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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, FAASLD, AGAF
Section Editor: Stephen J Traub, MD
Deputy Editor: Jonathan Grayzel, MD, FAAEM

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jun 21, 2017.

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 [1].
Acetaminophen is a component of hundreds of over-the-counter and prescription medications used
worldwide.

Although the drug is considered safe when taken at usual therapeutic doses (up to 4000 mg every 24 hours),
overdose of acetaminophen has been recognized since 1966 to cause fatal and nonfatal hepatic necrosis
[2,3]. It is suspected that even repeated therapeutic or slightly excessive doses can be hepatotoxic in
susceptible individuals, such as alcoholics [4-9]. Acetaminophen is one of the most commonly reported
products causing drug-induced liver injury (DILI) [1,3,10,11], and is the most common cause of acute liver
failure (ALF) in the United States – accounting for 50 percent of all reported cases and approximately 20
percent of liver transplant cases [12-16].

The pathophysiology, clinical manifestations, and diagnosis of acetaminophen intoxication will be reviewed
here. Treatment of this condition and poisoning in children are discussed separately. (See "Acetaminophen
(paracetamol) poisoning in adults: Treatment" and "Management of acetaminophen (paracetamol) poisoning
in children and adolescents" and "Clinical manifestations and diagnosis of acetaminophen (paracetamol)
poisoning in children and adolescents".)

EPIDEMIOLOGY — Acetaminophen is widely available, found in numerous products, and people commonly
underestimate its toxicity [10]. In addition, a substantial percentage of patients ingest excessive amounts of
acetaminophen because they misunderstand dosing directions or fail to recognize that acetaminophen is
found in more than one medication they are using [17]. Such errors occur most often among patients with
limited literacy or heavy acetaminophen use.

Not surprisingly, acetaminophen remains a major cause of overdose and overdose-related liver failure and
death in the United States and many other countries [12,18]. If overdose is identified early enough, mortality
rates are extremely low. However, once acute liver failure has developed, mortality is approximately 28
percent, and a third of patients require liver transplantation [19]. A national network established in 1998 to
track cases of ALF in the United States found that nearly half the episodes of ALF are attributable to
acetaminophen [13,20]. Data from this group demonstrate that intentional (suicidal) and unintentional
(chronic) poisonings account equally for cases of acetaminophen-associated hepatic failure [13,20].

A retrospective review of all cases of acetaminophen overdose that occurred over 10 years in the Calgary
region of Canada noted the following [21]:

● Of 1543 patients, 70 (4.5 percent) developed hepatotoxicity, and 15 died during their initial hospital
admission.

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● Risk factors for hepatotoxicity included unintentional overdose (odds ratio [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).

Patients are also at risk for hepatotoxicity when taking prescription products that combine APAP with opioids.
Over 130 million prescriptions were written for such products in 2010 [3]. Moreover, at least 6 percent of such
prescriptions for such combination products exceeded the 4000 mg maximum daily dose for acetaminophen
[3,19,22]. Among patients with an unintentional acetaminophen overdose, 63 percent were using
APAP/opioid compounds [20]. In consequence, the US Food and Drug Administration and a number of other
agencies now require that lower doses of acetaminophen be used in combination products, and some
manufacturers have reduced the amounts of acetaminophen included [11].

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):

● 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
[23].

● Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a
24-hour period [24,25].

● 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 [24].

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract (duodenum) [26]. Serum
concentrations peak between one-half and two hours after an oral therapeutic dose [27]. The presence of
food may delay the timing of absorption [26]. Peak serum concentrations are generally 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 [28-30]. 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 [29,31]. Half-lives greater than four hours have been noted in patients who develop hepatotoxicity
[32].

BIOCHEMICAL TOXICITY — Metabolism of APAP occurs within the hepatic microsomes. At therapeutic
doses, 90 percent of acetaminophen is metabolized in the liver to sulfate and glucuronide conjugates via
sulfotransferase (SULT) and UDP-glucuronosyl transferases (UGT) [26]. These conjugated metabolites are
then excreted in the urine [26,27,33,34]. Approximately 2 percent is excreted in the urine unchanged. The
remaining acetaminophen is metabolized via oxidation by 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) [7,34-39].

