Continuing Education Activity

Acetaminophen is one of the most commonly used analgesics and antipyretics. Although relatively safe at therapeutic doses, acetaminophen poisoning causes hepatic necrosis. Acetaminophen toxicity is the second most common cause of liver transplantation worldwide and the most common cause of liver failure in the United States. Responsible for 56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States. Notably, around 50% of these poisonings are unintentional, often resulting from patients misinterpreting dosing instructions or unknowingly consuming multiple acetaminophen-containing products.

The mortality associated with acetaminophen overdose is low if recognized and treated within the first 8 hours. Factors such as alcohol use, genetics, age, medications, herbal supplements, and nutritional status can enhance acetaminophen's ability to damage the liver. In addition to liver failure, affected patients may experience renal failure as a consequence of acetaminophen toxicity. This activity reviews the etiology, evaluation, treatment, and management of acetaminophen toxicity while highlighting the interprofessional team's importance in managing and preventing this problem.

Objectives:

• Implement effective screening protocols to identify patients at risk of acetaminophen overdose or toxicity in various healthcare settings.

• Differentiate between acetaminophen toxicity and other potential causes of liver dysfunction, ensuring accurate and targeted interventions.

• Select evidence-based strategies to ensure timely initiation of treatment for acetaminophen toxicity and promote optimal patient outcomes.

• Collaborate with hepatologists, critical care specialists, toxicologists, psychiatrists, and pharmacists to optimize the management of acetaminophen toxicity and enhance overall patient care.

Introduction

Acetaminophen toxicity is prevalent, primarily due to the drug's widespread availability and the common perception of its safety. In the United States, acetaminophen toxicity is the leading cause of liver failure. Over 60 million Americans use acetaminophen weekly, often unknowingly, due to its presence in various combination products, particularly those containing opioids and diphenhydramine.[1][2][3] Acetaminophen, also known as N-acetyl-para-aminophenol or paracetamol, functions as an antipyretic and analgesic with a mechanism distinct from nonsteroidal anti-inflammatory medications. Although its mode of action, specifically the selective inhibition of cyclooxygenase in the brain, is not fully understood, acetaminophen effectively alleviates fever and pain. In addition, it may inhibit prostaglandin synthesis in the central nervous system and directly affect the hypothalamus to produce an antipyretic effect.[4]

If left untreated, acetaminophen toxicity can lead to both fatal and non-fatal hepatic necrosis. Timely intervention is essential in preventing fulminant liver failure and the need for liver transplantation. Activated charcoal should be administered within the first hour and N-acetylcysteine within the first 8 hours. The most reliable predictor of toxicity is correlating the time of ingestion with the serum acetaminophen concentration using the Revised Rumack-Matthew nomogram. Patients whose levels fall above the treatment line at 4 hours require N-acetylcysteine. A striking 50% of cases result from unintentional overdoses, highlighting a crucial need for healthcare professionals to properly educate patients regarding the proper dosing of acetaminophen and its presence in prescribed and over-the-counter preparations.

Etiology

Acetaminophen is available in immediate-release and extended-release formulations. The dosage forms available are capsules, elixir, gel, oral and intravenous solutions, liquid, tablets, suppositories, syrup, and dissolve packs. When taken at therapeutic doses, acetaminophen has a good safety profile. The therapeutic doses are:

• 10 to 15 mg/kg/dose in children every 4 to 6 hours with a maximum dose of 80 mg/kg/d
• 325 to 1000 mg/dose in adults every 4 to 6 hours, with a maximum daily dose of 4 g/d

Toxicity is likely to develop in adults at:

• >12 g over a 24 hours
• 7.5 to 10 g in a single dose
• Doses >350mg/kg

Toxicity in children occurs following a single dose of 150 mg/kg or 200 mg/kg in otherwise healthy children aged 1 to 6.

Acetaminophen is fully absorbed in the duodenum within 2 hours of ingestion. Foods and medications that decrease gastric emptying can delay absorption. The liver metabolizes 89% of acetaminophen, leading to saturation of the sulfation and glucuronidation pathways and depletion of hepatic glutathione stores. The result is the production of a toxic, highly reactive compound that causes a cascade of oxidative hepatocyte injury.

