Pediatric Acetaminophen Toxicity Clinical Presentation

Patients with acetaminophen (APAP)-induced hepatotoxicity present in 4 clinical stages. Physical findings vary and primarily depend on the stage of hepatotoxicity.

Stage 1 (0.5-24 h [0-1 d] postingestion)

The first stage lasts for 24 hours. Patients have anorexia, nausea, vomiting, malaise, and diaphoresis. These clinical signs are nonspecific, and, hence, patients might inadvertently be given additional doses of an acetaminophen (APAP)-containing product for treatment.

Some patients remain asymptomatic, but they still have the risk to develop clinically significant toxicity.

Neurologic, respiratory, and cardiac symptoms are rare in stage 1. If central nervous system (CNS) involvement and/or severe metabolic acidosis (elevated anion gap) are present, consider co-ingestants.

The physical findings are typically nonspecific. Pallor, diaphoresis, and compromised hydration status due to repeated emesis and increased insensible losses may be present. Malaise and fatigue are reported.

Serum studies are typically within normal limits. About 12 hours postingestion, subclinical elevation of serum liver transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) occurs.

Stage 2 (24-72 h [1-3 d] postingestion)

The second stage begins 24 hours after ingestion and lasts for another 48 hours. Stage 1 symptoms become less evident than before and/or resolve.

Patients present with pain and tenderness in the right upper quadrant. Liver enlargement (hepatomegaly) can be present. Some patients may report decreased urinary output (oliguria). Vital signs show tachycardia and hypotension as indicators of ongoing volume losses.

Acute pancreatitis (eg, abdominal pain, elevated lipase, p-amylase) has been reported in patients who concurrently drink alcohol.

Serum studies reveal elevated ALT and AST levels, prothrombin (PT) times, and bilirubin values. Renal function abnormalities (eg, blood urean nitrogen [BUN], creatinine) may also be present and indicate nephrotoxicity.

Stage 3 (72-120 h [3-5 d] postingestion)

Stage 3 develops 3-5 days after ingestion. Symptoms seen in stage 1 (eg, anorexia, nausea, vomiting, malaise) reappear along with signs of hepatic failure with jaundice, hypoglycemia, bleeding (coagulopathies), encephalopathy, and/or sepsis. Renal failure and cardiomyopathy may also occur.

Physical findings reflect clinically significant hepatic injury, such as abdominal pain, jaundice, and gastrointestinal (GI) bleeding due to coagulopathy. Encephalopathy and cerebral edema due to severe hepatic injury occurs. Clinical signs and symptoms of multiorgan failure are noted.

Severe toxicity is evident on sera laboratory studies. Lactic acidosis, prolonged PT or international normalized ratio (INR), markedly elevated ALT and AST (≥10,000 IU/L), elevated total bilirubin level of more than 4 mg/dL (primarily indirect) and hyperammonemia are reported.

Hepatic centrilobular necrosis is diagnosed on liver biopsy. Almost 4% of patients who develop this degree of hepatotoxicity progress to fulminant hepatic failure.

Renal involvement from acute tubular necrosis is evident with abnormal renal function studies, proteinuria, hematuria and granular casts on urinalysis. Acute renal failure occurs in 25% of patients with significant hepatotoxicity and in more than 50% of those with hepatic failure.

Death is most common during stage 3, with multiorgan failure as the primary cause.

Stage 4 (5-14 d [5-21 d] postingestion)

Stage 4 occurs 5-14 days after ingestion. This stage can last as long as 21 days. Patients either have a complete recovery of liver function and resolution of physical findings or they die.

In patients who recover, the period to normalization may take several weeks. Hepatic histiologic recovery lags behind clinical recovery and can take as long as 3 months to resolve.

Acetaminophen (APAP)-induced hepatotoxicity does not cause chronic hepatic dysfunction.