicity extended beyond their respective areas of expertise. The lessons learned from acetaminophen hepatotoxicity also may affect the future way gastroenterologists and other internists view interactions between drugs and the liver. In the wake of the acetaminophen experience, it appears less likely that drug-induced liver injury will be as readily written off as an entirely unpredictable immunologic event whose experimental pathology resides in circulating or tissue-bound immune complexes containing the offending drug in some form or other, and whose therapy inexorably includes corticosteroids. Modern day drugs are now being recognized as often-potent compounds whose toxicities (as well as their actions) in many cases result from a chemical reaction between the drug (or metabolite) and structures (receptors) within a cell. The time may have come when Hyman Zimmerman’s message on Received July 30, 1979. Accepted September 7.5, 1979. Address requests for reprints to: Martin Black, M.D., Department of Medicine, Temple University School of Medicine, 3401 North Broad Street, Philadelphia, Pennsylvania 19140. The author would like to thank Drs. Snorri Thorgeirsson and Barry Rumack for their assistance in preparing this manuscript. 0 1980 by the American Gastroenterological Association 0016~5085/80/020382-11$02.25

drug hepatotoxicity7-3 at last finds a receptive and sympathetic audience. Acetaminophen hepatotoxicity is a solid example of the “toxic metabolite hypothesis” (Figure l).‘-” When massive overdose with this drug occurs, an arylating metabolite of the drug, produced in the liver cell, overwhelms the hepatocytes defense mechanisms and causes the cell to die. A handful of other reports indicate that the sequence of events can take place in the setting of ingestion of much lesser amounts of acetaminophen over a protracted period of time.12m16 Immunologic mechanisms do not appear to participate in the reaction. This experience by no means excludes immunologic mechanisms in other drug toxicities affecting the liver, of course, but it clearly establishes that chemical-induced liver-cell necrosis in laboratory animals has a significant human constituency. Its relevance to other presently unexplained forms of drug-induced liver injury is uncertain, but represents a challenge for the future.

Chemistry and Pharmacology of Acetaminophen Acetaminophen (paracetamol) is a derivative of para-aminophenol, and like its analogues, phenacetin (acetophenetidin) and acetanilid (Figure Z), was introduced into clinical medicine as an antipyretic agent in the late nineteenth century.” Acetanilid was soon discarded as being too toxic for human use, and for many years the foremost paraaminophenol derivative used in humans was phenacetin. Only during the last 20-30 yr has acetaminophen been increasingly preferred to phenacetin, particularly since nephrotoxicity was tied to longterm phenacetin ingestion.18.19 Both acetanilid and phenacetin are extensively and rapidly metabolized to acetaminophen in humans,” accounting for the antipyretic effect of administered acetanilid and much of that of phenacetin.20.2’ Acetaminophen has mild analgesic and antipyretic properties that are very comparable to those

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of aspirin.2’-25 It is a major component of over 200 formulations available for the relief of headaches, coughs, and colds.” However, unlike aspirin it has little antiinflammatory activity and is less valuable as an antirheumatic agent. Following oral ingestion, acetaminophen is rapidly absorbed and peak plasma concentrations are reached in 30-60min. The drug distributes uniformly throughout most body fluids (Vd = 0.7-0.75 l/kg) and is only modestly bound (25%)to plasma proteins. It is primarily metabolized NHCOCH3 I

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by conjugation with glucuronide or sulfate, and the plasma half-life ranges between l-3 hr. When taken in therapeutic doses, neither acetaminophen nor phenacetain have appreciable side effects. Patients occasionally do show habituation to these and other analgesic drugs, and they may consume considerable amounts of analgesic preparations over protracted periods of time. It is in this setting that “analgesic nephropathy” has been recognized,18.‘9 and phenacetin has been incriminated as the most frequent causative agent. However, because of the presence of other analgesic-antipyretic compounds in phenacetin-containing proprietary preparations, their contributions to the renal damage Methemoglobinemia is relacannot be excluded.‘” tively common with phenacetin ingestion, but generally it is not clinically evident except in acute overdosage or chronic abuse situations. It also was noted to occur following acetanilid ingestion,” but it is not seen with acetaminophen.

