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Cited by 10Drug-Induced Hepatotoxicity and ProtectionMetabolomics and Mass Spectrometry StudiesLiver Disease Diagnosis and Treatment

The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index; none of the 46 sources its claims cite is checked for support yet.

Metabolomic Analysis of Pediatric Patients with Idiosyncratic Drug-Induced Liver Injury According to the Updated RUCAM

Open access
Andújar-Vera, Francisco, Alés-Palmer, María Luisa, Muñoz-de-Rueda, Paloma, Iglesias-Baena, Iván, Ocete-Hita, Esther·2023·International Journal of Molecular Sciences
DOI 10.3390/ijms241713562PMC PMC10487599
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Abstract

Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case–control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696–0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injury.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This observational case–control study applied untargeted plasma metabolomics to pediatric idiosyncratic drug-induced liver injury (DILI) diagnosed with updated RUCAM, finding distinct metabolic profiles versus controls. A five-metabolite model distinguished DILI from controls with an AUC of 0.817 (95% CI 0.696–0.913), and primary bile acid biosynthesis plus taurine/hypotaurine metabolism were significantly altered.

Key findings

  • After excluding patients with cancer, the analyzed sample comprised 32 children with DILI and 66 controls; untargeted metabolomics identified 195 significantly differential variables (FDR < 0.05), with 28 variables corresponding to 20 metabolites reported in Table 2.
  • A biomarker model combining hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine (16:1/0:0), glycocholic acid, and taurocholic acid yielded an AUC of 0.817 (95% CI 0.696–0.913); cross-validation correctly classified 23 children with hepatotoxicity but misclassified 10, and correctly classified 56 controls while misclassifying 12.
  • Pathway analysis showed significant involvement of primary bile acid biosynthesis and taurine/hypotaurine metabolism (p < 0.05), with bile acids elevated in children with hepatotoxicity.
  • The paper states this is the first study to apply metabolomics to characterize idiosyncratic DILI in children.

Methods

  • Observational case–control study of pediatric patients aged 0–15 years; initial population was 143 children, including 55 diagnosed with DILI and 88 controls, with 45 oncology patients noted and cancer patients later excluded from metabolomic analysis.
  • DILI diagnosis used updated RUCAM and criteria based on ALT, ALP, bilirubin, and R value; plasma samples were analyzed by untargeted HPLC–MS/MS using an Agilent 1290 chromatograph coupled to a QTOF5600 mass spectrometer.
  • Data were processed in MetaboAnalyst 5.0 with normalization, log transformation, and autoscaling; analyses included Student’s t-test, PCA, PLS-DA, VIP scores, pathway analysis, and ROC curve analysis.

Limitations

  • The paper states that many molecules remained unidentified due to lack of experimental fragmentation spectra, and assigning a single molecular formula was sometimes difficult.
  • The paper states the study was limited by a reduced number of samples, due to few pediatric DILI patients allowing sample use and difficulty obtaining pediatric controls; it also states that because metabolomics was performed after RUCAM-based diagnosis, it cannot conclude whether bile acid alteration is a consequence or cause of DILI, and that the sample size did not allow differentiation between drugs acting via BSEP inhibition versus other mechanisms.
  • The text makes evident additional constraints: cancer patients were excluded after initial analysis, outliers were removed, the final analyzed sample was smaller than the initially described population, and the authors state that further validation in an independent cohort is required.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms241713562

Cites

62 of 62 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Metabolomic analysis revealed clear differences between pediatric DILI patients and healthy controls.

    “The results revealed clear differences between the two groups.”
    • Also stated in: § 2.1. Data Matrix and Analytical Validation · hedged
      “Furthermore, two distinct clusters can be observed among the groups included in the study, indicating significant differences in metabolomic composition within these groups.”
    • Also stated in: § 3. Discussion · boosted
      “The untargeted metabolomic analysis performed on this group of children revealed clear differences between those who developed DILI and those who did not.”
    Quote in the paperSubstantial claim
  • Findingown data

    Subsequent analysis confirmed that alteration of these metabolites significantly affected bile acid biosynthesis pathways.

