Researchers are discovering how paracetamol damages the liver

Disease and treatment 21. jun 2019 2 min Resident Physician Cecilie Brøckner Siggaard Written by Morten Busch

An overdose of paracetamol can be deadly. Although paracetamol poisoning causes no symptoms initially, it may have catastrophic effects on the liver. These people often feel fine for up to several days after an overdose, but the paracetamol activates a mechanism that slowly but surely degrades the liver. Researchers now believe they have discovered new knowledge about this mechanism. They hope to eventually be able to counteract the liver damage caused by both paracetamol poisoning and other liver diseases.

Many people decide to take an overdose of painkillers when life becomes too hard and unmanageable. The pills often contain paracetamol which, when taken in large quantities, immediately poisons the body because it kills liver cells.

“We theorized that paracetamol poisoning damages liver cells through two steps. The first step is paracetamol and its waste products causing direct damage, whereas the second step is less well known. Our study suggests that the direct damage from paracetamol activates macrophages – immune system cells – that potentially increase liver cell damage and that the degree of macrophage activation is crucial in determining the outcome of paracetamol poisoning. If this can be confirmed in larger studies, it opens up new options for treatment and monitoring people with paracetamol poisoning,” says a main author, Cecilie Brøckner Siggaard, Resident Physician, Aarhus University Hospital.

Fortunate circumstances complicated the study

Previous studies have primarily investigated paracetamol poisoning at the later stages after people have already developed liver damage, but the researchers wanted to identify the early signs of what occurs when paracetamol degrades the liver after poisoning.

“For people admitted with paracetamol poisoning who subsequently develop liver cell damage, we can measure elevated values of soluble haemoglobin scavenger receptor (sCD163) and soluble mannose receptor (sMR) shortly after the overdose. These markers show that the macrophages have been activated in the liver. These values decline again among the people who do not develop significant liver cell damage.”

However, otherwise fortunate circumstances complicated the study. Fewer people than before are now experiencing paracetamol poisoning because today it can only be purchased in small packages in Denmark and other countries. However, the researchers measured the markers among 49 people with early mild paracetamol poisoning from Aarhus University Hospital and 30 people from the Royal Infirmary of Edinburgh with severe acute liver damage following paracetamol poisoning.

“Among the people with mild paracetamol poisoning, those who showed signs of liver cell damage had significantly higher levels of sCD163 than those who did not. However, the people with acute liver damage from Edinburgh had the highest values. This indicates that sCD163 can help us to identify, at an earlier stage, the people who later develop severe liver cell damage.”

May be a general mechanism

The researchers still do not understand exactly what mechanism is initiated when paracetamol degrades the liver and activates the immune system. Initially, however, the goal was primarily to determine whether they could use these markers to differentiate between people at high risk and people who appear to avoid severe liver damage.

“These markers will potentially enable us to separate these groups relatively easily so that we can focus our efforts on the people at high risk of developing severe liver damage.”

The study also surprisingly provided the researchers with new knowledge about N-acetylcysteine, an antidote to paracetamol poisoning, which reduced marker levels among everyone with poisoning – those who had liver cell damage and those who did not. This was also subsequently confirmed among healthy controls.

“We know that N-acetylcysteine works by neutralizing paracetamol and its waste products directly, but our results indicate that it also presumably directly affects the macrophages. This is new knowledge and can potentially explain why people with other liver diseases treated with N-acetylcysteine experience positive effects.”

However, more studies are required before concluding further on the underlying mechanism behind how N-acetylcysteine works and the importance of macrophages for liver cell damage after paracetamol poisoning. For now, the researchers are delighted that they have apparently discovered a breakthrough that may also be able to help people other than those with paracetamol poisoning.

“We are currently measuring sCD163 among people with viral hepatitis before and after treatment; the values are elevated and then decline after treatment. Previously, we showed that sCD163 is a marker of the severity of fatty liver disease and declines after treatment. If sCD163 is consistently reliable as a biomarker in liver disease in general, we can use these measurements to monitor liver cell damage from a variety of causes.”

Macrophage markers soluble CD163 and soluble mannose receptor are associated with liver injury in patients with paracetamol overdose” has been published in the Scandinavian Journal of Gastroenterology. In 2014, the Novo Nordisk Foundation awarded a grant to Henning Grønbæk, Department of Clinical Medicine, Aarhus University for the project Inflammatory Liver Diseases and the Role of Hepatic Macrophages.

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