Common Cause Of Drug-induced Liver Injury Research Articles

Spectrum of drug-induced liver injury in a tertiary hospital in southern India.

Background Anti-tuberculosis drugs are thought to account for about 50% of drugs that cause liver injury in India. We show that the spectrum of drugs is much wider than previously reported. Methods We evaluated all patients with unexplained acute liver injury presenting during 2006-2016 using a structured proforma for drug-induced liver injury (DILI). The Roussel Uclaf Causality Assessment Method was used to assess causality. Results DILI was found in 143 of 2534 patients with acute liver injury. Nineteen patients had probable ayurvedic DILI. The other common causes of DILI were statins (16 patients) and anti-tuberculosis drugs (11 patients). Eight patients had DILI post-liver transplant. Fluconazole was the most common cause of post-liver transplant DILI. Chronic DILI (abnormal liver function test after 12 months of stopping the suspected drug) was found in 2 patients. Conclusion In otherwise unexplained acute liver injury, DILI due to ayurvedic drugs should be sought. DILI should be considered in post-liver transplant patients. Patients with DILI should be monitored for at least 12 months to exclude progression to chronic DILI.

Genetics of drug-induced liver injury: Current knowledge and future prospects.

Idiosyncratic drug-induced liver injury (DILI) remains an important clinical problem, both during drug development and the prescription of a range of licensed drugs. Although rare, the consequences are serious. Ongoing studies on genetic risk factors for DILI, especially genomewide association studies, have resulted in the identification of a number of genetic risk factors, including particular HLA alleles and a few non-HLA genes, both immune-related and metabolic. Some non-HLA associations, such as N-acetyltransferase 2 in isoniazid DILI and interferon regulatory factor 6 in interferon-beta DILI are likely to be drug-specific due to the role of the associated gene, but there is also evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs. Increased knowledge of genetic risk factors should assist in better understanding underlying DILI mechanisms and help improve methods for identifying hepatotoxic drugs early in development. HLA allele-specific T cell proliferation together with in silico prediction of drug binding to specific HLA proteins have confirmed genetic findings for certain common causes of DILI. However, studies in hepatocytes exposed to high drug concentrations suggest toxicity that is not dependent on genotype also occurs. It seems likely that susceptibility to DILI involves several genetic risk factors combining with other factors that affect drug levels. Despite recent progress in detecting genetic risk factors for DILI, low positive predictive values mean that general implementation of genotyping prior to prescription of potentially hepatotoxic drugs is not useful currently.

From the Editor’s Desk...

From the Editor’s Desk...

Acute Liver Failure: Indian Perspective.

Acute Liver Failure: Indian Perspective.

Liver injury induced by paracetamol and challenges associated with intentional and unintentional use.

Drug induced liver injury (DILI) is a common cause of acute liver injury. Paracetamol, also known as acetaminophen, is a widely used anti-pyretic that has long been established to cause liver toxicity once above therapeutic levels. Hepatotoxicity from paracetamol overdose, whether intentional or non-intentional, is the most common cause of DILI in the United States and remains a global issue. Given the increased prevalence of combination medications in the form of pain relievers and antihistamines, paracetamol can be difficult to identify and remains a significant cause of acute hepatotoxicity, as evidenced by its contribution to over half of all acute liver failure cases in the United States. This is especially concerning given that, when co-ingested with other medications, the rise in serum paracetamol levels may be delayed past the 4-hour post-ingestion mark that is currently used to determine patients that require medical therapy. This review serves to describe the clinical and pathophysiologic features of hepatotoxicity secondary to paracetamol and provide an update on current available knowledge and treatment options.

Etiology and Pattern of Drug Induced Liver Injury in a Tertiary Care Hospital of Nepal

Drug induced liver injury (DILI) is one of the common cause of liver toxicity. Most of the drugs used today are hepatotoxic. DILI accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. It is the single most common adverse drug reaction leading to a halt in the development of new medication by pharmaceutical company, failure of new drug to obtain regulatory approval, and withdrawal or restriction of existing drug from the market. The aim of this study is to evaluate common causes and patterns of DILI in our setting. Twenty-seven patients were enrolled in the study. Ant tubercular drugs were most common cause of DILI, accounting for 48.2%. Other common causes of DILI were paracetamol (14.8%) and NSAID’s (11.1%). The most common pattern of liver injury seen was mixed pattern which was present in63%, followed by cholestatic and hepatocellular pattern. Hence, we should be very careful while prescribing these frequently used drugs.

