Study Drug-induced Liver Injury (DILIN)Nov 20, 2004 | www.medicalnewstoday.com The National Institutes of Health (NIH) has launched a network of five clinical centers and a data coordinating center to conduct studies over the next three years of patients who have suffered severe liver injury because of both prescription and “over-the-counter medications,” nutritional supplements, alternative medicines and herbals. The DILIN centers are located in North Carolina, Indiana, San Francisco, Michigan, and Connecticut, and will be awarded $2.25 million per year.
One objective of DILIN is to develop standardized definitions and instruments to identify and fully characterize cases of drug-induced liver injury. With a systematic way of classifying drug-induced liver injury, researchers will be able to analyze the epidemiology and clinical issues of liver injury and collect biological samples that can be used to study the causes of liver toxicity using biochemical, serological, and genetic testing. The DILIN is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the institutes of the NIH.
Another objective of DILIN is to establish a registry of patients who have experienced severe drug induced liver injury. “Part of the difficulty in studying drug-induced liver disease is the absence of a sufficient cohort of well-characterized patients in whom to carry out clinical, genetic, immunological and biochemical investigation,” says Jose Serrano, M.D., Ph.D, director, NIDDKs' Liver and Biliary Diseases Program and coordinator of the DILIN. “DILIN will help to eliminate this barrier and advance the understanding of drug-induced liver injury forward,” he adds.
Drug-induced liver injury occurs in all age groups, but most cases occur within the elderly population because they take more medications than younger persons and also use multiple medications. Furthermore, drug-induced liver injury is the most common reason why drugs are not approved by the Food and Drug Administration (FDA) or are removed from the market after they have been approved.
Most drugs that can cause liver injury are entirely safe for the majority of patients taking them. The reason why some patients are susceptible to liver injury from a drug is rarely known. “It is likely a result of many interrelated factors that involve complex interactions between our genes and the environment,” says Jay Hoofnagle, M.D., director, NIDDK Liver Diseases Research Branch. “Liver injury is unpredictable and variable in clinical presentation, making causality very tough to assess,” explains Hoofnagle.
At present, DILIN has developed protocols for both retrospective and prospective studies of drug-induced liver disease. The retrospective study will establish a registry of patients who have taken one of four specific drugs since 1994 and developed liver injury later. The four drugs are isoniazid, phenytoin, valproic acid, and clavulanic acid/amoxicillin. These drugs were chosen because they are widely prescribed and have definite clinical presentation. A minimum of 50 cases of each form of drug-induced liver disease will be collected along with an equal number of patients who have taken the drugs safely (controls). The researchers will obtain clinical and DNA information from each patient.
The prospective study will focus on enrolling patients who recently suffered an adverse liver reaction after taking any drug or herbal medicine. These patients will be followed over time to find out what happens to them as a result of their injury. Patients who have not sustained liver injury, but who have taken any of the drugs in question, will also be enrolled in the prospective study.
“Overall, we believe that the DILIN will bring greater focus and interest to the study of drug-induced liver injury and help to develop better ways to prevent, detect, and treat this growing liver problem,” says Paul Watkins, M.D., chair, the DILIN Steering Committee and principal investigator for the center in North Carolina.
The DILIN researchers have also developed diagnostic criteria and measures for grading causality in patients with drug-induced liver disease and will prospectively assess these instruments for sensitivity and specificity. Patient enrollment is ongoing.
The DILIN consists of the following principal investigators and centers:
Dr. Paul Watkins, University of North Carolina, Chapel Hill, North Carolina
Dr. Naga Chalasani, University of Indiana, Indianapolis, Indiana
Dr. Timothy Davern, University of California, San Francisco, California
Dr. Robert Fontana, University of Michigan, Ann Arbor, Michigan
Dr. Herbert Bonkovsky, University of Connecticut, Hartford, Connecticut
Dr. James Rochon, (Data Coordinating Center), Duke University, Raleigh-Durham, North Carolina