Epidemiology Hepatotoxicity

of Acetaminophen

Davidson and Eastham”’ can be credited with the first English-language report of acetaminopheninduced hepatic necrosis in humans, the report appearing more than 70 yr after the drug’s introduction into clinical medicine. These authors described two inmates of a Scottish mental institution who died after ingestion of massive overdoses of the drug. Importantly, they identified the first patient’s demise as a motivating factor for the second patient’s attempt.

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Thereafter the number of reported cases in the United Kingdom began to increase rapidly”‘-“” and eventually reached epidemic proportions. Volanss4 considered that extensive media coverage of the phenomenon was at least partially responsible for the astounding increase in acetaminophen-related deaths that occurred in the United Kingdom in the early seventies. Its newly found acceptance as a major method of suicide in the United Kingdom was surely attested to by the experience of Prescott et a1.35 who recently encountered one poor soul who was admitted to a Scottish hospital on 31 occasions for acetaminophen self-poisoning. The number of cases encountered in the United States appears to have been proportionately much les? despite the equal availability of the medications. Although there may be psychosocial explanations to account for this difference, it is not unlikely that a lack of comparable publicity concerning the disorder in the United States has played a critical role. Nevertheless, Dr. Barry Rumack (Director, Rocky Mountain Poison Center, Denver, Col.) who presently holds the IND in the United States for Nacetylcysteine administration in overdose cases (see below) believes that there has been a significant increase in the number of overdose patients seen (or recognized) in U.S. hospitals over the past 2-3 yr (personal communication), and an increasing number of reports have been appearing recently in U.S. the house officers medical journals.37-41 Certainly, staffing the Emergency Room of my own institution claim to be seeing many more such patients than their predecessors. Perhaps as a reflection of such a trend, one of the leading manufacturers of an acetaminophen brand-name product has recently circulated to all physicians specific instructions on how to manage such patients (see below).

Clinical Aspects Hepatotoxicity

of Acetaminophen

Liver injury will develop in all patients who ingest sufficient acetaminophen (a “predictable” hepatotoxin), becoming evident biochemically within 24-48 hr of the time of ingestion. Typically such massive ingestions represent deliberate suicide attempts, but occasionally patients have taken large amounts of the drug when obtunded by alcohol or of drug necesnarcotic ingestion.42-44 The amounts sary to produce liver damage in an adult may be as little as 10 g”’ corresponding to 15 “double-strength Tylenol” tablets or 30 “regular strength” tablets. Caution has been urged, however, in assessing the number of tablets claimed to have been taken by the patient45 and greater reliance needs to be placed on measured blood levels of the drug. A good correla-