    “Subsequent analysis, focused on the metabolic pathways signaled by these metabolites, confirmed that the alteration of these metabolites significantly affected bile acid biosynthesis pathways.”
    Quote in the paperSubstantial claim
  • Findingown data

    Student's t-test revealed 195 significantly differential variables with FDR < 0.05.

    “Student’s t-test revealed 195 significantly differential variables, with an error correction factor false discovery rate (FDR) < 0.05.”
    Quote in the paperSubstantial claim
  • Findingown data

    The most frequently implicated drugs in DILI in this study were antimicrobials.

    “In the present study, the most frequently implicated drugs in DILI were antimicrobials.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity.

    “The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity.”
    Quote in the paperSubstantial claim
  • It may state two separate claims as one. 25
  • Probably not a substantial claim. 24

  • It may state two separate claims as one.

    Findingown data

    Most significant variables presented poor chromatographic retention; many molecules overlapped within the same retention time, suggesting they were polar in nature.

    “Most of the variables found to be significant presented poor chromatographic retention. Moreover, many molecules overlapped within the same retention time, suggesting they were polar in nature.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Model fit was R2 = 0.57 and Q2 = 0.48 for three components, and a permutation test gave p < 0.01.

    “The fit of the model and its predictive capacity were measured by the R2 value. For three components, R2 = 0.57 and Q2 = 0.48. A permutation test based on 100 observations was then conducted (see Figure 4A), obtaining p < 0.01, which was significant for the multivariable model obtained.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Five metabolites were combined: hydroxydecanoylcarnitine and octanoylcarnitine had high values in the control group, while lysophosphatidylcholine (16:1/0:0), glycocholic acid, and taurocholic acid had high values in children with DILI.

    “Accordingly, the following five metabolites were tentatively identified and combined; on the one hand, hydroxydecanoylcarnitine and octanoylcarnitine, with high values in the control group; on the other hand, lysophosphatidylcholine (16:1/0:0), glycocholic acid, and taurocholic acid, with high values in children with DILI.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The >30% difference in metabolites was assumed to be caused by the biological conditions of the individuals.

  • It may state two separate claims as one.

    Findingown data

    Cross-validation correctly classified 23 children with hepatotoxicity and misclassified 10; in controls, 56 were classified correctly and 12 were misclassified.

    “The results based on cross-validation correctly classified 23 children with hepatotoxicity, but misclassified 10. In the control group, 56 children were classified correctly, and 12 were misclassified.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Some commonly used drugs were identified as differential, indicating some children were taking other medications, mainly antipyretics.

    “In addition, some commonly used drugs were identified as differential, indicating that some of the children in the study were taking other medications, mainly antipyretics.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    PLS-DA groups presented good separation; two principal components explained more than 60% of the supervised model.

    “As can be seen in Figure 3B, the groups presented good separation. Only two of the principal components were needed to explain more than 60% of the supervised model.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Table 2 shows 28 variables identified, corresponding to 20 metabolites.

    “Table 2 shows the 28 variables that were identified, which corresponded to 20 metabolites.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The >30% difference in metabolites was assumed to be caused by the biological conditions of the individuals.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    Many molecules remained unidentified due to lack of experimental fragmentation spectra, and it was sometimes difficult to assign a single molecular formula to a metabolite.

    “In the present study, unfortunately, many molecules remained unidentified, due to the lack of experimental fragmentation spectra. Moreover, on some occasions, it was difficult to exactly assign a single molecular formula to a metabolite.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    The analytical analysis was highly reproducible, with retention time drift of no more than 0.1 min between samples.

