Paracetamol overdose: NAPQI and glutathione depletion
In paracetamol overdose the safe routes are overloaded, so more drug becomes the toxic molecule NAPQI, which damages the liver once glutathione, the liver's own protective molecule, runs out.
Remember
Once the safe routes are overloaded and glutathione is used up, NAPQI builds up and kills liver cells; the treatment, acetylcysteine, helps to restore glutathione.
At a normal dose, most paracetamol is made harmless in the liver. This is conjugation, which means attaching a group (glucuronide or sulphate) so that it leaves in the urine.
A small fraction is instead converted by cytochrome P450, a family of liver enzymes, into NAPQI (N-acetyl-p-benzoquinone imine), a toxic molecule. Glutathione, the liver's own protective molecule (an antioxidant), normally mops up NAPQI at once.
In an overdose the safe routes become saturated, which means they are working at full capacity, so more paracetamol is pushed down the NAPQI route. Glutathione stores are used up, and NAPQI accumulates. It binds to proteins in liver cells (hepatocytes) and causes oxidative stress, meaning that reactive oxygen-containing molecules overwhelm the cell's defences. The result is hepatocellular necrosis, which is death of liver cells.
Early symptoms are mild and are usually minor until at least 48 hours after the overdose, so a patient can look well while liver cells are being injured. The treatment is acetylcysteine, which helps the liver to restore its glutathione. It works best when started early, but it does not reverse existing liver damage.
Key facts
- Normal handling
- At normal doses most paracetamol is made harmless by conjugation, and the products leave in the urine.
- Toxic route
- A small fraction is turned into NAPQI by cytochrome P450 enzymes.
- In overdose
- The safe routes are overloaded, glutathione is used up and NAPQI builds up.
- Mechanism of injury
- The damage is direct chemical toxicity from NAPQI, not an immune attack.
- Treatment
- Acetylcysteine helps the liver to restore glutathione, but it does not reverse existing liver damage.
Exam traps
- More glucuronide and sulphate conjugates would protect the liver, because they are safe, inactive products that leave in the urine; in overdose these pathways become saturated, which is the problem.
- Reduced kidney excretion of paracetamol does not explain the liver injury, because paracetamol is cleared mainly by the liver (the urine carries mostly its conjugates) and the injury is explained by what happens inside hepatocytes.
- Paracetamol itself does not directly block energy production in mitochondria; mitochondrial damage does occur, but it occurs later, as a consequence of NAPQI injury.
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