Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis Authors Michael J Burns, MD Scott L Friedman, MD Anne M Larson, MD, FACP, AGAF Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2012. | This topic last updated: Oct 12, 2012. INTRODUCTION Since its clinical introduction in 1955, acetaminophen (N-acetyl-p-aminophenol; APAP; paracetamol) has become the most widely used analgesic-antipyretic in the United States. Acetaminophen is a component of hundreds of over-the-counter and prescription medications used worldwide. Although the drug is remarkably safe when taken at usual therapeutic doses, overdose of acetaminophen has been recognized since 1966 to cause fatal and nonfatal hepatic necrosis [1]. It is suspected that even repeated therapeutic or slightly excessive doses can be hepatotoxic in susceptible individuals, such as alcoholics [2-7]. Acetaminophen poisoning has become the most common cause of acute liver failure in the United States [8-12]. The pathophysiology, clinical manifestations, and diagnosis of acetaminophen intoxication will be reviewed here. Treatment of this condition is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".) EPIDEMIOLOGY Acetaminophen is widely available, and lay people commonly underestimate its toxicity. Not surprisingly, acetaminophen remains a major cause of overdose and overdose-related liver failure and death in the United States and many other countries [8,13]. A national network established to track cases of acute liver failure in the United States found that nearly half the episodes are attributable to acetaminophen, and such cases appear to be increasing as a percentage of all acute liver failure events [9,14]. Data from this group demonstrate that intentional (suicidal) and unintentional (chronic) poisonings account equally for cases of acetaminophen-associated hepatic failure [9]. A retrospective review of all cases of acetaminophen overdose that occurred over 10 years in the Calgary region of Canada noted the following [15]: Of 1543 patients, 70 (4.5 percent) developed hepatotoxicity and 15 died during their initial hospital admission. Risk factors for hepatotoxicity included unintentional overdose (OR 5.18; 95% CI 3.00-8.95), alcohol abuse (OR 2.21; 95% CI 1.30-3.76), and underlying liver disease (OR 3.50; 95% CI 1.57-7.77). PHARMACOKINETICS Acetaminophen is available in both immediate-release and sustained-release formulations (table 1). The therapeutic dose is 10 to 15 mg/kg per dose in children and 325 to 1000 mg per dose in adults, given every four to six hours, with a maximum recommended daily dose of 80 mg/kg in children or 4 g in adults. The toxic dose may vary among individuals according to baseline glutathione levels and other factors (see 'Clinical factors influencing toxicity' below). Section Editors Stephen J Traub, MD Michele Burns Ewald, MD Deputy Editor Jonathan Grayzel, MD, FAAEM

http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full#

Page 1 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

Toxicity is unlikely to result from a single dose of less than 150 mg/kg in a child or 7.5 to 10 g for an adult [16]. Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period [17,18]. Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peak aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 1000 IU/L) unless appropriately treated [17]. Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Serum concentrations peak between one-half and two hours after an oral therapeutic dose [19]. Peak serum concentrations are reached within four hours following overdose of immediate-release preparations, but may be delayed beyond four hours when drugs that delay gastric emptying (eg, opiates, anticholinergic agents) are coingested or following overdose of extended releases preparations [20-22]. Therapeutic serum concentrations range from 10 to 20 mcg/mL (65 to 130 micromol/L). Elimination half-lives range from two to four hours for all acetaminophen preparations, but the elimination phase may be delayed in onset for extended-release preparations due to prolonged tablet dissolution and absorption [21,23]. Half-lives greater than four hours have been noted in patients with hepatotoxicity [24]. BIOCHEMICAL TOXICITY At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates, which are then excreted in the urine [19,25,26]. Approximately 2 percent is excreted in the urine unchanged. The remaining acetaminophen is metabolized via the hepatic cytochrome P450 (CYP2E1, CYP1A2, CYP3A4 subfamilies) mixed function oxidase pathway into a toxic, highly reactive, electrophilic intermediate, N-acetyl-pbenzoquinoneimine (NAPQI) (figure 1) [5,26-29]. Appropriate acetaminophen doses produce a small amount of NAPQI which is rapidly conjugated with hepatic glutathione, forming nontoxic cysteine and mercaptate compounds that are excreted in the urine [25,30]. However, with toxic doses of a acetaminophen the sulfation and glucuronidation pathways are saturated, and more acetaminophen is metabolized to NAPQI via the cytochrome P450 enzymes [31]. When hepatic glutathione stores are depleted by approximately 70 to 80 percent, NAPQI begins to react with hepatocytes, and injury ensues [17,25,32,33]. NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, forming NAPQI-protein adducts [34-36]. This process is irreversible and leads to oxidative injury and hepatocellular centrilobular necrosis [37-39]. Although not fully characterized, lipid peroxidation and mitochondrial injury likely play a role in the progression of hepatocellular injury [14,40]. In addition, it appears that the release of cytokines and reactive nitrogen and oxygen species from damaged hepatocytes also play a role in the spread of hepatic injury. Cytokine release from hepatocytes may initiate a secondary inflammatory response from Kupffer cells and other inflammatory cells, extending the zone of hepatic injury [41-45]. This secondary injury occurs during stage II of clinical toxicity. (See 'Clinical manifestations' below.) CLINICAL FACTORS INFLUENCING TOXICITY Liver damage from acetaminophen ingestion can occur in four circumstances: Excessive intake of acetaminophen Excessive cytochrome P450 activity Decreased capacity for glucuronidation or sulfation Depletion of glutathione stores A number of factors may influence the propensity of acetaminophen to cause hepatotoxicity through the mechanisms listed above, including concomitant use of alcohol or other drugs, comorbid illnesses, advancing age, genetic makeup, and nutritional status [39].
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 2 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

