Drug-induced liver injury: Is it time for genetics to change our clinical practice?
Authors: Pietro Invernizzi
Journal: Journal of Hepatology (2010)

Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injuryJournal of HepatologyVol. 53Issue 6PreviewCo-amoxiclav is one of the most common causes of drug-induced liver injury (DILI). Although there are previous reports of genetic associations between HLA class II and co-amoxiclav-related DILI, studies to date have been based on very small numbers from single centres only. In order to address this problem we have investigated the role of HLA class II DRB1 and DQB1 in 61 cases of co-amoxiclav DILI as part of a UK-wide multicentre study. Full-Text PDF Co-amoxiclav is a combination antibiotic containing amoxicillin trihydrate, a β-lactam antibiotic, with the potent β-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 [1van den Broek J.W. Buennemeyer B.L. Stricker B.H. Cholestatic hepatitis caused by a combination of amoxicillin and clavulanic acid (Augmentin).Ned Tijdschr Geneeskd. 1988; 132: 1495-1497PubMed Google Scholar, 2Andrade R.J. Lucena M.I. Fernandez M.C. Pelaez G. Pachkoria K. Garcia-Ruiz E. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005; 129: 512-521PubMed Google Scholar, 3Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (1934 e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar]. Although DILI is a very rare event, co-amoxiclav is one of the most common causes of DILI [2Andrade R.J. Lucena M.I. Fernandez M.C. Pelaez G. Pachkoria K. Garcia-Ruiz E. et al.Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.Gastroenterology. 2005; 129: 512-521PubMed Google Scholar, 3Chalasani N. Fontana R.J. Bonkovsky H.L. Watkins P.B. Davern T. Serrano J. et al.Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology. 2008; 135 (1934 e1921–1924): 1924-1934Abstract Full Text Full Text PDF PubMed Scopus (658) Google Scholar]. DILI is a rare idiosyncratic adverse drug reaction associated with commonly used drugs, mostly non-steroidal anti-inflammatory drugs, paracetamol, and antimicrobial agents [4Kaplowitz N. Idiosyncratic drug hepatotoxicity.Nat Rev Drug Discov. 2005; 4: 489-499Crossref PubMed Scopus (853) Google Scholar, 5Verma S. Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury.Gut. 2009; 58: 1555-1564Crossref PubMed Scopus (132) Google Scholar]. Mainly because of the lack of internationally accepted criteria for DILI, data on the incidence of DILI cases are extremely variable [6Meier Y. Cavallaro M. Roos M. Pauli-Magnus C. Folkers G. Meier P.J. et al.Incidence of drug-induced liver injury in medical inpatients.Eur J Clin Pharmacol. 2005; 61: 135-143Crossref PubMed Scopus (166) Google Scholar, 7Sgro C. Clinard F. Ouazir K. Chanay H. Allard C. Guilleminet C. et al.Incidence of drug-induced hepatic injuries: a French population-based study.Hepatology. 2002; 36: 451-455Crossref PubMed Scopus (601) Google Scholar]. It should be noted that half of the cases of acute liver failure are due to drug hepatotoxicity [4Kaplowitz N. Idiosyncratic drug hepatotoxicity.Nat Rev Drug Discov. 2005; 4: 489-499Crossref PubMed Scopus (853) Google Scholar, 5Verma S. Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury.Gut. 2009; 58: 1555-1564Crossref PubMed Scopus (132) Google Scholar]. Recent major methodological and technological advances in many fields of basic science (i.e. the use of animals with various gene knockouts [[8]Ong M.M. Latchoumycandane C. Boelsterli U.A. Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities.Toxicol Sci. 2007; 97: 205-213Crossref PubMed Scopus (143) Google Scholar]) 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]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar]. 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]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar]. Unfortunately, as in many other complex conditions (i.e. autoimmune diseases [10Invernizzi P. Future directions in genetic for autoimmune diseases.J Autoimmun. 2009; 33: 1-2Crossref PubMed Scopus (47) Google Scholar, 11Invernizzi P. Gershwin M.E. The genetics of human autoimmune disease.J Autoimmun. 2009; 33: 290-299Crossref PubMed Scopus (70) Google Scholar]), 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 [12Hautekeete M.L. Horsmans Y. Van Waeyenberge C. Demanet C. Henrion J. Verbist L. et al.HLA association of amoxicillin–clavulanate-induced hepatitis.Gastroenterology. 1999; 117: 1181-1186Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 13O’Donohue J. Oien K.A. Donaldson P. Underhill J. Clare M. MacSween R.N. et al.Co-amoxiclav jaundice: clinical and histological features and HLA class II association.Gut. 2000; 47: 717-720Crossref PubMed Scopus (224) Google Scholar, 14Donaldson P.T. Daly A.K. Henderson J. Graham J. Pirmohamed M. Bernal W. et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury.J Hepatol. 2010; 53: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 15Andrade R.J. Lucena M.I. Alonso A. Garcia-Cortes M. Garcia-Ruiz E. Benitez R. et al.HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.Hepatology. 2004; 39: 1603-1612Crossref PubMed Scopus (140) Google Scholar]. Indeed, an association has been reported between HLA-DRB1∗15 and co-amoxiclav-related DILI in two out of three studies focused on this topic (Table 1) [12Hautekeete M.L. Horsmans Y. Van Waeyenberge C. Demanet C. Henrion J. Verbist L. et al.HLA association of amoxicillin–clavulanate-induced hepatitis.Gastroenterology. 