Clin Liver Dis 11 (2007) 525–548

Acetaminophen Hepatotoxicity Anne M. Larson, MD, FACP, AGAF Division of Gastroenterology, Hepatology Section, University of Washington, 1959 NE Pacific Street, Box 356174, Seattle, WA 98195-6174, USA

Acetaminophen (N-acetyl-p-aminophenol or APAP), a mild nonnarcotic analgesic and antipyretic agent, is widely used as a pain reliever and fever reducer. It is available in hundreds of single-ingredient and combination over-the-counter (OTC) products, and also in numerous prescription products. Its use has achieved great popularity, with more than 1 billion tablets sold annually in the United States [1]. APAP was first introduced for prescription use in 1955, and subsequently approved by the Food and Drug Administration (FDA) in 1960 as an OTC 325-mg immediate-release tablet [2]. A 500-mg immediate-release capsule and tablet were approved in 1973 and 1975, respectively [2]. Based on available literature, the FDA determined that acetaminophen was generally safe and effective, and that the maximum safe daily dosage should be no greater than 4 g in a 24-hour period. APAP is effective and safe when consumed as recommended (1–4 g per day). By 1966, however, there were reports of fatal and nonfatal hepatic necrosis following large suicidal ingestions [3–5]. It is now well documented that ingestion of a single dose of more than 10 to 15 g can cause severe or fatal liver injury secondary to massive hepatic necrosis [6]. There are emerging data that ingestion of daily doses of less than 10 g on consecutive days carries a risk for liver injury in some individuals [7]. It has also been suggested that APAP hepatotoxicity may occur in those ingesting therapeutic doses under certain conditions, such as fasting or alcohol use (see later discussion) [8–15]. APAP may even cause transient asymptomatic elevation in serum aminotransferases at therapeutic doses [16,17].

Epidemiology The American Association of Poison Control Centers notes that APAPrelated calls make up about 10% of all calls to poison control centers. E-mail address: [email protected] 1089-3261/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2007.06.006 liver.theclinics.com

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Between 1995 and 1999, APAP was the leading cause of poisoning in the United States [2,7,18]. Annually during this time period there were more than 56,000 emergency visits for APAP poisoning (intentional and unintentional), leading to more than 26,000 hospitalizations and about 458 deaths. Of these, unintentional overdoses accounted for more than 13,000 emergency visits with more than 2,000 hospitalizations and 100 deaths [18]. Although a decrease in calls was seen between 1995 and 1999 (111,175 to 108,102), there were 133,125 APAP-related calls generated in 2004 [19]. The proportion of APAP-induced acute liver failure (ALF) cases has alarmingly increased between 1998 (21%) and 2003 (51%) [20]. About half of these cases were unintentional poisonings [19,20]. APAP poisoning remains is a significant concern in other countries also [21–23].

Drug metabolism General Exogenous products are hepatically metabolized predominantly by two mechanisms (Fig. 1) [24]. During phase 1 metabolism, polar groups are added to the molecule being processed by way of oxidation, reduction, or hydrolysis. These reactions are catalyzed by the cytochrome P450 system of mixed function oxidases (CYP), a family of membrane-bound hemoproteins located in the smooth endoplasmic reticulum of the centrilobular (zone 3) hepatocytes. There are numerous CYPs that participate in the metabolism of exogenous compounds. Although many drugs are converted to active compounds by this process, toxic byproducts, such as free radicals, may also be formed [25]. During phase 2 metabolism, molecules are conjugated with glucuronic acid, sulfates, or glutathione (GSH) by way of the UDPglucuronyl transferases, sulfotransferases, and glutathione S-transferases.

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Fig. 1. Drug metabolism. Phase I reactions are catalyzed by the cytochrome P450s. Phase II reactions are catalyzed by one of several enzymes, such as UDP-glucuronyl-transferase, sulfotransferases, and glutathione S-transferases. The toxic metabolites that are formed can lead to hepatic injury.

