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Official reprint from UpToDate® www.uptodate.com ©2012 UpToDate®

AuthorsMichael J Burns, MDScott L Friedman, MDAnne M Larson, MD, FACP, AGAF

Section EditorsStephen J Traub, MDMichele Burns Ewald, MD

Deputy EditorJonathan Grayzel, MD, FAAEM

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

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 acomponent 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 beenrecognized since 1966 to cause fatal and nonfatal hepatic necrosis [1]. It is suspected that even repeated therapeutic orslightly excessive doses can be hepatotoxic in susceptible individuals, such as alcoholics [2-7]. Acetaminophenpoisoning 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. Notsurprisingly, acetaminophen remains a major cause of overdose and overdose-related liver failure and death in theUnited 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 theepisodes are attributable to acetaminophen, and such cases appear to be increasing as a percentage of all acute liverfailure events [9,14]. Data from this group demonstrate that intentional (suicidal) and unintentional (chronic) poisoningsaccount 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 ofCanada 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 (OR2.21; 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, givenevery four to six hours, with a maximum recommended daily dose of 80 mg/kg in children or 4 g in adults. The toxic dosemay vary among individuals according to baseline glutathione levels and other factors (see 'Clinical factors influencingtoxicity' below).

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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-hourperiod [17,18].

Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity (defined as peakaspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 1000 IU/L) unlessappropriately treated [17].

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Serum concentrations peak betweenone-half and two hours after an oral therapeutic dose [19]. Peak serum concentrations are reached within four hoursfollowing overdose of immediate-release preparations, but may be delayed beyond four hours when drugs that delaygastric emptying (eg, opiates, anticholinergic agents) are coingested or following overdose of extended releasespreparations [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 bedelayed in onset for extended-release preparations due to prolonged tablet dissolution and absorption [21,23]. Half-livesgreater 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 sulfateand glucuronide conjugates, which are then excreted in the urine [19,25,26]. Approximately 2 percent is excreted in theurine 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-p-benzoquinoneimine (NAPQI) (figure 1) [5,26-29].

Appropriate acetaminophen doses produce a small amount of NAPQI which is rapidly conjugated with hepaticglutathione, forming nontoxic cysteine and mercaptate compounds that are excreted in the urine [25,30]. However, withtoxic doses of a acetaminophen the sulfation and glucuronidation pathways are saturated, and more acetaminophen ismetabolized to NAPQI via the cytochrome P450 enzymes [31]. When hepatic glutathione stores are depleted byapproximately 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 ofhepatocellular injury [14,40]. In addition, it appears that the release of cytokines and reactive nitrogen and oxygenspecies from damaged hepatocytes also play a role in the spread of hepatic injury. Cytokine release from hepatocytesmay initiate a secondary inflammatory response from Kupffer cells and other inflammatory cells, extending the zone ofhepatic injury [41-45]. This secondary injury occurs during stage II of clinical toxicity. (See 'Clinicalmanifestations' below.)

CLINICAL FACTORS INFLUENCING TOXICITY — Liver damage from acetaminophen ingestion can occur in fourcircumstances:

Excessive intake of acetaminophenExcessive cytochrome P450 activityDecreased capacity for glucuronidation or sulfationDepletion of glutathione stores

A number of factors may influence the propensity of acetaminophen to cause hepatotoxicity through the mechanismslisted above, including concomitant use of alcohol or other drugs, comorbid illnesses, advancing age, genetic makeup,and nutritional status [39].

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Acute alcohol ingestion — Acute alcohol ingestion is NOT a risk factor for hepatotoxicity and may even be protectiveby 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 remainscontentious. 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 fordeveloping hepatotoxicity following a SINGLE overdose of acetaminophen and management need not be altered for thispatient group [18,52].

In one multicenter study of 2540 patients with acetaminophen overdose, chronic alcohol use did not increase theincidence of hepatotoxicity in low-risk patients (those treated with NAC within eight hours of ingestion or withacetaminophen 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 alcoholconsumption was not associated with a significantly worsened prognosis [18]. There is a single reported case of achronic alcohol user in whom hepatotoxicity developed despite a low predicted risk for this complication by the modifiedRumack-Matthew nomogram [54].

