Drug-induced liver injury: Is it time for genetics to change our clinical practice?

Abstract

Co-amoxiclav is a combination antibiotic containing amoxicillin trihydrate, a b-lactam antibiotic, with the potent b-lactamase inhibitor clavulanic acid. It is one of the most prescribed antibiotic worldwide both because of its large spectrum of action and for its general good safety. Amongst the possible side-effects of co-amoxiclav are diarrhea, vomiting, and thrush, which do not usually require medical attention. It can also induce allergic reactions and, as all antimicrobial agents, pseudomembranous colitis. Lastly, co-amoxiclav is known to have caused drug-induced liver injury (DILI) in some patients [1–3]. Although DILI is a very rare event, co-amoxiclav is one of the most common causes of DILI [2,3]. DILI is a rare idiosyncratic adverse drug reaction associated with commonly used drugs, mostly non-steroidal anti-inflammatory drugs, paracetamol, and antimicrobial agents [4,5]. Mainly because of the lack of internationally accepted criteria for DILI, data on the incidence of DILI cases are extremely variable [6,7]. It should be noted that half of the cases of acute liver failure are due to drug hepatotoxicity [4,5]. Recent major methodological and technological advances in many fields of basic science (i.e. the use of animals with various gene knockouts [8]) have contributed to a breakthrough in the understanding of the mechanisms underling DILI. Based on the fact that a unique predisposition is required to develop a DILI, over the last few years several research groups have tried to understand the role of genetics in DILI [9]. However, the literature on DILI contains large numbers of publications that have attempted to identify the responsible genes by evaluating small numbers of single nucleotide polymorphisms in one or few specific candidate genes by means of case–control study designs [9]. Unfortunately, as in many other complex conditions (i.e. autoimmune diseases [10,11]), such approaches have led to few insights into the genetic basis of DILI, mainly because of its rarity and the consequent difficulty to find large numbers of affected individuals. A possible exception is the quite consistent findings of an association between the co-amoxiclav-induced liver injury and some human leukocyte antigen (HLA) alleles [12–15]. Indeed, an association has been reported between