Meeting Report: Recent Research Advances in DILI 2009 

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By Neil Kaplowitz, MD

This is a brief report of the above cited meeting which I attended as AASLD’s representative. I can say without any reservation that this was a superb meeting with a particular focus on genetics of drug-induced liver injury (DILI). The work of several companies and the Serious Adverse Event Consortium identified strong genetic associations in several examples including flucloxacillin, ximelagatran, Augmentin®, and lumiracoxib; all had specific human leukocyte antigen (HLA) associations pointing to a key role of genetic variations of the adaptive immune system in determining susceptibility.

There are two caveats:

1)    The frequency of the variations of HLA in these case studies in the general population seriously limits the practical application of testing as many patients who do not develop toxicity would not be treated (i.e. poor positive predictive value). Ultimately, the consensus that developed at this meeting is that genome-wide association studies (GWAS) (1 million Single nucleotide polymorphisms [SNPs]) will not be sufficient and the field needs to move quickly to whole genome sequencing.
2)    The “hits” in these case studies may not be representative of the bulk of  examples of idiosyncratic hepatotoxicity. The debate centered on whether genetic susceptibility will be determined by combinations of common polymorphisms or rare genetic variations (single mutations). The next phase of research may answer this; if the former, much larger numbers of well characterized cases from registries in the U.S. (Drug-induced Liver Injury Network [DILIN]) and Europe will be needed.

The remainder of the meeting focused on animal and cell models and various pathophysiologic processes and the use of inbred mouse strains and transcriptomics and metabolomics to identify these processes. This is an active research area in academia as well as industry.

In summary, this was a cutting edge scientific meeting and I was delighted to participate. It especially underscored the terrific science being conducted by industry partners and the cooperation of the three main groups (industry, academia/AASLD, and FDA) in addressing a major clinical problem which is highly relevant to AASLD membership. Also, as you know, the talks, slides and discussion will be available online shortly. 

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