Multiple overdoses — In contrast to chronic alcoholics with an isolated ingestion, chronic alcoholics appear to be atincreased 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 patientpopulation [7]. Alcohol acts at least in part by induction of CYP2E1, which results in the shunting of a greater fraction ofacetaminophen through the CYP2E1 pathway and enhanced generation of NAPQI [50,51]. The net effect is an increasedclearance rate of acetaminophen [57] and associated increased risk for hepatotoxicity. (See "Pathogenesis of alcoholicliver disease".)

In addition to increased CYP2E1 pathway activity, several other factors may predispose alcoholics to severeacetaminophen-induced hepatotoxicity. The chronic alcoholic is more often malnourished, more likely to have a period ofrecent fasting, and more likely to have depleted hepatic glutathione stores than the nonalcoholic, all of which predisposeto hepatic injury [5,56,58-60]. Chronic alcoholics may also have a decreased capacity to synthesize a mitochondrialglutathione 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) ofacetaminophen is controversial. The question of increased risk was raised in one report of 161 regular users of alcoholwho developed hepatotoxicity following acetaminophen ingestion with therapeutic intent [3]. Although according topatient reports 54 percent had ingested 6 grams or less per day and 30 percent had taken less than 4 g/day, the overallmortality rate reached 20 percent [3].

Despite this concerning finding, there is no evidence from prospective controlled trials that therapeutic doses ofacetaminophen cause hepatotoxicity in chronic alcohol users [7,52,60-64]. In one prospective, double-blind, randomizedstudy of 201 alcoholics given maximal therapeutic doses (total 4 g/day) or placebo for two days showed no statisticaldifference in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentrations [64]. Similarly, asmaller controlled prospective study of 20 patients with chronic liver disease (including alcoholic cirrhosis) did notdevelop 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 atincreased risk for acetaminophen-induced hepatic injury [7,63,65]. Although the acetaminophen elimination half-life inthis 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

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confers hepatoprotection following overdose [66].

Medications — Concomitant use of drugs that induce CYP2E1 enzymes can cause hepatotoxicity in the absence ofovert acetaminophen overdose, and may worsen the outcome of an intentional overdose. Examples of medicationswhich alter CYP2E1 activity include anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) andantituberculosis drugs (eg, isoniazid and rifampin) [65,67,68].

Drugs such as trimethoprim-sulfamethoxazole and zidovudine may potentiate acetaminophen hepatotoxicity bycompeting for glucuronidation pathways, resulting in increased CYP2E1-dependent metabolism of acetaminophen [69].Herbal supplements may potentially amplify acetaminophen-induced injury [70]. Patients should be questionedspecifically about the use of herbal supplements since they are widely used, but often not mentioned during a routinemedical interview.

Nutritional status — Malnutrition and a period of fasting may predispose to acetaminophen hepatotoxicity, but evidenceis limited [5,61,71]. Hepatic glucuronidation is normally dependent upon hepatic carbohydrate reserves. In the fasting ormalnourished state, glucuronidation of acetaminophen is reduced which leads to enhanced microsomal metabolism andincreased production of the toxic NAPQI metabolite [5,72,73]. Depleted glutathione stores, also associated with thefasting 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 ofacetaminophen within 24 hours) [5]. Patients at greatest risk appear to be those that consume repeated excessivedoses, not a single overdose.

Genetics — Polymorphisms exist in the cytochrome isoenzymes that contribute to diminished or excessive oxidativemetabolism of acetaminophen [75,76]. The clinical relevance of these polymorphisms is unknown. Impairedglucuronidation 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 thanfive years old appear less susceptible to toxicity [14,78-80]. Young children are probably protected via an increasedsupply and regeneration of glutathione and greater activity of conjugation enzymes [81,82]. However, following repeatedexcessive 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 foundtobacco use to be an independent risk factor for mortality following acetaminophen overdose independent of the amountof 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 forsubsequent toxicity. Patients who accidentally poison themselves with repeated excessive doses in an attempt to relievepain or treat fever are more likely to have established risk factors for hepatotoxicity (eg, fasting, chronic ethanol use) andare more likely to present late, when the toxic effects of acetaminophen are already established. In one study of 71patients admitted with acetaminophen toxicity, patients in the accidental-overdose group had higher rates of severehepatotoxicity, hepatic coma, and death than those who attempted suicide, even though the latter had ingested moreacetaminophen [6].

