Acetaminophen hepatotoxicity

Clin Liver Dis 7 (2003) 351 – 367

Acetaminophen hepatotoxicity Matthew Q. Bromer, DO, Martin Black, MD* Abdominal Organ Transplantation Program, and Division of Gastroenterology, Temple University School Of Medicine, Philadelphia, PA 19140, USA

Acetaminophen (known in the United Kingdom and elsewhere in the world as paracetamol) has been the quintessential predictable hepatotoxin in humans for at least three decades, and, astonishingly, more than 38 years after the first report of its hepatotoxic properties appeared [1] it remains unregulated and freely available in pharmacies and supermarkets around the world. It is the leading cause of overdose deaths in many western countries, is the most frequent cause of fulminant liver failure in the United States, and in a recent survey exceeded cases from other drugs and acute viral hepatitis combined [2]. The metabolic basis of the liver-cell necrosis has been explored in exquisite detail, and its principal antidote identified as a consequence of the early observations on pathogenesis. This was superbly described in a prior fascicle on the subject by the late Hy Zimmerman [3] whose contributions to our understanding of mechanisms of drug hepatotoxicity cannot be over-stated. Little new information on the mechanism of acetaminophen hepatotoxicity has been developed since that review but the authors have made an attempt in this piece to update Dr. Zimmerman’s chapter. Additionally, the authors have chosen to explore the current status of three controversial areas of acetaminophen—liver interactions. These comprise liver injury in the pediatric population, the alcohol-acetaminophen interaction, and acetaminophen autoprotection.

Mechanism of acetaminophen hepatotoxicity The basic features of acetaminophen hepatotoxicity were defined in a series of laboratory experiments performed by Mitchell and colleagues in the early 1970s [4– 10]. Liver cell injury results from hepatic metabolism of acetaminophen by way of cytochrome P450 enzymes to a reactive (electrophilic) metabolite called n-acetyl-quinoneimine (NAPQI), (Fig. 1). The metabolite is inactivated by * Corresponding author. E-mail address: [email protected] (M. Black). 1089-3261/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1089-3261(03)00025-4

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Fig. 1. Metabolism of acetaminophen including identification of metabolic sites affected by factors enhancing toxicity. A, Enhanced by increased dose; CYP450 induction by alcohol, isoniazid, phenobarbitol and possibly phenytoin. Also by inhibition of glucuronidation, by fasting or glucuronyl transferase inhibition. All of these lead to enhanced toxicity; B, inhibited by fasting and glucuronyl transferease deficiency (Gilbert’s syndrome) leads to increased toxicity; C, Inhibited by glutathione deficiency because of fasting or inhibited synthesis by alcohol intake. (From Zimmerman HJ. Acetaminophen. Clin Liver Dis 1988;2:523; with permission.)

glutathione in a process that may or may not require involvement of the enzyme glutathione reductase. If a large quantity of acetaminophen is ingested (such as with an intentional suicidal overdose) glutathione becomes depleted to the point whereby NAPQI reacts with critical elements in the liver-cell (whose precise identity was not discovered in early experiments) and cellular necrosis ensues [11]. Some species variability exists with respect to dose needed to elicit liver-cell necrosis but most species appear susceptible to the compound. Dose-response relationships in given species were impacted by pre-treatment of animals with agents that modified oxidative metabolism of acetaminophen or glutathione

