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Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and diagnosis
Authors: Michael J Burns, MD; Scott L Friedman, MD; Anne M Larson, MD, FACP, AGAF Section Editors: Stephen J Traub, MD; Michele Burns Ewald, MD Deputy Editor: Jonathan Grayzel, MD, FAAEM Last literature review version 18.1: January 2010 | This topic last updated: September 21, 2009 INTRODUCTION — Since its clinical introduction in 1955, acetaminophen (N-acetyl-paminophenol; 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 . 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 accounts for more overdoses and overdose deaths each year in the United States than any other pharmaceutical agent . More than 1200 cases of severe hepatic injury and 21 deaths were attributed to acetaminophen intoxication during 2003, accounting for 23 percent of all pharmaceuticalrelated deaths reported that year . 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 [9,13]. Data from this group demonstrate that intentional (suicidal) and unintentional (chronic) poisonings account equally for cases of acetaminophen-associated hepatic failure . A retrospective review of all cases of acetaminophen overdose that occurred over ten years in the Calgary region of Canada noted the following: • Of 1543 patients, 70 (4.5 percent) developed hepatotoxicity and 15 died during their
initial hospital admission.
57-7. Serum concentrations peak between one-half and two hours after an oral therapeutic dose .28]. opiates. N-acetyl-p-benzoquinoneimine (NAPQI) (algorithm 1) [5. highly reactive.21].23. BIOCHEMICAL TOXICITY — At therapeutic doses.24]. and underlying liver disease (OR 3. forming nontoxic cysteine and mercaptate compounds that are excreted in the urine [23.18. • • • Toxicity is unlikely to result from a single dose of less than 150 mg/kg in a child or Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver 7.5 to 10 g for an adult . given every 4 to 6 hours. alcohol abuse (OR 2. but the elimination phase may be delayed in onset for extended-release preparations due to prolonged tablet dissolution and absorption [19. However. with a maximum recommended daily dose of 80 mg/kg in children or 4 g in adults. greater than 12 g over a 24-hour period [15. CYP3A4 subfamilies) mixed function oxidase pathway into a toxic. Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. PHARMACOKINETICS — Acetaminophen is available in both immediate-release and sustained-release formulations (table 1). The toxic dose may vary among individuals according to baseline glutathione levels and other factors (see 'Clinical factors influencing toxicity' below). or following overdose of extended releases preparations [18-20]. with toxic doses of a acetaminophen the sulfation and glucuronidation pathways are saturated. anticholinergic agents) are coingested. 95% CI 1. and more acetaminophen is metabolized to NAPQI via the cytochrome P450 enzymes . 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates. When hepatic glutathione 2 . CYP1A2.77). Half-lives greater than 4 hours have been noted in patients with hepatotoxicity . electrophilic intermediate.16]. 95% CI 1. The remaining acetaminophen is metabolized via the hepatic cytochrome P450 (CYP2E1.30-3. The therapeutic dose is 10 to 15 mg/kg per dose in children and 325 to 1000 mg per dose in adults. Elimination half-lives range from 2 to 4 hours for all acetaminophen preparations. Therapeutic serum concentrations range from 10 to 20 mcg/mL. toxicity (defined as peak aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 1000 IU/L) unless appropriately treated . Peak serum concentrations are reached within four hours following overdose of immediaterelease preparations but may be delayed beyond four hours when drugs that delay gastric emptying (eg.50.21. which are then excreted in the urine [17.24-27]. Appropriate acetaminophen doses produce a small amount of NAPQI which is rapidly conjugated with hepatic glutathione. Approximately two percent is excreted in the urine unchanged.76). 95% CI 3.00-8.95).• Risk factors for hepatotoxicity included unintentional overdose (OR 5.
There is a single reported case of a chronic alcohol user in whom 3 . comorbid illnesses.30. advancing age. extending the zone of hepatic injury [39-43].38]. including concomitant use of alcohol or other drugs. lipid peroxidation and mitochondrial injury likely play a role in the progression of hepatocellular injury [13. Chronic alcohol ingestion increases CYP2E1 activity two-fold and depletes glutathione levels [3. decreasing the amount of NAPQI produced [44-47]. 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) (graph 1) . 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 [16. This process is irreversible and leads to oxidative injury and hepatocellular centrilobular necrosis [35-37]. Chronic alcohol ingestion — The role of chronic alcohol ingestion in acetaminopheninduced hepatotoxicity remains contentious. and injury ensues [15. genetic makeup.31]. This secondary injury occurs during stage II of clinical toxicity (see 'Clinical manifestations' below). 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. In one multicenter study of 2540 patients with acetaminophen overdose. Cytokine release from hepatocytes may initiate a secondary inflammatory response from Kupffer cells and other inflammatory cells. NAPQI begins to react with hepatocytes. In another report of 560 patients with severe acetaminophen-induced hepatotoxicity. forming NAPQI-protein adducts [32-34]. thereby. Although not fully characterized.48.23.49]. In addition. a history of excessive alcohol consumption was not associated with a significantly worsened prognosis . and nutritional status . 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. 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. NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules.50].stores are depleted by approximately 70 to 80 percent.