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These enzymes are rarely responsible for toxic metabolite formation and their nontoxic products are generally ready for excretion [26]. Acetaminophen metabolism About 2% of APAP is excreted in the urine unchanged [27–30]. More than 90% is metabolized by way of conjugationdtwo thirds through glucuronidation (UDP-glucuronosyltransferases) and one third through sulfation (sulfotransferases) (Fig. 2) [29–31]. The nontoxic inactive conjugates are largely excreted in the urine and bile. Approximately 5% to 9% undergoes oxidative conversion by way of the CYPs (CYP1A2, CYP2A6, CYP2E1, CYP3A4) to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) [9,30,32–35]. CYP2E1 is the major source of NAPQI, but with less contribution from the remaining enzymes [30,36].

Fig. 2. Metabolism of acetaminophen. Most APAP is conjugated to either glucuronide or sulfate. That portion which is oxidized to NAPQI is further detoxified by glutathione transferase. If this system is overwhelmed, NAPQI binds to cellular targets leading to hepatocellular necrosis. (From Zimmerman HJ. Acetaminophen hepatotoxicity. Clin Liver Dis 1998;2:527; with permission.)

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NAPQI is a highly reactive two-electron species that can act as an electrophile or an oxidant. It is rapidly metabolized by conjugation to intracellular GSH forming a nontoxic APAP–GSH conjugate (3-[glutathioneS-yl]-APAP) [28,37,38]. Further processing leads to its urinary excretion as mercapturic acid and cysteine conjugates [27]. APAP is also oxidized by myeloperoxidase and the peroxidase function of cyclooxygenase-1 (COX-1), the clinical significance of which is unknown [27,39–41].

Acetaminophen hepatotoxicity APAP is an established dose-related hepatotoxin and can potentially lead to hepatocellular injury by three different mechanisms, individually or in combination. The most common method of toxicity is overdose (ingestion of more than 10 to 15 g in adults and 150 mg/kg in children), which overwhelms the hepatic detoxification process [42]. There are reports of toxicity occurring with doses less than 10 g and even at therapeutic doses [7,20,43–45]. Excessive CYP activation as a result of other medications or herbs may lead to increased free radical formation with the possibility of hepatocellular injury [46–48]. Depletion of GSH stores (by overdose, malnutrition [49,50], or alcohol ingestion [9,51]) results in the inability to detoxify many reactive metabolites and may increase risk for hepatotoxicity. The importance of this mechanism remains controversial [52,53]. The precise means of hepatocyte death remains speculative. The degree of hepatic toxicity correlates with the activity of the catalyzing enzyme systems and GSH availability. Therapeutic doses of APAP result in small quantities of NAPQI that are easily detoxified by GSH. Excessive doses of APAP lead to the saturation of the glucuronic acid or sulfate pathways, shunting more APAP into the CYP system. Increased metabolism of APAP by CYP2E1, in turn, increases the amount of NAPQI produced [54]. Glutathione stores within the liver are limited and may be depleted in an attempt to keep up with the increased NAPQI levels [37]. When GSH stores are reduced by 70% to 80%, the detoxification capacity of the liver is exceeded and NAPQI accumulates, thereby interacting with and destroying hepatocytes and other cells [55–57]. In the absence of GSH, covalent binding of NAPQI to the cysteine groups on hepatocyte macromolecules occurs forming NAPQI-protein adducts [58–60]. This process is the initial and irreversible step in the development of cell injury [61–63]. Glutathione depletion further contributes to cellular oxidant stress [27,64]. With NAPQI binding to critical cellular targets, such as mitochondrial proteins, mitochondrial dysfunction and loss of cellular ATP occurs [65,66]. The hepatocytes subsequently experience overall energy failure [67–70]. The ultimate result is alteration in calcium homeostasis, mitochondrial dysfunction with ATP depletion, DNA damage, and intracellular protein modification [28,62,69,71]. These events lead to necrotic cell death.

