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Publications (254)
Background
Hyman Zimmerman observed that hepatocellular (HC) drug-induced liver injury (DILI) with jaundice had a mortality rate of ≥10% (Hy’s Law). Hy’s Law does not specify the timing of liver tests nor the definition of HC DILI versus cholestatic or mixed (C/M) DILI. We aimed to assess the validity of Hy’s Law in the prospective Drug-Induced Liv...
The attribution of drug-induced liver injury (DILI) to specific herbal and dietary supplements (HDS) is confounded by inaccurate labels and undisclosed ingredients. The US Drug-Induced Liver Injury Network (DILIN) determines the attribution of injury to an agent through its structured expert opinion causality assessment process, but without the use...
The incidence of drug-induced liver injury (DILI) is not known for most prescription medications. We aimed to estimate the incidence of DILI for commonly prescribed outpatient drugs.
To establish a baseline estimate of DILI incidence, we used the estimated incidence (EI) of amoxicillin/clavulanate DILI from a previous population-based study in Icel...
Background
The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.
Methods
Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants w...
Background/Objective
Slowing the progression of diabetic kidney disease (DKD) is critical. We conducted a randomized controlled trial to target risk factors for DKD progression.
Methods
We evaluated the effect of a pharmacist-led intervention focused on supporting healthy behaviors, medication management, and self-monitoring on decline in estimate...
Background
Azithromycin (AZ) is a widely used antibiotic. The aim of this study was to characterise the clinical features, outcomes, and HLA association in patients with drug‐induced liver injury (DILI) due to AZ.
Methods
The clinical characteristics of individuals with definite, highly likely, or probable AZ‐DILI enrolled in the US Drug‐Induced L...
Background
In April 2022, French Lentil and Leek Crumble (FLLC), a new frozen food preparation manufactured by Daily Harvest™ (containing Tara flour) was offered as a natural high‐protein meal product. Soon thereafter, widespread anecdotal reports of acute gastrointestinal symptoms with liver injury were reported, leading to its voluntary withdrawa...
There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with c...
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 populati...
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...
Background
Vaso‐occlusive episodes (VOC) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence‐based guidelines. We tested existing guidelines and hypothesized a patient‐specific protocol (PSP) written...
Objective:
To investigate HLA alleles associated with anti-epileptics (AEDs) liver injury in African Americans (AA).
Methods:
21 AA with AED DILI, 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included.
Results:
HLA-B*53:01 was significantly associated with aromatic AED-DILI (OR: 4.52, 95% CI: 2.42-8.44, P = 1.46x10-5)...
Introduction:
The diagnosis of DILI is difficult. We reviewed cases in the DILIN Prospective Study that were adjudicated to have liver injury due to other causes to discover pearls for improved diagnostic accuracy.
Methods:
Cases are adjudicated by expert opinion and scored from 1 (definite DILI) to 5 (unlikely DILI). Confirmed cases (1-3) were...
Anemia is common in older adults, but often unexplained. Previously, we conducted a randomized, controlled trial of intravenous (IV) iron sucrose to study its impact on the 6-minute walk test and hemoglobin in older adults with unexplained anemia and ferritin levels of 20–200 ng/mL. In this report, we present for the first time the response of hemo...
Unlabelled:
OBJECTIVES
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 to 2020, 105 patients with hepatotoxicity attributed to trimetho...
Multiparametric quantitative imaging biomarkers (QIBs) offer distinct advantages over single, univariate descriptors because they provide a more complete measure of complex, multidimensional biological systems. In disease, where structural and functional disturbances occur across a multitude of subsystems, multivariate QIBs are needed to measure th...
BACKGROUND
Drug-induced liver injury (DILI) due to amoxicillin–clavulanate (AC) has been associated with HLA-A*02:01, HLA-DRB1*15:01 and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS).
METHODS
Transcriptome-wide association (TWAS) and genome-...
This paper is the fifth in a five-part series on statistical methodology for performance assessment of multi-parametric quantitative imaging biomarkers (mpQIBs) for radiomic analysis. Radiomics is the process of extracting visually imperceptible features from radiographic medical images using data-driven algorithms. We refer to the radiomic feature...
Background:
Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic and human leukocyte antigen (HLA) associations of turmeric-associated liver injury enrolled the U.S. Drug Induced Liver Injury Network (DILIN).
Methods:
All adjudicated cases...
This manuscript is the third in a five-part series related to statistical assessment methodology for technical performance of multi-parametric quantitative imaging biomarkers (mp-QIBs). We outline approaches and statistical methodologies for developing and evaluating a phenotype classification model from a set of multiparametric QIBs. We then descr...