LIVER TRANSPLANTATION AND DEATH WITHIN 4 MONTHS OF SUSPECTED DRUG-INDUCED LIVER INJURY (DILI) FROM AMOXICILLIN

Introduction Antibiotic prescription is not without risk. We present a case of suspected Drug induced liver injury (DILI) secondary to amoxicillin. Case Description An 18-year-old African American male presents from an outside hospital for acute liver failure. Initially, he reports developing “yellow eyes” on day 5 of taking amoxicillin, which was prescribed by his primary care provider for sore throat and a positive rapid strep test. He is an athlete with no significant medical history or antibiotic use prior to this encounter. He does not drink alcohol, smoke or do illicit drugs. Extensive workup following the AASLD (American Association for Study of Liver Diseases) guidelines was unremarkable for biliary, autoimmune, infectious, genetic, obstructive, veno-occlusive, alcohol or salicylic acid-induced causes. Laboratory tests show a hepatocellular pattern without significant peripheral eosinophilia (AEC 110). The patient receives a liver transplant but has a hospital course complicated by bacteremia and multi-organ failure resulting in death. Discussion There is yet to be a reliable method to predict, diagnose, and risk assess DILI. The two most common causes of DILI are acetaminophen and amoxicillin-clavulanic acid. Amoxicillin alone is less likely to cause DILI, although it may, and it can be associated with a mixed hepatocellular/cholestatic picture. The chronologic association between initiation of antibiotic and the onset of liver injury is pertinent. Immediate hypersensitivity reactions are IgE mediated and can occur within 1 hour after last drug administration. Delayed reactions are often T lymphocyte specific and can occur more than 1 hour after the last drug administration.

Heavy Consumption of Alcohol is Not Associated With Worse Outcomes in Patients With Idiosyncratic Drug-induced Liver Injury Compared to Non-Drinkers

The relationship between alcohol consumption and idiosyncratic drug-induced liver injury (DILI) is not well understood. We investigated the relationship between heavy consumption of alcohol and characteristics and outcomes of patients with DILI enrolled in the Drug-induced Liver Injury Network (DILIN) prospective study. We collected data from 1198 individuals with definite, highly likely, or probable DILI enrolled in the DILIN study from September 2004 through April 2016. At enrollment, all participants were asked about alcohol consumption; those with any alcohol consumption during previous 12 months were asked to complete the Skinner questionnaire to assess drinking history. Heavy consumption of alcohol was defined as more than 3 drinks, on average, per day by men or more than 2 drinks, on average, per day by women. Of the 601 persons who reported consuming at least 1 alcoholic drink in the preceding 12 months, 348 completed the Skinner questionnaire and 80 reported heavy consumption of alcohol. Heavy drinkers were younger (average age, 42 years) than non-drinkers (average age, 49 years) and a higher proportion were men (63% of heavy drinkers vs 35% of nondrinkers) (P< .01 for each comparison). Anabolic steroids were the most common cause of DILI among heavy drinkers (in 13% vs 2% in non-drinkers) (P < .001). Heavy drinkers had significantly higher peak serum levels of alanine aminotransferase (1323 U/L) than non-drinkers (754 U/L) (P = .02) and higher levels of bilirubin (16.1 mg/dL vs 12.7 mg/dL in non-drinkers) (P = .03) but there was no significant difference in liver-related death or liver transplantation between heavy drinkers (occurred in 10%) vs non-drinkers (occurred in 6%) (P = .18). In an analysis of data from the DILIN, we found anabolic steroids to be the most common cause of DILI in individuals who are heavy consumers of alcohol. Compared to non-drinkers, DILI was not associated with a greater proportion of liver-related deaths or liver transplantation in heavy drinkers.

The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study.

