- Email: [email protected]
Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen
International Immunopharmacology xxx (xxxx) xxxx
Contents lists available at ScienceDirect
International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen Qingmei Maa, Wenjuan Yanga, Lu Wanga, Li Maa, Yanmei Jinga, Jiamei Wanga, Xinyue Liua,b, a b
⁎
Department of Pharmacogenomics Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Hepatotoxicity Adverse drug reactions Genetic polymorphism Biomarkers Pharmacogenomics
Drug-induced liver injury is an important adverse drug reaction. Due to the lack of specificity in clinical symptoms and pathological features, there are still no reliable diagnostic biomarkers, so drug-induced liver injury is a diagnosis of exclusion. The article reviews the relevant advances in the association between novel human leukocyte antigen gene polymorphisms and drug-induced liver injury in order to identify potential biomarkers and provide a new method for the prediction and diagnosis of drug-induced liver injury. Henceforth, while studying the association between them, it will also need that the large sample and prospective studies to gain supporting evidence to implement translational application, so as to improve the safety and effectiveness of medication and achieve individualized treatment.
1. Introduction Liver is an important organ of drug metabolism. Most drugs or their active metabolites accumulate in the liver, which causes easily liver injury. Therefore, liver injury is one of the most common adverse drug reactions [1], and the second most common cause of drug attrition during development as well as for post-marketing withdrawal [2]. With the continuous update of clinical medication and the application of multi-drug combination, drug-induced liver injury (DILI) has become the most common cause of acute liver injury [3]. Severely, it can cause liver failure, even life-threatening [4]. In the United States, the incidence of DILI is 2.7 per 100,000 persons [5]. In mainland China, the incidence rate is 23.80 per 100,000 persons [6] and has an escalating trend. This phenomenon may be related to different regions, ethnic groups, population bases, types of drugs, unregulated use of drugs and dietary supplements. DILI is a general term for different types of liver injury [7] and is also a potential serious consequence of the clinical treatment. According to pathogenesis, DILI includes intrinsic DILI (InDILI) and idiosyncratic DILI (iDILI) [8]. The former with short latency is related to drug dosage and is commonly the direct cause of liver damage, clinically N - acetaminophen (APAP) is the most common; the latter has nothing to do with drug dosage and is relatively rare with complex pathogenetic mechanisms and manifestations in clinical practice [8], thence, many studies have focused on iDILI at present. Depending on
the course of disease, DILI can be classified as chronic or acute. Chronic DILI occurs when serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin (TBil) increase continuously and abnormally more than 6 months [9]. Clinically, acute DILI is more common, of which 15–20% can evolve into chronic [10]. In addition, in terms of the R-value defined as serum ALT/upper limit of normal (ULN) dividing by serum ALP/ULN, iDILI can be divided into hepatocellular injury (R ≥ 5), cholestatic (R < 2) and mixed type (2 < R < 5) [8]. According to different classification, it can help clinicians improve the diagnostic efficiency and reduce the pain of patients. DILI is an adverse drug reaction caused by multiple factors. Risk factors for DILI include age, gender, race, alcohol, pregnancy, underlying diseases, genetic polymorphisms and other host-dependent risk factors [11]. Besides that, there are some drug-dependent risk factors including dose and hepatic drug metabolism, lipophilicity, concomitant drug and hepatobiliary transport inhibition [11]. Among them, genetic polymorphisms account for approximately 20–30% of individual differences in drug response [1,12], which partly cause DILI, and the predisposition of patients to DILI may also vary among different races [13]. Therefore, clinicians and researchers should pay attention to the identification of DILI. The lack of specificity in clinical symptoms and pathological features about DILI, there are no normative diagnostic tests, so its diagnosis always relies on the exclusive method in terms of a history of
⁎ Corresponding author at: Department of Pharmacogenomics Laboratory Center, Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, China. E-mail address: [email protected] (X. Liu).
https://doi.org/10.1016/j.intimp.2019.106037 Received 30 August 2019; Received in revised form 6 November 2019; Accepted 7 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Qingmei Ma, et al., International Immunopharmacology, https://doi.org/10.1016/j.intimp.2019.106037
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
screening tool to predict PM-DILI risk. Nevertheless, it might make uncertainties and bias due to the small size of PM-DILI in this study, so lots of larger, independent studies are indispensable to further explore.
known medication exposure and a thorough evaluation for alternative etiologies [10,12]. To overcome this problem, it needs that specific and sensitive biomarkers go beyond the traditional methods of diagnosing DILI based on biochemical parameters including ALT, AST, and ALP. With the proposal of precision medicine, there are more and more researches in the association of DILI with human leukocyte antigen (HLA) alleles. Petros et al. [14] believed that finding the genetic predisposition to DIIL in patients may reduce the risk of drug resistance and improve curative effect. It had already been reported widely that DILI was associated with immune response, which was induced by abnormal activation of T cells. Kaliyaperumal et al. [15] discovered that the specificity of drug-metabolite-protein product presented by HLA molecules was determined by the unique physicochemical properties of the peptide-binding groove encoded in the major histocompatibility complex (MHC) region of chromosome 6, thereby activating specific T cells, which may be a key step in immune mechanism that mediates DILI. Subsequently, Kullak-Ublick et al. [16] argued that HLA polymorphisms played an important role in DILI susceptibility. The significant associations have been described that genetic polymorphisms and HLA alleles played a crucial role in adverse drug reactions [17,18]. In recent years, researchers analyzed the correlation between HLA alleles and DILI induced by various drugs through genome-wide association study (GWAS), and found that single nucleotide polymorphisms (SNPs) of HLA alleles could be used as the clinical basis to support DILI [15]. Therefore, the article reviews the correlations, underlying mechanisms and clinical applications between DILI and novel HLA alleles, providing strong evidence that HLA alleles can be used as specific biomarkers and prognostic indicators for the diagnosis of liver injury caused by certain drugs, in order to improve the safety and effectiveness of medication and achieve individualized treatment.
2.2. The genetic susceptibility of HLA-C*03:02 to methimazole-DILI Methimazole (MMI) is an anti-thyroid drug used for the treatment of Graves' disease (GD). It has been reported that administration of MMI may cause liver injury, most of which is cholestatic type [27,28]. Recently, Xuesong Li et al. [29] sequenced HLA class Ⅰ and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-drug-induced liver injury (MMI-DILI) cases and 118 MMI-tolerant controls, then found that the frequency of HLA-C*03:02 in the MMI-DILI cases, cholestatic/mixed liver damage and the MMI-tolerant controls were 6.7% (5/75), 6.4% (4/62) and 0.4% (1/231) respectively, which were significantly different from the controls (OR = 15.4, 95% CI = 1.77–133.9, adjusted P = 0.0292; OR = 14.9, 95% CI = 2.38–182.9, adjusted P = 0.0323; respectively). In addition, molecular docking study indicated that MMI could interact with HLA-C*03:02. This study analyses the effect of HLA alleles on the genetic susceptibility to MMI-DILI primarily, and realizes an increased risk of MMI-DILI in carriers with HLA-C*03:02. Meanwhile, it demonstrates that genetic factors play an important role in the course of MMI-DILI, contributing to a further understanding of the pathogenesis of MMI-DILI. 2.3. The effect of HLA-B*35:02 on minocycline-DILI Currently, the ongoing Drug-induced Liver Injury Network (DILIN) prospective study in the United States has found that antibiotics are the main cause of DILI [30]. Minocycline, a cause of DILI, can lead to characteristic clinical features like systemic arthralgias and detectable autoantibodies arising, similar to that of autoimmune hepatitis [31]. Urban et al. [32] found an increased risk of minocycline-DILI in carriers with HLA-B*35:02 in Caucasian patients using genome-wide genotyping. The results indicated that 16% HLA-B*35:02 carrier frequency in DILI cases compared to 0.6% in the population controls; HLAB*35:02 carriers had similar clinical manifestations and outcomes compared to non-carriers. These results suggest that HLA-B*35:02 may be the risk allele for minocycline-DILI. If HLA-B*35:02 can be proved to be a useful diagnostic biomarker for minocycline-DILI in other populations, it may reduce the risk of liver injury caused by minocycline during treatment and help to distinguish DILI from autoimmune hepatitis [33].
