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Adverse drug reactions and organ damage: The liver

  • Anna Licata
    Correspondence
    Corresponding author at: Sezione di Gastroenterologia ed Epatologia, DIBIMIS, Università di Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy. Tel.: +39 091 655 2280; fax: +39 091 6552156.
    Affiliations
    Sezione di Gastroenterologia & Epatologia, Dipartimento di Medicina Interna e Specialistica, DiBiMIS, Università di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy
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Published:January 27, 2016DOI:https://doi.org/10.1016/j.ejim.2015.12.017

      Highlights

      • Drug induced liver injury is the most challenging acute or chronic liver disease handles by physicians.
      • Drug induced liver injury depends on the interplay between drug, host and environmental risk factors.
      • Drug induced liver injury DILI encompass a wide spectrum of diseases with varying clinical/histological features.
      • Drug induced liver injury is an exclusion diagnosis in which clinical judgment remain essential.
      • Patients with hepatocellular liver injury induced by drugs are at risk of acute liver failure.

      Abstract

      Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin–clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.

      Abbreviations:

      DILI (Drug-induced liver injury), ADRs (Adverse drug reactions), HDS (Herbal and/or dietary supplement), APAP (N-acetyl-P-aminophenol), ALF (Acute liver failure), NSAIDs (Non-steroidal anti-inflammatory drugs), AMC (Amoxicillin–clavulanate), INH (Isoniazid), ALT (Alanine aminotransferase), ALP (Alkaline phosphatase), RUCAM (Roussel Uclaf causality assessment method), DIAIH (Drug-induced autoimmune hepatitis), NAC (N-acetyl cysteine), miRNAs (MicroRNAs), ABC (ATP binding cassette), Th (T helper), IL (Interleukin), MDR-3 (Multi drug resistance-3), HLA (Human leukocytes antigen), GWAS (Genome wide association studies), NAT-2 (N-acetyltransferase-2), SNPs (Single-nucleotide polymorphisms), SLCO1B1 (Solute carrier organic anion transporter family member 1B1), OATP1B1 (Organic anion transporting polypeptide-1)

      Keywords

      1. Introduction

      Drug-induced liver injury (DILI) encompasses adverse drug reactions (ADRs) involving the liver after the administration of a xenobiotic, such a drug or herbal and/or dietary supplement (HDS), at the usual dose interval [
      • Einar S.
      Bjornssn. Drug-induced liver injury: an overview over the most critical compounds.
      ]. Theoretically, most drugs are capable of inducing DILI, owing to the liver's pivotal role in drug metabolism.
      The two main categories of DILI are intrinsic/dose-dependent and idiosyncratic/dose-independent, with the latter form being relatively uncommon. Liver injuries due to acetaminophen (N-acetyl-p-aminophenol [APAP]) are typically associated with an excessive dose. APAP overdose is a frequent cause of acute liver failure (ALF) requiring liver transplantation [

      Lee W. Acetaminophen-related acute liver failure in the United States. Hepatol Res;38 (S1):S3-8.

      ,
      • Ostapowicz G.
      • Fontana R.J.
      • Schiodt F.V.
      • et al.
      Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.
      ]. Most cases of DILI are due to unpredictable reactions and, traditionally, were believed to be dose-independent. However, drugs with a daily dose of less than 50 mg are very rarely associated with DILI, as demonstrated independently by two different research groups [
      • Lucena M.I.
      • Andrade R.J.
      • Fernández M.C.
      • Pachkoria K.
      • Pelaez G.
      • Durán J.A.
      • et al.
      Determinants of the clinical expression of amoxicillin–clavulanate hepatotoxicity: a prospective series from Spain.
      ,
      • Lammert C.
      • Einarsson S.
      • Saha C.
      • Niklasson A.
      • Bjornsson E.
      • Chalasani N.
      Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.
      ]. Thus, many drugs that were previously associated with idiosyncratic DILI are now considered to act in a dose-dependent manner. Nevertheless, the possibility of idiosyncratic DILI should always be considered in a patient with acute or chronic liver damage, independent of a possible underlying liver condition (e.g., non-alcoholic steatohepatitis or non-alcoholic fatty liver disease). As the diagnosis of DILI remains one of exclusion, DILI is one of the most challenging disorders to be managed by physicians and hepatologists [
      • Chalasani N.
      • Hayashi P.H.
      • Bonkovsky H.L.
      • Navarro V.J.
      • Lee W.M.
      • Fontana R.J.
      • et al.
      Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.
      ].
      Many drugs have been associated with DILI. Antibiotics and antimicrobials accounted for more than 46% of all DILI cases in the Drug-Induced Liver Injury Network (DILIN) cohort from the United States [
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      ]. Among antibiotics, amoxicillin–clavulanate (AMC) was the most frequently implicated agent, a finding confirmed in prospective DILI studies in Iceland and Spain [
      • Björnsson E.S.
      • Bergmann O.M.
      • Björnsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ,

      Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-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(2):512–21.

      ]. Non-steroidal anti-inflammatory drugs (NSAIDs), statins, and HDS can also lead to DILI. In recent years, there has been an increase in the number of people who prefer alternative therapies, such as HDS, to commonly used drugs whose safety and efficacy have been demonstrated by controlled clinical studies. For example, the use of HDS has increased to 3.7% in Italy, 20% in the United Kingdom, and 40% in the United States [
      • Navarro V.J.
      • Barnhart H.
      • Bonkovsky H.L.
      • Davern T.
      • Fontana R.J.
      • Grant L.
      • et al.
      Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.
      ,
      • A Licata A.
      • Macaluso F.S.
      • Craxì A.
      Herbal hepatotoxicity: a hidden epidemic.
      ]. Given the easy availability of HDS via the Internet, people purchase what they deem to be the correct preparation directly, without consulting a physician or pharmacist. Unfortunately, patients, even those previously diagnosed with chronic liver disease, are reluctant to disclose their use of nonconventional therapies [
      • Vitalone A.
      • Menniti-Ippolito F.
      • Moro P.
      • Firenzuoli F.
      • Raschetti R.
      • Mazzanti G.
      Suspected adverse reactions associated with herbal products used for weight loss: a case series reported to the Italian National Institute of Health.
      ].
      An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market [
      • Navarro V.J.
      • Senior J.R.
      Drug-related hepatotoxicity.
      ]. Recent examples of drug withdrawal in the United States and in Europe include troglitazone, bromfenac [
      • Lee W.M.
      Drug-induced hepatotoxicity.
      ] and others. DILI is the most common cause of ALF in the United States [
      • Reuben A.
      • Koch D.G.
      • Lee W.M.
      Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.
      ] and Europe [
      • Wei G.
      • Bergquist A.
      • Broomé U.
      • Lindgren S.
      • Wallerstedt S.
      • Almer S.
      • et al.
      Acute liver failure in Sweden: etiology and outcome.
      ]. To increase awareness of DILI, facilitate clinical management, and improve prognosis, the American College of Gastroenterology developed practice guidelines for the diagnosis and management of idiosyncratic DILI, using an evidence-based approach [
      • Chalasani N.
      • Hayashi P.H.
      • Bonkovsky H.L.
      • Navarro V.J.
      • Lee W.M.
      • Fontana R.J.
      • et al.
      Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.
      ]. Currently, however, there are no guidelines in Europe regarding when to suspect DILI, how to confirm a diagnosis of DILI, or how to manage DILI once it is has been recognized. Many researchers in Europe are investigating DILI, and there is a need for a larger European network.
      The purpose of this review is to prompt physicians to consider DILI whenever they are managing a patient with an unexplained liver injury. This review should assist physicians in accurately diagnosing DILI and improving outcomes, given that the disorder is sometimes responsible for ALF and occasionally requires liver transplantation. The use of biomarkers and the impact of pharmacogenetic studies are also discussed.

