Paracetamol is the world’s most popular pain killer, but it could also potentially trigger the most dangerous kind of liver disease. In the hectic world we live today, it is almost impossible for one to work for a whole day without having a headache or feeling any kind of discomfort that’ll make them want to take a pain killer. Paracetamol (acetaminophen) has been a life saver over the years; however, research has shown that it is the leading cause of liver failure in the United States and many other countries.
At the normal therapeutic doses of 1 to 4 gram per day, paracetamol is a very effective relief for fever and all kinds of pain. Consumption of a single dose of over 6g in adults or 150g in children can cause acute liver and kidney toxicity due to the production of a very highly active metabolite called N-acetyl-p-benzoquinone imine (NAPQI).
How does the body break down paracetamol?
The liver and the kidney (to a lesser extent) are the main organs that break down paracetamol. This metabolism takes place through there different pathways.
- Glucoronidation pathway
- Sulfation pathway
- Oxidation pathway
The glucoronidation pathway is the most active pathway of acetaminophen metabolism, followed by the sulfation pathway. These two pathways break down acetaminophen to give a non-toxic metabolite which is excreted out of the body. However, a very small portion of the drug (about 5%) is oxidized to produce the toxic reactive metabolite NAPQI, which causes liver damage.
Pathways shown in blue and purple colors (glucoronidation and sulfation) produce non-toxic metabolite, but the pathway in red color produces the toxic NAPQI.
Image source
How Paracetamol liver Toxicity Happens
When we take more than 4 grams of paracetamol a day, the sulfation pathway becomes saturated and shuts off, while the glucoronidation and oxidation pathways increase. With a further increase in the dosage, the glucoronidation pathway also becomes saturated, leaving only the oxidation pathway, thereby causing an increased production and accumulation of NAPQI.
Normally, in a healthy liver, only a very small amount of NAPQI is produced, and this small quantity is inactivated or neutralized by an antioxidant called glutathione, which binds to it and makes it inactive, so that it can be excreted in the urine.
In the case of paracetamol overdose, the liver produces excessive amount of NAPQI, much more than the available glutathione can inactivate. When this happens, it depletes the glutathione store, and the excessive NAPQI begins to attack critical proteins of the liver.
NAPQI binds to the cysteine groups of liver proteins, and forms protein adducts. It targets and destroys the mitochondrial proteins and ion channels of the liver, thereby leading to ionic imbalance, loss of energy production, and cell death.
This pathway shows how NAPQI inhibits the electron transport chain, and shuts down energy production in the liver.
Is there a Remedy?
Considering that paracetamol-induced liver toxicity happens primarily because of depletion of glutathione, it is safe to say that replenishing the glutathione store would be an effective remedy. Research has shown that N-actetylcysteine (NAC) is an effective antidote for paracetamol overdose. NAC replenishes the body’s glutathione store of the body, mops up reactive oxygen species in the mitochondria and enhances the sulfation pathway.
If NAC is administered within 8 hours after paracetamol overdose, it reduces the risk of liver damage to less than 5% but if the drug is not administered within 10 hours of overdose, liver failure occurs, followed by kidney failure and consequently, death.
Final Notes
From the above, we can deduce that paracetamol overdose can be very fatal. Prevention, they say, is better than cure, so the best remedy remains to take only the recommended doses, and avoid any form of drug abuse. So the next time you want to pop that paracetamol pill, ask yourself, am I taking a pain killer, or am I destroying my liver?
References:
https://academic.oup.com/bjaed/article/14/4/153/293533
https://www.pharmgkb.org/pathway/PA165986279
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1403265/
https://emedicine.medscape.com/article/820200-overview#a1
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