ERAP-1 and ERAP-2 Variants in Liver Injury After COVID-19 mRNA Vaccination: A US Multicenter Study.

INTRODUCTION: The aim of this study is to describe the presenting features, genetic factors, and outcomes of 23 adults who developed liver injury after coronavirus disease 2019 (COVID-19) mRNA vaccination. METHODS: Patients with suspected COVID-19 vaccine hepatitis were enrolled into the Drug-Induced Liver Injury Network. Causality was assessed using the Drug-Induced Liver Injury Network expert opinion score. High-resolution HLA sequencing was undertaken using Illumina platform. RESULTS: Amongst the 16 high causality cases, median time to onset was 16 days, median age was 63 years, and 75% were female. The injury was hepatocellular in 75% with a median alanine aminotransferase of 497 U/L, and 37% had jaundice. An antinuclear antibody and smooth muscle antibody were detectable in 27% and 36%, but only 12% had an elevated immunoglobulin G level. During follow-up, 37% received a short course of corticosteroids, and 88% fully recovered by 6 months with no deaths observed. HLA alleles associated with autoimmune hepatitis were not overrepresented compared with controls, but an ERAP-2 variant (rs1263907) and the ERAP-1 Hap6 haplotype were significantly overrepresented in the high causality cases vs controls ( P = 0.026 and 5 × 10 -5 , respectively). DISCUSSION: Acute liver injury may arise within 8 weeks of COVID-19 mRNA vaccination that is generally mild and self-limited in most patients. The absence of an association with the AIH HLA alleles combined with the significant ERAP-2 and ERAP-1 Hap6 haplotype associations implicates a unique but very rare host immune response to vaccine-derived antigens in the pathogenesis of COVID-19 vaccine hepatotoxicity.

Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations.

OBJECTIVE: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI. METHODS: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort. RESULTS: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac. CONCLUSIONS: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses.

Amiodarone and Dronedarone Causes Liver Injury with Distinctly Different Clinical Presentations.

OBJECTIVE: To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database. METHODS: Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020. RESULTS: Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes. CONCLUSION: Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.

Clinical features, outcomes, and HLA risk factors associated with nitrofurantoin-induced liver injury.

BACKGROUND & AIMS: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN). METHODS: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661). RESULTS: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10-4), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10-5), and non-NTF DILI (OR 3.34, p = 0.003). CONCLUSION: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies. IMPACT AND IMPLICATIONS: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.

When Is Suspected Drug-Induced Liver Injury (DILI) Not DILI? An Analysis of Unlikely Cases From the Drug-Induced Liver Injury Network.

INTRODUCTION: Diagnosis of drug-induced liver injury (DILI) is difficult. We reviewed cases in the DILI Network prospective study that were adjudicated to have liver injury due to other causes to discover pearls for improved diagnostic accuracy. METHODS: Cases were adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were compared with unlikely cases (5). RESULTS: One hundred thirty-four of the 1,916 cases (7%) were unlikely DILI. Alternative diagnoses were autoimmune hepatitis (20%), hepatitis C (20%), bile duct pathology (13%), and hepatitis E (8%). DISCUSSION: Thorough evaluation, including follow-up, is essential to minimize incorrect diagnosis of idiosyncratic DILI.

The Impact of Patient Age and Corticosteroids in Patients With Sulfonamide Hepatotoxicity.

INTRODUCTION: Sulfonamides are widely used to treat and prevent various bacterial and opportunistic infections. The aim of this study was to describe the clinical presentation and outcomes of a large cohort of patients with sulfonamide hepatotoxicity. METHODS: Between 2004 and 2020, 105 patients with hepatotoxicity attributed to trimethoprim/sulfamethoxazole (TMP-SMZ) (n = 93) or other sulfonamides (n = 12) were enrolled. Available liver biopsies were reviewed by a single hepatopathologist. RESULTS: Among the 93 TMP-SMZ cases, 52% were female, 7.5% younger than 20 years, and the median time to drug-induced liver injury (DILI) onset was 22 days (range: 3-157). Younger patients were significantly more likely to have rash, fever, eosinophilia, and a hepatocellular injury pattern at onset that persisted at the peak of liver injury compared with older patients ( P < 0.05). The 18 (19%) TMP-SMZ patients treated with corticosteroids had more severe liver injury and a higher mortality but a trend toward more rapid normalization of their laboratory abnormalities compared with untreated patients. During follow-up, 6.2% of the TMP-SMZ patients died or underwent liver transplantation. Chronic DILI developed in 20% and was associated with cholestatic injury at onset and higher peak total bilirubin levels. DISCUSSION: Sulfonamide hepatotoxicity is characterized by a short drug latency with frequent hypersensitivity features at onset. Subject age is an important determinant of the laboratory profile at presentation, and patients with cholestasis and higher total bilirubin levels were at increased risk of developing chronic DILI. Corticosteroids may benefit a subgroup of patients with severe injury, but further studies are needed.