Appropriate acetaminophen doses produce a small amount of NAPQI which is rapidly conjugated with
hepatic glutathione (GSH), forming nontoxic cysteine and mercaptate compounds that are excreted in the
urine [26,33,40]. However, with toxic doses of acetaminophen, the sulfation and glucuronidation pathways
become saturated, and more acetaminophen is shunted to the cytochrome P450 enzymes and metabolized
to NAPQI [41]. When hepatic glutathione stores are depleted by approximately 70 to 80 percent, NAPQI
begins to react with cellular proteins and injury ensues [24,33,42,43]. Serum protein adducts, markers of
toxicity, have been detected as early as one hour after APAP treatment [26].

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NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, particularly
mitochondrial proteins, forming NAPQI-protein adducts [44-46]. This process is irreversible. The formation of
these adducts leads to oxidative hepatocyte injury, alteration of the mitochondrial ATP-synthase α-subunit,
and hepatocellular centrilobular necrosis [47-49]. Toxic free radicals (eg, peroxynitrite) form nitro-tyrosine
adducts within the mitochondria [11,36,38]. Injury to the mitochondrial DNA and ATP-synthase causes
cessation of ATP synthesis [11]. Lipid peroxidation and membrane injury may play a role in the progression of
hepatocellular injury [36,50]. In addition, release of cytokines, apoptosis-inducing factor (AIF), endonuclease
G (EndoG), and reactive nitrogen and oxygen species from damaged mitochondria play a role in the spread
of hepatic injury. Cytokine and cellular content release from hepatocytes may initiate a secondary
inflammatory response from Kupffer cells and other inflammatory cells, extending the zone of hepatic injury
[51-55]. Damage-associated molecular pattern (DAMP) products (eg, nuclear fragments, mitochondrial DNA)
recruit inflammatory cells via the innate immune system [37,56]. This secondary injury occurs during stage II
of clinical toxicity.(See 'Clinical manifestations' below.)

A number of advances have been made in clarifying the mechanisms of acetaminophen toxicity [11,57],
including the role of chemokines (in particular CCR2 positive monocytes) [58], the activation of the
inflammasome [59], and the contribution of hepatic stellate cells [60] and liver repair [61]. New models for
studying the drug’s toxicity include organoids [62] and ex-vivo perfused human liver [63].

CLINICAL FACTORS INFLUENCING TOXICITY — Liver damage secondary to acetaminophen ingestion


can develop under several circumstances:

● Excessive intake of acetaminophen (most important)

● Delay between acetaminophen ingestion and N-acetylcysteine therapy

● 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 these
mechanisms, including concomitant use of alcohol or other drugs, comorbid illnesses, advancing age, genetic
makeup, and nutritional status [49].

Acute alcohol ingestion — Alcohol is a substrate of the CYP2E1 enzyme. One research group found that
hepatotoxicity was lower in patients who took an acute APAP overdose with alcohol compared to those who
did not consume alcohol – 5.1 versus 15.2 percent, respectively [64]. Acute alcohol ingestion does not
appear to be a risk factor for hepatotoxicity and may even be protective by competing with acetaminophen for
CYP2E1 and, thereby, decreasing the amount of NAPQI produced [64-69].

Chronic alcohol ingestion — The role of chronic alcohol ingestion in acetaminophen-induced hepatotoxicity
remains contentious. Chronic alcohol ingestion - 18 or more standard alcoholic drinks (250 mg/dL) -
enhances and increases the synthesis and activity of CYP2E1 activity twofold and depletes glutathione
stores and synthesis [5,22,26,64,70,71]. There appears to be no evidence of increased hepatotoxicity in
chronic alcoholics who take therapeutic doses of APAP [64].

Single overdose — Chronic alcoholics do NOT appear to be at increased risk compared with non-
alcoholics for developing hepatotoxicity following a SINGLE overdose of acetaminophen and management
need not be altered for this patient group [25,72].

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 N-acetylcysteine [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) [73].

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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 [25]. 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 [74].

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 [4-9,75,76]. Delayed recognition of toxicity and continued use of the drug likely account for
much of the morbidity in this patient population [9,11]. 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 [70,71]. The net effect is an increased clearance rate of acetaminophen [77]
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 [7,76,78-80]. Chronic alcoholics may also have a decreased capacity
to synthesize a mitochondrial glutathione transport protein, thus enhancing susceptibility of mitochondria to
NAPQI [78,81].

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 [5].
Although according to patient reports 54 percent had ingested 6 g or less per day and 30 percent had taken
less than 4 g/day, the overall mortality rate reached 20 percent [5].