BackgroundToxic liver diseases are mainly caused by drug-induced liver injury (DILI). We assessed incidences and outcomes of DILI including associated factors for mortality.MethodsWe performed a population-based study of hospitalized patients with DILI. Information was retrieved from the Nationwide Hospital Admission Data using ICD-10 code of toxic liver diseases (K71) and additional codes (T36–T65). The associated factors were analyzed with log-rank test, univariate and multiple cox regression analysis.ResultsDuring 2009–2013, a total of 159,061 (average 21,165 per year) admissions were related to liver diseases. 6,516 admissions (1,303 per year) were due to toxic liver diseases. The most common type of toxic liver disease was acute hepatitis (33.5 %). In-hospital and 90-day mortality rates were 3.4 % and 17.2 %. DILI with cirrhosis yielded the highest in-hospital and 90-day mortality rates (15.8 % and 47.4 %). Acetaminophen, cirrhosis and age ≥ 60 years were seen in 0.5 %, 8.3 % and 50.1 % of patients who died versus 5 %, 2.3 % and 32.4 % of survivors. Factors associated with mortality were cirrhosis (HR 2.72, 95 % CI: 2.33–3.19), age ≥60 years (HR 2.16, 95 % CI: 1.96–2.38), human immunodeficiency viral infection (HR 2.11, 95 % CI: 1.88–2.36), chronic kidney disease (HR 1.59, 95 % CI: 1.33–1.90), chronic obstructive pulmonary disease and bronchiectasis (HR 1.55, 95 % CI: 1.17–2.04), malnutrition (HR 1.43, 95 % CI: 1.10–1.86) and male (HR 1.31, 95 % CI: 1.21–1.43). Acetaminophen DILI yielded lower risks of mortality (HR 0.24, 95 % CI: 0.13–0.42). The most common causes of DILI were acetaminophen (35.0 %) and anti-tuberculous drugs (34.7 %).ConclusionsDILI is an uncommon indication for hospitalization carrying lower risks of death except in patients with non-acetaminophen, cirrhosis, elderly or concomitant diseases.

Model for end-stage liver disease score as a predictor of short-term outcome in patients with drug-induced liver injury

Objectives. The purposes of this study were to investigate the clinical presentation, cause and outcome of drug-induced liver injury (DILI) and to evaluate the predictive value of the model for end-stage liver disease (MELD) score in DILI. Methods. Patients diagnosed with DILI between January 1, 2010 and December 31, 2012 in the Emergency Department at Asan Medical Center in Seoul, Korea were analyzed retrospectively. The primary end point was poor outcome, defined as liver transplantation or death within 30 days of the initial hospital visit. Results. Of 213 patients, 13.1% had a 30-day poor outcome. Folk remedies were the most common cause of DILI in 147 patients (69%). Univariate logistic regression analysis showed that multiple drugs (odds ratio [OR] 2.30, 95% confidence interval [CI]: 1.03–5.15), concurrent alcohol consumption (OR 3.69, 95% CI: 1.03–13.18), white blood cell (WBC) count (OR 1.17, 95% CI: 1.07–1.28), hemoglobin (Hb) (OR 0.60, 95% CI: 0.49–0.74), platelet count (OR 0.993, 95% CI: 0.987–0.998), total bilirubin (OR 1.09, 95% CI: 1.06–1.13) and MELD (OR 1.23, 95% CI: 1.15–1.32) were significantly associated with 30-day poor outcomes. Multivariate analysis showed that the MELD (OR 1.21, 95% CI: 1.12–1.30) and Hb (OR 0.77, 95% CI: 0.61–0.98) were independent predictors of poor outcome. For 30-day mortality, the c-statistics for MELD alone and for combination of MELD and Hb were 0.93 (95% CI: 0.89–0.97) and 0.94 (95% CI: 0.90–0.97), respectively. Conclusion. The outcome of patients with DILI was poor. MELD score and Hb were reliable predictors of short-term outcome in patients with DILI.

Drug-Induced Liver Injury

Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of "English language" and "humans" and custom date range of "January 1, 2000." The authors also manually searched bibliographies from key references and included seminal references before the year2000.

