Paracetamol poisoning

Paracetamol poisoning can cause gastroenteritis within a few hours and liver damage within 1-3 days after ingestion. The severity of liver damage after a single acute overdose can be predicted by the plasma paracetamol concentration.

Treatment with acetylcysteine prevents or minimizes paracetamol hepatotoxicity.

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Pathogenesis

Paracetamol is contained in more than 100 over-the-counter medications, including medicines for children (capsules, tablets and syrups) and preparations used for coughs and colds. Many prescription medicines also contain paracetamol. Due to this, paracetamol overdose is common. The main toxic metabolite of paracetamol, N-acetyl-b-benzoquinoneimine, is produced by the cytochrome P450 enzyme system of the liver; it is detoxified in the liver by glutathione. Acute overdose depletes the glutathione stores in the liver. As a result, N-acetyl-b-benzoquinoneimine accumulates, causing necrosis of hepatocytes, and damage to other organs (kidneys, pancreas) is possible. Theoretically, alcoholic liver disease and poor nutrition may increase the risk of injury because the hepatocyte enzyme system is altered to produce increased amounts of N-acetyl-b-benzoquinoneimine and, due to depletion (which is typical in alcoholics), leads to decreased glutathione stores. However, it is unclear whether the risk is actually increased. Alcohol intake may be protective because liver P450 enzymes preferentially metabolize ethanol and, as a result, are unable to produce toxic N-acetyl-b-benzoquinoneimine.

For poisoning, an acute overdose of a total of >150 mg/kg body weight (about 7 g for adults) within 24 hours is required.

Chronic overuse or repeated overdoses lead to liver damage in rare cases. Chronic overdoses usually result from taking an inappropriately high amount of the drug to treat pain, rather than from deliberate poisoning.

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Symptoms paracetamol poisoning

Mild poisoning may be asymptomatic, or symptoms may be minimal within 48 hours of taking the drug.

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Acute single overdose of paracetamol

Clinical symptoms, which pass through 4 stages, include anorexia, vomiting, nausea, pain in the right hypochondrium. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity may increase, and in severe poisoning - total bilirubin and INR. An increase in AST activity >1000 U/L is more likely as a result of paracetamol poisoning than in chronic hepatitis or alcoholic liver disease. Renal failure and pancreatitis are possible, sometimes without liver failure. After 5 days, liver damage either regresses or progresses to multiple organ failure, which is often fatal.

Paracetamol overdose should be considered in all patients with non-accidental drug ingestion that may be a suicidal attempt, as overdose is common. Furthermore, in the early stages, overdose symptoms are minimal, it is potentially fatal but treatable, and patients with altered consciousness or post-suicidal may not report it.

The probability and severity of liver damage can be predicted by the amount of the drug taken, or more accurately by its concentration in the blood. If the time of drug intake is known, the Ramack-Matthew nomogram can be used to predict the severity of liver damage. If the time of drug intake is unknown, the nomogram cannot be used. In case of a single acute overdose of the traditional or fast-acting form (absorbed 7-8 minutes faster) of paracetamol, its concentration is measured 4 hours after intake and the values are plotted on the nomogram. If the concentration is 150 mcg/ml (990 mmol/l) and there are no symptoms of intoxication, the risk of liver damage is very low. A higher concentration indicates the possibility of liver failure. In case of an overdose of prolonged-release paracetamol (which has 2 concentration peaks with an interval of 4 hours), its concentration is measured 4 hours after intake and again 4 hours later. Treatment is indicated if one of the indicators exceeds the Rumack-Matthew line parameters.

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Chronic paracetamol overdose

Symptoms may be absent or resemble those of acute overdose. The Ramek-Matthew nomogram is not used, but the probability of clinically significant liver failure can be estimated based on aminotransferase activity and paracetamol concentration in the blood. With normal AST and ALT values (<50 U/L) and paracetamol concentration <10 μg/ml, liver damage is unlikely. If aminotransferase activity is within normal limits, but paracetamol concentration is >10 μg/ml and there is a possibility of liver damage, AST and ALT activity should be re-measured within 24 hours. If enzyme activity is not increased upon repeated measurement, the risk of liver failure is low; with increased activity, liver damage can be assumed. Liver damage should also be assumed in case of initially high aminotransferase activity, regardless of paracetamol concentration in the blood.

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Stages

Stage	Time since admission	Description
I	0-24 h	Anorexia, nausea and vomiting
II	24-72 h	Pain in the right hypochondrium (characteristic); ALT, AST, and in severe poisoning, total bilirubin and INR may be elevated
III	72-96 h	Vomiting and signs of liver failure; ALT, AST, total bilirubin and INR peak; renal failure and pancreatitis develop in some cases
IV	>5 days	Regression of liver damage or its progression to multiple organ failure (sometimes fatal)

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Treatment paracetamol poisoning

If paracetamol is suspected to be present in the gastrointestinal tract, activated carbon is prescribed. The antidote for paracetamol poisoning is acetylcysteine. It is a precursor of glutathione, which reduces the toxicity of paracetamol by increasing the glutathione reserve in the liver and, possibly, by other mechanisms.

In acute poisoning, acetylcysteine is prescribed if the probability of liver damage is based on the dose of paracetamol or its concentration in the blood plasma. The drug is most effective in the first 8 hours after poisoning.

In chronic poisoning, acetylcysteine is prescribed for the first 24 hours if liver damage is likely (ALT and AST are not elevated, paracetamol concentration is slightly increased). If ALT and AST are not elevated during a repeat study (after 24 hours), acetylcysteine administration is stopped. In case of an increase in AST and ALT, daily monitoring of enzymes and continuation of acetylcysteine therapy until these parameters are normalized are necessary. If liver damage is likely (especially with high transaminase activity on admission), a full course of acetylcysteine therapy is administered.

Acetylcysteine is equally effective when administered intravenously and orally. Intravenously, the drug is administered as a continuous infusion. A loading dose of 150 mg/kg in 200 mL of 5% glucose or 0.9% sodium chloride solution is administered over 15 min; then a maintenance dose of 50 mg/kg in 500 mL of 5% glucose or 0.9% sodium chloride solution is administered over 4 h; then 100 mg/kg in 1000 mL of 5% glucose or 0.9% sodium chloride solution is administered over 16 h. When treating children, dosage adjustments are necessary to reduce the total volume of fluid administered; consultation with the Poison Control Center is recommended.

The loading dose of acetylcysteine when taken orally is 140 mg/kg, then 17 additional doses of 70 mg/kg are prescribed every 4 hours. Because of the unpleasant taste, the drug is prescribed in a 1:4 dilution with a carbonated drink or juice, but its use may still cause vomiting. If vomiting occurs, antiemetics can be prescribed; if vomiting occurs within 1 hour after taking an antiemetic, it is taken again.

Treatment of liver failure is supportive. Patients with fulminant liver failure may require liver transplantation.

Forecast

With appropriate treatment, mortality is low. By 24-48 hours, poor prognostic signs include:

• pH <7.3 after adequate infusion therapy;
• INR>3;
• creatinine >2.6;
• hepatic encephalopathy stage III (confusion and drowsiness, semi-conscious state) or stage IV (stupor and coma);
• hypoglycemia and thrombocytopenia.

The above parameters are examined 24 and 48 hours after poisoning. Acute paracetamol poisoning does not lead to the development of liver cirrhosis.

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