A revised electronic version of RUCAM for the diagnosis of DILI.

BACKGROUND AND AIMS: Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling. APPROACH AND RESULTS: RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories. CONCLUSIONS: RECAM is an evidence-based update that is at least as capable as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM's increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.

Clinical characteristics of antiepileptic-induced liver injury in patients from the DILIN prospective study.

BACKGROUND & AIMS: Antiepileptic drugs (AEDs) are a common cause of drug-induced liver injury (DILI). Over the last few decades, several newer AEDs were approved for marketing in the United States, and they are increasingly prescribed for indications other than seizures. Contemporaneous data related to trends and characteristics of AED-related liver injury are sparse. METHODS: We report the trends, characteristics, and outcomes of patients with AED-related DILI enrolled into the DILIN Prospective Study between 2004 and 2020. RESULTS: Among 1,711 participants with definite, highly likely, or probable DILI, 66 (3.9%) had AED-related DILI (lamotrigine [n = 18], phenytoin [n = 16], carbamazepine [n = 11], valproate [n = 10], gabapentin [n = 4], and others [n = 7]). The frequency of AED-related liver injury significantly decreased during the study period (from 8.5% of cases during 2004-2007 to 2.6% during 2015-2020, p = 0.01). AEDs other than phenytoin were commonly prescribed for non-seizure indications. Compared to non-AEDs, patients with AED-related liver injury were younger (mean age 38.5 vs. 50.1 years-old, p <0.001) and more likely African American (27% vs. 12%, p = 0.008). DRESS was common with liver injury caused by lamotrigine, phenytoin, and carbamazepine, but not valproate or gabapentin. Liver injury severity was moderate to severe in the majority: 5 died, and 3 underwent orthotopic liver transplantation (OLT). No patient with lamotrigine-related DILI, including 13 with hepatocellular jaundice, died or needed OLT, while 3 out of 16 patients (19%) with phenytoin-related DILI either died or required OLT. CONCLUSION: The frequency of AED-related liver injury significantly decreased over the last 2 decades in our experience. AED-related liver injury has several distinctive features, including a preponderance in African American patients and those with immunoallergic skin reactions, with outcomes depending on the type of AED involved. LAY SUMMARY: Medications used to treat epilepsy may sometimes cause severe liver injury. However, several new medications have been approved over the last 2 decades and they may not be as toxic to the liver as older antiepileptic medications (AEDs). This study shows that overall liver injury due to AEDs is decreasing, likely due to decreasing use of older AEDs. Liver injury due to AEDs appears to be more common in African Americans and is commonly associated with allergic skin reactions.

Garcinia cambogia, Either Alone or in Combination With Green Tea, Causes Moderate to Severe Liver Injury.

BACKGROUND & AIMS: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G cambogia either alone (n = 5) or in combination with green tea (n = 16) or Ashwagandha (n = 1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G cambogia and 103 patients from other HDS. RESULTS: Patients who took G cambogia were between 17 and 54 years, with liver injury arising 13-223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G cambogia group (P < .018), the median time for improvement in total bilirubin was significantly lower compared with the control groups (10 vs 17 and 13 days; P = .03). The presence of HLA-B∗35:01 allele was significantly higher in the G cambogia containing HDS (55%) compared with patients because of other HDS (19%) (P = .002) and those with acute liver injury from conventional drugs (12%) (P = 2.55 × 10-6). CONCLUSIONS: The liver injury caused by G cambogia and green tea is clinically indistinguishable. The possible association with HLA-B∗35:01 allele suggests an immune-mediated mechanism of injury. CLINICAL TRIALS: gov number: NCT00345930.

Incidence of Hepatitis E Infection in American Patients With Suspected Drug-Induced Liver Injury Is Low and Declining: The DILIN Prospective Study.