PP022—Variations in drug-induced liver injury (DILI) between different prospective dili registries

e24 Volume 35 Number 8S PP022—VARIATIONS IN DRUG-INDUCED LIVER INJURY (DILI) BETWEEN DIFFERENT PROSPECTIVE DILI REGISTRIES I. Medina-Caliz; A. Gonzalez-Jimenez; F. Bessone; N. Hernandez; A. Sanchez; M. Di Pace; M. Arrese; J.R. Brahm; A. Ruiz; J. Arancibia; D. Kershenobich; A. Loaeza; M. Girala; N. Mendez-Sanchez; M. Davalos; M. Lizarzabal; E. Mengual; C. Stephens; M. Robles-Diaz; R.J. Andrade; and M.I. Lucena H.U. Virgen de la Victoria, Universidad de Malaga, IBIMA, CIBEReHD, Malaga, Spain; H del Centenario, Rosario, Argentina; H de Clinicas, Montevideo, Uruguay; Pontificia Universidad Catolica de Chile; H Clinico Universitario de Chile, Santiago, Chile; H General de Mexico, Mexico City, Mexico; H. de Clinicas Asuncion, Asuncion, Paraguay; Fundacion Clinica Medica Sur, Mexico City, Mexico; H Rebagliati, Lima, Peru; and H Maracaibo, Maracaibo, Venezuela, Bolivarian Republic Of Introduction: DILI differs across geographical areas due to differential drug polices, prescription habits, drug consumption, and genetic factors. In this study, we have compared DILI cases included in the recently established Latin American DILI Network with those in the Spanish DILI Registry and the US Drug-Induced Liver Injury Network to identify differences in phenotypic presentations and causative agents. Patients (or Materials) and Methods: Demographic, clinical parameters, and causative agents were compared between 98 Latin American, 851 Spanish, and 300 US DILI cases. Results: The Latin American cases had a mean age of 54 years with a predominance of females (61%), whereas mean age and female proportion in the Spanish and US DILI cases were 54 years with 49% females and 48 years with 60% females, respectively. The most common type of liver damage in all 3 registries was hepatocellular injury. Jaundice was frequently seen in the registries, with 70%, 66%, and 69% of the Latin American, Spanish, and US DILI cases, respectively. Hospitalization occurred in 51% of the Latin American DILI cases, with 57% and 60% of the Spanish and US cases requiring hospitalization. Liver-related death or liver transplantation occurred in 5.1%, 3.6%, and 6.0% of the Latin American, Spanish, and US cases, respectively. The main causative agents in Latin America included nimesulide, diclofenac, nitrofurantoin, cyproterone acetate, and various herbal remedies, whereas amoxicillin-clavulanate predominated in the other 2 registries, followed by ibuprofen in Spain and nitrofurantoin in the United States. Conclusion: The Latin American DILI cases demonstrate similar phenotypic characteristics as observed in registers outside Latin America with respect to type of injury and severity. Female sex predominates in the Latin America and US registries. With regard to causative agents, elevated representation of NSAIDs, hormonal treatments, and herbal remedies were seen in Latin America, whereas antibiotics were more common causes of DILI in Spain and the United States. Funding Source: Agencia Espanola del Medicamento, SAS P10CTS-6470, FIS PI12-00620, iSAEC. CIBERehd by ISCIII. Disclosure of Interest: None declared.

Epidemiology of drug-induced liver injury in China

The epidemiology of drug-induced liver injury (DILI) in China has rarely been studied before. The aim of the present study was to determine the etiology of DILI in a Chinese population by reporting a systematic analysis of the Chinese literature published from 1994 to 2011. A comprehensive database search of the Chinese literature was performed to obtain all the relevant studies. The data, including the drug names and patients' sex, age, clinical classification, and prognosis, were collected and analyzed. In this research, we found 279 studies including 24 112 patients. There were 265 studies that reported the sex of 21 789 patients, 11 787 men and 10 002 women. The therapeutics included (but were not limited to) tuberculostatics, complementary and alternative medicines (CAMs), antibiotics, NSAIDs, antineoplastics, central nervous system agents, antithyroid drugs, and immunomodulators. Of these drugs, tuberculostatics and CAMs were the most common etiologies of DILI in China. DILI in China has a different etiology from that in Europe and USA. NSAIDs, which are the most common causes of DILI in western populations, are uncommon in China. Therefore, government, physicians, and patients should pay more attention to these drugs in DILI.

Closing the gap on drug-induced liver injury

Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety. (HEPATOLOGY 2012;)

Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure

Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety.