DIFFERENTIAL DIAGNOSIS — Unlike most other causes of hepatitis, acetaminophen-induced hepatitis is acute inonset, progresses rapidly, is characterized by marked elevation of plasma aminotransferases (>3000 IU/L), and isassociated with a rising PT. Chronic acetaminophen poisoning in the alcohol user is also characterized by markedlyelevated aminotransferases (>3000 IU/L), combined with hypovolemia, jaundice, coagulopathy, hypoglycemia, and acuterenal 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

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("shock liver"), which usually follows a period of severe prolonged hypotension. (See "Approach to the patient withabnormal liver function tests".)

Dramatic elevations in the serum total bilirubin level (>10 mcg/mL) can result in a false positive serum assay foracetaminophen 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 userhave an AST to ALT ratio greater than two [2,3]. Aminotransferase values are also markedly lower in patients withalcoholic hepatitis, and rarely exceed 500 IU/L. (See "Clinical manifestations and diagnosis of alcoholic liverdisease" 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 recognizeacetaminophen poisoning in order to minimize subsequent morbidity and mortality. The clinical course of poisoning isoften 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. Centralnervous system depression and elevated anion gap metabolic acidosis are rarely seen after massiveacetaminophen 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 hepatotoxicityand, 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 hepaticaminotransferases (AST, ALT) occur. Occasionally, aminotransferases may rise as early as 8 to 12 hours afteracetaminophen ingestion in severely poisoned patients [91].

Of patients that develop hepatic injury, over one half will demonstrate aminotransferase elevation within 24 hours and allhave elevations by 36 hours [91]. As stage II progresses, patients develop right upper quadrant pain, with liverenlargement and tenderness. Elevations of prothrombin time (PT) and total bilirubin, oliguria, and renal functionabnormalities may become evident.

Acute pancreatitis has been described in case reports [92,93]. In some patients, concurrent alcohol use contributes toboth hepatotoxicity and pancreatitis [94].

Stage III (72 to 96 hours) — Liver function abnormalities peak from 72 to 96 hours after ingestion. The systemicsymptoms of stage I reappear in conjunction with jaundice, confusion (hepatic encephalopathy), a marked elevation inhepatic enzymes, hyperammonemia, and a bleeding diathesis (picture 1). Signs of severe hepatotoxicity include plasmaALT and AST levels that often exceed 10,000 IU/L, prolongation of the PT or INR, hypoglycemia, lactic acidosis, and atotal bilirubin concentration above 4.0 mg/dL (primarily indirect). Acute renal failure occurs in 10 to 25 percent of patientswith significant hepatotoxicity and in more than 50 percent of those with frank hepatic failure [28,95,96]. Death mostcommonly occurs in this stage, usually from multiorgan system failure [28]. (See 'Acute kidney injury (acute renalfailure)' below.)

Stage IV (four days to two weeks) — Patients who survive stage III enter a recovery phase that usually begins by dayfour and is complete by seven days after overdose [52]. Recovery can be slower in severely ill patients; symptoms andlaboratory values may not normalize for several weeks. Histologic changes in the liver vary from cytolysis to centrilobularnecrosis. The centrilobular region (zone III) is preferentially involved because it is the area of greatest concentration ofCYP2E1 and therefore the site of maximal production of NAPQI. Histologic recovery lags behind clinical recovery andmay take up to three months. When recovery occurs, it is complete; chronic hepatic dysfunction is not a sequela of

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acetaminophen poisoning.

Acute kidney injury (acute renal failure) — The incidence of renal dysfunction is related to the severity of theacetaminophen ingestion. Renal impairment has been estimated to occur in less than 2 percent of all patients (includingthose with minimal disease), 5 percent of cases with liver involvement but no hepatic failure, 10 percent of severepoisonings, and as many as 53 percent of cases with acute hepatic failure [96,97]. It is possible in the last setting that ahepatorenal-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, sothat 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 berequired during the acute episode [96]. There is no evidence that acetylcysteine, which is given to minimizehepatotoxicity, has any protective effect on the kidney.