2. Researches in the association of DILI with HLA 2.1. The correlation between polygonum multiflorum-DILI and HLAB*35:01 Currently, the use of traditional Chinese medicine in China and abroad seems to be increasingly popular [19,20], with more than 100 medicinal preparations reported to induce liver injury, and these Clinical Practice Guidelines established by European Association for the Study of the Liver (EASL) recommend that physicians may consider herbal medicines and dietary supplements as potential causative agents for liver injury [11]. Polygonum multiflorum (PM), as a traditional herbal medicine for nourishing liver and kidney [21], has been widely used, causing an increasingly high incidence of liver injury. It has been reported that PM-drug-induced liver injury (PM-DILI) accounts for approximately 30% of liver injury cases of Chinese herbal medicine in China [22,23]. However, the mechanism of PM-DILI has not been clarified. It has been found that the occurrence of PM-DILI may be related to immune response in previous clinical case studies and animal experiments [24,25]. In recent months, Honghao Zhou et al. [26] firstly studied the association between HLA-B*35:01 and PM-DILI. They developed the polit study that the HLA regions of 11 patients with PMDILI were sequenced, and found that HLA-B*35:01 expressed significantly. Subsequently, HLA-B polymerase chain reaction-sequence based typing (PCR-SBT) was used to validate the candidate allele in 15 patients with PM-DILI, 33 patients with other drug-DILI and 99 population controls, and detected that HLA-B*35:01 was a high-risk allele of PM-DILI, which was consistent with the polit study. Finally, prospective cohort study further identified the influence of HLA-B*35:01 on PMDILI. This study mainly discovers that HLA-B*35:01 is a genetic risk factor for PM-DILI, and is also a potential predictable biomarker. This is the first time that finds the correlation between PM-DILI and HLAB*35:01, and HLA-B*35:01 may be expected to become a new diagnostic aid in favor of determining PM-DILI and turn into a pre-emptive
2.4. Carbamazepine hypersensitivity and HLA-A*31:01 Carbamazepine is an antiepileptic drug used to treat epilepsy, trigeminal neuralgia and bipolar disorder [34]. About 3–10% of patients taking carbamazepine will develop anaphylaxis [35]. Adaptive immune responses occur because carbamazepine or its metabolites bind to specific HLA molecules that stimulate T cell responses [36], causing a variety of life-threatening hypersensitivities including serious cutaneous adverse reactions (SCAR) such as mild maculopapular exanthemas to hypersensitivity syndrome (DRESS), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and DILI [20,37]. Nicoletti et al. [38] performed the genotyping that indicated 33% carbamazepine-DILI patients were HLA-A*31:01 carriers (OR = 7.3, 95% CI = 2.47–23.67, P = 0.0004). Then, they made a meta-analysis of GWAS studies and found that HLA-A*31:01 was the strongest genetic predisposing factor for severe adverse reactions caused by carbamazepine in the European populations, and patients with HLA-A*31:01 were prone to DILI. For the first time, the study evaluates whether HLA-A*31:01 is a risk factor for DILI after taking carbamazepine. Further trans-ethnic meta-analysis of the GWAS and plenty of original studies of carbamazepine-DILI are therefore needed to identify potential causal alleles in diverse 2
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
Table 1 The associations between DILI and HLA allele. Drug
HLA Allele
Population
Cases/controls
OR
PM Methimazole Minocycline Carbamazepine Flucloxacillin
B*35:01 C*03:02 B*35:02 A*31:01 B*57:01
Terbinafine
A*33:01
pi:11, re:15/132, pr:72 40/118 25/10588 12/8438 51/282 197/6835 14/10588 15
143.9 [26] 15.4 [29] 29.6 [32] 7.3 [38] 80.6 [41] 36.6 [44] 40.5 [48] NR [49]
AC
DRB1*15:01-DRB5*01:01-DQB1*06:02 DRB1*15:01 DRB1*07a DRB1*15:01-DQB1*06:02 A*02:01 A*30:02 B*18:01
Chinese Chinese Caucasian European European European European, American European, African American, East Asian Belgian Scottish British European European Spanish Spanish
35/300 22/134 61/231 177/219 177/219 75/885 75/885
NR [51] 9.25 [52] 0.18 [50] 3.3 [53] 2.2 [53] 6.7 [54] 2.9 [54]
PM, Polygonum multiflorum; AC, Amoxicillin-clavulanate; pi, the pilot study; re, the replication study; pr, the prospective cohort study; OR, odds ratio; NR, not reported. a The protective factor.
A recent genetic analysis was performed on 862 DILI patients from European and USA, and demonstrated a significant association between HLA-A*33:01 and DILI patients due to terbinafine and possibly fenofibrate and ticlopidine [48]. In this study, DILI is caused by several drugs, so there is limited specificity. In order to identify potential HLA alleles associated with only terbinafine-DILI, and determine the mechanism between them, recently, Fontana et al. [49] performed high-resolution confirmatory HLA sequencing using the Ilumin MiSeq platform for the DNA samples of 15 patients with terbinafine-DILI from DILIN, and found that 10 of the 11 European participants carried HLA-A*33:01, B*14:02, and C*08:02 haplotype, which were strongly correlated and might co-induce DILI and had the conformity with previous results [48]. Molecular docking studies suggested that terbinafine may interact with HLA-A*33:01 and HLA-A*33:03. These results indicate that HLAA*33:01 may be a risk factor for terbinafine-DILI.
populations. 2.5. New findings of flucloxacillin in genetic factors causing DILI Flucloxacillin is an oral β-lactam antibiotic used for the treatment of soft tissue infections caused by Staphylococcus aureus (S. aureus) [39], it is also one of the causes of DILI. The incidence of DILI induced by flucloxacillin is 8.5 per 100,000 persons, and 35 per 100,000 persons in those taking one consecutive flucloxacillin and 110.5 per 100,000 persons in those aged > 70 years who have taken flucloxacillin more than twice [40]. Meanwhile, Daly et al. showed that HLA-B*57:01 had a highly significant association with DILI and an 80-fold increased risk of flucloxacillin-DILI in HLA-B*57:01 carriers by the GWAS analysis (OR = 80.6; 95% CI = 22.8–284.9) [41]. This is an interesting discovery because HLA-B*57:01 is also associated with abacavir hypersensitivity, but it was not reported that these patients developed DILI [42]. Although flucloxacillin-DILI is correlated with HLA-B*57:01, conventional genetic tests for HLA-B*57:01 before the prescription of flucloxacillin may have no significant clinical relevance, because the positive predictive value of HLA-B*57:01 is as low as 0.12% [33,43] and the overall sensitivity and specificity of genotyping of susceptible individuals are too weak to predict. After the discovery of the association between HLA-B*57:01 and flucloxacillin-DILI, Nicoletti et al. [44] used GWAS analysis to further verify whether HLA-B*57:01 was a genetic risk factor for flucloxacillinDILI, to identify other related genetic factors, and to evaluate the correlation between flucloxacillin-DILI risk factors and other penicillininduced DILI. The results showed that HLA-B*57:01 was the major risk factor for flucloxacillin-DILI (allelic OR = 36.62, P = 2.67 × 10−97), which was consistent with previous results [41,45], and HLA-B*57:03 also showed an association (OR = 79.21, P = 1.2 × 10−6). HLAB*57:03 is a rare gene, and the functional interpretation of rare alleles remains challenging and is one of the important frontiers of contemporary pharmacogenomics [46]. It is still imperative to clarify HLAB*57:01 as a key susceptible factor of flucloxacillin-DILI before applying it into a clinical setting.
2.7. The genetic factors of amoxicillin-clavulanate-DILI It is known that amoxicillin-clavulanate (AC) is the most common causal drug of iDILI with 10–13% of hospitalizations [50]. The correlation of AC-drug-induced liver injury (AC-DILI) and HLA has been commonly studied, hereon we just make a brief introduction. In 1999, Hautekeete et al. [51] firstly found the association of ACDILI with HLA in Europeans and the frequency of HLA-DRB1*15:01DRB5*01:01-DQB1*06:02 in AC-DILI patients was significantly higher compared to the controls. Subsequently, amounts of researches were replicated to validate the link between HLA-DRB1*15:01 and AC-DILI while observing a novel protective factor: HLA-DRB1*07 [52,53]. Furthermore, others also showed the relationship of AC-DILI with some HLA alleles including HLA-A*02:01, HLA-A*30:02 and HLA-B*18:01 [54,55]. For more detailed information, please see the list in Table 1. 3. Underlying pathogenesis 3.1. HLA- mediated DILI The mechanism of InDILI has been well understood, while the researches on the pathogenesis of iDILI are still challenging due to its complexity and variability. As mentioned above, some HLA alleles have been found to be associated with iDILI by GWAS, however, this association is rare and the idiosyncratic HLA allele matches with the specific drug (Table 1). Moreover, there is still no much reliable evidence for the correlation, and it is an intractable problem to achieve clinical practice at present. Nevertheless, it suggests that DILI may be related to
2.6. The role of HLA alleles in terbinafine-DILI Terbinafine is an oral antifungal agent used to treat superficial fungal infections of the skin and nails, and causes DILI [47]. Due to the lack of a sensitive and reliable method to detect liver injury, it is still difficult to clearly diagnose DILI cases caused by terbinafine, which may lead to missed and delayed diagnosis. 3
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
makes a vast difference to the occurrence and development of DILI, which is expected to break through the conundrum in distinguishing DILI from liver injury caused by other causes. In researches in the association of DILI with HLA, as an emerging hotspot, there are still a lot of unsolved problems. Although EASL has issued Clinical Practice Guidelines for DILI based on the latest research progress and best evidence of DILI [11], recommending that HLA genotyping can be applied to detect and diagnose DILI in specific clinical situations, there are still many limitations: (1) There is no standard and reliable method to diagnose DILI; (2) The sample size is extremely limited, and the lack of large sample replication studies leads to have few strong evidence; (3) The lack of prospective studies and randomized controlled trials; (4) There are many confounding factors in the researches; (5) The limited knowledge of the characteristics of detection results in DILI and non-DILI patients. It is difficult to distinguish; (6) Some recommendations in published guidelines are relatively weak. Nevertheless, with the emergence and update of new medical technologies, part of the clinicians and researchers have begun to shift their focus to DILI studies. Therefore, HLA alleles, as novel biomarkers for the diagnosis of DILI, maybe provide a new method for the detection, treatment and prevention of DILI patients and others who have acute liver failure and liver transplantation secondary to DILI, so as to reduce the medical burden, improve the safety and effectiveness of medication and achieve individualized treatment.