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It has been shown in rodents, however, that covalent binding to hepatic proteins in isolation does not cause hepatotoxicity [67,72,73]. There is a growing body of evidence suggesting that inflammatory mediators (eg, IFNg) trigger the innate immune system, leading to influx of NK/NKT cells, neutrophils, Kupffer cells, and macrophages that participate in the development and propagation of hepatocyte injury [74–77]. Controversy remains as to whether neutrophils aggravate this process [78,79]. It has therefore been proposed that acetaminophen toxicity occurs in two phases: a metabolic phase and an oxidative phase [80]. Factors influencing acetaminophen hepatotoxicity Age The metabolism of APAP is age dependent [81]. Infants and children process APAP predominantly by way of sulfation. Metabolism by glucuronidation increases over time and becomes the predominant pathway between ages 5 and 12 years [81,82]. Children less than 5 years of age seem to be less susceptible to APAP hepatotoxicity, possibly because of lower production of NAPQI and a greater degree of conjugation [8,81,83–85]. Overdose in juveniles and older populations may have an increased incidence of hepatotoxicity and hepatotoxicity may occur at lower doses [86–89]. Genetics Polymorphisms exist in the cytochrome isoenzymes that may contribute to diminished metabolism, lack of metabolism, or excessive metabolism of a compound [90]. The clinical relevance of these polymorphisms in the setting of APAP ingestion is unknown. Chronic liver disease Patients who have chronic liver disease who do not regularly consume alcohol are not at increased risk for APAP-induced liver injury [15,91]. CYP activity in patients who have severe liver disease is unchanged or reduced and does not seem to be inducible [91–93]. Data are mixed as to whether GSH is reduced or increased in the setting of chronic liver disease [91]. Alcohol (therapeutic misadventure) The role of alcohol in the generation of APAP hepatotoxicity remains contentious [38,52,94,95]. Acute alcohol intake may actually be protective because the alcohol competes with APAP for CYP [10,96–100]. Chronic alcohol ingestion modifies CYP2E1 activity and depletes GSH levels [52,101]. Chronic alcohol ingestion increases CYP2E1 activity twofold, an effect that lasts for up to 10 days following abstinence [12,102–104]. Alcohol also inhibits the rate of GSH synthesis leading to accelerated GSH turnover and it impairs mitochondrial transport of GSH (with sequestration within the mitochondria) [105]. Both of these features would suggest that

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hepatotoxicity in this setting could occur with lesser amounts of APAP. Poor nutrition in alcoholics could also contribute to decreased GSH [9,106,107]. Chronic alcoholics do not seem to be at increased risk for toxicity following a single time-point overdose, particularly if they are treated within 8 hours or are below the probable toxicity line on the Rumack-Matthew nomogram (Fig. 3 and later discussion) [108–110]. Smaller doses, however, used with therapeutic intent for pain complaints, have been reported to result in severe or even fatal disease in chronic drinkers [9,11–13,51]. Other investigators have not found an association between alcohol use and APAP hepatotoxicity [111,112]. Nevertheless, the FDA has issued an alcohol warning to patients taking APAP if they are using more than three drinks a day [113]. Drugs The evidence for a significant clinical impact of drug-induced CYP induction on APAP hepatotoxicity remains incomplete [114]. Anticonvulsants and antituberculous medications induce the CYPs [46,115,116]. Isoniazid and halothane can enhance CYP2E1 [117]. Phenytoin, carbamazepine, and phenobarbital induce CYP3A4 and increase production of NAPQI [46,118–120]. Phenytoin and phenobarbital have also been shown to inhibit APAP glucuronidation in human hepatocytes [121]. Zidovudine and trimethoprim-

Fig. 3. Rumack-Matthew nomogram. This nomogram shows the relationship between plasma acetaminophen concentration, time after drug ingestion, and the risk for hepatotoxicity. The thick diagonal line of possible hepatotoxicity represents a 25% likelihood of disease. (Adapted from Rumack BH, Matthews H. Acetaminophen poisoning and toxicity. Pediatrics 1975;55:873; with permission.)