Despite this concerning finding, there is no evidence from prospective controlled trials that therapeutic doses
of acetaminophen cause hepatotoxicity in chronic alcohol users [9,72,80-84]. 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 [84]. 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 [83].

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; however, APAP metabolism is
reduced in the cirrhotic liver [9,64,69,78,83,85]. The acetaminophen elimination half-life in this patient
population is prolonged by an average of 2 to 2.5 hours (up to more than 4 hours); however, accumulation of
the drug does not occur with repeated administration [11,83]. More importantly, cytochrome P450 enzyme
activity is low and cannot be induced in these patients, which confers some hepatoprotection following
overdose [86]. It is generally recommended that patients with cirrhosis, particularly if decompensated, take
acetaminophen at a dose of no more than 2000 mg per day [64].

Medications and herbal products — Concomitant use of drugs or herbal products that induce CYP2E1
enzymes can predispose to hepatotoxicity in the absence of overt acetaminophen overdose, and may worsen
the outcome of an intentional overdose [87]. Examples of medications which alter CYP2E1 activity include
certain anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) and antituberculosis drugs (eg,
isoniazid and rifampin) [85,88,89].

Drugs such as trimethoprim-sulfamethoxazole, opioids and zidovudine may potentiate acetaminophen


hepatotoxicity by competing for glucuronidation pathways, resulting in increased CYP2E1-dependent
metabolism of acetaminophen [90]. Herbal supplements may potentially amplify acetaminophen-induced
injury [91]. Herbal products that may enhance the CYP450 activity include St. John’s wort, garlic, and
germander [1,11]. Patients should be questioned specifically about the use of herbal supplements since they

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are widely used, but often not mentioned during a routine medical interview. The Schisandra plant group may
have protective effects against APAP hepatotoxicity [11,92].

Nutritional status — Malnutrition and a period of fasting predispose to acetaminophen hepatotoxicity


[7,11,81,93]. 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 NAPQI [7,94,95]. Depleted glutathione stores, also
associated with the fasting and malnourished state, compromise detoxification of NAPQI and predispose to
hepatic injury [96]. In one study, recent fasting appeared to increase hepatotoxicity in patients with a
moderate overdose (4 to 10 g of acetaminophen within 24 hours) [7]. 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 [97,98]. The clinical relevance of these polymorphisms is unknown.
Impaired glucuronidation secondary to Gilbert's syndrome appears to enhance toxicity [99]. Variation in other
enzymes involved in APAP metabolism, including UGT, SULT, GST, N-deacetylase, NAT2, and fatty acid
amide hydrolase have been identified [100].

Age — APAP metabolism appears to be age-dependent and older patients appear more likely to develop
hepatotoxicity following acute overdose, whereas children less than five years old appear less susceptible to
toxicity [20,101-103]. Adults over 40 years of age have a greater risk of acute liver failure, liver
transplantation, and death following overdose [22]. Young children are probably protected via an increased
supply and regeneration of glutathione and greater activity of conjugation enzymes [104,105]. However,
following repeated excessive acetaminophen doses, young children are no less susceptible to hepatic injury
[106].

Tobacco — Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism [107,108]. One
review found tobacco use to be an independent risk factor for mortality following acetaminophen overdose
independent of the amount of tobacco consumed [109]. Mortality was greatest in smokers who also drink
alcohol.

Pattern of use — The dose and pattern of acetaminophen use is an important consideration when assessing
the risk for subsequent toxicity. Patients who accidentally poison themselves with repeated excessive doses
(supratherapeutic dosing) 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 to medical care 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 compared to those who attempted suicide, even though the latter had ingested
more acetaminophen [8].

Phosphate Levels — There appears to be an association between low phosphate levels and better clinical
outcomes following acetaminophen overdose [11,110,111]. It is postulated that this is most likely due to
enhanced cell regeneration aided by hepatocyte phosphate uptake to regenerate ATP.

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 (often
>3000 IU/L), and is associated with a rising prothrombin time (PT)/international normalized ratio (INR).
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 over 50 percent of these patients [4,5,38,112].

Other diagnoses that should be considered in patients with evidence of acute hepatic dysfunction include
alcoholic hepatitis, other drug- or toxin-induced hepatitis, viral hepatitis, hepatobiliary disease, Reye's
syndrome, and ischemic hepatitis ("shock liver"), which usually follows a period of severe prolonged
hypotension. (See "Approach to the patient with abnormal liver biochemical and function tests".)
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Dramatic elevations in the serum total bilirubin level (>10 mcg/mL) are uncommon following acetaminophen
overdose but can cause a false positive serum assay for acetaminophen in patients with acute viral
hepatitis, which may delay recognition of the underlying problem [113]. (See "Hepatitis A virus infection in
adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis B virus: Screening and
diagnosis".)