INTRODUCTION: Hepatitis E virus (HEV) infection rarely causes icteric hepatitis, yet 10%-40% of adult Americans have serological evidence of previous infection. The aim of this study was to investigate the incidence, presentation, and outcome of acute and previous HEV infection in a large cohort of patients with suspected drug-induced liver injury (DILI). METHODS: Serum samples from 2012 patients enrolled in the DILI Network were tested for anti-HEV immunoglobulin G (IgG). Those with detectable anti-HEV IgG underwent testing for anti-HEV IgM; those with detectable anti-HEV immunoglobulin m (IgM) were tested for HEV RNA. RESULTS: Anti-HEV IgG was detected in 407 (20%) patients and associated with increasing subject age and earlier year of enrollment. The median age of seropositive subjects was more than a decade higher than seronegative subjects (59.8 vs 48.7 years). The overall prevalence of anti-HEV declined from 22% (2004-2011) to 18% (2012-2019), suggestive of a cohort effect. The frequency of acute hepatitis E (median ALT = 1231 IU/L) also decreased from 3% (2004-2008) to 1.2% (2009-2013) to 0.6% (2014-2019). These results suggest that acute HEV infection is usually subclinical and was much more frequent in this cohort before 2004. DISCUSSION: Acute HEV infection accounts for less than 1% of suspected American DILI cases and is more frequent in older men. Previous HEV infection is also most commonly seen in older individuals. Clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice.

HLA-B*35:01 and Green Tea-Induced Liver Injury.

BACKGROUND AND AIMS: Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS: Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS: Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

Leflunomide-induced liver injury: Differences in characteristics and outcomes in Indian and US registries.

BACKGROUND: Leflunomide, a disease-modifying anti-rheumatic drug, has been associated with elevations of serum aminotransferases. Herein, we describe the clinical, laboratory features and outcomes of 17 patients with leflunomide/teriflunomide hepatotoxicity from two large drug-induced liver injury (DILI) registries. METHODS: Consecutive, adjudicated cases of leflunomide (n = 16)-or teriflunomide (n = 1)-related DILI from a single centre in Bangalore, India and the multicentre US Drug-Induced Liver Injury Network (DILIN) were reviewed. RESULTS: Nine (0.8%) of the 1070 Indian patients and 8 (0.5%) of the 1400 DILIN patients fulfilled the criteria for DILI because of leflunomide- or teriflunomide. 89% of the Indian cases were women and all were associated with severe cutaneous adverse reaction (SCAR) and a median drug latency of 49 days, whereas 37.5% of the DILIN cases were female, none exhibited SCAR and the median drug latency was 166 days. Hepatocellular injury (70%) was more common in women than men (92% vs. 20%) and was associated with younger mean age (41 vs. 59 years), higher peak INR (2.3 vs. 1.2) and higher mortality (58% vs. 0%). Mortality was observed in six patients from India (2 of the three with myocarditis) and one received liver transplantation from the USA. CONCLUSION: Leflunomide-induced liver injury is predominantly hepatocellular. Leflunomide hepatotoxicity is more likely accompanied by SCAR, a short latency and a higher mortality in the Indian cohort, with a predominance of females, compared to US DILIN patients. The differences in skin involvement, immunoallergic features and outcomes among subjects from India vs. the USA suggest that genetic or environmental factors are important in the pathogenesis of liver injury.

Development and Validation of a Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 Months for Patients With Suspected Drug-Induced Liver Injury.

BACKGROUND & AIMS: Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. METHODS: A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index-patients with scores higher than 2 were considered to have significant comorbidities. RESULTS: Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1-13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04-1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2-0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86-0.94) in the discovery cohort and 0.91 (95% CI, 0.83-0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. CONCLUSIONS: We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.

Antimicrobials and Antiepileptics Are the Leading Causes of Idiosyncratic Drug-induced Liver Injury in American Children.

OBJECTIVES: The aim of this study was to provide an overview of the presenting features, etiologies, and outcomes of children enrolled in the Drug-induced Liver Injury Network (DILIN) prospective and retrospective studies. METHODS: Consecutive definite, highly likely, or probable cases in children enrolled into the ongoing DILIN prospective and retrospective studies between September 2004 and February 2017 were reviewed. RESULTS: Fifty-seven cases were adjudicated as definite (14), highly likely (30), or probable (13) DILI. Median age was 14.3 years (1.7-17.9), 67% female, and 82% Caucasian. At DILI onset, 82% had hepatocellular injury with a median alanine aminotransferase of 411 U/L (33-4185), alkaline phosphatase 203 U/L (62-1177), and total bilirubin 3.3 mg/dL (0.2-33.9). The median duration of suspect medication use was 55 days (1-2789) and the most frequently implicated individual agents were minocycline (n = 11) and valproate (n = 6). Sixty-three percent were hospitalized and 3 (5%) underwent liver transplant within 1 month of DILI onset. Among 46 children followed for at least 6 months, 8 (17%) met criteria for chronic DILI with 6 of them having persistent liver injury at 24 months of follow-up. A genome-wide association study in 39 Caucasian children focusing on regions associated with pediatric cholestatic liver disease failed to demonstrate any single nucleotide polymorphism associated with DILI susceptibility or outcome. CONCLUSIONS: Antimicrobials (51%) and antiepileptic drugs (21%) are the most frequently implicated agents in pediatric DILI patients. Although the majority of cases are self-limited, there is potential for serious morbidity including acute liver failure, chronic liver injury, and death.