      2. Epidemiology and risk factors for idiosyncratic DILI

      The clinical diagnosis of DILI is one of exclusion, owing to a lack of reliable and confirmatory tests. Accordingly, it is difficult to establish the exact burden of DILI on the healthcare system. Registries of idiosyncratic DILI cases have been established in different Western [
      • Björnsson E.S.
      • Bergmann O.M.
      • Björnsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ,

      Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-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(2):512–21.

      ,
      • Hoofnagle J.H.
      Drug-Induced Liver Injury Network (DILIN).
      ,
      • Sgro C.
      • Clinard F.
      • Ouazir K.
      • Chanay H.
      • Allard C.
      • Guilleminet C.
      • et al.
      Incidence of drug-induced hepatic injuries: a French population-based study.
      ] and Asian [
      • Takikawa H.
      • Murata Y.
      • Horiike N.
      • Fukui H.
      • Onji M.
      Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006.
      ] countries. Registry data have greatly improved knowledge regarding the etiologies, pathogenic mechanisms, and clinical outcomes of DILI [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ]. Patients enrolled in DILI registries are usually middle-aged women (mean age: 50 years) who require hospitalization. The clinical presentation is most often consistent with hepatocellular liver damage, followed by a cholestatic or mixed presentation. In population-based studies, the crude annual incidence of DILI has been reported as 19.1 cases per 100,000 inhabitants in Iceland [
      • Björnsson E.S.
      • Bergmann O.M.
      • Björnsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ], and 13.9 cases per 100,000 inhabitants in France [
      • Sgro C.
      • Clinard F.
      • Ouazir K.
      • Chanay H.
      • Allard C.
      • Guilleminet C.
      • et al.
      Incidence of drug-induced hepatic injuries: a French population-based study.
      ].
      Some routinely used drugs are more hepatotoxic than others. AMC, which has been associated with cholestatic liver injury, is the most frequently prescribed antimicrobial agent worldwide, with more than 70 million prescriptions each year in the United States alone. In a study of DILI in an Icelandic population, AMC was the most frequently implicated agent, with an estimated DILI risk of 1 case per 2350 AMC users. Using data from the DILIN database, Fontana [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ] showed that AMC was responsible for almost 120 cases of DILI each year. In contrast, isoniazid (INH), with fewer than 200,000 prescriptions per year, was responsible for 50 DILI cases per year. Therefore, INH seems to be more hepatotoxic than AMC. Patients treated with INH should have their aminotransferase levels checked after 15 days of therapy and monthly thereafter. An elevation of less than five-fold above the upper limit of normal (ULN) is typical and will often normalize without discontinuation of the drug. By contrast, in DILI registries such drugs as beta-blockers or calcium channel blockers, despite their large use among patients suffering from cardiovascular disease, are poorly responsible of DILI, probably due to their scarce hepatotoxicity. Statins, although rarely showed idiosyncratic liver injury, sometimes can be associated with severe outcome [
      • Navarro V.J.
      • Senior J.R.
      Drug-related hepatotoxicity.
      ,

      Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005;42(2):481–9

      ].
      Multifactorial mechanisms appear to underlie DILI [

      Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: interactions between drug properties and host factors. J. Hepatol. 2015 ;63(2):503–14

      ]. Drug-related risk factors include the drug's chemical features, dose, route, and duration of administration. Host-related risk factors include the patient's age, sex, genetics, previous episodes of DILI, and underlying chronic liver disease. Environmental risk factors include the patient's metabolic features (e.g., obesity), diet type, alcohol, coffee, and tobacco consumption, multidrug therapy, immune state (e.g., immunocompromised), and nutritional status [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ,

      Chen M, Suzuki A, Borlak J, Andrade RJ, Lucena MI. Drug-induced liver injury: interactions between drug properties and host factors. J. Hepatol. 2015 ;63(2):503–14

      ,
      • Ghabril M.
      • Chalasani N.
      • Björnsson E.
      Drug-induced liver injury: a clinical update.
      ] (Fig. 1). According to the international literature, women develop DILI more often than men, perhaps because women are the main consumers of herbal products. Polypharmacy is a frequent cause of ADRs and longer hospital stays in the elderly [
      • Nobili A.
      • Licata G.
      • Salerno F.
      • Pasina L.
      • Tettamanti M.
      • Franchi C.
      • et al.
      Polypharmacy, length of hospital stay, and in–hospital mortality among elderly patients in internal medicine wards. The Reposi study.
      ]. Aging results in a broad range of physiological changes that decrease the tolerability profile of drugs. In addition, cognitive disorders may worsen compliance to with multidrug therapy [
      • Mannucci P.M.
      NobiliA: Reposi investigators.
      ].
      Figure thumbnail gr1
      Fig. 1Pathogenesis of DILI is multifactorial and depends on complex interplay made by the interaction among drug, host and environmental factors. The multi-drug therapy and the immune compromised status are features mainly characterizing the elderly, which consequently become an “at risk condition” for ADRs.