the immune response, contributing to the understanding of the pathogenesis of DILI. There are some hypotheses about DILI pathogenesis. The “hapten hypothesis” states that a drug or its metabolites bind to cellular or circulating protein in a covalent way and the complex interacts with the peptide-binding groove of a specific HLA molecule in order to determine an individual’s susceptibility to DILI [16]. In addition, there is the hypothesis of the pharmacological interaction with immune receptors (p-i) concept, in which some drugs or their metabolites are considered foreign antigens that may bind directly to HLA molecules or T-cell receptors, independent of antigen presentation. Without adaptation, it may trigger activation and proliferation of T cells, leading to hepatocyte damage [56,57]. Furthermore, some drugs bind to the peptide-binding groove of HLA molecules to alter the shape and chemistry of peptides that can bind to a particular HLA protein [58]. These theories may conduce to recognizing DILI and improving the efficiency and safety of drug development and reduce the waste of medical resources. 3.2. Other potential mechanisms Although there is substantial evidence to support the pathogenesis of HLA-mediated DILI, there are exceptions which may be other factors. For example, drug metabolites are the classic view of the pathogenesis of DILI, mainly mediated by cytochromes P-450 (CYP), further, ATP depletion, mitochondrial injury, apoptosis, inflammation, oxidative stress, covalent binding to nucleic acids or lipids, or occurrence of lipid peroxidation also has a certain effect [59]. In addition, Morgan et al. [60] proposed that the inhibition of bile salt export pump (BSEP) by medication may be involved in the pathogenesis of DILI. Currently, Cirulli et al. [61] confirmed that a missense variant (rs2476601) in the PTPN22 gene was associated with DILI risk. This is the first time that a pharmacogenomic variant is related to liver injury induced by various drugs, so it makes progress. These mechanisms may be responsible for some DILI cases, and they may be synergistic or antagonistic in DILI. That is to say, since the pathogenesis of DILI is extremely complex, there is still a long way to go.
Funding This work was supported by Scientific Research Project of Gansu Medical and Health Industry [Grant No. GSWSKY2017-31], Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [Grant No. CY2017-MS17]. Author contributions Qingmei Ma wrote parts of the manuscript and made the table; Wenjuan Yang and Lu Wang searched relevant materials and wrote parts of the manuscript; Li Ma, Yanmei Jing and Jiamei Wang revised the manuscript; Xinyue Liu contributed to the conception and suggestion, and reviewed the manuscript.
4. Clinical applications
Declaration of Competing Interest
It is necessary to consider severe adverse drug reactions and various additional factors including the availability, efficacy and safety of medication, reliable clinical and experimental evidence, permissive environmental factors, and the sensitivity and specificity of the pharmacogenetic tests in the routine clinical implementation [62]. In clinical practice, there are some tests for the correlation between HLA and adverse reactions caused by certain drugs, such as HLA-B*57:01 and abacavir, HLA-B*58:01 and allopurinol. Because the incidence of DILI is too low to warrant the cost-effectiveness of genetic screening, so the detections that are routinely employed are impracticable for the time being. However, it will be of great help to risk management of DILI if new biomarkers can be found to reliably predict DILI, and its empirical and translational application can be used to assess whether patients can use a certain drug or closely monitor a certain drug at the early stage of use to determine the occurrence of liver injury. Overall, the benefit of association between HLA alleles and DILI had controversy in terms of the implementation of genotyping to evaluate the relative risks of DILI [63].
None. References [1] V.M. Lauschke, M. Ingelman-Sundberg, The importance of patient-specific factors for hepatic drug response and toxicity, Int. J. Mol. Sci. 17 (2016), https://doi.org/ 10.3390/ijms17101714. [2] J.L. Stevens, T.K. Baker, The future of drug safety testing: expanding the view and narrowing the focus, Drug Discov. Today 14 (2009) 162–167, https://doi.org/10. 1016/j.drudis.2008.11.009. [3] Y. Pan, M. Cao, D. You, G. Qin, Z. Liu, Research progress on the animal models of drug-induced liver injury: current status and further perspectives, Biomed Res. Int. 2019 (2019) 1283824, https://doi.org/10.1155/2019/1283824. [4] E. Bjornsson, Review article: drug-induced liver injury in clinical practice, Aliment. Pharmacol. Ther. 32 (2010) 3–13, https://doi.org/10.1111/j.1365-2036.2010. 04320.x. [5] M. Vega, et al., The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of delaware, Drug Saf. 40 (2017) 783–787, https://doi.org/ 10.1007/s40264-017-0547-9. [6] T. Shen, et al., Incidence and etiology of drug-induced liver injury in Mainland China, Gastroenterology 156 (2019) 2230–2241, https://doi.org/10.1053/j.gastro. 2019.02.002 e2211. [7] R.J. Fontana, Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives, Gastroenterology 146 (2014) 914–928, https://doi.org/10.1053/j. gastro.2013.12.032. [8] N.P.A.C.G. Chalasani, et al., Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury, Am. J. Gastroenterol. 109 (2014) 950–966, https://doi.org/10.1038/ajg.2014.131 quiz 967.
5. Conclusions HLA allele polymorphisms and specific drug-induced liver injury are increasingly being studied. HLA alleles have the most complex genetic polymorphisms in the human genome and play a crucial role in immune response, which is one of the risk factors of DILI. At present, a mass of studies on the relationship between HLA and DILI have found that HLA 4
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
[9] R.J. Fontana, et al., Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct, Drug Saf. 32 (2009) 55–68, https://doi.org/10. 2165/00002018-200932010-00005. [10] J.G. Stine, N. Chalasani, Chronic liver injury induced by drugs: a systematic review, Liver Int. 35 (2015) 2343–2353, https://doi.org/10.1111/liv.12958. [11] European Association for the Study of the Liver, e.e.e. Electronic address, C. Clinical Practice Guideline Panel, m. Panel, E.G.B. representative, EASL Clinical Practice Guidelines: Drug-induced liver injury, J. Hepatol 70 (2019) 1222–1261 doi:10. 1016/j.jhep.2019.02.014. [12] S.C. Sim, M. Kacevska, M. Ingelman-Sundberg, Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects, Pharmacogenomics J. 13 (2013) 1–11, https://doi.org/10.1038/tpj.2012.45. [13] F.Q. Hou, Z. Zeng, G.Q. Wang, Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes, Cell Biochem. Biophys. 64 (2012) 77–83, https://doi.org/10.1007/s12013-012-9373-y. [14] Z. Petros, et al., HLA-B(*)57 allele is associated with concomitant anti-tuberculosis and antiretroviral drugs induced liver toxicity in Ethiopians, Front. Pharmacol. 8 (2017) 90, https://doi.org/10.3389/fphar.2017.00090. [15] K. Kaliyaperumal, et al., Pharmacogenomics of drug-induced liver injury (DILI): Molecular biology to clinical applications, J. Hepatol. 69 (2018) 948–957, https:// doi.org/10.1016/j.jhep.2018.05.013. [16] G.A. Kullak-Ublick, et al., Drug-induced liver injury: recent advances in diagnosis and risk assessment, Gut 66 (2017) 1154–1164, https://doi.org/10.1136/gutjnl2016-313369. [17] M. S, et al., Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir, Lancet (London, England) 359 (2002) 727–732. [18] C. Wh, et al., Medical genetics: a marker for Stevens-Johnson syndrome, Nature 428 (2004) 486. [19] Y. Zhu, et al., Hepatobiliary and pancreatic: Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients, J. Gastroenterol. Hepatol. 