    “As can be seen in the chromatogram, the analysis was highly reproducible, since the overlapping of all the signals was perfectly apparent, indicating little to no variability in the retention time drift by which the different metabolites could be detected.”
    • Also stated in: § 2.1. Data Matrix and Analytical Validation · plain
      “This finding was corroborated by reviewing different signals throughout the chromatogram and evaluating the changes in retention times; in no case did the metabolites drift from one sample to another by more than 0.1 min.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Premisecitation

    The current diagnosis of drug-induced liver injury is based on determination of transaminases and serum bilirubin levels that are not specific for DILI.

    “Moreno-Torres et al. in a recent review (June 2022) recognized that the current diagnosis of drug-induced liver injury is based on determination of transaminases and serum bilirubin levels that are not specific for DILI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Moreno-Torres et al. in a recent review (June 2022) source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Idiosyncratic DILI is complex, multifactorial, not predictable, species-specific, cannot be reproduced; the patient is the sole source of the study.

    “Idiosyncratic toxicity is more common. This is a complex, multifactorial disease that may involve factors associated with the poison, the patient, and/or the environment. They are not predictable and are species-specific; thus, they cannot be reproduced. As a consequence, the patient is the sole source of the study.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Teschke, 2019, Idiosyncratic DILI: Analysis of 46,266 Cases Assessed for Causality by RUCAM and Published From 2014 to Early 2019, Front. Pharmacol. source
    • cites [2] Teschke, 2021, Mechanism of Idiosyncratic Drug Induced Liver Injury (DILI): Unresolved Basic Issues, Ann. Transl. Med. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Metabolomics can help establish markers of severity and/or chronicity of DILI.

    “Recent studies in adults showed that metabolomics can help establish markers of severity and/or chronicity of DILI.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] He, 2022, Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury, Front. Pharmacol. source
    • cites [50] Zhao, 2022, Alteration of Bile Acids and Omega-6 PUFAs Are Correlated with the Progression and Prognosis of Drug-Induced Liver Injury, Front. Immunol. source

  • Probably not a substantial claim.

    Premisereasoning

    There are limitations preventing metabolomics research findings from being translated into general clinical practice.

    “but there are still limitations preventing these research findings from being translated into general clinical practice”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Moreno-Torres, M., Quintás, G., and Castell, J.V. (2022). The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment. Metabolites, 12. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Elevated circulating bile acids are associated with NAFLD risk factors; metabolomic studies show global alterations in bile acid composition in steatosis; bile acids have been studied as a therapeutic target in NAFLD.

    “Elevated circulating levels of bile acids have been associated with major risk factors for non-alcoholic fatty liver disease (NAFLD), including insulin resistance and type 2 diabetes mellitus [43,44]. In addition, metabolomic studies conducted in the adult population have revealed global alterations in bile acid composition in individuals with simple steatosis compared with healthy controls [45,46”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [43] Ma, 2014, Bile Acids, Obesity, and the Metabolic Syndrome, Best Pract. Res. Clin. Gastroenterol. source
    • cites [44] Manco, M. (2017). Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. Children, 4. source
    • cites [45] Dasarathy, 2011, Elevated Hepatic Fatty Acid Oxidation, High Plasma Fibroblast Growth Factor 21, and Fasting Bile Acids in Nonalcoholic Steatohepatitis, Eur. J. Gastroenterol. Hepatol. source
    • cites [46] Kalhan, 2011, Plasma Metabolomic Profile in Nonalcoholic Fatty Liver Disease, Metabolism source
    • cites [47] Younossi, 2019, Obeticholic Acid for the Treatment of Non-Alcoholic Steatohepatitis: Interim Analysis from a Multicentre, Randomised, Placebo-Controlled Phase 3 Trial, Lancet source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The most frequently implicated drugs in adult DILI are amoxicillin-clavulanate, flucloxacillin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and anabolic steroids.

    “The most frequently implicated drugs in the adult population are amoxicillin–clavulanate, flucloxacillin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and anabolic steroids such as bodybuilding agents [20].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Teschke, 2018, Top-Ranking Drugs out of 3312 Drug-Induced Liver Injury Cases Evaluated by the Roussel Uclaf Causality Assessment Method, Expert Opin. Drug Metab. Toxicol. source

  • It may state two separate claims as one.

