Categorization of drugs implicated in causing liver injury: ... : Hepatology (original) (raw)
Liver Injury/Regeneration
Categorization of drugs implicated in causing liver injury: Critical assessment based on published case reports
1The National University Hospital of IcelandReykjavikIceland
2Faculty of MedicineUniversity of IcelandReykjavikIceland
3Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD
*Address reprint requests to: Einar S. Björnsson, M.D., Ph.D., Professor of Gastroenterology and Hepatology, The National University Hospital of Iceland, 101 Reykjavik, Iceland. E‐mail: [email protected]. Address reprint requests to: Jay H. Hoofnagle, M.D., Liver Disease Research Branch, National Institutes of Health, Room 655, 6707 Democracy Boulevard, Bethesda, MD 20892‐5450. E‐mail: [email protected].
Abstract
An important element in assessing causality in drug‐induced liver injury is whether the implicated agent is known to cause hepatotoxicity. We classified drugs into categories based on the number of published reports of convincingly documented, clinically apparent, idiosyncratic liver injury. Drugs described in the website LiverTox (http://livertox.nih.gov) were classified into five categories based on the number of published cases (category A, ≥50; category B, 12‐49; category C, 4‐11; category D, 1‐3; category E, none). Case reports in categories C and D were individually reanalyzed using the Roussel Uclaf Causality Assessment Method. Drugs with fatal cases or with rechallenge were noted. Among 671 individual drugs or closely related agents, 353 (53%) were considered convincingly linked to liver injury in published case reports; 48 (13%) were assigned to category A, 76 (22%) were assigned to category B, 96 (27%) were assigned to category C, and 126 (36%) were assigned to category D. Another 7 (2%) were direct hepatotoxins but only in high doses and placed in a separate category (T). The remaining 318 (47%) drugs had no convincing case report of hepatoxicity in the literature (category E). All except one in category A have been available since 1999, 98% had at least one fatal case and 89% a positive rechallenge. In category B, 54% had a fatal case and 41% a rechallenge. Drugs in categories C and D less frequently had instances of fatal (23% and 7%) or rechallenge cases (26% and 11%). Conclusion: Documentation of hepatoxicity in the medical literature is variable, and many published instances do not stand up to critical review. A standardized system for categorizing drugs for hepatotoxicity potential will help develop objective and reliable, computer‐based instruments for assessing causality in drug‐induced liver injury. (Hepatology 2016;63:590–603)
© 2015 by the American Association for the Study of Liver Diseases