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sulfamethoxazole lead to impaired glucuronidation by competing for glucuronyl transferase, shunting more drug to CYP2E1 [122]. Cimetidine, an inhibitor of CYP2E1 [123] in animals, may decrease the risk for toxicity; however, human studies have not supported this [124,125]. Patients should be questioned about use of herbal supplements and complementary medication use [126]. Many of these drugs are hepatotoxic themselves (eg, INH), and few clinically significant drug–APAP interactions have been well documented. Nutritional status Fasting, which contributes to depletion of GSH and induction of CYP2E1, has been reported to enhance APAP toxicity, particularly in the setting of chronic alcohol consumption [9,127,128]. Fasting also leads to glycogen depletion with decreased glucuronidation, in turn causing enhanced production of toxic metabolites [9,12]. In a mouse model of nonalcoholic steatohepatitis, hepatic steatosis inhibited CYP2E1 induction and protected against APAP-induced liver injury [129]. Both would suggest that nutritional status contributes to APAP hepatotoxicity. Recent reviews, however, have concluded that there is insufficient evidence to support the theory of malnutrition and increased toxicity [53,130]. Tobacco use Tobacco smoke contains several potent inducers of CYP1A2 and has been shown to induce oxidative metabolism [131–133]. A retrospective report found tobacco use to be an independent risk factor for mortality following APAP poisoning (odds ratio 3.64; 1.23–10.75) [134]. The risk did not depend on the quantity of tobacco consumed. Mortality was even greater in those smokers also consuming alcohol [134]. Autoprotection Despite the well-known dose-related relationship to hepatotoxicity, there are individuals who report chronically ingesting ‘‘toxic’’ doses of APAP without ill effect [135]. These patients are most often consuming combination narcotic/APAP products for pain relief and have consumed gradually increasing quantities of the product over time [136–138]. The mechanism of this tolerance is unclear. The phenomenon has also been demonstrated in rodents [138].

Clinical presentation Clinical stages Several distinct stages occur following excessive APAP ingestion. The first 24 hours following ingestion (stage 1) are characterized by nonspecific gastrointestinal irritation with nausea, vomiting, abdominal pain, anorexia,

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lethargy, malaise, and diaphoresis [96]. Pallor and mild hepatic tenderness may be present on physical examination [54,139]. If measured, the laboratory studies are typically normal, but mild liver enzyme elevations may be seen as early as 8 to 12 hours following ingestion [140]. Patients may not present for medical care, and these early symptoms usually subside over the course of this period. If seen, patients may be mistakenly considered recovered. The latent phase (stage 2) develops over the next 24 to 72 hours following ingestion. Patients often appear well, but subclinical and biochemical evidence of hepatotoxicity begins to appear. The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) start to increase. All patients who have hepatotoxicity develop elevated aminotransferases within 24 to 36 hours [140]. Patients may develop right upper quadrant pain and notice jaundice. Elevations in total bilirubin and prothrombin time (PT/ INR) occur. Nephrotoxicity and oliguria may develop during this stage. The hepatic stage (stage 3) develops 72 to 96 hours after ingestion. It is the phase of overt hepatocellular necrosis and death most commonly occurs during this time period [141]. Signs and symptoms vary depending on the severity of the liver injury, and if treated early this stage is minimal. Anorexia, nausea, vomiting, abdominal pain, malaise, and confusion (hepatic encephalopathy) may develop. Jaundice may appear or worsen and serum AST and ALT are severely elevated. The AST can be 10,000 IU/L or higher, and may be more elevated than the ALT. Levels up to 48,000 IU/L have been reported. The degree of aminotransferase elevation corresponds roughly to the degree of centrilobular hepatocellular damage. Elevation of the AST and ALT usually peaks by 72 hours after acute ingestion. Renal insufficiency occurs in more than 50% and is generally attributable to acetaminophen-induced acute tubular necrosis with a component of dehydration [139,142,143]. The exact mechanism of renal cellular injury is uncertain. Clinically, proteinuria, hematuria, and granular casts are seen [142]. Renal injury is unrelated to the degree of liver injury [144]. Hypophosphatemia secondary to renal phosphate loss may develop, even in the absence of liver damage. Other metabolic derangements may accompany this stage. Pancreatitis has been reported [145]. Hypoglycemia is a poor prognostic sign and is attributable to the damaged liver’s inability to mobilize glycogen stores and perform gluconeogenesis. There are also inappropriately high insulin levels seen [146]. Lactic acidosis usually presents more than 1 to 2 days after ingestion and is secondary to tissue hypoxia with poor hepatic clearance of lactate [147,148]. A PT/INR that continues to increase after days 3 to 4 is ominous and can be associated with up to 93% mortality [149,150]. Patients may develop progressive CNS symptoms of lethargy, confusion, and coma, and may require intubation. As encephalopathy progresses, cerebral edema develops and may result in cerebral herniation. Indicators of a poor outcome include development of acute liver failure, PT greater than 100 seconds, grade 3 or 4 encephalopathy, cerebral edema, renal failure, and metabolic acidosis (pH!7.3) (see later discussion). Death

