Saving lives following acetaminophen overdose: New approach could help

Acetaminophen, the active ingredient in Tylenol and a component of more than 600 other over-the-counter and prescription medications, is one of the most commonly used drugs in the United States. The U.S. Food and Drug Administration recently lowered the maximum dosage allowed in prescription medications and imposed new labeling requirements in response to concerns over the risk of accidental overdose.

"Acetaminophen is a great drug when taken in appropriate doses; however, it's also known to quickly cause life-threatening liver injury when a person takes too much," said Udayan Apte, Ph.D., assistant professor of pharmacology, toxicology and therapeutics at the University of Kansas Medical Center and the study's senior investigator. "I think our approach has tremendous potential for saving the lives of overdose patients with severe liver failure."

More than 50,000 emergency room visits annually in the United States are associated with acetaminophen overdose. Although only a fraction of those cases lead to acute liver failure, those patients who suffer liver failure often die from it because there are few treatment options available.

The researchers were able to successfully cure mice that had received fatal doses of acetaminophen by boosting the liver's natural ability to heal itself. "While it is known that liver regeneration plays a key role in recovery for those who survive an acetaminophen overdose, we did not know the mechanisms of how that works. This study is the first comprehensive analysis of mechanisms involved in liver regeneration after acute liver failure from acetaminophen overdose," said Bharat Bhushan, a doctoral candidate at the University of Kansas Medical Center who worked on the research.

Among organs, the liver is unique for its ability to regenerate following an injury, a phenomenon seen in both mice and humans. The team first conducted a set of experiments to pinpoint why the liver does not regenerate naturally after a high dose of acetaminophen. They revealed the source of the breakdown to be a protein known as beta-catenin. By boosting beta-catenin production in mice given high doses of acetaminophen, the researchers were able to speed up the liver's regenerative capabilities and counteract the deadly cascade of events that would typically lead to liver failure. The mice completely recovered.

"A similar approach should also work in humans," said Apte. The team's next step is to refine the technique to see if it can be safely applied in human patients. They are also working to develop biomarkers that doctors can use to monitor a patient's liver recovery during treatment.

Apte said the study is unique because it focuses on enhancing the liver's natural recovery capability instead of attempting to directly address the damage done by the drug overdose, which is where most previous research has focused. "We think the opportunity for intervention lies in understanding the mechanisms of recovery rather than the mechanisms of injury," said Apte. "Acetaminophen has been studied for two decades, but nobody has ever looked at how it relates to the regeneration process."

Acetaminophen presents a high risk of overdose precisely because it is found in so many medications and is used by everyone from babies to the elderly. Accidental overdoses often occur when a person takes multiple medications containing the drug without realizing they are exceeding the total dosage limit. Adults should take no more than 4 grams in 24 hours.

The current therapy for acetaminophen overdose requires treatment to be started within a few hours of an overdose, which is not possible in many cases. The only other option is a liver transplant, which can be difficult to arrange in the short time available in cases of acute liver failure.

Bharat Bhushan presented the findings during the Experimental Biology 2014 meeting on Tuesday, April 29.