      3. Clinical features and diagnosis of DILI: causality assessment systems

      Clinically, DILI represents a wide spectrum of diseases with diverse biochemical and histologic features. A clinical picture resembling acute hepatitis is the most common clinical presentation of acute liver disease of all etiologies and is pathognomonic of DILI. Other clinical features of hepatotoxicity may also be present, such as cholestatic hepatitis, nodular regeneration, cirrhosis, non-alcoholic fatty liver disease, veno-occlusive disease, and vanishing bile duct [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ]. Liver biopsy may support the clinical diagnosis when typical histopathologic findings are detected [
      • Suzuki A.
      • Brunt E.M.
      • Kleiner D.E.
      • et al.
      The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.
      ]. However, histologic evaluation is infrequently performed in favor of Fibroscan®, and DILI patterns are often defined through biochemical data alone. Due to the lack of pathognomonic features or specific diagnostic criteria, there is no consensus regarding adequate terminology for defining the various clinical patterns of DILI.
      Consensus criteria for a diagnosis of DILI [
      • Aithal G.P.
      • Watkins P.B.
      • Andrade R.J.
      • Larrey D.
      • Molokhia M.
      • Takikawa H.
      • et al.
      Case definition and phenotype standardization in drug-induced liver injury.
      ] include a chronological relationship between drug intake and hepatitis onset, as well as the presence of any one of the following conditions: an alanine aminotransferase (ALT) level of more than five-fold above the ULN; an alkaline phosphatase (ALP) level of more than two-fold above the ULN; or an ALT level of more than three-fold above the ULN, with the simultaneous elevation of bilirubin levels to more than two-fold above the ULN. The liver injury pattern can be assessed by the R value, where R = (ALT/ULN)/(ALP/ULN), with R ≥ 5 reflecting a hepatocellular pattern, 2 < R < 5 reflecting a mixed pattern, and R ≤ 2 reflecting a cholestatic pattern of liver injury.
      Although many patients with mild liver damage are diagnosed in the outpatient clinic, those with severe liver injury commonly require hospitalization and, occasionally, intensive care as a bridge to liver transplantation. The hepatocellular pattern of liver injury exposes patients to a risk of ALF. Hy's rule [
      • Zimmerman H.J.
      Hepatotoxicity. The adverse effects of drugs and other chemicals on the liver.
      ] predicts a mean rate of mortality (or liver transplantation, as a surrogate marker) of 10% for jaundiced patients with acute hepatocellular damage. This rule, originally observed by Zimmerman, was recently confirmed in at least two studies [

      Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-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(2):512–21.

      ,

      Björnsson E, Olsson R. Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005;42(2):481–9

      ]. These studies identified additional variables, such older age, female sex, and AST levels, to be independently associated with poor outcome. APAP, halothane, and cocaine toxicity, as well as mushroom poisoning, typically result in acute or subacute liver failure. Toxicity by NSAIDs, such as diclofenac and nimesulide, results in massive necrosis.
      Patients with cholestatic liver damage usually present with jaundice and itching. The canalicular pattern is characterized by an increase in conjugated bilirubin, ALP, and γ-glutamyltranspeptidase levels, with minimal to no elevation of aminotransferase levels. Steroids typically produce this pattern of hepatotoxicity. The mixed pattern of liver damage resembles features of hepatocanalicular damage, recalling acute biliary obstruction. Hypersensitivity features sometimes occur and are important clues to aid in the diagnosis. Typical examples of drugs that cause mixed liver damage are AMC, macrolides, neuroleptics, and similar compounds [
      • Andrade R.
      • Robles M.
      • Fernández-Castañer A.
      • López-Ortega S.
      • López-Vega M.C.
      • Lucena M.I.
      Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.
      ].
      From a nosographic perspective, there is a propensity to try to distinguish the various patterns of liver damage and to associate specific drugs with each pattern. However, it is not always possible to make such associations. The clinical pattern of hepatotoxicity may vary depending on the interaction between drug factors (e.g., dose, bioavailability, and duration of treatment) and host factors (e.g., age, sex, and drug absorption). For example, AMC frequently causes acute cholestasis or cholestatic hepatitis in men over 65 years old, whereas a mixed pattern is more likely in younger patients [
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug induced liver injury in the United States.
      ]. Nimesulide, an NSAID that is commonly used for osteoarticular pain relief, can cause hepatocellular damage in young women, sometimes leading to ALF requiring liver transplantation. In men, however, cholestatic liver damage is more frequently observed [
      • Van Steenbergen W.
      • Peeters P.
      • De Bondt J.
      • Staessen D.
      • Büscher H.
      • Laporta T.
      • et al.
      Nimesulide-induced acute hepatitis: evidence from six cases.
      ] (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Pattern of liver damage is not always the same with a given drug. For example, AMC frequently causes acute cholestasis or cholestatic hepatitis in men over 65 years old, whereas a mixed pattern is more likely in younger. Nimesulide causes hepatocellular damage in young women, sometimes leading to ALF requiring liver transplantation. In men cholestatic liver damage is more frequently observed.
      DILI is largely diagnosed through a detailed clinical history, biochemical tests, hepatobiliary imaging, and liver biopsy [
      • Chalasani N.
      • Hayashi P.H.
      • Bonkovsky H.L.
      • Navarro V.J.
      • Lee W.M.
      • Fontana R.J.
      • et al.
      Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.
      ]. Some diagnostic algorithms are available, such as the Roussel Uclaf causality assessment method (RUCAM) [
      • Danan G.
      • Benichou C.
      Causality assessment of adverse reactions to drugs — I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.
      ,
      • Benichou C.
      • Danan G.
      • Flahault A.
      Causality assessment of adverse reactions to drugs — II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.
      ] and the Maria & Victorino assessment method. RUCAM scores employ the temporal relationship between drug intake and clinical presentation (latency), the clinical course after drug discontinuation (dechallenge), and the response upon rechallenge. The Maria & Victorino assessment score [
      • Maria V.A.
      • Victorino R.M.
      Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis.
      ] subsequently published adds to the parameters the exclusion of alternative causes of liver injury and the coexistence of extrahepatic and immune-allergic manifestations (e.g., fever, rash, arthralgia, eosinophilia). Hepatotoxicity causality assessment scores show low concordance with each other, because they assign different weights to each criterion. The clinical utility of RUCAM results from the topics that it requires the clinician to addressed in cases of suspected hepatotoxicity, which improve the consistency of clinical judgment [
      • Lucena M.I.
      Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity.
      ].