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resulting from cerebral edema, multiorgan-system organ failure, or sepsis generally occurs 3 to 5 days following ingestion. Approximately 70% of patients survive acute liver failure and enter the recovery stage (stage 4) by 4 days to 2 weeks after ingestion. Most patients recover completely by 7 days, but recovery may be slower in those who were more severely ill [110]. Complete functional recovery can be expected. Differential diagnosis Although the history often leads to an accurate diagnosis, other causes of hepatotoxicity and ALF must be considered. Acute APAP hepatotoxicity is characterized by marked elevations in the aminotransferases, usually more than 3,000 IU/L. Other diagnoses to be considered include viral hepatitis, drug- or toxin-induced hepatitis, Reye syndrome, acute fatty liver of pregnancy, and ischemic hepatitis (‘‘shock liver’’). Alcoholic hepatitis and acute deterioration of chronic liver disease should be considered, but the aminotransferases are generally more modestly elevated (usually !500 IU/L). Chronic acetaminophen toxicity in a chronic alcohol user, however, may also present with markedly elevated enzymes. Histopathology Zone 3 (centrilobular) hepatocellular necrosisdthe classic hepatotoxic lesiondis characteristic of APAP injury. The centrilobular region is the area of greatest concentration of CYP2E1, and therefore the site of maximal production of NAPQI [151]. Also present may be passive congestion and scattered mononuclear and polynuclear lymphocytes. Once the patient recovers clinically, histologic improvement may take up to 3 months. Permanent liver damage is rare if the patient survives, with complete restoration of hepatic architecture the rule [152].

Treatment Assessment of overdose Prompt recognition of APAP intoxication is imperative to management and prevention of hepatocellular injury, liver failure, and death. Identifying patients who have intentionally taken substantial amounts of APAP is often less problematic than identifying those who have an unintentional overdose. The history of the amount of APAP ingested in both cases, however, is often unreliable. Patients may be unwilling or unable to admit to the amount or timing of the overdose. The vague or symptom-free latent phase may further confuse the clinical picture. Careful attention must be paid to the type of product ingested, quantity of APAP used, intent of the ingestion (intentional, unintentional), pattern of ingestion (single dose, repeated dosing), and other medications, drugs, herbs, or toxins consumed.

