Conference examines latest research on drug-induced liver injury

A recent conference examined issues relating to drug-induced liver injury (DILI), the primary cause of acute liver failure in the U.S. The proceedings of the conference are summarized in a paper appearing in the March 2006 issue of Hepatology, the official journal of the American Association for the Study of Liver Diseases (AASLD). Published by John Wiley & Sons, Inc., Hepatology is available online via Wiley InterScience at http://www.interscience.wiley.com/journal/hepatology.

Held in Atlanta, GA in September 2005, the conference focused on idiosyncratic DILI, the most problematic form, in which a combination of genetic and non-genetic factors unexpectedly make some patients susceptible to drug injury. There are currently no valid animal models for studying idiosyncratic DILI, and it is difficult to study it in humans since its incidence is relatively rare. The Drug-Induced Liver Injury Network was established in 2003 with the aim of creating a registry of DILI patients and advancing research and treatment methods that could benefit those suffering from DILI. "The Single Topic Conference provided an opportunity for basic, translational and clinical researchers to 'sit at the same table' in discussions about the promise and challenges of DILI research," the authors state.

Discovering the factors involved in idiosyncratic DILI will hopefully lead to the development of clinical tests that can identify those patients susceptible to it so that injury can be avoided. "The identity of these factors should also shed light on underlying mechanisms and thereby allow development of safer drugs," the authors note. Safety issues are a major reason for failure of drugs in clinical trials, and DILI is the most common factor for failure to approve drugs or restrict their use.

There are instances where liver damage caused by certain drugs has been documented. This is the case with acetaminophen, which can predictably cause liver damage within a certain time period after ingesting a toxic dose. However, these instances shed little light on idiosyncratic DILI, which affects only a small number of patients using a given drug. In order to fully understand what makes certain people susceptible to certain drugs, it is necessary to study large numbers of patients who have experienced and recovered from idiosyncratic DILI. This is the focus of two studies currently being conducted by the DILIN in which patients' DNA, lymphocytes and serum is being examined in an attempt to tease out what causes susceptibility to idiosyncratic DILI, so that diagnostic tools can be created that will help identify those patients most at risk. One important component is that all subjects have agreed to long-term participation in the studies. This could play a vital role in understanding DILI; as insight is gained into why certain drugs cause liver damage in some people, DILIN will continue to have access to these patients for future studies.

The authors conclude: "There appeared to be great enthusiasm for the resources being created by the DILIN network and a general optimism regarding the ability to use these resources to identify the susceptibility factors underlying idiosyncratic DILI."

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Article: "Drug-Induced Liver Injury: Summary of a Single Topic Clinical Research Conference," Paul B. Watkins, Leonard B. Seeff, Hepatology; March 2006 (DOI: 10.1002/hep.21095).


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