31 (2016) 1476–1482, https://doi.org/10.1111/jgh.13323. [20] J.H. Hoofnagle, E.S. Bjornsson, Drug-induced liver injury—types and phenotypes, N Engl J Med 381 (2019) 264–273, https://doi.org/10.1056/NEJMra1816149. [21] L. Lin, et al., Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: a review, J. Ethnopharmacol. 159 (2015) 158–183, https://doi.org/10.1016/j.jep.2014.11.009. [22] X. Lei, et al., Liver damage associated with polygonum multiflorum Thunb.: a systematic review of case reports and case series, Evid. Based Complement. Alternat. Med. 2015 (2015) 459749, https://doi.org/10.1155/2015/459749. [23] R. Wang, et al., Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review, Expert Rev. Gastroenterol. Hepatol. 12 (2018) 425–434, https://doi.org/10.1080/17474124.2018.1427581. [24] Y.K. Meng, et al., Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPARgamma, Acta Pharmacol. Sin. 38 (2017) 1340–1352, https://doi.org/10.1038/aps. 2017.32. [25] L. He, et al., Immunological synergistic mechanisms of trans-/cis-stilbene glycosides in Heshouwu-related idiosyncratic liver injury, Sci. Bull. 748–751 (2017). [26] C. Li, et al., HLA-B*35:01 allele is a potential biomarker for predicting polygonum multiflorum-induced liver injury in humans, Hepatology (Baltimore, Md.) 70 (2019) 346–357, https://doi.org/10.1002/hep.30660. [27] L. Gallelli, O. Staltari, C. Palleria, G. De Sarro, M. Ferraro, Hepatotoxicity induced by methimazole in a previously healthy patient, Curr. Drug Saf. 4 (2009) 204–206. [28] S. Jin, et al., Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole-induced liver injury, Basic Clin. Pharmacol. Toxicol. (2019), https://doi.org/10.1111/bcpt.13284. [29] X. Li, et al., Association of HLA-C*03:02 with methimazole-induced liver injury in Graves' disease patients, Biomed. Pharmacother. 117 (2019) 109095, , https://doi. org/10.1016/j.biopha.2019.109095. [30] N. Chalasani, et al., Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States, Gastroenterology 135 (6) (2008) 1924–1934.e4, https://doi.org/10.1053/j.gastro.2008.09.011. [31] E. Bjornsson, et al., Drug-induced autoimmune hepatitis: clinical characteristics and prognosis, Hepatology (Baltimore, MD) 51 (2010) 2040–2048, https://doi.org/10. 1002/hep.23588. [32] T.J. Urban, et al., Minocycline hepatotoxicity: clinical characterization and identification of HLA-B *35:02 as a risk factor, J. Hepatol. 67 (2017) 137–144, https:// doi.org/10.1016/j.jhep.2017.03.010. [33] K.E. Clare, M.H. Miller, J.F. Dillon, Genetic factors influencing drug-induced liver injury: do they have a role in prevention and diagnosis? Curr. Hepatol. Rep. 16 (2017) 258–264, https://doi.org/10.1007/s11901-017-0363-9. [34] V.L. Yip, A.G. Marson, A.L. Jorgensen, M. Pirmohamed, A. Alfirevic, HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review, Clin. Pharmacol. Ther. 92 (2012) 757–765, https://doi.org/10.1038/clpt.2012. 189. [35] A.G. Marson, et al., The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial, Lancet (London, England) 369 (2007) 1000–1015, https://doi.org/10.1016/s0140-6736(07)60460-7. [36] C.Y. Cheng, et al., HLA associations and clinical implications in T-cell mediated
[37] [38]
[39]
[40]
[41]
[42] [43]
[44]
[45]
[46]
[47] [48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58] [59]
[60]
[61]
[62] [63]
5
drug hypersensitivity reactions: an updated review, J. Immunol. Res. 2014 (2014) 565320, , https://doi.org/10.1155/2014/565320. J. Uetrecht, D.J. Naisbitt, Idiosyncratic adverse drug reactions: current concepts, Pharmacol. Rev. 65 (2013) 779–808, https://doi.org/10.1124/pr.113.007450. P. Nicoletti, et al., Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions, Clin. Pharmacol. Ther. (2019), https://doi.org/10.1002/ cpt.1493. S. Russmann, J.A. Kaye, S.S. Jick, H. Jick, Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database, Br. J. Clin. Pharmacol. 60 (2005) 76–82, https://doi.org/10.1111/j.1365-2125.2005.02370.x. K. Wing, et al., Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study, J. Antimicrob. Chemother. 72 (2017) 2636–2646, https://doi.org/10.1093/jac/dkx183. A.K. Daly, et al., HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin, Nat. Genet. 41 (2009) 816–819, https://doi.org/ 10.1038/ng.379. W.L. Fan, et al., HLA association with drug-induced adverse reactions, J. Immunol. Res. 2017 (2017) 3186328, https://doi.org/10.1155/2017/3186328. V.L. Yip, A. Alfirevic, M. Pirmohamed, Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review, Clin. Rev. Allergy Immunol. 48 (2015) 165–175, https://doi.org/10.1007/s12016-014-8418-y. P. Nicoletti, et al., Drug-induced liver injury due to flucloxacillin: relevance of multiple human leukocyte antigen alleles, Clin. Pharmacol. Ther. 106 (2019) 245–253, https://doi.org/10.1002/cpt.1375. M.M. Monshi, et al., Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury, Hepatology (Baltimore, Md.) 57 (2) (2013) 727–739, https://doi.org/ 10.1002/hep.26077. V.M. Lauschke, M. Ingelman-Sundberg, Prediction of drug response and adverse drug reactions: from twin studies to next generation sequencing, Eur. J. Pharm. Sci. 130 (2019) 65–77, https://doi.org/10.1016/j.ejps.2019.01.024. M. Kaushal, P. Tolani, N. Kumar, S. Sharma, Terbinafine-induced liver injury, Natl. Med. J. India 30 (2017) 321–323, https://doi.org/10.4103/0970-258X.239071. P. Nicoletti, et al., Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study, Gastroenterology 152 (2017) 1078–1089, https://doi.org/10.1053/j.gastro.2016. 12.016. R.J. Fontana, et al., The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine, J. Hepatol. 69 (2018) 1317–1325, https://doi.org/10. 1016/j.jhep.2018.08.004. P.T. Donaldson, et al., Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury, J. Hepatol. 53 (2010) 1049–1053, https://doi.org/10.1016/j.jhep.2010.05.033. M.L. Hautekeete, et al., HLA association of amoxicillin-clavulanate–induced hepatitis, Gastroenterology 117 (1999) 1181–1186, https://doi.org/10.1016/s00165085(99)70404-x. J. O'Donohue, et al., Co-amoxiclav jaundice: clinical and histological features and HLA class II association, Gut 47 (2000) 717–720, https://doi.org/10.1136/gut.47. 5.717. P.T. Donaldson, et al., Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury, J. Hepatol. 53 (2010) 1049–1053, https://doi.org/10.1016/j.jhep.2010.05.033. M.I. Lucena, et al., Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles, Gastroenterology 141 (2011) 338–347, https://doi.org/10.1053/j.gastro.2011.04.001. C. Stephens, et al., HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity, PLoS ONE 8 (2013) e68111, , https://doi.org/10.1371/ journal.pone.0068111. C.B. Chen, et al., An updated review of the molecular mechanisms in drug hypersensitivity, J. Immunol. Res. 2018 (2018) 6431694, https://doi.org/10.1155/ 2018/6431694. W.J. Pichler, et al., Pharmacological interaction of drugs with immune receptors: the p-i concept, Allergol. Int. 55 (2006) 17–25, https://doi.org/10.2332/allergolint. 55.17. P.T. Illing, et al., Immune self-reactivity triggered by drug-modified HLA-peptide repertoire, Nature 486 (2012) 554–558, https://doi.org/10.1038/nature11147. G. Tarantino, M.N. Di Minno, D. Capone, Drug-induced liver injury: is it somehow foreseeable? World J. Gastroenterol. 15 (2009) 2817–2833, https://doi.org/10. 3748/wjg.15.2817. R.E. Morgan, et al., Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development, Toxicol. Sci.: Off. J. Soc. Toxicol. 118 (2010) 485–500, https://doi.org/10.1093/toxsci/kfq269. E.T. Cirulli, et al., A missense variant in PTPN22 is a risk factor for drug-induced liver injury, Gastroenterology 156 (2019) 1707–1716.e1702, https://doi.org/10. 1053/j.gastro.2019.01.034. E.J. Phillips, S.A. Mallal, Pharmacogenetics of drug hypersensitivity, Pharmacogenomics 11 (2010) 973–987, https://doi.org/10.2217/pgs.10.77. G.P. Aithal, A.K. Daly, Preempting and preventing drug-induced liver injury, Nat. Genet. 42 (2010) 650–651, https://doi.org/10.1038/ng0810-650.