1999; 117: 1181-1186Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 13O’Donohue J. Oien K.A. Donaldson P. Underhill J. Clare M. MacSween R.N. et al.Co-amoxiclav jaundice: clinical and histological features and HLA class II association.Gut. 2000; 47: 717-720Crossref PubMed Scopus (224) Google Scholar, 15Andrade R.J. Lucena M.I. Alonso A. Garcia-Cortes M. Garcia-Ruiz E. Benitez R. et al.HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.Hepatology. 2004; 39: 1603-1612Crossref PubMed Scopus (140) Google Scholar].Table 1Reported HLA associations in co-amoxiclav-induced liver injury. Open table in a new tab In the current issue of the Journal of Hepatology, Donaldson et al. [[14]Donaldson P.T. Daly A.K. Henderson J. Graham J. Pirmohamed M. Bernal W. et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury.J Hepatol. 2010; 53: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar] confirm the already known HLA association with DRB1∗15 and also provide novel relevant data. In particular, they report a novel protective association with DRB1∗07 within the HLA region [[14]Donaldson P.T. Daly A.K. Henderson J. Graham J. Pirmohamed M. Bernal W. et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury.J Hepatol. 2010; 53: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The major strength of this study is the typing of the largest collection of DNA (n = 61) from patients with co-amoxiclav-related DILI (Table 1), and the inclusion, for the first time, of a control group of patients exposed to co-amoxiclav but showing no toxicity. We should note, however, that although the authors must be commended for their enormous multicentric effort in collecting DNA from this very rare condition, 61 cases is a small series to be typed in a genetic association study. Furthermore, the results herein, similar to other gene descriptions in DILI patients, do not include functional analysis. The publication of the first high-density genome-wide association study (GWAS) in cases with DILI due to an antimicrobial agent, flucloxacillin [[16]Daly A.K. Donaldson P.T. Bhatnagar P. Shen Y. Pe’er I. Floratos A. et al.HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.Nat Genet. 2009; 41: 816-819Crossref PubMed Scopus (839) Google Scholar], has now opened a new era in the field of DILI which will surely allow substantial advances in our mechanistic understanding of DILI [[9]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar]. It should be noted that this first GWAS identified HLA variants as risk factors for liver toxicity due to flucloxacillin. Although it has been suggested that genetic associations for DILI are generally drug specific [[9]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar], the HLA class I and II genes are emerging as major players in the predisposition to most forms of DILI [[9]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar]. HLA genes play a crucial role in the host immune response because they are involved in antigen presentation [17Klein J. Sato A. The HLA system. First of two parts.N Engl J Med. 2000; 343: 702-709Crossref PubMed Scopus (551) Google Scholar, 18Klein J. Sato A. The HLA system. Second of two parts.N Engl J Med. 2000; 343: 782-786Crossref PubMed Scopus (314) Google Scholar]. For this reason, the immunologic idiosyncrasy may be mediated by the HLA system and DILI may be linked with certain HLA genes [[9]Daly A.K. Day C.P. Genetic association studies in drug-induced liver injury.Semin Liver Dis. 2009; 29: 400-411Crossref PubMed Scopus (88) Google Scholar]. Unfortunately, since Donaldson et al. did not perform a GWAS with their unique collection of DNA, their current candidate gene study can only confirm the role of HLA genes in co-amoxiclav-related liver toxicity, but it cannot exclude that other genes also have a role in the predisposition to this form of DILI [[14]Donaldson P.T. Daly A.K. Henderson J. Graham J. Pirmohamed M. Bernal W. et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury.J Hepatol. 2010; 53: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The main aim of genetic studies on DILI is their contribution in aiding prediction in individual patients [[19]Russmann S. Jetter A. Kullak-Ublick G.A. Pharmacogenetics of drug-induced liver injury.Hepatology. 2010; 52: 748-761Crossref PubMed Scopus (136) Google Scholar], in line with the rapid advances in genetics-based personalized medicine. The issue is of major clinical relevance and the expectation is very high [[5]Verma S. Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury.Gut. 2009; 58: 1555-1564Crossref PubMed Scopus (132) Google Scholar]. However, because the current first wave of GWAS allows for the identification of only rare genetic variants [[11]Invernizzi P. Gershwin M.E. The genetics of human autoimmune disease.J Autoimmun. 2009; 33: 290-299Crossref PubMed Scopus (70) Google Scholar] and because DILI is a very rare condition [[5]Verma S. Kaplowitz N. Diagnosis, management and prevention of drug-induced liver injury.Gut. 2009; 58: 1555-1564Crossref PubMed Scopus (132) Google Scholar], the initial insights into genetic factors affecting DILI susceptibility do not require the establishment of genetic screening tests that will guide and/or change clinical practice. Considering the study by Donaldson et al. [[14]Donaldson P.T. Daly A.K. Henderson J. Graham J. Pirmohamed M. Bernal W. et al.Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury.J Hepatol. 2010; 53: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar], shall we perform the HLA mapping in all patients who have to be treated with co-amoxiclav? Would we prescribe co-amoxiclav to subjects who have HLA DRB1∗15? I suspect that we are moving in the right direction, but these questions will require more time to be answered. The author declared that the he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.