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conjugation of NAPQI. Thus, phenobarbital or methylcholanthrene pre-treatment (which stimulate oxidative metabolism) led to enhanced liver-cell necrosis from a given acetaminophen dose, while cobaltous chloride or piperonyl butoxide (which inhibit oxidative metabolism) protected against normally toxic doses. Depletion of hepatic glutathione by starvation or administration of diethylmaleate similarly augmented hepatic necrosis by a given acetaminophen dose, while administration of glutathione [8] or n-acetylcysteine [12] protected against hepatotoxicity. It was a direct consequence of these experiments that led to emergence of cysteamine [13] and then n-acetylcysteine (Mucomyst1) as an effective treatment of acetaminophen overdose [12]. The precise nature of liver-cell death occurring as a result of NAPQI generation was not established in the early experiments and remains a subject of continued speculation. While necrosis could be correlated with the amount of covalently bound radio-labeled acetaminophen in the early studies, later studies showed that this did not always apply [14,15]. This led to recognition that the binding of the electrophilic metabolite involved interaction with non-critical receptors in the hepatocyte and the critical ones. It has been established that 5% to 10% of therapeutic quantities of acetaminophen is oxidized through the cytochrome P450 enzyme CYP2E1 [16]. This percentage is increased at the time the conjugation pathways become saturated and more NAPQI is generated. Although other P450 enzymes, such as CYP3A4 and CYP1A2 have been thought to contribute, pharmacologic studies have shown that the in vivo involvement of these two enzymes is negligible compared with CYP2E1 [17,18]. CYP2E1 knockout mice given APAP, ethanol, and isopentanol still developed hepatotoxicity suggesting the action of other CYP enzymes [19]. One of these others may be CYP2A6. Inhibition of CYP2A6, like CYP2E1, with disulfiram, 4-methylpyrazole, and diethyl-dithiocarbamate significantly decreased NAPQI formation [20]. The coadministration of sucrose and APAP (Pentazocine) in rats seems to increase alanine aminotransferase levels 20-fold compared with those receiving an equivalent dose of APAP alone [21]. The specific metabolic pathway through which this effect occurs is not known. NAPQI reacts either as an electrophile or as an oxidant. As an electrophile NAPQI depletes soluble and protein-bound thiols and attacks structures within the hepatocyte causing damage through unknown mechanisms. The ability of dithiothreitol to prevent the loss of protein-bound thiols implies their oxidation in the presence of NAPQI [22]. As an oxidant it reacts with soluble thiols such as glutathione to form glutathione disulfide while depleting NADPH [23]. The depletion of NADPH that occurs during the detoxification of NAPQI may be caused by the reduction in the transformation of glutathione disulfide to glutathione by glutathione reductase rather than from a direct oxidation of NADPH by NAPQI [22]. Chen et al [24] provided ‘‘direct evidence’’ for the formation of a labile ipso adduct between glutathione and NAPQI. This adduct was reversible back to NAPQI in neutral and basic conditions and may represent the form in which intercompartmental movement occurs. Once in a new compartment, oxidation or modification of protein thiols can take place.

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The greatest injury occurs in the centrizonal hepatocytes (Zone 3) that surround the hepatic venules, in which lies the greatest lobular concentration of CYP2E1 [25]. The formation of oxygen radicals that led to acetaminopheninduced hepatotoxicity within the different zones (1 to 3) is related to oxygen gradients, presence of thiols (glutathione), and amount of CYP2E1 and is well described in a recent review using carbon tetrachloride as an example [26]. Harman et al [23] showed the hepatocyte death caused by NAPQI was preceded by a collapse of the mitochondrial membrane potential and a depletion of ATP, similar to other mitochondrial poisons. Further study should continue to unravel the mechanisms of NAPQI formation, its transport within the hepatocyte, and the crucial steps that lead to hepatocellular injury.

Acetaminophen hepatotoxicity in the pediatric population The routine use of acetaminophen at therapeutic doses has been shown to be safe even in ill, hospitalized adolescents and children [27,28]. Infants and young children may also be less susceptible and at lower risk for developing toxic reactions to acetaminophen compared with adults [29,30]. Even so, there are differences in conjugation of acetaminophen metabolites as compared with adults, and typically delays in presentation and treatment that contribute to the significant risks of severe hepatocellular injury in the pediatric population [31]. Over a 4-year period acetaminophen was one of the most common and most costly specific agents implicated in poison related hospitalizations in children [32]. Although acetaminophen toxicity is one of the leading causes of fulminant hepatic failure in adults [33 –35] fatal overdoses in children are uncommon relative to the amount of acetaminophen used. The physician’s desk reference lists 100 different products that contain acetaminophen produced by 25 different companies [36]. The ease with which acetaminophen can be obtained may generate a feeling that acetaminophen cannot be harmful. Metabolism of acetaminophen in children is probably similar to adults, however, the development of acetaminophen hepatotoxicity in children may occur less frequently than in adults because children have greater glutathione supplies to bind NAPQI [37] or they have slower oxidative metabolism. Children with protein-calorie malnutrition may be unable to detoxify acetaminophen because of low glutathione stores [38]. Medicines that induce the P450 oxidative system, in addition to the decreased oral intake in the setting of an acute febrile illness both lead to hepatotoxicity similar to adults because of increased production of NAPQI and decreased glutathione stores, respectively. In a study of 44 children from 2 months to 10 years old who were referred with fever, however, a mean total daily acetaminophen dose of 92 mg/kg produced some abnormalities in liver function, but severe liver injury was rare. The maximum daily dose in a single patient in this study was 171 mg/kg [39]. The doses that are considered toxic are not well defined and may vary based on age, genetics, medicines, and other factors. Nutritional and drug-drug interactions are more