Medications — Concomitant use of drugs that induce CYP2E1 enzymes can cause hepatotoxicity in the absence of overt acetaminophen overdose.) In addition to increased CYP2E1 pathway activity. several other factors may predispose alcoholics to severe acetaminophen-induced hepatotoxicity.54. The effect of chronic ethanol ingestion in conjunction with repeated. double-blind. In one prospective.59]. thus enhancing susceptibility of mitochondria to NAPQI [56. Examples of medications which alter CYP2E1 activity 4 . Multiple overdoses — In contrast to chronic alcoholics with an isolated ingestion. 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 . More importantly. the overall mortality rate reached 20 percent . more likely to have a period of recent fasting.5862]. and may worsen the outcome of an intentional overdose. there is no evidence from prospective controlled trials that therapeutic doses of acetaminophen cause hepatotoxicity in chronic alcohol users [7.61. accumulation of the drug does not occur with repeated administration . 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 . Despite this concerning finding. 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. Although the acetaminophen elimination half-life in this patient population may be prolonged. Delayed recognition of toxicity and continued use of the drug likely account for much of the morbidity in this patient population . which results in the shunting of a greater fraction of acetaminophen through the CYP2E1 pathway and enhanced generation of NAPQI [48. chronic alcoholics appear to be at increased risk for hepatotoxicity following ingestion of multiple supratherapeutic doses of acetaminophen [2-7.49].53. 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 . The net effect is an increased clearance rate of acetaminophen  and associated increased risk for hepatotoxicity. (See "Pathogenesis of alcoholic liver disease".54].56-58]. all of which predispose to hepatic injury [5. Alcohol acts at least in part by induction of CYP2E1.50. cytochrome P450 enzyme activity is low and cannot be induced in this patient population. and more likely to have depleted hepatic glutathione stores than the nonalcoholic. which confers hepatoprotection following overdose . therapeutic doses (up to 4 g/day) of acetaminophen is controversial. Similarly. The chronic alcoholic is more often malnourished. Chronic alcoholics may also have a decreased capacity to synthesize a mitochondrial glutathione transport protein.hepatotoxicity developed despite a low predicted risk for this complication by the modified Rumack-Matthew nomogram . 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].
Herbal supplements may potentially amplify acetaminophen-induced injury . when the toxic effects of acetaminophen are already established.71]. fasting. Tobacco — Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism [82. Nutritional status — Malnutrition and a period of fasting may predispose to acetaminophen hepatotoxicity.69]. chronic ethanol use) and are more likely to present late. and death than those who attempted suicide. carbamazepine.66].70. Patients should be questioned specifically about the use of herbal supplements since they are widely used. hepatic coma. not a single overdose. Patients at greatest risk appear to be those that consume repeated excessive doses. Genetics — Polymorphisms exist in the cytochrome isoenzymes that contribute to diminished or excessive oxidative metabolism of acetaminophen [73.59. 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. Hepatic glucuronidation is normally dependent upon hepatic carbohydrate reserves. recent fasting appeared to be increase hepatotoxicity in patients with a moderate overdose (four to ten grams of acetaminophen within 24 hours) . also associated with the fasting and malnourished state. phenobarbital.74]. One review found tobacco use to be an independent risk factor for mortality following acetaminophen overdose independent of the amount of tobacco consumed . In one study. but evidence is limited [5. Drugs such as trimethoprim-sulfamethoxazole and zidovudine may potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways. In one study of 71 patients admitted with acetaminophen toxicity. 5 . Mortality was greatest in smokers who also drink alcohol. compromise detoxification of NAPQI and predispose to hepatic injury . In the fasting or malnourished state. However. but often not mentioned during a routine medical interview. resulting in increased CYP2E1-dependent metabolism of acetaminophen .65. and phenytoin) and antituberculosis drugs (eg. glucuronidation of acetaminophen is reduced which leads to enhanced microsomal metabolism and increased production of the toxic NAPQI metabolite [5. even though the latter had ingested more acetaminophen . young children are no less susceptible to hepatic injury . following repeated excessive acetaminophen doses.include anticonvulsants (eg. Age — Older patients appear more likely to develop hepatotoxicity following acute overdose whereas children less than five years old appear less susceptible to toxicity [13. The clinical relevance of these polymorphisms is unknown. isoniazid and rifampin) [63.83]. Impaired glucuronidation secondary to Gilbert's syndrome appears to enhance toxicity .80]. Pattern of use — The pattern of acetaminophen use is an important consideration when assessing the risk for subsequent toxicity.76-78]. patients in the accidentaloverdose group had higher rates of severe hepatotoxicity. Young children are probably protected via an increased supply and regeneration of glutathione and greater activity of conjugation enzymes [79. Depleted glutathione stores.
