Excessive ingestion of paracetamol can cause severe liver damage and is one of the most common causes of poisoning worldwide.
Since 1955, paracetamol has been the most commonly used antipyretic (reduces fever) and analgesic (reduces pain). Paracetamol, also known as acetaminophen, is an affordable over-the-counter as well as a prescription drug. It is preferred over other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) as it has lesser side effects. Chronic use, unintentional or intentional use or the use of paracetamol in combination with other drugs or addictive substances can cause severe liver damage (hepatotoxicity).
Paracetamol, like other NSAIDs, inhibits pain and fever pathways mediated by the Cyclooxygenase (COX) enzymes. Paracetamol specifically inhibits the COX-2 enzyme to slow down fever and unlike aspirin, it does not harm the gastric lining making it safe for consumption. It also obstructs many neurotransmitter pathways to decrease pain. Although paracetamol is not as effective as diclofenac or ibuprofen to treat intense muscle pain caused by rheumatoid arthritis or athletic injuries, it works for pain after a dental procedure and simple fevers.
After oral ingestion, the paracetamol is absorbed into the intestines and 50-60% of it is converted into inactive metabolites that are excreted out through urine. Out of the remaining, 5-10% of the paracetamol is converted into a reactive form called N-acetyl-para-benzo-quinine imine (NAPQI) which is responsible for hepatotoxicity. The level for NAPQI corresponds to the amount of paracetamol ingested. Doses of paracetamol above 200 mg/kg can lead to liver damage.
At non-toxic levels, NAPQI gets metabolised by the liver and is excreted out through urine. In higher doses, NAPQI binds to mitochondrial proteins to form protein adducts which deplete liver antioxidants and increases oxidative stress that can rupture the mitochondria. The damaged mitochondria release apoptotic factors and enzymes that break down DNA which can cause cell death. Higher levels of NAPQI can also form several reactive oxygen species and toxic free radicals which brings about oxidative damage, and DNA fragmentation, thus promoting cell damage.
The only approved treatments for paracetamol poisoning are N-acetylcysteine (NAC), gastric lavage and in extreme cases, liver transplant. NAC works by scavenging NAPQI and thus preventing protein adduct formation. NAC has been the reigning antidote to treat paracetamol-induced liver damage for over 40 years. However, due to having severe side effects and being ineffective, standard doses of NAC may not be enough for extreme overdose cases. Hence, scientists are developing other approaches like repurposing previous drugs and herbal alternatives. Ramachandran et al have summarised these alternative therapies in a review article that was published in Toxicological Sciences.
Metformin, a drug used for treating type-2 diabetes has the added advantage of treating paracetamol poisoning. A 2015 study showed that metformin was able to reduce paracetamol hepatotoxicity by inhibiting the oxidative stress pathways in mice. However, the high dose of metformin administered in animal models to treat hepatotoxicity is concerning as it is 4 times more than the therapeutic dose given to humans.
Another drug called fomepizole or 4-methylpyrazole which is commonly used for alcohol poisoning was able to curb the liver damage caused by paracetamol. Fomepizole prevents protein adduct formation and reduces mitochondrial injury. It also inhibited some of the key enzymes that aggravate oxidative stress and prevented the formation of NAQPI. Fomepizole is better than NAC on grounds of having higher therapeutic efficacy and lesser side effects.
A research team from Duke NUS Medical School and National Heart Centre Singapore further explored the signalling mysteries of paracetamol hepatotoxicity. They found that an immune chemical called Interleukin-11 or IL11 exacerbates the damage caused by the drug. They used anti-IL 11 antibody therapy in mice and observed that not only did the treatment abate liver damage but also promoted liver regeneration. From these results, the scientists confirmed that IL-11 causes liver damage and the anti-IL 11 treatment could help with paracetamol poisoning in humans. The results of this study were published in Science Translational Medicine.
Uncontrolled paracetamol ingestion and hepatotoxicity is a critical problem that can have far-reaching consequences. Its low cost and easy manufacturing make it a universal and easily accessible analgesic and antipyretic. Several therapeutic solutions are emerging to curb drug-induced damage and enhance liver regeneration. These solutions are especially beneficial for those who suffer from chronic pain and other muscle-related disorders.
Author: Parvathi Nair