Epidemiology

Acetaminophen toxicity accounts for 50% of all reported cases of liver failure in the United States and 20% of all liver transplants. If discovered and treated quickly, the associated morbidity and mortality are low. Once liver failure develops, the mortality increases to 28%, with one-third requiring a liver transplant. Although acetaminophen poisoning is more common in children, adults are more likely to develop hepatotoxicity. Acetaminophen poisoning is responsible for 56,000 emergency department visits, 2600 hospitalizations, and 500 deaths annually in the United States, with 50% of these cases being unintentional overdoses.[5][6][7] Approximately 30,000 pediatric acetaminophen poisoning cases are reported to the National Poison Data System annually.

Factors that increase the risk of hepatotoxicity include underlying liver disease, alcohol use disorder, and unintentional overdose. Combination opioid prescriptions containing acetaminophen are an additional risk contributing to acetaminophen poisoning. The United States Food and Drug Administration now requires a lower dose of acetaminophen in all combination products. 

Pathophysiology

Acetaminophen is rapidly absorbed from the gastrointestinal tract and reaches therapeutic levels in 30 minutes to 2 hours. Overdose levels peak at 4 hours unless other factors are included, such as the co-ingestion of an agent that slows gastric motility or if the acetaminophen is in an extended-release form.[8][9] Acetaminophen has an elimination half-life of 2 hours but can be as long as 17 hours once hepatic injury develops. In the liver, acetaminophen conjugates to nontoxic, water-soluble metabolites that are excreted in the urine.[9]

Metabolism

Approximately 90% of acetaminophen is metabolized in the liver by the hepatic microsomes via sulfotransferase and UDP-glucuronosyl transferases, forming sulfate and glucuronide conjugates that are excreted in the urine.[10][11]

About 8% of acetaminophen is metabolized by hepatic cytochrome P450 subfamilies—CYP2E1, CYP1A2, and CYP3A4—through the mixed-function oxidase pathway, generating a toxic, highly reactive, electrophilic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). 

The remaining 2% of acetaminophen is excreted unchanged in the urine.

At therapeutic doses, acetaminophen produces minimal amounts of NAPQI, which swiftly conjugates with hepatic glutathione to produce nontoxic cysteine and mercaptate compounds excreted in the urine. However, in cases of acetaminophen toxicity, an increased production of NAPQI occurs, depleting hepatic glutathione stores.

NAPQI gains an additional aryl group and binds covalently to cysteine groups on hepatic macromolecules, particularly mitochondrial proteins, forming NAPQI-protein adducts. The process initiates an irreversible cascade. The results of NAPQI-protein adduct formation include:

• Oxidative hepatocyte injury
• Alteration of the mitochondrial ATP-synthase alpha-subunit
• Hepatocellular centrilobular necrosis

Processes that contribute to the propagation of hepatic injury include:

• Generation of nitrotyrosine adducts within mitochondria by toxic free radicals, such as peroxynitrite
  • Results in damage to mitochondrial DNA and ATP-synthase, halting ATP synthesis
• Lipid peroxidation and membrane damage
• Release of cytokines, apoptosis-inducing factor, endonuclease G, and reactive nitrogen and oxygen species from damaged mitochondria
  • Causes a secondary inflammatory response 
• Recruitment of inflammatory cells through the innate immune system by damage-associated molecular pattern (DAMP) products, such as nuclear fragments and mitochondrial DNA
  • Typically manifests during clinical stage II 

Clinical Factors Affecting Toxicity

Several factors can increase the risk of acetaminophen-induced liver damage. In some cases, patients may develop subclinical toxicity following repeated therapeutic dosing.