    Premisecitation

    Little use has been made of metabolomics in the study of hepatotoxicity in adults, with no studies in children.

    “Although some preliminary exploratory research has been conducted [16,17,18], little use has been made of this technique in the study of hepatotoxicity in adults, with no studies in children.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Castell, 2015, LC-MS Untargeted Metabolomic Analysis of Drug-Induced Hepatotoxicity in HepG2 Cells, Electrophoresis source
    • cites [17] Iruzubieta, 2015, The Need for Biomarkers in Diagnosis and Prognosis of Drug-Induced Liver Disease: Does Metabolomics Have Any Role?, BioMed Res. Int. source
    • cites [18] Grootveld, M. (2015). Metabolic Profiling: Disease and Xenobiotics, The Chemical Society. Issues in Toxicology 21. source

  • It may state two separate claims as one.

    Interpretationown data

    Some metabolites were related to drug delivery at specific times without producing a harmful effect, but others such as primary bile acids participated directly in the metabolism of interest, provoking a direct effect on liver function.

    “Of these metabolites, some were related to drug delivery at specific times without producing a harmful effect, but others, such as primary bile acids, participated directly in the metabolism of interest, provoking a direct effect on liver function.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    These metabolites could be a putative biomarker for prediction or confirmation of DILI, or predict its triggering at an early stage through possible monitoring of blood levels.

    “These metabolites could be a putative biomarker for prediction or confirmation of DILI, or even predict its triggering at an early stage through possible monitoring of blood levels.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    PCA showed perfect grouping of QC samples, validating reproducibility of injections.

    “Figure 2 shows a perfect grouping of the QC samples, thus validating the analysis in terms of reproducibility in the injections.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Various animal studies and in vitro models have identified changes in the metabolomic profile in the presence of DILI.

    “Various animal studies and in vitro models have identified changes in the metabolomic profile in the presence of DILI [13,16,22,23,24,25,26,27,28,29,30,31,32,33,34,35].”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [13] Mattes, 2014, Detection of Hepatotoxicity Potential with Metabolite Profiling (Metabolomics) of Rat Plasma, Toxicol. Lett. source
    • cites [16] Castell, 2015, LC-MS Untargeted Metabolomic Analysis of Drug-Induced Hepatotoxicity in HepG2 Cells, Electrophoresis source
    • cites [22] Gonzalez, 2012, Serum UPLC-MS/MS Metabolic Profiling in an Experimental Model for Acute-Liver Injury Reveals Potential Biomarkers for Hepatotoxicity, Metabolomics source
    • cites [23] Kumar, 2012, Discovery of Common Urinary Biomarkers for Hepatotoxicity Induced by Carbon Tetrachloride, Acetaminophen and Methotrexate by Mass Spectrometry-Based Metabolomics, J. Appl. Toxicol. JAT source
    • cites [24] Li, Z., Li, Q., Geng, L., Chen, X., and Bi, K. (2013). Use of the Local False Discovery Rate for Identification of Metabolic Biomarkers in Rat Urine Following Genkwa Flos-Induced Hepatotoxicity. PLoS ONE, 8. source
    • cites [25] Lu, 2010, NMR-Based Metabonomic Analysis of the Hepatotoxicity Induced by Combined Exposure to PCBs and TCDD in Rats, Toxicol. Appl. Pharmacol. source
    • cites [26] Buness, A., Roth, A., Herrmann, A., Schmitz, O., Kamp, H., Busch, K., and Suter, L. (2014). Identification of Metabolites, Clinical Chemistry Markers and Transcripts Associated with Hepatotoxicity. PLoS ONE, 9. source
    • cites [27] Conotte, 2014, A Metabonomic Evaluation of the Monocrotaline-Induced Sinusoidal Obstruction Syndrome (SOS) in Rats, Toxicol. Appl. Pharmacol. source
    • cites [28] Peng, J., Cai, S., Wang, L., Zhao, N., Zhang, T., Chen, Z., and Meng, F. (2014). A Metabonomic Analysis of Serum from Rats Treated with Ricinine Using Ultra Performance Liquid Chromatography Coupled with Mass Spectrometry. PLoS ONE, 9. source
    • cites [29] Gonzalez, 2014, Quantitative Proteomic Analysis of Hepatocyte-Secreted Extracellular Vesicles Reveals Candidate Markers for Liver Toxicity, J. Proteom. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In pediatric medicine, DILI is rare but has high morbidity and mortality and is one of the most common causes of acute liver failure; diagnosis is challenging due to low incidence and phenotypic variability.

