NIH Liver Injury Network Expands

Abstract

Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United States and is becoming an increasingly important health concern as more people take prescription, over-the-counter, and herbal medications. Liver injury is also the major reason drugs fail to win approval from the US Food and Drug Administration. Although the incidence of DILI is unclear—relying on spontaneous reporting from health care professionals—serious adverse drug reactions account for about 4.7% of hospital admissions in the United States. But a huge underreporting of adverse reactions in general suggests cases of DILI may also be much higher. In 2003, the NIDDK funded the Drug Induced Liver Injury Network (DILIN), comprised of 5 clinical centers: University of North Carolina at Chapel Hill, Indiana University School of Medicine, University of California at San Francisco, University of Michigan at Ann Arbor, the University of Connecticut at Hartford, and Duke University as the project's data coordinating center, collecting information from the 5 clinical centers. Preliminary data on DILI from the 5 clinical centers has been published by Chalasani N et al in Gastroenterology 2008;135(6):1924–1934. Recently DILIN has been expanded to include more clinical sites and it currently involves collaboration among investigators at 9 clinical study centers plus the data coordinating center at Duke. The network includes Indiana University, Indianapolis; Mayo Clinic, Rochester, MN; Thomas Jefferson University/University of Pennsylvania, Philadelphia; University of California, San Francisco; University of California, Los Angeles; University of Michigan, University of North Carolina, Chapel Hill; University of Southern California, Los Angeles; and the University of Texas Southwestern, Dallas. Other collaborating sites are Rutgers University Cell and DNA Repository, Piscataway, NJ; and the NIH/NCI and NIDDK/NIH, both in Bethesda, MD. The network is sponsoring retrospective and prospective DILI studies with corresponding patient registries. The retrospective study is aimed to unravel the mystery behind DILI caused by certain “signature” drugs in only a slim minority of people while their use if ubiquitous. The study has now expanded to examine seven specific drugs and one drug category: isoniazid, phenytoin, clavulanic acid/amoxicillin, and valproic acid, nitrofurantoin, trimethoprim-sulfamethoxazole, minocycline, and quinolone antibiotics. DILI signs and symptoms resulting from these agents are relatively well defined, providing the opportunity to explore common environmental and genetic contributors. The retrospective registry houses clinical details about DILI episodes along with DNA and blood samples. The prospective study is allowing scientists to study idiosyncratic DILI during the initial phase: from first presentation onward. Included are cases of DILI caused by all prescription and over-the-counter medications, herbals, and nutritional supplements. Once enrolled, patients are followed for a minimum of 6 months but possibly as long as 20 years. Controls—volunteers with similar drug exposure but no DILI—will be enrolled for comparison. For more details, see https://dilin.dcri.duke.edu. Both studies are enabling investigators to examine the clinical, genetic, immunological, and environmental risk factors in slightly different ways.