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Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study.

ABSTRACT: The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established.The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months.Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 ?U/L, alanine aminotransferase 727? U/L, alkaline phosphatase 331 ?U/L, and total bilirubin 3.9? mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury.Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen.

SUBMITTER: Molleston JP

PROVIDER: S-EPMC3634369 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other

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Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study.

Molleston Jean P JP Fontana Robert J RJ Lopez M James MJ Kleiner David E DE Gu Jiezhun J Chalasani Naga N

Journal of pediatric gastroenterology and nutrition 20110801 2

<h4>Background</h4>The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established.<h4>Patients and methods</h4>The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at ...[more]

PMID: 21788760

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Project description:Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence. Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher's exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes. Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol-water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs. Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.

Project description:Background & aimsThe Drug-Induced Liver Injury Network is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study.MethodsIn an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI.ResultsAmong 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation, and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P = .09) and mortality was significantly higher (16% vs 5.2%; P < .001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared with those without liver disease (6.7% vs 1.5%; P = .006). Forty-one cases with latency ≤7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared with individuals younger than 65 years, individuals 65 years or older (n = 149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died.ConclusionsMortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared with patients without. Additional studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Dataset Information

Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study.

Publications

Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study.

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