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

Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation
Literature review current through: Aug 2023.
This topic last updated: Mar 13, 2023.

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 people with alcohol use disorders [4-9]. Acetaminophen is one of the most commonly reported products causing drug-induced liver injury [1,3,10,11] and is the most common cause of acute liver failure 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 and 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 acute liver failure in the United States found that nearly half the episodes of acute liver failure 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.

Risk factors for hepatotoxicity included unintentional overdose (odds ratio [OR] 5.18; 95% CI 3.00-8.95), alcohol use disorder (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 acetaminophen with opioids. Over 130 million prescriptions were written for such products in 2010 [3]. Moreover, at least 6 percent of such prescriptions exceeded the 4000 mg maximum daily dose for acetaminophen [3,19,22]. Among patients with an unintentional acetaminophen overdose, 63 percent were using acetaminophen/opioid compounds [20]. In consequence, the US Food and Drug Administration (FDA) 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]. An interrupted time-series analysis of a hospitalization database and multicenter liver failure study group (39,606 and 465 cases of combined acetaminophen/opioid toxicity, respectively) found a significant decrease in hospitalizations for acetaminophen/opioid compounds since 2011, correlating with the FDA announcement limiting acetaminophen to 325 mg in combined opioid formulations [23]. Since 2011, the incidence of hospitalization for combined acetaminophen and opioid toxicity decreased from 12.2 to 4.4/100,000 hospitalizations (absolute difference 7.8 cases/100,000 hospitalizations, 95% CI 6.6-9.0), and the percentage of acute liver failure cases from combined acetaminophen and opioid products decreased from 27.4 to 5.3 percent (absolute difference 21.8 percent, 95% CI 15.5-32.4).

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 that may influence 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 [24].

Toxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period [25,26].

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 [25].

Acetaminophen is rapidly and completely absorbed from the gastrointestinal tract (duodenum) [27]. Serum concentrations peak between one-half and two hours after an oral therapeutic dose [28]. The presence of food may delay the timing of absorption [27]. 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-release preparations [29-31]. 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 [30,32]. Half-lives greater than four hours have been noted in patients who develop hepatotoxicity [33].

BIOCHEMICAL TOXICITY — Metabolism of acetaminophen 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) [27]. These conjugated metabolites are then excreted in the urine [27,28,34,35]. 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) [7,35-40].

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 [27,34,41]. 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 [42]. When hepatic glutathione stores are depleted by approximately 70 to 80 percent, NAPQI begins to react with cellular proteins, and injury ensues [25,34,43,44]. Serum protein adducts, markers of toxicity, have been detected as early as one hour after acetaminophen treatment [27].

NAPQI arylates and binds covalently to the cysteine groups on hepatic macromolecules, particularly mitochondrial proteins, forming NAPQI-protein adducts [45-47]. This process is irreversible. The formation of these adducts leads to oxidative hepatocyte injury, alteration of the mitochondrial ATP-synthase alpha-subunit, and hepatocellular centrilobular necrosis [48-50]. Toxic free radicals (eg, peroxynitrite) form nitrotyrosine adducts within the mitochondria [11,37,39]. 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 [37,51]. 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 [52-56]. Damage-associated molecular pattern (DAMP) products (eg, nuclear fragments, mitochondrial DNA) recruit inflammatory cells via the innate immune system [38,57]. 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 [11,58], including the role of chemokines (in particular C-C chemokine receptor type 2 [CCR2]-positive monocytes) [59], the activation of the inflammasome [60], and the contribution of hepatic stellate cells [61] and liver repair [62]. New models for studying the drug's toxicity include organoids [63] and ex-vivo perfused human liver [64].

CLINICAL FACTORS THAT MAY INFLUENCE 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 (NAC) 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 [50].

In one retrospective review of data from a national acute liver injury registry, acetaminophen-induced acute liver failure was noted to be more common and severe in women [65]. However, this trend has not been consistently noted in prior studies, and there are insufficient data to state unequivocally that women are at greater risk for acetaminophen-induced liver failure.