(See "Overview of hepatitis A virus infection in adults" and "Serologic diagnosis of hepatitis B virus infection". Reye's syndrome. is characterized by marked elevation of plasma aminotransferases (>3000 IU/L). and acute renal failure in greater than 50 percent of these patients [2. which usually follows a period of severe prolonged hypotension. and malaise. Such symptoms in acetaminophen-poisoned patients are usually due to coingestants. (See "Acetaminophen (paracetamol)-induced acute kidney injury (acute renal failure)". physicians must promptly recognize acetaminophen poisoning in order to minimize subsequent morbidity and mortality. vomiting.3]. Some patients remain asymptomatic. occasionally. 6 . and ischemic hepatitis ("shock liver"). alcoholic hepatitis and chronic acetaminophen poisoning in the alcohol user have an AST to ALT ratio greater than two [2. coagulopathy. and rarely exceed 500 IU/L. which may delay recognition of the underlying problem .26. aminotransferases may rise as early as 8 to 12 hours after acetaminophen ingestion in severely poisoned patients .DIFFERENTIAL DIAGNOSIS — Unlike most other causes of hepatitis. and do not reliably predict subsequent hepatotoxicity [50. Aminotransferase values are also markedly lower in patients with alcoholic hepatitis. stage I symptoms usually resolve and patients appear to improve clinically while subclinical elevations of hepatic aminotransferases (AST. lethargy. nephrotoxicity become evident. other drug. combined with hypovolemia.) Unlike acute acetaminophen poisoning. diaphoresis. However.85]. ALT) occur. Chronic acetaminophen poisoning in the alcohol user is also characterized by markedly elevated aminotransferases (>3000 IU/L). jaundice. and is associated with a rising PT.3. hypoglycemia.) 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. Stage II (24 to 72 hours) — From 24 to 72 hours after ingestion. (See "Clinical manifestations and diagnosis of alcoholic liver disease" and "Patterns of plasma aspartate and alanine aminotransferase levels with and without liver disease". the clinical and laboratory evidence of hepatotoxicity and. Initially.5 to 24 hours) — In the first 24 hours after overdose. pallor.) CLINICAL MANIFESTATIONS — The initial manifestations of acetaminophen poisoning are often mild and nonspecific. patients often manifest nausea.) Other diagnoses that should be considered in patients with evidence of hepatic dysfunction include alcoholic hepatitis. Laboratory studies are typically normal. Stage I (0. (See "Approach to the patient with abnormal liver function tests". The clinical course of poisoning is often divided in four sequential stages.or toxin-induced hepatitis. viral hepatitis. progresses rapidly. Central nervous system depression and elevated anion gap metabolic acidosis are rarely seen after massive acetaminophen overdose . hepatobiliary disease. Occasionally.87]. acetaminopheninduced hepatitis is acute in onset.
hypoglycemia. Histologic changes in the liver vary from cytolysis to centrilobular necrosis.Of patients that develop hepatic injury. The systemic symptoms of stage I reappear in conjunction with jaundice. usually from multiorgan system failure . Acute renal failure occurs in 25 percent of patients with significant hepatotoxicity and in more than 50 percent of those with frank hepatic failure [26. concurrent alcohol use contributes to both hepatotoxicity and pancreatitis . it is complete. and renal function abnormalities may become evident. In some patients. assessment of severity. with liver enlargement and tenderness. Acute pancreatitis has been described in case reports [90. The general approach to any poisoned patient should include the following elements: • Whenever possible. lactic acidosis. single or repeated doses). pattern of use (eg.91]. the 7 . Recovery can be slower in severely ill patients. over one half will demonstrate aminotransferase elevation within 24 hours and all have elevations by 36 hours . a history should be obtained to elicit the dose. oliguria. DIAGNOSIS General approach and serum acetaminophen concentration — A serum acetaminophen level must be obtained in every patient suspected of an intentional overdose. and prediction of toxicity. chronic hepatic dysfunction is not a sequela of acetaminophen poisoning. and a bleeding diathesis (picture 1). Signs of severe hepatotoxicity include plasma ALT and AST levels that often exceed 10. Acute renal failure is manifested by elevations of blood urea nitrogen and creatinine along with proteinuria. 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. patients develop right upper quadrant pain. and time of the ingestion. evaluation should include identification of the agents involved.0 mg/dL (primarily indirect). Stage III (72 to 96 hours) — Liver function abnormalities peak from 72 to 96 hours after ingestion. and granular casts on urinalysis. Acute renal failure is due primarily to acute tubular necrosis. Death most commonly occurs in this stage.93]. confusion (hepatic encephalopathy).000 IU/L. In all patients with suspected acetaminophen overdose. (See "Acetaminophen (paracetamol)-induced acute kidney injury (acute renal failure)". hematuria. When recovery occurs.) Stage IV (4 days to 2 weeks) — Patients who survive stage III enter a recovery phase that usually begins by day 4 and is complete by 7 days after overdose . a marked elevation in hepatic enzymes. As stage II progresses. hyperammonemia. Histologic recovery lags behind clinical recovery and may take up to 3 months. suicidal or not). Elevations of prothrombin time (PT) and total bilirubin. and a total bilirubin concentration above 4. intent of use (ie. symptoms and laboratory values may not normalize for several weeks. prolongation of the PT or INR.
