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Hepatotoxicity of paracetamol
Last reviewed: 05.07.2025
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In adults, liver necrosis develops after taking at least 7.5-10 g of the drug, but the actual dose of the drug is difficult to estimate, since vomiting develops quickly, and anamnesis data are unreliable.
Alcohol, by inducing enzymes, increases the hepatotoxicity of paracetamol, so that in patients with alcoholism, liver damage can develop with a daily intake of only 4-8 g of the drug, and in the case of concomitant liver disease - with an even smaller dose.
The polar metabolite of paracetamol binds predominantly to glutathione in the liver. When glutathione reserves are depleted, the paracetamol metabolite arylates nucleophilic macromolecules essential for hepatocyte function, thus causing liver necrosis.
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Symptoms
Nausea and vomiting develop within a few hours of taking a toxic dose of paracetamol. Consciousness is not impaired. Apparent improvement occurs after about 48 hours; then, on about the 3rd or 4th day, the patients' condition worsens, liver pain and jaundice appear. Transaminase activity increases, and prothrombin levels fall. In more severe cases, the condition rapidly worsens with the development of acute liver necrosis. Without treatment, acute tubular necrosis develops in 25-30% of cases. Significant hypoglycemia and myocardial damage are observed.
Histological changes in the liver
Histological examination reveals zone 3 necrosis, signs of fatty degeneration, and a minor inflammatory reaction. Massive collagen degradation may be observed, but it does not lead to cirrhosis.
Chronic damage
Long-term (about 1 year) use of paracetamol (3-4 g/day) can lead to chronic liver damage. Concomitant liver diseases and alcoholism increase the damaging effect of paracetamol.
Treatment
Gastric lavage is performed. The patient is hospitalized. Since signs of necrosis in the liver appear late, clinical improvement should not serve as a basis for a favorable prognosis.
Forced diuresis and hemodialysis do not increase the excretion of paracetamol and its metabolites already bound to tissue proteins.
Treatment is aimed at restoring glutathione reserves in hepatocytes. Unfortunately, glutathione penetrates liver cells poorly. Therefore, glutathione precursors and substances with similar effects are used. Treatment is assessed by the concentration of paracetamol in plasma. This concentration is plotted on a semi-logarithmic scale of concentration versus time and is considered relative to the segment of the straight line connecting the points that correspond to 200 μg/ml after 4 hours and 60 μg/ml after 12 hours. If the patient's paracetamol concentration is below this segment, liver damage is mild and treatment may not be necessary.
When administered intravenously, acetylcysteine (mukomist, parvolex) is rapidly hydrolyzed to cysteine. It is administered at a dose of 150 mg/kg in 200 ml of 5% glucose solution for 15 minutes, then 50 mg/kg in 500 ml of 5% glucose solution for 4 hours and
100 mg/kg in 1 l of 5% glucose solution for the next 16 hours (total dose 300 mg/kg for 20 hours). This treatment is given to all patients with liver damage caused by paracetamol, even if more than 15 hours have passed since its administration. It may also be useful in other forms of FPN.
The use of N-acetylcysteine within 16 hours of taking the drug is so effective that liver damage from paracetamol poisoning is now rare.
In the case of a fulminant course, a liver transplant may be required. Survival is good, so psychological rehabilitation is not difficult to carry out.
Forecast
Among all patients admitted to the general hospital, mortality was 3.5%. Late hospitalization, coma, increased PT, metabolic acidosis, and renal dysfunction worsen the prognosis.
The severity of drug-induced injury can be assessed using nomograms that take into account the concentration of paracetamol in the blood and the time after taking the drug. Death occurs on the 4th-18th day.
Cardiopulmonary and renal failure, often seen in older people, increases the risk of liver damage even after taking moderate doses of paracetamol.
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