      4. Drugs frequently involved in DILI

      Almost any class of drug can be involved in idiosyncratic DILI. Nonetheless, in the United States, antimicrobials and antidepressant/antipsychotics are the most commonly implicated drug classes, followed by NSAIDs, antiplatelet agents, statins, and HDS [
      • Chalasani N.
      • Hayashi P.H.
      • Bonkovsky H.L.
      • Navarro V.J.
      • Lee W.M.
      • Fontana R.J.
      • et al.
      Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.
      ]. Since 2000, we have followed a prospective cohort of consecutive DILI patients at our tertiary referral center. This cohort primarily consists of women (54%), with a mean age of 54 years. We reported that almost 25% of patients in the DILI cohort had preexisting compensated chronic liver disease. A hepatocellular pattern was observed in 53% of cases, followed by cholestatic (27%) and mixed patterns (20%). The most frequently involved drugs were NSAIDs (~40%), followed by antibiotics, immunosuppressants, antiplatelet agents, antidiabetic drugs, and statins. In the 24% of DILI cases, two or more drugs were involved [
      • Licata A.
      • Butera G.
      • Maida M.
      • Calvaruso V.
      • Cappello M.
      • Craxì A.
      • et al.
      Drug-induced liver inujry: the impact of non steroidal anti-inflammatory drugs (NSAIDS).
      ] (see Table 1 and Fig. 3). Nimesulide was the most commonly implicated NSAID, responsible for hepatocellular DILI in women and the cholestatic/mixed type in men [
      • Van Steenbergen W.
      • Peeters P.
      • De Bondt J.
      • Staessen D.
      • Büscher H.
      • Laporta T.
      • et al.
      Nimesulide-induced acute hepatitis: evidence from six cases.
      ,
      • Licata A.
      • Calvaruso V.
      • Cappello M.
      • Craxì A.
      • Almasio P.L.
      Clinical course and outcomes of drug-induced liver injury: nimesulide as the first implicated medication.
      ]. Among antibiotics, we reported the impact of AMC-induced [
      • Licata A.
      • Randazzo C.
      • Butera G.
      • Calvaruso V.
      • Calì A.
      • Cappello M.
      • et al.
      Pattern of drug induced liver injury: the impact of amoxicillin–clavulanate on severity of clinical course.
      ] and fluoroquinolone-induced [
      • Licata A.
      • Randazzo C.
      • Morreale I.
      • Butera G.
      • D'Alessandro N.
      • Craxì A.
      Fluoroquinolone-induced liver injury: three new cases and a review of the literature.
      ] liver injury.
      Table 1Clinical features of 157 patients with drug induced liver injury seen at our tertiary referral center: the impact of NSAIDs.
      NSAIDs (n = 61)Other drugs (n = 96)p
      Age (years)48.1 ± 18.455.1 ± 17.60.02
      Duration of drug intake (days)11.2 ± 24.660.1 ± 114.2<0.001
      Latency (weeks)29.2 ± 16.257.1 ± 90.60.02
      Hepatic encephalopathy at diagnosis5 (8.2%)1 (1.1%)0.02
      Pattern of DILI
       Hepatocellular42 (68.8%)41 (42.7%)0.006
       Cholestatic11 (18.0%)32 (33.3%)
       Mixed8 (13.2%)23 (24.0%)
      ALT (IU/L)744.2 ± 755.7427.6 ± 512.20.02
      Eosinophils (%)1.9 ± 1.93.1 ± 4.20.02
      Stiffness (KPa)9.4 ± 6.611.3 ± 8.40.6
      Figure thumbnail gr3
      Fig. 3Drugs commonly involved as causes of drug induced liver injury in a cohort of 157 patients prospectively followed at our tertiary referral center.
      From our prospectively followed DILI cohort, we recently identified a small group of 12 patients who had drug-induced autoimmune hepatitis (DIAIH). Liver biopsy specimens from these patients featured severe portal inflammation and lymphoplasmacytic infiltrates. Despite their briefer drug exposure period compared to DILI patients, DIAIH patients displayed higher aminotransferase and γ-globulin values [
      • Licata A.
      • Maida M.
      • Cabibi D.
      • Butera G.
      • Macaluso F.S.
      • Alessi N.
      • et al.
      Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.
      ]. These data support the importance of correctly distinguishing between DIAIH and DILI, and emphasize the key role of liver biopsy in the diagnosis, prognosis, and follow-up of affected patients [
      • Suzuki A.
      • Brunt E.M.
      • Kleiner D.E.
      • et al.
      The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury.
      ,
      • Licata A.
      • Maida M.
      • Cabibi D.
      • Butera G.
      • Macaluso F.S.
      • Alessi N.
      • et al.
      Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.
      ].

      5. APAP-induced liver injury

      APAP-induced hepatotoxicity represents one of the best examples of predictive DILI, causing rapid liver injury in the centrilobular region [
      • Lee W.M.
      Drug-induced hepatotoxicity.
      ]. Liver damage can be intentional (e.g., attempted suicide) or accidental (e.g., inadvertent drug intake in excess of the intended dose over several days). APAP is widely used as an analgesic and is available in many nonprescription and prescription products, including in combination with opioids [
      • Doyon S.
      • Klein-Schwartz W.
      Hepatotoxicity despite early administration of intravenous N-acetylcysteine for acute acetaminophen overdose.
      ]. For this reason, APAP overdose is the most common cause of ALF and death due to analgesics [
      • Craig D.G.
      • Lee A.
      • Hayes P.C.
      • Simpson K.J.
      Review article: the current management of acute liver failure.
      ,
      • Bronstein A.C.
      • Spyker D.A.
      • Cantilena Jr., L.R.
      • Green J.L.
      • Rumack B.H.
      • Giffin S.L.
      Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th annual report.
      ] in Anglo-Saxon countries, with over 500 deaths per year in the United States. The inappropriate use of APAP results in 78,000 visits to the emergency room annually, at an annual cost of more than $86 million [
      • Larson A.M.
      • Polson J.
      • Fontana R.J.
      • Davern T.J.
      • Lalani E.
      • Hynan L.S.
      • et al.
      Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.
      ,
      • Budnitz D.S.
      • Lovegrove M.C.
      • Crosby A.E.
      Emergency department visits for overdoses of acetaminophen containing products.
      ].
      Patients presenting to the emergency room with a report of APAP ingestion are assessed for treatment with N-acetyl cysteine (NAC), which is effective in most cases if given early. Onset of liver damage can only be prevented within about 8 to 10 h of APAP ingestion. Thus, the time to NAC administration is the most relevant factor in preventing injury by APAP. A careful medical history, clarifying the quantity ingested, the blood concentration of APAP, and the extreme values of ALT (up to 3000 UI/L), help clinicians to differentiate between APAP poisoning and other causes of ALF (e.g., viral hepatitis, ischemia) [
      • Lee W.M.
      Drug-induced hepatotoxicity.
      ]. There are limitations to the use of ALT as a biomarker for assessing patient status after APAP ingestion. Although serum ALT levels are elevated as a rule, they may take more than 72 h to peak. For the best outcome, NAC should be administered as soon as possible after APAP ingestion, while promptly diagnosing the patient.
      Recently, Ward et al. [
      • Ward J.
      • Kanchagar C.
      • Veksler-Lublinsky I.
      • Lee R.C.
      • McGill M.R.
      • Jaeschke H.
      • et al.
      Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.
      ] identified a set of 11 small, noncoding microRNAs (miRNAs) whose profiles and dynamics can discriminate APAP hepatotoxicity from ischemic acute hepatitis. Wang et al. [
      • Wang K.
      • Zhang S.
      • Marzolf B.
      • Troisch P.
      • Brightman A.
      • Hu Z.
      • et al.
      Circulating microRNAs, potential biomarkers for drug-induced liver injury.
      ] demonstrated that, in mice overdosed with APAP, blood levels of miRNA 122 and 192 were increased. The same miRNAs were subsequently detected in human plasma as well [
      • Starkey Lewis P.J.
      • Dear J.
      • Platt V.
      • Simpson K.J.
      • Craig D.G.
      • Antoine D.J.
      • et al.
      Circulating microRNAs as potential markers of human drug-induced liver injury.
      ].
      Although dose is a predictor of outcome in patients with APAP toxicity, the actual toxic dose remains unclear [
      • Duffull S.B.
      • Isbister G.K.
      Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.
      ]. Most international guidelines recommend 200 mg/kg or 10 g as the toxic dose. Currently, the gold standard for starting NAC therapy is a single serum APAP concentration above the nomogram between 4 and 24 h from ingestion [
      • Daly F.F.
      • Fountain J.S.
      • Murray L.
      • Graudins A.
      • Buckley N.A.
      Panel of Australian and New Zealand clinical toxicologists. Guidelines for the management of paracetamol poisoning in Australia and New Zealand — explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres.
      ]. A recently published Australian study on patients presenting with APAP overdose at a tertiary referral center showed that the median dose of APAP ingested was 10 g among 1303 patients (1140 women, median age of 27 years). In 22% of patients, the APAP concentration was above the nomogram line. For many years, guidelines for patients presenting with APAP overdose within 8 h of ingestion recommended a “wait and see” approach while testing the serum APAP concentration. However, current guidelines suggest that more than 90% of patients with a reported dose greater than 50 g will require treatment with NAC. Therefore, NAC should be started immediately in these patients [
      • Duffull S.B.
      • Isbister G.K.
      Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.
      ].
      Finally, ALF due to APAP toxicity has a better overall survival rate (70%) compared to ALF due to DILI by other drugs (58%), despite the initial severity of APAP overdose. This phenomenon could be due to the rapid evolution of the clinical course, which also induces rapid hepatocyte regeneration and, thus, resolution of liver damage [
      • Chalasani N.
      • Hayashi P.H.
      • Bonkovsky H.L.
      • Navarro V.J.
      • Lee W.M.
      • Fontana R.J.
      • et al.
      Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.
      ,
      • Reuben A.
      • Koch D.G.
      • Lee W.M.
      Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study.
      ].