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likely than genetic differences in metabolism to contribute to toxicity at conventional doses of acetaminophen [28]. In 1997, regional poison control centers in the United States reported 94 fatal acetaminophen overdoses in children, most of which were associated with suicidal intentions. Of these 94 cases, only 25% occurred because of unintentional therapeutic error or intentional misuse without suicide intent [40]. There are two major patterns of acetaminophen abuse: first, the large single dose usually taken as a suicide gesture and second, the ‘‘chronic’’ ingestion of acetaminophen which occurs at the time patients take doses for ailments such as headache or fever that exceed therapeutic recommendations over days to weeks. The former usually ingest higher doses, have higher blood concentrations, and normally present earlier after ingestion making therapy with n-acetylcysteine more often effective. The latter group may ingest adult preparations (higher doses) or overthe-counter preparations unknowingly containing acetaminophen, present later in the development of hepatotoxicity and more often develop severe hepatotoxicity. Clinical features of toxicity and approach to therapy may be different in children less than 6 years of age compared with teenagers [39]. Younger children may present later because the ingestion is more likely accidental and there is delayed recognition of toxicity by the caregiver. A lack of understanding regarding the hepatotoxic effects by both children and parents may contribute to inappropriate dosing of acetaminophen, the failure to recognize those at risk, and the delay of diagnosis and treatment of intoxication. Teenagers are more likely to intentionally overdose with a large single ingestion. In an attempt to characterize demographic and clinical factors associated with pediatric acetaminophen overdose and identify risk factors of hepatocellular injury, Alander et al [41] performed a retrospective review of 322 pediatric charts from Kansas City and Seattle between 1988 to 1997. Patient characteristics are listed in Table 1. Intentional overdoses made up 43.5% of cases and were most often older and female. In contrast, the unintentional or dosing error overdoses were younger without significant sex predominance. Hepatic failure developed in four of 322 patients, one of whom died of multisystem organ failure and two others who were listed did not require liver transplantation. The risks that were associated with the development of hepatocellular injury in this study were between ages 10 to 17 years, presentation longer than 24 hours after ingestion, intentional overdose, ingested dose >150 mg/kg, and white race. Rivera-Pinera et al [42] reviewed 73 charts of pediatric patients who were admitted for acetaminophen overdose from several centers in California to determine the outcome of acetaminophen overdose in a selected pediatric population, to assess the factors that could have contributed to toxic effects in the liver, and to determine the role that liver transplantation played in management. All but one of these centers was a liver transplant center. Patient characteristics are listed in Table 1. Of the 73 patients, 28 had abnormal liver tests, all of which indicated severe injury. Six of the 28 underwent liver transplant, five of which were less than 10 years old. The other 22 underwent more ‘‘conservative measures,’’ including N-acetylcysteine therapy or close

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Table 1 Demographic characteristics in case series of pediatric patients with acetaminophen overdose Study Number of patients (N) Age Mean ± SEM Range

Alander 2000 [1]

Rivera-Penera 1997 [55]

James 2002 [22]

Heubi 1998 [18]

Mohler 2000 [44]

322

73

41

47

1039

7.9 ± 6.1 2 mo – 17 y

N/A < 10 y (14) 11 – 19 y (59)