Combinations of multiple quantitative imaging biomarkers (QIBs) are often able to predict the likelihood of an event of interest such as death or disease recurrence more effectively than single imaging measurements can alone. The development of such multiparametric quantitative imaging and evaluation of its fitness of use differs from the analogous...
Background and aim:
Nitrofurantoin (NTF) is a widely used short -term for treating and long-term for preventing urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-liver injury (NTF-DILI) among individuals enrolled by the Drug Induced Liver Injury Network (DILIN).
Methods:
Seventy-e...
Background/ aims:
Hepatitis E Virus (HEV) infection rarely causes icteric hepatitis yet 10 to 40% of adult Americans have serological evidence of prior infection. The aim of this study was to investigate the incidence, presentation, and outcome of acute and prior HEV infection in a large cohort of patients with suspected drug-induced liver injury...
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, adjudi...
Background & Aims
The utility of liver biopsy in diagnosing or staging idiosyncratic drug-induced liver injury (DILI) is unclear. The aim of this study was to determine whether liver histology impacted causality assessment in suspected DILI using a novel simulation model.
Methods
Fifty patients enrolled in the DILI Network (DILIN) who had liver bi...
Background and aims:
Roussel Uclaf Causality Assessment Method (RUCAM) for drug-induced liver injury (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 modelling.
Appro...
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 liver injury due...
Background
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 (adju...
Background
NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT‐proBNP response and whether the therapeutic goal of NT‐proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduce...
Background/ aims:
Allopurinol can cause HLA class I associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown.
Methods:
11 of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug Induced Liver Injury Network were adjudicated as def...
Objectives
Painful vaso-occlusive episodes (VOE) are the most common reason for emergency department (ED) visits experienced by patients with sickle cell disease (SCD). The National Heart, Lung and Blood Institute (NHLBI) evidence-based recommendations for VOE treatment are based primarily on expert opinion. In this randomized controlled trial (RCT...
Background
: Kratom is a botanical product used as an opium substitute with abuse potential.
Methods
: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort.
Results
: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All wer...
Background:
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.
Methods:
Among 1414 patients enrolled in the U.S. Drug Induced Liver Injury Network who underwent formal c...
Multiple raters are often needed to be used interchangeably in practice for measurement or evaluation. Assessing agreement among these multiple raters via agreement indices are necessary before their participation. While the intuitively appealing agreement indices such as coverage probability and total deviation index, and relative area under cover...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Introduction:
Drug-induced liver injury (DILI) is a diagnosis of exclusion, and it can be challenging to adjudicate when there are multiple comorbidities and concomitant medications. In this study, we tested the hypothesis that comorbidity burden impacts the causality adjudication in patients with suspected DILI.
Methods:
We studied consecutive...
Background and aim:
Trimethoprim-sulfamethoxazole (TMP-SMX) is an important cause of idiosyncratic drug induced liver injury (DILI), but its genetic risk factors are not well understood. We investigated the relationship between variants in the HLA Class I and II genes and well characterized cases of TMP-SMX DILI.
Methods:
European American and A...
Background and aims:
The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network.
Methods:
All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-...
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...
With the application of genetic testing to contemporary medical diagnostics and practice, it has become apparent that the phenotypes of many disorders are modulated by host genetic factors. The aim of the current study was to determine whether selected single nucleotide polymorphisms (SNPs) unrelated to the human leukocyte antigen region or other i...
Objectives:
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 betw...
Background:
Bodybuilding supplements can cause a profound cholestatic syndrome.
Aim:
To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements.
Methods:
Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were a...
Aims:
Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anemia of the elderly in HF. Thus, we aimed to determine the incidence of anemia, to characterize diagnostic testing patterns for potentially reversible causes of anemia, and to evaluate the independent association between incident anemia and long-term...
Purpose of review:
There are three liver-specific causality assessment tools currently available to guide clinical diagnosis of Drug-Induced Liver Injury (DILI): Roussel-Uclaf Causality Assessment Method (RUCAM), Digestive-Disease-Week Japan 2004 scale (DDW-J), and Clinical Diagnostic Scale (CDS). The purpose of this review is to assess these tool...
[This corrects the article DOI: 10.1371/journal.pone.0206389.].
Objectives:
This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.
Background:
In patients with heart failure with reduced ejection fraction (HFrEF), it is unclear if lowering natriuretic peptides reflects structural and functional changes in the heart. This study aims to assess the assoc...
