Acetaminophen Toxicity 

Because acetaminophen (APAP) is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world (contained in >100 products), it is reported by the American Association of Poison Control Centers to be one of the most common pharmaceuticals associated with both intentional and unintentional poisoning and toxicity. Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, APAP toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and is the second most common cause of liver failure requiring transplantation.

Acetaminophen is also known as paracetamol and N -acetyl-p-aminophenol (APAP). This agent is available in the United States as 325-mg and 500-mg immediate-release (IR) tablets, and as a 650-mg extended-release (ER) preparation marketed for the treatment of arthritis. Various children's dissolvable, chewable, suspension, and elixir formulations of APAP are available. Acetaminophen is a component of many over-the-counter (OTC) cold and analgesic medications and prescription combinations, including codeine-acetaminophen (Tylenol #3) and oxycodone-acetaminophen (Percocet).

In an attempt to decrease the risks of potential APAP toxicity in the United States, a number of pharmaceutical regulatory changes have been introduced. In 2009, the US Food and Drug Administration (FDA) required that nonprescription and prescription APAP-containing medications provide information regarding the risks of APAP-induced hepatotoxicity.^{[1, 2]} The FDA is considering the removal of APAP from some popular analgesic combination products (Vicodin) and possibly decreasing the recommended maximum daily dose. The FDA is also considering other changes to APAP-related recommendations, including the following:

• Safe daily dose for healthy individuals
• Safe daily dose in chronic liver disease
• Safe daily dose when used with alcohol
• Appropriate dose for efficacy
• Package size restrictions
• Pediatric dosing
• Acetaminophen narcotic combinations

In January 2011, the FDA announced it was asking manufacturers of prescription APAP combination products to limit the maximum amount of the drug in these products to 325 mg per tablet, capsule, or other dosage unit.^[3] The FDA believes that such a limitation will reduce the risk of hepatoxicity, liver failure, and death related to APAP overdose.^[3]

See also Liver Transplants, Liver Transplantation, Pediatric Acetaminophen Toxicity, Pediatric Liver Transplantation, and Transfusion Requirements in Liver Transplantation.

Production of the toxic metabolite of acetaminophen (APAP), N -acetyl-p-benzoquinone imine (NAPQI), in excess of an adequate store of conjugating glutathione, is associated with hepatocellular damage, necrosis, and hepatic failure. Additional mechanisms of acetaminophen-induced toxicity are also postulated. Currently, the maximum recommended daily dose of APAP is 4 g in adults and 90 mg/kg in children. Toxicity is associated with a single acute APAP ingestion of 150 mg/kg or approximately 7-10 g in adults. The ingested amount at which toxicity may occur may be lower in the settings of chronic ethanol use or diminished nutritional states, fasting, or viral illness with dehydration, or if substances or medications that are known to induce the activity of the APAP-metabolizing cytochrome P (CYP) oxidative enzymes are concurrently being ingested. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen APAP is rapidly absorbed from the stomach and small intestine and primarily metabolized by conjugation in the liver to nontoxic, water-soluble compounds that are eliminated in the urine.

In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to the reactive metabolite NAPQI. NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation, or a reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of hepatocellular proteins, forming NAPQI-protein adducts.

This causes an ensuing cascade of oxidative damage and mitochondrial dysfunction. The subsequent inflammatory response propagates hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extrahepatic organs, such as the kidney, and can contribute to some degree of extrahepatic organ dysfunction.

The antidote for APAP poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. This agent is a precursor of glutathione and, as such, increases the concentration of glutathione available for the conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP, functions as an anti-inflammatory and antioxidant, and has positive inotropic effects. In addition, NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality, even when NAC is administered in the setting of established hepatotoxicity.

NAC is maximally hepatoprotective when administered within 8 hours of an acute APAP ingestion. When indicated, however, NAC should be administered, regardless of the time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure, even in the absence of measurable serum APAP levels.