• Acute alcohol ingestion: The risk of hepatotoxicity may decrease when acetaminophen is consumed concurrently with alcohol. Both acetaminophen and alcohol serve as substrates for the CYP2E1 enzyme. A study suggests a 10% reduction in hepatic toxicity, possibly attributed to reduced NAPQI production.[12][13]

• Chronic alcohol ingestion: Despite increasing the synthesis and activity of CYP2E1 2-fold and depleting glutathione stores and synthesis, no evidence indicates that chronic alcohol ingestion causes an increased incidence of hepatic toxicity with therapeutic doses of acetaminophen.[12] Patients with chronic alcohol use are also not at increased risk of hepatotoxicity with acute acetaminophen toxicity. Chronic alcohol use does, however, increase the risk of hepatotoxicity with repeated supratherapeutic acetaminophen doses. Because chronic alcohol use upregulates the CYP2E1 enzyme, more acetaminophen is processed through the CYP2E1 enzyme, increasing the production of NAPQI. The upregulation of CYP2E1, combined with the increased risk of malnutrition, recent fasting, and low glutathione stores, predisposes patients with alcohol use disorder to hepatotoxicity from repeated supratherapeutic doses.

• Chronic liver disease: Patients with chronic liver disease who abstain from alcohol do not face an elevated risk of hepatotoxicity when ingesting acetaminophen. Although the half-life of acetaminophen increases by approximately 2 hours, there is no accumulation of acetaminophen with repeated dosing. Individuals with cirrhosis exhibit low P450 enzyme activity, offering some protection in the context of acetaminophen toxicity.

• Concurrent medications and herbal supplements: Medications that induce CYP2E1 enzymes, such as carbamazepine, or compete for glucuronidation pathways, such as trimethoprim-sulfamethoxazole and opioids, increase the risk of hepatotoxicity. Herbal supplements such as St John wort, garlic, and germander may enhance the CYP450 activity.

• Nutritional status: Hepatic glucuronidation depends on liver carbohydrate reserves. Fasting or malnutrition decreases the glucuronidation of acetaminophen, causing an increased production of NAPQI.

• Age: The risk of hepatotoxicity increases with age. Children younger than 5 appear less susceptible to hepatotoxicity unless they receive repeated supratherapeutic doses or acetaminophen. The increased supply and regeneration of glutathione and greater activity of conjugation enzymes in children are likely reasons for the lower risk of hepatotoxicity.

• Genetics: The link to genetic polymorphisms that cause acetaminophen's diminished or excessive oxidative metabolism is unclear. Patients affected by Gilbert syndrome are at risk for increased toxicity.

• Tobacco use: Tobacco use induces CYP1A2 enzymes and is an independent risk factor for mortality after acetaminophen overdose. The highest mortality is associated with patients who smoke and drink alcohol.[13]

• Serum phosphate: Low serum phosphate levels result in decreased acetaminophen toxicity, likely due to enhanced cell regeneration supported by hepatocyte phosphate uptake to regenerate ATP.

Histopathology

The histological features of acetaminophen toxicity reveal cytolysis and centrilobular necrosis. These changes result from an increased concentration of CYP2E1 enzymes, causing a high local concentration of NAPQI.[14] Clinical recovery precedes histopathological recovery. Histopathologic recovery may take 3 months, but when it occurs, it is complete. Residual hepatic insufficiency is not a long-term sequelae of acetaminophen poisoning.

History and Physical

Most patients with acetaminophen toxicity are initially asymptomatic or present with mild, nonspecific symptoms. Obtaining a detailed history, including accurate timing, formulation, dosage, and any co-ingestants, is essential for proper diagnosis. The clinical course of acetaminophen toxicity consists of 4 stages.[15]

Stage I

• First 30 minutes to 24 hours
• Possibly asymptomatic
• May experience nausea, vomiting, diaphoresis, pallor, lethargy, and malaise
• Laboratory values are generally normal, but aminotransferase levels may increase within 8 to 12 hours
• Central nervous system depression and elevated anion gap metabolic acidosis are possible with a >30 g ingestion

Stage II

• 24 to 72 hours
• Laboratory results reveal hepatotoxicity and nephrotoxicity
• Clinically, the patient appears improved, but laboratory values worsen
• Right upper quadrant pain and hepatomegaly
• Evidence of abnormal prothrombin time (PT) and total bilirubin, along with oliguria and renal function abnormalities
• Case reports indicate acute pancreatitis 

