Predicting and preventing acute drug-induced liver injury: what's new in 2010?
BACKGROUND
The field of drug-induced liver injury (DILI) continues to expand in terms of global registries and with new agents added every year. Given the need to improve on our current methods of preclinical testing and monitoring for DILI during both clinical trials and in the post-approval setting, there is increasing research aimed at better understanding why injury occurs and who is most susceptible. To this end, the active pursuit of biomarkers that will predict injury prior to its occurrence and genetic testing that can identify individuals at risk of DILI continue to be at the forefront.


METHODS
While alanine aminotransferase (ALT) testing remains the workhorse of biochemical monitoring, it only detects hepatic injury after it has occurred and, therefore, is not a true predictor. The utility and shortcomings of ALT and other liver tests are reviewed along with a synopsis of several other candidate biomarkers that are being studied. In addition, we review the recent data supporting testing for genetic predisposition to DILI and how identifying clinical risk factors may translate into better means for preventing DILI.


RESULTS
We update the basis on which age and gender are considered risk factors for DILI, and review the latest reports detailing the association of several candidate genes and the development of DILI in a susceptible patient. Human leukocyte antigen-B*5701 is closely linked to the hypersensitivity reaction seen with abacavir, and such screening has been successfully incorporated into HIV treatment around the globe and offers the promise that testing for other genetic markers will soon become a routine part of clinical practice. At present, candidate genes conferring specific susceptibility to DILI have been identified for a relatively few agents (e.g., flucloxacillin, amoxicillin-clavulanate, ximelagatran and isoniazid), but many more are under study. Preventing DILI often comes down to avoiding the use of potentially hepatotoxic drugs in certain situations, and we review the clinical scenarios in which this is most relevant.


CONCLUSIONS
Given the number and range of studies aimed at identifying predictors of DILI, the focus of this review is to summarize what we consider to be the most relevant new information published on the topics of clinical and genetic factors that predispose to DILI, the use of biomarkers as predictors of acute DILI, along with advances in prevention strategies.
Liss
Gordon
G
Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007, USA.
Rattan
Sushil
S
Lewis
James H
JH
D000082:Acetaminophen / Q000009:adverse effects; D000328:Adult; D000368:Aged; D000375:Aging; D000410:Alanine Transaminase / Q000097:blood; D019980:Amoxicillin-Potassium Clavulanate Combination / Q000009:adverse effects; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D000995:Antitubercular Agents / Q000009:adverse effects; D015415:Biomarkers / Q000032:analysis; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D012307:Risk Factors
D018712:Analgesics, Non-Narcotic; D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D015415:Biomarkers; D004364:Pharmaceutical Preparations; D000082:Acetaminophen; D019980:Amoxicillin-Potassium Clavulanate Combination; D000410:Alanine Transaminase; D007538:Isoniazid