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 accidental poisoning.

Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen also is 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. Various children's chewable, suspension, and elixir formulations of acetaminophen also are available. Acetaminophen is also a component of many over-the-counter medications and prescription combinations, such as propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet).

Pathophysiology: The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults. The at-risk dose may be lower in some susceptible patient populations, such as persons with alcohol abuse. When dosing recommendations are followed, the risk of hepatotoxicity is extremely small.

Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic agents. These water-soluble conjugates are then eliminated in the urine.

In acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugative pathways of metabolism become saturated. Excess APAP is then oxidatively metabolized in the liver via the mixed function oxidase P450 system to a toxic 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 reduced glutathione stores, NAPQI covalently binds to vital proteins and the lipid bilayer of hepatocyte membranes. The result is hepatocellular death and centrilobular liver necrosis.

The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and increases glutathione availability to bind to NAPQI. It may also enhance sulfate conjugation of any unmetabolized APAP. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations, and this vasodilatory effect on microcirculatory blood flow enhances local oxygen delivery to peripheral tissues. These vasodilating effects decrease morbidity and mortality even in the setting of established hepatotoxicity.

NAC is most effective when administered within 8 hours of 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:

• In the US: 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 and the second most common cause of liver failure requiring transplantation in the United States.

Mortality/Morbidity: The majority of patients with APAP 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 malnutrition, AIDS, chronic ethanol abuse, or anorexia nervosa may be at increased risk for morbidity because of deficient glutathione stores and inadequate detoxification of NAPQI. Patients with enhanced ability to make NAPQI due to induction of the P450 system, specifically cyp2E1, may be at increased risk of morbidity. The agents that induce this enzyme activity include rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or chronic ethanol ingestion.

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

History: The course of acetaminophen toxicity generally is divided into 4 phases. Clinical evidence of end-organ (hepatic, renal) toxicity is often delayed 24-48 hours postingestion.

• Because antidotal therapy is most effective when initiated within 8 hours postingestion, 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 acetaminophen's toxic metabolite, NAPQI, in excess of an adequate store of glutathione necessary to conjugate it, leads to NAPQI-induced hepatocellular necrosis and hepatic failure.

• Additional mechanisms of acetaminophen-induced toxicity are postulated as well.

Gastritis and Peptic Ulcer Disease
Gastroenteritis
Hepatitis
Pancreatitis
Toxicity, Mushroom - Amatoxin

Other Problems to be Considered:

Vomiting of unclear etiology
Hepatic failure
Hepatorenal syndrome

Lab Studies:

• Acetaminophen serum concentration

• A serum acetaminophen concentration drawn 4 or more hours after a single ingestion may be plotted on the Rumack-Matthew nomogram as a guide to recommended NAC therapy. The nomogram is not applicable after multiple or chronic ingestions. It may be less reliable following ingestions that include anticholinergics or opioids or extended-release formulations.

• The serum APAP concentration should be measured after any intentional overdose because the history of acetaminophen ingestion may not be elicited. Clinical toxicity may not be evident soon after overdose, and the risk of morbidity increases when the initiation of NAC therapy is delayed. (See Special Concerns for information regarding extended-relief acetaminophen.)

• Transaminase levels

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours postingestion and peak at about 72 hours.

• Toxicity is defined as serum AST or ALT levels greater than 1000 IU/L.

• Measures of hepatic function

• Serum glucose

• Prothrombin time (PT) and bilirubin

• Electrolytes and creatinine

• Lactate

• Renal failure has been shown to coexist with or, rarely, be independent of liver toxicity in overdose. One study indicated that this is more likely to occur in alcoholic persons. Renal failure usually is not observed acutely but rather within 2-3 days of overdose.

• Human chorionic gonadotropin (HCG) in females of childbearing age

• Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation.

• Delay in treating pregnant patients with antidotal therapy is associated with fetal demise.

• A type and crossmatch should be drawn for the treatment of active bleeding in the face of coagulopathy.

• Urinalysis: Proteinuria and hematuria may be seen with acute tubular necrosis (ATN), usually in conjunction with hepatic failure.

• Arterial blood gas: Poor prognosis is associated with an arterial pH less than 7.30 (which fails to correct with fluid administration), serum creatinine greater than 3.4 mg/dL, PT greater than 100s, and elevated lactate greater than 3.5 mmol/L.

Imaging Studies:

• CT scan of the head

• CT scan may reveal cerebral edema in patients with late presentation and encephalopathy.

• Consider in patients with altered mental status.

• Ultrasound

• Ultrasound may reveal mild hepatic enlargement in late presentation.

• If clinically indicated, this is usually an inpatient procedure.

Procedures:

• Gastric lavage

• Gastric lavage has no proven efficacy in isolated acetaminophen overdose.

Prehospital Care: Stabilize immediate life-threatening conditions and initiate supportive care.

Emergency Department Care:

• Supportive therapy, including IV fluids, oxygen, and cardiac monitor

• Gastric decontamination

• Oral activated charcoal (AC) avidly adsorbs acetaminophen and should be administered if the patient presents within 1 hour of ingestion.
• Oral AC may be of benefit after 1 hour if the ingestion involves an agent that delays gastric emptying or slows GI motility.

• Administer N-acetylcysteine, if indicated. Early administration of NAC, within 8 hours of ingestion, is nearly 100% hepatoprotective.

• Assess for evidence of other life-threatening co-ingestions.

Consultations:

• Medical toxicologist, available through consultation with a regional poison control center

• Consultation with a medical toxicologist is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants.

• If fulminant hepatic failure is present, consult a hepatologist and transplant surgeon.