      6. Pathogenic mechanisms of DILI

      After biotransformation by the cytochrome P450 system, a drug can become an active metabolite that is less toxic, more hydrophilic, and ready to be eliminated. Subsequently, UDP-glucuronosyltransferase, sulfotransferase, and glutathione-S-transferase hydrolyze the metabolite. Transport of the metabolite out of hepatocytes is mediated by the ATP binding cassette (ABC) transporter superfamily [
      • Moitra K.
      • Dean M.
      Evolution of ABC transporters by gene duplication and their role in human disease.
      ]. In general, drugs can either directly affect hepatocytes/cholangiocytes or elicit an innate or adaptive immune reaction [
      • Lee W.M.
      Drug-induced hepatotoxicity.
      ]. In most cases bioactivation of a drug leads to a reactive metabolite that causes mitochondrial dysfunction, cytoskeletal breakdown, and cell membrane disruption. In other cases, however, bioactivation can influence the transport of proteins (e.g., MDR-3), resulting in an interruption of bile flow and bilirubin excretion, causing cholestasis [
      • Yun C.H.
      • Okerholm R.A.
      • Guengerich F.P.
      Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation.
      ,
      • Beaune P.
      • Dansette P.M.
      • Mansuy D.
      • Kiffel L.
      • Finck M.
      • Amar C.
      • et al.
      Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug.
      ,
      • Trauner M.
      • Meier P.J.
      • Boyer J.L.
      Molecular pathogenesis of cholestasis.
      ].
      As an alternative to direct action, hepatocyte stress results in the activation of the innate immune system through natural killer cells of the liver, which kill cells through the Fas/Fas ligand pathway. Kupffer cells contribute to the progression of liver damage by producing proinflammatory mediators, cytokines, and chemokines, mediating cytotoxicity by degrading the extracellular matrix, and promoting cell adhesion and leukocyte infiltration. This mechanism, commonly known as apoptosis, is considered a non- or low-inflammatory process, due to the rapid removal of apoptotic cells [
      • Luedde T.
      • Kaplowitz N.
      Schwabe RFCell death and cell death responses in liver disease: mechanisms and clinical relevance.
      ]. The adaptive immune system is also involved in the pathogenesis of liver damage. If an active metabolite is able to act as a hapten and covalently bind host proteins, then the immune system will perceive the metabolite as foreign, triggering an inappropriate T-cell response [

      Festjens N, Vanden Berghe T, Vandenabeele P. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response. Biochim. Biophys. Acta 2006;1757(9-10):1371–87

      ]. This necrotic process is the type of liver damage observed after APAP hepatotoxicity. A third form of cell death, necroptosis, incorporates features of both necrosis and apoptosis [
      • Linkermann A.
      • Green D.R.
      Necroptosis.
      ]. Necroptosis is better characterized in the setting of TNF-induced cell death (e.g., patients with acute hepatocellular DILI), although it may also occur in acutely developing conditions, such as ischemia-reperfusion injury.