15 1.5 – 17 y

N/A 5 wk – 10 y

2.3 all < 7 yrs

20 (27) 53 (73)

8 (20) 33 (80)

12 (29)d 27 (57)

519 (50) 520 (50)

36 (49) 37 (51)

29 (71) 12 (29)

N/A N/A

N/A N/A

389 ± 219a 284 ± 207b N/A N/A

N/A

N/A

N/A

96 – 819 23c

60 – 420 24

20 – 200 68

# h: 37 ± 29a # h: 6.9 ± 7.9b 47 (64)

N/A 2 – 24 h 41 (100)

1 d – 6 wks N/A 9 (19)

N/A N/A 0 (0)

0 (0)

7

0d

N/A

28 (38)

9

45 (96)

N/A

6 (8) 2 (2.7)

1 0 (0)

4 (8.5) 23 (49)

0 0

Sex, # (%) Male 114 (35.4) Female 208 (64.6) Race White 183 (56.8) Non-White 139 (43.2) Acetaminophen Dose (mg/kg ingested) Mean ± SEM 309 ± 838 Range 4 – 8,333 Acetaminophen Dose 106 > 150 mg/kg Time from ingestion to presentation > 24 hours 16 (5.4) < 24 hours 280 (94.6) N-acetylcysteine 82 (25.5) therapy, # (%) Mild Hepatocellular 23 (7.1) injury Severe Hepatocellular 4 (1.2) injury Transplantation, # (%) 0 (0) Death, # (%) 1 (0.31) N/A Not available. a < 10 y.o., b 11 – 19 y.o., c > 250 mg/kg, d 2 pts not available

monitoring. Five of the six transplanted patients survived, as did 21 out of 22 monitored patients. The death that occurred in the ‘‘conservative measures’’ group did so 10 days after admission despite N-acetylcysteine therapy. Factors that contributed to hepatotoxicity in this study included age < 10 years, delays in the onset of symptoms after a potentially toxic ingestion, delays in N-acetylcysteine treatment, unintentional multiple overdosing, concomitant use of P450-inducing medications, use of non-pediatric formulations, and failure to read or understand label instructions. James et al [43] performed a retrospective analysis of acute acetaminophen poisoning over 10 years from a single center in Arkansas. They performed sensitivity and specificity testing to determine which clinical findings best

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identified those patients with the lowest risk for acetaminophen-related hepatotoxicity after an acute overdose. Excluded were patients with drug concentrations below the possible ‘‘hepatotoxicity’’ line on the Rumack-Matthews nomogram, arrival >24 hours after ingestion, an unknown time of ingestion, chronic ingestion, or failure to have obtained coagulation and liver function tests within the first 24 hours. Forty-one charts fulfilled study criteria. Demographic characteristics are shown in Table 1. All patients were treated with N-acetylcysteine. Laboratory findings within the first 24 hours after ingestion were unable to predict the eventual development of hepatotoxicity. Normal PT, AST, or ALT values within 48 hours of ingestion was the best predictor of ‘‘low risk.’’ Their conclusions were that ‘‘all patients at risk for the development of acetaminophenrelated hepatotoxicity should be treated with NAC until at least 48 hours postingestion.’’ Treatment beyond this would be patient dependent. (A similar point was made by Schmidt et al [63] for overdoses in adults). Heubi et al [44] reviewed 47 cases of acetaminophen overdoses caused by ‘‘therapeutic misadventures’’ reported to the Food and Drug Administration and from one other hospital in Ohio. All patients were < 10 years of age. Cases of intentional overdose or single unintentional overdose, cases in which histologic findings were inconsistent with acetaminophen related toxicity, and cases where the role of acetaminophen was unclear were excluded. Patient characteristics were shown in Table 1. Dosage duration available for 33 patients ranged from 1 day to 6 weeks. Twenty-three patients were given adult preparations, many of whom were < 2 years of age. The mortality rate was high in this study as compared with others with less than half-surviving. Additionally, 4 of the 20 surviving patients underwent liver transplantation. Mohler et al [45] performed a prospective, observation study to determine whether pediatric patients with acute, mild to moderate acetaminophen exposures, treated with home monitoring alone develop signs and symptoms of hepatic injury. Cases included in this study were gathered from phone calls to a regional poison center over a 25-month period. Patients were all < 7 years of age and had an acute maximum possible acetaminophen exposure of \200 mg/kg. Previous decontamination, ingestion of extended-release preparations, medical issues that may increase susceptibility to hepatotoxicity, and indeterminable ingestions were excluded. Patient characteristics are listed in Table 1. All patients were managed from home. Review of signs and symptoms of early and late acetaminophen toxicity, a 4 to 6 hour follow-up call and a 72-hour follow-up call were included in the protocol. Of the 1039 patients, all patients did well without signs or symptoms of toxicity. Their conclusion was that acute acetaminophen exposures up to 200 mg/kg could be monitored at home because they ‘‘do not develop signs or symptoms of hepatic injury.’’ These analyses illustrate some of the important factors that will help in the prevention, recognition, evaluation, and treatment of pediatric patients with acetaminophen poisoning in the future. Death from acetaminophen, however still occurs in children. For this reason instructions for parents regarding appropriate pain and fever therapy should be carefully detailed.