toxic screening of blood and urine for other ingested drugs should be performed.98]. or those predicted to develop toxicity based on history and initial serum acetaminophen concentration. and should not be used [50. After a single acute overdose of an immediate-release preparation. the administration of antidotes and enhancement of drug elimination. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment". Evaluation after acute overdose — The risk of toxicity is best predicted by relating the time of ingestion to the serum acetaminophen concentration. (See 'Clinical factors influencing toxicity' above. 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 [94. alcohol use. when appropriate. prevention of drug absorption. 8 . a serum concentration should be obtained immediately at the time of presentation.98]. patients with serum acetaminophen concentrations above the line joining 200 mcg/mL at 4 hours and 25 mcg/mL 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 [15. serum total bilirubin level. a serum acetaminophen concentration should be drawn four and 24 hours after presentation. it should be drawn immediately. If any doubt exists about the time of ingestion.5 mcg/mL at 16 hours ("high hepatic toxicity") have a 90 percent incidence of severe hepatotoxicity and a mortality rate of up to 24 percent [15. The level should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC therapy (graph 1) . Without antidotal therapy. relates serum acetaminophen concentration to the time of ingestion as a predictor of hepatotoxicity.95].) and also (see "Decontamination of poisoned adults" and "Enhanced elimination of poisons"). and. As originally reported. ALT. (See "General approach to drug poisoning in adults".97]. anticonvulsant drug use. and urinalysis. Treatment of acetaminophen poisoning is discussed separately.) • Management consists of supportive care. In those with established toxicity.presence of coingestants. The original nomogram.) • All patients with a clear history of acetaminophen overdose should undergo measurement of serum acetaminophen concentration. Serum concentrations drawn before 4 hours may not represent peak values. AST. amylase. A serum concentration should also be obtained four hours following the time of acute ingestion or presentation. BUN and creatinine. In patients with intentional ingestions or unreliable histories. recent fasting). Gilbert's disease. and the existence of comorbid conditions that may predispose to the development of hepatic injury (eg. based on large numbers of overdose patients not treated with antidote. If the ingestion was more than four hours prior to presentation. prothrombin time with INR. additional laboratory tests should include electrolytes. Untreated patients with serum acetaminophen concentrations above the line joining 300 mcg/mL at 4 hours and 37.
There is presently insufficient experience to know whether the Rumack-Matthew nomogram can accurately assess risk following acute overdose of sustained-release acetaminophen products. including specific questions about dosing and the pattern of use. often nonspecific. severe hepatic toxicity (AST > 1000 IU) may occasionally occur when patients have serum acetaminophen concentrations below the "possible hepatic toxicity" line. and Great Britain. 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 .101].8 mcg/mL at 16 hours are considered at "possible risk" for hepatotoxicity and treatment with NAC is standard [44. Canada.98]. Patients in the United States with serum acetaminophen concentrations above the line connecting 150 mcg/mL at 4 hours and 18. the incidence of severe hepatotoxicity was 0 to 3 percent for those patients with serum acetaminophen concentrations below the "possible hepatic toxicity" line [59. the goal of evaluation is to identify patients who need NAC treatment based upon a combination of 9 .6.and 8-hour serum acetaminophen concentration be measured and treatment with NAC initiated if either concentration is above the "possible hepatic toxicity" line of the nomogram [19.103]. clinicians should ask about acetaminophen.96. This margin of safety was created to allow for variations in acetaminophen measurements among laboratories and possible errors in the estimated time of ingestion. Signs and symptoms are insidious in onset. which is still used in Australia. Until more clinical experience has been gained. The incidence of nomogram failure using the modified line is extraordinary small .100. viral syndrome).102]. alcohol users). and easily confused with alternative diagnoses (eg. In one study of 2023 patients treated with oral NAC for acute acetaminophen overdose. our recommendation is to follow the conservative approach of the manufacturer. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment". Acetaminophen serum concentrations are frequently therapeutic in the chronic overdose population and concentrations do not correlate with toxicity as with the acute overdose [3. Even with NAC treatment. The 25 percent margin of safety also likely protects susceptible patients who are at higher risk for developing hepatotoxicity (eg.99]. This is no evidence to support lowering the treatment line further for these patients. When inquiring about potentially toxic drugs. There were no deaths in this group of treated patients .53.) 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.patients with serum acetaminophen concentrations below the "probable hepatic toxicity" line did not develop severe hepatotoxicity and no fatalities were reported (graph 1) [15. Some authorities (including the manufacturer) recommend that both a 4. as suggested by some authorities [26. This modified treatment line is 25 percent lower than the original treatment line ("probable hepatic toxicity"). When the diagnosis of chronic acetaminophen intoxication is suspected.99].
clinical. and acetaminophen concentrations >10 mcg/mL. If a patient has a detectable acetaminophen concentration but is without signs. or access the World Health Organization's list of international poison centers 10 . MD. or ingestion of greater than 4 grams over 24 hours AND have an increased susceptibility to hepatotoxicity (eg. UpToDate wishes to acknowledge Dr. risk factors for toxicity. • • Liver tenderness. TREATMENT — The management of acetaminophen overdose. As an example. Patients with a history of chronic. If the serum acetaminophen concentration is undetectable and aminotransferases are normal.99. then treatment is likely not necessary . fasting. supratherapeutic serum acetaminophen concentrations (greater than 20 mcg/mL). they result from a delay in seeking medical attention.who. in recognition of poisoning. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment". chronic alcohol use. call the United States Poison Control Network at 1-800-222-1222 1222 (www. regardless of the initial serum acetaminophen concentration [98. MPH. or in the institution of appropriate therapy. who passed away in March 2009. or are ill-appearing. regardless of the measured serum acetaminophen concentration. jaundice. excessive acetaminophen ingestion should be considered to have acetaminophen-induced hepatotoxicity when aminotransferases are elevated. NAC therapy is not necessary.) PROGNOSIS — The outcome of acetaminophen intoxication is nearly always good if the antidote. elevations of aminotransferases. and laboratory data.int/ipcs/poisons/centre/directory/en). Thus. Patients are at increased risk for developing acetaminophen-induced hepatotoxicity if they have any of the following findings: • Ingestion of greater than 7. when fulminant hepatic failure and death occur from acetaminophen poisoning.104]. 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 . use of P450-inducing drugs) [14. or risk factors for toxicity and without elevations of aminotransferases. including antidotal treatment with N-acetylcysteine (NAC). Treatment is clearly recommended if serum acetaminophen concentrations are potentially toxic by the nomogram with respect to the time of the last dose. No deaths have been reported in any of the large studies of acetaminophen overdose provided NAC was given within 10 hours of ingestion. Shannon's 1-800-222. and those with history of excessive ingestion. Treatment with NAC is recommended for all patients with liver tenderness.historical. is administered in a timely fashion.5 to 10 g of acetaminophen over 24 hours. ACKNOWLEDGMENT — We are saddened by the untimely death of Michael Shannon. symptoms. is discussed elsewhere.50].) ADDITIONAL RESOURCES — To obtain emergent consultation with a medical toxicologist. N-acetylcysteine (NAC). Supratherapeutic acetaminophen concentrations (greater than 20 mcg/mL). (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".