    “In pediatric medicine, DILI is a rare clinical situation. However, it has high morbidity and mortality, and it is one of the most common causes of acute liver failure. Furthermore, its diagnosis is clinically challenging due to its low incidence and phenotypic variability [6,7,8].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Kuna, 2018, Models of Drug Induced Liver Injury (DILI)—Current Issues and Future Perspectives, Curr. Drug Metab. source
    • cites [7] Andrade, 2019, EASL Clinical Practice Guidelines: Drug-Induced Liver Injury, J. Hepatol. source
    • cites [8] DiPaola, 2019, US Drug Induced Liver Injury Network Antimicrobials and Antiepileptics Are the Leading Causes of Idiosyncratic Drug-Induced Liver Injury in American Children, J. Pediatr. Gastroenterol. Nutr. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Childhood is characterized by growth and development, organ maturation, and variability in drug kinetics and response, making children especially vulnerable to adverse drug effects.

    “Childhood is characterized by growth and development, with a gradual process of organ and system maturation and consequent variability in drug kinetics and response [3]. This circumstance makes the child especially vulnerable to the adverse effects of medications.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Shi, 2017, Drug-Induced Liver Injury in Children: Clinical Observations, Animal Models, and Regulatory Status, Int. J. Toxicol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    According to Ocete-Hita et al., the incidence of adverse drug reactions in children is 15.1 per 1000 children, representing 2% of pediatric hospital admissions, similar to adults; fewer than 8% may present liver involvement.

    “According to Ocete-Hita et al. [9], the incidence of adverse drug reactions in children is 15.1 per 1000 children. This represents 2% of admissions to a pediatric hospital, which is similar to the rate observed for adult patients. Fewer than 8% of these children may present liver involvement, which can range from a slight increase in transaminases to fulminant hepatitis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] 2013, Hepatotoxicity due to drugs or natural products in children, An. Pediatr. (Barc)

  • It may state two separate claims as one.

    Study design and conductreasoning

    The study was completed with 32 children with DILI and 66 controls after excluding cancer patients because cancer might interfere with the study aim.

    “These children presented similar and differential characteristics, very probably due to the cancer, and were excluded from the analysis because this circumstance might have interfered with the study aim, i.e., to detect specific biomarkers of liver toxicity (see Figure 3A).”
    • Also stated in: § 2.2. Statistical Analysis · plain
      “Therefore, the study was completed with 32 children with DILI and 66 controls.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Carnitine has hepatoprotective effects against various agents, and carnitine administration could ameliorate NAFLD.

    “Acetyl-L-carnitine is an effective substrate for mitochondrial energy metabolism. Carnitine also has free-radical-scavenging activity that enhances antioxidant status [53]. The hepatoprotective effects of carnitine against various agents, including acetaminophen, sodium valproate, and arsenic, have been proposed and demonstrated [53,54,55].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Alotaibi, 2016, Prophylactic and Therapeutic Potential of Acetyl-L-Carnitine against Acetaminophen-Induced Hepatotoxicity in Mice, J. Biochem. Mol. Toxicol. source
    • cites [54] Sepand, 2018, Acetyl-l-Carnitine Attenuates Arsenic-Induced Liver Injury by Abrogation of Mitochondrial Dysfunction, Inflammation, and Apoptosis in Rats, Environ. Toxicol. Pharmacol. source
    • cites [55] Lheureux, 2005, Science Review: Carnitine in the Treatment of Valproic Acid-Induced Toxicity—What Is the Evidence?, Crit. Care source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Scientifically valid information for pediatric prescriptions is scarce; adult information is often used because clinical trials in children are difficult to perform.