Acute alcohol ingestion Acute alcohol ingestion is NOT a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for CYP2E1 and, thereby, decreasing the amount of NAPQI produced [46-49]. Chronic alcohol ingestion The role of chronic alcohol ingestion in acetaminophen-induced hepatotoxicity remains contentious. Chronic alcohol ingestion increases CYP2E1 activity two-fold and depletes glutathione levels [3,50,51]. Single overdose Chronic alcoholics do NOT appear to be at increased risk compared with nonalcoholics for developing hepatotoxicity following a SINGLE overdose of acetaminophen and management need not be altered for this patient group [18,52]. In one multicenter study of 2540 patients with acetaminophen overdose, chronic alcohol use did not increase the incidence of hepatotoxicity in low-risk patients (those treated with NAC within eight hours of ingestion or with acetaminophen concentration less than the probable hepatic toxicity line of the original Rumack-Matthew nomogram) (figure 2) [53]. In another report of 560 patients with severe acetaminophen-induced hepatotoxicity, a history of excessive alcohol consumption was not associated with a significantly worsened prognosis [18]. There is a single reported case of a chronic alcohol user in whom hepatotoxicity developed despite a low predicted risk for this complication by the modified Rumack-Matthew nomogram [54]. Multiple overdoses In contrast to chronic alcoholics with an isolated ingestion, chronic alcoholics appear to be at increased risk for hepatotoxicity following ingestion of multiple supratherapeutic doses of acetaminophen [2-7,55,56]. Delayed recognition of toxicity and continued use of the drug likely account for much of the morbidity in this patient population [7]. Alcohol acts at least in part by induction of CYP2E1, which results in the shunting of a greater fraction of acetaminophen through the CYP2E1 pathway and enhanced generation of NAPQI [50,51]. The net effect is an increased clearance rate of acetaminophen [57] and associated increased risk for hepatotoxicity. (See "Pathogenesis of alcoholic liver disease".) In addition to increased CYP2E1 pathway activity, several other factors may predispose alcoholics to severe acetaminophen-induced hepatotoxicity. The chronic alcoholic is more often malnourished, more likely to have a period of recent fasting, and more likely to have depleted hepatic glutathione stores than the nonalcoholic, all of which predispose to hepatic injury [5,56,58-60]. Chronic alcoholics may also have a decreased capacity to synthesize a mitochondrial glutathione transport protein, thus enhancing susceptibility of mitochondria to NAPQI [58,61]. The effect of chronic ethanol ingestion in conjunction with repeated, therapeutic doses (up to 4 g/day) of acetaminophen is controversial. The question of increased risk was raised in one report of 161 regular users of alcohol who developed hepatotoxicity following acetaminophen ingestion with therapeutic intent [3]. Although according to patient reports 54 percent had ingested 6 grams or less per day and 30 percent had taken less than 4 g/day, the overall mortality rate reached 20 percent [3]. Despite this concerning finding, there is no evidence from prospective controlled trials that therapeutic doses of acetaminophen cause hepatotoxicity in chronic alcohol users [7,52,60-64]. In one prospective, double-blind, randomized study of 201 alcoholics given maximal therapeutic doses (total 4 g/day) or placebo for two days showed no statistical difference in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentrations [64]. Similarly, a smaller controlled prospective study of 20 patients with chronic liver disease (including alcoholic cirrhosis) did not develop hepatotoxicity when given acetaminophen at 4 g/day for two weeks [63]. Chronic liver disease Patients with chronic liver disease who do not regularly ingest alcohol do NOT appear to be at increased risk for acetaminophen-induced hepatic injury [7,63,65]. Although the acetaminophen elimination half-life in this patient population may be prolonged, accumulation of the drug does not occur with repeated administration [63]. More importantly, cytochrome P450 enzyme activity is low and cannot be induced in this patient population, which
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 3 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

confers hepatoprotection following overdose [66]. Medications Concomitant use of drugs that induce CYP2E1 enzymes can cause hepatotoxicity in the absence of overt acetaminophen overdose, and may worsen the outcome of an intentional overdose. Examples of medications which alter CYP2E1 activity include anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) and antituberculosis drugs (eg, isoniazid and rifampin) [65,67,68]. Drugs such as trimethoprim-sulfamethoxazole and zidovudine may potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways, resulting in increased CYP2E1-dependent metabolism of acetaminophen [69]. Herbal supplements may potentially amplify acetaminophen-induced injury [70]. Patients should be questioned specifically about the use of herbal supplements since they are widely used, but often not mentioned during a routine medical interview. Nutritional status Malnutrition and a period of fasting may predispose to acetaminophen hepatotoxicity, but evidence is limited [5,61,71]. Hepatic glucuronidation is normally dependent upon hepatic carbohydrate reserves. In the fasting or malnourished state, glucuronidation of acetaminophen is reduced which leads to enhanced microsomal metabolism and increased production of the toxic NAPQI metabolite [5,72,73]. Depleted glutathione stores, also associated with the fasting and malnourished state, compromise detoxification of NAPQI and predispose to hepatic injury [74]. In one study, recent fasting appeared to be increase hepatotoxicity in patients with a moderate overdose (4 to 10 grams of acetaminophen within 24 hours) [5]. Patients at greatest risk appear to be those that consume repeated excessive doses, not a single overdose. Genetics Polymorphisms exist in the cytochrome isoenzymes that contribute to diminished or excessive oxidative metabolism of acetaminophen [75,76]. The clinical relevance of these polymorphisms is unknown. Impaired glucuronidation secondary to Gilbert's syndrome appears to enhance toxicity [77]. Age Older patients appear more likely to develop hepatotoxicity following acute overdose whereas children less than five years old appear less susceptible to toxicity [14,78-80]. Young children are probably protected via an increased supply and regeneration of glutathione and greater activity of conjugation enzymes [81,82]. However, following repeated excessive acetaminophen doses, young children are no less susceptible to hepatic injury [83]. Tobacco Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism [84,85]. One review found tobacco use to be an independent risk factor for mortality following acetaminophen overdose independent of the amount of tobacco consumed [86]. Mortality was greatest in smokers who also drink alcohol. Pattern of use The pattern of acetaminophen use is an important consideration when assessing the risk for subsequent toxicity. Patients who accidentally poison themselves with repeated excessive doses in an attempt to relieve pain or treat fever are more likely to have established risk factors for hepatotoxicity (eg, fasting, chronic ethanol use) and are more likely to present late, when the toxic effects of acetaminophen are already established. In one study of 71 patients admitted with acetaminophen toxicity, patients in the accidental-overdose group had higher rates of severe hepatotoxicity, hepatic coma, and death than those who attempted suicide, even though the latter had ingested more acetaminophen [6]. DIFFERENTIAL DIAGNOSIS Unlike most other causes of hepatitis, acetaminophen-induced hepatitis is acute in onset, progresses rapidly, is characterized by marked elevation of plasma aminotransferases (>3000 IU/L), and is associated with a rising PT. Chronic acetaminophen poisoning in the alcohol user is also characterized by markedly elevated aminotransferases (>3000 IU/L), combined with hypovolemia, jaundice, coagulopathy, hypoglycemia, and acute renal failure in greater than 50 percent of these patients [2,3,28,87]. Other diagnoses that should be considered in patients with evidence of hepatic dysfunction include alcoholic hepatitis, other drug- or toxin-induced hepatitis, viral hepatitis, hepatobiliary disease, Reye's syndrome, and ischemic hepatitis
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 4 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