Contents lists available at ScienceDirect
International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp
Research advances in the association of drug-induced liver injury with polymorphisms in human leukocyte antigen Qingmei Maa, Wenjuan Yanga, Lu Wanga, Li Maa, Yanmei Jinga, Jiamei Wanga, Xinyue Liua,b, a b
⁎
Department of Pharmacogenomics Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China
A R T I C LE I N FO
A B S T R A C T
Keywords: Hepatotoxicity Adverse drug reactions Genetic polymorphism Biomarkers Pharmacogenomics
Drug-induced liver injury is an important adverse drug reaction. Due to the lack of specificity in clinical symptoms and pathological features, there are still no reliable diagnostic biomarkers, so drug-induced liver injury is a diagnosis of exclusion. The article reviews the relevant advances in the association between novel human leukocyte antigen gene polymorphisms and drug-induced liver injury in order to identify potential biomarkers and provide a new method for the prediction and diagnosis of drug-induced liver injury. Henceforth, while studying the association between them, it will also need that the large sample and prospective studies to gain supporting evidence to implement translational application, so as to improve the safety and effectiveness of medication and achieve individualized treatment.
1. Introduction Liver is an important organ of drug metabolism. Most drugs or their active metabolites accumulate in the liver, which causes easily liver injury. Therefore, liver injury is one of the most common adverse drug reactions [1], and the second most common cause of drug attrition during development as well as for post-marketing withdrawal [2]. With the continuous update of clinical medication and the application of multi-drug combination, drug-induced liver injury (DILI) has become the most common cause of acute liver injury [3]. Severely, it can cause liver failure, even life-threatening [4]. In the United States, the incidence of DILI is 2.7 per 100,000 persons [5]. In mainland China, the incidence rate is 23.80 per 100,000 persons [6] and has an escalating trend. This phenomenon may be related to different regions, ethnic groups, population bases, types of drugs, unregulated use of drugs and dietary supplements. DILI is a general term for different types of liver injury [7] and is also a potential serious consequence of the clinical treatment. According to pathogenesis, DILI includes intrinsic DILI (InDILI) and idiosyncratic DILI (iDILI) [8]. The former with short latency is related to drug dosage and is commonly the direct cause of liver damage, clinically N - acetaminophen (APAP) is the most common; the latter has nothing to do with drug dosage and is relatively rare with complex pathogenetic mechanisms and manifestations in clinical practice [8], thence, many studies have focused on iDILI at present. Depending on
the course of disease, DILI can be classified as chronic or acute. Chronic DILI occurs when serum alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin (TBil) increase continuously and abnormally more than 6 months [9]. Clinically, acute DILI is more common, of which 15–20% can evolve into chronic [10]. In addition, in terms of the R-value defined as serum ALT/upper limit of normal (ULN) dividing by serum ALP/ULN, iDILI can be divided into hepatocellular injury (R ≥ 5), cholestatic (R < 2) and mixed type (2 < R < 5) [8]. According to different classification, it can help clinicians improve the diagnostic efficiency and reduce the pain of patients. DILI is an adverse drug reaction caused by multiple factors. Risk factors for DILI include age, gender, race, alcohol, pregnancy, underlying diseases, genetic polymorphisms and other host-dependent risk factors [11]. Besides that, there are some drug-dependent risk factors including dose and hepatic drug metabolism, lipophilicity, concomitant drug and hepatobiliary transport inhibition [11]. Among them, genetic polymorphisms account for approximately 20–30% of individual differences in drug response [1,12], which partly cause DILI, and the predisposition of patients to DILI may also vary among different races [13]. Therefore, clinicians and researchers should pay attention to the identification of DILI. The lack of specificity in clinical symptoms and pathological features about DILI, there are no normative diagnostic tests, so its diagnosis always relies on the exclusive method in terms of a history of
⁎ Corresponding author at: Department of Pharmacogenomics Laboratory Center, Department of Clinical Laboratory Center, Lanzhou University Second Hospital, Lanzhou 730030, China. E-mail address: [email protected] (X. Liu).
https://doi.org/10.1016/j.intimp.2019.106037 Received 30 August 2019; Received in revised form 6 November 2019; Accepted 7 November 2019 1567-5769/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: Qingmei Ma, et al., International Immunopharmacology, https://doi.org/10.1016/j.intimp.2019.106037
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
screening tool to predict PM-DILI risk. Nevertheless, it might make uncertainties and bias due to the small size of PM-DILI in this study, so lots of larger, independent studies are indispensable to further explore.
known medication exposure and a thorough evaluation for alternative etiologies [10,12]. To overcome this problem, it needs that specific and sensitive biomarkers go beyond the traditional methods of diagnosing DILI based on biochemical parameters including ALT, AST, and ALP. With the proposal of precision medicine, there are more and more researches in the association of DILI with human leukocyte antigen (HLA) alleles. Petros et al. [14] believed that finding the genetic predisposition to DIIL in patients may reduce the risk of drug resistance and improve curative effect. It had already been reported widely that DILI was associated with immune response, which was induced by abnormal activation of T cells. Kaliyaperumal et al. [15] discovered that the specificity of drug-metabolite-protein product presented by HLA molecules was determined by the unique physicochemical properties of the peptide-binding groove encoded in the major histocompatibility complex (MHC) region of chromosome 6, thereby activating specific T cells, which may be a key step in immune mechanism that mediates DILI. Subsequently, Kullak-Ublick et al. [16] argued that HLA polymorphisms played an important role in DILI susceptibility. The significant associations have been described that genetic polymorphisms and HLA alleles played a crucial role in adverse drug reactions [17,18]. In recent years, researchers analyzed the correlation between HLA alleles and DILI induced by various drugs through genome-wide association study (GWAS), and found that single nucleotide polymorphisms (SNPs) of HLA alleles could be used as the clinical basis to support DILI [15]. Therefore, the article reviews the correlations, underlying mechanisms and clinical applications between DILI and novel HLA alleles, providing strong evidence that HLA alleles can be used as specific biomarkers and prognostic indicators for the diagnosis of liver injury caused by certain drugs, in order to improve the safety and effectiveness of medication and achieve individualized treatment.
2.2. The genetic susceptibility of HLA-C*03:02 to methimazole-DILI Methimazole (MMI) is an anti-thyroid drug used for the treatment of Graves' disease (GD). It has been reported that administration of MMI may cause liver injury, most of which is cholestatic type [27,28]. Recently, Xuesong Li et al. [29] sequenced HLA class Ⅰ and class Ⅱ in a well-characterized phenotypic cohort with 40 MMI-drug-induced liver injury (MMI-DILI) cases and 118 MMI-tolerant controls, then found that the frequency of HLA-C*03:02 in the MMI-DILI cases, cholestatic/mixed liver damage and the MMI-tolerant controls were 6.7% (5/75), 6.4% (4/62) and 0.4% (1/231) respectively, which were significantly different from the controls (OR = 15.4, 95% CI = 1.77–133.9, adjusted P = 0.0292; OR = 14.9, 95% CI = 2.38–182.9, adjusted P = 0.0323; respectively). In addition, molecular docking study indicated that MMI could interact with HLA-C*03:02. This study analyses the effect of HLA alleles on the genetic susceptibility to MMI-DILI primarily, and realizes an increased risk of MMI-DILI in carriers with HLA-C*03:02. Meanwhile, it demonstrates that genetic factors play an important role in the course of MMI-DILI, contributing to a further understanding of the pathogenesis of MMI-DILI. 2.3. The effect of HLA-B*35:02 on minocycline-DILI Currently, the ongoing Drug-induced Liver Injury Network (DILIN) prospective study in the United States has found that antibiotics are the main cause of DILI [30]. Minocycline, a cause of DILI, can lead to characteristic clinical features like systemic arthralgias and detectable autoantibodies arising, similar to that of autoimmune hepatitis [31]. Urban et al. [32] found an increased risk of minocycline-DILI in carriers with HLA-B*35:02 in Caucasian patients using genome-wide genotyping. The results indicated that 16% HLA-B*35:02 carrier frequency in DILI cases compared to 0.6% in the population controls; HLAB*35:02 carriers had similar clinical manifestations and outcomes compared to non-carriers. These results suggest that HLA-B*35:02 may be the risk allele for minocycline-DILI. If HLA-B*35:02 can be proved to be a useful diagnostic biomarker for minocycline-DILI in other populations, it may reduce the risk of liver injury caused by minocycline during treatment and help to distinguish DILI from autoimmune hepatitis [33].