Stage III

• 72 to 96 hours
• Aminotransferase levels peak, with values exceeding 10,000 IU/L
• More pronounced symptoms, including jaundice, confusion, hyperammonemia, abnormal aminotransferases, and bleeding diathesis, along with recurrence of symptoms from stage 1
• Acute renal failure in 50% of patients with frank liver failure and 10% to 25% of patients with significant liver damage
• Indirect hyperbilirubinemia
• Prolonged PT
• Hypoglycemia
• Lactic acidosis
• The most common stage for death to occur due to multisystem organ failure

Stage IV

• If the patient survives stage 3
• Recovery phase
• Typically begins by day 4 and completes by day 7
• Symptoms and laboratory values may require several weeks to normalize
• Histopathologic changes in the liver become evident

Acute renal failure due to acute tubular necrosis manifests as an elevated blood urea nitrogen and creatinine, proteinuria, hematuria, and granular and epithelial cell casts on urinalysis. The incidence is less than 2% of all patients, 5% of cases with liver involvement but no hepatic failure, 10% of severe poisonings, and nearly 53% of cases with acute hepatic failure. The renal function generally returns to normal in 1 to 4 weeks. Some patients may require dialysis during this time.

Evaluation

Overall Approach

Relating the time of initial ingestion to the serum acetaminophen concentration provides a more accurate prediction of the risk of hepatotoxicity than relying on the dose history.

The initial evaluation begins with the following:

• Identifying the agents involved
• Assessing severity
• Predicting the toxicity

Essential historical information to gather includes:

• Elicit the dose
• Elicit the intent
• Pattern of use
• Time of ingestion
• Presence of co-ingestants
• Presence of comorbid conditions or medications such as Gilbert disease, alcohol use, or anti-seizure medications

The diagnosis of acetaminophen toxicity begins with obtaining a serum acetaminophen level, regardless of symptoms. If the timing of ingestion is unclear, an acetaminophen level should be obtained at the time of presentation and again 4 hours after the first dose. Additional recommended investigations include:

• Serum aminotransferase levels
• PT and international normalized ratio (INR) 
• Electrolytes
• Blood urea nitrogen and creatinine
• Serum total bilirubin concentration
• Amylase
• Urinalysis
• Human chorionic gonadotropin in women of childbearing age
• Arterial or venous blood gas and serum lactate in critically ill patients or those with altered mental status
• Screening of blood and urine for other ingested drugs
• Electrocardiogram in patients with an intentional overdose
• Salicylate level
• Computed tomography scan of the head in the presence of altered mental status

Evaluation After Ingestion of Immediate-Release Acetaminophen

• Obtain a serum acetaminophen level 4 hours after swallowing the first dose.
• Obtain serum acetaminophen level immediately if the ingestion was over 4 hours before presentation.
• Determine the need for N-acetylcysteine based on the Revised Rumack-Matthew nomogram.[16][17][18] 
• Administer empiric N-acetylcysteine if ingestion occurred more than 8 hours before presentation or the results of the serum levels exceed 8 hours after the first dose.

If the timing of ingestion is unknown, obtain the following immediately:

• Serum acetaminophen level
• Electrolytes
• Blood urea nitrogen and creatinine
• Serum total bilirubin concentration
• Serum transaminases

A nondetectable serum acetaminophen level drawn between 2 and 4 hours on an assay that detects acetaminophen at a minimum level of 10 mcg/mL likely excludes toxicity. 

Evaluation After Ingestion of Extended-Release Formulation or Co-Ingestion with Anticholinergics or Opioids

An extended-release formulation of acetaminophen is labeled for use every 8 hours or more. Clinicians use the Revised Rumack-Matthew nomogram to assess patients who ingest an extended-release formulation or co-ingest anticholinergic or opioid medications. If the initial 4-hour acetaminophen level is ≤10 mcg/mL, a repeat level is unnecessary. If the acetaminophen level between 4 and 12 hours is below a level indicating the need for acetylcysteine but >10 mcg/mL (66 µmol/L), another acetaminophen level should be obtained in 4 to 6 hours. 