("shock liver"), which usually follows a period of severe prolonged hypotension. (See "Approach to the patient with abnormal liver function tests".) Dramatic elevations in the serum total bilirubin level (>10 mcg/mL) can result in a false positive serum assay for acetaminophen in patients with acute viral hepatitis, which may delay recognition of the underlying problem [88]. (See "Overview of hepatitis A virus infection in adults" and "Serologic diagnosis of hepatitis B virus infection".) Unlike acute acetaminophen poisoning, alcoholic hepatitis and chronic acetaminophen poisoning in the alcohol user have an AST to ALT ratio greater than two [2,3]. Aminotransferase values are also markedly lower in patients with alcoholic hepatitis, and rarely exceed 500 IU/L. (See "Clinical manifestations and diagnosis of alcoholic liver disease" and "Patterns of plasma aspartate and alanine aminotransferase levels with and without liver disease".) CLINICAL MANIFESTATIONS The initial manifestations of acetaminophen poisoning are often mild and nonspecific, and do not reliably predict subsequent hepatotoxicity [52,89]. However, physicians must promptly recognize acetaminophen poisoning in order to minimize subsequent morbidity and mortality. The clinical course of poisoning is often divided in four sequential stages. Stage I (0.5 to 24 hours) In the first 24 hours after overdose, patients often manifest nausea, vomiting, diaphoresis, pallor, lethargy, and malaise. Some patients remain asymptomatic. Laboratory studies are typically normal. Central nervous system depression and elevated anion gap metabolic acidosis are rarely seen after massive acetaminophen overdose [90]. Such symptoms in acetaminophen-poisoned patients are usually due to coingestants. Stage II (24 to 72 hours) From 24 to 72 hours after ingestion, the clinical and laboratory evidence of hepatotoxicity and, occasionally, nephrotoxicity become evident. (See 'Acute kidney injury (acute renal failure)' below.) Initially, stage I symptoms usually resolve and patients appear to improve clinically while subclinical elevations of hepatic aminotransferases (AST, ALT) occur. Occasionally, aminotransferases may rise as early as 8 to 12 hours after acetaminophen ingestion in severely poisoned patients [91]. Of patients that develop hepatic injury, over one half will demonstrate aminotransferase elevation within 24 hours and all have elevations by 36 hours [91]. As stage II progresses, patients develop right upper quadrant pain, with liver enlargement and tenderness. Elevations of prothrombin time (PT) and total bilirubin, oliguria, and renal function abnormalities may become evident. Acute pancreatitis has been described in case reports [92,93]. In some patients, concurrent alcohol use contributes to both hepatotoxicity and pancreatitis [94]. Stage III (72 to 96 hours) Liver function abnormalities peak from 72 to 96 hours after ingestion. The systemic symptoms of stage I reappear in conjunction with jaundice, confusion (hepatic encephalopathy), a marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis (picture 1). Signs of severe hepatotoxicity include plasma ALT and AST levels that often exceed 10,000 IU/L, prolongation of the PT or INR, hypoglycemia, lactic acidosis, and a total bilirubin concentration above 4.0 mg/dL (primarily indirect). Acute renal failure occurs in 10 to 25 percent of patients with significant hepatotoxicity and in more than 50 percent of those with frank hepatic failure [28,95,96]. Death most commonly occurs in this stage, usually from multiorgan system failure [28]. (See 'Acute kidney injury (acute renal failure)' below.) Stage IV (four days to two weeks) Patients who survive stage III enter a recovery phase that usually begins by day four and is complete by seven days after overdose [52]. Recovery can be slower in severely ill patients; symptoms and laboratory values may not normalize for several weeks. Histologic changes in the liver vary from cytolysis to centrilobular necrosis. The centrilobular region (zone III) is preferentially involved because it is the area of greatest concentration of CYP2E1 and therefore the site of maximal production of NAPQI. Histologic recovery lags behind clinical recovery and may take up to three months. When recovery occurs, it is complete; chronic hepatic dysfunction is not a sequela of
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 5 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