2. Researches in the association of DILI with HLA 2.1. The correlation between polygonum multiflorum-DILI and HLAB*35:01 Currently, the use of traditional Chinese medicine in China and abroad seems to be increasingly popular [19,20], with more than 100 medicinal preparations reported to induce liver injury, and these Clinical Practice Guidelines established by European Association for the Study of the Liver (EASL) recommend that physicians may consider herbal medicines and dietary supplements as potential causative agents for liver injury [11]. Polygonum multiflorum (PM), as a traditional herbal medicine for nourishing liver and kidney [21], has been widely used, causing an increasingly high incidence of liver injury. It has been reported that PM-drug-induced liver injury (PM-DILI) accounts for approximately 30% of liver injury cases of Chinese herbal medicine in China [22,23]. However, the mechanism of PM-DILI has not been clarified. It has been found that the occurrence of PM-DILI may be related to immune response in previous clinical case studies and animal experiments [24,25]. In recent months, Honghao Zhou et al. [26] firstly studied the association between HLA-B*35:01 and PM-DILI. They developed the polit study that the HLA regions of 11 patients with PMDILI were sequenced, and found that HLA-B*35:01 expressed significantly. Subsequently, HLA-B polymerase chain reaction-sequence based typing (PCR-SBT) was used to validate the candidate allele in 15 patients with PM-DILI, 33 patients with other drug-DILI and 99 population controls, and detected that HLA-B*35:01 was a high-risk allele of PM-DILI, which was consistent with the polit study. Finally, prospective cohort study further identified the influence of HLA-B*35:01 on PMDILI. This study mainly discovers that HLA-B*35:01 is a genetic risk factor for PM-DILI, and is also a potential predictable biomarker. This is the first time that finds the correlation between PM-DILI and HLAB*35:01, and HLA-B*35:01 may be expected to become a new diagnostic aid in favor of determining PM-DILI and turn into a pre-emptive
2.4. Carbamazepine hypersensitivity and HLA-A*31:01 Carbamazepine is an antiepileptic drug used to treat epilepsy, trigeminal neuralgia and bipolar disorder [34]. About 3–10% of patients taking carbamazepine will develop anaphylaxis [35]. Adaptive immune responses occur because carbamazepine or its metabolites bind to specific HLA molecules that stimulate T cell responses [36], causing a variety of life-threatening hypersensitivities including serious cutaneous adverse reactions (SCAR) such as mild maculopapular exanthemas to hypersensitivity syndrome (DRESS), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and DILI [20,37]. Nicoletti et al. [38] performed the genotyping that indicated 33% carbamazepine-DILI patients were HLA-A*31:01 carriers (OR = 7.3, 95% CI = 2.47–23.67, P = 0.0004). Then, they made a meta-analysis of GWAS studies and found that HLA-A*31:01 was the strongest genetic predisposing factor for severe adverse reactions caused by carbamazepine in the European populations, and patients with HLA-A*31:01 were prone to DILI. For the first time, the study evaluates whether HLA-A*31:01 is a risk factor for DILI after taking carbamazepine. Further trans-ethnic meta-analysis of the GWAS and plenty of original studies of carbamazepine-DILI are therefore needed to identify potential causal alleles in diverse 2
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
Table 1 The associations between DILI and HLA allele. Drug
HLA Allele
Population
Cases/controls
OR
PM Methimazole Minocycline Carbamazepine Flucloxacillin
B*35:01 C*03:02 B*35:02 A*31:01 B*57:01
Terbinafine
A*33:01
pi:11, re:15/132, pr:72 40/118 25/10588 12/8438 51/282 197/6835 14/10588 15
143.9 [26] 15.4 [29] 29.6 [32] 7.3 [38] 80.6 [41] 36.6 [44] 40.5 [48] NR [49]
AC
DRB1*15:01-DRB5*01:01-DQB1*06:02 DRB1*15:01 DRB1*07a DRB1*15:01-DQB1*06:02 A*02:01 A*30:02 B*18:01
Chinese Chinese Caucasian European European European European, American European, African American, East Asian Belgian Scottish British European European Spanish Spanish
35/300 22/134 61/231 177/219 177/219 75/885 75/885
NR [51] 9.25 [52] 0.18 [50] 3.3 [53] 2.2 [53] 6.7 [54] 2.9 [54]
PM, Polygonum multiflorum; AC, Amoxicillin-clavulanate; pi, the pilot study; re, the replication study; pr, the prospective cohort study; OR, odds ratio; NR, not reported. a The protective factor.
A recent genetic analysis was performed on 862 DILI patients from European and USA, and demonstrated a significant association between HLA-A*33:01 and DILI patients due to terbinafine and possibly fenofibrate and ticlopidine [48]. In this study, DILI is caused by several drugs, so there is limited specificity. In order to identify potential HLA alleles associated with only terbinafine-DILI, and determine the mechanism between them, recently, Fontana et al. [49] performed high-resolution confirmatory HLA sequencing using the Ilumin MiSeq platform for the DNA samples of 15 patients with terbinafine-DILI from DILIN, and found that 10 of the 11 European participants carried HLA-A*33:01, B*14:02, and C*08:02 haplotype, which were strongly correlated and might co-induce DILI and had the conformity with previous results [48]. Molecular docking studies suggested that terbinafine may interact with HLA-A*33:01 and HLA-A*33:03. These results indicate that HLAA*33:01 may be a risk factor for terbinafine-DILI.
populations. 2.5. New findings of flucloxacillin in genetic factors causing DILI Flucloxacillin is an oral β-lactam antibiotic used for the treatment of soft tissue infections caused by Staphylococcus aureus (S. aureus) [39], it is also one of the causes of DILI. The incidence of DILI induced by flucloxacillin is 8.5 per 100,000 persons, and 35 per 100,000 persons in those taking one consecutive flucloxacillin and 110.5 per 100,000 persons in those aged > 70 years who have taken flucloxacillin more than twice [40]. Meanwhile, Daly et al. showed that HLA-B*57:01 had a highly significant association with DILI and an 80-fold increased risk of flucloxacillin-DILI in HLA-B*57:01 carriers by the GWAS analysis (OR = 80.6; 95% CI = 22.8–284.9) [41]. This is an interesting discovery because HLA-B*57:01 is also associated with abacavir hypersensitivity, but it was not reported that these patients developed DILI [42]. Although flucloxacillin-DILI is correlated with HLA-B*57:01, conventional genetic tests for HLA-B*57:01 before the prescription of flucloxacillin may have no significant clinical relevance, because the positive predictive value of HLA-B*57:01 is as low as 0.12% [33,43] and the overall sensitivity and specificity of genotyping of susceptible individuals are too weak to predict. After the discovery of the association between HLA-B*57:01 and flucloxacillin-DILI, Nicoletti et al. [44] used GWAS analysis to further verify whether HLA-B*57:01 was a genetic risk factor for flucloxacillinDILI, to identify other related genetic factors, and to evaluate the correlation between flucloxacillin-DILI risk factors and other penicillininduced DILI. The results showed that HLA-B*57:01 was the major risk factor for flucloxacillin-DILI (allelic OR = 36.62, P = 2.67 × 10−97), which was consistent with previous results [41,45], and HLA-B*57:03 also showed an association (OR = 79.21, P = 1.2 × 10−6). HLAB*57:03 is a rare gene, and the functional interpretation of rare alleles remains challenging and is one of the important frontiers of contemporary pharmacogenomics [46]. It is still imperative to clarify HLAB*57:01 as a key susceptible factor of flucloxacillin-DILI before applying it into a clinical setting.
2.7. The genetic factors of amoxicillin-clavulanate-DILI It is known that amoxicillin-clavulanate (AC) is the most common causal drug of iDILI with 10–13% of hospitalizations [50]. The correlation of AC-drug-induced liver injury (AC-DILI) and HLA has been commonly studied, hereon we just make a brief introduction. In 1999, Hautekeete et al. [51] firstly found the association of ACDILI with HLA in Europeans and the frequency of HLA-DRB1*15:01DRB5*01:01-DQB1*06:02 in AC-DILI patients was significantly higher compared to the controls. Subsequently, amounts of researches were replicated to validate the link between HLA-DRB1*15:01 and AC-DILI while observing a novel protective factor: HLA-DRB1*07 [52,53]. Furthermore, others also showed the relationship of AC-DILI with some HLA alleles including HLA-A*02:01, HLA-A*30:02 and HLA-B*18:01 [54,55]. For more detailed information, please see the list in Table 1. 3. Underlying pathogenesis 3.1. HLA- mediated DILI The mechanism of InDILI has been well understood, while the researches on the pathogenesis of iDILI are still challenging due to its complexity and variability. As mentioned above, some HLA alleles have been found to be associated with iDILI by GWAS, however, this association is rare and the idiosyncratic HLA allele matches with the specific drug (Table 1). Moreover, there is still no much reliable evidence for the correlation, and it is an intractable problem to achieve clinical practice at present. Nevertheless, it suggests that DILI may be related to
2.6. The role of HLA alleles in terbinafine-DILI Terbinafine is an oral antifungal agent used to treat superficial fungal infections of the skin and nails, and causes DILI [47]. Due to the lack of a sensitive and reliable method to detect liver injury, it is still difficult to clearly diagnose DILI cases caused by terbinafine, which may lead to missed and delayed diagnosis. 3
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
makes a vast difference to the occurrence and development of DILI, which is expected to break through the conundrum in distinguishing DILI from liver injury caused by other causes. In researches in the association of DILI with HLA, as an emerging hotspot, there are still a lot of unsolved problems. Although EASL has issued Clinical Practice Guidelines for DILI based on the latest research progress and best evidence of DILI [11], recommending that HLA genotyping can be applied to detect and diagnose DILI in specific clinical situations, there are still many limitations: (1) There is no standard and reliable method to diagnose DILI; (2) The sample size is extremely limited, and the lack of large sample replication studies leads to have few strong evidence; (3) The lack of prospective studies and randomized controlled trials; (4) There are many confounding factors in the researches; (5) The limited knowledge of the characteristics of detection results in DILI and non-DILI patients. It is difficult to distinguish; (6) Some recommendations in published guidelines are relatively weak. Nevertheless, with the emergence and update of new medical technologies, part of the clinicians and researchers have begun to shift their focus to DILI studies. Therefore, HLA alleles, as novel biomarkers for the diagnosis of DILI, maybe provide a new method for the detection, treatment and prevention of DILI patients and others who have acute liver failure and liver transplantation secondary to DILI, so as to reduce the medical burden, improve the safety and effectiveness of medication and achieve individualized treatment.