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tion exists between the plasma acetaminophen level and the probability of development of liver dam, age. 32,33.46.47 If one plots the level on a semilogarithmic plot of plasma acetaminophen concentration versus time after ingestion, then liver damage can be expected if the point falls above a line connecting the 200 pg/ml point at 4 hr with the 50 pg/ml point at 12 hr. Utilization of such a nomogram has become an essential prerequisite in the planning of treatment for the disorder.“g A small number of patients have been reported44.48 in whom ingestion of acetaminophen in the setting of chronic alcohol ingestion or concomitant barbiturate therapy produced a greater degree of liver damage than might otherwise have been predicted. The suggestion has been implicit that ingestion of alcohol or barbiturate “induces” the hepatic microsomal mixed-function oxidase system, which serves to augment the amount of “toxic metabolite” (see below) formed for any given dose of acetaminophen. These observations need to be appreciated when developing strategies for therapy based upon level data. The clinical course of acute acetaminophen overdose follows a fairly consistent pattern. In the first few hours, the patient is nauseated and occasionally vomits, and may be moderately obtunded (particularly if sedating drugs were ingested along with the acetaminophen). These symptoms rapidly disappear and within 24 hr of the ingestion the patient appears fully recovered. However, if the ingestion was sufficient to produce liver injury then this becomes evident biochemically some 48-72 hr after the ingestion. Laboratory features of acetaminophen hepatotoxicity resemble other forms of acute necroinflammatory liver disease with prominent increases in the serum glutamicoxaloacetic and glutamicpyruvate transaminase (SGOT and SGPT) levels (often into the several thousands) and lesser increases in the serum alkaline phosphatase. The more explosive nature of the drug-related disorder is reflected by the early and severe coagulation disturbance (prolonged prothrombin time, etc.43.49) at a time when there may be only modest hyperbilirubineniia. The histopathologic appearances of the liver at biopsy or autopsy reveal a variably extensive centrizonal necrosis without steatosis and with a relatively light inflamhepatic matory infiltrate.26~29~4” Death from fulminant failure secondary to acetaminophen-induced hepatic necrosis occurs from 4-18 days after drug ingestion.4” Recovery from the acute episode is normally followed by return of the hepatic architecture to normal within 3 mo.“’ Other organs may also manifest biochemical and histopathologic evidence of acute toxicity. The kidneys are perhaps the next most frequently damaged organ with extensive

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1980

Acetaminophen

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HEPATOXICITY

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tubular necrosis being found in some autopsied The heart, too, occasionally shows cases. 26~2”~*Y~31~51 evidence of acute damage.2y.3”.5’

Mechanisms

of Hepatotoxicity

As stated previously, there is a considerable body of evidence pointing to the participation of a metabolite of acetaminophen rather than the parent drug in production of hepatocellular necrosis, thereby establishing acetaminophen hepatotoxicity as an example of the “toxic metabolite hypothesis” (Figure 1). Pretreatment regimens in experimental animals that modulate the activity of the hepatic microsomal mixed-function oxidase system greatly influence the extent of liver-cell necrosis observed after intraperitoneal administration of acetaminophen. Thus, whereas naive mice demonstrate extensive necrosis after administration of doses of 750 mg/kg acetaminophen and only limited necrosis with a 3% mg/kg dose, phenobarbital-pretreated mice (in which the activity of the microsomal mixed-function oxidase system is greatly enhanced) show extensive necrosis after a 3%mg/kg dose.52 Conversely, piperonyl butoxide or cobaltous chloride pretreated mice (in which the microsomal mixed function oxi-

probable

mechanism

of acetaminophen

hepatotoxicity.

dase system is inhibited,““,“” show little necrosis with that the 750-mg/kg dose.‘l These studies established acetaminophen-induced liver-cell necrosis was not only mediated via a metabolite of the drug, but that the microsomal mixed-function oxidase system was importantly involved in its formation. In further support of this concept was the observation that the brunt of injury from acetaminophen in both laboratory animals5’~5”~“7 and humans2ti.29.4” falls upon the centrizonal hepatocytes, in which the greatest lobular concentration of the microsomal mixed-function oxidase system is located.‘“.“” Initial hypotheses regarding the chemical reactions leading to formation of the “toxic metabolite” have focussed on a preliminary N-hydroxylation reaction with subsequent dehydration to an imidoquinone compound (Figure 3).‘X1’2 Such a sequence commencing with N-hydroxylation of an aromatic amine would be a counterpart of the processes mediating activation of certain carcinogens” and comparable to reactions converting Z-acetylaminofluorene to its toxic metabolite.““,“’ However, recent studies by Hinson et al. in hamsters”“,“” have questioned this sequence of reactions for acetaminophen. These workers demonstrated that although N-hydroxyacetaminophen appeared to be a metabolite of N-hy-

