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Scientists have shown for the first time that the deterioration of cells in a damaged liver can activate a process associated with ageing and impaired function, which then transmits to otherwise healthy organs elsewhere in the body.
They also identified a key protein that could be manipulated to prevent such multi-organ failure.
The findings could have major implications for our understanding of how diseases in different parts of the body interact with each other, and what happens as people age.
As the body gets older, cells become tired and stop working effectively. This process – called cell senescence – is a common effect of ageing but can also be triggered by diseases at any stage of life.
Senescence of liver cells following acute severe liver disease – which can be caused by a number of diseases including viral infections or toxins such as paracetamol overdose – can cause irreparable damage, leading to liver failure and can often lead to multi-organ failure.
The study, led by the University of Edinburgh and CRUK Scotland Institute, identified that in mice with sudden liver failure, once a large enough number of liver cells were damaged, senescence started to appear in other organs, including the kidneys, lungs and brain, causing them to fail.
Researchers identified a key biological pathway involving TGFβ – a protein linked to the immune system – which, when blocked in mice, prevented the senescence in liver cells from spreading to other organs.
In the future, treatments to block this pathway could prevent multi-organ failure in patients with severe liver injury, experts say.
Levels of liver cell senescence were also a powerful indicator of disease outcome in patients with severe liver damage.
Researchers from the Royal Free London examined liver tissue biopsies from 34 people with acute severe liver disease. High levels of liver cell senescence early in disease were linked to an increased risk of multi-organ failure and the need for liver transplantation.
There is currently no test to predict how sudden liver failure will progress when it begins. Monitoring liver cell senescence could help to identify those most at risk, including those likely to need a liver transplant, the research team says.
The Royal Free London team consisted of Professor Rajiv Jalan, from the UCL Institute for Liver and Digestive Health and a consultant hepatologist at the Royal Free Hospital, Professor Alberto Quaglia, from the UCL Cancer Institute and Fausto Andreola, senior research fellow.
Professor Jalan said: “Our findings provide the first insight into why severe liver injury results in the failure of other organs, such as the brain and kidneys, and death. We were able to validate these novel and exciting observations in patients, providing a route to develop biomarkers that can be measured in the blood to identify those at risk, and new therapies to treat severe liver disease.”
The study, principally funded by the Wellcome Trust and Cancer Research UK, is published in the journal Nature Cell Biology. The research team involved a collaboration between groups located at the CRUK Scotland Institute and those at Newcastle University and University College London, based at the Royal Free Hospital.
The study’s principal investigator, Professor Tom Bird of the University of Edinburgh’s Centre for Inflammation Research and the CRUK Scotland Institute, said: “The implications of the findings are potentially very profound. This may be a means by which severe disease, even in a single organ, can snowball into the failure of many organs in the body. But it can also teach us about ways to prevent this happening, both in sudden disease and potentially in a range of diseases occurring over years or even decades as we age.”
Morag Foreman, head of discovery researchers at Wellcome, said: “This is an exciting set of findings, unlocking crucial new insights with the potential to transform our understanding of multi-organ failure."
(Pictured L-R: Professor Rajiv Jalan and Fausto Andreola)
