Semin Liver Dis 2009; 29(4): 335-336
DOI: 10.1055/s-0029-1240001
FOREWORD

© Thieme Medical Publishers

Making the World a Safer Place

Robert J. Fontana1
  • 1Associate Professor of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
Further Information

Publication History

Publication Date:
13 October 2009 (online)

Drug-induced liver injury (DILI) is an area of increasing interest to me and to multiple stakeholders including academia, industry, regulatory agencies, practitioners, and the general public. In the past 2 years, several approved drugs had restrictions placed on their use (e.g., telithromycin), and others were removed from the marketplace altogether (e.g., nefazodone) due to unpredictable and potentially severe hepatotoxicity. In addition, the development of promising new drugs was halted due to hepatotoxicity (e.g., ximelagatran and lumiracoxib). Although liver injury from an individual drug is rare, with an estimated incidence of only 1 to 100 episodes per 1,000,000 patient-years, the overall incidence of DILI in the general U.S. population may exceed 40,000 cases per year. Establishing a diagnosis of DILI is invariably retrospective and delayed due to the need to exclude other more common causes of liver injury and to follow patients after discontinuation of the suspect drug for clinical improvement (i.e., de-challenge). Furthermore, an increasing proportion of patients are on multiple medications, and each drug may be associated with a variable latency period as well as variable biochemical injury patterns and severity at presentation. Finally, there is no objective laboratory test to confirm a diagnosis of DILI. As a result of these complex circumstances, it is not surprising that research into risk factors and outcomes with DILI has been limited.

In this issue of Seminars in Liver Disease, Lauren Bell and Naga Chalasani succinctly summarize the epidemiology of DILI in the United States and abroad. With prospectively captured data from a growing number of DILI registries, the “phenotyping” of DILI patients is improving. As a result of these efforts, previous assumptions regarding the role of gender, alcohol, underlying liver disease, and subject age in DILI susceptibility are being challenged. Long-term follow-up studies, as summarized by Einar Björnsson, demonstrate that a subgroup of DILI patients develop clinically significant chronic liver disease for unclear reasons. At the same time, other studies are demonstrating the potential diagnostic and prognostic value of prototypical histological features and injury patterns in DILI patients, as reviewed by David Kleiner. However, the need for simple, reliable, and accurate causality assessment methods remains essential to move the field forward. Paul Hayashi reviews the limitations of currently available diagnostic methods (e.g., the Roussel Uclaf Causality Assessment Model [RUCAM], expert opinion) and the need to develop a more objective and reproducible computerized causality assessment method that can be built off of well-vetted cases and published reports. Vic Navarro provides an overview on the growing problem of liver injury attributed to herbal and dietary supplements and some of the issues regarding regulatory oversight in this billion-dollar industry. Finally, Mark Russo and colleagues present an analysis of the published literature on statin hepatotoxicity and provide some perspective regarding the safety of these drugs in patients with underlying liver disease.

Application of modern laboratory methods may soon improve our ability to more confidently identify patients with DILI. Paul Watkins examines the potential utility of lymphocyte transformation assays and drug-protein adducts in improving the specificity and rapidity of diagnosis. Proteomics, transcriptomics, and metabolomics may also help clarify the role of aberrant host metabolism versus host adaptation in the pathogenesis of DILI. Furthermore, Ann Daly and Chris Day summarize the promises and limitations of genome-wide association studies compared with traditional candidate gene approaches in the etiopathogenesis of DILI. Convincing proof of concept examples of statin myopathy as well as flucloxacillin-induced cholestasis demonstrate that specific loci in the genome of afflicted individuals can be identified using powerful genomic platforms. Finally, the biological and scientific rationales for implicating variations in host immune response in DILI patients are nicely reviewed by Jack Uetrecht.

Overall, multiple promising initiatives are underway to improve our understanding of the epidemiology, diagnosis, susceptibility, and natural history of DILI. In particular, high-throughput genotyping platforms hold the promise of personalized medicine wherein drug efficacy can be maximized, while adverse events are minimized for an individual patient. To achieve this goal, ongoing prospective registries with collection of blood, urine, and liver tissue samples from well-characterized DILI patients and suitable controls will prove essential. At the same time, the ability to improve dissemination of knowledge of human and animal liver toxicology is being pursued through the development of the LiverTox Web site. This collaborative effort of the National Library of Medicine and the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) will assist clinicians and researchers alike by providing annotated references of the world's literature of more than 900 approved drugs, as well as classic teaching cases provided by the Drug-Induced Liver Injury Network. In summary, the prospect of being able to more accurately diagnose and eventually predict rare adverse drug reactions like DILI is improving. Hopefully, clinicians, investigators, and regulators will find this issue of Seminars in Liver Disease to be a valuable comprehensive update of worldwide efforts to improve the safety of medications.

Robert J FontanaM.D. 

Associate Professor of Medicine, University of Michigan Medical Center

3912 Taubman Center, Ann Arbor, MI 48109-0362

Email: rfontana@med.umich.edu

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