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droxyphenacetin, it did not appear to be formed during cytochrome P450-mediated hydroxylation of acetaminophen. They left open the possibility that N-acetylimidoquinone may be the ultimately reactive metabolite, but doubted that this compound was formed after a preliminary N-hydroxylation step. Additional data in this area are required to resolve the issue. The information that presently exists regarding the biochemical and molecular processes that mediate necrosis of the liver cell once the acetaminophen toxic metabolite has overwhelmed the hepatocyte’s defense mechanisms is also incomplete and occasionally inconsistent. In studies utilizing coadministration of tracer amounts of tritiated acetaminophen together with unlabeled drug to intact laboratory animals, the amount of labeled drug covalently bound to hepatic tissues closely paralleled the severity of hepatocellular necrosis.“* Thus, for doses of drug that were insufficient to produce necrosis there was negligible binding demonstrated, whereas with doses able to produce necrosis considerable covalent binding was observed.67 Phenobarbital pretreatment of animals greatly increased covalent binding of previously non-necrogenic doses of acetaminophen,e7 while piperonyl butoxide or cobaltous chloride pretreatment markedly reduced covalent binding with the larger doses of acetaminophen.“’ Autoradiographic studies further established that binding of drug was maximal in centrilobular hepatocytes where necrosis was several hours.“7 Covalent binding of drug to hepatic tissues was inversely related to hepatic glutathione concentrationW and proceeded very rapidly when intracellular glutathione concentrations fell below 30X8” (see below). Investigation of the characteristics of acetaminophen covalent binding to hepatic tissues in “in vitro” experiments confirmed the participation of the microsomal-mixed function oxidase system” and the regulating role of glutathione.” Species differences in susceptibility to acetaminophen-induced hepatic necrosis were also found to parallel the kinetics of “in vitro” covalent binding of drugs.70 Thus, these observations clearly established that acetaminophen-induced liver-cell necrosis was intimately related with, and preceded by, a chemical interaction of acetaminophen toxic metabolite with certain macromolecular structures within the liver cell. The interaction presumably involves sulfhydryl groups of protein components of the endoplasmic reticulum, proximate to the site of formation of the toxic metabolite (the very fact of its being highly re‘For a detailed discussion of the kinetics and other aspects of covalent binding of drug metabolites to hepatic tissues, the reader is referred to the review by Gillette.7’,72

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active makes it improbable that it migrates any significant distance within the cell), but precise localization of the receptor(s) has yet to be identified. Although the foregoing series of observations offers an appealing and internally consistent explanation for the metabolic basis of acetaminophen induced hepatic necrosis, other data have been elicited which tend to muddy the waters a little. Labadarios and coworkers demonstrated that pretreatment of mice with cw-mercaptopropionylglycine (a-MPG), a sulfhydryl-containing compound, offered a significant protection against hepatic necrosis from acetaminophen without appreciably affecting the amount of drug covalently bound to hepatic tissues.73 Comparable observations were made by Gerber and coworkers’* employing N-acetylcysteine. Both studies underscore the potential for exaggerating the biologic significance of the demonstration of covalent binding of drug to hepatic tissues. In this regard, the studies supplement earlier works75~76that had indicated that a metabolite of a drug could become covalently bound to hepatic tissues in considerable amounts without evidence of significantly impaired organ function. Such observations emphasize the present need for caution when extrapolating drug binding data to organ function in the intact animal, and suggest that it might become more critical in the future to identify covalent binding of a drug (or metabolite) at a specific site within the hepatocyte rather than demonstrate a great amount of drug binding to entirely uncharacterized receptors. “In vivo” covalent binding of drug to liver tissue is followed, within a relatively short period of time, by electron-microscopic evidence of considerable disruption and vacuolation of the endoplasmic reticulum of the hepatocyte.” Increased diene conjugation and formation of malondialdehyde” support the concept of the occurrence of lipid peroxidation as the basis of these changes, and some protection from the injurious effects of the acetaminophen toxic metabolite is provided by pretreatment with antioxidants.‘* However, despite this evidence of an early involvement of the endoplasmic reticulum, there appears to be remarkably little impairment of several of the organelle’s enzyme systems. Thus, cytochrome P450 content,77~79~80aminopyrine deethylmorphine demethylase,” aniline methylase,BO hydroxylase,7’.79.80 and glucuronyl transferasem.m all show relatively modest changes in activity in studies extending as long as 24 hr after acetaminophen administration. These observations are in marked contrast to those that have been made in carbon tetrachloride-poisoned animals in which dramatic decreases of enzyme activitya’-” parallel the electron-microscopic evidence of disruption of the endoplasmic reticu1um.86.8’ The significance of these dif-