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The American Academy of Pediatrics published a list of recommendations to parents regarding acetaminophen therapy [28]. It is important for the administering adult to understand the appropriate dose, frequency, duration of therapy, and the strength and formulation of acetaminophen to be given to each child. Substituting adult formulations should be avoided. Van der Marel et al [46] showed that acetaminophen plasma concentrations were higher in patients receiving rectal administration as compared with those receiving oral administration. Although oral administration did not always reach the 10 to 20 mg/L therapeutic levels, it is preferred over rectal administration unless specifically instructed by a physician. The time to peak levels and therefore the dosing interval (6– 8 hours) is different with rectal preparations when compared with oral preparations [47]. The perception that increasing doses has a better effect should be abolished. Many products contain acetaminophen and the use of more than one of these at a time may increase the risk for hepatotoxicity. Reading the labels on bottles containing acetaminophen for indicated dosages and frequency of dosages is always recommended. Pharmacists should be informed that children are taking acetaminophen before filling new prescriptions. Young children should have medicine administered by an adult caregiver. Treatment of children beyond 2 to 3 days should be done under the care of a physician. There are immediaterelease and sustained-release formulations that have different pharmacokinetics. Stork et al [48] demonstrated a 4.02 hour half-life in an extended-relief preparation compared with 2.56 hours for regular-release after a 75 mg/kg ingestion in a healthy subject. Cetaruk et al [49] showed a prolonged elimination phase of 5 to 14 hours after ingestion of toxic doses of acetaminophen. Ho et al [50] reported a case of a young woman who took Tylenol PM1 who presented 45 minutes after ingestion and was treated with activated charcoal and NAC. Her peak levels occurred about 10 hours after ingestion. Bizovi et al [51] reported a similar case where the patient also had a known gastric motility disorder and her peak serum levels were reached 14 hours after ingestion of long acting acetaminophen [52]. Refractory fever should be treated with other methods including alternating with ibuprofen or sponge baths. Symptoms of toxicity are vague therefore acetaminophen toxicity should be part of the differential diagnosis for multiple clinical presentations. A patients past medical history, list of medications, and the exact formulation, dosage, and route of administration of acetaminophen are important in providing expedient diagnosis and treatment in cases of pediatric overdose. Recognition by physicians of those medical conditions that may increase the risk for hepatotoxicity, including diabetes mellitus, obesity, malnutrition, prolonged fasting, family history of hepatotoxic reaction, or concomitant viral infection may help prevent delay in treatment. If hepatic injury is found and acetaminophen may be playing a role, early treatment with NAC is advised. Fever in itself makes patients uncomfortable and complete normalization of the temperature is not necessary and may not be possible. Education of parents and young children about the dangers of acetaminophen can help prevent hepatotoxicity and potentially be life-saving.

