Drug-induced Liver Injury In Children Research Articles

Pharmacogenomic Predictors of Antibiotic-Associated Drug-Induced Liver Injury in Critically Ill Children: Observational Study Results

INTRODUCTION. The pathogenesis of antibiotic-associated drug-induced liver injury (DILI) in children has not been fully elucidated to date. Certain genotypes in patients increase the probability of developing DILI. Therefore, the identification of pharmacogenetic markers associated with DILI in children is essential.АIM. This study aimed to identify pharmacogenetic biomarkers of new-onset DILI associated with tigecycline and meropenem in children.MATERIALS AND METHODS. This prospective observational study was conducted in the Morozov Children’s CityClinical Hospital from 1 February 2020 to 1 September 2021. The study analysed the incidence and types of antibiotic-associated adverse drug reactions (ADRs) in 100 critically ill children aged 0 to 17 years (44 boys and 56 girls). Pharmacogenetic testing was performed in children with ADRs (n=30) to identify potential mechanisms involved in the development of their ADRs. The authors isolated and tested DNA from buccal epithelium swabs using the Agena Bioscience iPLEX® PGx Pro-based VeriDose® Core Panel covering 68 single nucleotide polymorphisms (SNPs) or short insertions and deletions (INDELs) and 5 copy number variants (CNVs).RESULTS. The odds of developing DILI associated with meropenem and tigecycline were higher in carriers of the homozygous cytochrome genotype CYP3A5*3/*3 (OR: 12.6, 95% CI: 1.9–79.4, r=6.54, p=0.011) than in patients with the heterozygous genotype CYP3A5*1A/*3. The odds were even higher in patients not carrying the CYP3A5*1A/*3 genotype (OR: 17.14, 95% CI: 1.79–16.3, r=6.24, p=0.013). The detection of the CYP3A5*3/*3 genotype had a prognostic accuracy of 76.7%, a sensitivity of 82%, and a specificity of 74% in predicting the risk of DILI associated with meropenem and tigecycline. Moreover, children with DILI carried the heterozygous genotype SLCO1B1*1/*5 (rs4149056 polymorphism) more often than children with other adverse reactions associated with meropenem and tigecycline (r=9.8, p=0.002).CONCLUSION. The results of this study prove the prognostic significance of the homozygous cytochrome genotype CYP3A*3/*3 as an indicator of a potential risk for developing DILI associated with meropenem and tigecycline in children in critical conditions.The study was registered at ClinicalTrials.gov under No. NCT04141657 on 24 October 2019.

Drug-Induced Liver Injury in Paediatrics: A Short Review

Drug-induced liver injury (DILI) is an under-recognized cause of paediatric liver disease. Although DILI in children accounts for about 1% of all reported adverse drug reactions throughout all age groups and less than 10% of all clinical DILI cases, it is responsible for about 20% of acute liver failure (ALF) cases. A wide range of drugs, herbal products and nutritional supplements have been associated with the development of DILI through dose-dependent, idiosyncratic or indirect mechanism. Limited literature is available in pediatric population, making DILI a still challenging diagnosis. An accurate medical history is of pivotal importance and should investigate about drug consumption, clinical and laboratory findings, individual and family risk factors for drug-related side effects or comorbidities, the timing of the injury onset after the implicated agent has been started (latency). Clinical presentation of DILI varies from asymptomatic or very mild to serious and sometimes fatal conditions; laboratory tests may be helpful in ruling out other causes of liver injury but, with few exceptions, they are aspecific. Early suspicion and prompt withdrawal of the offending drug play a key role for a successful management of most cases.
 Rarely a specific therapy is available, as for acetaminophen toxicity, treated with N-acetylcysteine, and sodium valproate toxicity, where carnitine may be beneficial. Although controlled trials are not available yet, corticosteroids and ursodeoxycholic acid can be considered if no improvement is proven after discontinuation of drug.
 The present short review is not intended to deal with all aspects concerning DILI but to focus on epidemiology, pathogenesis, clinical features, practical management and current challenges in paediatric age.