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ferences in regard to the biochemical and molecular pharmacology of acetaminophen-induced liver-cell necrosis remains to be resolved. It should be recognized that although the microsomal mixed-function oxidase system is centrally involved in generating the acetaminophen toxic metabolite, this pathway plays a minor role in the overall disposition of the drug when it is ingested in therapeutic doses (Fig. 3). Thus, 85-90% of acetaminophen is normally metabolized by glucuronide or sulfate conjugation, leaving a relatively small amount to be metabolized via other pathways including the mixed-function oxidase system.8R-g1 Glutathione conjugation of the product of the oxidation step yields mercapturic acid derivatives, which normally account for less than 5% of the ingested dose.A9-9’ Studies in patients taking overdoses of acetaminophen have demonstrated that glucuronide and sulfate conjugation are both saturable processes,89.“1 although one group of investigators have suggested that exogenous sulfate administration could increase the extent of sulfate conjugation of toxic doses of acetaminophen.92.93 Interestingly, Douglas et a1.94have recently elicited data indicating impaired glucuronidation of acetaminophen given in pharmacologic doses in six individuals with Gilbert’s syndrome, a disorder characterized by decreased bilirubin UDP glucuronyl transferase activity.“’ As to whether this places such individuals at increased risk from acetaminophen overdose is presently unknown. After the ingestion of amounts of acetaminophen in excess of the dose necessary to saturate these conjugation processes, metabolism via the mixedfunction oxidase system, followed by glutathione conjugation of the oxidized metabolite, becomes significantly augmented, and urinary mercapturic acid metabolite excretion is increased.8Y-Y’ When the hepatocellular glutathione concentration has become critically depleted and no longer available in sufficient amount to inactivate this product of acetaminophen oxidation, the metabolite reacts with macromolecules within the hepatocyte initiating the series of events that lead to the cell’s death.

Experimental Therapy

Background

to Nucleophil

As depicted schematically in Figure 1, the hepatocyte possesses a well-developed “defense system” to protect it against the destructive potential of highly reactive compounds like the acetaminophen toxic metabolite. The microsomal epoxide hydratase enzyme(s) is one component of that system that has been fairly well characterized9,96-98 and shown to

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play a critical role in the further metabolism of reactive arene oxides such as that formed during the microsomal metabolism of bromobenzene.9.98.99 At this time a comparable role has not been identified for it with respect to metabolism of the acetaminophen toxic metabolite that appears to be primarily detoxified by glutathione conjugation. This latter reaction is normally mediated via a cytoplasmic family of enzymes, the glutathione S-transferases.‘W-‘03 However, available evidence suggests that the rate-limiting factor in glutathione conjugation of the acetaminophen toxic metabolite (at least in the acute ingestion situation) is the intracellular concentration of the nucleophil, glutathione, rather than, say, the level of glutathione S-transferase activity. Thus, animal pretreatment regimens that modulate the hepatocellular concentrations of glutathione influence the extent of hepatocellular necrosis produced by given doses of acetaminophen.” Administration of diethylmaleate and like substances,‘” protein depletion,‘05 or fasting for prolonged periods of timelm all significantly lower basal hepatocellular glutathione concentrations and render experimental animals susceptible to liver-cell necrosis from lower-thanusual doses of acetaminophen.“~‘““~‘“’ Conversely, regimens that replenish intrahepatocytic glutathione (e.g., cysteine, methionine) or supply comparable sulfhydryl acceptors (e.g., cysteamine, dimercaprol, etc.=.“) offer protection against doses of acetaminophen that would otherwise result in extensive livercell necrosis. These later regimens are effective if given before acetaminophen administration and for a short period of time afterward. This postexposure interval is presumably accounted for by the time the hepatocyte takes to become critically depleted of its glutathione stores during maximal toxic metabolite synthesis. It is now recognized as a fortunate circumstance, one which offers the attending physician the opportunity for therapeutic intervention utilizing administration of glutathione precursor compounds and similar nucleophils.