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Alcohol-acetaminophen interaction The existence of a true drug interaction occurring with acetaminophen and alcohol has been recognized since the late 1970s [53] and was characterized in much detail by Zimmerman and Maddrey [54] in their report in 1995. They assembled 165 cases culled from the literature or from a short-term registry and explored aspects of the interaction including patient demographics, amount of alcohol consumption, acetaminophen doses, clinical presentation, laboratory features, histopathologic descriptions, natural history, and outcomes data. They, thus, complimented the numerous prior literature citations and the few that followed. One might have concluded that the existence of such a drug interaction, referred to as ‘‘therapeutic misadventure’’ by Zimmerman and Maddrey [54], was an incontrovertible and scientifically based fact of clinical medicine. This has not been the case, however, and several reports have appeared in recent times in attempts to discredit the concept of an alcohol-acetaminophen interaction [56]. As discussed previously in this article, the hepatotoxicity that occurs from acetaminophen is related to its toxic metabolite, n-acetyl-quinoneimine (NAPQI). The increased production of NAPQI through the enhancement of the cytochrome P450 enzyme CYP2E1 or the depletion of glutathione, responsible for its detoxification, are recognized as the critical factors related to hepatotoxicity. Alcohol has been shown to modify the activity of CYP2E1 and deplete glutathione levels. This relationship thus provides a scientific explanation for the clinical reports of Zimmerman and Maddrey [54] and others who accept the concept of this alcohol-acetaminophen interaction. One of the most important factors in determining who develops hepatotoxicity is the relative dose and timing of ethanol and acetaminophen ingestion. Those who suggest that there is a lack of clinical data to support the alcohol-acetaminophen interaction, question the accuracy of the histories taken in the numerous case series and then proceed to draw definitive, yet opposite, conclusions from only a handful of clinical studies that themselves carry the same inherent problems [30,56]. Following an acute ingestion of alcohol, inhibition of CYP2E1 occurs as long as ethanol is present [55]. NAPQI formation was reduced after acute ethanol ingestion in both healthy volunteers and in animals with prior chronic consumption of ethanol [57 – 60]. After clearance of ethanol (750 cc wine, six 12 ounce cans of beer, or 9 ounces of 80 proof liquor) ingested in a single evening, the fraction of NAPQI was increased by 22% compared with a 5% increase in NAPQI after a dextrose infusion [61]. Chronic ethanol use increases CYP2E1 activity by a factor of two in actively drinking alcoholics and lasts for 5 to10 days after abstinence from ethanol [62]. In another study, this induction lasted 8 days following the cessation of alcohol [63]. This action suggests that there may be a window for acetaminophen hepatotoxicity in patients who are ingesting alcohol, both acutely and chronically. Kuffner et al [64] took patients entering an alcohol detoxification unit and gave subjects either placebo or 1000 mg of acetaminophen four times daily for 2 consecutive days after alcohol was eliminated. In these 102 patients transaminases did not exceed 200 U/L, but alcoholics with trans-