Causality Evaluation of Drug-Induced Liver Injury in Newborns and Children in the Intensive Care Unit Using the Updated Roussel Uclaf Causality Assessment Method

Purpose: Drug-induced liver injury (DILI) is a common adverse reaction in the clinic; however, there are relatively few reports of DILI in critically ill newborns and children. Making use of the Pediatric Intensive Care database (PIC), this study identifies which drugs are related to DILI in neonates and children in China. Methods: Using the PIC, we screened for patients whose liver was suspected of being injured by drugs during hospitalization. The medicine they used was then assessed by the Roussel Uclaf Causality Assessment Method (RUCAM). At the same time, we also collated drug combinations that may affect CYP (Cytochrome P) enzyme metabolism, which may cause DILI. Results: A total of 13,449 patients were assessed, of whom 77 newborns and 261 children were finally included. The main type of liver injury in neonates was mixed (83.1%), while the hepatic injury types of children were mostly distributed between hepatocellular (59.4%) and cholestatic (28.4%). In terms of the RUCAM assessment, the drugs that were most considered to cause or be associated with hepatic injury in newborns were medium and long chain fat emulsions (17%), sodium glycerophosphate (12%), and meropenem (9%); while omeprazole (11%), methylprednisolone sodium succinate (10%), and meropenem (8%) were the primary culprits of DILI in children. Drug combinations frequently seen in neonates that may affect CYP enzyme metabolism are omeprazole + budesonide (16.9%), dexamethasone + midazolam (10.4%), and midazolam + sildenafil (10.4%). In children, the commonly used drug combinations are fentanyl + midazolam (20.7%), ibuprofen + furosemide (18.4%), and diazepam + omeprazole (15.3%). Conclusions: In this study, medium and long chain fat emulsions and sodium glycerophosphate have been strongly associated with DILI in newborns, while omeprazole and methylprednisolone sodium succinate play an important role in the DILI of children. Also, attention should be paid to the effect on CYP enzymes when using multiple drugs at the same time. In future DILI cases, it is advisable to use the latest RUCAM for prospective study design so that complete case data and high RUCAM scores can be collected.

Signal Detection of Potentially Drug-Induced Liver Injury in Children Using Electronic Health Records.

Background: This study proposes a quantitative 2-stage procedure to detect potential drug-induced liver injury (DILI) signals in pediatric inpatients using an data warehouse of electronic health records (EHRs).Methods: Eight years of medical data from a constructed database were used. A two-stage procedure was adopted: (i) stage 1: the drugs suspected of inducing DILI were selected and (ii) stage 2: the associations between the drugs and DILI were identified in a retrospective cohort study.Results: 1,196 drugs were filtered initially and 12 drugs were further potentially identified as suspect drugs inducing DILI. Eleven drugs (fluconazole, omeprazole, sulfamethoxazole, vancomycin, granulocyte colony-stimulating factor (G-CSF), acetaminophen, nifedipine, fusidine, oseltamivir, nystatin and meropenem) were showed to be associated with DILI. Of these, two drugs, nystatin [odds ratio[OR]=1.39, 95%CI:1.10–1.75] and G-CSF (OR = 1.91, 95%CI:1.55–2.35), were found to be new potential signals in adults and children. Three drugs [nifedipine [OR = 1.77, 95%CI:1.26–2.46], fusidine [OR = 1.43, 95%CI:1.08–1.86], and oseltamivi r [OR = 1.64, 95%CI:1.23–2.18]] were demonstrated to be new signals in pediatrics. The other drug-DILI associations had been confirmed in previous studies.Conclusions: A quantitative algorithm to detect potential signals of DILI has been described. Our work promotes the application of EHR data in pharmacovigilance and provides candidate drugs for further causality assessment studies.

An electronic medical records-based approach to identify idiosyncratic drug-induced liver injury in children

Drug-induced liver injury (DILI) is the leading cause of liver failure in the United States and the most common cause of drug recall. As opposed to the recognized direct toxicity of super-therapeutic acetaminophen or chemotherapeutic agents in children, limited data exists for pediatric populations on the incidence of idiosyncratic DILI (iDILI) that may develop independently of drug dose or duration of administration. To improve the detection of adverse drug reactions at our hospital, we utilized electronic medical records-based automated trigger tools to alert providers of potential iDILI. Clinical criteria concerning for iDILI were defined as serum ALT > 5x or serum bilirubin > 1.5x upper limit of normal in the setting of medication exposure. Over a two year period, 12 patients were identified as having possible or probable iDILI. Out of the identified patients, three were males, and the mean age was 10.8 years. Implicated agents included eight antibiotics, two anti-epileptics, one anti-psychotic, and one anti-inflammatory medication. Roussel-Uclaf Causality Assessment Methods identified one “possible” case, 11 “probable” cases, and one “highly probable” case of iDILI. Improved awareness and more vigilant programming can generate better data on iDILI and improve our understanding of the condition and its incidence in children.