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All patients suspected of APAP ingestion should undergo prompt measurement of serum APAP concentration. APAP is rapidly absorbed from the gastrointestinal tract within 30 to 60 minutes and reaches peak plasma values within 1 to 3 hours [29]. Ideally, plasma APAP levels should be obtained between 4 and 24 hours following ingestion. A negative value does not preclude a significant ingestion and false positive levels have been seen in patients who have hyperbilirubinemia (O10 mg/mL) [153–155]. NAPQI-protein adducts are released into the circulation following hepatic injury and can be measured by high-performance liquid chromatography [156]. The serum concentration of these adducts correlates positively with serum AST activity [156]. Adducts can be detected even in the setting of negative serum APAP levels. Adducts have been identified in some patients who have indeterminate ALF and no reported history of APAP ingestion, suggesting that these cases were missed APAP overdoses [157]. Because measurement of serum NAPQI-protein adducts reliably identified acetaminophen toxicity, they may be a useful diagnostic test for cases lacking historical data or other clinical information. Unfortunately, their measurement is not routinely available in most centers. There is no correlation between the dose of APAP reportedly ingested and the serum APAP concentration measured [158,159]. The most widely accepted approach to determine the risk for hepatotoxicity following acute single time-point ingestion is to plot the serum APAP concentration on the Rumack-Matthew nomogram (see Fig. 3). The original nomogram is a semilogarithmic graph of serum APAP concentration versus time from ingestion [42]. Patients whose APAP concentration exceeds the lowest plotted line postingestion have a probable risk for hepatotoxicity. The FDA required a lower safety line (25% lower than the original) be used to allow for errors in plasma assays and estimated ingestion time [53,160]. Patients who have levels above this line are considered to be at possible risk for hepatotoxicity, and it is this nomogram that is most commonly used in the United States [160]. Treatment is recommended if serum levels of APAP exceed this concentration [96]. Controversy remains, however, over which line to use [161]. The nomogram was developed for single time-point overdoses. It cannot be used to accurately predict risk for hepatotoxicity if patients have taken multiple large doses over time, if the precise time of ingestion is unknown, or if patients have been taking an extended-release product [162]. These patients represent a significant portion of APAP overdoses, particularly in the United States [19,20,163]. There have been attempts to develop treatment algorithms in these settings [164,165]. Management APAP hepatotoxicity is a potentially treatable illness. In fact, serious hepatotoxicity is rare if the antidote, N-acetylcysteine (NAC, Mucomyst, Acetadote) can be administered within 8 to 10 hours following an acute

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overdose, regardless of the initial APAP concentration [160,166–168]. Once signs of ALF (eg, encephalopathy, coagulopathy) have developed, however, the risk for complications and death increase significantly [109]. If the patient presents within 4 hours following an acute ingestion, gastric lavage may be useful in decreasing the pill load [169]. During this time period, activated charcoal reduces APAP absorption by 50% to 90% in simulated overdose, and decreases serum APAP concentration [170,171]. It can be administered in a single dose of 1 g per kilogram body weight. Activated charcoal also reduces NAC absorption somewhat; however, this has not been shown to decrease its overall effectiveness [172]. NAC is a glutathione precursor and was first used for the treatment of APAP poisoning in 1977 [173,174]. Its mechanism of action is threefold. It increases glutathione stores, it acts as a glutathione substitute that binds with NAPQI, and it enhances sulfate conjugation [28,175–179]. NAC also has anti-inflammatory, antioxidant, inotropic, and vasodilating effects that may further benefit the patient [180–183]. N-acetylcysteine is the treatment of choice following an APAP overdose. It is indicated when any of the following conditions apply [184]:  Serum APAP concentration following acute ingestion is above the ‘‘possible hepatic toxicity’’ line on the Rumack-Matthew nomogram  Estimated single ingestion of greater than 150 mg/kg (7.5 g) in an adult, or there is a delay in acquiring a serum APAP concentration  Time of ingestion is not known and the serum APAP level is greater than 10 mg/mL  Laboratory evidence of any hepatotoxicity and a history of supratherapeutic APAP ingestion  Repeated supratherapeutic ingestion and a serum APAP concentration greater than 10 mg/mL It is best to err on the side of treating when not all the factors are clear, because NAC is relatively safe. Treatment should be started within 8 to 10 hours of an acute APAP overdose, but it is still indicated as late as 24 hours after ingestion [109,160,168,180]. In patients who develop no evidence of liver injury, NAC may be safely discontinued [185–188]. Current evidence suggests that even late administration of NAC is beneficial to patients who develop ALF [180–183]. In these patients, NAC treatment should be continued until clinical improvement occurs and the INR is less than 2.0 [34,182]. Oral administration The standard of care is a promptly started 72-hour course of oral NAC. This medication is given as a loading dose of 140 mg/kg followed by a maintenance dose of 70 mg/kg every 4 hours for a total of 17 doses (total dose 1330 mg/kg) [160]. If a dose is lost because of emesis, it must be repeated. If the 4-hour plasma APAP concentration is below the toxic level, further maintenance doses can be discontinued [160].