      7. Biomarkers of DILI

      Currently, there are no clearly identified biomarkers of DILI that are useful for monitoring patients on drug therapy for early detection of hepatotoxicity or for making an appropriate diagnosis. Traditionally, ALT, ALP, and total bilirubin levels have been used clinically to identify the various types of DILI. However, patterns of liver injury may be categorized by the pathological conditions and underlying events, such apoptosis, necrosis, and necroptosis, inflammation, oxidative stress, and immune system activation, all of which contribute to liver injury.
      Studies have recently proposed candidate biomarkers for liver injury and mitochondrial dysfunction, all of which are related to the potential mechanisms involved in DILI pathogenesis. Not all of these biomarkers are used clinically [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ,
      • Luedde T.
      • Kaplowitz N.
      Schwabe RFCell death and cell death responses in liver disease: mechanisms and clinical relevance.
      ] (Table 2). For example, cytokines T helper (Th) 1-type (IL-12, IFN-γ, IL-2, IL15) and Th2-type (IL-4, IL-5, IL-13) are usually activated in response to acute immune stimuli. If the inflammatory state does not resolve, then chronic inflammation could evolve into an adaptive immune response, with activation of Th17/Th9 cell types, resulting in a poor prognosis [
      • Steuerwald N.M.
      • Foureau D.M.
      • Norton H.J.
      • Zhou J.
      • Parsons J.C.
      • Chalasani N.
      Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance.
      ]. Recently, miRNA 122 and miRNA 192 have emerged as liver-specific biomarkers in DILI. Levels of these miRNAs parallel ALT levels during hepatotoxicity, increasing early in the course of liver damage. These miRNAs may have prognostic significance in patients with ALF after APAP overdose [
      • Wang K.
      • Zhang S.
      • Marzolf B.
      • Troisch P.
      • Brightman A.
      • Hu Z.
      • et al.
      Circulating microRNAs, potential biomarkers for drug-induced liver injury.
      ]. Another group of biomarkers includes molecules related to the apoptotic and/or necrotic process [
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ,
      • Rutherford A.E.
      • Hynan L.S.
      • Borges C.B.
      • Forcione D.G.
      • Blackard J.T.
      • Lin W.
      • et al.
      Serum apoptosis markers in acute liver failure: a pilot study.
      ,
      • Chung R.T.
      • Stravitz R.T.
      • Fontana R.J.
      • Schiodt F.V.
      • Mehal W.Z.
      • Reddy K.R.
      • et al.
      Pathogenesis of liver injury in acute liver failure.
      ]. Finally, an emerging area being studied for biomarkers in patients with DILI is proteomics, with studies examining both serum and urine [
      • Bell L.N.
      • Vuppalanchi R.
      • Watkins P.B.
      • Bonkovsky H.L.
      • Serrano J.
      • Fontana R.J.
      • et al.
      Serum proteomic profiling in patients with drug-induced liver injury.
      ].
      Table 2Established and emerging biomarkers associated with acute and chronic liver damage (modified from Fontana
      • Fontana R.J.
      Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspective.
      ).
      MarkerPattern of injuryDisease
      Liver injury biomarkers
      ALT, AST, AP bilirubinAcute and chronic liver injuryAll liver disease, hepatitis, viral and autoimmune, NASH, NAFLD
      Sorbitol dehydrogenaseAcute liver injuryAcute liver disease
      Glutatione S-transferaseLiver and kidney injury (mitochondrial damage)Chronic liver disease
      Glutamate dehydrogenaseChronic liver injuryChronic liver disease
      Serum cytokines pattern
       Th 1 (IL-2, IFNγ, IL-12,IL-15)Acute liver injuryAcute liver disease
       Th2 (IL-4, IL-5, IL-13)Acute liver injuryAcute liver disease
       Th9/Th17Chronic liver injuryChronic liver disease
      miRNAs
      miR-122Acute and chronic liver injuryAPAP overdosing
      miR-192Acute and chronic liver injuryAPAP overdosing
      Cell death biomarkers
      HMGB-1 (High mobility group box1)Acute liver injury (Necrosis)APAP overdosing
      Cytokeratin (CK) 18 fragmentsAcute and chronic liver injuryALD, NASH, viral hepatitis
      M-30Acute liver injury (Apoptosis)Acute liver failure
      M-65Acute liver injury (total hepatocytes death)Acute liver failure
      Proteomics biomarkers
      Fructose biphosphonate aldolase B, apolipoprotein E, apolipoprotein AAcute and chronic liver injuryAcute and chronic liver disease

      8. Pharmacogenetic impact of DILI

      Susceptibility to drugs depends on the presence of genetic variations among gene classes, such as those involved in drug disposition/transport, cellular stress, and inflammatory and immune response genes, including the human leukocytes antigen (HLA) system [
      • Andrade R.J.
      • Robles M.
      • Ulzurrun E.
      • Lucena M.I.
      Drug-induced liver injury: insights from genetic studies.
      ,
      • Daly A.K.
      Drug-induced liver injury: past, present and future.
      ]. Different drugs may share specific genetic susceptibility variants [
      • Lucena M.I.
      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • Garcia-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry. The dilemma of the relationship to autoimmune hepatitis.
      ]. Furthermore, as some patients experience multiple DILI episodes caused by different drugs, there may exist a subgroup of individuals that is predisposed to DILI [
      • Lucena M.I.
      • Kaplowitz N.
      • Hallal H.
      • Castiella A.
      • Garcia-Bengoechea M.
      • Otazua P.
      • et al.
      Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry. The dilemma of the relationship to autoimmune hepatitis.
      ]. Because genetic susceptibility is an important feature of severe ADRs [
      • Wilke R.
      • Lin D.W.
      • Roden D.
      • Watkins P.B.
      • Flockhart D.
      • Zineh I.
      • et al.
      Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges.
      ,
      • Becquemont L.
      Pharmacogenomics of adverse drug reactions: practical applications and perspectives.
      ], there is a growing interest in developing genetic tests to identify people at risk for adverse events before prescription.
      The success of genome-wide association studies (GWAS) in identifying susceptibility genes for polygenic diseases [
      • Wellcome Trust Case Control Consortium
      Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls.
      ] has led to an interest to applying GWAS to serious ADRs [
      • Daly A.
      Using genome-wide association studies to identify genes important in serious adverse drug reactions.
      ]. In general, GWAS are particularly suitable for detecting small effects. However, the small number of analyzed cases limits the ability of GWAS to detect significant effects [
      • Urban T.J.
      • Shen Y.
      • Stolz A.
      • Chalasani N.
      • Fontana R.J.
      • Rochon J.
      • et al.
      Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs.
      ]. To overcome this limitation, large networks have been established in the United States and Europe, facilitating recruitment of patients with DILI [
      • Hoofnagle J.H.
      Drug-Induced Liver Injury Network (DILIN).
      ,
      • Molokhia M.
      • McKeigue P.
      EUDRAGENE: European collaboration to establish a case–control DNA collection for studying the genetic basis of adverse drug reactions.
      ].

      8.1 HLA, immune response, and DILI susceptibility

      A traditional example of HLA association with idiosyncratic DILI is represented by halothane, a general anesthetic that was an important cause of acute hepatitis in the operation room. Previous studies have described associations between HLA genes and liver damage caused by halothane [
      • Otsuka S.
      • Yamamoto M.
      • Kasuya S.
      • Ohtomo H.
      • Yamamoto Y.
      • et al.
      HLA antigens in patients with unexplained hepatitis followinghalothaneanesthesia.
      ], diclofenac, and/or chlorpromazine [

      Berson A, Freneaux E, Larrey D, Lepage V, Douay C, Mallet C, et al. Possible role of HLA in hepatotoxicity — an exploratory study in 71 patients with drug-induced idiosyncratic hepatitis. J. Hepatol.1994, 20:336–342.