acetaminophen poisoning. Acute kidney injury (acute renal failure) The incidence of renal dysfunction is related to the severity of the acetaminophen ingestion. Renal impairment has been estimated to occur in less than 2 percent of all patients (including those with minimal disease), 5 percent of cases with liver involvement but no hepatic failure, 10 percent of severe poisonings, and as many as 53 percent of cases with acute hepatic failure [96,97]. It is possible in the last setting that a hepatorenal-type syndrome, as well as direct toxicity, contributes to the development of renal failure. Acute kidney injury is manifested by elevations of blood urea nitrogen and creatinine along with proteinuria, hematuria, and granular and epithelial cell casts on urinalysis. Acute kidney injury is due primarily to acute tubular necrosis [87,98]. Vascular endothelial damage also can occur, so that both direct toxicity and ischemia may contribute to the tubular injury [98]. Renal function spontaneously returns to the previous baseline within one to four weeks, although dialysis may be required during the acute episode [96]. There is no evidence that acetylcysteine, which is given to minimize hepatotoxicity, has any protective effect on the kidney. DIAGNOSIS General approach and serum acetaminophen concentration A serum acetaminophen level must be obtained in every patient suspected of an intentional overdose. The general approach to any poisoned patient should include the following elements: Whenever possible, evaluation should include identification of the agents involved, assessment of severity, and prediction of toxicity. In all patients with suspected acetaminophen overdose, a history should be obtained to elicit the dose, intent of use (ie, suicidal or not), pattern of use (eg, single or repeated doses), and time of the ingestion, the presence of coingestants, and the existence of comorbid conditions that may predispose to the development of hepatic injury (eg, alcohol use, Gilbert's disease, anticonvulsant drug use, recent fasting). (See 'Clinical factors influencing toxicity' above.) All patients with a clear history of acetaminophen overdose should undergo measurement of serum acetaminophen concentration. If any doubt exists about the time of ingestion, a serum concentration should be obtained immediately at the time of presentation. A serum concentration should also be obtained four hours following the time of acute ingestion or presentation. In those with established toxicity, or those predicted to develop toxicity based on history and initial serum acetaminophen concentration, additional laboratory tests should include electrolytes, BUN and creatinine, serum total bilirubin level, prothrombin time with INR, AST, ALT, amylase, and urinalysis. In patients with intentional ingestions or unreliable histories, toxic screening of blood and urine for other ingested drugs should be performed. (See "General approach to drug poisoning in adults".) Management consists of supportive care, prevention of drug absorption, and, when appropriate, the administration of antidotes and enhancement of drug elimination. Treatment of acetaminophen poisoning is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".) and also (see "Decontamination of poisoned adults" and "Enhanced elimination of poisons"). Evaluation after acute overdose The risk of toxicity is best predicted by relating the time of ingestion to the serum acetaminophen concentration. The dose history should not be used as studies have found no correlation between the amount of acetaminophen reportedly ingested and the serum concentration measured [99,100].
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 6 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration should be drawn four and 24 hours after presentation. If the ingestion was more than four hours prior to presentation, it should be drawn immediately. The level should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC therapy (figure 3) [101]. Serum concentrations drawn before four hours may not represent peak values, and should not be used [52,102]. The original nomogram, based on large numbers of overdose patients not treated with antidote, relates serum acetaminophen concentration to the time of ingestion as a predictor of hepatotoxicity (figure 2). Without antidotal therapy, patients with serum acetaminophen concentrations above the line joining 200 mcg/mL (1320 micromol/L) at 4 hours and 25 mcg/mL (165 micromol/L) at 16 hours ("probable hepatic toxicity") have a 60 percent incidence of severe hepatotoxicity (AST greater than 1000 IU/L) and a mortality rate of 5 percent [17,103]. Untreated patients with serum acetaminophen concentrations above the line joining 300 mcg/mL (1980 micromol/L) at 4 hours and 37.5 mcg/mL (250 micromol/L) at 16 hours ("high hepatic toxicity") have a 90 percent incidence of severe hepatotoxicity and a mortality rate of up to 24 percent [17,103]. As originally reported, patients with serum acetaminophen concentrations below the "probable hepatic toxicity" line did not develop severe hepatotoxicity and no fatalities were reported [17,101,103]. Patients in the United States with serum acetaminophen concentrations above the line connecting 150 mcg/mL (990 micromol/L) at 4 hours and 18.8 mcg/mL (125 micromol/L) at 16 hours are considered at "possible risk" for hepatotoxicity and treatment with NAC is standard (figure 3) [46,104]. This modified treatment line is 25 percent lower than the original treatment line ("probable hepatic toxicity"), which is still used in Australia, Canada, and Great Britain. This margin of safety was created to allow for variations in acetaminophen measurements among laboratories and possible errors in the estimated time of ingestion. The incidence of nomogram failure using the modified line is extraordinary small [54]. The 25 percent margin of safety also likely protects susceptible patients who are at higher risk for developing hepatotoxicity (eg, alcohol users). This is no evidence to support lowering the treatment line further for these patients, as suggested by some authorities [28,105,106]. Even with NAC treatment, severe hepatic toxicity (AST >1000 IU) may occasionally occur when patients have serum acetaminophen concentrations below the "possible hepatic toxicity" line. In one study of 2023 patients treated with oral NAC for acute acetaminophen overdose, the incidence of severe hepatotoxicity was 0 to 3 percent for those patients with serum acetaminophen concentrations below the "possible hepatic toxicity" line [61,104]. There were no deaths in this group of treated patients [104]. There is presently insufficient experience to know whether the Rumack-Matthew nomogram can accurately assess risk following acute overdose of sustained-release acetaminophen products. Some authorities (including the manufacturer) recommend that both a four- and eight-hour serum acetaminophen concentration be measured and treatment with NAC initiated if either concentration is above the "possible hepatic toxicity" line of the nomogram [21,107]. It is likely that a single acetaminophen concentration plotted on the nomogram and below the treatment line is adequate to exclude the need for NAC treatment [52]. Until more clinical experience has been gained, our recommendation is to follow the conservative approach of the manufacturer. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".) Evaluation after repeated (chronic) overdose Diagnosis of chronic acetaminophen intoxication is often difficult and requires the combination of an astute history and recognition of typical clinical and laboratory abnormalities. Signs and symptoms are insidious in onset, often nonspecific, and easily confused with alternative diagnoses (eg, viral syndrome). When inquiring about potentially toxic drugs, clinicians should ask about acetaminophen, including specific questions about dosing and the pattern of use. Acetaminophen serum concentrations are frequently therapeutic in the chronic overdose population and concentrations do not correlate with toxicity as with the acute overdose [3,6,55,108]. When the diagnosis of chronic acetaminophen intoxication is suspected, the goal of evaluation is to identify patients who need NAC treatment based upon a combination of historical, clinical, and laboratory data. Patients are at increased risk for developing acetaminophen-induced hepatotoxicity if they have any of the following findings:
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 7 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