FV. Paracetamol overdosage: Pharmacological considerations and clinical management. Hepatology 1995. RJ. FP. N Engl J Med 1995. Assessment and treatment of acetaminophen overdose. et al. WM. Polson. 30:104. Clin Pharmacokinet 1982. 6. WC. et al. Acute Liver Failure Study Group: lowering the risks of hepatic failure. SE. 25:290. 22:767. Ann Intern Med 1986. Lee. 75:85. Mitchell. WC. DG. 4. WM. 11 . Fontana. Smilkstein. 5512:497. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: Analysis of instances of therapeutic misadventure. Prospective Study. Clin Pharmacol Ther 2002. Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter. Forrest. HJ. AM. Association of acetaminophen hepatotoxicity with fasting and ethanol use. RC. 20. TV. Schiodt. Acetaminophen-induced hepatic necrosis. K. J Clin Gastroenterol 1987. 18. Makin. Cetaruk. Clements. Hepatology 2005. Hurlbut. Walter. DJ. Hepatotoxicity following the therapeutic use of antipyretic analgesics. et al. Klein-Schwartz. W. 19. Maddrey. 14. Ann Emerg Med 1997. DR. 42:1364. Christensen.S. in particular. AJ. 3. Acute liver necrosis following overdosage of paracetamol. 28:549. 137:947. 9:180. Drugs 1983. Eastham. 21. 17. Larson. Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. et al. LB. 15. Semin Liver Dis 2003. et al. 7. Paloucek.many contributions to pediatric medicine and emergency medicine. Ostapowicz. P. Aks. 3:740. Wendon. 16. FG. Watson. Casey. 22:335. 104:399. FV. Lee. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. J. Bizovi. 23:217. Acad Emerg Med 1996. Schiodt. Ann Intern Med 2002. Fontana. Ott. Jollow. 22. 40:6. 10:765. WM. A 7-year experience of severe acetaminopheninduced hepatotoxicity (1987-1993). Prescott. E. REFERENCES 1. Zimmerman. Sholar JB. Prescott. 9. 2. 109:1907. et al. Douglas. WN. TL. FA. FV. Litovitz. JAMA 1994. Br Med J 1966. EW. Hepatology 2004. 7:93. 12. Rochling. DC. et al. Tighe. 11. Use of UpToDate is subject to the Subscription and License Agreement. Hepatic effects of acetaminophen. JR. G. GD. 23. Delayed toxic acetaminophen level after initial 4-hour nontoxic level. Clinical pharmacokinetics of paracetamol. 71:221. 8. MJ. Acetaminophen and the U. Block. 2003 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. BA. RK. Lee. S. Seeff. KM. WA. J. HJ. N Engl J Med 1997. 272:1845. Tylenol Extended Relief Overdose. Protective role of glutathione. J Toxicol Clin Toxicol 1994. R. F. 5. DL. Dart. Am J Emerg Med 2004. Zimmerman. JA. 187:211. Lee. his work as our section editor for pediatric toxicology and prior editorial work in pediatric resuscitation. Clin Pharm 1991. Williams. A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). LF. Whitcomb. WM. Acetaminophen toxicity in an urban county hospital. JA. Davidson. 333:1118. RJ. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Acetaminophen hepatotoxicity in alcoholics: A therapeutic misadventure. Paloucek. 32:431. Gastroenterology 1995. GD. Lewis. WZ. Maddrey. Benson. Schiodt. LF. Potter. Acute liver failure in the United States. Am J Med 1983. 10. 337:1112. Enhanced toxicity in alcoholics. J Pharmacol Exp Ther 1973. 13. IV. Cuccherini. Bondesen. Drug-induced hepatotoxicity. Ann Emerg Med 1996.