DIAGNOSIS

General approach and serum acetaminophen concentration — A serum acetaminophen level must be obtained inevery 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, andprediction of toxicity. In all patients with suspected acetaminophen overdose, a history should be obtained to elicitthe 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 developmentof hepatic injury (eg, alcohol use, Gilbert's disease, anticonvulsant drug use, recent fasting). (See 'Clinical factorsinfluencing toxicity' above.)

All patients with a clear history of acetaminophen overdose should undergo measurement of serumacetaminophen concentration. If any doubt exists about the time of ingestion, a serum concentration should beobtained immediately at the time of presentation. A serum concentration should also be obtained four hoursfollowing the time of acute ingestion or presentation.

In those with established toxicity, or those predicted to develop toxicity based on history and initial serumacetaminophen concentration, additional laboratory tests should include electrolytes, BUN and creatinine, serumtotal bilirubin level, prothrombin time with INR, AST, ALT, amylase, and urinalysis. In patients with intentionalingestions 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, theadministration of antidotes and enhancement of drug elimination. Treatment of acetaminophen poisoning isdiscussed 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 serumacetaminophen concentration. The dose history should not be used as studies have found no correlation between theamount of acetaminophen reportedly ingested and the serum concentration measured [99,100].

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After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration should bedrawn four and 24 hours after presentation. If the ingestion was more than four hours prior to presentation, it should bedrawn immediately. The level should be evaluated according to the modified Rumack-Matthew nomogram to determinethe need for NAC therapy (figure 3) [101]. Serum concentrations drawn before four hours may not represent peakvalues, and should not be used [52,102].

The original nomogram, based on large numbers of overdose patients not treated with antidote, relates serumacetaminophen concentration to the time of ingestion as a predictor of hepatotoxicity (figure 2). Without antidotaltherapy, patients with serum acetaminophen concentrations above the line joining 200 mcg/mL (1320 micromol/L) at 4hours and 25 mcg/mL (165 micromol/L) at 16 hours ("probable hepatic toxicity") have a 60 percent incidence of severehepatotoxicity (AST greater than 1000 IU/L) and a mortality rate of 5 percent [17,103]. Untreated patients with serumacetaminophen concentrations above the line joining 300 mcg/mL (1980 micromol/L) at 4 hours and 37.5 mcg/mL (250micromol/L) at 16 hours ("high hepatic toxicity") have a 90 percent incidence of severe hepatotoxicity and a mortality rateof 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 (990micromol/L) at 4 hours and 18.8 mcg/mL (125 micromol/L) at 16 hours are considered at "possible risk" for hepatotoxicityand treatment with NAC is standard (figure 3) [46,104]. This modified treatment line is 25 percent lower than the originaltreatment line ("probable hepatic toxicity"), which is still used in Australia, Canada, and Great Britain. This margin ofsafety was created to allow for variations in acetaminophen measurements among laboratories and possible errors in theestimated time of ingestion. The incidence of nomogram failure using the modified line is extraordinary small [54]. The 25percent 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 bysome authorities [28,105,106].

Even with NAC treatment, severe hepatic toxicity (AST >1000 IU) may occasionally occur when patients have serumacetaminophen concentrations below the "possible hepatic toxicity" line. In one study of 2023 patients treated with oralNAC for acute acetaminophen overdose, the incidence of severe hepatotoxicity was 0 to 3 percent for those patientswith serum acetaminophen concentrations below the "possible hepatic toxicity" line [61,104]. There were no deaths inthis group of treated patients [104].

There is presently insufficient experience to know whether the Rumack-Matthew nomogram can accurately assess riskfollowing 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 NACinitiated if either concentration is above the "possible hepatic toxicity" line of the nomogram [21,107]. It is likely that asingle acetaminophen concentration plotted on the nomogram and below the treatment line is adequate to exclude theneed for NAC treatment [52]. Until more clinical experience has been gained, our recommendation is to follow theconservative approach of the manufacturer. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".)

