Gastroenterology

Gastroenterology

Volume 138, Issue 7, June 2010, Pages 2246-2259
Gastroenterology

Reviews in Basic and Clinical Gastroenterology
Risk Factors for Idiosyncratic Drug-Induced Liver Injury

https://doi.org/10.1053/j.gastro.2010.04.001Get rights and content

Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.

Section snippets

Age

Age is a risk factor for DILI, but only from specific medications.1, 2 Younger age is a risk factor for certain medications such as valproic acid and for Reye syndrome, associated with aspirin use.1, 2 As age increases, so does the risk of liver injury from compounds such as erythromycin, halothane, isoniazid, nitrofurantoin, and flucloxacillin.1, 2, 12 The risk of hepatotoxicity from isoniazid increases significantly with age.1, 8 In a large study of patients in a US tuberculosis clinic, the

Genetic Risk Factors

Because of their rarity and unpredictability, idiosyncratic DILI events are considered to have a strong genetic basis,12, 15, 16, 17, 18, 19 but significant association between certain genetic traits and DILI has been shown for only a few compounds.15, 16, 17, 18, 100 Even when such an association has been observed, generally the odds ratio (OR) of a given haplotype to increase the risk of DILI has been rather low (with the exception of flucloxacillin).100 DILI is likely a complex genetic

Future Directions

DILI is a problem that is important not only to patients, but also to physicians, regulatory agencies, and drug developers. Although we have gained insight into its pathogenic mechanisms, we have much to learn about its clinical manifestations and factors that might be used in the diagnosis and determination of prognosis. Prospective registries are an important source of data, but firm and systematically established postmarketing surveillance methods urgently are required. Pharmaceutical

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    Conflicts of interest Dr Chalasani has served as a paid consultant within the preceding 12 months to Teva, Eli Lilly, Karobio, Salix, Debiovision, Amylin, Genentech, Abbott, and Gilead on issues related to drug safety, and has research support from Eli Lilly and Monarch LifeSciences; and Dr Björnsson has served as a paid consultant for Astellas Pharma Europe, AstraZeneca, and Karobio.

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