Evaluation After Repeated Supratherapeutic Ingestion 

Repeated supratherapeutic ingestions are multiple ingestions that occur over more than 24 hours. Serum concentrations are generally at therapeutic levels, and using the Revised Rumack-Matthew nomogram is not helpful in this setting. The decision to initiate N-acetylcysteine therapy should be based on a thorough history, physical examination, and laboratory evaluation. Serum acetaminophen, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels should be obtained if a patient with suspected repeated supratherapeutic ingestions meets any of the following criteria:

• Ingested more than 6 g/d or 150 mg/kg/d over 24 to 48 hours
• Ingested more than 4 g/d or 100 mg/kg/d for longer than 48 hours 
• Presents with abdominal pain or right upper quadrant tenderness, nausea, vomiting, jaundice, altered mental status, or appears acutely ill

Treatment / Management

The treatment of acetaminophen poisoning is dependent on the timing of drug ingestion. If the patient presents within 1 hour of ingestion, gastrointestinal decontamination should be attempted with activated charcoal (AC). Some studies suggest using activated charcoal if the patient presents within 4 hours of ingestion, as it has been shown to decrease acetaminophen absorption, reduce the need for N-acetylcysteine, and lower the risk of liver injury when administered within 4 hours of ingestion.[19][20][21][22] Use beyond 1 hour is most effective with large ingestions or with ingestion of an extended-release form or any medication that can delay gastric emptying. Contraindications to activated charcoal include gastrointestinal obstruction and an unprotected airway. Orogastric lavage or whole bowel irrigation is not recommended.[23][24][25]

Four to Eight Hours After Ingestion

The 4-hour serum acetaminophen level should be plotted on the Revised Rumack-Matthew nomogram. If the patient's serum acetaminophen level falls at or above the treatment line, N-acetylcysteine administration is necessary. The treatment threshold is 150 mcg/mL or 990 µmol/L at 4 hours and 4.69 mcg/mL or 31.3 µmol/L at 24 hours. These levels place the patient at possible risk for hepatotoxicity, and treatment with N-acetylcysteine is standard. Patients who have ingested an extended-release formulation or co-ingested an opiate or anticholinergic medication may need a repeat acetaminophen level in 4 to 6 hours.

More than Eight Hours After Ingestion

In cases of suspected acute ingestion exceeding 150 mg/kg or a total dose of 7.5 g, and when serum acetaminophen levels are unavailable until after 8 hours from ingestion, healthcare professionals should initiate N-acetylcysteine therapy while awaiting acetaminophen levels. Beyond 8 hours, the risk of liver injury increases as the time to administration of N-acetylcysteine increases. Discontinuing N-acetylcysteine is appropriate when acetaminophen levels fall below the treatment line on the Revised Rumack-Matthew nomogram and liver function tests are normal.

Patients with repeated supratherapeutic ingestions with a serum acetaminophen concentration ≥20 mcg/mL or 132 µmol/L or elevated aminotransferases warrant N-acetylcysteine. Clinicians should administer N-acetylcysteine to patients with any evidence of liver injury and a history of acetaminophen ingestion. Patients can still benefit from N-acetylcysteine up to 24 hours after the initial ingestion or until acetaminophen is no longer detectable in the serum. N-acetylcysteine is an antioxidant that diminishes hepatic necrosis, decreases neutrophil infiltration, improves microcirculatory blood flow, and increases tissue oxygen delivery. Hemodialysis can also be an effective treatment, especially with concurrent renal failure. 

Acetaminophen, AST, ALT, and INR should be measured every 12 hours following the initiation of N-acetylcysteine.[26] If the AST or ALT exceeds 1000 IU/L, encephalopathy should be monitored, and serum bicarbonate, glucose, and creatinine should be measured every 12 hours.

Dialysis may be necessary if the patient develops acute kidney injury. Indications for dialysis include refractory fluid overload, severe hyperkalemia, severe metabolic acidosis, and uremia. Dose adjustments for patients with alcohol use disorder or those who are chronically ill are not required. Dialysis is considered safe for use during pregnancy.