Analysis of chemotherapy drug-induced liver injury in children with acute lymphoblastic leukemia based on RUCAM scale

Objective To analyze the characteristics of drug-induced liver injury (DILI) in children with acute lymphoblastic leukemia (ALL), so as to improve the physician′s understanding of chemotherapy DILI, and to guide clinical rational drug use. Methods One hundred and forty-three cases with ALL diagnosed in the Department of Hematology and Oncology in the First Affiliated Hospital of Zhengzhou University from January 2012 to December 2016 were analyzed retrospectively.Based on DILI diagnostic criteria and the RUCAM scale, the cases with a score of ≥3 points were considered to have chemotherapy DILI.Grouped by gender, age, immunotyping, risk and stage of chemo-therapy, the incidence of DILI was compared.The situation after DILI prevention was compared between two groups which was grouped according to whether the application of hepatoprotective drugs. Results One hundred and eight cases (75.52%) had DILI, 66 cases (61.11%) showed clinical manifestations of liver injury, and 42 cases (38.89%) had no clinical symptoms.Among all the cases 57.41%(62 cases) were mild liver damage, 25%(27 cases) were moderate liver injury and 17.59%(19 cases) were severe liver damage.The clinical types which were hepatocellular accounting for 79.63%(86 cases), cholestatic 7.41%(8 cases) and mixed 12.96%(14 cases). Male were 80 cases (79.21%) and female 28 cases(66.67%), but the incidence of DILI between different gender group had no statistical difference (χ2=2.524, P=0.112). Seventy-five cases(77.32%) were 8 points accounted for 21 cases(19.45%), 6-8 points accounted for 59 cases(54.63%)and 3-5 points accounted for 28 cases(25.92%). Eighty-nine patients (92.71%) were effective in the hepatoprotective group and 8 patients (66.67%) in the no hepatoprotective therapy group.The difference between the 2 groups was statistically significant (χ2=5.317, P=0.021). Conclusions The clinical symptoms of drug-induced liver injury in children with ALL chemotherapy are lack of specificity.They are mainly characterized by mild liver injury.The clinical type of hepatic injury is common in hepatocellular.The RUCAM score was mostly 6 to 8.There is no relationship between the incidence in ALL and gender, age, type of leukemia.The incidence with moderate risk type is higher than that of the standard and high-risk type.The incidence in induction remission stage is highest.Application of hepatoprotective drugs is beneficial to DILI prognosis. Key words: Child; Acute lymphoblastic leukemia; RUCAM scale; Chemotherapy; Drug-induced liver injury

Antituberculosis Drug-induced Liver Injury in Children: Incidence and Risk Factors During the Two-month Intensive Phase of Therapy.

As one of the most frequent and serious adverse reactions during tuberculosis (TB) treatment, antituberculosis drug-induced liver injury (ATLI) in children has been studied insufficiently compared with adults. We aimed to determine the incidence and risk factors of ATLI in children during the first 2 months of TB therapy. A total of 41 children with TB and treated with first-line anti-TB drugs were prospectively followed-up for the development of ATLI. Liver function tests were performed at baseline and after 2 weeks of therapy. Subsequent tests were conducted at 4, 6 and 8 weeks if the initial 2-week measurement was abnormal or if symptoms of hepatotoxicity were reported. ATLI was detected in 11 (27%) patients within 14 to 42 days from the start of therapy, with most of them (54%) occurred after 2 weeks. TB treatment was stopped immediately in 6 of 11 patients who developed ATLI, and no recurrent hepatotoxicity after drug reintroductions in these patients. Univariate analysis showed that ATLI was significantly associated with TB meningitis (P < 0.01), hypoalbuminemia (P < 0.05) and hepatotoxic comedications (P < 0.01). Age, sex, nutritional status, HIV status and baseline liver function abnormalities were not associated with ATLI. Multivariate analysis identified hypoalbuminemia and hepatotoxic comedications (both P < 0.1) tend to be independently associated with ATLI. Children with hypoalbuminemia and use of hepatotoxic comedications are suggested to be monitored closely for the development of ATLI.