Unlike acute acetaminophen poisoning, acute alcoholic hepatitis and chronic acetaminophen poisoning in the
alcohol user have an AST to ALT ratio greater than two [4,5]. Aminotransferase values are also markedly
lower in patients with alcoholic hepatitis, and rarely exceed 500 IU/L. (See "Clinical manifestations and
diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis" and "Approach to the patient with abnormal
liver biochemical and function tests", section on 'Laboratory tests'.)

CLINICAL MANIFESTATIONS — The initial manifestations of acetaminophen poisoning are often mild and
nonspecific, and do not reliably predict subsequent hepatotoxicity [72,114]. 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. After massive acetaminophen overdose, central nervous system depression and elevated
anion gap metabolic acidosis may be seen, albeit rarely [115,116]. Such symptoms in acetaminophen-
poisoned patients are usually due to coingestants, such as diphenhydramine, opioids, or aspirin. Serum
aminotransferase concentrations are often normal, but may rise as early as 8 to 12 hours after ingestion in
severely poisoned patients [117].

Stage II (24 to 72 hours) — From 24 to 72 hours after ingestion, the laboratory evidence of hepatotoxicity,
and occasionally nephrotoxicity, become evident. (See 'Acute kidney injury (acute renal failure)' below.)

Initially, stage I symptoms resolve and patients appear to improve clinically while worsening subclinical
elevations of hepatic aminotransferases (AST, ALT) develop.

Of patients that develop hepatic injury, over one half will demonstrate aminotransferase elevation within 24
hours and all have elevations by 36 hours [117]. 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 [118].

Acute pancreatitis has been described in case reports [119,120]. In some patients, concurrent alcohol use
contributes to both hepatotoxicity and pancreatitis [121].

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 (image 1). Signs of severe
hepatotoxicity include plasma ALT and AST levels that often exceed 10,000 IU/L, prolongation of the PT/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 [38,118,122,123]. Death most commonly occurs in this stage, usually from
multiorgan system failure [38]. (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 [72]. 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 acetaminophen poisoning.

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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
[118,123,124]. 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 [112,125]. Vascular endothelial damage also can
occur, so that both direct toxicity and ischemia may contribute to the tubular injury [125].

Renal function spontaneously returns to the previous baseline within one to four weeks, although dialysis
may be required during the acute episode [123]. 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 high index of suspicion is often
required to diagnose APAP poisoning. Therefore, as the serum acetaminophen concentration is the basis for
diagnosing acute acetaminophen poisoning and determining the need for treatment, a concentration should
be measured in every patient suspected of an intentional or unintentional 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), 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
"Gastrointestinal decontamination of the poisoned patient" and "Enhanced elimination of poisons".)

Evaluation after acute overdose

Ingestion of immediate-release acetaminophen — The risk of hepatotoxicity is best predicted by


relating the time of ingestion to the serum acetaminophen concentration. The dose history should not be
used to predict hepatotoxicity as studies have found no correlation between the amount of acetaminophen
reportedly ingested and the serum concentration measured [126,127].

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After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration


should be drawn four hours after reported ingestion. If the ingestion was more than four hours prior to
presentation, the serum acetaminophen concentration should be measured immediately. The concentration
should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for NAC
therapy (figure 3) [128]. Serum concentrations drawn before four hours may not represent peak values, and
should not be used [72,129].

If the timing of ingestion is unknown or unclear, a serum acetaminophen concentration should be drawn
immediately and then repeated after four hours. An undetectable initial concentration must not be
misinterpreted to mean that hepatotoxicity is not present. The patient must still be observed and a repeat
concentration measured at four hours.

If the initial concentration is undetectable, the decision whether to treat with NAC is based on the presence or
absence of clinical and laboratory signs of hepatotoxicity. If there is any doubt, NAC therapy should be
started. If a patient presents with an unknown time of ingestion, treatment with NAC should be initiated
empirically, prior to results of serum APAP concentration and liver function testing. (See "Acetaminophen
(paracetamol) poisoning in adults: Treatment" and "Gastrointestinal decontamination of the poisoned patient"
and "Enhanced elimination of poisons".)

