Efficacy and Safety of Compound Glycyrrhizin in the Treatment of Drug- Induced Liver Injury in Pediatric Cancer Patients: A Retrospective Cohort Study

Efficacy and Safety of Compound Glycyrrhizin in the Treatment of Drug- Induced Liver Injury in Pediatric Cancer Patients: A Retrospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Compound Glycyrrhizin in the Treatment of Drug- Induced Liver Injury in Pediatric Cancer Patients: A Retrospective Cohort Study Yuanpei Wang, Guifeng Li, Jinhang Du, Fengjiao Wang, Yamei Meng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6694007/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Drug-induced liver injury (DILI) caused by chemotherapy poses significant health risks for pediatric cancer patients and remains a serious clinical challenge. Currently, there are no clearly recommended pharmacological treatments specifically for managing DILI in children. Here, we assessed the efficacy and safety of Compound glycyrrhizin (CG) in treating DILI among children with cancer. Methods Data from a retrospective cohort study were analyzed to compare CG and magnesium isoglycyrrhizinate (MgIG) for treatment of DILI. We used the Roussel Uclaf causality assessment method (RUCAM) to evaluate patients with DILI. Patients with RUCAM scores ≥ 6 were included in the study. Propensity score matching was used to balance the baseline characteristics. The primary outcome was the proportion of patients with alanine aminotransferase (ALT) normalization at week 4 after CG and MgIG administration. The safety comparison between the two drugs was conducted by analyzing records of drug-related adverse events. Result A total of 234 eligible subjects were enrolled into two groups: 117 in the CG group and 117 in the MgIG group. Overall, 68.38% of patients in the CG group and 69.23% in the MgIG group achieved ALT normalization at week 4, with no statistically significant difference between the groups. ALT normalization rates increased gradually over time in both groups, yet no significant differences were observed at weeks 1, 2, or 3. Median ALT levels declined from baseline throughout the 4-week treatment period in both groups; however, differences between groups remained statistically insignificant at all time points. Similarly, the proportion of AST normalization showed no significant intergroup differences. Notably, a greater reduction in AST levels was observed in the MgIG group at week 3 (P = 0.032), but this difference was not maintained by week 4. In terms of safety, adverse events occurred in 1.71% of patients in the CG group and 5.12% in the MgIG group, without significant differences ( P = 0.281). Conclusion The efficacy and safety of CG and MgIG for treatment of DILI were comparable in children with cancer. This study provided preliminary evidence that CG is an effective and safe treatment for children with chemotherapy-induced liver injury. Drug-induced liver injury Pediatric cancer Compound glycyrrhizin Magnesium isoglycyrrhizinate Roussel Uclaf causality assessment method Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The liver is the primary organ responsible for the metabolism of many chemotherapeutic agents, making it particularly vulnerable to treatment-related damage. Liver injury induced by chemotherapy is common among children undergoing cancer treatment [ 1 ]. Drug-induced liver injury (DILI) is a frequently underdiagnosed condition that can result in severe acute or chronic liver disease in pediatric patients, accounting for approximately 10% of all DILI cases [ 2 ]. The main strategy for managing DILI is early discontinuation of the offending drug and avoiding re-exposure [ 3 ]. However, discontinuing the drug may compromise the treatment of the primary disease, such as cancer, posing a significant challenge in pediatric care. Furthermore, effective treatment options for DILI remain limited, with only a few regimens currently approved [ 4 ]. In clinical practice, liver-protective agents, such as compound glycyrrhizin (CG), polyene phosphatidylcholine, reduced glutathione, and tiopronin, are often used to manage DILI in children with cancer in China and other countries, despite the lack of robust evidence supporting their efficacy in this population [ 5 , 6 ]. CG is an active ingredient extracted from the roots of Glycyrrhiza glabra . It contains glycyrrhizin as the primary active component, along with glycine and cysteine hydrochloride. CG has demonstrated a variety of biological activities, including antioxidant and anticancer properties, and has been used clinically since 1979 for the treatment of chronic hepatitis in Japan [ 7 ]. Previous studies suggest that CG exerts hepatoprotective effects by targeting multiple pathways involved in reducing the inflammatory response, mitigating liver tissue damage, and promoting the repair of damaged liver cells [ 8 , 9 ]. Additionally, CG has been shown to decrease alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in a small trial involving patients with DILI [ 10 ]. However, there is limited evidence to support the use of CG in pediatric cancer patients experiencing DILI. Therefore, this study aims to evaluate the efficacy and safety of CG in treating DILI in the pediatric