High-Risk Ingestion

High-risk ingestion consists of a dose of >30g. These patients may require intubation to protect their airway, intravenous fluids and vasopressors, and bicarbonate for metabolic acidosis. Patients with a high-risk ingestion are at an increased risk of developing fulminant liver failure. Activated charcoal should be administered even if beyond 4 hours, and N-acetylcysteine should be initiated immediately. In addition to N-acetylcysteine, hemodialysis is indicated in patients with an acetaminophen concentration >900 mcg/mL. 

N-acetylcysteine Management

N-acetylcysteine protects against liver toxicity if administered within 8 hours of acetaminophen ingestion. The effectiveness remains unchanged whether initiated between 0 and 4 hours or 4 and 8 hours. N-acetylcysteine acts by preventing the binding of NAPQI to hepatic macromolecules by acting as a substitute for glutathione, serving as a precursor for sulfate, and reducing NAPQI back to acetaminophen. Indications for N-acetylcysteine include:

• A serum acetaminophen level within the toxic range according to the Revised Rumack-Matthew nomogram
• An  N-acetyl-para-aminophenol level greater than 10 mcg/mL with an unknown time of ingestion
• A dose of acetaminophen >140 mg/kg ingested more than 8 hours before presentation
• Abnormal labs with ingestion >24 hours before presentation
• Ingestion with any evidence of liver injury [27]

Either oral or intravenous (IV) N-acetylcysteine is acceptable. Intravenous N-acetylcysteine is preferred for patients with intractable vomiting, those who refuse oral intake, those at risk for aspiration, or those who are pregnant or have fulminant liver failure. The IV form may decrease the length of the hospital stay and may be tolerated better by the patient, as the oral form tastes and smells like rotten eggs. The oral form also requires 18 doses given 4 hours apart, with the total treatment time being 72 hours. In comparison, the IV form requires only 20 hours of treatment. 

Oral N-acetylcysteine: The oral regimen consists of 18 doses administered 4 hours apart, resulting in a total treatment time of 72 hours. The protocol begins with administering a 140 mg/kg oral loading dose followed by 70 mg/kg every 4 hours until achieving the stop criteria. Patients weighing over 100 kg receive a maximum 100 mg/kg dose. 

Intravenous N-acetylcysteine: Approximately 10% to 20% of patients may experience nonallergic or non–IgE-mediated anaphylactic reactions to N-acetylcysteine with the IV form within the first 5 hours. 

Two IV protocols are available:

• 21-hour intravenous protocol
• An initial loading dose of 150 mg/kg IV is administered over 60 minutes.
• Next, a dose of 50 mg/kg is administered over 4 hours or 12.5 mg/kg/h IV for 4 hours.
• Finally, a dose of 100 mg/kg is administered over 16 hours or 6.25 mg/kg/h IV for 16 hours.

For children weighing <40 kg, the dose remains the same, but a different diluent protocol prevents fluid overload and excess free water, leading to hyponatremia, seizures, and death.

• Simplified 20-hour intravenous protocol
• This protocol combines the first 2 steps of the 21-hour protocol.
• A dose of 50 mg/kg is administered over 4 hours for a total of 200 mg/kg over 4 hours.
• Next, a dose of 6.25 mg/kg is administered over 16 hours for 100 mg/kg over 16 hours. 

Studies reveal that the 20-hour protocol reduces the risk of non–IgE-mediated anaphylactic reactions to N-acetylcysteine by 50%.[28]

In cases of high-risk ingestions, where reports indicate liver injury with ingestions exceeding 50 g or serum acetaminophen concentrations surpassing 500 mg/L or 3300 µmol/L, some clinicians suggest administering a higher dose of N-acetylcysteine. Consulting a poison center or medical toxicologist is advisable. If not available, a reasonable alternative is to increase the final infusion rate of the 21-hour protocol to 12.5 mg/kg/h. Patients undergoing hemodialysis do not need an adjustment of oral N-acetylcysteine, but IV N-acetylcysteine infusion rates are 12.5 mg/kg/h during hemodialysis. 