![Immune analytes significantly associated with death [before 6 months]...](publication/328523274/figure/tbl2/AS:11431281272072390@1723842038225/Immune-analytes-significantly-associated-with-death-before-6-months-among-Subjects-with_Q320.jpg)
Changes in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum...
More detailed description of the acute liver failure study group protocol and consortium: Clinical centers currently participating in the acute liver failure study group.
(DOCX)
Causative agents of acute drug-induced liver injury among subjects from the DILI.
(DOCX)
More detailed description of the drug-induced liver injury network protocol: Clinical centers participating in DILIN since its inception in 2003.
(PDF)
Causative agents of acute drug-induced liver injury among subjects from the acute liver failure registry.
(PDF)
Purpose of Review
Drug-induced liver injury (DILI) is a complex diagnosis dominantly based of exclusion.
Recent Findings
Currently available causality assessment instruments are considered to be suboptimal. Expert opinion appears to be best method to adjudicate causality, but is impractical to implement on a wide scale basis. Thus, new approaches...
Background and aims:
Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. Study aims include a description of the presenting features and outcomes of patients with terbinafine hepatotoxicity as well as investigation of the role of HLA-A ∗33:01 METHODS: Consecutive high causality cases of terbinafine he...
Drug-induced liver injury can lead to changes of the biliary tree that resemble sclerosing cholangitis. These changes can be seen on magnetic resonance cholangiopancreatography. Idiosyncratic drug-induced liver injury (DILI) has a variable presentation including cholestatic liver injury,1 in which case magnetic resonance imaging (MRI) is often perf...
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the United States. Multiple risk factors contribute to DKD development, yet few interventions target more than a single DKD risk factor at a time. This manuscript describes the study protocol, recruitment, and baseline participant characteristics for the Simult...
Measurements serve as the basis for evaluation in almost all scientific disciplines, especially in physical sciences, medical studies, and health care. Issues related to reliable and accurate measurement have evolved over many decades. Requiring a measurement to be identical to the truth is sometimes impractical or impossible either because (i) the...
Background:
As the potential for cancer therapy-related cardiac dysfunction is increasingly recognized, there is a need for the standardization of echocardiographic measurements and cut points to guide treatment. The aim of this study was to determine the reproducibility of cardiac safety assessments across two academic echocardiography core labor...
We evaluated whether low-grade albuminuria or black race modulates ambulatory blood pressure (BP) or nocturnal BP response to the DASH diet. Among 202 adults enrolled in the DASH multicenter trial who were fed the DASH or control diet for 8 weeks, reductions in 24-hour daytime and nighttime SBP and DBP were significantly larger for DASH compared to...
Background:
Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended.
Aims:
The aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate.
Methods...
Background:
Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure...
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 Af...
While racial variation in ambulatory blood pressure (BP) is known, patterns of diurnal dipping in the context of diabetic kidney disease have not been well defined. The authors sought to determine the association of race with nocturnal dipping status among participants with diabetic kidney disease enrolled in the STOP-DKD (Simultaneous Risk Factor...
Drug-induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities is poorly characterized, particularly when fatalities occur >26 weeks after DILI onset. We analyzed patients in the US Drug-Induced Liver Injury Network prospective study having a fatal outcome wi...
Background and purpose:
We compared the association of low estimated glomerular filtration rate (eGFR) with stroke outcomes among patients with hypertension and without hypertension.
Methods:
We used the China stroke registry to identify patients on discharge with the diagnosis of stroke in 2012 and 2013. Low eGFR was defined as <60 mL/min/1.73...
Background & aims:
Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline DILI in a well-phenotyped cohort of patients.
Methods:
Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compare...
Background and 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 histologic features of liver injury in 212 adults enrolled in the Drug-Induced Liver I...
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 in...
Background & aims:
We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors.
Methods:
We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior...
Background:
There is no broadly accepted standard method for assessing the quality of echocardiographic measurements in clinical research reports, despite the recognized importance of this information in assessing the quality of study results.
Methods:
Twenty unique clinical studies were identified reporting echocardiographic data quality for de...
Background and aims:
Amoxicillin-clavulanate (AC) is the most frequent cause of idiosyncratic drug-induced injury (DILI) in the US DILI Network (DILIN) registry. Here, we examined a large cohort of AC-DILI cases and compared features of AC-DILI to those of other drugs.
Methods:
Subjects with suspected DILI were enrolled prospectively, and cases...
The 36-Item Short Form Health Survey (SF-36) has been widely used to measure quality of life. Reliability has been traditionally assessed by intraclass correlation coefficient (ICC), which is equivalent to Cronbach's alpha theoretically. However, it is a scaled assessment of reliability and does not indicate the extent of differences because of mea...