Evaluation after repeated (chronic) overdose — Diagnosis of chronic acetaminophen intoxication is often difficult andrequires the combination of an astute history and recognition of typical clinical and laboratory abnormalities. Signs andsymptoms 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 questionsabout dosing and the pattern of use. Acetaminophen serum concentrations are frequently therapeutic in the chronicoverdose 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 whoneed NAC treatment based upon a combination of historical, clinical, and laboratory data. Patients are at increased riskfor developing acetaminophen-induced hepatotoxicity if they have any of the following findings:

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Ingestion of greater than 7.5 to 10 g of acetaminophen over 24 hours, or ingestion of greater than 4 grams over24 hours AND have an increased susceptibility to hepatotoxicity (eg, chronic alcohol use, fasting, use of P450-inducing drugs) [16,52].

Liver tenderness, jaundice, or are ill-appearing.

Supratherapeutic acetaminophen concentrations (greater than 20 mcg/mL, or 130 micromol/L). Patients with ahistory of chronic, excessive acetaminophen ingestion should be considered to have acetaminophen-inducedhepatotoxicity when aminotransferases are elevated, regardless of the measured serum acetaminophenconcentration.

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 withhistory of excessive ingestion, risk factors for toxicity, and acetaminophen concentrations >10 mcg/mL (65 micromol/L). Ifa patient has a detectable acetaminophen concentration but is without signs, symptoms, or risk factors for toxicity andwithout elevations of aminotransferases, then treatment is likely not necessary [52]. If the serum acetaminophenconcentration is undetectable and aminotransferases are normal, NAC therapy is not necessary. Treatment is clearlyrecommended if serum acetaminophen concentrations are potentially toxic by the nomogram with respect to the time ofthe last dose. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment".)

ADDITIONAL RESOURCES — To obtain emergent consultation with a medical toxicologist, call the United StatesPoison 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 withN-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 ofacetaminophen overdose provided NAC was given within 10 hours of ingestion, regardless of the initial serumacetaminophen concentration [103,104,109]. As an example, one study of 333 consecutive acetaminophen overdosecases found that hepatotoxicity occurred in only 4 percent of patients and mortality was less than 1 percent when NACwas 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 appropriatetherapy.

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 readinglevel, and they answer the four or five key questions a patient might have about a given condition. These articles arebest 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 gradereading 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 toyour patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” andthe keyword(s) of interest.)

Basics topics (see "Patient information: Acetaminophen poisoning (The Basics)")

SUMMARY AND RECOMMENDATIONS — Important elements of the presentation and diagnosis of

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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 thismedication. 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 amongindividuals, 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 foran adult. Toxicity IS likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a24-hour period. (See 'Epidemiology' above and 'Pharmacokinetics' above.)

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Serum concentrations peakbetween one-half and two hours after an oral therapeutic dose. Peak serum concentrations are reached withinfour hours following overdose of immediate-release preparations but may be delayed when drugs that slowgastric emptying (eg, opiates, anticholinergic agents) are coingested or following overdose of extended releasepreparations. 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 alcoholingestion, chronic liver disease, medications that affect the CYP2E1 enzyme system of the liver, malnutrition, andolder age. (See 'Clinical factors influencing toxicity' above.)

Unlike most other causes of hepatitis, acetaminophen-induced hepatitis is acute in onset, progresses rapidly, ischaracterized by marked elevation of plasma aminotransferases (>3000 IU/L), and is associated with a risingprothrombin time. Chronic acetaminophen poisoning in the alcohol user is also characterized by markedlyelevated 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 predictsubsequent hepatotoxicity. Thus, measurement of the serum acetaminophen concentration is critical wheneveroverdose is suspected. The symptoms and signs of the four stages of acetaminophen overdose are described inthe 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 acuteoverdose of an immediate-release preparation, a serum acetaminophen concentration should be drawn 4 and 24hours after presentation. If the ingestion was more than four hours prior to presentation, it should be drawnimmediately. The level should be evaluated according to the modified Rumack-Matthew nomogram to determinethe need for NAC therapy (figure 3). Use of the nomogram in the setting of acute and chronic overdose ofacetaminophen is described in the text. (See 'Diagnosis' above.)