    “However, the scientifically valid information on which prescriptions for children are currently based is very scarce. In many cases, the information used is that available for the adult population, since clinical trials in children are difficult to perform [4,5].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Amin, 2015, Drug-Induced Liver Injury in Children, Curr. Opin. Pediatr. source
    • cites [5] Ye, 2021, Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method, Front. Pharmacol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Adult humans are characterized by individual metabolic phenotypes; metabolic profiles can predict susceptibility to DILI.

    “Adult humans are characterized by individual metabolic phenotypes [37,38,39,40,41]; there are areas of the metabolome unique to each individual that remain stable over time. “Metabolic profiles” can be detected that allow us to predict which individuals may present ways of metabolizing drugs that make them more susceptible to presenting DILI [17].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [37] Lindon, 2006, Pharmaco-Metabonomic Phenotyping and Personalized Drug Treatment, Nature source
    • cites [38] Huang, 2008, A Metabonomic Characterization of CCl4-Induced Acute Liver Failure Using Partial Least Square Regression Based on the GC/MS Metabolic Profiles of Plasma in Mice, J. Chromatogr. B source
    • cites [39] Liu, 2010, Metabonomics Study of Urine from Sprague–Dawley Rats Exposed to Huang-Yao-Zi Using 1H NMR Spectroscopy, J. Pharm. Biomed. Anal. source
    • cites [40] Lu, 2013, Integrated Analysis of Transcriptomics and Metabonomics Profiles in Aflatoxin B1-Induced Hepatotoxicity in Rat, Food Chem. Toxicol. source
    • cites [41] Shima, 2011, Influences of Methamphetamine-Induced Acute Intoxication on Urinary and Plasma Metabolic Profiles in the Rat, Toxicology source
    • cites [17] Iruzubieta, 2015, The Need for Biomarkers in Diagnosis and Prognosis of Drug-Induced Liver Disease: Does Metabolomics Have Any Role?, BioMed Res. Int. source

  • Probably not a substantial claim.

    Premisecitation

    RUCAM is considered a key diagnostic tool for DILI.

    “These are guided by the standards of the internationally recognized Roussel Uclaf Causality Assessment Method, which is considered a key diagnostic tool for DILI [11].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Hosack, 2023, Drug-Induced Liver Injury: A Comprehensive Review, Ther. Adv. Gastroenterol. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Metabolomics has contributed to the understanding of the underlying mechanisms of DILI.

    “Metabolomics has undoubtedly contributed to the understanding of the underlying mechanisms of DILI”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Moreno-Torres, M., Quintás, G., and Castell, J.V. (2022). The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment. Metabolites, 12. source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    The accumulation of intrahepatic cytotoxic bile acids due to drug-induced alterations in bile acid homeostasis could be an important factor contributing to the development of DILI in susceptible children.

    “The accumulation of intrahepatic cytotoxic bile acids due to drug-induced alterations in bile acid homeostasis could be an important factor contributing to the development of DILI in susceptible children.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The described strategy enables precise monitoring of DILI and determining the degree of functional recovery of the affected liver, beyond the mere absence of enzyme markers in the blood.

    “enabling precise monitoring of DILI and determining the degree of functional recovery of the affected liver, beyond the mere absence of enzyme markers in the blood.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    The described strategy represents a more direct and specific diagnostic approach for DILI.

    “Specifically, this strategy represents a more direct and specific diagnostic approach”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    One cannot rule out the possibility that the alteration of bile acids might be the cause determining DILI and not its consequence.