Treatment Therapeutic approaches to acetaminophen overdose have included attempts to reduce the drugs absorption from the GI tract by administering either activated charcoal or cholestyramine,‘” or to enhance its removal from the plasma by using hemodialysis,‘” or charcoal column hemoperfusion.““~‘” Neither of those approaches has gained wide acceptance, the attempt to impede absorption failing if initiated more than 60 min after the acetaminophen ingestion, and charcoal column hemoperfusion being incapable of clearing important quantities of paracetamO1.l10 With respect to hemodialysis, the avail-

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able information is less convincing that this type of therapy is ineffective, but the amounts of drug capable of being removed by this technique do not exceed 10% of the orally ingested dose.lm However, since therapy with glutathione precursors or like compounds is so dramatically effective, the question of hemodialysis efficacy can probably be considered m00t.112 The introduction of nucleophil therapy with glutathione precursor compounds (cysteine or methionine) or other sulfhydryl compounds (cysteamine, N-acetylcysteine) in acetaminophen overdose resulted directly from the observations ofthe protecting role played by glutathione in laboratory animals as described above.68.89 In light of the inability of exogenously administered glutathione to penetrate the hepatocyte, the first compound studied was cysteamine, a sulfhydryl nucleophil that had been utilized earlier in studies on ionizing radiation in humans.l13 In 1974, Prescott et al. in Scotland reported their experience with intravenous cysteamine in seven episodes of massive acetaminophen overdoses.33 The preparation was administered within 410 hr of the time of acetaminophen ingestion. In five of these episodes the peak SGOT and SGPT levels did not rise above normal levels; in the other two the transaminase increases were minimal. These results were achieved in the face of 4hr plasma acetaminophen concentrations well in the range predicted to produce severe hepatocellular necrosis in the untreated state. Cysteamine therapy was not without unpleasant side-effects, however. Flushing, followed by anorexia, nausea and vomiting, and reversible central nervous system toxicity were noted in all patients. Confirmation of the efficacy of this treatment in preventing development of severe heptocellular necrosis if given in time came from other British centers,l14 although one group was not as impressed.‘15 The unpleasant side effects of cysteamine therapy, however, led to a search for a more acceptable alternative. Oral methioninell’ and intramuscular dimercafound to offer moderate protection pro1”4 were against acetaminophen-induced liver necrosis with fewer side-effects, but the most attractive prospect appears to be N-acetylCySteine.“7.11R This compound has been marketed in the United States for a number of years as a mucolytic agent (Mucomyst), and is normally administered by inhalation. Peterson and administered the drug orally to a single Rumack”’ patient who had taken a potentially heptotoxic dose of acetaminophen 8 hr earlier, and they recorded only modest liver function abnormalities. Prescott, et a1.‘18 administered N-acetylcysteine intravenously (initial dose of 150 mg/kg infused over 15min period