population. Additionally, the efficacy and safety of CG will be compared with magnesium isoglycyrrhizinate (MgIG), which has been approved by the Chinese Food and Drug Administration for the treatment of acute DILI [ 11 ]. Method A total of 3,671 inpatient data from the Children’s Hospital of Soochow University is a 3-year (2021–2023) retrospective cohort study. The following parameters were collected for all enrolled patients: 1) demographic information (such as gender, age, and body mass index (BMI)); 2) disease history; 3) information regarding drugs that may have caused liver injury, including time of symptom onset after starting the drug and the time of recovery after stopping the drug; 4) serum biochemical parameters before and during DILI, including levels of serum ALT, AST, alkaline phosphatase (ALP), total bilirubin (TBIL), as well as the international normalized ratio (INR); 5) the safety of CG and MgIG among the pediatric cancer patients with DILI was record by adverse events, such as drug eruption, hypotension and serum potassium; and 6) medical records to rule out other causes of liver injury. Study population Candidate subjects were enrolled into one of the two situations: pediatric cancer patients who received only CG injections (brand name: Meineng) or only MgIG injections (brand name: Ganmei) for DILI therapy were identified. CG and MgIG were administered intravenously at a daily dose of 20 mL and 10 mL respectively. All patient details were deidentified. We then excluded cases with the following condtions: 1) Viral hepatitis: such as hepatitis A, B, C, D, E; Epstein-Barr virus (EBV), cytomegalovirus (CMV); 2) Fatty liver disease, hepatolenticular degeneration and hepatobiliary organic lesions; 3) Autoimmune liver disease; 4) Hereditary metabolic liver disease; 5) Hypoxic injury of tissues and organs of the whole body caused by infection; 6) Hemodynamic abnormalities such as hypotension, shock, and vascular occlusive disease, and others not appropriate to be included after assessment by the investigators. The criteria for suspected DILI [ 12 ] that includes meeting one of the following thresholds: 1) ALT ≥ 5 × the upper limit of normal (ULN); 2) ALP ≥ 2 × ULN; and 3) ALT ≥ 3 × ULN concomitant with TBIL ≥ 2 × ULN. These patients were further evaluated using the Roussel Uclaf causality assessment method (RUCAM) to evaluate the relationship between the drugs used during the period of hospitalization and the patient’s liver injury [ 13 ]. Patients with RUCAM scores equal to or above 6 were enrolled in the study. All evaluations were performed independently by the three authors. The website Hepatoxic ( http://www.hepatox.org/ ) and drug instructions were used as the drug information source to verify the relationship between the drugs and hepatotoxicity. A 1:1 propensity score matching (PSM) was applied to ensure even distribution of confounders in the CG group and the MgIG group. Eligible DILI patterns were categorized as hepatocellular, cholestatic, and mixed, based on the value of R. The R value is calculated as R = (ALT/ULN)/(ALP/ULN). An ALT ≥ 3 × ULN and R ≥ 5 was termed hepatocellular, ALP ≥ 2 × ULN and R ≤ 2 was cholestatic, while ALT ≥ 3 × ULN, ALP ≥ 2 × ULN and 2 < R < 5 was classified as mixed. DILI was further categorized as mild, moderate, severe, and fatal/transplant. Mild DILI was defined as TBIL < 2.5 × ULN and INR < 1.5; moderate DILI as TBIL ≥ 2.5 × ULN or INR ≥ 1.5; severe DILI as TBIL ≥ 5 × ULN or INR ≥ 1.5; ascites or hepatic encephalopathy, and another organ failure due to DILI [ 14 ]. Study endpoint The primary endpoint of the study was the proportion of patients with serum ALT normalization at week 4, and the time required for ALT normalization. The secondary endpoints include: 1) the proportions of patients with ALT normalization at weeks 1, 2, and 3; 2) the changes of ALT at weeks 1, 2, 3 and 4; and 3) the proportions of patients with AST normalization and the changes of AST at weeks 1, 2, 3 and 4. Statistical analysis A propensity score for each patient was calculated using multivariable logistic regression. The covariates included in the analysis were gender, age, BMI, baseline ALT level, AST level, ALP level, and TBIL level. We used the caliper matching algorithm to match patients treated with CG or MgIG 1:1 without replacement. Data processing and analysis were performed using R version 4.4.0 (2024-04-24), along with Zstats 1.0 ( www.zstats.net ). Values were given as medians and interquartile ranges or as percentages where appropriate. Inter-group differences were assessed using either the Mann-Whitney U test or the Kruskal-Wallis test. Categorical variables were analyzed using the χ 2 test, the Cochran-Mantel-Haenszel χ 2 test, or Fisher’s exact test as appropriate. Two-sided 95% confidence levels (CIs) were calculated. Result Demographic characteristics A total of 3,671 pediatric cancer patients were screened for the study, of which 2,787 were received only CG injections and the remaining were received only MgIG injections. After excluding cases via secondary diagnosis, serum biochemical parameters and RUCAM score, 189 patients in CG group and 144 patients in MgIG group remained. The final analysis included 117 matched pairs