      ]. More recently, a study of the HLA genotyping has been carried out on patients with AMC-related DILI. Although this form of DILI usually does not manifest typical immune-related features, an association with the HLADRB1*15:01 allele was reported [
      • O'Donohue J.
      • Oien K.A.
      • Donaldson P.
      • Underhill J.
      • Clare M.
      • MacSween R.M.
      MillsPR: co-amoxiclav jaundice: clinical and histological features and HLA classII association.
      ]. Subsequent studies using candidate genes and GWAS methods identified multiple HLA class I and II associations [
      • Lucena M.I.
      • Molokhia M.
      • Shen Y.
      • Urban T.J.
      • Aithal G.P.
      • Andrade R.J.
      • et al.
      Susceptibility to amoxicillin–clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
      ]. In our study of 12 patients with DIAIH, we identified a genetic susceptibility to nimesulide and other xenobiotics [
      • Licata A.
      • Maida M.
      • Cabibi D.
      • Butera G.
      • Macaluso F.S.
      • Alessi N.
      • et al.
      Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.
      ], supporting the hypothesis of an autoimmune pathogenesis in these patients (Table 3). Recently, the concept that HLA alleles are risk factors for flucloxacillin-, ximelagatran-, and lumiracoxib-induced liver injury [
      • Monshi M.
      • Faulkner L.
      • Gibson A.
      • Jenkins R.E.
      • Farrell J.
      • Earnshaw C.J.
      • et al.
      HLA B*57:01 restricted activation of drug-specific T-cells provides the immunological basis for flucloxacillin-induced liver injury.
      ,
      • Kindmark A.
      • Jawaid A.
      • Harbron C.G.
      • Barratt B.J.
      • Bengtsson O.F.
      • Andersson T.B.
      • et al.
      Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis.
      ,
      • Singer J.B.
      • Lewitzky S.
      • Leroy E.
      • Yang F.
      • Zhao X.
      • Klickstein L.
      • et al.
      A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury.
      ] has become more widely accepted. Hepatotoxicity arising from these agents appears to involve the immune system, with DILI resulting from inappropriate T-cell responses, possibly due to skewing of the T-cell repertoire [
      • Illing P.T.
      • Vivian J.P.
      • Dudek N.L.
      • Kostenko L.
      • Chen Z.
      • Bharadwaj M.
      • et al.
      Immune self-reactivity triggered by drug-modified HLA peptide repertoire.
      ,
      • Ostrov D.A.
      • Grant B.J.
      • Pompeu Y.A.
      • Sidney J.
      • Harndahl M.
      • Southwood S.
      • et al.
      Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire.
      ,
      • Daly A.
      Pharmacogenomics of adverse events.
      ].
      Table 3HLA and non-HLA genes associated with drug induced liver injury (DILI) (modified from Daly
      • Daly A.
      Pharmacogenomics of adverse events.
      ).
      HLA associated genes
      Pattern of reactionDrugsHLA loci
      LiverHepatocellular/Cholestatic typeAmoxicillin–clavulanateDRB1*1501-DQB1*0602 A*0201
      Cholestatic typeFlucloxacillinB*5701
      Hepatocellular typeXimelagatranDRB1*0701-DQA1*0201
      Cholestatic typeTiclopidineA*3303
      Cholestatic typeLumiracoxibDRB1*1501-DQB1*0602
      Hepatocellular/Mixed typeNimesulideDRB1*0708-DQB1*0204 DRB1*0713-DQB1*0206
      Hepatocellular typeKetoprofenDRB1*0413-DQB1*0306
      Hepatocellular typeGreen TeaDRB1*0103-DQB1*0205
      Non-HLA associated genes
      Drug metabolism and transporters (ATP binding cassette)Liver injuryPhase II
      IsoniazidNAT2
      DiclofenacUGT2B7
      UGT1A
      Myopathy/Liver injurySimvastatinTransporters SLCO1B1
      Liver injuryDiclofenacABCB11 ABCC2
      Hepatocellular1549
      Cholestatic1774
      Immune and inflammatory systemLiver injuryDiclofenacIL-4 C590A
      IL-10 C627A
      Liver injuryAnti tubercular drugsIL-6
      Liver injuryAmoxicillin–clavulanateSTAT-4
      FlucloxacillinSTAT3
      Anti tubercular drugsST6GAL1
      A few studies have investigated the association between cytokine genetic polymorphisms and the risk of DILI. In 2004, Aithal [
      • Aithal G.P.
      • Ramsay L.
      • Daly A.K.
      • Sonchit N.
      • Leathart J.B.
      • Alexander G.
      • et al.
      Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity.
      ] reported that the frequencies of variant alleles for interleukin (IL)-10 and IL-4 were significantly higher in patients with diclofenac-induced liver damage compared to subjects who received diclofenac but did not develop hepatitis. Liang et al. [
      • Liang X.
      • Zhang J.
      • Zhu Y.
      • Lu Y.
      • Zhou X.
      • Wang Z.
      • et al.
      Specific genetic polymorphisms of IL10–592 AA and IL10–819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients.
      ] showed that IL-10–592 AA and IL-10–819 TT genotypes significantly increased the incidence of DILI in breast cancer patients. However, another study failed to confirm these results [
      • Pachkoria K.
      • Lucena M.I.
      • Crespo E.
      • Ruiz-Cabello F.
      • Lopez-Ortega S.
      • Fernandez M.A.
      • et al.
      Analysis of IL-10, IL-4 and TNF-alpha polymorphisms in drug-induced liver injury (DILI) and its outcome.
      ]. Nonetheless, it seems that cytokine genetic polymorphisms are biologically likely risk factors that may contribute to the risk of DILI, given that polymorphisms for IL-6, STAT3, and HSPA1L confer a higher risk of developing hepatotoxicity from antitubercular drugs [
      • Wang J.
      • Chen R.
      • Tang S.
      • Lv X.
      • Wu S.
      • Zhang Y.
      • et al.
      Analysis of IL-6, STAT3 and HSPA1L gene polymorphisms in anti-tuberculosis drug-induced hepatitis in a nested case–control study.
      ].
      GWAS of DILI have failed to identify novel single-nucleotide polymorphisms (SNPs) in HLA genes showing strong effects [
      • Urban T.J.
      • Shen Y.
      • Stolz A.
      • Chalasani N.
      • Fontana R.J.
      • Rochon J.
      • et al.
      Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs.
      ]. However, further analysis of data obtained from patients with DILI induced by flucloxacillin [
      • 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.
      ] showed that patients with HLA-B*57:01 have a significant association with a SNP close to ST6GAL1, a gene contributing to B-cell activation responses [
      • Nasirikerani M.
      • Segal B.H.
      • Ostberg J.R.
      • Urbasic A.
      • Lau J.
      • et al.
      Altered granulopoietic profile and exaggerated acute neutrophilic inflammation in mice with targeted deficiency in the sialyltransferase ST6gGal1.
      ]. Moreover, Lucena et al. [
      • Lucena M.I.
      • Molokhia M.
      • Shen Y.
      • Urban T.J.
      • Aithal G.P.
      • Andrade R.J.
      • et al.
      Susceptibility to amoxicillin–clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
      ] showed a significant association for a SNP in the STAT4 gene in their examination of DILI cases. STAT4 triggers activation of IL-12 and IL-23 signaling during T-cell responses [
      • Korman B.D.
      • Kastner D.L.
      • Gregersen P.K.
      • Remmers E.F.
      STAT4: genetics, mechanisms, and implications for autoimmunity.
      ]. This SNP has been previously associated with other autoimmune diseases, representing another likely risk factor for DILI.