Role of innate and adaptive immunity during drug-induced liver injury

Drug-induced liver injury (DILI) is a major human health concern and is the most frequent cause of FDA boxed warnings and the removal of drugs from the market. Idiosyncratic DILI (IDILI) is highly variable in its time to onset and no one clear hypothesis exists to explain the mechanism. The general belief is most cases of IDILI involve some immune mediated component; however no animal models can recapitulate human IDILI. Despite numerous drugs that have IDILI potential, the most common cause of DILI is acetaminophen (APAP) overdose. APAP in animal models and in patients is a dose-dependent hepatotoxicant resulting in severe centrilobular necrosis and a robust inflammatory response. In this review we will compare the existing hypotheses for potential causes of IDILI and discuss the potential roles of immune involvement in DILI. Additionally we will focus on what we have learned from the mechanisms of APAP toxicity (protein adduction, mitochondrial dysfunction, oxidant stress, DNA damage, release of damage associated molecular patterns (DAMPs)) and useful interventions to alleviate APAP-toxicity (reduced protein binding, scavenging of reactive oxygen, induction of autophagy). Mechanistically APAP-induced liver injury appears to be fundamentally different from IDILI, however, there are potential critical events shared between APAP-induced liver injury and IDILI. The strategies and methods currently being used to study APAP-induced liver injury are described in this review. This improved insight into mechanisms of APAP-induced injury with initiation, propagation and inflammation may also help to better understand IDILI.

Clinical course and outcomes of drug-induced liver injury: Nimesulide as the first implicated medication

Drug-induced liver injury (DILI) is the most common cause of death from acute liver failure, and accounts for approximately 13% of cases of acute liver failure in the United States. The clinical presentation of DILI covers a wide spectrum, from asymptomatic liver test abnormalities to symptomatic acute liver disease, prolonged jaundice and disability, or overt acute or subacute liver failure. The aim of our study was to evaluate the number of DILI cases admitted to our Unit and to identify the drugs responsible. Thus, we reviewed all clinical records of patients with DILI admitted to our Unit from 1996 to 2006. A database was constructed, reporting demographic, clinical features at onset, laboratory results, suspected drugs and follow-up. Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data. Forty-six patients were admitted with a diagnosis of DILI. Presentation was jaundice in 22 patients and hepatic failure in 3 (all attributed to nimesulide). Liver damage was of a cytolytic pattern in 19 cases (41%), cholestatic in 15 (33%) and mixed in 12 (26%). Jaundice was found to be higher in nimesulide-induced liver damage compared to other drugs (p=0.007). Three out of 14 patients with nimesulide-induced DILI developed encephalopathy and/or ascites. Time of recovery in the nimesulide group was significantly lower than DILI from other drugs (p<0.001). Non-steroidal anti-inflammatory drugs, psychotropic drugs and antimicrobials are the most common causes of DILI. Nimesulide-induced DILI is usually reversible upon discontinuation of the drug, but occasionally progresses to liver failure.

HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

Idiosyncratic drug-induced liver injury: an overview

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The majority of adverse liver reactions are idiosyncratic, occurring in most instances 5 – 90 days after the causative medication was last taken. The diagnosis of DILI is clinical, based on history, probability of the suspect medication as a cause of liver injury and exclusion of other hepatic disease. DILI can be hepatocellular (predominant rise in alanine transaminase), cholestatic (predominant rise in alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more than twice the upper limit of normal in patients with hepatocellular liver injury implies severe DILI, with a mortality of ∼ 10% and with an incidence rate of 0.7 – 1.3 per 100,000. Although acute liver failure is rare, 13 – 17% of all acute liver failure cases are attributed to idiosyncratic drug reactions. Response to drug withdrawal may be delayed up to 1 year with cholestatic liver injury with occasional subsequent progressive cholestasis known as the vanishing bile duct syndrome. Overall, chronic disease may occur in up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the most common cause of DILI. Statins rarely cause significant liver injury whereas antiretroviral therapy is associated with hepatotoxicity in 10% of treated patients. Multiple mechanisms of DILI have been implicated, including TNF-α-activated apoptosis, inhibition of mitochondrial function and neoantigen formation. Risk factors for DILI include age, sex and genetic polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients with human immunodeficiency virus, the presence of chronic viral hepatitis increases the risk of antiretroviral therapy hepatotoxicity. Over the next decade, the combination of accurate case ascertainment of DILI via clinical networks and the application of genomics and proteomics will hopefully lead to accurate prediction of risk of DILI, so that pharmacotherapy can be optimised with avoidance of adverse hepatic events.