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 acetaminophen overdose with alcohol compared with those who did not consume alcohol: 5.1 versus 15.2 percent, respectively [66]. 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 [66-71].

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 [5,22,27,66,72,73]. There appears to be no evidence of increased hepatotoxicity in people with chronic alcohol use disorders who take therapeutic doses of acetaminophen [66].

Single overdose — People with chronic alcohol use disorders do not appear to be at increased risk compared with those without for developing hepatotoxicity following a single overdose of acetaminophen, and management need not be altered for this patient group [26,74].

In one multicenter study of 2540 patients with acetaminophen overdose, chronic alcohol use did not increase the incidence of hepatotoxicity in low-risk patients (those treated with NAC within eight hours of ingestion or with acetaminophen concentration less than the probable hepatic toxicity line of the original Rumack-Matthew nomogram) (figure 2) [75].

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 [26]. 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 [76].

Multiple overdoses — In contrast to an isolated ingestion, people with chronic alcohol use disorders appear to be at increased risk for hepatotoxicity following ingestion of repeated, supratherapeutic doses of acetaminophen [4-9,77,78]. 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 [72,73]. The net effect is an increased clearance rate of acetaminophen [79] and associated increased risk for hepatotoxicity. (See "Pathogenesis of alcohol-associated liver disease".)

In addition to increased CYP2E1 pathway activity, several other factors may predispose people with alcohol use disorders to severe acetaminophen-induced hepatotoxicity. These patients are 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 [7,78,80-82]. People with chronic alcohol use disorders may also have a decreased capacity to synthesize a mitochondrial glutathione transport protein, thus enhancing susceptibility of mitochondria to NAPQI [80,83].

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 [9,74,82-86]. One prospective, double-blind, randomized study of 201 patients with chronic alcohol use disorders 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 [86]. Similarly, a smaller controlled prospective study of 20 patients with chronic liver disease (including alcohol-related cirrhosis) did not develop hepatotoxicity when given acetaminophen at 4 g/day for two weeks [85].

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, acetaminophen metabolism is reduced in the cirrhotic liver [9,66,71,80,85,87]. 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 [11,85]. More importantly, cytochrome P450 enzyme activity is low and cannot be induced in these patients, which confers some hepatoprotection following overdose [88]. It is generally recommended that patients with cirrhosis, particularly if decompensated, take acetaminophen at a dose of no more than 2000 mg per day [66].

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 [89]. Examples of medications that alter CYP2E1 activity include certain anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) and antituberculosis drugs (eg, isoniazid and rifampin) [87,90,91].

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 [92]. Herbal supplements may potentially amplify acetaminophen-induced injury [93]. 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 are widely used but often not mentioned during a routine medical interview. The Schisandra plant group may have protective effects against acetaminophen-related hepatotoxicity [11,94].

Nutritional status — Malnutrition and a period of fasting predispose to acetaminophen hepatotoxicity [7,11,83,95,96]. 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 [7,97,98]. Depleted glutathione stores, also associated with the fasting and malnourished state, compromise detoxification of NAPQI and predispose to hepatic injury [99]. 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 [100,101]. The clinical relevance of these polymorphisms is unknown. Impaired glucuronidation secondary to Gilbert's syndrome appears to enhance toxicity [102]. Variation in other enzymes involved in acetaminophen metabolism, including UDP-glucuronosyl transferases (UGT), sulfotransferase (SULT), glutathione S-transferase (GST), N-deacetylase, N-acetyltransferase-2 (NAT2), and fatty acid amide hydrolase have been identified [103].

Age — Acetaminophen 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 [20,104-106]. 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 [107,108]. However, following repeated excessive acetaminophen doses, young children are no less susceptible to hepatic injury [109].

Tobacco — Tobacco smoke contains CYP1A2 inducers and increases oxidative metabolism [110,111]. One review found tobacco use to be an independent risk factor for mortality following acetaminophen overdose independent of the amount of tobacco consumed [112]. 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.