Ingestion of greater than 7.5 to 10 g of acetaminophen over 24 hours, or ingestion of greater than 4 grams over 24 hours AND have an increased susceptibility to hepatotoxicity (eg, chronic alcohol use, fasting, use of P450inducing drugs) [16,52]. Liver tenderness, jaundice, or are ill-appearing. Supratherapeutic acetaminophen concentrations (greater than 20 mcg/mL, or 130 micromol/L). Patients with a history of chronic, excessive acetaminophen ingestion should be considered to have acetaminophen-induced hepatotoxicity when aminotransferases are elevated, regardless of the measured serum acetaminophen concentration. Treatment with NAC is recommended for all patients with liver tenderness, elevations of aminotransferases, supratherapeutic serum acetaminophen concentrations (greater than 20 mcg/mL, 130 micromol/L), and those with history of excessive ingestion, risk factors for toxicity, and acetaminophen concentrations >10 mcg/mL (65 micromol/L). If a patient has a detectable acetaminophen concentration but is without signs, symptoms, or risk factors for toxicity and without elevations of aminotransferases, then treatment is likely not necessary [52]. If the serum acetaminophen concentration is undetectable and aminotransferases are normal, NAC therapy is not necessary. Treatment is clearly recommended if serum acetaminophen concentrations are potentially toxic by the nomogram with respect to the time of the last dose. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".) ADDITIONAL RESOURCES To obtain emergent consultation with a medical toxicologist, call the United States Poison Control Network at 1-800-222-1222, or access the World Health Organization's list of international poison centers (www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html). TREATMENT The management of acetaminophen overdose, including antidotal treatment with N-acetylcysteine (NAC), is discussed elsewhere. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".) PROGNOSIS The outcome of acetaminophen intoxication is nearly always good if the antidote, N-acetylcysteine (NAC), is administered in a timely fashion. No deaths have been reported in any of the large studies of acetaminophen overdose provided NAC was given within 10 hours of ingestion, regardless of the initial serum acetaminophen concentration [103,104,109]. As an example, one study of 333 consecutive acetaminophen overdose cases found that hepatotoxicity occurred in only 4 percent of patients and mortality was less than 1 percent when NAC was rapidly administered [110]. Thus, when fulminant hepatic failure and death occur from acetaminophen poisoning, they result from a delay in seeking medical attention, in recognition of poisoning, or in the institution of appropriate therapy. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Acetaminophen poisoning (The Basics)") SUMMARY AND RECOMMENDATIONS Important elements of the presentation and diagnosis of
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 8 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

acetaminophen overdose are described below. Management of acetaminophen overdose is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment" and "Management of acetaminophen (paracetamol) poisoning in children and adolescents".) Acetaminophen can be fatal in overdose, but the lay public often under-appreciates the potential dangers of this medication. The therapeutic dose is 10 to 15 mg/kg per dose in children and 325 to 1000 mg per dose in adults, with a maximum recommended daily dose of 80 mg/kg in children or 4 g in adults. The toxic dose varies among individuals, but toxicity is unlikely to result from a single dose of less than 150 mg/kg in a child or 7.5 to 10 g for an adult. Toxicity IS likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period. (See 'Epidemiology' above and 'Pharmacokinetics' above.) Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Serum concentrations peak between one-half and two hours after an oral therapeutic dose. Peak serum concentrations are reached within four hours following overdose of immediate-release preparations but may be delayed when drugs that slow gastric emptying (eg, opiates, anticholinergic agents) are coingested or following overdose of extended release preparations. The biochemical pathways leading to toxicity are described in the text. (See 'Pharmacokinetics' above and 'Biochemical toxicity' above.) Clinical factors that can predispose patients to injury from acetaminophen ingestion include chronic alcohol ingestion, chronic liver disease, medications that affect the CYP2E1 enzyme system of the liver, malnutrition, and older age. (See 'Clinical factors influencing toxicity' above.) Unlike most other causes of hepatitis, acetaminophen-induced hepatitis is acute in onset, progresses rapidly, is characterized by marked elevation of plasma aminotransferases (>3000 IU/L), and is associated with a rising prothrombin time. Chronic acetaminophen poisoning in the alcohol user is also characterized by markedly elevated aminotransferases (>3000 IU/L), combined with hypovolemia, jaundice, coagulopathy, hypoglycemia, and acute renal failure in greater than 50 percent of these patients. (See 'Differential diagnosis' above.) The initial manifestations of acetaminophen poisoning are often mild and nonspecific, and do not reliably predict subsequent hepatotoxicity. Thus, measurement of the serum acetaminophen concentration is critical whenever overdose is suspected. The symptoms and signs of the four stages of acetaminophen overdose are described in the text. Severe overdose can result in liver failure. (See 'Clinical manifestations' above.) The risk of toxicity is best predicted by relating the time of ingestion to the serum acetaminophen concentration. Therapeutic serum concentrations range from 10 to 20 mcg/mL (65 to 130 micromol/L). After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration should be drawn 4 and 24 hours after presentation. If the ingestion was more than four hours prior to presentation, it should be drawn immediately. The level should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC therapy (figure 3). Use of the nomogram in the setting of acute and chronic overdose of acetaminophen is described in the text. (See 'Diagnosis' above.)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Davidson DG, Eastham WN. Acute liver necrosis following overdose of paracetamol. Br Med J 1966; 2:497. 2. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986; 104:399.
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisoniphen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 9 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

3. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995; 22:767. 4. Maddrey WC. Hepatic effects of acetaminophen. Enhanced toxicity in alcoholics. J Clin Gastroenterol 1987; 9:180. 5. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845. 6. Schidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med 1997; 337:1112. 7. Benson GD. Hepatotoxicity following the therapeutic use of antipyretic analgesics. Am J Med 1983; 75:85. 8. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004; 22:335. 9. Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology 2004; 40:6. 10. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333:1118. 11. Ostapowicz G, Fontana RJ, Schidt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947. 12. Lee WM. Acute liver failure in the United States. Semin Liver Dis 2003; 23:217. 13. Chun LJ, Tong MJ, Busuttil RW, Hiatt JR. Acetaminophen hepatotoxicity and acute liver failure. J Clin Gastroenterol 2009; 43:342. 14. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364. 15. Myers RP, Li B, Fong A, et al. Hospitalizations for acetaminophen overdose: a Canadian population-based study from 1995 to 2004. BMC Public Health 2007; 7:143. 16. Lewis RK, Paloucek FP. Assessment and treatment of acetaminophen overdose. Clin Pharm 1991; 10:765. 17. Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983; 25:290. 18. Makin AJ, Wendon J, Williams R. A 7-year experience of severe acetaminophen-induced hepatotoxicity (19871993). Gastroenterology 1995; 109:1907. 19. Forrest JA, Clements JA, Prescott LF. Clinical pharmacokinetics of paracetamol. Clin Pharmacokinet 1982; 7:93. 20. Bizovi KE, Aks SE, Paloucek F, et al. Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med 1996; 28:549. 21. Cetaruk EW, Dart RC, Hurlbut KM, et al. Tylenol Extended Relief overdose. Ann Emerg Med 1997; 30:104. 22. Tighe TV, Walter FG. Delayed toxic acetaminophen level after initial four hour nontoxic level. J Toxicol Clin Toxicol 1994; 32:431. 23. Douglas DR, Sholar JB, Smilkstein MJ. A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). Acad Emerg Med 1996; 3:740. 24. Schidt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 2002; 71:221. 25. Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973; 187:211. 26. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000; 67:275. 27. Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol Pharmacol 1980; 18:536. 28. Bessems JG, Vermeulen NP. Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol 2001; 31:55. 29. Thummel KE, Lee CA, Kunze KL, et al. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 10 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

human CYP3A4. Biochem Pharmacol 1993; 45:1563. 30. Kaplowitz N. Acetaminophen hepatoxicity: what do we know, what don't we know, and what do we do next? Hepatology 2004; 40:23. 31. Lee SS, Buters JT, Pineau T, et al. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 271:12063. 32. Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am 1984; 2:103. 33. Gemborys MW, Mudge GH, Gribble GW. Mechanism of decomposition of N-hydroxyacetaminophen, a postulated toxic metabolite of acetaminophen. J Med Chem 1980; 23:304. 34. James LP, Mayeux PR, Hinson JA. Acetaminophen-induced hepatotoxicity. Drug Metab Dispos 2003; 31:1499. 35. Roberts DW, Pumford NR, Potter DW, et al. A sensitive immunochemical assay for acetaminophen-protein adducts. J Pharmacol Exp Ther 1987; 241:527. 36. Pumford NR, Hinson JA, Potter DW, et al. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice. J Pharmacol Exp Ther 1989; 248:190. 37. Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 1973; 187:195. 38. Black M. Acetaminophen hepatotoxicity. Gastroenterology 1980; 78:382. 39. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003; 349:474. 40. Knight TR, Fariss MW, Farhood A, Jaeschke H. Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice. Toxicol Sci 2003; 76:229. 41. Michael SL, Pumford NR, Mayeux PR, et al. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology 1999; 30:186. 42. Blazka ME, Wilmer JL, Holladay SD, et al. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995; 133:43. 43. Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology 2004; 127:1760. 44. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2006; 2:493. 45. Ishida Y, Kondo T, Ohshima T, et al. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminopheninduced acute liver injury. FASEB J 2002; 16:1227. 46. Rumack BH, Peterson RC, Koch GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med 1981; 141:380. 47. Thummel KE, Slattery JT, Nelson SD. Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen. J Pharmacol Exp Ther 1988; 245:129. 48. Schmidt LE, Dalhoff K, Poulsen HE. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Hepatology 2002; 35:876. 49. Slattery JT, Nelson SD, Thummel KE. The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 1996; 60:241. 50. Perrot N, Nalpas B, Yang CS, Beaune PH. Modulation of cytochrome P450 isozymes in human liver, by ethanol and drug intake. Eur J Clin Invest 1989; 19:549. 51. Lucas D, Mnez C, Girre C, et al. Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase. Alcohol Clin Exp Res 1995; 19:362. 52. Smilkstein MJ. Acetaminophen. In: Goldfrank's Toxicologic Emergencies, Goldfrank LR, Flomenbaum NE, Lewin NA, et al. (Eds), Appleton & Lange, Stamford 1998. p.541. 53. Smilkstein, MJ. Chronic ethanol use and acute acetaminophen overdose toxicity. J Toxicol Clin Toxicol 1998; 36:476. 54. Cheung L, Potts RG, Meyer KC. Acetaminophen treatment nomogram. N Engl J Med 1994; 330:1907.
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 11 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

