A ‘Genetic Score’ to Predict Whether a Medication May Cause a Patient Liver Injury

The Context: Many drugs cause liver injury in certain patients, and this is a leading cause of acute liver failure in the United States. A major issue for physicians is that it is hard to know which patients are at risk for liver injury before prescribing them the medication.

The Study: A new genetic test developed using organoids, 3D clusters of liver tissue derived from stem cells, by NYSCF – Robertson Stem Cell Investigator Takanori Takebe, MD, of Cincinnati Children’s Hospital establishes a ‘polygenic risk score’ that indicates whether a patient will be at risk for drug-induced liver injury (DILI). The study appears in Nature Medicine.

The Importance: The new test has the potential to determine whether a patient’s unique genetic makeup will put them at risk for DILI, both informing the design of clinical trials and helping physicians determine which drugs to prescribe.

DILI is an old and dangerous problem for patients, drug developers, and physicians. It’s hard to predict, and can often cause acute liver damage.

“So far, we have had no reliable way of determining in advance whether a medication that usually works well in most people might cause liver injury among a few,” Jorge Bezerra, MD, Director of the Division of Gastroenterology, Hepatology, and Nutrition at Cincinnati Children’s explained in a press release.

“That has caused a number of promising medications to fail during clinical trials, and in rare cases, also can cause serious injury from approved medications. If we could predict which individuals would be most at-risk, we could prescribe more medications with more confidence,” he continued.

Take, for example, the case of Fasigliam, a diabetes medication that was pulled from clinical trials after a small number of participants showed increased enzyme levels indicative of possible DILI. Since the researchers had no way of determining why these patients had this reaction and who might develop it later on, the drug was discontinued.

A Promising New Tool for Determining Genetic Risk of DILI

Dr. Takebe’s team developed their genetic score using liver organoids: 3D clusters of human liver tissue made from stem cells. First, they examined hundreds of published genetic studies (which together analyzed more than 20,000 gene variants) that had identified many genetic factors that may put one at risk for DILI.

Then, the team used this data to develop a model that predicts which combinations of factors could increase risk of an adverse reaction. Testing of the model in the organoids for over a dozen medications, along with previously collected patient data, indicated that the score was accurate, holding promise for its ability to one day protect patients from DILI.

Looking to the Future

Dr. Takebe hopes that the score will one day help patients and providers understand risk for DILI.

“Our genetic score will potentially benefit people directly as a consumer diagnostic-like application, such as 23andMe and others. People could take the genetic test and know their risk of developing DILI,” noted Dr. Takebe.

The researchers plan to continue testing their model in more diverse populations to further validate its predictive power. They will also work on scaling it up to prepare it for clinical use so that physicians and drug developers can identify individual risk before enrolling patients in clinical trials or prescribing them medications that could be harmful.

Journal Article:

Polygenic architecture informs potential vulnerability to drug-induced liver injury.
Masaru Koido, Eri Kawakami, Junko Fukumura, Yui Noguchi, Momoko Ohori, Yasunori Nio, Paola Nicoletti, Guruprasad P. Aithal, Ann K. Daly, Paul B. Watkins, Hisashi Anayama, Yvonne Dragan, Tadahiro Shinozawa & Takanori Takebe. Nature Medicine. 2020. DOI: 10.1038/s41591-020-1023-0