Why good medications are sometimes bad for the liver

The University of North Carolina at Chapel Hill is one of five clinical centers nationwide to receive funds from the National Institutes of Health to study why good medications are sometimes bad for the liver.

During the next seven years, the Drug-Induced Liver Injury Network, or DILIN, will study patients who have suffered severe liver injury caused by prescription and over-the-counter medications, nutritional supplements, alternative medicines and herbals.

Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, DILIN will be the first large-scale investigation of severe liver injury associated with drugs.

Other DILIN centers along with UNC are at the University of Indiana at Indianapolis, University of California at San Francisco, University of Michigan at Ann Arbor and University of Connecticut at Hartford.

Duke University is the project's data coordinating center, collecting information from the five clinical centers.

Drug-induced liver injury is the most common cause of sudden liver failure nationwide and the most common reason why new drugs fail to obtain approval by the U.S. Food and Drug Administration, said Dr. Paul Watkins, DILIN Steering Committee chairman and the study's principal investigator at UNC.

"This is the case even though drugs that cause liver injury are usually entirely safe for the majority of patients taking them," he added. The main purpose of DILIN is to find and study people who have experienced liver injury due to medications, said Watkins, who is Verne S. Caviness distinguished professor of medicine, professor of pharmacotherapy and director of the General Clinical Research Center at UNC. "This is the only way we can identify inherited and other factors that explain why a particular patient is susceptible when most are not," he said.

Researchers will use DNA analysis based on blood samples to identify possible genetic risk factors for such liver injury.

"Once a drug has been associated with severe liver injury, physicians are understandably hesitant to prescribe it, even if it may provide the best benefit for that patient," said Dr. Mark Russo, assistant professor of medicine and DILIN investigator at UNC.

One goal of the network is to develop testing that will identify patients who are at risk and, therefore, should not receive treatment with certain drugs.

Patients diagnosed with potentially severe liver injury due to any medication are eligible if enrolled within six months of the event. These people will be followed over time to find out what happens as a result of their injury. People who have not sustained liver injury but who have taken any of the medications in question also will be enrolled for comparison.

In addition to enrolling patients as they are brought to medical attention, DILIN is establishing a registry of patients who at any time since 1994 developed severe liver injury due to one of four specific drugs. The four are the tuberculosis drug isoniazid, the anti-seizure medications phenytoin and valproic acid, and the antibiotic amoxicillin-clavulanate potassium.

"Eligible patients from anywhere in North Carolina or neighboring states who are willing to come to UNC can be enrolled now," Watkins said. "Overall, we believe that the network will bring greater focus and interest to the study of drug-induced liver injury and will help to develop better ways to prevent, detect and treat this growing problem," Watkins said.

DILIN also may provide important insight into medical problems beyond liver injury induced by drugs, he added.

"Drug-induced liver injury is an ideal model to study how genes and environment interact to produce disease in some but not all people. We hope the factors identified by DILIN research will provide clues to susceptibility to the many diseases that represent an interaction with the environment."