T. et al. LE. Corcoran. 35. ZX. C. Kaplowitz. 47. PR. Mechanism of decomposition of Nhydroxyacetaminophen. Schmidt. CS. Acetaminophen hepatotoxicity. ED. 41. et al. N. NR. M. Thummel KE. Pineau. 31. Nalpas. 28. by ethanol and drug intake. Pumford. Black. TF. J Med Chem 1980. Slattery. JT. J Pharmacol Exp Ther 1988. Expert Opin Drug Metab Toxicol 2006. 133:43. GH. 33. Acetaminophen hepatoxicity: what do we know. Crit Rev Toxicol 2001. Alcohol Clin Exp Res 1995. 45:1563. 16:1227. 30. N Engl J Med 2003. II. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. 45. SD. et al. A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury. Kaplowitz. 141:380. Slattery. Lucas. Buters. Potter. Oxidation of acetaminophen to N-acetyl-paminobenzoquinone imine by human CYP3A4. Kalhorn. KE. GB. K. Knight. 271:12063. SD. Mitchell. T. Potter. Poulsen. SS. Hepatology 2002. Potter. 2:493. DW. The complex interaction between ethanol and acetaminophen. 30:186. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Perrot. Lee. 60:241. Role of innate immunity in acetaminophen-induced hepatotoxicity. WZ. Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase. 31:1499. 42. Ohshima. Mayeux. 38. Modulation of cytochrome P450 isozymes in human liver. 76:229. et al. Kondo. KE. Y. 2:103. Koch. 29. JT. LP. RG. Mudge. Michael. 23:304. J Pharmacol Exp Ther 1989. BH. what don't we know. 241:527. Acetaminophen overdose: 662 cases with evaluation of oral acetylcysteine treatment. Acetaminophen overdose. 40:23. Mayeux. JT. FASEB J 2002. Rumack. Peterson. ZX. Pumford. et al. EC. Yang. DW. Nelson. NR. Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen. Clin Pharmacol Ther 1996. JR. GW. Role of lipid peroxidation as a mechanism of liver injury after acetaminophen overdose in mice. Thummel. Role of covalent binding in vivo. Kunze. Govindarajan. 35:876. NR. Hinson. 39. BH. MW. Eur J Clin Invest 1989. Drug Metab Dispos 2003. and what do we do next?. Vaishnav. Menez. J Biol Chem 1996. Liu. James. 248:190. A. et al. 31:55. NP. Jaeschke. T. 49. Dalhoff. Nelson SD. Liu. 26. JA. J Pharmacol Exp Ther 1973. Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms. Roberts. S. 37. Drug-induced hepatotoxicity. Blazka. 78:382. 32. Amara IA. Hinson. Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate. MW. 18:536. analogues and protective approaches. SL. 25. CH. YN. et al. PT. Vermeulen. a postulated toxic metabolite of acetaminophen. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Pharmacol Exp Ther 1987. Lee. 19:549. Linden. Acetaminophen-induced hepatotoxicity. Slattery JT. Manyike. Farhood. Gastroenterology 2004. HE. Emerg Med Clin North Am 1984. Girre. et al. 349:474. Rumack. DJ. Toxicol Appl Pharmacol 1995. Ishida. C. 43. GG. Fariss. Beaune. H. Horning. 19:362. Lee. Gemborys. PH. DW. D. Hepatology 2004. 44. CA. Immunochemical quantitation of 3(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophentreated mice. Toxicol Sci 2003. Arch Intern Med 1981. B. 36. Clin Pharmacol Ther 2000. A sensitive immunochemical assay for acetaminophen-protein adducts. Biochem Pharmacol 1993. 245:129. Kaplowitz. 67:275. Gribble. Kharasch. N. Holladay. N. 12 . ME. 187:195. WM. Thummel. 34. 46. Mol Pharmacol 1980. 27. Gastroenterology 1980. Role of proinflammatory cytokines in acetaminophen hepatotoxicity. JG.24. Hepatology 1999. N-acetyl-pbenzoquinoneimine. KL. et al. 40. TR. 127:1760. JL. JA. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Acetaminophen-induced hepatic necrosis. PR. Bessems. 48. Jollow. Wilmer. JR. Pumford. N. Mitchell.
GD. 68. Wells. Rex. Flomenbaum. Rumack. Thummel. Treatment of pain or fever with paracetamol (Acetaminophen) in the alcoholic patient: a systematic review. Effect of glucose and gluconeogenic substrates on fasting-induced suppression of acetaminophen glucuronidation in the rat. Biochem Pharmacol 1989. Connecticut 1998. Critchley. DJ. MJ. 10:602. Girre. World Rev Nutr Diet 1978. RC. 7:123. Lauterburg. Alcohol Clin Exp Res 1996. 40:3. JP. et al. Meyer. 20:25A. Benson. Am J Ther 2000. NA (Eds). 64. Increased metabolism of acetaminophen in chronic alcoholic patients. 54. Hispard. WGE. Prescott.50. AE. LR. Lieber. Biochem Pharmacol 1987. Lee. BH. Koff. Powell. 16:707. EK. GD. Acetaminophen metabolism in patients with different cytochrome P450-2E1 genotypes. Nolan. 65. Gastroenterology 1992. Acetaminophen. J Am Coll Nutr 1991. 29:124. VF. Velez. Clin Pharmacol Ther 1983. 72. Acetaminophen in chronic liver disease. S. Analgesics and glutathione. S. 71. McLean. et al. 26:483. 52. Uetrecht. C. M. 53. alcohol and the liver. EK. Jollow. 36:427. MG. 93:94. 29:1153. Stolpman. S. Takase. 55. CA. 17:170. MJ. Chronic ethanol use and acute acetaminophen overdose toxicity. Clin Pharmacol Ther 1979. Shriner. Chest 1994. Bogdan. Schiodt. RG. J Toxicol Clin Toxicol 2002. Lewin. Bondesen. PM. Price. Hum Exp Toxicol 1992. Stamford. ME. Benson. SM. Nimmo. 59. 56. 70.541. 57. Glutathione deficiency in alcoholics: Risk factor for paracetamol hepatotoxicity. 38:289. et al. Cooksley. 66. KC. JG. Paracetamol. Kuffner. Aliment Pharmacol Ther 2002. KE. Severe hepatotoxicity in a patient receiving both acetaminophen and zidovudine. In: Goldfrank's Toxicologic Emergencies. 73. Gregson. Farrell. LF. GR. et al. Cheung. GP. Postgrad Med 1992. et al. Tsutsumi. Price. KG. Br J Clin Pharmacol 1986. Palombo. Lauterburg. N Engl J Med 1994. J Toxicol Clin Toxicol 1998. Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis. Miller. 22:649. 102:577. CM. Potts. et al. VF. 11:265. 161:2247. Jollow. et al. JD. et al. K. Alcohol Clin Exp Res 1993. FV. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. MB. 69. Br J Clin Pharmacol 2000. 33:95. double-blind. p. JA. placebocontrolled trial. Kuffner. Olyaei. 51. Harrison. Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose. 105:408. Alcohol. 9:225. 62. liver. activity of hepatic microsomal metabolizing enzymes. De Morais. Drug metabolism in liver disease. Goetz. Sandblom. Nutrition and the intracellular site of toxic injury. Inter-subject and ethnic differences in paracetamol metabolism. Estes. L. 75. D. 60. D. Goldfrank. and nutrition. 49:291. Dart. DK. 12:133. PG. LW. BH. A. Kumar. 330:1907. Smilkstein. E. 13 . RE. Y. Recognizing acetaminophen hepatotoxicity in chronic alcoholics. BH. High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. 138:852. GM. C. 91:241. Tolman. Acetaminophen hepatoxicity: the first 35 years. 63. 74. Appleton & Lange. RS. GC. The therapeutic use of acetaminophen in patients with liver disease. 36:476. S. Smilkstein. Am J Ther 2002. Rumack. O'Grady. Am J Ther 2005. Gut 1988. et al. Am J Med 1992. Bray. Arch Intern Med 2001. 61. RC. Dart. Ueshima. Mechanism of fasting induced potentiation of acetaminophen hepatotoxicity in the rat. NE. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. 58. Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized. BH. Acetaminophen treatment nomogram. Arch Surg 2003. WM. 67.
92. Nephron 1988. et al. Goldstein. Analysis of factors responsible for continuing mortality after paracetamol overdose. "Dear Doctor" Tylenol ER letter. 5:292. Wians. Rumack. 2:1097. BH. Vet Hum Toxicol 1994. AJ. Lancet 1995. and covalent binding. RB. 99. Acetaminophen induced pancreatitis. MJ. N Engl J Med 1988. Rumore. Park. Day. Caldarola. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. 346:547. Fort Washington. J. S. Nawaz. BH. 77. LE. 30:13. MM. 145:2019. Ping. Am J Gastroenterol 1986. 81. et al. 29:223. JM. 96. RA. The impact of current tobacco use on the outcome of paracetamol poisoning. Temple AR. 138:428. WG. 101. Kaysen. Matthew. Clin Chim Acta 2008 Jan 26 [Epub ahead of print]. Hum Toxicol 1986. Roper. Henderson. EA. 50:55. Knapp. R. TR. Semin Dial 1992. RG. Orsulak. R. Mitchell. Pond. Influence of age-dependent pharmacokinetics and metabolism on acetaminophen hepatotoxicity. 81:203. BA. WZ. Carracio. Bridger. nonprotein sulfhydryl depletion. Mofenson. 316:1724. E. AH. Schmidt. JAJH. 107:201. PA. Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hall. Liver toxicity after acetaminophen ingestion: Inadequacy of the dose estimate as an index of risk. TR. 94. MH. January 3. A. HC. Ther Drug Monit 1998. 97. Hum Toxicol 1986. Arch Intern Med 1985. Dalhoff. Alexander. Ambre. 10:267. KW. JA. Hassett. Caraccio. J Pharm Sci 1992. Kim. Singer. J Toxicol Clin Toxicol 1991. 5:201. KW. 86. The effects of age and glutathione depletion on hepatic glutathione turnover in vivo determined by acetaminophen probe analysis. McBride. LF. TG. 98. JM. Acetaminophen overdose in young children: Treatment and effects of alcohol and other additional ingestants in 417 cases. BH. H. 20:371. Seo. 82. The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction. 1995. 20:427. McNeil Consumer Products Company. Effect of active and passive cigarette smoking on CYP1A2-mediated phenacetin disposition in Chinese subjects. et al. JB. Acetaminophen hepatotoxicity associated with alcoholic pancreatitis. APAP levels within 4 hours: Are they useful?. GA. Paracetamol (acetaminophen) poisoning. Kulig. False positive acetaminophen concentration in patients with liver injury. AT. 79. Prescott. 93. A.Nelson. et al. K. Br Med J 1979. 83. Rumack. 88. Paracetamol (acetaminophen) poisoning resulting in acute renal failure without hepatic coma. 76. 84. 81:579. et al. Tredger. Aliment Pharmacol Ther 2003. 36:350. Pediatrics 1975. 5:179. RN. 90. JG. Finn. Acetaminophen intoxication. Xiao. Ann Emerg Med 1995. Cohen. Read. 85. Y. ZZ. 144:1509. BH.and nephrotoxicity in Sprague-Dawley rats: Role of tissue accumulation. Davenport. SM. Rumack.and age-dependent acetaminophen hepato. Abbott. GD. 213:54. Semin Liver Dis 1990. Mant. PV. Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen. Vaishnav. N Z Med J 1994. J. Erickson. Hemorrhagic pancreatitis associated with acetaminophen overdose. Williams. 14 . Am J Dis Child 1984. Stillwell. Runyon. Mofenson. Tarloff. et al. 80. et al. 89. M. Douglas. RS. Dong. Sex. SD. Illingworth. 238:500. 55:871. SX. Flanagan. Polson. 95. SD. G. V. 102. F. Smilkstein. K. et al.. Steckler. 87. JR. Glucksman. 78. Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen poisoning. 18:979. GL. Deaths from low dose paracetamol poisoning. H. BH. BMJ 1998. 100. 91. Blaiklock. 319:1557. M. Proudfoot. HC. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. JAMA 1977. Rumack. 26:49. Smilkstein. Khairallah. MJ. DR. RJ. J Pharmacol Exp Ther 1980. Chronic paracetamol poisoning in children: A warning to health professionals. PJ. Fundam Appl Toxicol 1996. Critchley. Acetaminophen poisoning and toxicity. Vale. J Appl Toxicol 2000. Lauterburg. Arch Intern Med 1984.