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Topic 340 Version 13.0

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GRAPHICS

Common dosage forms of acetaminophen (paracetamol)

Preparation Strength Examples of US trade names

Extended releasecaplet

650 mg Tylenol Arthritis Pain

Extra strengthtablets, capsules,caplets, gelcaps,geltabs

500 mg Genapap Extra Strength, Genebs Extra Strength, Tylenol ExtraStrength, Medpap Extra Strength, Aspirin Free Anacin®Maximum Strength, Cetafen Extra, Redutemp, Valorin Extra

Tablets 325 mg Cetafen, Genapap, Genebs ,Tylenol, Valorin, Mapap

160 mg Mapap

Chewable tablets 80 mg Children's Genapap, Children's Mapap, Children's Tylenol

160 mg Junior Strength Tylenol

Liquid, syrup, elixir,suspension

160 mg/5mL (32mg/mL)

Redutemp, Children's Genapap, Children's Silapap, Children'sMapap Children's Tylenol

500 mg/15mL (33.3mg/mL)

Tylenol Sore Throat

Drops* 100 mg/mL(80 mg/0.8mL)

Infant Genapap, Infantaire, Infant's Silapap Liquiprin forChildren, Infant's Mapap, Infant's Tylenol

Suppositories 80, 120,325, 650mg

Acephen, Feverall, Mapap

Intravenoussolution•

10 mg/mL Ofirmev

*As of 2011, in an effort to minimize pediatric dosing errors, the Consumer Healthcare ProductsAssociation, in conjunction with the US Federal Drug Administration, is phasing out formulations thatcontain 100 mg per ml (infant acetaminophen drops) so that pediatric liquid preparations obtained in theUnited 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 dropspreparations purchased by caregivers before this phase out.

•NOTE: Tenfold dosing errors and toxicity from intravenous acetaminophen have occurred in smallchildren when the calculated dose in mg is INCORRECTLY administered as the volume in mL because theconcentration of the solution is 10 mg/mL. In the United States, intravenous acetaminophen isnot licensed for use in children under two years of age.

Acetaminophen metabolism

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At therapeutic doses, 90 percent of acetaminophen is metabolizedin the liver to sulfate and glucuronide conjugates that are thenexcreted in the urine. One-half of the remaining acetaminophen isexcreted unchanged in the urine and one-half is metabolized viathe hepatic cytochrome P450 (CYP2E1, CYP1A2, CYP3A4subfamilies) mixed function oxidase pathway to N-acetyl-p-benzoquinoneimine (NAPQI), which is hepatotoxic. With normaldoses (blue arrows), NAPQI is rapidly conjugated to hepaticglutathione, forming nontoxic cysteine and mercaptatecompounds that are excreted in the urine. With toxic doses (redarrow), the sulfate and glucuronide pathways become saturated,resulting in an increased fraction of acetaminophen beingmetabolized by cytochrome P450 enzymes. Once glutathionestores are depleted, NAPQI begins to accumulate and hepaticinjury ensues.

Severity of acetaminophen intoxication

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The Rumack-Matthews nomogram summarizes the relationshipbetween plasma acetaminophen concentration (in !g/mL or!mol/L), the time after drug ingestion, and the risk of hepatictoxicity. The thick diagonal line of possible hepatic toxicityrepresents a 25 percent likelihood of disease. A relatively lowlevel (such as 10 !g/mL) is safe soon after ingestion, butassociated with appreciable risk at 24 hours since it reflects ahigh 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 femalewho took an overdose of acetaminophen demonstrates a

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heterogenous poorly enhancing liver with areas of lowerattenuation due to acute fatty replacement. Note also the patentrecanalized paraumbilical vein coursing through the ligamentumteres (arrow).Courtesy of Jonathan Kruskal, MD.

Acetaminophen poisoning nomogram

This nomogram should only be used after a single acuteacetaminophen ingestion. The line indicates the level at whichtoxicity is possible after acetaminophen overdose. A serumacetaminophen level should be obtained four or more hours after aningestion to ensure that a peak level has occurred. Patients whoingest extended-release preparations should have a second level

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drawn four hours after the first level to assess for an additional risein serum concentration. The level should be plotted in relationshipto the time of ingestion to determine the likelihood of toxicity andthe need for treatment. Caution should be used in assessing thereliability of the time of ingestion. This nomogram cannot be usedfor ingestions that occurred greater than 24 hours prior topresentation, repeated supratherapeutic oral ingestions, oriatrogenic intravenous overdose.Original nomogram from: Rumack BH, Matthew H. Acetaminophen poisoningand toxicity. Pediatrics 1975; 55:871. Copyright © 1975 by the AAP. Updatedversion 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.