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AASLD-FDA-NIH-PhRMA*- Hepatotoxicity Special Interest Group Meeting
2008 Presentations
Was it the drug, or a disease? How to determine it. [PDF] 
Don C. Rockey
Abstract
Drugs cause liver injury (i.e. drug-induced liver injury (DILI)) infrequently, but when they do, such reactions may be devastating.1-3 Further, DILI often leads to the need for a drug (often an effective one) to be removed from the market. Many different drugs cause DILI, but drug reactions are characterized by great variability in clinical presentation. Drug reactions vary in terms not only of their clinical and biochemical “signature”, but also in terms of the timing from drug ingestion to clinical presentation. Indeed, while it is most common for drug reactions to become evident soon after beginning the drug, evidence of liver injury may not be apparent after ingestion of some drugs for many months, or even years. Drug reactions may be idiosyncratic or dose related, and in some situations, the patient may “adapt” to the drug, and evidence of DILI may wane.
One of the major issues surrounding DILI is assigning causation to a specific drug. This is a result of the fact that patients often take many drugs, that many drugs do not have typical clinical signatures, and that in many cases, critical data are missing. Currently, we do not have definitive objective criteria or a gold standard method for diagnosis. Causality assessment tools have been developed, such as the RUCAM, in hopes of more accurately assigning causality of DILI to a specific drug.4-7 However, RUCAM is difficult to use and is used often by clinicians. It is almost a certainty that a better causality process is needed. In this session, a method of causality developed by the DILIN will be reviewed.
References
- Zimmerman HJ. Drug-induced liver disease. Clin Liver Dis 2000;4:73-96, vi. [PMID 11232192]
- Bissell DM, Gores GJ, Laskin DL, Hoofnagle JH. Drug-induced liver injury: mechanisms and test systems. Hepatology 2001;33:1009-13. [PMID 11283870]
- Watkins PB, Seeff LB. Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006;43:618-31. [PMID 16496329]
- Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331-6. [PMID 8229111]
- Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26:664-9. [PMID 9303497]
- Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001;33:123-30. {PMID 11124828]
- Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007;11:477-505. {PMID 17723916]
- Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129:512-21. [PMID 16083708]
- Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz B, Borraz Y, Pachkoria K, et al. Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 2006;44:1581-8. [PMID 17133470]
- Bjornsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury. Aliment Pharmacol Ther 2007;25:1411-21. [PMID 17539980]
Biography
Rockey, Don C.
Professor of Medicine
Education
Virginia Polytech. Inst. & St. Univ. (Blacksburg, VA), B.S. 1980
Medical College of Virginia (Richmond, VA), M.D. 1984
Univ. of California at San Francisco, internal medicine residency, 1984-8
Univ. of California at San Francisco, gastroenterology fellowship, 1988-92
Positions
1984-85 Intern (Categorical Medicine), University of California, San Francisco (UCSF) 1985-87 Resident (Categorical Medicine), UCSF 1987-88 Chief Resident (Categorical Medicine), UCSF 1988-89 Clinical Fellow, Gastroenterology, UCSF 1989-92 Research Fellow, Gastroenterology, UCSF 1992-95 Clinical Instructor and Attending Physician, UCSF 1995-96 Assistant Professor of Medicine and Attending Physician, UCSF 1997-02 Associate Professor of Medicine, Duke University Medical Center (DUMC) 1997-05 Director, Hepatology and the Duke Liver Center, DUMC 2002-05 Professor of Medicine, DUMC 2005-Professor of Medicine, Chief, Digestive Diseases and Liver Division, University of Texas, Southwestern
Honors
1980 Summa Cum Laude 1982 A.H. Strauss Award (academic excellence) 1983 Alpha Omega Alpha (AOA, Jr. year) 1983 A.D. Williams Award (top student in Junior Clinical Clerkships) 1983 Merck Award (academic excellence) 1984 William Branch Porter Award in Medicine (top student in Internal Medicine) 1984 Herman Hertzberg Award (excellence in service and scholarship) 1990 Senior Fellow Award, American Gastroenterological Association 1992 Research Scholar (Industry) Award, American Gastroenterological Association 1992 Liver Scholar Award, American Liver Foundation 1994 Young Scholar Award, World Congress of Gastroenterology 1995 Glaxo Institute of Digestive Health Research Award 1996 Miles and Shirley Fiterman Basic Research Award 2000 Clinical Scientist Research Award, Burroughs Wellcome Fund 2001 American Society of Clinical Investigation 2005 Fellow, American Gastroenterological Association 2007 American Association of Physicians.
Career
Don was Director of the Liver Center, and Hepatology at Duke University Medical Center before moving to UT Southwestern in 2005. His training has been in clinical, translational, and basic research and he has maintained focused efforts in these areas. He has performed basic research resulting in translation of specific therapeutics from the laboratory to patients. Drug-induced liver injury has become a specific research focus over the last 5 years, during which he has been actively involved with the ongoing DILIN network, serving as co-chair for the Causality Committee.
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Date created: April 29, 2008 |
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