The human liver has a remarkable ability to regenerate after moderate injury, but can’t self-repair after sudden, severe damage, which in western regions such as the U.S. is most commonly caused by either accidental or intentional paracetamol (acetaminophen) overdose. In such cases of acute liver failure, recovery is unlikely and without a liver transplant the patient will almost inevitably die.
Studies headed by a research team at the Cancer Research U.K. Beatson Institute and Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh, now suggest that a class of drug that is in development for treating cancer could represent a life-saving option for acute liver failure. Their studies in human tissues and in mouse models found that after severe injury, a signaling pathway mediated by transforming growth factor–ß (TGFß) pitches hepatocytes into a state of senescence, or permanent growth arrest, which stops the cells from replicating and regenerating the damaged tissue. Tests in experimental animals showed that using drug molecules to blocking TGFß signaling improved liver regeneration and increased survival, even when treatment was delayed by several days.
“Through our research so far we have identified a potential treatment for acute liver failure, which may prevent the need for transplant,” comments Thomas G. Bird, Ph.D., Beatson Institute research lead and Wellcome Trust Fellow. The scientists, working with colleagues across Europe and in the U.S., report their results in a paper in Science Translational Medicine, which is titled, “TGFß inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.”
Acute liver failure affects about 2,000 patients in the U.S. every year. Although this degree of catastrophic damage to the liver can be caused by viruses, toxins, or medical intervention, in the western world it most commonly results from an overdose of paracetamol. “Most of the patients we see with this type of critical liver injury are otherwise physically healthy, and have accidentally or, often, sadly, intentionally taken an overdose of paracetamol,” Dr. Bird notes.
The prospect of recovering from acute liver injury is largely dependent on the extent of damage, the researchers suggest. Clinical scoring systems can predict whether a patient will survive or whether the liver will fail to regenerate. And while outcomes have improved “modestly” with better supportive care, once the damage reaches a tipping point of severity, there are no effective treatments. “… recovery is unlikely, and, unless liver transplantation occurs, death usually ensues,” the authors write. Unfortunately, the pathophysiological mechanisms that underlie the processes that hold back liver regeneration and promote organ failure aren’t well understood, and this has held back the development of new treatments.
As a result, liver transplantation may be the only option, but organs are in short supply, and transplantation has lifelong consequences. “While transplant offers incredible life-saving opportunities for these patients, it does mean a major operation and a lifetime of medication and with around 300 adults and children in the U.K. in need of a liver transplant at any one time, it cannot be guaranteed,” Dr. Bird adds.
The U.K. researchers’ initial analyses of liver samples from acute liver failure patients showed that within days of acute injury, previously healthy liver tissue started to express multiple markers of hepatocellular senescence. In effect, the greater the severity of liver damage, the greater the degree of cell senescence. “… worsening acute liver injury in humans results in a proportional expression of senescent markers by hepatocytes, associated with a reduced capacity for liver regeneration,” the authors write.
Tests in separate mouse models of liver injury demonstrated that liver cells started to express a senescence-associated gene signature within just 24 hours of paracetamol-induced liver injury, and this led to hepatocyte growth arrest. Further analyses showed that senescence was orchestrated by macrophage-produced TGFß, which was central to a signaling pathway that triggered senescence to spread between hepatocytes, starting at the site of injury and necrosis. When the researchers either knocked out the macrophages or deleted TGFß1 in relevant mouse models, liver injury still occurred, but the animals demonstrated improved liver regenerative capacity.
In an attempt to block TGFß signaling pharmacologically, the authors turned to a small molecule drug, AZ12601011, which inhibits TGFß receptor 1 (TGFß R1), the receptor for TGFß. They showed that hepatocellular senescence could be held back by administering the compound to experimental mice within 12 hours of liver-toxic carbon tetrachloride administration. In parallel with demonstrating reduced cell senescence, the treated animals’ livers were also better able to regenerate. Administering AZ12601011 to mice at the same time as a lethal dose of paracetamol similarly resulted in significant clinical improvements over the following 16 hours, and increased survival.
Conventional treatment of paracetamol toxicity using N-acetylcysteine requires drug administration within eight hours of overdose in humans, or within four hours in mice. Encouragingly, the researchers found that treating animals using AZ12601011 or another TGFßR1 inhibitor SB525334 even 12 hours after paracetamol overdose still reduced senescence, held back damaging effects on the liver, and improved regenerative capacity, in parallel with reducing local TGFß pathway activation.
While clinical trials evaluating TGFßR1 and TGFß inhibition as a treatment for cancer are in progress, the new findings in mouse models of acute liver failure do not demonstrate that blocking either TGFßR1 or TGFß would have therapeutic effects against severe liver injury in humans. This will first need extensive safety and efficacy studies, the authors point out. Nevertheless, they suggest, “… we have shown that severe acute hepatic necrosis induces the spread of senescence to remaining viable hepatocytes, which impairs hepatocyte-mediated regeneration. This process is therapeutically modifiable, thus providing the potential for developing future therapies to treat this devastating condition.”
“New treatments like this, which set liver regeneration free and may prevent the need for liver transplants, would make a huge difference for these patients,” concludes Dr. Bird. “They may also allow us to use the livers available for transplantation for other patients with different forms of liver disease who might otherwise die whilst waiting for a suitable liver donor.”