of patients with DILI (234 patients in total). The study flow diagram is shown in Fig. 1 . PSM was used to identify 117 well-matched pairs of patients, one of whom received CG and the other of whom received MgIG, from 234 candidate patients with DILI (Fig. 2 ). The baseline characteristics of the two groups before and after PSM, including demographics, are summarized in Table 1 . After PSM, female : male ratio is 42:75, mean (± SD) age is 7.24 ± 3.66 years, BMI is 15.64 ± 3.01, ALT is 351.49 ± 160.92 IU/L, AST is 194.21 ± 156.18 IU/L, ALP is 183.20 ± 94.86 IU/L, and TBIL is 12.93 ± 9.69 µmol/L in CG group. In MgIG group, 47 were girls, constituting 40.17%, slightly outnumbering boys (59.83%), the mean (± SD) age is 7.14 ± 3.61 years, BMI is 15.43 ± 2.57, ALT is 389.81 ± 215.08 IU/L, AST is 221.69 ± 188.21 IU/L, ALP is 182.62 ± 70.02 IU/L, and TBIL is 13.33 ± 8.56 µmol/L. Table 1 Patient characteristics before and after propensity score matching. Variable Before PSM After PSM CG (n = 189) MgIG (n = 144) Statistic P SMD CG (n = 117) MgIG (n = 117) Statistic P SMD Gender, n (%) χ²=5.302 0.021 χ²=0.453 0.501 Female 88 (46.56) 49 (34.03) -0.265 42 (35.90) 47 (40.17) 0.087 Male 101 (53.44) 95 (65.97) 0.265 75 (64.10) 70 (59.83) -0.087 Age (years) Mean ± SD 6.54 ± 3.56 7.88 ± 3.93 t = 3.248 0.001 0.341 7.24 ± 3.66 7.14 ± 3.61 t = 0.207 0.836 -0.027 BMI Mean ± SD 15.57 ± 2.57 15.84 ± 2.94 t = 0.864 0.388 0.089 15.64 ± 3.01 15.43 ± 2.57 t = 0.571 0.569 -0.081 ALT (IU/L) Mean ± SD 340.24 ± 210.31 405.64 ± 243.61 t = 2.573 0.011 0.268 351.49 ± 160.92 389.81 ± 215.08 t=-1.543 0.124 0.178 AST (IU/L) Mean ± SD 196.36 ± 194.13 217.63 ± 180.59 t = 1.021 0.308 0.118 194.21 ± 156.18 221.69 ± 188.21 t=-1.215 0.226 0.146 ALP(IU/L) Mean ± SD 188.87 ± 87.93 180.91 ± 73.19 t=-0.901 0.368 -0.109 183.20 ± 94.86 182.62 ± 70.02 t = 0.054 0.957 -0.008 TBIL (µmol/L) Mean ± SD 12.72 ± 9.19 14.10 ± 9.46 t = 1.338 0.182 0.146 12.93 ± 9.69 13.33 ± 8.56 t=-0.337 0.737 0.047 SD, standard deviation; SMD, Standardized mean difference; IU, international unit The distribution of clinical diagnoses was comparable between the two groups. In the CG group, 101 patients (86.32%) were diagnosed with acute lymphoblastic leukemia (ALL), while 16 patients (13.68%) had other diagnoses. Similarly, in the MgIG group, 109 patients (93.16%) had ALL, and 8 patients (6.84%) were diagnosed with other conditions. The difference in diagnostic distribution between the two groups was not statistically significant (P = 0.130). The mean length of hospitalization was 6.85 days in the CG group and 7.48 days in the MgIG group. This difference was also not statistically significant ( t = -0.85, P = 0.397). Based on the R value, all patients in the CG group were classified as having hepatocellular injury; no cases of cholestatic or mixed-type DILI were observed. In contrast, the MgIG group was predominantly characterized by hepatocellular injury (99.15%), with a small proportion of mixed-type DILI (0.85%). Regarding the severity of DILI, 97.44% of patients in the CG group were classified as having mild DILI, and 2.56% as moderate. In the MgIG group, 98.29% of patients had mild DILI, while 1.71% had moderate DILI. There were no statistically significant differences between the two groups in terms of DILI type or severity ( P > 0.999; Table 2 ). Table 2 DILI characteristics of children with DILI. Variables CG (n = 117) MgIG (n = 117) P Clinical diagnosis, n (%) 0.130 Acute lymphoblastic leukemia 101 (86.32) 109 (93.16) Others 16 (13.68) 8 (6.84) Length of hospitalization (days), Mean ± SD 6.85 ± 5.07 7.48 ± 6.12 0.397 DILI type, n (%) > 0.999 Hepatocellular 117 (100.00) 116 (99.15) Mixed 0 (0.00) 1 (0.85) DILI level, n (%) > 0.999 Mild 114 (97.44) 115 (98.29) Moderate 3 (2.56) 2 (1.71) SD: standard deviation, Data are presented as n (%), where n is the actual number with available data. Efficacy Primary endpoint To assess the therapeutic efficacy of the CG and MgIG groups in managing DILI, we compared ALT normalization rates at week 4. ALT levels normalized in 68.38% of patients (n = 80) in the CG group and 69.23% (n = 81) in the MgIG group. The difference between the two groups was not statistically significant ( P > 0.999) (Fig. 3 ). Secondary Endpoint At week 1, the proportion of participants achieving ALT normalization was 8.55% (10 subjects) in the CG group and 5.98% (7 subjects) in the MgIG group. By week 2, these proportions increased to 28.21% (33 subjects) for CG group and 34.19% (40 subjects) for MgIG group. At week 3, the rates further rose to 45.30% (53 subjects) in the CG group and 52.14% (61 subjects) in the MgIG group. Despite the gradual increase in ALT normalization rates over time in both groups, no statistically significant differences were observed between these two groups at any of the three time points (weeks 1, 2, or 3) (Fig. 3 ). The median ALT levels decreased from baseline across all four weeks in both the CG group and MgIG groups. At week 1, the median ALT levels were 124.80 IU/L in the CG group and 161.40 IU/L in the MgIG group. By week 2, they had declined to 67.15 IU/L and 50.30 IU/L, respectively. At week 3, the values further decreased to 50.75 IU/L in the CG group and 30.70 IU/L in the MgIG group. At