55. Rex DK, Kumar S. Recognizing acetaminophen hepatotoxicity in chronic alcoholics. Postgrad Med 1992; 91:241. 56. Schidt FV, Lee WM, Bondesen S, et al. Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose. Aliment Pharmacol Ther 2002; 16:707. 57. Girre C, Hispard E, Palombo S, et al. Increased metabolism of acetaminophen in chronically alcoholic patients. Alcohol Clin Exp Res 1993; 17:170. 58. Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29:1153. 59. Lieber CS. Alcohol, liver, and nutrition. J Am Coll Nutr 1991; 10:602. 60. Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000; 49:291. 61. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002; 40:3. 62. Dart RC, Kuffner EK, Rumack BH. Treatment of pain or fever with paracetamol (acetaminophen) in the alcoholic patient: a systematic review. Am J Ther 2000; 7:123. 63. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther 1983; 33:95. 64. Kuffner EK, Dart RC, Bogdan GM, et al. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial. Arch Intern Med 2001; 161:2247. 65. Benson GD, Koff RS, Tolman KG. The therapeutic use of acetaminophen in patients with liver disease. Am J Ther 2005; 12:133. 66. Farrell GC, Cooksley WG, Powell LW. Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes. Clin Pharmacol Ther 1979; 26:483. 67. Bray GP, Harrison PM, O'Grady JG, et al. Long-term anticonvulsant therapy worsens outcome in paracetamolinduced fulminant hepatic failure. Hum Exp Toxicol 1992; 11:265. 68. Nolan CM, Sandblom RE, Thummel KE, et al. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Chest 1994; 105:408. 69. Shriner K, Goetz MB. Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. Am J Med 1992; 93:94. 70. Estes JD, Stolpman D, Olyaei A, et al. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003; 138:852. 71. Lauterburg BH. Analgesics and glutathione. Am J Ther 2002; 9:225. 72. Price VF, Jollow DJ. Effect of glucose and gluconeogenic substrates on fasting-induced suppression of acetaminophen glucuronidation in the rat. Biochem Pharmacol 1989; 38:289. 73. Price VF, Miller MG, Jollow DJ. Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat. Biochem Pharmacol 1987; 36:427. 74. McLean AE. Nutrition and the intracellular site of toxic injury. World Rev Nutr Diet 1978; 29:124. 75. Ueshima Y, Tsutsumi M, Takase S, et al. Acetaminophen metabolism in patients with different cytochrome P4502E1 genotypes. Alcohol Clin Exp Res 1996; 20:25A. 76. Critchley JA, Nimmo GR, Gregson CA, et al. Inter-subject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol 1986; 22:649. 77. de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 1992; 102:577. 78. Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10:267. 79. Rumore MM, Blaiklock RG. Influence of age-dependent pharmacokinetics and metabolism on acetaminophen hepatotoxicity. J Pharm Sci 1992; 81:203. 80. Tarloff JB, Khairallah EA, Cohen SD, Goldstein RS. Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. Fundam Appl Toxicol 1996; 30:13. 81. Rumack BH. Acetaminophen overdose in young children. Treatment and effects of alcohol and other additional
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 12 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

ingestants in 417 cases. Am J Dis Child 1984; 138:428. 82. Lauterburg BH, Vaishnav Y, Stillwell WG, Mitchell JR. The effects of age and glutathione depletion on hepatic glutathione turnover in vivo determined by acetaminophen probe analysis. J Pharmacol Exp Ther 1980; 213:54. 83. Day A, Abbott GD. Chronic paracetamol poisoning in children: a warning to health professionals. N Z Med J 1994; 107:201. 84. Dong SX, Ping ZZ, Xiao WZ, et al. Effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition in Chinese subjects. Ther Drug Monit 1998; 20:371. 85. Seo KW, Park M, Kim JG, et al. Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen. J Appl Toxicol 2000; 20:427. 86. Schmidt LE, Dalhoff K. The impact of current tobacco use on the outcome of paracetamol poisoning. Aliment Pharmacol Ther 2003; 18:979. 87. Kaysen GA, Pond SM, Roper MH, et al. Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen. Arch Intern Med 1985; 145:2019. 88. Polson J, Wians FH Jr, Orsulak P, et al. False positive acetaminophen concentrations in patients with liver injury. Clin Chim Acta 2008; 391:24. 89. McBride, PV, Rumack, BH. Acetaminophen intoxication. Semin Dial 1992; 5:292. 90. Flanagan RJ, Mant TG. Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum Toxicol 1986; 5:179. 91. Singer AJ, Carracio TR, Mofenson HC. The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction. Ann Emerg Med 1995; 26:49. 92. Caldarola V, Hassett JM, Hall AH, et al. Hemorrhagic pancreatitis associated with acetaminophen overdose. Am J Gastroenterol 1986; 81:579. 93. Mofenson HC, Caraccio TR, Nawaz H, Steckler G. Acetaminophen induced pancreatitis. J Toxicol Clin Toxicol 1991; 29:223. 94. Erickson, RA, Runyon, BA. Acetaminophen hepatotoxicity associated with alcoholic pancreatitis. Arch Intern Med 1984; 144:1509,. 95. Davenport A, Finn R. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. Nephron 1988; 50:55. 96. Blakely P, McDonald BR. Acute renal failure due to acetaminophen ingestion: a case report and review of the literature. J Am Soc Nephrol 1995; 6:48. 97. Wilkinson SP, Moodie H, Arroyo VA, Williams R. Frequency of renal impairment in paracetamol overdose compared with other causes of acute liver damage. J Clin Pathol 1977; 30:141. 98. Bjrck S, Svalander CT, Aurell M. Acute renal failure after analgesic drugs including paracetamol (acetaminophen). Nephron 1988; 49:45. 99. Read RB, Tredger JM, Williams R. Analysis of factors responsible for continuing mortality after paracetamol overdose. Hum Toxicol 1986; 5:201. 100. Ambre J, Alexander M. Liver toxicity after acetaminophen ingestion. Inadequacy of the dose estimate as an index of risk. JAMA 1977; 238:500. 101. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871. 102. Douglas, DR, Smilkstein, MJ, Rumack, BH. APAP levels within 4 hours: Are they useful?. Vet Hum Toxicol 1994; 36:350. 103. Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J 1979; 2:1097. 104. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319:1557. 105. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995; 346:547. 106. Bridger S, Henderson K, Glucksman E, et al. Deaths from low dose paracetamol poisoning. BMJ 1998; 316:1724.
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 13 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