While there is universal agreement that NAC is effective for the prevention of hepatic injury when
administered soon after acetaminophen overdose, the exact guidelines for the initiation of treatment vary
throughout the world. The modified Rumack-Matthew Treatment nomogram (four hour concentration of 150
mg/L) has been used for many years and is our preferred tool to guide treatment because of its safety and
efficacy (figure 3) [128,130]. Using this approach, patients 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) [65,131].
Other guidelines using different treatment thresholds have been published and may be used in some
countries [132,133].

The original Rumack-Matthew 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 [24,134]. 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
[24,134]. As originally reported, patients with serum acetaminophen concentrations below the "probable
hepatic toxicity" line did not develop severe hepatotoxicity and no fatalities were reported [24,128,134].

The treatment line in the modified Rumack-Matthew Treatment nomogram is 25 percent lower than the
original treatment line ("probable hepatic toxicity") [81,131]. 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 [74]. The 25
percent margin of safety 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 [38,135,136].

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
[81,131]. There were no deaths in this group of treated patients [131].

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Ingestion of sustained-release acetaminophen — 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 [29,137]. 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 [72]. 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


(supratherapeutic dosing) 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 at therapeutic levels in the chronic overdose
population and concentrations do not correlate with toxicity as with the acute overdose [5,8,75,138]. The
Rumack-Matthew nomogram is not applicable in this setting.

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:

● Ingestion of greater than 7.5 to 10 g of acetaminophen over 24 hours, or ingestion of greater than 4 g
over 24 hours AND have an increased susceptibility to hepatotoxicity (eg, chronic alcohol use, fasting,
use of P450-inducing drugs) [23,72].

● Liver tenderness, jaundice, or are ill-appearing.

● Supratherapeutic serum acetaminophen concentrations (greater than 20 mcg/mL, or 130 micromol/L)


with or without ALT elevation [11,139,140]. 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). In addition, empiric early treatment with NAC is recommended for patients that present with
undifferentiated acute liver failure, as APAP toxicity is the leading cause of acute liver failure in industrialized
nations. 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 [11,72].
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".)

Evaluation following delayed presentation — Establishing the diagnosis of APAP poisoning in patients
who present greater than 24 hours to several days after ingestion can be challenging. Among late-presenting
patients with significant APAP poisoning, serum hepatotoxicity is invariably present, but a serum APAP
concentration may no longer be detectable. In these patients, distinguishing APAP-induced acute liver injury
from other causes of acute liver injury (ALI) is difficult; a history of APAP exposure may be absent or
unreliable.

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Assays to make the diagnosis in this setting are being developed. An observational cohort study reports that
an immunoassay that measures serum APAP-protein adducts can rapidly and accurately identify patients
with APAP-induced liver injury [141]. In this study, the point of care immunoassay (AcetaSTAT) had 100
percent sensitivity and 100 percent negative predictive value, compared with results of high performance
liquid chromatography (reference standard), for identifying patients with APAP-induced ALI. If these results
are validated in future clinical trials, this assay may provide a rapid means to distinguish APAP-induced ALI
from other causes of ALI and initiate appropriate management.

TREATMENT — The management of acetaminophen overdose, including antidotal treatment with N-


acetylcysteine (NAC), is discussed separately. (See "Acetaminophen (paracetamol) poisoning in adults:
Treatment" and "Management of acetaminophen (paracetamol) poisoning in children and adolescents".)

ADDITIONAL RESOURCES — Regional poison control centers in the United States are always available for
consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-
800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside
consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the
diagnosis and management of ingestions or overdoses. The World Health Organization provides a listing of
international poison centers at its website:
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html.

In addition to poison centers, liver transplant centers typically have transplant hepatologists available on call
at all times to aid in the management of patients with acetaminophen poisoning.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: General
measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused
by specific agents other than drugs of abuse".)

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 topic (see "Patient education: Acetaminophen poisoning (The Basics)")

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


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 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.)

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● Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract. Serum concentrations
peak between one-half and two hours after an oral therapeutic dose, although the presence of food may
slow this process. 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, medications that affect the CYP2E1 enzyme system of the liver, malnutrition, genetic
polymorphisms, 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 (often >3000 IU/L), and is
associated with a rising prothrombin time/international normalized ratio. 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 four hours after reported ingestion. 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.