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Intravenous administration Intravenous NAC was first available in Europe and Canada, and approved for use in the United States in 2004 [182,184,189]. Its use is recommended in the following situations [184]:  Patients who cannot tolerate oral NAC because of intractable vomiting and for whom further delay would result in decreased NAC efficacy  Patients who cannot use enteral NAC (eg, corrosive ingestion, gastrointestinal bleeding, obstruction, or perforation)  Patients who have ALF, because intravenous NAC results in higher serum concentrations and has been shown to be beneficial in this setting [190]  Patients who are pregnant. The higher serum concentrations achieved may facilitate transplacental delivery to the fetus. The superiority of intravenous to oral NAC in pregnancy is theoretical, however. Placental transfer of NAC has not been shown to occur in animal studies [191]. The loading dose consists of 150 mg/kg over 15 minutes, followed by 50 mg/kg over the next 4 hours and 100 mg/kg over the 16 hours thereafter. The total dose received is 300 mg/kg over 20 hours. This dosing regimen remains controversial, and others have suggested a higher loading dose with 140 mg/kg followed by 70 mg/kg every 4 hours for 12 doses [192]. Oral and intravenous regimens show similar efficacy when started within 10 hours of acetaminophen overdose [160,166,192,193]. When treatment is delayed beyond 10 hours, however, the oral regimen may be more effective, predominantly because of its larger total dose (1330 versus 300 mg/kg) [160,166,167,192,194]. Oral NAC has a bad taste and pungent odor (rotten eggs). Its predominant side effects include nausea, diarrhea, and rash. Vomiting is common. Nausea and vomiting can be minimized by diluting the NAC solution with juice or soda, holding one’s breath while taking the medication, or nasogastric tube administration. Adverse events following infusion of intravenous NAC range from 0.2% to 21% and include nausea, flushing, rash, pruritus, bronchospasm, rhinorrhea, hemolysis, fevers, chills, angioedema, hypotension, and anaphylaxis [184,187,194–200]. Many of these side effects occur when the drug is used endotracheally as a mucolytic, and asthmatics may be at particular risk [200]. Most of the reactions are mild and resolve with discontinuation of the infusion. Occasionally, patients require further treatment (ie, antihistamine or epinephrine), and rare deaths have been reported [196,197]. Slowing the infusion rate of the initial dose does not decrease efficacy or lower the incidence of adverse events [168]. Cimetidine inhibits cytochrome P-450 and theoretically would be believed to decrease NAPQI formation; however, its use as an adjunct to NAC has shown no benefit [124,125]. Hemodialysis seems to have limited efficacy and does not prevent hepatotoxicity. Further care remains supportive.