week 4, a slight rebound was observed, with median ALT levels rising to 67.60 IU/L in the CG group and 75.35 IU/L in the MgIG group. This primarily due to the need for continued chemotherapy treatment, was continued with the drugs implicated as causing the DILI during the hospitalization. Despite these fluctuations, no statistically significant differences were observed between these two groups at any of the four time points (weeks 1 to 4) (Fig. 4 ). Similarly, during weeks 1 to 4, there were no statistically significant differences in the proportion of AST normalization between the CG group and the MgIG group (Fig. 5 ). However, when analyzing changes in AST levels over the same period (Fig. 6 ), a statistically significant difference was observed at week 3, with the MgIG group showing a greater decrease compared to the CG group ( P = 0.032). By week 4, this difference was no longer significant, and AST changes between the two groups were comparable. Safety In the CG group and the MgIG group, adverse events were reported in 2 cases (1.71%) and 6 cases (5.12%), respectively. No abnormalities in serum potassium levels or serious adverse events were observed in either group. When stratified by specific adverse events—including drug eruptions and hypotension—no significant differences in safety were found between the two groups ( P = 0.281). A detailed summary of adverse events observed during the 4-week study drug administration period is presented in Table 3 . Table 3 Safety assessment of CG and MgIG for treatment of DILI. Variables CG (n = 117) MgIG (n = 117) P Total ADR, n (%) 2 (1.71) 6 (5.12) 0.281 ADR type, n (%) Drug eruption 1 (0.85) 5 (4.27) Hypotension 1 (0.85) 1 (0.85) Discussion This study aimed to evaluate the efficacy of compound CG and MgIG in reducing serum ALT and AST levels in pediatric cancer patients with DILI. The diagnosis and management of liver diseases, particularly DILI, remain a significant challenge for clinicians. In recent years, the incidence of DILI among children has shown an upward trend [ 15 ]. Previous studies have highlighted DILI as one of the leading causes of acute liver failure in the pediatric population [ 16 ]. However, clinical research data on DILI in children are still limited. Among hepatoprotective agents used in clinical practice, glycyrrhizin-based preparations—including CG and MgIG—are commonly administered in pediatric DILI cases in China, especially those involving hepatic inflammation and hepatocellular injury. CG possesses anti-inflammatory [ 8 ], immunomodulatory [ 17 ], and antioxidant properties [ 18 ], primarily by inhibiting pro-inflammatory cytokines and stabilizing hepatocyte membranes. It exerts hepatoprotective effects through the downregulation of inflammatory mediators and modulation of oxidative stress pathways [ 19 ]. Despite their widespread use, evidence regarding the efficacy and safety of CG and MgIG in pediatric populations remains scarce. Recent meta-analyses have demonstrated that both CG and MgIG effectively reduce ALT levels in adults with DILI [ 20 , 21 ]. In the present study, 234 pediatric patients with cancer-related DILI were assigned to either the CG group or the MgIG group, with 117 patients in each cohort. At week 4 of treatment, there was no statistically significant difference between the two groups in terms of ALT normalization. Similarly, the rates of AST normalization from week 1 to week 4 did not differ significantly between the groups. Safety outcomes were also comparable between the two treatments. Adverse events such as rash and hypotension occurred with similar frequency in both groups. Importantly, no serious adverse events, including death, were observed, further confirming the safety of both agents. Taken together, our findings suggest that CG and MgIG have comparable efficacy and safety profiles in the treatment of DILI in pediatric cancer patients. The results provide preliminary clinical evidence supporting the use of CG as an effective therapeutic option for children with drug-induced liver injury. Conclusions DILI is a significant contributor to pediatric liver disease and should be suspected in cases of acute liver enzyme elevation without a clear alternative cause. This study represents the first retrospective cohort investigation assessing the efficacy and safety of CG and MgIG in pediatric cancer patients with DILI. The findings demonstrate that both CG and MgIG are effective and well-tolerated treatments, offering preliminary evidence to support their use in this population. Further large-scale, prospective studies are warranted to validate these results and to establish definitive treatment guidelines for pediatric DILI. Abbreviations ALL, acute lymphoblastic leukemia ALP, alkaline phosphatase ALT, alanine aminotransferase AST, aspartate aminotransferase BMI, body mass index CG, compound glycyrrhizin CI, confidence level CMV, Cytomegalovirus DILI, drug induced liver injury EBV, Epstein-Barr virus INR, international normalized ratio IU, international unit MgIG, magnesium isoglycyrrhizinate PSM, propensity score matching RCT, randomized controlled trials RUCAM, Roussel Uclaf causality assessment method SD, standard deviation SMD, Standardized mean difference