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aminases greater than 120 U/L were excluded. This cohort of chronic alcoholics may have had underlying liver disease and may have ingested a dissimilar amount of alcohol than those included in the study increasing their susceptibility to acetaminophen toxicity. The conclusion of these investigators, that acetaminophen dose reduction was unnecessary in alcoholics, can hardly be considered justified. Schiodt et al [65] studied 71 patients with acetaminophen overdose. Chronic alcohol use, morbidity, and mortality were more frequent among the 21 accidental overdoses. Specific synergy between acetaminophen and alcohol was ‘‘not established,’’ possibly because there was a lack of defined criteria of chronic alcohol abuse. Lauterberg BH et al [66] previously had shown that alcoholics had low glutathione levels suggesting that lesser amounts of acetaminophen were capable of depleting glutathione levels below the critical threshold concentration where hepatocellular necrosis can begin. Zhao et al [67] showed that 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial glutathione. Whitcomb and Block [68] described 49 patients who developed hepatotoxicity from acetaminophen, 21of whom took the toxic amount unintentionally. All patients were adjudged to have taken more than 4 g in 24 hours (the manufacturers’ maximum recommended dose), but 10 were believed to have taken between four and 10 g in that period. In these patients recent fasting was found to occur more commonly then recent alcohol use, whereas in patients taking in excess of 10 g in 24 hours, which was more common than recent fasting. Thus, their study emphasized the role of poor nutritional intake in addition to excessive alcohol ingestion as a factor in promoting enhanced hepatotoxicity of acetaminophen in some drinkers. It is likely that this increased toxicity reflects both decreased hepatic glutathione stores and, as Whitcomb and Block hypothesize [68], decreased glucuronide conjugation with enhanced metabolism down CYP450 pathways. In a curious trans-Atlantic counterpoint, Makin and Williams [69] reported on their experience with acetaminophen hepatotoxicity and alcohol in the United Kingdom. They reviewed 553 patients with acetaminophen hepatotoxicity seen in their Unit between January 1987 and December 1993. Five-hundred and fifteen cases were adjudged to be deliberate suicide ingestions while the other 38 cases were classified as ‘‘therapeutic misadventure’’ —the category referred to by Zimmerman and Maddrey [54] for the alcohol-acetaminophen interaction in the United States. Heavy alcohol consumption was associated with suicidal ingestion more often than therapeutic misadventure and was generally encountered in patients taking larger quantities of acetaminophen. Alcohol consumption was not considered a factor in outcome, need for inotropic support, occurrence of renal insufficiency, disturbance of prothrombin time, and need for liver transplantation. While this experience was not without interest, if should be recognized that it represents a substantially different population of patients than that assembled by Zimmerman and Maddrey [54]. Most of the US patients represented single case reports rather than the experience of a single large liver transplant center with a

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national reputation in the field of acetaminophen overdose management. It does not refute the compounded efforts of numerous US and other national investigators. It is also relevant that an analysis of Danish patients collected in similar fashion to the report by Makin and Williams [71] reached different conclusions. Using multivariate analysis of 209 patients with single-dose acetaminophen overdose in a single center, Schiodt et al [70] showed that chronic alcohol abuse was an independent risk factor in relation to the clinical course and outcome of such overdoses. In comparing the clinical features of 57 (27.3%) patients with chronic alcohol intake and 45 (21.5%) with acute ingestion, chronic alcohol intake was significantly and independently associated with development of hepatic coma, a lower prothrombin index, lower platelet count, higher creatinine, and higher bilirubin [70]. Not surprisingly, this analysis attracted the attention of Makin and Williams [71] who critiqued the investigators for failing to recognize depression in their cohort of patients and disagreed with their definition of severe liver injury. The multiple reports of severe hepatotoxicity in alcoholic patients justify the belief that a genuine drug-drug interaction exists [72]. Caution should be taken when administering acetaminophen to patients with regular alcohol use following the FDA guidelines ‘‘not to use the drug after consuming more than three alcoholic drinks daily’’ [73]. Efforts to minimize the risks of acetaminophen in the setting of chronic alcohol use appear misguided at best.

Large dose acetaminophen ingestion without liver injury—autoprotection Recent clinical experience with combination narcotic and acetaminophen preparations has led to recognition of the phenomenon of acetaminophen ‘‘autoprotection.’’ Individuals have been encountered who admit to abuse of such combinations as Percocet1 or Vicodan1 (hydrocodone and acetaminophen) and consume increasing quantities of tablets to a point where the daily ingestion of acetaminophen far exceeds these amounts normally associated with death from liver failure in individuals ingesting the drug in a single dose. In one particular individual, more than 65 g of drug were being ingested in a daily routine without there being any abnormalities of liver function [15]. Although the number of identified individuals pursuing such a pattern of abuse is small, authorities in the field suspect far more drug abusers might be guilty of this type of behavior (FDA, personal communication). Review of the world’s literature at the time the senior investigator became aware of the clinical scenario was limited to a handful of studies in laboratory animals [74,75] leading to initiation of a comprehensive investigation of the phenomenon in mice. (The stimulus to the investigation was the argument presented by agents of the Drug Enforcement Agency (DEA) that humans could not ingest such quantities of acetaminophen without suffering severe hepatotoxicity. Therefore, they insisted that the individuals had to be selling the drugs—a far greater sin than ingesting vast quantities of a tightly regulated medication in the minds of the federal authority).