    “Although this seems to be the most probable theory, one cannot rule out the possibility that it might be the cause determining the DILI and not its consequence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Analytical validation was carried out using principal component analysis (PCA) to test the clustering of quality control samples injected during the analysis.

    “Analytical validation was carried out using principal component analysis (PCA) to test the clustering of quality control samples injected during the analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductreasoning

    The results obtained are an approximation of initial interest, with sample limitations.

    “The results obtained are an approximation of initial interest, with sample limitations”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: DILI in children is a rare health issue.

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    The approach described for studying patients with DILI is in accordance with similar studies considered innovative.

    “The approach we described for studying patients with drug-induced liver injury (DILI) is in accordance with similar studies considered innovative”
    Quote in the paperNot a substantial claim
36 of 36

  • The authors state this as an assumption.

    The hepatocyte endometabolome is likely to be mirrored to some extent by the hepatic exometabolome.

    “Assuming that the hepatocyte endometabolome is likely to be mirrored to some extent by the hepatic exometabolome, our aim in this study was to identify metabolic changes in the serum of pediatric DILI patients that reflect the differential features of childhood hepatotoxicity.”

  • The authors state this as an assumption.

    The >30% difference in metabolites was assumed to be caused by the biological conditions of the individuals.

    “This difference was the variability assumed to be caused by the biological conditions of the individuals.”

  • The paper relies on this without support.

    DILI in children is a rare health issue.

    “DILI in children is a rare health issue.”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • ROC classification counts exceed the analyzed group sizes

    Major

    The reported classification results account for 33 children with DILI (23 + 10) and 68 controls (56 + 12), but the analysis is stated to contain only 32 children with DILI and 66 controls. This makes the reported cross-validation results inconsistent with the stated sample sizes.

  • Metabolomic study sample is called both serum and plasma

    Major

    The sample described as collected for the metabolomic study is serum, whereas the preparation method describes plasma samples. These are different specimen types, and the text does not explain a change between them.

2 of 2

Citations

Cites

Flagged first, then by citations

1 of the 63 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 2013, Hepatotoxicity due to drugs or natural products in children, An. Pediatr. (Barc), 78, 248

Cited by

Sorted by citations

Related

Metadata

Authors
Andújar-Vera, F., Alés-Palmer, M. L., Muñoz-de-Rueda, P., Iglesias-Baena, I., & Ocete-Hita, E.
Affiliations
  • Instituto de Investigación Biosanitaria de Granada (ES)
  • Universidad de Granada (ES)
  • Research Support Unit, Biosanitary Research Institute ibs.GRANADA, 18012 Granada, Spain
  • Research Unit, GenActive Clinic & Research, 18193 Granada, Spain
  • Department of Pediatrics, University of Granada, 18016 Granada, Spain
Corresponding author
Alés-Palmer, María Luisa
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2023-09-01
Volume
24
Issue
17
Pages
13562
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms241713562
PMC
PMC10487599
OpenAlex
W4386397146
Semantic Scholar
f1c3c1f09457856263bd933524c5590bb4d7ee2e
Cited by
10
References
63
Citations by year
2026: 6 · 2025: 1 · 2024: 3
FWCI
1.55
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Repository of the University of Granada (University of Granada) (submittedVersion, cc-by)
Funders
  • Institute of Health Carlos III (PI17/01989, F2-0071-2015)
  • Servicio Andaluz de Salud (PI17/01989, F2-0071-2015)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Keywords
idiosyncratic drug-induced liver injury, RUCAM, bile acids, primary bile acid biosynthesis, taurine and hypotaurine metabolism, octanoylcarnitine, lysophosphatidylcholine, taurocholate, glycocholic acid
MeSH terms
Adult, Bile Acids and Salts, Child, Humans, Case-Control Studies, Metabolomics, Chemical and Drug Induced Liver Injury, Drug-Related Side Effects and Adverse Reactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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