Valorin®. Paracetamol overdose — Facts not misconceptions. Linden. MJ. Smilkstein. DK. 251:706. 104. Harvey. JB. Children's Mapap® Children's Tylenol ® Tylenol® Sore Throat Tablets 325 mg 160 mg Chewable tablets 80 mg 160 mg Liquid. 151:1189. Mapap® Mapap® Children's Genapap®. Spooner. Infant's Silapap® Liquiprin® for Children. 325 mg. syrup. gelcaps. Genebs® Extra Strength. Children's Genapap®. mg. S. caplets. Infantaire®. Kumar.Tylenol®. Children's Silapap®. Tylenol® Extra Strength. Ann Emerg Med 1991. Failure of physicians to recognize acetaminophen hepatotoxicity in chronic alcoholics. AC. elixir. JG. GRAPHICS Common dosage forms of acetaminophen Preparation Extended release caplet Extra strength tablets. C. Pharm J 1993. mg 80 mg. suspension 160 mg/5 mL (32 mg/mL) 500 mg/15 mL (33.8 mL) Infant Genapap®. geltabs Strength 650 mg Examples Tylenol ® Arthritis Pain 500 mg Genapap® Extra Strength. Bronstein.Infant's Mapap ® Infant's Tylenol® Acephen® Feverall® Mapap® Suppositories 120 650 mg.3 mg/mL) Drops 100mg/mL (80 mg/0.Medpap® Extra Strength. Genebs® . Rex. 20:1058. A 48-hour intravenous N-acetylcysteine protocol. Children's Tylenol® Junior Strength Tylenol® Redutemp®. Genapap®. Cetafen Extra ®. 105. mg. et al. Children's Mapap®. 120 325 mg 120 650 mg 15 . Arch Intern Med 1991. Aspirin Free Anacin® Maximum Strength.103. capsules. Acetaminophen overdose. Valorin Extra Cetafen®. Redutemp®.
One-half of the remaining acetaminophen is excreted unchanged in the urine and one-half is metabolized via the hepatic cytochrome P450 (CYP2E1. With toxic doses (red arrow). Once glutathione stores are depleted. 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine.Acetaminophen metabolism At therapeutic doses. CYP1A2. forming nontoxic cysteine and mercaptate compounds that are excreted in the urine. the sulfate and glucuronide pathways become saturated. With normal doses (blue arrows). CYP3A4 subfamilies) mixed function oxidase pathway to N-acetyl-p-benzoquinoneimine (NAPQI). Severity of acetaminophen intoxication 16 . which is hepatotoxic. NAPQI begins to accumulate and hepatic injury ensues. NAPQI is rapidly conjugated to hepatic glutathione. resulting in an increased fraction of acetaminophen being metabolized by cytochrome P450 enzymes.
30. | Subscription and License Agreement |Support Tag: [ecapp1002p. 55:873. The thick diagonal line of possible hepatic toxicity represents a 25 percent likelihood of disease. MD. © 2010 UpToDate.18-6FF8814DCB-6] Licensed to: UpToDate Individual Web – Do Quoc Huy 17 . and the risk of hepatic toxicity. All rights reserved. Adapted from Rumack. H. Courtesy of Jonathan Kruskal. the time after drug ingestion. but associated with appreciable risk at 24 hours since it reflects a high initial load which has now distributed into the tissues. Inc.com-123. Acute liver failure Contrast-enhanced CT scan of the liver in a 35-year-old female who took an overdose of acetaminophen demonstrates a heterogenous poorly enhancing liver with areas of lower attenuation due to acute fatty replacement.Relationship between plasma acetaminophen concentration (in µg/mL or µmol/L). BH. A relatively low level (such as 10 µg/mL) is safe soon after ingestion.83. Pediatrics 1975. Matthews.utd. Note also the patent recanalized paraumbilical vein coursing through the ligamentum teres (arrow).
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