Genetic Factors Influencing Drug-Induced Liver Injury: Do They Have a Role in Prevention and Diagnosis?

Abstract

Purpose of ReviewThe pathogenesis of DILI is currently unknown; however, research has shown strong genetic associations with some DILIs. This paper describes the variant alleles uncovered by GWAS and discusses their potential role as susceptibility biomarkers.Recent FindingsAn association with HLADRB1*15:01 and amoxicillin/clavulanate DILI has been shown by a number of research groups. The presence of the HLA-B*57:01 allele has been associated with an 81-fold increased risk of flucloxacillin DILI. The HLA-B*35:02 allele has significant association with minocycline DILI.SummaryWith the exception of abacavir for HIV therapy, no other prospective genetic screening tests have met the threshold for clinical application. This is largely because DILI incidence is too low to warrant the cost and effort associated with testing. Perhaps, with the development of personalised medicine, a panel of genes for disease susceptibility, drug efficacy and adverse reactions could be tested once off. This would change the cost-effectiveness paradigm, personalise healthcare and reduce DILI risk by avoiding medications in patients with specific HLA alleles.

Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent

“…certain HLA alleles). However, when used to prospectively predict patient-specific liver injury risks prior to drug prescription, these tests would have a high negative predictive value, yet a low positive predictive value due to the low incidence of idiosyncratic DILI (324). Instead, such tests serve more value as a diagnostic tool where liver injury patterns can be linked to particular drugs, thereby allowing effective continuation of other co-medicated drugs (325).…”

GSTM1 and GSTT1 genetic polymorphisms and their association with antituberculosis drug‑induced liver injury

“…Although the exact aetiology of DILI is not completely understood, it is considered a multifactorial disease which stems from a range of risk factors, including drugs used for treatment of TB and the dose, duration, hepatic metabolism and lipophilicity of those drugs, and other factors including sex, age and metabolism (2). Genetics has been proposed as a critical contributor to the pathogenesis of DILI (3). Thus, a focus has been placed on the potential influence of genetic factors in the development of ATDILI, in which a variety of genetic polymorphisms including in N-acetyltransferase 2 (NAT2), cytochrome P450 family 2 subfamily E member 1 (CYP2E1) and glutathione S-transferases [glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1)] have been reported to be associated with an increased risk of ATDILI (4).…”

Drug-Induced Liver Injury: Biomarkers, Requirements, Candidates, and Validation

“…The positive predictive value of the HLA markers is low whereas their negative predictive value is quite high. Thus, these HLA haplotypes may prove to be more beneficial in the diagnosis of DILI by being able to rule out a specific drug as the cause of the liver injury, however this is ultimately dependent on the frequency of DILI by a specific drug in a specific population (Clare et al, 2017).…”