Stopping Criteria

The definitive duration of N-acetylcysteine therapy is a matter of controversy. Although no universally accepted stopping criteria exist, a universally accepted parameter is that patients should receive a minimum of 300 mg/kg over 20 to 24 hours. The decision to discontinue N-acetylcysteine should be based on laboratory evidence of improvement, rather than solely on the duration of therapy.[26] A recent consensus statement recommends continuing N-acetylcysteine at a rate of at least 6.25 mg/kg/h or 70 mg/kg every 4 hours orally until the serum acetaminophen level is less than 10 mcg/mL, INR <2.0, the ALT and AST are normal for the patient or have decreased a minimum of 25% to 50% from their peak levels, and the patient is clinically well.[26] N-acetylcysteine should be continued past 72 hours if there is a fulminant hepatic failure until the patient receives a liver transplant, recovers, or dies.[29][30] 

Differential Diagnosis

The following list includes potential differential diagnoses:

• Hepatorenal syndrome
• Viral hepatitis
• Wilson disease
• Pancreatitis
• Acute tubular necrosis
• Amatoxin toxicity
• Cytomegalovirus infection
• Gastroenteritis
• Peptic ulcer disease
• Drug-induced or toxin-induced hepatitis
• Hepatobiliary disease
• Inborn errors of metabolism, including alpha1-antitrypsin deficiency or fatty acid oxidation abnormalities
• Reye syndrome
• Ischemic hepatitis

Clues to help differentiate acetaminophen as the cause of hepatitis include the acute onset and rapid progression with significant elevations of plasma aminotransferases (often >3000 IU/L) and its association with a rising PT and INR.

A significant increase in bilirubin levels is rare with acetaminophen toxicity. Bilirubin levels exceeding 1 mg/dL or 17 µmol/L may result in a false-positive serum assay for acetaminophen in patients with acute viral hepatitis, causing a potential delay in the identification of the underlying issue. Unlike acetaminophen toxicity, the AST-to-ALT ratio is typically greater than 2 in patients with acute alcohol-related hepatitis or hepatitis related to chronic acetaminophen toxicity. Serum aminotransferase levels rarely exceed 500 IU/L in patients with alcohol-related hepatitis. 

Pertinent Studies and Ongoing Trials

Fomepizole is an antidote for toxic alcohol poisoning with methanol and ethylene glycol. This medication inhibits alcohol dehydrogenase and CYP2E1. Studies suggest that fomepizole may have a role as adjunct therapy along with N-acetylcysteine in patients determined to be at high risk of developing liver failure due to acetaminophen toxicity. Fomepizole prevents acetaminophen oxidation, inhibits Jun-N-terminal kinase, and decreases the formation of oxidative metabolites. Case reports of fomepizole are increasing, showing promise in critically ill patients.[31] Healthcare guidelines do not currently recommend the routine use of fomepizole for acetaminophen toxicity.[32][33][34]

Prognosis

The incidence of hepatotoxicity for patients treated with N-acetylcysteine within 8 hours of acetaminophen ingestion is less than 10%, but it increases to approximately 40% when delayed beyond 16 hours. When treated promptly, the mortality associated with acetaminophen toxicity is less than 2%. However, if patients present late and develop severe liver failure, mortality is high. Approximately 1% to 3% of patients with severe liver failure require liver transplantation.[19][35][36] In general, children younger than 6 have a better prognosis than adults, primarily due to their greater capacity to detoxify acetaminophen. 

In patients with fulminant liver failure, the modified King's College Criteria helps to determine prognosis and provide insight as to which patients should receive care in a facility that offers liver transplants. The prognosis is poor without a liver transplant if the patient meets any of the following criteria:

• Arterial lactate >3.5 mmol/L after at least 1 L of early fluid resuscitation  
• Arterial lactate >3.0 mmol/L after adequate fluid resuscitation and restoration of tissue perfusion  
• Arterial pH <7.3 
• Grade III or IV encephalopathy with both a PT greater than 100 s and serum creatinine greater than 3.4 mg/dL or 300 µmol/L

Complications

Acetaminophen toxicity is associated with a variety of complications, ranging from mild to life-threatening, as follows:

• Acute tubular necrosis
• Hepatorenal syndrome
• Encephalopathy
• Bleeding diathesis
• Liver failure
• Renal failure
• Death
• Non–IgE-mediated anaphylaxis reaction to N-acetylcysteine
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Acute generalized exanthematous pustulosis

Postoperative and Rehabilitation Care

Patients may resume acetaminophen when they are clinically asymptomatic and have serum acetaminophen levels <10 mg/L, along with normal ALT, PT, and INR.