the immune response, contributing to the understanding of the pathogenesis of DILI. There are some hypotheses about DILI pathogenesis. The “hapten hypothesis” states that a drug or its metabolites bind to cellular or circulating protein in a covalent way and the complex interacts with the peptide-binding groove of a specific HLA molecule in order to determine an individual’s susceptibility to DILI [16]. In addition, there is the hypothesis of the pharmacological interaction with immune receptors (p-i) concept, in which some drugs or their metabolites are considered foreign antigens that may bind directly to HLA molecules or T-cell receptors, independent of antigen presentation. Without adaptation, it may trigger activation and proliferation of T cells, leading to hepatocyte damage [56,57]. Furthermore, some drugs bind to the peptide-binding groove of HLA molecules to alter the shape and chemistry of peptides that can bind to a particular HLA protein [58]. These theories may conduce to recognizing DILI and improving the efficiency and safety of drug development and reduce the waste of medical resources. 3.2. Other potential mechanisms Although there is substantial evidence to support the pathogenesis of HLA-mediated DILI, there are exceptions which may be other factors. For example, drug metabolites are the classic view of the pathogenesis of DILI, mainly mediated by cytochromes P-450 (CYP), further, ATP depletion, mitochondrial injury, apoptosis, inflammation, oxidative stress, covalent binding to nucleic acids or lipids, or occurrence of lipid peroxidation also has a certain effect [59]. In addition, Morgan et al. [60] proposed that the inhibition of bile salt export pump (BSEP) by medication may be involved in the pathogenesis of DILI. Currently, Cirulli et al. [61] confirmed that a missense variant (rs2476601) in the PTPN22 gene was associated with DILI risk. This is the first time that a pharmacogenomic variant is related to liver injury induced by various drugs, so it makes progress. These mechanisms may be responsible for some DILI cases, and they may be synergistic or antagonistic in DILI. That is to say, since the pathogenesis of DILI is extremely complex, there is still a long way to go.
Funding This work was supported by Scientific Research Project of Gansu Medical and Health Industry [Grant No. GSWSKY2017-31], Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [Grant No. CY2017-MS17]. Author contributions Qingmei Ma wrote parts of the manuscript and made the table; Wenjuan Yang and Lu Wang searched relevant materials and wrote parts of the manuscript; Li Ma, Yanmei Jing and Jiamei Wang revised the manuscript; Xinyue Liu contributed to the conception and suggestion, and reviewed the manuscript.
4. Clinical applications
Declaration of Competing Interest
It is necessary to consider severe adverse drug reactions and various additional factors including the availability, efficacy and safety of medication, reliable clinical and experimental evidence, permissive environmental factors, and the sensitivity and specificity of the pharmacogenetic tests in the routine clinical implementation [62]. In clinical practice, there are some tests for the correlation between HLA and adverse reactions caused by certain drugs, such as HLA-B*57:01 and abacavir, HLA-B*58:01 and allopurinol. Because the incidence of DILI is too low to warrant the cost-effectiveness of genetic screening, so the detections that are routinely employed are impracticable for the time being. However, it will be of great help to risk management of DILI if new biomarkers can be found to reliably predict DILI, and its empirical and translational application can be used to assess whether patients can use a certain drug or closely monitor a certain drug at the early stage of use to determine the occurrence of liver injury. Overall, the benefit of association between HLA alleles and DILI had controversy in terms of the implementation of genotyping to evaluate the relative risks of DILI [63].
None. References [1] V.M. Lauschke, M. Ingelman-Sundberg, The importance of patient-specific factors for hepatic drug response and toxicity, Int. J. Mol. Sci. 17 (2016), https://doi.org/ 10.3390/ijms17101714. [2] J.L. Stevens, T.K. Baker, The future of drug safety testing: expanding the view and narrowing the focus, Drug Discov. Today 14 (2009) 162–167, https://doi.org/10. 1016/j.drudis.2008.11.009. [3] Y. Pan, M. Cao, D. You, G. Qin, Z. Liu, Research progress on the animal models of drug-induced liver injury: current status and further perspectives, Biomed Res. Int. 2019 (2019) 1283824, https://doi.org/10.1155/2019/1283824. [4] E. Bjornsson, Review article: drug-induced liver injury in clinical practice, Aliment. Pharmacol. Ther. 32 (2010) 3–13, https://doi.org/10.1111/j.1365-2036.2010. 04320.x. [5] M. Vega, et al., The incidence of drug- and herbal and dietary supplement-induced liver injury: preliminary findings from gastroenterologist-based surveillance in the population of the state of delaware, Drug Saf. 40 (2017) 783–787, https://doi.org/ 10.1007/s40264-017-0547-9. [6] T. Shen, et al., Incidence and etiology of drug-induced liver injury in Mainland China, Gastroenterology 156 (2019) 2230–2241, https://doi.org/10.1053/j.gastro. 2019.02.002 e2211. [7] R.J. Fontana, Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives, Gastroenterology 146 (2014) 914–928, https://doi.org/10.1053/j. gastro.2013.12.032. [8] N.P.A.C.G. Chalasani, et al., Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury, Am. J. Gastroenterol. 109 (2014) 950–966, https://doi.org/10.1038/ajg.2014.131 quiz 967.
5. Conclusions HLA allele polymorphisms and specific drug-induced liver injury are increasingly being studied. HLA alleles have the most complex genetic polymorphisms in the human genome and play a crucial role in immune response, which is one of the risk factors of DILI. At present, a mass of studies on the relationship between HLA and DILI have found that HLA 4
International Immunopharmacology xxx (xxxx) xxxx
Q. Ma, et al.
[9] R.J. Fontana, et al., Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct, Drug Saf. 32 (2009) 55–68, https://doi.org/10. 2165/00002018-200932010-00005. [10] J.G. Stine, N. Chalasani, Chronic liver injury induced by drugs: a systematic review, Liver Int. 35 (2015) 2343–2353, https://doi.org/10.1111/liv.12958. [11] European Association for the Study of the Liver, e.e.e. Electronic address, C. Clinical Practice Guideline Panel, m. Panel, E.G.B. representative, EASL Clinical Practice Guidelines: Drug-induced liver injury, J. Hepatol 70 (2019) 1222–1261 doi:10. 1016/j.jhep.2019.02.014. [12] S.C. Sim, M. Kacevska, M. Ingelman-Sundberg, Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects, Pharmacogenomics J. 13 (2013) 1–11, https://doi.org/10.1038/tpj.2012.45. [13] F.Q. Hou, Z. Zeng, G.Q. Wang, Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes, Cell Biochem. Biophys. 64 (2012) 77–83, https://doi.org/10.1007/s12013-012-9373-y. [14] Z. Petros, et al., HLA-B(*)57 allele is associated with concomitant anti-tuberculosis and antiretroviral drugs induced liver toxicity in Ethiopians, Front. Pharmacol. 8 (2017) 90, https://doi.org/10.3389/fphar.2017.00090. [15] K. Kaliyaperumal, et al., Pharmacogenomics of drug-induced liver injury (DILI): Molecular biology to clinical applications, J. Hepatol. 69 (2018) 948–957, https:// doi.org/10.1016/j.jhep.2018.05.013. [16] G.A. Kullak-Ublick, et al., Drug-induced liver injury: recent advances in diagnosis and risk assessment, Gut 66 (2017) 1154–1164, https://doi.org/10.1136/gutjnl2016-313369. [17] M. S, et al., Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir, Lancet (London, England) 359 (2002) 727–732. [18] C. Wh, et al., Medical genetics: a marker for Stevens-Johnson syndrome, Nature 428 (2004) 486. [19] Y. Zhu, et al., Hepatobiliary and pancreatic: Comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients, J. Gastroenterol. Hepatol. 