TBIL, total bilirubin ULN, upper limit of normal Declarations Authors’ contributions W.W. designed the study and wrote the manuscript. Y.W. and G.L. analyzed the data and drafted the figure and table. Methodological support was provided by J.D. and F.W.. Y.M. and Z.Z. contributed to data analysis. All authors agreed on the journal to which the article will be submitted, gave final approval for the version to be published, and agreed to be accountable for all aspects of the work. Funding This work was supported by the grants from the Gusu Health Talents Project of Suzhou Municipal Health Commission (Grant No. GSWS2022062), the Tianqing Project of Jiangsu Province Pharmaceutical Committee (Grant No. Q202235) and Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University (Grant No. 2023xj037). The funders had no role in study design, data collection, analysis or interpretation of the data, preparation of the manuscript or decision to publish the results. Availability of data and materials The data used in this manuscript are available upon reasonable request by contacting the corresponding authors via email. Ethics approval and consent to participate The research proposal was approved by Children’s Hospital of Soochow University Ethics Committee (approval number 2024CS137). As this is a retrospective study, the requirement for informed consent was waived. All study methods were implemented in line with the involved guidelines of the Helsinki Declaration. Confidentiality of the information was secured throughout the study process. Furthermore, the collected data were anonymous. Clinical trial number Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest. References Cardenas V, Mankuzhy N, Mody R, McCaffery H, Fontana RJ, DiPaola F. 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Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials. Pharmacol Res. 2021;164:105404. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 13 Jun, 2025 Editor assigned by journal 11 Jun, 2025 Editor invited by journal 21 May, 2025 Submission checks completed at journal 20 May, 2025 First submitted to journal 20 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6694007","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":471540886,"identity":"8a22d827-8f55-446c-88f1-6c425de49e04","order_by":0,"name":"Yuanpei Wang","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Yuanpei","middleName":"","lastName":"Wang","suffix":""},{"id":471540887,"identity":"e2fb0031-80e6-472a-a09a-6d6bff2ee3e3","order_by":1,"name":"Guifeng Li","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Guifeng","middleName":"","lastName":"Li","suffix":""},{"id":471540888,"identity":"8635f5b8-8db5-4b5e-a807-5c639a0dd887","order_by":2,"name":"Jinhang Du","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Jinhang","middleName":"","lastName":"Du","suffix":""},{"id":471540889,"identity":"a56a32de-f6ef-4307-96a9-eb4df9fbdb18","order_by":3,"name":"Fengjiao Wang","email":"","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Fengjiao","middleName":"","lastName":"Wang","suffix":""},{"id":471540890,"identity":"31dcb855-5a90-4447-bec0-a43c93c6057f","order_by":4,"name":"Yamei Meng","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Yamei","middleName":"","lastName":"Meng","suffix":""},{"id":471540891,"identity":"b22e5b77-607f-4e0d-b835-bc1b40bbe084","order_by":5,"name":"Zexi Zhang","email":"","orcid":"","institution":"Soochow University","correspondingAuthor":false,"prefix":"","firstName":"Zexi","middleName":"","lastName":"Zhang","suffix":""},{"id":471540892,"identity":"08587a24-aa44-4ee2-b97b-7e383c959f51","order_by":6,"name":"Wenjuan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYBADZhBxIMFAQo6Nvf0A0VoYDzwosDHm4zmTQLxNBx98SEucJ+FggFeZwfGzh1/zVNxhBzIOAB12OL1NgiGB4UfFNtxazuSlWfOcecYMZCSAtOS2STceYOw5cxunFrMDOWbGuW2HmQ0O5BhAtMgcSGBmbMOj5fwboJZ/QC3n34C1pLNJJBjg13Ijx/hxbgNQyw2wLWkJBLXY33hjxvzn2GFmyRtgW2wM24CBfBCfXyT7c4w/zqg5nMx3Hsj48UdCXr69/eCDHxW4tQABmwSQSEYROoBPPRAwfwASdgQUjYJRMApGwUgGAAtmYh5/UvdgAAAAAElFTkSuQmCC","orcid":"","institution":"Children’s Hospital of Soochow University","correspondingAuthor":true,"prefix":"","firstName":"Wenjuan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-05-19 00:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6694007/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6694007/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84919471,"identity":"4d5f1f54-c0cd-422a-ab65-53c259525f46","added_by":"auto","created_at":"2025-06-18 19:33:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":173213,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow diagram.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCG, compound glycyrrhizin; MgIG, magnesium isoglycyrrhizinate; EBV, Epstein-Barr Virus; CMV, Cytomegalovirus; DILI, drug induced liver injury; ALT, alanine aminotransferase; ULN, upper limit of normal; ALP, alkaline phosphatase; TBIL, total bilirubin; RUCAM, Roussel Uclaf causality assessment method; PSM, propensity score matching; BMI, body mass index; AST, aspartate aminotransferase.