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'Aspirin a day' for the liver

Tuesday 27 January 2009

“An aspirin a day could help prevent liver damage caused by obesity, heavy drinking and drug use,” The Daily Telegraph reports. It adds that “millions of people susceptible to liver problems could have their lives prolonged by the painkiller”. It reports that a study in mice found that aspirin lessened the damage caused by paracetamol overdose. The researchers are said to believe the drug could do the same for other types of liver damage.

The newspaper has greatly over-inflated the implications of this study. Although the research gives a better understanding of the effects of paracetamol on the liver in mice, it is not yet clear whether these findings apply to humans.

Liver disease and liver damage are broad terms and cover a large array of conditions. For example, the damage caused by a paracetamol overdose is different to the fatty or fibrotic liver changes that are the result of alcohol abuse or obesity. Whether aspirin has any effect on other causes of liver disease or damage is unclear. This study’s findings do not support the suggestion that people should regularly take aspirin in the hope of warding off liver damage.

Where did the story come from?

Dr Avlin B. Imaeda and colleagues from Yale University and the University of Iowa carried out this research. The work was funded by the Ellison Medical Foundation and the National Institutes of Health. The study was published in the peer-reviewed Journal of Clinical Investigation .

What kind of scientific study was this?

In this animal study, the researchers looked at how acetaminophen (paracetamol) causes liver damage in mice, and whether drugs could prevent this damage. It is known that high exposure to paracetamol kills liver cells, and this initial damage activates the immune system leading to further tissue injury. The researchers wanted to look at the role of various proteins (called Tlr9, caspase-1, ASC, and Nalp3) that might be involved in the immune response, and if blocking their action would reduce the liver damage caused by paracetamol.

The first experiment involved a group of mice that had been genetically engineered to lack the Tlr9 protein and a group of normal mice. The researchers injected both groups with a dose of paracetamol that was high enough to cause liver damage and death. They then compared how many mice died in each group over 72 hours.

The researchers then treated another group of normal mice with chemicals that blocked the action of the Tlr9 protein to see if it prevented liver damage from paracetamol. The mice were first injected with paracetamol, which was then followed either by another injection immediately or an injection six, 14, or 28 hours later. The second injection contained one of two different Tlr9 blockers (ODN2088 or IRS954) or a control solution. The researchers then looked at markers of inflammation and immune response (in the experiment using ODN2088) in the mice or at their survival (in the experiment using IRS954). They also examined the biochemical role of Tlr9 in liver cells.

These investigations suggested the involvement of three proteins, caspase-1, ASC, and Nalp3 (which together form a complex group of proteins called the “Nalp3 inflammasome”), and another protein called Ipaf (which can also activate caspase-1). All these proteins are thought to play roles in the body’s inflammatory response. To explore this further, they used four types of mice that had been genetically engineered to lack these proteins (each strain lacking one of the proteins). They injected the genetically engineered mice and a group of normal mice with paracetamol and compared their survival over 72 hours. The researchers also looked at tissue from the mouse livers to identify tissue damage.

In their final experiment, the researchers tested whether aspirin (an anti-inflammatory drug) could block the effects of the Nalp3 inflammasome and therefore potentially protect the liver from damage. They first demonstrated that pre-treating the mice with aspirin reduced the white blood cell response when the mice’s abdominal cavity was injected with monosodium urate (MSU) crystals, a process that involves the Nalp3 inflammasome. They then pre-treated one group of mice with low-dose aspirin for 60-72 hours and left another group untreated. Both groups were then injected with paracetamol and survival over 72 hours was studied. They also looked at what effect giving aspirin at the same time as paracetamol had.

What were the results of the study?

The researchers found that fewer mice lacking the Trp9 protein died after exposure to a high dose of paracetamol than normal mice. They found that treating paracetamol-exposed mice with the Tlr9 blocker IRS954 also reduced deaths.

Further experiments suggested that a group of proteins called the “Nalp3 inflammasome” might be involved in the effects of paracetamol on the liver. Genetically engineered mice that lacked the components of this inflammasome (caspase-1, ASC, and Nalp3) were less likely to die after exposure to paracetamol than normal mice. These genetically engineered mice also had less liver damage when the tissue was examined under a microscope. Mice lacking a related protein called Ipaf were just as susceptible to the effects of paracetamol as normal mice.

Pre-treating mice with low-dose aspirin increased their survival after paracetamol exposure compared to no pre-treatment. Giving aspirin at the same time as paracetamol also improved survival, but not by as much as aspirin pre-treatment.

What interpretations did the researchers draw from these results?

The researchers concluded that they have identified a role for Tlp9 and the Nalp3 inflammasome in liver damage (hepatotoxicity) caused by paracetamol, and that pre-treatment with aspirin can reduce these effects.

This means that if aspirin is found to work similarly in humans, then adding aspirin to paracetamol tablets during the manufacturing process might reduce the risk of liver damage in people who have taken a paracetamol overdose.

What does the NHS Knowledge Service make of this study?

This study has been largely over-inflated by the news. These studies were carried out in mice and although they give a better understanding of the effects of paracetamol on the liver, it is not yet clear whether these findings apply to humans.

Even if aspirin were protective against paracetamol-induced liver damage, the study results suggest that pre-treatment with aspirin would be needed for the greatest effect, which is unlikely to be feasible in either intentional or non-intentional paracetamol overdose in humans.

Liver disease and liver damage are very broad terms and cover a vast number of conditions. Damage due to paracetamol toxicity is a separate issue from the fatty or fibrotic liver changes from excess alcohol or obesity, for example. Whether aspirin would have any effect on other causes of liver disease or damage is unclear. The results of this study do not suggest (as the news does) that people should start regularly taking aspirin in the hope of warding off liver damage.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Aspirin 'could cut liver damage'.

BBC online, 27 January 2009

Aspirin 'tackles liver damage caused from alcohol and obesity'.

Daily Mail, 27 January 2009

Aspirin 'can help prevent liver damage'.

The Daily Telegraph, 27 January 2009

Links to the science

Imaeda AB, Watanabe A, Sohail MA et al.

Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.

JClin Invest 2009; Published online January 26