      8.2 Drug disposition and transporter gene susceptibility

      A polymorphism of the N-acetyltransferase-2 (NAT-2) gene represents a well-known example of a genetic predisposition to DILI. NAT-2 is the enzyme responsible for the metabolism of INH. Several studies have reported that patients who are slow acetylators (i.e., homozygous for both NAT-2 alleles) completely lack enzyme activity and, therefore, are at risk for developing liver injury [
      • Metushi I.G.
      • Cai P.
      • Zhu X.
      • Nakagawa T.
      • Uetrecht J.P.
      A fresh look at the mechanism of isoniazid-induced hepatotoxicity.
      ]. However, being a slow acetylator is not sufficient [
      • Daly A.K.
      • Day C.P.
      Genetic association studies in drug-induced liver injury.
      ] to cause the toxicity, because many of the patients analyzed showed only mild increases of aminotransferase levels. These elevations resolved easily after transient drug withdrawal and usually did not recur when INH therapy resumed.
      Transporter genes in the ABC superfamily are biologically reasonable candidates for genetic susceptibility to DILI [
      • Geier A.
      • Wagner M.
      • Dietrich C.G.
      • Trauner M.
      Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration.
      ]. Some inherited forms of cholestasis result from specific mutations in the ABCB4 (MDR3) and ABCB11 (BSEP) genes [
      • Noe J.
      • Kullak-Ublick G.A.
      • Jochum W.
      • Stieger B.
      • Kerb R.
      • Haberl M.
      • et al.
      Impaired expression and function of the bile saltexport pump due to three novel ABCB11 mutations in intrahepaticcholestasis.
      ]. In addition, a great deal of evidence correlates cholestatic liver injury from diverse drugs to the presence of a polymorphism in the ABCB11 gene, which is also associated with intrahepatic cholestasis of pregnancy [
      • Lang C.
      • Meier Y.
      • Stieger B.
      • Beuers U.
      • Lang T.
      • Kerb R.
      • et al.
      Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug induced liver injury.
      ]. The ABCC2 (MRP2) gene has an important role in the biliary excretion of diverse glucuronide conjugates. Daly et al. [
      • Daly A.K.
      • Aithal G.P.
      • Leathart J.B.
      • Swainsbury R.A.
      • Dang T.S.
      • Day C.P.
      Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes.
      ] reported that a polymorphism in ABCC2 (C24T) was common among patients with diclofenac-induced liver injury. This result was consistent with the increased levels of active metabolites of diclofenac, largely toxic, in the absence of the polymorphism C24T, which results in low production of the MRP2 protein and, thus, the accumulation of the glucuronide. However, two polymorphisms of ABCC2 have been identified, one −1549 in linkage disequilibrium with C-24T, already known risk factor for hepatocellular liver injury, and a second at −1774 of ABCC2, which indeed is a risk factor for cholestatic and mixed liver damage [
      • Choi J.H.
      • Ahn B.M.
      • Yi J.
      • Lee J.H.
      • Nam S.W.
      • Chon C.Y.
      • et al.
      MRP2 haplotypes confer differential susceptibility to toxic liver injury.
      ].
      There are reports of associations between the UGT genotype and DILI. UGT2B7*2 is associated with an increased susceptibility to diclofenac-related DILI. The pathogenic mechanism could be due to high levels of the metabolite, diclofenac acylglucuronide [
      • Daly A.K.
      • Aithal G.P.
      • Leathart J.B.
      • Swainsbury R.A.
      • Dang T.S.
      • Day C.P.
      Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes.
      ].
      Statins are the most commonly prescribed agents for lowering low-density lipoprotein cholesterol levels, because of their excellent tolerability and safety. However, in some individuals, statins can cause liver and muscle damage, as evidenced by increased levels of aminotransferase and creatine-phosphokinase. These elevations are promptly reversed on drug discontinuation. Although typically asymptomatic, the increased levels can also become severe, leading to rhabdomyolysis [
      • Dalakas M.C.
      Toxic and drug-induced myopathies.
      ]. A GWAS involving simvastatin-induced myopathy cases identified an SNP in SLCO1B1. This gene encodes a transporter, organic anion transporting polypeptide-1 (OATP1B1), which is responsible for the transport of statins and other drugs from the bloodstream into the cell [
      • Link E.
      • Parish S.
      • Armitage J.
      • Bowman L.
      • Heath S.
      • Matsuda F.
      • et al.
      SLCO1B1 variants and statin-induced myopathy — a genome wide study.
      ]. The association between SLCO1B1 and statin-induced myopathy was subsequently confirmed [
      • Voora D.
      • Shah S.H.
      • Spasojevic I.
      • Ali S.
      • Reed C.R.
      • Salisbury B.A.
      • et al.
      The SLCO1B1*5 genetic variant is associated with statin-induced side effects.
      ]. Because the overall contribution of SLCO1B1 to hepatic transport is likely to vary across statins, the contribution of the SLCO1B1*5 polymorphism may vary among different statins [
      • Niemi M.
      Transporter pharmacogenetics and statin toxicity.
      ].

      Learning points

      • An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. It is the most common cause of ALF in western countries.
      • Almost all drug classes can be involved in idiosyncratic DILI. Antimicrobials, antidepressant/antipsychotics and NSAIDs are the most common implicated drugs classes followed by, anti-platelets agents, statins and HDS; recently, body building products and slimming aids have shown a relevant increase of consumption.
      • Hepatotoxicity by acetaminophen (APAP) represent the best example of predictive DILI, causing rapidly hepatocellular liver injury. Patients claimed APAP ingestion have to be assess for treatment with N-acetyl cysteine (NAC). Timing of NAC administration (8–10 H) is the most relevant factor in preventing injury by APAP.
      • There are no clearly identified biomarkers of DILI that are useful for monitoring patients on drug therapy for early detection of hepatotoxicity or for making an appropriate diagnosis. AST, ALT, AP and bilirubin are able to identify hepatocellular, cholestatic and/or mixed pattern of liver damage.
      • Susceptibility to drugs mainly depends on the presence of genetic variation among gene classes, such as drug disposition/transporters genes, inflammatory and immune response genes, including HLA system. There is growing interest in developing genetic tests to identify people at risk for adverse events before prescription.

      Concluding remarks

      This review was aimed at highlighting knowledge regarding the epidemiology, risk factors, clinical features, and diagnostic criteria of idiosyncratic and dose-related DILI. Diagnosis of DILI remains a debated issue, despite many efforts to identify proper diagnostic criteria and useful biochemical markers to assist physicians and predict outcomes. In this article, I have reported the most commonly implicated medications, the increasing use of HDS, the difficulties of diagnosis with currently available causality assessment methods, and the new biomarkers being developed for DILI. I have reviewed the issue of APAP overdose-related ALF and its management. I have also provided an update of the literature and discussion of the genetic susceptibility risks of patients with DILI. Nevertheless, substantial research is still needed before useful predictors of risk can be established to define patients susceptible to developing DILI.

      Conflict of interest

      None.

      Acknowledgment

      I am really thankful to Antonio Craxì for his valuable advice and support in reviewing the manuscript.

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