Jay H. Hoofnagle, M.D. Director, Liver Disease Research Branch Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health, Bethesda, Maryland, U.S.A.
LiverTox Update FDA PHARMA Meeting March 26, 2014 University of Maryland
LiverTox Website on drug-induced liver disease Collaborative effort between the Liver Disease Research Branch, NIDDK and the National Library of Medicine (NLM). Source of reliable information on the clinical features, course and outcome of liver injury due to prescription and non-prescription drugs, herbals and dietary supplements Aims: advance knowledge and support research on drug induced liver injury March 2014
LiverTox Three components General introduction Individual drug sections (~650) Interactive component to enter findings from specific cases and provide comments Text is concise, formulaic, anonymous March 2014
Drug Sections Overview of the drug (1-2 pages) Background Hepatotoxicity Mechanism of injury Outcome and Management Representative cases Chemical structure Link to product label (package insert) Annotated references with PubMed links March 2014
LiverTox Includes drugs that cause liver injury And those that do not Largely those in current use in the U.S. Prescription and Non-Prescription Herbals and Dietary Supplements Drugs or Substances of Abuse [Alcohol is a drug!] March 2014
Drugs described in LiverTox Drug Names in NLM Computerized Database 23,270 Number of Different Agents 1884 Topical Agents 310 New Agents, HDS Agents of Abuse Agents Approved in US 1639 Agents Appropriate for LiverTox 909 Master List of Agents for LiverTox 1061 Special Agents 420 Foods Vaccines Plasma Products iv Solutions Rarely used Agents Veterinary Agents Estimates: March 2014 In LiverTox (March 2014) 666
Number of Agents Discussed 1000 900 800 700 600 500 400 300 200 100 0 445 412 666 Zimmerman [1999] Kaplowitz [2013] LiverTox March 2014
LiverTox Agents added in 2013 Antihistamines and anticholinergics Antineoplastic agents Cytotoxic antibiotics Topoisomerase and aromatase inhibitors Pyrimidine analogues, taxanes immunomodulatory agents Endothelin receptor inhibitors Sedatives and hypnotics (including herbals) Opioids and opiate receptor blockers Miscellaneous: rilpiviridine, elvitegravir, locraserin, nefazodone, avanafil, flavocoxid, khat, ketamine March 2014
Updating LiverTox Careful proofreading for grammar, spelling, clarity and accuracy Updating of references (PubMed) Checking current status (Daily Med) Adding pronunciation (USP Dictionary) Adding clinical cases A work in progress March 2014
LiverTox Web Activity Soft release: April 2012 Official release: October 2012 AASLD: November 2012, October 2013 Editorial in Hepatology: February 2013 Web activity: steadily increasing Comments from users: mostly positive Issues of contention: Herbals March: 2014
Web Activity: LiverTox 3,000,000 2,500,000 2,000,000 Number of Hits per month 2.4 million 1,500,000 1.1 million 1,000,000 500,000 0 Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13
Web Activity: LiverTox 200,000 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0 Visits Unique Visitors Jun-12 Jul-12 Aug-12 Sep-12 Oct-12 Nov-12 Dec-12 Jan-13 Feb-13 Mar-13 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13
Case Report Section ~100 Cases from DILIN entered in LiverTox Provides formulaic history and clinical course, table and graph of serial laboratory results, calculation of latency, severity and completeness scores and RUCAM RUCAM and severity scores are being compared to those from DILIN and discrepancies analyzed in detail March 2014
Case Report Section
Case Report Section
CASE REPORT REGISTRY: Data entry, page 1
CASE REPORT REGISTRY: Summary Report
CASE REPORT REGISTRY: Summary Report, continued
LiverTox: 2014 Finish proof-reading, editing and updating of current drug records Add introductory sections on management, rare phenotypes, and likelihood scores Add another 100 drugs (anti-neoplastics, gastrointestinal, HDS, vitamins, hormones) Add DILIN cases judged as very likely or definite to Submit a Case section Einar Bjornsson & Ynto Sjoerd March 2014