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/c821edb090ea4df014169ed7.png"},{"id":84919462,"identity":"133472f4-cddd-4730-a9a7-b3ecd4df3f8f","added_by":"auto","created_at":"2025-06-18 19:33:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41393,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCharacteristics of patients before and after PSM.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePSM, propensity score matching; CG, compound glycyrrhizin; MgIG, magnesium isoglycyrrhizinate.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/96b81e3839cb4f33a0b9ba5f.png"},{"id":84919464,"identity":"76600597-1431-47e8-a919-2d118cf99d1a","added_by":"auto","created_at":"2025-06-18 19:33:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":31259,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eALT normalization at weeks 1, 2, 3 and 4 for all subjects.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/29800cfdfde87327b98bf9e9.png"},{"id":84919470,"identity":"fe46412b-8e8e-43d8-8e45-e2169df724d5","added_by":"auto","created_at":"2025-06-18 19:33:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":48110,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe changes of ALT value at baseline, weeks 1, 2, 3 and 4 (median with 95% CI).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/3147accb454e9c584132dd1a.png"},{"id":84919472,"identity":"645f4f3a-c2a0-44d5-9b70-406d891e1269","added_by":"auto","created_at":"2025-06-18 19:33:50","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":41574,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAST normalization at weeks 1, 2, 3 and 4 for all subjects.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/679bf694a9afcd4bad6c8ff2.png"},{"id":84919466,"identity":"cc1cb4db-0863-4c49-8a24-39af1dad9d34","added_by":"auto","created_at":"2025-06-18 19:33:50","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":47267,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe changes of AST value at baseline, weeks 1, 2, 3 and 4 (median with 95% CI).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/63cab39e775a8f6b56f29733.png"},{"id":84921307,"identity":"87319f45-fe27-4de7-853b-18e2c3b35f37","added_by":"auto","created_at":"2025-06-18 19:49:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1159628,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6694007/v1/9c7822c8-d27d-4d0c-94e9-bce995760548.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Compound Glycyrrhizin in the Treatment of Drug- Induced Liver Injury in Pediatric Cancer Patients: A Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe liver is the primary organ responsible for the metabolism of many chemotherapeutic agents, making it particularly vulnerable to treatment-related damage. Liver injury induced by chemotherapy is common among children undergoing cancer treatment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Drug-induced liver injury (DILI) is a frequently underdiagnosed condition that can result in severe acute or chronic liver disease in pediatric patients, accounting for approximately 10% of all DILI cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The main strategy for managing DILI is early discontinuation of the offending drug and avoiding re-exposure [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, discontinuing the drug may compromise the treatment of the primary disease, such as cancer, posing a significant challenge in pediatric care. Furthermore, effective treatment options for DILI remain limited, with only a few regimens currently approved [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn clinical practice, liver-protective agents, such as compound glycyrrhizin (CG), polyene phosphatidylcholine, reduced glutathione, and tiopronin, are often used to manage DILI in children with cancer in China and other countries, despite the lack of robust evidence supporting their efficacy in this population [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. CG is an active ingredient extracted from the roots of \u003cem\u003eGlycyrrhiza glabra\u003c/em\u003e. It contains glycyrrhizin as the primary active component, along with glycine and cysteine hydrochloride. CG has demonstrated a variety of biological activities, including antioxidant and anticancer properties, and has been used clinically since 1979 for the treatment of chronic hepatitis in Japan [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Previous studies suggest that CG exerts hepatoprotective effects by targeting multiple pathways involved in reducing the inflammatory response, mitigating liver tissue damage, and promoting the repair of damaged liver cells [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Additionally, CG has been shown to decrease alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in a small trial involving patients with DILI [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, there is limited evidence to support the use of CG in pediatric cancer patients experiencing DILI. Therefore, this study aims to evaluate the efficacy and safety of CG in treating DILI in the pediatric population. Additionally, the efficacy and safety of CG will be compared with magnesium isoglycyrrhizinate (MgIG), which has been approved by the Chinese Food and Drug Administration for the treatment of acute DILI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eA total of 3,671 inpatient data