New Approach Could Save Lives Following Acetaminophen Overdose

Scientists successfully cure mice of acute liver failure after an overdose of acetaminophen by boosting the liver’s ability to heal itself

Released: 24-Apr-2014 11:00 AM EDT
Embargo expired: 29-Apr-2014 12:15 PM EDT
Source Newsroom: Federation of American Societies for Experimental Biology (FASEB)
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Citations Experimental Biology, April-2014

Newswise — SAN DIEGO (April 29, 2014) – A new technique could offer a lifesaving treatment option for patients with acute liver failure following an overdose of acetaminophen, a condition that accounts for half of all acute liver failure cases in the United States annually.

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 will present the findings during the Experimental Biology 2014 meeting on Tuesday, April 29 from 9:15 – 9:30 a.m. at the Hepatic Regenerative Medicine: Coping with Injury via Survival, Proliferation and Stem Cells minisymposium in Room 17B, San Diego Convention Center.

The study was supported by funding from the National Institutes of Health and the American Association for the Study of Liver Diseases.

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About Experimental Biology 2014
Experimental Biology is an annual meeting comprised of more than 14,000 scientists and exhibitors from six sponsoring societies and multiple guest societies. With a mission to share the newest scientific concepts and research findings shaping clinical advances, the meeting offers an unparalleled opportunity for exchange among scientists from across the United States and the world who represent dozens of scientific areas, from laboratory to translational to clinical research. www.experimentalbiology.org

About the American Society for Investigative Pathology (ASIP)
ASIP is a society of biomedical scientists who investigate mechanisms of disease. Investigative pathology is an integrative discipline that links the presentation of disease in the whole organism to its fundamental cellular and molecular mechanisms. ASIP advocates for the practice of investigative pathology and fosters the professional career development and education of its members. www.asip.org

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