Drug-Induced Liver Injury in Children

Drug-induced liver injury (DILI) is relatively rare among children but can cause substantial morbidity and mortality. Here, we summarize the literature on pediatric DILI including a focus on commonly used classes of drugs. The incidence of pediatric DILI remains poorly defined. Antimicrobials and antiepileptic medications are the most commonly reported causes of pediatric idiosyncratic DILI in the US DILI network (DILIN) experience. DILI among children being treated for cancer appears to be underreported, and recent literature clearly implicates newer classes of agents such as tumor necrosis factor-α inhibitors as potentially hepatotoxic. Many drugs trigger signature patterns of DILI; autoimmune hepatitis secondary to minocycline is an example. DILI should be suspected whenever a child presents with evidence of liver injury. Familiarity with established patterns of DILI secondary to specific agents can facilitate recognition of cases. Active reporting of cases by clinicians to registries such as US DILIN remains critical to a continuing understanding of the causes and risk factors of DILI among children.

Chemotherapy induced liver toxicity in children with malignant diseases

Abstract A broad spectrum of chemotherapy is being used in the therapy of childhood cancers, which may induce liver injury, impairing quality of life and efficacy of the treatment. History of, especially viral, liver diseases may increase toxicity. The aim of the paper is to assess the incidence, type and grade, predisposing factors and treatment options of drug-induced liver injury in children with malignant diseases under cytostatic therapy at the Hemato-Oncology Department of the Pediatric Clinic 2 from Targu-Mures, over a time period spanning from 2012 to 2017. The results of the study may serve as a foundation for such treatment strategies which would enable optimal outcomes with fewer cases of liver toxicity. During this period, we treated 26 patients with acute lymphoblastic leukemia (ALL), two patients with acute myeloblastic leukemia (AML), one patient with lymphoma and seven with solid tumors. We found liver toxicity in 77% of the patients treated for ALL, mainly during the maintenance therapy (65%) with oral 6-mercaptopurine and methotrexate. The most common clinical signs were anorexia, nausea, vomiting, abdominal pain and faltering weight gain. Cholestasis developed in two patients, while hepatocytolysis was the most common observed event (n = 24). Liver fibrosis, hypersplenism, portal hypertension and esophageal varices were found in two patients. One patient required endoscopic ligation of esophageal varices. Elevation of serum bilirubin appeared in two patients, while hypoproteinemia was observed in nine patients. None of the patients developed acute liver failure. We treated liver toxicity with hydration, alkalinization, i.v. Aspatofort, Aminosteril-N Hepa 8%, oral acetylcysteine, silymarin, ursodeoxycholic acid, Liv-52, Sargenor, and Essentiale forte. We found hepatotoxicity in 77% of the ALL patients undergoing chemotherapy, similar results have been published by other authors. Hepatotoxicity may develop through direct hepatic effects of cytostatics, or a preexisting liver disease impairs the metabolism and excretion of the drug, increasing its toxic effects. In our patients hepatotoxicity can be explained mainly by direct liver-injury, previous infections with hepatotropic viruses, such as cytomegalovirus, were detected only in three patients. Liver injury appeared in 77% of our ALL patients; 65% occurred during maintenance therapy with oral 6-mercaptopurine and methotrexate. Close followup of liver function during chemotherapy is mandatory for optimal results.

Drug-induced liver injury in children – Case series from Mumbai

Drug-induced liver injury is one of the most common and most important forms of injury to the liver, accounting for over 20%–40% of all instances of fulminant hepatic failure. We present five cases, of which four were started on antituberculosis therapy and one was started on a therapy for seizures with carbamazepine. All of them showed adverse reactions on the liver and its functioning as was evident by the raised liver enzymes or jaundice.

Clinical Spectrum and Outcome of Pediatric Drug Induced Liver Injury.

Limited literature is available in pediatric population regarding drug-induced liver injury (DILI) making it a diagnostic challenge. This study was thus planned to determine the clinical spectrum and the outcome of DILI in children. All patients with DILI under 18 y of age were retrospectively reviewed and details regarding clinical presentation, Roussel Uclaf Causality Assessment Method (RUCAM) scale, drugs implicated, biochemical abnormalities and outcome were noted. DILI constituted 3.7% of all children with liver disease. Cases were divided into the hepatocellular (18, 50%), cholestatic (10, 27.8%), and mixed pattern (8, 22.2%). Complementary and alternative medicines (CAM) and antitubercular (ATT) drugs accounted for three-fourth cases of total DILI (39% and 33% cases respectively). Overall, 4 (11%) patients died and 5 (14%) patients progressed to chronic DILI. Presence of ascites, non-hepatocellular injury pattern and high serum total IgG levels were significantly associated with unfavourable outcome (death or chronicity).

