Idiosyncratic drug-induced liver injury (DILI) is the uncommon, yet leading cause for drug withdrawal from the market. It can cause serious clinical outcomes including acute liver failure and the need for liver transplantation. The priority of patient care involves around elimination of the iatrogenic “harm” caused by a therapeutic agent. Nevertheless, recognizing culprit drugs and individuals at risk for DILI pose a significant challenge. 

Various risk factors play an important role in increasing the susceptibility of DILI. Among which, genetic factors predisposing individuals at risk, the role of the drugs’ physicochemical and toxicological properties and their interactions with host and environmental factors are crucial. There are multiple impact of these factors on mechanisms involved in DILI. 

The authors of the current review summarized the following; 1) drug properties related to hepatotoxicity, 2) host factors considered to alter an individuals’ risk for DILI and clinical phenotypes, and 3) drug-host interactions. 

It has been observed that both drug properties and host factors are multi-layered, affecting multiple mechanisms, and likely interact at multiple levels to assess DILI susceptibility, clinical phenotypes and outcome. Certain combinations of drugs and host factors have known to cause additive interactions on DILI risks. One of analysis suggested higher incidence of mitochondrial liability among the drugs with an increased pediatric reporting frequency. Cholestatic manifestation, high lipophilicity and biliary excretion were more frequent among the drugs correlated with a higher reporting frequency in the elderly, which is attributed to the interactions between specific drug properties and age-biased attributes. 

Drug-host interactions are also found between specific drug properties and host genetic variants. A trial showed that an association was found between SOD2Ala/Ala genotype and increased risk of developing cholestatic/mixed injury induced by drugs with mitochondrial hazard. Another study revealed a positive interaction between drugs containing a carbocyclic system with aromatic rings (e.g. NSAIDs) and a genetic variant, ABCC11 c.133 CC in DILI susceptibility. Furthermore, sexual dimorphism (XX vs. XY) may play a vital role in gender-specific susceptibility of neurons and splenocytes to different cytotoxic agents. However, further investigations are warranted, as current knowledge is still scarce and inadequate for accurate risk prediction of DILI.

Source: Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: Interactions between drug properties and host factors. J Hepatol. 2015 Aug;63(2):503-14.