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In an attempt to simulate the clinical circumstance, a regimen was conceived in which standard laboratory mice were subjected to progressively increasing daily intraperitoneal injections of acetaminophen beginning with a dose of 50 mg/kg body weight. This was gradually increased to a point where the mice received 350 mg/kg daily on the seventh day. Twenty-four hours later pre-treated mice and litter mates received a single intraperitoneal dose of acetaminophen. Calculation of the LD50 in litter-mates yielded a figure of 350 mg/kg. The LD50 in the pre-treated mice was 4 times this value at 1350 mg/kg thereby confirming that pre-treatment had rendered the mice immune to normally toxic doses. Histopathologic examination of the liver in pretreated mice at the end of the conditioning regimen revealed moderate liver-cell injury, hepatocellular hypertrophy and an inflammatory infiltrate, but nothing like the extensive necrosis observed in non-pretreated mice given a single dose of 500 mg/kg acetaminophen. Immunohistochemical staining for cysteinyl-acetaminophen protein adducts (resulting from covalent binding of NAPQI to intracellular targets) showed positive reaction in centrilobular hepatocytes of pretreated mice in the absence of administration of a toxic dose of acetaminophen. Following a toxic dose, however, the distribution of the adducts was quite dissimilar in pretreated and non-pretreated mice. In the latter animals, adduct staining was concentrated in the centrilobular hepatocytes (where the bulk of injury occurred) whereas in the pretreated animals it was less intense in the centrilobular area and extended uniformly into the normally spared regions adjacent to the portal tracts. This implied that the pretreatment regimen radically altered the location of acetaminophen metabolism and NAPQI formation after a large acetaminophen dose. Acetaminophen pre-treatment was associated with a constellation of changes in the liver that accounted for the failure of normally lethal doses of the drug to produce liver-cell necrosis. The cytochromes P450 in the centrilobular region of the lobule became down regulated and metabolism was shifted to the periportal regions. Glulathione production is more effective in this periportal zone and enhanced detoxification of NAPQI resulted (Fig. 1). Thus, prolonged acetaminophen ingestion is likely to alter the lobular distribution of acetaminophen metabolism, including NAPQI formation, in a manner, which allows the liver to inactivate NAPQI more efficiently. Liver-cell necrosis is thereby diminished. The adaptive changes that take place with the conditioning regimen also involve enhanced hepatocyte proliferation. APAP pre-treatment led to a greater than fourfold increase in cell proliferation, and its abrogation following pretreatment with colchicine led to reduction (but not disappearance) of protection from the pre-treatment regimen. Thus, this series of investigations confirmed the clinical impression that it is feasible to build tolerance to the hepatotoxic effects of APAP, and is consistent with patient claims of being able to consume quantities of acetaminophen that in susceptible individuals would cause massive hepatic necrosis. The investigation also pointed out the crucial importance of the zonal mismatch in NAPQI generation and glutathione conjugation in APAP overdose cases. The interplay of these events, which result in diminished hepatotoxicity of a customarily toxic dose of acetaminophen is reproduced in Fig 2.

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Fig. 2. Graphic representation of APAP pretreatment-induced cellular changes that lead to APAPautoprotection in mice. (From Shayiq RM, Roberts DW, Rothstein K, et al. Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: An explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology 1999;29:451; with permission.)

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How generalizable the observations are remain unclear but similar autoprotection has been recognized with carbon tetrachloride [76,77] and other hepatotoxins [78].

Summary Unlike the bulk of medications, described in this fascicle, that cause liver injury in humans, acetaminophen is a non-prescription drug that can be purchased in drug stores and supermarkets without a physician’s involvement. Death or severe injury is far more likely to occur with its use than with all the other medications considered in this study. Whereas attempts to control the quantity of drug ingested have been made in the United Kingdom and elsewhere in Europe, no comparable moves have taken place in the United States. The Food and Drug Administration claims to have concerns about the situation, [73] however, but has yet to make an effort to more closely regulate the marketing and distribution of the drug. It is to be hoped that this will not be the case by the time the next issue of Drug Hepatotoxicity is scheduled for this series.

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