Tailored drug therapy for mitigating drug-induced liver injury: is this the era of genetic screening?

Abstract

Idiosyncratic drug-induced liver injury (DILI) is the single most frequent adverse drug reaction (ADR) causing drug withdrawal from the market. It accounts for more than a half of acute liver failure in the USA. The advent of genomics has made great progress in pharmacogenetics and pharmacogenomics. Many studies concerning genetic tests in DILI have emerged, raising the question of: is it beneficial to tailor drug treatment for alleviating DILI based on these genetic studies? A compendium of positive genetic-association studies in DILI exist (Table 1). Most are related to the genetic polymorphisms of the drug metabolizing enzymes and some emphasize an association of HLA with DILI, but there are very little data regarding genetic polymorphisms of acquired immunity. Although a biomarker to predict idiosyncratic DILI is urgently needed, there is still no official recommendation for genotyping prior to initiating drug therapy in order to reduce the incidence of DILI. Why is the application of pharmaco genomics in DILI and other ADRs unable to keep abreast of the recent progress in genomic knowledge and techniques? Many obstacles seem to convert the initial optimism and expectation into skepticism. While the genetic approach for predicting therapeutic efficacy and safety is a crucial way of establishing optimal personalized medicine, many complex problems emerge when interpreting available genetic data. First, prospective clinical trails with genetic tests are an appropriate way to obtain beneficial information with little bias, but their value may be counteracted by their study designs. Through regular monitoring, they provide the opportunity to identify susceptible patients with a mild form of hepatotoxicity. Most trials warrant discontinuation of the drug when serum aminotransferase levels rise to three–five-times the upper limit of normal (ULN), or when serum bilirubin levels are elevated by two–threetimes the ULN. It is questionable whether these cohorts would have developed severe hepatotoxicity had therapy been continued. Therefore, cases with severe DILI or ‘Hy’s rule’ are rarely detected, even in large clinical trials, because of the low incidence of severe cases and the early discontinuation of the involved drug. Mild liver dysfunction cannot be neglected but is always less clinically significant and is easily confused with other background noise, such as fatty liver. For the US Drug-Induced Liver Injury Network (DILIN), the criterion for enrolling DILI patients is elevated serum transferase to more than five-times the ULN. The recruitment criteria and definition of DILI in genetic studies are diverse and include patients with mild DILI (Table 1). Second, many DILI patients may have the adaptation phenomenon, which means that they resume normal or near-normal liver function without discontinuing the incriminating drug. Such adaptation is observed in more than a half of patients with anti-tuberculosis DILI. However, prospective trials cannot always discriminate adaptors owing to early drug withdrawal. Furthermore, there is no consensus regarding the diagnosis of DILI in these genetic studies, such that the DILIN and the US FDA have recently endeavored to standardize the nomenclature and causality assessment through a series of workshops. The other skepticism of genetic tests involves environmental factors that may alter the gene expression of drug-metabolizing enzymes and drug responses. These include age, gender, nutritional status, drug co-administration, alcohol consumption, food, chronic viral hepatitis infection, fatty liver and comorbidities. The triangle interaction of drug, host genetic factors and environmental factors forms an intricate network pertinent to human drug responses. However, decisions regarding which environmental factors are important and which may influence incriminated drugs remain inconsistent.