The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine.

BACKGROUND & AIMS: Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01. METHODS: Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform. RESULTS: All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03. CONCLUSIONS: Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians. LAY SUMMARY: A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.

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

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements.

Bile duct loss during the course of drug-induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug-induced liver injury with histologically proven bile duct loss. All cases of drug-induced liver injury enrolled into a prospective database over a 10-year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty-six of the 363 patients (7%) with drug-, herbal-, or dietary-supplement-associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50%-75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. CONCLUSION: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. (Hepatology 2017;65:1267-1277).

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840.

Idiosyncratic Drug Induced Liver Injury in African-Americans Is Associated With Greater Morbidity and Mortality Compared to Caucasians.

OBJECTIVES: Idiosyncratic drug induced liver injury (DILI) is a rare but potentially serious liver disorder and a major cause of significant liver injury. Limited data exist on racial differences in DILI incidence, presentation, and course. METHODS: We compared the causative agents, clinical features, and outcomes of DILI among self-described African-Americans and non-Hispanic whites (Caucasians) enrolled in the DILIN Prospective Study. Individuals with definite, highly likely, or probable DILI enrolled between September 2004 and February 2016 were included in this analysis. RESULTS: 144 African-Americans and 841 Caucasian patients met the eligibility criteria. Causal medications varied by race: trimethoprim/sulfamethoxazole being the most common cause among African-Americans (7.6 vs. 3.6%) followed by methyldopa (4 vs. <1%), phenytoin (5 vs. <1%), isoniazid (4 vs. 4%), and amoxicillin/clavulanate (4.1 vs. 13.4%). The severity of illness, however, tended to be greater in African-Americans than Caucasians as determined by peak mean bilirubin (14.3 vs. 12.8 mg/dl), INR (1.9 vs. 1.6), and DILIN severity score (3.0 vs. 2.6). The frequency of severe cutaneous reactions was significantly higher in African-Americans (2.1 vs. 0.36% in Caucasians, P=0.048). African-Americans also had higher rates of hospitalization (76.7 vs. 57.6%, P<0.001), liver transplantation or liver related death by 6 months (10.2 vs. 5.8%, P=0.02 after controlling for selected covariates), and chronic DILI (24 vs. 16%, P=0.06). CONCLUSIONS: The most common DILI causative agents differ between African-Americans and Caucasians. African-Americans are more likely to have severe cutaneous reactions and more severe liver injury leading to worse outcomes, including death and liver transplant.

Associations of gender and a proxy of female menopausal status with histological features of drug-induced liver injury.

BACKGROUND & AIM: Gender and menopause may contribute to type and severity of drug-induced liver injury (DILI) by influencing host responses to injury. The aim of this study was to assess the associations of gender and female age 50 [a proxy of menopause] with histological features of liver injury in 212 adults enrolled in the Drug-Induced Liver Injury Network (DILIN) registry. METHODS: All participants had a causality score of at least 'probable', a liver biopsy within 30 days of DILI onset, and no prior chronic liver disease. Biochemical and histological injury types were classified as hepatocellular or cholestatic/mixed injury. The cohort was divided into three gender/age categories: men (41.0%), women <50 years (27.4%) and women ≥50 years of age (31.6%). Interaction of gender and age category (≥50 or not) was assessed. RESULTS: Hepatocellular injury was more prevalent in women <50 years vs. others (P=.002). After adjusting for biochemical injury types, black race and possible ageing effects, more severe interface hepatitis was noted in biopsies of women <50 years compared to those of men and women ≥50 years (P=.009 and P=.055 respectively). Compared to those of men, biopsies of women showed greater plasma cell infiltration, hepatocyte apoptosis, hepatocyte rosettes and lobular disarray but less iron-positive hepatocytes and histological cholestasis (P<.05). These associations persisted after excluding cases of amoxicillin/clavulanic acid, anabolic steroids or nitrofurantoin DILI which showed gender-specific distributions. CONCLUSION: Gender and a proxy of menopause were associated with various features of inflammation and injury in DILI.