Repeated supratherapeutic dosing — Patients may accidentally develop clinically significant poisoning from repeated ingestions of supratherapeutic doses of acetaminophen in an attempt to relieve pain or treat fever. These patients 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 with those who attempted suicide, even though the latter had ingested more acetaminophen [8].

Repeated therapeutic dosing — Subclinical toxicity (mild, self-limited, clinically insignificant transaminase elevations) may develop following repeated therapeutic dosing. In a randomized, controlled trial of 145 healthy adults taking maximal therapeutic doses of acetaminophen (4 g/day) for 10 days, 31 to 44 percent developed a maximum ALT >3 times the upper limit of normal (>120 U/L) as compared with 0 percent in the control group [113]. An observational study of 24 healthy adult volunteers treated with 4 g/day of acetaminophen for 10 days demonstrated subclinical ALT elevations in 58 percent of study participants [114].

Phosphate concentration — There appears to be an association between low serum phosphate concentrations and better clinical outcomes following acetaminophen overdose [11,115,116]. 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 aminotransferase concentrations (>3000 IU/L) combined with hypovolemia, jaundice, coagulopathy, hypoglycemia, and acute renal failure in over 50 percent of these patients [4,5,39,117].

Other diagnoses that should be considered in patients with evidence of acute hepatic dysfunction include alcohol-related 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".)

Dramatic elevations in the serum total bilirubin level (>1 mg/dL; >17 micromol/L) 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 [118]. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis" and "Hepatitis B virus: Screening and diagnosis in adults".)

Unlike acute acetaminophen poisoning, acute alcohol-related hepatitis and chronic acetaminophen poisoning in the alcohol user have an aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio greater than two [4,5]. Aminotransferase values are also markedly lower in patients with alcohol-related hepatitis and rarely exceed 500 IU/L. (See "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and 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 [74,119]. 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 [120,121]. 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 [122].

Stage II (24 to 72 hours) — From 24 to 72 hours after ingestion, the laboratory evidence of hepatotoxicity, and occasionally nephrotoxicity, becomes 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 (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) develop.

Of patients who develop hepatic injury, over one-half will demonstrate aminotransferase elevation within 24 hours, and all have elevations by 36 hours [122]. As stage II progresses, patients develop right upper quadrant pain with liver enlargement and tenderness. Elevations of PT and total bilirubin, oliguria, and renal function abnormalities may become evident [123].

Acute pancreatitis has been described in case reports [124,125]. In some patients, concurrent alcohol use contributes to both hepatotoxicity and pancreatitis [126].

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 or 68 micromol/L, (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 [39,123,127,128]. Death most commonly occurs in this stage, usually from multiorgan system failure [39]. (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 [74]. 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.

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 [123,128,129]. 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 [117,130]. Vascular endothelial damage also can occur, so that both direct toxicity and ischemia may contribute to the tubular injury [130].

Renal function spontaneously returns to the previous baseline within one to four weeks, although dialysis may be required during the acute episode [128]. There is no evidence that acetylcysteine, which is given to minimize hepatotoxicity, has any protective effect on the kidney.

EVALUATION AND DIAGNOSIS

General approach and serum acetaminophen concentration — A high index of suspicion is often required to diagnose acetaminophen 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, presence of coingestants, and existence of comorbid conditions that may predispose to the development of hepatic injury (eg, alcohol use, Gilbert's disease, antiseizure medication use, recent fasting). (See 'Clinical factors that may influence 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, blood urea nitrogen and creatinine, serum total bilirubin level, prothrombin time (PT) with international normalized ratio (INR), aspartate aminotransferase (AST), alanine aminotransferase (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 [131,132].

After a single acute overdose of an immediate-release preparation, a serum acetaminophen concentration should be drawn four hours after the reported time of 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 N-acetylcysteine (NAC) therapy (figure 3) [133]. Serum concentrations drawn before four hours may not represent peak values and should not be used [74,134].

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 or eight hours have passed since the presumed time of ingestion, treatment with NAC should be initiated empirically, prior to results of serum acetaminophen concentration and liver function testing. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment" and "Gastrointestinal decontamination of the poisoned patient" and "Enhanced elimination of poisons".)