107. Temple AR. "Dear Doctor" Tylenol ER letter. Fort Washington, PA. McNeil Consumer Products Company. January 3, 1995. 108. Kumar S, Rex DK. Failure of physicians to recognize acetaminophen hepatotoxicity in chronic alcoholics. Arch Intern Med 1991; 151:1189. 109. Smilkstein MJ, Bronstein AC, Linden C, et al. Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann Emerg Med 1991; 20:1058. 110. Spooner, JB, Harvey, JG. Paracetamol overdose Facts not misconceptions. Pharm J 1993; 251:706. Topic 340 Version 13.0

http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full#

Page 14 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

GRAPHICS
Common dosage forms of acetaminophen (paracetamol)
Preparation
Extended release caplet Extra strength tablets, capsules, caplets, gelcaps, geltabs Tablets

Strength
650 mg 500 mg

Examples of US trade names

Tylenol Arthritis Pain Genapap Extra Strength, Genebs Extra Strength, Tylenol Extra Strength, Medpap Extra Strength, Aspirin Free Anacin Maximum Strength, Cetafen Extra, Redutemp, Valorin Extra Cetafen, Genapap, Genebs ,Tylenol, Valorin, Mapap Mapap Children's Genapap, Children's Mapap, Children's Tylenol Junior Strength Tylenol Redutemp, Children's Genapap, Children's Silapap, Children's Mapap Children's Tylenol Tylenol Sore Throat

325 mg 160 mg

Chewable tablets

80 mg 160 mg

Liquid, syrup, elixir, suspension

160 mg/5 mL (32 mg/mL) 500 mg/15 mL (33.3 mg/mL)

Drops*

100 mg/mL (80 mg/0.8 mL) 80, 120, 325, 650 mg 10 mg/mL

Infant Genapap, Infantaire, Infant's Silapap Liquiprin for Children, Infant's Mapap, Infant's Tylenol Acephen, Feverall, Mapap

Suppositories

Intravenous solution

Ofirmev

*As of 2011, in an effort to minimize pediatric dosing errors, the Consumer Healthcare Products Association, in conjunction with the US Federal Drug Administration, is phasing out formulations that contain 100 mg per ml (infant acetaminophen drops) so that pediatric liquid preparations obtained in the United States after that time will all contain a concentration of 32 mg/ml (160 mg per 5 mL). However, 100 mg per mL solutions are likely to continue to be given to children from infant acetaminophen drops preparations purchased by caregivers before this phase out. NOTE: Tenfold dosing errors and toxicity from intravenous acetaminophen have occurred in small children when the calculated dose in mg is INCORRECTLY administered as the volume in mL because the concentration of the solution is 10 mg/mL. In the United States, intravenous acetaminophen is not licensed for use in children under two years of age.

Acetaminophen metabolism

http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full#

Page 15 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

At therapeutic doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine. One-half of the remaining acetaminophen is 2012 UpToDate, Inc. All rights reserved. | Subscription and License Agreement | Release: 20.11 - C20.37 excreted unchanged Web - Rafael Oscar Madera | Support Tag: [ecapp0503p.utd.com-190.122.99.115-7CDC0446ABLicensed to: UpToDate Individualin the urine and one-half is metabolized via 6.17.14-178115368] cytochrome P450 (CYP2E1, CYP1A2, CYP3A4 the hepatic subfamilies) mixed function oxidase pathway to N-acetyl-pbenzoquinoneimine (NAPQI), which is hepatotoxic. With normal doses (blue arrows), NAPQI is rapidly conjugated to hepatic glutathione, forming nontoxic cysteine and mercaptate compounds that are excreted in the urine. With toxic doses (red arrow), the sulfate and glucuronide pathways become saturated, resulting in an increased fraction of acetaminophen being metabolized by cytochrome P450 enzymes. Once glutathione stores are depleted, NAPQI begins to accumulate and hepatic injury ensues.

Severity of acetaminophen intoxication

http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full#

Page 16 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

The Rumack-Matthews nomogram summarizes the relationship between plasma acetaminophen concentration (in !g/mL or !mol/L), the time after drug ingestion, and the risk of hepatic toxicity. The thick diagonal line of possible hepatic toxicity represents a 25 percent likelihood of disease. A relatively low level (such as 10 !g/mL) is safe soon after ingestion, but associated with appreciable risk at 24 hours since it reflects a high initial load which has now distributed into the tissues.
Adapted from Rumack, BH, Matthews, H, Pediatrics 1975; 55:873.

Acute liver failure

Contrast-enhanced CT scan of the liver in a 35-year-old female who took an overdose of acetaminophen demonstrates a
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 17 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

heterogenous poorly enhancing liver with areas of lower attenuation due to acute fatty replacement. Note also the patent recanalized paraumbilical vein coursing through the ligamentum teres (arrow).
Courtesy of Jonathan Kruskal, MD.

Acetaminophen poisoning nomogram

This nomogram should only be used after a single acute acetaminophen ingestion. The line indicates the level at which toxicity is possible after acetaminophen overdose. A serum acetaminophen level should be obtained four or more hours after an ingestion to ensure that a peak level has occurred. Patients who ingest extended-release preparations should have a second level
http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full# Page 18 of 19

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis

11/15/12 8:58 AM

drawn four hours after the first level to assess for an additional rise in serum concentration. The level should be plotted in relationship to the time of ingestion to determine the likelihood of toxicity and the need for treatment. Caution should be used in assessing the reliability of the time of ingestion. This nomogram cannot be used for ingestions that occurred greater than 24 hours prior to presentation, repeated supratherapeutic oral ingestions, or iatrogenic intravenous overdose.
Original nomogram from: Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871. Copyright 1975 by the AAP. Updated version reproduced with permission from: Dart RC, Rumack BH. Acetaminophen (Paracetamol). In: Medical Toxicology, 3rd ed, Dart RC (Ed), Lippincott Williams & Wilkins, Philadelphia 2004. Copyright 2004 Lippincott Williams & Wilkins.

http://www.uptodate.com/contents/acetaminophen-paracetamol-poisonihen+poisoning&selectedTitle=3%7E45&view=print&displayedView=full#

Page 19 of 19