Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the Drug‐Induced Liver Injury Network (DILIN)

Background & AimsBecause of the lack of objective tests to diagnose drug‐induced liver injury (DILI), causality assessment is a matter of debate. Expert opinion is often used in research and industry, but its test–retest reliability is unknown. To determine the test–retest reliability of the expert opinion process used by the Drug‐Induced Liver Injury Network (DILIN).MethodsThree DILIN hepatologists adjudicate suspected hepatotoxicity cases to one of five categories representing levels of likelihood of DILI. Adjudication is based on retrospective assessment of gathered case data that include prospective follow‐up information. One hundred randomly selected DILIN cases were re‐assessed using the same processes for initial assessment but by three different reviewers in 92% of cases.ResultsThe median time between assessments was 938 days (range 140–2352). Thirty‐one cases involved >1 agent. Weighted kappa statistics for overall case and individual agent category agreement were 0.60 (95% CI: 0.50–0.71) and 0.60 (0.52–0.68) respectively. Overall case adjudications were within one category of each other 93% of the time, while 5% differed by two categories and 2% differed by three categories. Fourteen per cent crossed the 50% threshold of likelihood owing to competing diagnoses or atypical timing between drug exposure and injury.ConclusionsThe DILIN expert opinion causality assessment method has moderate interobserver reliability but very good agreement within one category. A small but important proportion of cases could not be reliably diagnosed as ≥50% likely to be DILI.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111130/1/liv12540.pd

Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72563/1/j.1365-2893.2005.00581.x.pd

Drug-Induced Liver Injury Network (DILIN) Prospective Study: Rationale, Design and Conduct

Drug-induced liver injury (DILI) is an uncommon adverse drug reaction of increasing importance to the medical community, pharmaceutical industry, regulatory agencies and the general public

Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity

IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals

Liver injury from herbals and dietary supplements in the U.S. Drug‐Induced Liver Injury Network

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108649/1/hep27317.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/108649/2/hep27317-sup-0001-supptbl1.pd

Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally

Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled

Hepatic histological findings in suspected drug‐induced liver injury: Systematic evaluation and clinical associations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102713/1/hep26709.pd

Hepatotoxicity Due to Hydroxycut: A Case Series

Muscletech Hydroxycut® (Iovate Health Sciences Research, Oakville, Ontario) was a popular weight loss supplement that was recalled by the manufacturer in May 2009 based on reports of hepatotoxicity associated with this supplement

Causes, Clinical Features, and Outcomes From a Prospective Study of Drug-Induced Liver Injury in the United States

Background and Aims Idiosyncratic drug-induced liver injury (DILI) is among the most common causes of acute liver failure in the United States, accounting for approximately 13% of cases. A prospective study was begun in 2003 to recruit patients with suspected DILI and create a repository of biological samples for analysis. This report summarizes the causes, clinical features, and outcomes from the first 300 patients enrolled. Methods Patients with suspected DILI were enrolled based on predefined criteria and followed up for at least 6 months. Patients with acetaminophen liver injury were excluded. Results DILI was caused by a single prescription medication in 73% of the cases, by dietary supplements in 9%, and by multiple agents in 18%. More than 100 different agents were associated with DILI; antimicrobials (45.5%) and central nervous system agents (15%) were the most common. Causality was considered to be definite in 32%, highly likely in 41%, probable in 14%, possible in 10%, and unlikely in 3%. Acute hepatitis C virus (HCV) infection was the final diagnosis in 4 of 9 unlikely cases. Six months after enrollment, 14% of patients had persistent laboratory abnormalities and 8% had died; the cause of death was liver related in 44%. Conclusions DILI is caused by a wide array of medications, herbal supplements, and dietary supplements. Antibiotics are the single largest class of agents that cause DILI. Acute HCV infection should be excluded in patients with suspected DILI by HCV RNA testing. The overall 6-month mortality was 8%, but the majority of deaths were not liver related