Using the treatment nomogram — 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) [133,135]. 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) [67,136]. Other guidelines using different treatment thresholds have been published and may be used in some countries [137,138].

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 [25,139]. 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 [25,139]. As originally reported, patients with serum acetaminophen concentrations below the "probable hepatic toxicity" line did not develop severe hepatotoxicity, and no fatalities were reported [25,133,139].

The treatment line in the modified Rumack-Matthew treatment nomogram is 25 percent lower than the original treatment line ("probable hepatic toxicity") [83,136]. 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 [76]. 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 [39,140,141].

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 [83,136]. There were no deaths in this group of treated patients [136].

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 [30,142]. 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 [74]. 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 supratherapeutic ingestion — The diagnosis of acetaminophen toxicity following a repeated supratherapeutic ingestion (RSTI) 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 or RSTI population, and concentrations do not correlate with toxicity as with the acute overdose [5,8,77,143]. The Rumack-Matthew nomogram is not applicable in this setting.

Assessing risk for hepatotoxicity — When a RSTI of acetaminophen is known or 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 an increased susceptibility to hepatotoxicity (eg, chronic alcohol use, fasting, use of P450-inducing drugs (table 2)) [24,74].

Abdominal pain or liver tenderness, nausea, vomiting, jaundice, or are ill appearing.

Supratherapeutic serum acetaminophen concentrations (greater than 20 mcg/mL, or 130 micromol/L) with or without ALT elevation [11,144,145].

Elevated ALT or AST concentration (≥50 U/L) on presentation. Patients with a history of RSTI of acetaminophen should be considered to have acetaminophen-induced hepatotoxicity when aminotransferases are elevated, regardless of the measured serum acetaminophen concentration.

Elevated acetaminophen-aminotransferase multiplication product on presentation. An elevated product predicts significant hepatotoxicity independent of the time of ingestion [146].

Need for treatment with n-acetylcysteine — In the setting of a RSTI, treatment with NAC is clearly indicated if serum acetaminophen concentrations are potentially toxic by the nomogram with respect to the time of the last dose. Treatment with NAC is recommended for all patients with an RSTI and clinical signs of toxicity (eg, liver tenderness), elevations of aminotransferases (ALT or AST ≥50 U/L), 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 who present with undifferentiated acute liver failure, as acetaminophen toxicity is the leading cause of acute liver failure in industrialized nations. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment" and "Management of acetaminophen (paracetamol) poisoning in children and adolescents".)

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 [11,74]. If the serum acetaminophen concentration is undetectable (<10 mcg/mL, 65 micromol/L) and aminotransferases are normal (ALT or AST <50 U/L), NAC therapy is not necessary. At presentation, an ALT concentration <50 U/L and acetaminophen-aminotransferase multiplication product <1500 mcg/mL (9,900 micromol/L) x U/L appear to be highly predictive in ruling out patients that develop significant hepatotoxicity (ALT >1000 U/L).  

Four studies of patients following an RSTI of acetaminophen (collectively, 625 patients) have consistently demonstrated that all patients who present with an ALT <50 U/L do not develop significant hepatotoxicity (ALT >1000 U/L), provided their presenting acetaminophen concentration is low [147-150]. In two of these studies, an initial acetaminophen-aminotransferase multiplication product <1500 mcg/mL (9,900 micromol/L) x U/L predicted that patients would not develop significant hepatotoxicity (ALT >1000 U/L). Definitive recommendations based on these studies cannot be made due to their largely retrospective and nonrandomized design, inconsistent follow-up of patients, and, most importantly, the wide range of patients (40 to 100 percent in different studies) treated with NAC despite an ALT <50 and/or an initial acetaminophen-aminotransferase multiplication product below 1500 mcg/mL (9,900 micromol/L) x U/L.

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

Assays to make the diagnosis in this setting are being developed. An observational cohort study reports that an immunoassay that measures serum acetaminophen-protein adducts can rapidly and accurately identify patients with acetaminophen-induced liver injury [151]. 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 acetaminophen-induced acute liver injury. If these results are validated in future clinical trials, this assay may provide a rapid means to distinguish acetaminophen-induced acute liver injury from other causes of acute liver injury and initiate appropriate management.

