Introduction
Background
Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and unintentional poisoning.
Acetaminophen is also known as paracetamol and N -acetyl-p-aminophenol (APAP). It is available in the United States as 325-mg and 500-mg immediate-release tablets, and as a 650-mg extended-release preparation marketed for the treatment of arthritis. Various children's dissolvable, chewable, suspension, and elixir formulations of acetaminophen are available. Acetaminophen is a component of many over-the-counter cold and analgesic medications and prescription combinations, including propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet). Hepatotoxicity associated with acetaminophen misuse and overdose is well recognized.
In 2009, the US Food and Drug Administration (FDA) announced requirements for nonprescription and prescription containing medication to provide new information regarding acetaminophen-induced hepatotoxicity.1,2 Additionally, the FDA is examining possible removal of acetaminophen from some popular analgesic combination products (eg, Vicodin) and possibly lowering the maximum daily dose. The FDA is currently evaluating whether changes need to be made for acetaminophen regarding 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
Pathophysiology
The maximum recommended daily dose of acetaminophen 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, malnourishment, or diminished nutritional status, fasting, or viral illness with dehydration, or if substances or medications that are known to induce the activity of the CYP oxidative enzymes are being used. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.
Acetaminophen 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 a reactive metabolite, N -acetyl-p-benzoquinone-imine (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 reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts.
An ensuing cascade of oxidative damage, mitochondrial dysfunction, and the subsequent inflammatory response propagate hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extra-hepatic organs, such as the kidney, and can contribute to some degree of extra-hepatic organ dysfunction.
The antidote for acetaminophen poisoning is N -acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and as such, increases glutathione conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP. NAC functions as an anti-inflammatory and antioxidant and has positive inotropic effects. 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 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 acetaminophen levels.
Frequency
United States
Acetaminophen is one of the most common pharmaceutical agents involved in overdose, as reported to the American Association of Poison Control Centers. APAP toxicity is the most common cause of hepatic failure requiring liver transplantation in Great Britain. In the United States, acetaminophen toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure, and it is the second most common cause of liver failure requiring transplantation in the United States.
Mortality/Morbidity
The majority of patients with acetaminophen overdose survive with supportive care alone, in conjunction with antidotal therapy. If correctly treated in a timely manner, most patients do not suffer significant sequelae.
- Case series report that fewer than 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or liver transplantation occurs in less than one 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 oxidative CYP enzymes, CYP2E1, CYP1A2, CYP2A6, or CYP3A4, may be at increased risk of morbidity due to 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 of age appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate APAP through sulfation, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported an alternative pediatric-specific therapy, treatment in children should be the same as in adults.
Clinical
History
The course of acetaminophen toxicity generally is divided into 4 phases. Clinical evidence of end-organ (hepatic or occasionally renal) toxicity is often delayed 24-48 hours postingestion.
- Because antidotal therapy is most effective when initiated within 8 hours post-ingestion, the clinician must obtain an accurate history of the time(s) of ingestion, the quantity, and formulation of acetaminophen ingested, and any co-ingestants, which may delay APAP absorption (eg, anticholinergic drugs or opioids).
- Because a patient's history may be inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms. After a single ingestion, NAC therapy is guided by the serum APAP concentration.
- Phase 1 (0-24 h)
- Asymptomatic
- Anorexia
- Nausea or vomiting
- Malaise
- Subclinical rise in serum transaminases levels begins at about 12 hours postingestion
- Phase 2 (18-72 h)
- Right upper quadrant abdominal pain, anorexia, nausea, vomiting
- Continued rise in serum transaminases levels
- Phase 3 (72-96 h)
- Centrilobular hepatic necrosis with continued abdominal pain
- Jaundice
- Coagulopathy
- Hepatic encephalopathy
- Nausea and vomiting
- Renal failure
- Fatality
- Phase 4 (4 d to 3 wk)
- Complete resolution of symptoms
- Complete resolution of organ failure
Physical
Physical examination findings vary, depending on the phase of toxicity.
- Phase 1
- Pallor
- Malaise
- Vomiting
- Diaphoresis
- Phase 2
- Right upper quadrant abdominal tenderness
- Tachycardia
- Hypotension
- Phase 3
- Tender hepatic edge
- Jaundice
- Evidence of coagulopathy, including gastrointestinal (GI) bleeding
- Evidence of hepatic encephalopathy
- Phase 4: Resolution
Causes
- Production of APAP's toxic metabolite, 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 postulated as well.
More on Toxicity, Acetaminophen |
 Overview: Toxicity, Acetaminophen |
| Differential Diagnoses & Workup: Toxicity, Acetaminophen |
| Treatment & Medication: Toxicity, Acetaminophen |
| Follow-up: Toxicity, Acetaminophen |
| References |
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References
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Further Reading
Keywords
acetaminophen toxicity, paracetamol, N-acetyl-p-aminophenol, APAP, analgesic agent, antipyretic agent, N-acetyl-p-benzoquinone-imine, NAPQI, hepatocellular death, hepatocellular necrosis, centrilobular liver necrosis, N -acetylcysteine, NAC, fulminant hepaticfailure, hepatic encephalopathy, renal failure, coagulopathy, diaphoresis, acetaminophen toxicity, acetaminophen overdose, APAP toxicity, APAP overdose, hepatotoxicity, acetaminophen poisoning, APAP poisoning