Consultations

If a patient exhibits a progressive increase in aminotransferase levels and worsening coagulopathy, encephalopathy, or multisystem organ failure despite N-acetylcysteine treatment, consulting a liver transplant team is necessary. Consultation with a medical toxicologist or poison center is recommended for patients with high-risk ingestions or patients who do not fit within the typical diagnostic or treatment protocols.

Deterrence and Patient Education

Acetaminophen, also known as  N-acetyl-para-aminophenol or paracetamol, is a widely used medication, both independently and in combination with numerous other medications worldwide. Despite its widespread use, acetaminophen is the leading cause of liver failure worldwide and the second most common indication for liver transplantation in the United States. At therapeutic levels, acetaminophen is generally considered safe. However, instances of acetaminophen toxicity often arise due to patient misconceptions about dosing or a lack of awareness regarding its presence in multiple medications they may be consuming. Intentional ingestion of large doses also contributes to toxicity. Effective management of patients necessitates a thorough history of critical dosage details, formulations, and timing.

Although there is a comprehensive understanding of acetaminophen toxicity and its treatment, patients achieve optimal outcomes when healthcare professionals intervene within the first 8 hours. Beyond this timeframe, mortality rates increase with each passing hour. Patients presenting within the first 1 to 4 hours may undergo activated charcoal administration to remove acetaminophen from the stomach, improving their prognosis. Various factors, such as concurrent alcohol consumption, age, genetics, other medications, and herbal supplements, can heighten the risk of acetaminophen toxicity. Complications extend beyond liver failure and may include kidney failure, encephalopathy, and death.

Treatment involves the administration of N-acetylcysteine, which helps prevent further liver damage. The duration of treatment typically spans 20 to 72 hours, depending on the specific formulation used. Some patients may require an extended treatment course based on the extent of liver damage. Clinicians monitor liver function tests and other laboratory values to determine the optimal cessation point for treatment. Severe cases may progress to liver failure, necessitating a liver transplant for survival. At the same time, patients who avoid such complications typically experience complete histopathologic resolution of the damage within approximately 3 months.

Patient education is crucial, emphasizing the importance of storing acetaminophen out of reach of children. Caregivers should be well-informed about appropriate pediatric dosing and the availability of acetaminophen in various formulations for infants, children, and adults. All caregivers should receive guidance on reading medication labels accurately. Furthermore, patients must be educated about the heightened risk of toxicity when combining medications, stressing the importance of avoiding such practices.[36]

Enhancing Healthcare Team Outcomes

Patients at risk of fulminant hepatic failure due to acetaminophen poisoning may require a liver transplant. Early identification and proper management of acetaminophen toxicity are crucial to minimize morbidity and mortality. A comprehensive, multidisciplinary approach is essential to provide patient-centered care and reduce the need for liver transplantation. Healthcare professionals across various specialties, including emergency medicine, critical care, psychiatry, hepatology, toxicology, surgery, and advanced practice clinicians, must be well-versed in diagnosing and managing acetaminophen toxicity. This expertise includes recognizing expected clinical presentations, understanding treatment protocols, and ensuring the timely initiation of treatment.

Nurses and pharmacists play vital roles in educating patients and caregivers about the potential toxicity of acetaminophen. A strategic approach based on evidence-based outcomes is necessary to optimize patient results. Effective interprofessional communication is crucial for seamless patient care. By incorporating skill, strategy, and communication principles, healthcare professionals can deliver enhanced patient care, reducing morbidity, mortality, and healthcare costs.