Drug-Induced Liver Injury in Children: Clinical Observations, Animal Models, and Regulatory Status.

Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. The culprit drugs in cDILI are similar but not identical to DILI in adults (aDILI). This is demonstrated by recent findings that a drug frequently associated with aDILI (amoxicillin/clavulanate) was rarely associated with cDILI and that the drug basiliximab caused only cDILI but not aDILI. The fatality in reported cDILI studies ranged from 4% to 31%. According to the US Food and Drug Administration-approved drugs labels, valproic acid, dactinomycin, and ampicillin appear more likely to cause cDILI. In contrast, deferasirox, isoniazid, dantrolene, and levofloxacin appear more likely to cause aDILI. Animal models have been explored to mimic children's increased susceptibility to valproic acid hepatotoxicity or decreased susceptibility to acetaminophen or halothane hepatotoxicity. However, for most drugs, animal models are not readily available, and the underlying mechanisms for the differential reactions to DILI between children and adults remain highly hypothetical. Diagnosis tools for cDILI are not yet available. A critical need exists to fill the knowledge gaps in cDILI. This review article provides an overview of cDILI and specific drugs associated with cDILI.

Progress of diagnosis and treatment of drug induced liver injury in children

Drug induced liver injury(DILI ) is one of the most common factors causing liver damage and liver failure in children.And in most cases, patients' manifestations lack characteristic features.Thus, patients will develop gastrointestinal symptoms such as jaundice, nausea, vomiting and abdominal abstention until serious hepatic dysfunction.Futhermore, some patients are likely to develop acute liver failure, even death, without drug discontinuation and timely intervening measures.Early diagnosis and effective therapies considerably make sense.This review aims to illustrate the mechanism, manifestations, diagnosis and treatment of DILI in children, in order to promote the early treatment of the disease, reduce the serious complications and improve survival rate in clinical work. Key words: Child; Drug induced liver injury; Diagnosis; Treatment

Drug-induced liver injury in children.

Drug-induced liver injury (DILI) is an underrecognized cause of pediatric liver disease, accounts for almost 20% of pediatric acute liver failure cases, and is a major reason for liver transplantation in the USA. This article reviews the pathogenesis of DILI, approach to diagnosis and management, and highlights recent pediatric DILI case series. Select individuals have an increased propensity to develop DILI. Known genetic polymorphisms of enzymes and host factors play an important role in medication management and influence the clinical outcome in 20-25% of all drug therapies. Children are more likely to have mitochondrial dysfunction from drugs, increasing their susceptibility to severe liver injury or acute liver failure. Antibiotics and central nervous system agents account for the majority of pediatric DILI in the West, although herbals are becoming more common. Clinical features of DILI vary and overlap so exclusion of other conditions, identification of latency period and risk factors, and use of a searchable database can aid evaluation. Treatment consists of cessation of the offending agent and supportive care. Areas needing further research include elucidating mechanisms, identifying at risk individuals, and therapeutic interventions.

Clinical characteristics and outcomes of drug-induced liver injury in children: a study of 184 cases

Clinical characteristics and outcomes of drug-induced liver injury in children: a study of 184 cases

Epidemiology and risk factors for idiosyncratic drug-induced liver injury.

Idiosyncratic drug-induced liver injury (DILI) is, like other adverse effects of drugs, underreported and underestimated in most epidemiological studies based on registries of DILI cases and reporting systems (e.g., Medwatch). The same is probably true for prospective population-based studies, although they are much more likely to mirror the true incidence of DILI. Despite these challenges, the epidemiology of DILI remains of utmost importance and is gradually coming into better focus. A recent population based study found a crude incidence of ∼19 cases per 100,000 per year. Certain agents are particularly noteworthy for their DILI risk. Amoxicillin-clavulanate continues to be the most commonly implicated agent occurring in ∼1 out of 2,300 users. Some others that standout with significantly higher risk include azathioprine and infliximab. Although statin-induced hepatotoxicity has been well documented, the risk is probably quite low. Overall, the majority of DILI in children and adults is associated with either antibiotics or anticonvulsants. Drug-induced liver injury associated with intravenously given drugs does not show any major differences from DILI due to orally administered agents. Unfortunately, our understanding of pretherapy risk assessment remains rudimentary for the most part.

Characteristics of Idiosyncratic Drug‐induced Liver Injury in Children

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.