With aggressive supportive care and antidotal therapy, the mortality rate associated with acetaminophen (APAP) hepatotoxicity is less than 2%. If correctly treated in a timely manner, most patients do not suffer significant sequelae; thus, patients who survive should be expected to have a return of normal hepatic function.

Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or the need for liver transplantation occurs in less than half of these patients.

Patients with chronic ethanol use or diminished nutritional status may be at increased risk for morbidity because of deficient glutathione stores and a subsequent inability to conjugate and detoxify NAPQI. Patients who use substances that are known to induce the activity of the APAP-metabolizing oxidative cytochrome P (CYP) enzymes, CYP2E1, CYP1A2, CYP2A6, or CYP3A4, may be at increased risk of morbidity due to the enhanced production of NAPQI. Agents and substances that induce CYP enzyme activity are numerous but include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, chronic ethanol ingestion, and tobacco use.

Pediatric patients younger than 5 years appear to fare better than adults after acute APAP poisoning, perhaps owing to a greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, as no controlled studies have supported an alternative pediatric-specific therapy, treatment in children should be the same as in adults.

A number of screening measurements have been studied as prognostic indicators of poor outcome after APAP ingestion, subsequently necessitating liver transplantation. The most widely used of these predictors are the King’s College Criteria, which have been well-validated for the prediction of poor outcome and need for liver transplantation after an isolated APAP overdose. The criteria consist of the following laboratory abnormalities, any one of which should prompt urgent transplantation consultation:

• pH less than 7.30 after fluid resuscitation
• Creatinine level greater than 3.3 mg/dL
• Prothrombin time (PT) greater than 1.8 time control or PT greater than 100 seconds or international normalized (INR) greater than 6.5)
• Grade III or higher encephalopathy

Other prognostic screening tools that have been studied in regard to prediction of the need for liver transplantation include the Acute Physiology and Chronic Health Evaluation II (APACHE II) score of a patient on the first hospital day.^[4] This study found that the APACHE II score was found to be accurate but cumbersome to apply.

Alternative early predictors also include changes in serum phosphate, an indirect representation of the balance between the development of renal failure and hepatic regeneration. Serum phosphate concentrations greater than 1.2 mmol/L measured at 48-96 hours after overdose were sensitive and specific for increased mortality.^[5]

Finally, elevations in blood lactate have also been studied as prognostic indicators after acute APAP overdose.^[6] Blood lactate levels greater than 3.5 mmol/L before fluid resuscitation or greater than 3 mmol/L after fluid resuscitation were found to be sensitive and specific indicators of survival. In comparison with the King’s College Criteria, there was not significant difference in the time to early identification of patients who required transplantation.

In summary, a number of laboratory and clinical findings can facilitate the early identification of patients who have overdosed on APAP and will be at high risk of death without liver transplantation. A number of these indicators require further study. For those patients who develop critical illness, consult a regional poison control center for guidance and consider early transfer and consultation with a transplantation center.

Because acetaminophen (APAP) is commonly considered an innocuous over-the-counter (OTC) drug, it is important to advise patients of the potential risks associated with the inappropriate use of APAP.

Educate parents of the proper APAP dosing for children and the danger associated with misusing various APAP preparations of different concentrations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Because the infant suspension (drops) is a more concentrated formulation than the elixirs (100 mg/mL vs 32 mg/Ml, respectively), misuse can be a potential source of therapeutic error.

Parents should always be given clear dose and formulation instructions based on the age and weight of the child. Parents should also be instructed to carefully examine OTC medications that may contain APAP in combination formulations.

Educate patients of the increased potential for renal toxicity associated with concurrent APAP and nonsteroidal anti-inflammatory drug (NSAID) analgesic use, or chronic ethanol use.

For patient education information, see (Tylenol) Poisoning and Poisoning. The US Food and Drug Administration (FDA) has patient and caregiver education resources through its Consumer Health Information Website.