31 (2016) 1476–1482, https://doi.org/10.1111/jgh.13323. [20] J.H. Hoofnagle, E.S. Bjornsson, Drug-induced liver injury—types and phenotypes, N Engl J Med 381 (2019) 264–273, https://doi.org/10.1056/NEJMra1816149. [21] L. Lin, et al., Traditional usages, botany, phytochemistry, pharmacology and toxicology of Polygonum multiflorum Thunb.: a review, J. Ethnopharmacol. 159 (2015) 158–183, https://doi.org/10.1016/j.jep.2014.11.009. [22] X. Lei, et al., Liver damage associated with polygonum multiflorum Thunb.: a systematic review of case reports and case series, Evid. Based Complement. Alternat. Med. 2015 (2015) 459749, https://doi.org/10.1155/2015/459749. [23] R. Wang, et al., Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review, Expert Rev. Gastroenterol. Hepatol. 12 (2018) 425–434, https://doi.org/10.1080/17474124.2018.1427581. [24] Y.K. Meng, et al., Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPARgamma, Acta Pharmacol. Sin. 38 (2017) 1340–1352, https://doi.org/10.1038/aps. 2017.32. [25] L. He, et al., Immunological synergistic mechanisms of trans-/cis-stilbene glycosides in Heshouwu-related idiosyncratic liver injury, Sci. Bull. 748–751 (2017). [26] C. Li, et al., HLA-B*35:01 allele is a potential biomarker for predicting polygonum multiflorum-induced liver injury in humans, Hepatology (Baltimore, Md.) 70 (2019) 346–357, https://doi.org/10.1002/hep.30660. [27] L. Gallelli, O. Staltari, C. Palleria, G. De Sarro, M. Ferraro, Hepatotoxicity induced by methimazole in a previously healthy patient, Curr. Drug Saf. 4 (2009) 204–206. [28] S. Jin, et al., Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole-induced liver injury, Basic Clin. Pharmacol. Toxicol. (2019), https://doi.org/10.1111/bcpt.13284. [29] X. Li, et al., Association of HLA-C*03:02 with methimazole-induced liver injury in Graves' disease patients, Biomed. Pharmacother. 117 (2019) 109095, , https://doi. org/10.1016/j.biopha.2019.109095. [30] N. Chalasani, et al., Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States, Gastroenterology 135 (6) (2008) 1924–1934.e4, https://doi.org/10.1053/j.gastro.2008.09.011. [31] E. Bjornsson, et al., Drug-induced autoimmune hepatitis: clinical characteristics and prognosis, Hepatology (Baltimore, MD) 51 (2010) 2040–2048, https://doi.org/10. 1002/hep.23588. [32] T.J. Urban, et al., Minocycline hepatotoxicity: clinical characterization and identification of HLA-B *35:02 as a risk factor, J. Hepatol. 67 (2017) 137–144, https:// doi.org/10.1016/j.jhep.2017.03.010. [33] K.E. Clare, M.H. Miller, J.F. Dillon, Genetic factors influencing drug-induced liver injury: do they have a role in prevention and diagnosis? Curr. Hepatol. Rep. 16 (2017) 258–264, https://doi.org/10.1007/s11901-017-0363-9. [34] V.L. Yip, A.G. Marson, A.L. Jorgensen, M. Pirmohamed, A. Alfirevic, HLA genotype and carbamazepine-induced cutaneous adverse drug reactions: a systematic review, Clin. Pharmacol. Ther. 92 (2012) 757–765, https://doi.org/10.1038/clpt.2012. 189. [35] A.G. Marson, et al., The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial, Lancet (London, England) 369 (2007) 1000–1015, https://doi.org/10.1016/s0140-6736(07)60460-7. [36] C.Y. Cheng, et al., HLA associations and clinical implications in T-cell mediated
[37] [38]
[39]
[40]
[41]
[42] [43]
[44]
[45]
[46]
[47] [48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58] [59]
[60]
[61]
[62] [63]
5
drug hypersensitivity reactions: an updated review, J. Immunol. Res. 2014 (2014) 565320, , https://doi.org/10.1155/2014/565320. J. Uetrecht, D.J. Naisbitt, Idiosyncratic adverse drug reactions: current concepts, Pharmacol. Rev. 65 (2013) 779–808, https://doi.org/10.1124/pr.113.007450. P. Nicoletti, et al., Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions, Clin. Pharmacol. Ther. (2019), https://doi.org/10.1002/ cpt.1493. S. Russmann, J.A. Kaye, S.S. Jick, H. Jick, Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: cohort study using data from the UK General Practice Research Database, Br. J. Clin. Pharmacol. 60 (2005) 76–82, https://doi.org/10.1111/j.1365-2125.2005.02370.x. K. Wing, et al., Quantification of the risk of liver injury associated with flucloxacillin: a UK population-based cohort study, J. Antimicrob. Chemother. 72 (2017) 2636–2646, https://doi.org/10.1093/jac/dkx183. A.K. Daly, et al., HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin, Nat. Genet. 41 (2009) 816–819, https://doi.org/ 10.1038/ng.379. W.L. Fan, et al., HLA association with drug-induced adverse reactions, J. Immunol. Res. 2017 (2017) 3186328, https://doi.org/10.1155/2017/3186328. V.L. Yip, A. Alfirevic, M. Pirmohamed, Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review, Clin. Rev. Allergy Immunol. 48 (2015) 165–175, https://doi.org/10.1007/s12016-014-8418-y. P. Nicoletti, et al., Drug-induced liver injury due to flucloxacillin: relevance of multiple human leukocyte antigen alleles, Clin. Pharmacol. Ther. 106 (2019) 245–253, https://doi.org/10.1002/cpt.1375. M.M. Monshi, et al., Human leukocyte antigen (HLA)-B*57:01-restricted activation of drug-specific T cells provides the immunological basis for flucloxacillin-induced liver injury, Hepatology (Baltimore, Md.) 57 (2) (2013) 727–739, https://doi.org/ 10.1002/hep.26077. V.M. Lauschke, M. Ingelman-Sundberg, Prediction of drug response and adverse drug reactions: from twin studies to next generation sequencing, Eur. J. Pharm. Sci. 130 (2019) 65–77, https://doi.org/10.1016/j.ejps.2019.01.024. M. Kaushal, P. Tolani, N. Kumar, S. Sharma, Terbinafine-induced liver injury, Natl. Med. J. India 30 (2017) 321–323, https://doi.org/10.4103/0970-258X.239071. P. Nicoletti, et al., Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study, Gastroenterology 152 (2017) 1078–1089, https://doi.org/10.1053/j.gastro.2016. 12.016. R.J. Fontana, et al., The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine, J. Hepatol. 69 (2018) 1317–1325, https://doi.org/10. 1016/j.jhep.2018.08.004. P.T. Donaldson, et al., Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury, J. Hepatol. 53 (2010) 1049–1053, https://doi.org/10.1016/j.jhep.2010.05.033. M.L. Hautekeete, et al., HLA association of amoxicillin-clavulanate–induced hepatitis, Gastroenterology 117 (1999) 1181–1186, https://doi.org/10.1016/s00165085(99)70404-x. J. O'Donohue, et al., Co-amoxiclav jaundice: clinical and histological features and HLA class II association, Gut 47 (2000) 717–720, https://doi.org/10.1136/gut.47. 5.717. P.T. Donaldson, et al., Human leucocyte antigen class II genotype in susceptibility and resistance to co-amoxiclav-induced liver injury, J. Hepatol. 53 (2010) 1049–1053, https://doi.org/10.1016/j.jhep.2010.05.033. M.I. Lucena, et al., Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles, Gastroenterology 141 (2011) 338–347, https://doi.org/10.1053/j.gastro.2011.04.001. C. Stephens, et al., HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity, PLoS ONE 8 (2013) e68111, , https://doi.org/10.1371/ journal.pone.0068111. C.B. Chen, et al., An updated review of the molecular mechanisms in drug hypersensitivity, J. Immunol. Res. 2018 (2018) 6431694, https://doi.org/10.1155/ 2018/6431694. W.J. Pichler, et al., Pharmacological interaction of drugs with immune receptors: the p-i concept, Allergol. Int. 55 (2006) 17–25, https://doi.org/10.2332/allergolint. 55.17. P.T. Illing, et al., Immune self-reactivity triggered by drug-modified HLA-peptide repertoire, Nature 486 (2012) 554–558, https://doi.org/10.1038/nature11147. G. Tarantino, M.N. Di Minno, D. Capone, Drug-induced liver injury: is it somehow foreseeable? World J. Gastroenterol. 15 (2009) 2817–2833, https://doi.org/10. 3748/wjg.15.2817. R.E. Morgan, et al., Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development, Toxicol. Sci.: Off. J. Soc. Toxicol. 118 (2010) 485–500, https://doi.org/10.1093/toxsci/kfq269. E.T. Cirulli, et al., A missense variant in PTPN22 is a risk factor for drug-induced liver injury, Gastroenterology 156 (2019) 1707–1716.e1702, https://doi.org/10. 1053/j.gastro.2019.01.034. E.J. Phillips, S.A. Mallal, Pharmacogenetics of drug hypersensitivity, Pharmacogenomics 11 (2010) 973–987, https://doi.org/10.2217/pgs.10.77. G.P. Aithal, A.K. Daly, Preempting and preventing drug-induced liver injury, Nat. Genet. 42 (2010) 650–651, https://doi.org/10.1038/ng0810-650.