TREATMENT — The management of acute 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 — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

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

Toxic doseAcetaminophen can be fatal in overdose, but the potential dangers are often underappreciated. (See 'Epidemiology' above and 'Pharmacokinetics' above.)

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.

PharmacokineticsAcetaminophen 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. (See 'Pharmacokinetics' above.)

Mechanism of toxicity – Hepatic cytochrome P450 metabolism of acetaminophen into a toxic, highly reactive, electrophilic intermediate N-acetyl-p-benzoquinoneimine (NAPQI) occurs when the safer sulfation and glucuronidation pathways are saturated and hepatic glutathione stores are depleted (figure 1). NAPQI arylates and binds covalently to hepatic macromolecules initiating a cascade of oxidative hepatocyte injury. (See 'Biochemical toxicity' above.)

Predisposing factors – Clinical factors that can predispose patients to injury from repeated, supratherapeutic acetaminophen ingestion include medications that induce CYP2E1 activity (table 2), malnutrition, genetic polymorphisms, and older age. The role of chronic alcohol ingestion is uncertain. (See 'Clinical factors that may influence toxicity' above.)

Clinical manifestations – 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 manifestations are classically described to occur in four stages. (See 'Clinical manifestations' above.)

Stage I (0.5 to 24 hours) – Asymptomatic or nausea, vomiting, diaphoresis, pallor, lethargy, and malaise. Laboratory studies are typically normal, but serum aminotransferase concentrations may start to increase.

Stage II (24 to 72 hours) – Right upper quadrant abdominal pain develops, and laboratory evidence of hepatotoxicity, and occasionally nephrotoxicity, becomes evident.

Stage III (72 to 96 hours) - Liver function abnormalities peak and patients develop jaundice, confusion (hepatic encephalopathy), hyperammonemia, prolongation of the prothrombin time (PT)/international normalized ratio (INR), hypoglycemia, lactic acidosis, and elevated total bilirubin concentration. Death can occur, usually from multiorgan system failure from fulminant hepatic failure.

Stage IV (four days to two weeks) – Recovery stage in patients who survive Stage III.

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 PT/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 greater than 50 percent of these patients. (See 'Differential diagnosis' above.)

Diagnosis – Measurement of the serum acetaminophen concentration confirms diagnosis. 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. (See 'Evaluation and diagnosis' above and 'Evaluation after acute overdose' above.)  

Therapeutic serum concentrations range from 10 to 20 mcg/mL (65 to 130 micromol/L)

The risk of toxicity after a single acute overdose of an immediate-release preparation is best predicted by relating the time of ingestion to the serum acetaminophen concentration. The level should be evaluated according to the modified Rumack-Matthew nomogram to determine the need for N-acetylcysteine (NAC) therapy (figure 3).

In certain clinical scenarios, it can be difficult to determine the risk of hepatotoxicity associated with exposure to acetaminophen:

-Time of ingestion is unknown – Treatment with NAC based on last known time prior to ingestion, or if detectable serum acetaminophen concentration or elevated serum transaminase concentrations and a history consistent with acetaminophen exposure regardless of the serum acetaminophen concentration. (See "Acetaminophen (paracetamol) poisoning in adults: Treatment", section on 'When time of ingestion is unclear or unknown'.)

-Ingestion of a sustained-release drug formulation – Obtain both a four- and eight-hour serum acetaminophen concentration and treat with NAC if either concentration is above the "possible hepatic toxicity" line of the nomogram. (See 'Ingestion of sustained-release acetaminophen' above.)

-Repeated supratherapeutic ingestion – Acetaminophen serum concentrations can be at therapeutic levels and do not correlate with toxicity as with the acute overdose. The Rumack-Matthew nomogram is not applicable in this setting. Patients at risk of developing hepatotoxicity are described in the text. (See 'Evaluation after repeated supratherapeutic ingestion' above.)

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Topic 340 Version 47.0

References

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