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followed by continuous infusion of 50 mg/kg for 4 hr 16 hr) to 15 patients and 100 mg/kg for subsequent with plasma concentrations of acetamiqpphen in the range known to be associated with severe liver damage. Eleven of the patients manifested little or no rise subsequently in SGOT and SGPT levels. One patient treated at 7-9s hr after acemminophen ingestion and all 3 treated at greater than 10 hr after ingestion showed marked increases in SGOT and SGPT levels. The N-acetylcysteine was well tolerated in both studies, causing only mild nausea and occasional vomiting. These observations confirmed that N-acetylcysteine was an effective therapy without significant toxicity, and led to its widespread utlization in management of acetaminophen overdose in the United States. Presently a nationwide study is being conducted by Dr. Barry Rumack of the Rocky Mountain Poison Center in Denver, Colorado. Over 2000 patients have been reported to the Center, and of those who received N-aCfZ!tykysteine orally within 24 hr of the time of acetaminophen ingestion, no deaths are known to have occurred (Dr. Rumack, personal communication). In the small number of patients known to have died from acetaminophen overdose during the period of the study, treatment had been delayed in all until at least 36 hr after the ingestion. The protocol for treatment requires that overdose patients be identified as soon as possible and closely questioned as to the time and amount of acetaminophen ingested. If the ingestion occurred within 24 hr of presentation, then a large bore tube should be passed to perform gastric lavage, and Mucomyst therapy should be commenced. A loading dose (140 mg/kg body weight) is given orally and followed at four l-hr intervals by 70 mg/kg, orally, for a further seventeen doses. While therapy is being administered, the blood level of acetaminophen should be determined by using one of the available spectrophotometric methods”g; if, when plotted on the nomogram,33 this indicates that the concentration of drug is in the range likely to lead to hepatotoxicity, then the full course of therapy should be completed. If the point falls below the toxicity line, then therapy can be discontinued. Patients who develop evidence of hepatotoxicity should be given full supportive measures as for severe acute viral hepatitis.“” The Rocky Mountatin Poison Center in Denver, Colorado may be contacted day or night (toll-free number 800-525-6115) to advise on any aspects of therapy. It should be recognized that the use of Nacetylcysteine in acetaminophen overdose is not yet an officially approved form of treatment, but such approval from the Food and Drug Administration is believed imminent.

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1980

Conclusions The investigations reported herein have firmly established acetaminophen hepatotoxicity as an outstanding example of “toxic metabolite” mediation of tissue damage in humans. It should be added, therefore, to a growing list of metabolite-mediated toxicities, including carbon tetrachloride hemethoxyflurane nephrotoxicity,‘z’-‘24 patotoxicity,“” salicylazosulfapyridine bone marrow toxicity,“’ etc. Since hepatotoxicity from acetaminophen is most commonly encountered in overdose situations where it clearly is dose-related (and predictable), it remains uncertain what relationship this particular example of liver injury in humans has to idiosyncratic (or nonpredictable) forms of drug-induced liver injury. This author, along with other workers in this area, is of the opinion that most types of nonpredictable drug-induced liver injury are mediated through nonimmunologic processes, of which toxic metabolite generation (and/or inadequate inactivation) appears the most likely.“” There is little objective data to support this hypothesis, however, just as there is little or no data to support a role for immunologic processes.126 Nevertheless, the reporting of acetaminophen-related liver injury in a small number of patients ingesting lesser amounts of the drug over protracted periods of time’“-‘6 succeeds in bringing the disorder closer to the area of idiosyncratic drug-induced liver injury. Accordingly, it will undoubtedly serve as a model for toxic drug interactions with the liver and encourage the scientific community to perform comparable chemical, pharmacologic, toxicologic, biochemical, and clinical investigations in the many other examples of drug-induced liver injury in humans. The lack of large numbers of affected patients and the absence of animal models may well impede rapid progress in their full resolution, but the acetaminophen example at least provides us with an awareness of the tools which are needed.

References 1. Zimmerman HJ: Clinical and laboratory manifestations of hepatotoxicity. Ann NY Acad Sci 104:954-987, 1963 2. Zimmerman HJ: The spectrum of hepatotoxicity. Perspect Biol Med 12:135-161, 1968 3. Zimmerman HJ: Hepatotoxicity. The Adverse Effects of Drugs and other Chemicals on the Liver. New York, Appleton-Century-Crofts, 1978 4. Miller EC, Miller AS: Mechanisms of chemical carcinogens: nature of proximate carcinogens and interactions with macromolecules. Pharmacol Rev 18805-838, 1966 5. Magee PN, Barnes JM: Carcinogenic nitroso compounds. Adv Cancer Res 10:163-246, 1967 6. Farber E: Biochemistry of carcinogenesis. Cancer Res 28:1859-1869, 1968

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