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Recognizing Drug-Induced Liver Injury: Current Problems, Possible Solutions

¹ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9151, USA
² Office of Pharmacoepidemiology and Statistical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA

Correspondence: Address correspondence to: John R. Senior, M.D., Office of Pharma-coepidemiology and Statistical Science, Food and Drug Administration HFD-030, 5600 Fishers Lane—Parklawn Building 15B-33B, Rockville, Maryland 20857, USA; e-mail:seniorj{at}cder.fda.gov

Currently there are three major problems in understanding drug-induced liver injury (DILI): (1) reliably establishing whether the liver disease was caused by the drug, or by another process; (2) determining the true incidence of and clinical risk factors for drug-induced hepatotoxicity; and (3) elaborating the mechanisms by which injury occurs to hepatocytes and other liver cells. We have focused here on the first two problems, as issues that may be amenable to actions in the near future, but the third may take substantially longer to work out. The first problem requires sufficient information for medical differential diagnosis. There are no pathognomonic indicators of DILI; even liver biopsy is not diagnostic. Making the correct attribution of causality requires analyzing the temporal relationship of drug exposure to illness and excluding all other possible causes. The second problem, determining incidence, cannot be done entirely adequately using currently available methods, whether by clinical trials, by spontaneous adverse event reports, or by retrospective epidemiologic studies. There is need for prospective safety studies to establish the true incidence of DILI caused by a drug, to identify risk factors for it, and to collect biologic materials for analytic studies toward better understanding mechanisms of DILI.

Key Words: Causality attribution • diagnosis of exclusion • information required • true incidence • risk factors • prospective safety study • hepatotoxicity mechanisms

Abbreviations: AERS, adverse event reporting system • AHRQ, Agency for Healthcare Research and Quality • ALF, acute liver failure • ALP, alkaline phosphatase activity in serum • ALT, alanine aminotransferase activity in serum • APAP, N-acetyl-para-aminophenol (acetaminophen) • AST, aspartate aminotransferase activity in serum • CAM, complementary and alternative medicine • CIOMS, Council for International Medical Sciences • DILI, drug-induced liver injury • DILIN, Drug-Induced Liver Injury Network • DSMB, data and safety monitoring board • FDA, Food and Drug Administration • INR, internationalized ratio (of prothrombin time elevation) • NIDDK, National Institute of Diabetes, Digestive and Kidney Diseases • NIH, National Institutes of Health • OTC, over-the-counter (medications) • RUCAM, Roussel-Uclaf causality assessment method • TBL, serum total bilirubin concentration

Toxicologic Pathology, Vol. 33, No. 1, 155-164 (2005)
DOI: 10.1080/01926230590522356


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