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There has been a recent suggestion that patients who have APAP poisoning and lack of significant symptoms could be discharged home with instructions to self-administer NAC [201]. In the current climate of American health care, this may become more commonplace. Careful follow-up would be essential, however. Treatment of the therapeutic misadventure is more difficult. Patients who have been ingesting APAP over a period of time often present with fully developed liver injury or acute liver failure. Acute liver failure Patients who develop ALF should be managed in specialty centers where liver transplantation is available. Improved survival has been demonstrated in patients being managed at these centers [109]. NAC should be administered until transplantation or recovery, evidenced by an INR less than 2.0 [199,202]. It is inadvisable to use fresh frozen plasma to treat the coagulopathy, because the INR is an important prognostic indicator of patient status. Use of plasma is recommended only for line placement and active bleeding. Mortality More than 90% of all patients who have APAP poisoning can be expected to recover completely [109]. Patients at risk for hepatotoxicity and who are not treated with NAC have an overall mortality rate of 5.3% to 24% [32,166] and greater than 50% in those falling into the high risk category. The mortality rate is generally less than 1% if NAC is given in a timely fashion [160]. In patients who develop ALF who do not receive life-saving transplant, mortality approaches 30% [20,149,163]. Liver transplantation Orthotopic liver transplantation (OLT) is indicated in those who progress to severe ALF. APAP poisoning is the leading cause of drug-induced liver failure in the United States requiring OLT [163]. Because a significant number of patients survive without transplantation, however, it becomes necessary to determine who will ultimately die without transplantation. Prognostic factors have been identified that facilitate decision-making with regard to necessity of liver transplantation. Concern has been raised regarding support after transplantation and the risk that those who make suicide attempts may repeat the process, even after a transplant. Some centers rarely or never offer transplantation for acetaminophen poisoning for this reason. One of the most widely used prognostic models was developed at King’s College in London [109,203–205]. Because those who have APAP hepatotoxicity have a more favorable outcome, their prognostic model was divided accordingly (Fig. 4) [203]. Ninety percent of patients who had APAPinduced ALF whose blood pH failed to correct to greater than 7.3 with

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Acetaminophen-Induced ALF • Arterial pH <7.3 (irrespective of the grade of encephalopathy) OR • Grade III or IV encephalopathy AND • Prothrombin time >100 seconds AND • Serum creatinine >3.4 mg/dL (301 µmol/L)

All Other Causes of ALF • Prothrombin time >100 seconds (irrespective of the grade of encephalopathy) OR Any three of the following (irrespective of the grade of encephalopathy) 1. Age <10 years or >40 years 2. Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions 3. Duration of jaundice before onset of encephalopathy >7 days 4. Prothrombin time >50 seconds 5. Serum bilirubin >18 mg/dL (308 µmol/L)

Fig. 4. King’s College Criteria: criteria predictive of a poor outcome in the setting of hepatotoxicity from acetaminophen and from all other causes. (Adapted from O’Grady JG, Alexander GJM, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439.)

resuscitation perished without transplantation. For those who met the second set of three criteria, a mortality rate of 81% without transplantation was seen. These criteria have been validated in other cohorts [109]. In addition, it has been shown that patients who develop cerebral edema carry a mortality rate of greater than 90% [109]. The PT/INR is also a useful prognostic indicator of mortality in APAP-induced ALF, particularly if it continues to increase after day four [150]. Others have supported the measurement of coagulation factor V as the best prognostic indicator of survival [206,207]; however, this has generally been viewed as less accurate than the King’s College criteria [206], and its use remains controversial.

Summary Acetaminophen is a safe and effective medication, and given the vast amount consumed it carries a relatively low rate of hepatotoxicity. It can be used safely in patients who have chronic liver disease, although the maximum safe dose remains unclear. The complete mechanism of hepatocellular injury and cell death remains to be defined. Misuse of the product is the most frequent cause of hepatotoxicity. That nearly half of overdoses in the United States are unintentional is of significant concern, and patients should be educated regarding the potential for liver injury. Determining which patients are at risk for severe hepatotoxicity remains difficult and the development of assays for NAPQI-protein adducts may aid in identifying these individuals. Prompt medical intervention minimizes liver injury

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