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GRAPHICS

Common dosage forms of acetaminophen (paracetamol)

Preparation Strength Examples of US trade names

Extended release 650 mg Tylenol Arthritis Pain


caplet

Extra strength 500 mg Genapap Extra Strength, Genebs Extra Strength, Tylenol
tablets, capsules, Extra Strength, Medpap Extra Strength, Aspirin Free Anacin®
caplets, gelcaps, Maximum Strength, Cetafen Extra, Redutemp, Valorin Extra
geltabs

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, 160 mg/5 mL (32 Redutemp, Children's Genapap, Children's Silapap, Children's
elixir, suspension mg/mL) Mapap Children's Tylenol

500 mg/15 mL Tylenol Sore Throat


(33.3 mg/mL)

Drops* 100 mg/mL (80 Infant Genapap, Infantaire, Infant's Silapap Liquiprin for
mg/0.8 mL) Children, Infant's Mapap, Infant's Tylenol

Suppositories 80, 120, 325, 650 Acephen, Feverall, Mapap


mg

Intravenous 10 mg/mL Ofirmev



solution

* 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.

Graphic 79854 Version 5.0

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Acetaminophen metabolism

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 excreted unchanged in the urine
and one-half is metabolized via the hepatic cytochrome P450 (CYP2E1,
CYP1A2, CYP3A4 subfamilies) mixed function oxidase pathway to N-acetyl-p-
benzoquinoneimine (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.

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Severity of acetaminophen intoxication

The Rumack-Matthews nomogram summarizes the relationship between


plasma acetaminophen concentration (in µg/mL or µmol/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 µg/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.

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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. Note
also the patent recanalized paraumbilical vein coursing through the
ligamentum teres (arrow).

Courtesy of Jonathan Kruskal, MD.

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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
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.

* Note that mg/L is the same concentration as mcg/mL.

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.

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Contributor Disclosures
Michael J Burns, MD Nothing to disclose Scott L Friedman, MD Grant/Research/Clinical Trial Support:
Bristol Myers Squibb; Abbvie; Enanta; Zafgen. Consultant/Advisory Boards: 3-V Biotherapeutics; Abbvie
Pharmaceuticals; Chemocentryx Therapeutics; Deerfield Consulting; DeuteRx; DS Biosciences; Eli Lilly
Pharmaceuticals; Enanta Pharmaceuticals; Fractyl Bioscience; Genkyotex; GNI Group; Immune
Pharmaceuticals; Ironwood Pharmaceuticals; Isis Pharmaceuticals; Janssen Pharmaceuticals; Jecure
Therapeutics; Madrigal Pharmaceuticals; Metacrine; Metagenix; Merck; Novartis; Ocera Therapeutics; Pfizer;
Raptor Pharmaceuticals; Roche/Genentech; RuiYi [NASH therapeutics]; Shire; Synageva BioPHarma;
Takeda; Teva; Tobira Therapeutics; Zafgen [NASH therapeutics]; Galectin Therapeutics [NASH therapeutics
(GR-MD-02)]; Galmed [NASH therapeutics (Aramchol)]; Genfit [NASH therapeutics (Elafibrinor)]; Nimbus
Therapeutics [NASH therapeutics (ACC1&2 inhibitor)]; Intercept [NASH therapeutics (Obeticholic acid)];
Viking Therapeutics; Scholar Rock; Northern Biologics; Angion Biomedica; Akarna Therapeutics; Blade;
Boehringer Ingelheim; Bristol Myers Squibb; Daichi Sankyo; Debio [Fibrosis therapeutics]; Conatus [Fibrosis
therapeutics (Emricasan)]; Nitto [Fibrosis therapeutics (Liposomal siHSP47)]; Kinemed [Fibrosis diagnostics];
Exalenz Biosciences; Fibrogen [Fibrosis diagnostics (CTGF MoAb)]; Sandhill Medical Devices [Fibrosis
diagnostics (Fibroscan)]; Blueprint Medicines, Can-Fite Biopharma [Liver cancer therapeutics]; Glycotest
[Liver cancer diagnostics]; Tokai [Liver metabolism]. Equity Ownership/Stock Options: Akarna Therapeutics;
BirdRock Bio; Blade Therapeutics; Conatus; DeuteRx; Exalenz; Galectin; Galmed; Genfit; Glympse;
Intercept; Jecure Therapeutics; Nimbus; Northern Biologics; Scholar Rock; Tobira Therapeutics; Intercept;
Gilead. Anne M Larson, MD, FACP, FAASLD, AGAF Nothing to disclose Stephen J Traub, MD Nothing to
disclose Jonathan Grayzel, MD, FAAEM Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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