from the Children\u0026rsquo;s Hospital of Soochow University is a 3-year (2021\u0026ndash;2023) retrospective cohort study. The following parameters were collected for all enrolled patients: 1) demographic information (such as gender, age, and body mass index (BMI)); 2) disease history; 3) information regarding drugs that may have caused liver injury, including time of symptom onset after starting the drug and the time of recovery after stopping the drug; 4) serum biochemical parameters before and during DILI, including levels of serum ALT, AST, alkaline phosphatase (ALP), total bilirubin (TBIL), as well as the international normalized ratio (INR); 5) the safety of CG and MgIG among the pediatric cancer patients with DILI was record by adverse events, such as drug eruption, hypotension and serum potassium; and 6) medical records to rule out other causes of liver injury.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eCandidate subjects were enrolled into one of the two situations: pediatric cancer patients who received only CG injections (brand name: Meineng) or only MgIG injections (brand name: Ganmei) for DILI therapy were identified. CG and MgIG were administered intravenously at a daily dose of 20 mL and 10 mL respectively. All patient details were deidentified. We then excluded cases with the following condtions: 1) Viral hepatitis: such as hepatitis A, B, C, D, E; Epstein-Barr virus (EBV), cytomegalovirus (CMV); 2) Fatty liver disease, hepatolenticular degeneration and hepatobiliary organic lesions; 3) Autoimmune liver disease; 4) Hereditary metabolic liver disease; 5) Hypoxic injury of tissues and organs of the whole body caused by infection; 6) Hemodynamic abnormalities such as hypotension, shock, and vascular occlusive disease, and others not appropriate to be included after assessment by the investigators. The criteria for suspected DILI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] that includes meeting one of the following thresholds: 1) ALT\u0026thinsp;\u0026ge;\u0026thinsp;5 \u0026times; the upper limit of normal (ULN); 2) ALP\u0026thinsp;\u0026ge;\u0026thinsp;2 \u0026times; ULN; and 3) ALT\u0026thinsp;\u0026ge;\u0026thinsp;3 \u0026times; ULN concomitant with TBIL\u0026thinsp;\u0026ge;\u0026thinsp;2 \u0026times; ULN. These patients were further evaluated using the Roussel Uclaf causality assessment method (RUCAM) to evaluate the relationship between the drugs used during the period of hospitalization and the patient\u0026rsquo;s liver injury [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Patients with RUCAM scores equal to or above 6 were enrolled in the study. All evaluations were performed independently by the three authors. The website Hepatoxic (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.hepatox.org/\u003c/span\u003e\u003cspan address=\"http://www.hepatox.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and drug instructions were used as the drug information source to verify the relationship between the drugs and hepatotoxicity. A 1:1 propensity score matching (PSM) was applied to ensure even distribution of confounders in the CG group and the MgIG group. Eligible DILI patterns were categorized as hepatocellular, cholestatic, and mixed, based on the value of R. The R value is calculated as R = (ALT/ULN)/(ALP/ULN). An ALT\u0026thinsp;\u0026ge;\u0026thinsp;3 \u0026times; ULN and R\u0026thinsp;\u0026ge;\u0026thinsp;5 was termed hepatocellular, ALP\u0026thinsp;\u0026ge;\u0026thinsp;2 \u0026times; ULN and R\u0026thinsp;\u0026le;\u0026thinsp;2 was cholestatic, while ALT\u0026thinsp;\u0026ge;\u0026thinsp;3 \u0026times; ULN, ALP\u0026thinsp;\u0026ge;\u0026thinsp;2 \u0026times; ULN and 2\u0026thinsp;\u0026lt;\u0026thinsp;R \u0026lt;\u0026thinsp;5 was classified as mixed. DILI was further categorized as mild, moderate, severe, and fatal/transplant. Mild DILI was defined as TBIL\u0026thinsp;\u0026lt;\u0026thinsp;2.5 \u0026times; ULN and INR\u0026thinsp;\u0026lt;\u0026thinsp;1.5; moderate DILI as TBIL\u0026thinsp;\u0026ge;\u0026thinsp;2.5 \u0026times; ULN or INR\u0026thinsp;\u0026ge;\u0026thinsp;1.5; severe DILI as TBIL\u0026thinsp;\u0026ge;\u0026thinsp;5 \u0026times; ULN or INR\u0026thinsp;\u0026ge;\u0026thinsp;1.5; ascites or hepatic encephalopathy, and another organ failure due to DILI [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy endpoint\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of the study was the proportion of patients with serum ALT normalization at week 4, and the time required for ALT normalization. The secondary endpoints include: 1) the proportions of patients with ALT normalization at weeks 1, 2, and 3; 2) the changes of ALT at weeks 1, 2, 3 and 4; and 3) the proportions of patients with AST normalization and the changes of AST at weeks 1, 2, 3 and 4.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eA propensity score for each patient was calculated using multivariable logistic regression. The covariates included in the analysis were gender, age, BMI, baseline ALT level, AST level, ALP level, and TBIL level. We used the caliper matching algorithm to match patients treated with CG or MgIG 1:1 without replacement. Data processing and analysis were performed using R version 4.4.0 (2024-04-24), along with Zstats 1.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.hepatox.org/\" target=\"_blank\"\u003ewww.zstats.net\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.zstats.net\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Values were given as medians and interquartile ranges or as percentages where appropriate. Inter-group differences were assessed using either the Mann-Whitney U test or the Kruskal-Wallis test. Categorical variables were analyzed using the \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test, the Cochran-Mantel-Haenszel \u003cem\u003eχ\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e test, or Fisher\u0026rsquo;s exact test as appropriate. Two-sided 95% confidence levels (CIs) were calculated.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDemographic characteristics\u003c/h2\u003e \u003cp\u003eA total of 3,671 pediatric cancer patients were screened for the study, of which 2,787 were received only CG injections and the remaining were received only MgIG injections. After excluding cases via secondary diagnosis, serum biochemical parameters and RUCAM score, 189 patients in CG group and 144 patients in MgIG group remained. The final analysis included 117 matched pairs of patients with DILI (234 patients in total). The study flow diagram is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. PSM was used to identify 117 well-matched pairs of patients, one of whom received CG and the other of whom received MgIG, from 234 candidate patients with DILI (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The baseline characteristics of the two groups before and after PSM, including demographics, are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. After PSM, female : male ratio is 42:75, mean (\u0026plusmn;\u0026thinsp;SD) age is 7.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.66 years, BMI is 15.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.01, ALT is 351.49\u0026thinsp;\u0026plusmn;\u0026thinsp;160.92 IU/L, AST is 194.21\u0026thinsp;\u0026plusmn;\u0026thinsp;156.18 IU/L, ALP is 183.20\u0026thinsp;\u0026plusmn;\u0026thinsp;94.86 IU/L, and TBIL is 12.93\u0026thinsp;\u0026plusmn;\u0026thinsp;9.69 \u0026micro;mol/L in CG group. In MgIG group, 47 were girls, constituting 40.17%, slightly outnumbering boys (59.83%), the mean (\u0026plusmn;\u0026thinsp;SD) age is 7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61 years, BMI is 15.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.57, ALT is 389.81\u0026thinsp;\u0026plusmn;\u0026thinsp;215.08 IU/L, AST is 221.69\u0026thinsp;\u0026plusmn;\u0026thinsp;188.21 IU/L, ALP is 182.62\u0026thinsp;\u0026plusmn;\u0026thinsp;70.02 IU/L, and TBIL is 13.33\u0026thinsp;\u0026plusmn;\u0026thinsp;8.56 \u0026micro;mol/L.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePatient characteristics before and after propensity score matching.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eBefore PSM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c12\" namest=\"c7\"\u003e \u003cp\u003eAfter PSM\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCG (n\u0026thinsp;=\u0026thinsp;189)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMgIG (n\u0026thinsp;=\u0026thinsp;144)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eStatistic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eCG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMgIG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eStatistic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSMD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eχ\u0026sup2;=5.302\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eχ\u0026sup2;=0.453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e88 (46.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49 (34.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e42 (35.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e47 (40.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101 (53.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e95 (65.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e75 (64.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e70 (59.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e-0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.54\u0026thinsp;\u0026plusmn;\u0026thinsp;3.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.88\u0026thinsp;\u0026plusmn;\u0026thinsp;3.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;3.248\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.24\u0026thinsp;\u0026plusmn;\u0026thinsp;3.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;0.207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e-0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.84\u0026thinsp;\u0026plusmn;\u0026thinsp;2.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;0.864\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e15.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;0.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e-0.081\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (IU/L)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e340.24\u0026thinsp;\u0026plusmn;\u0026thinsp;210.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e405.64\u0026thinsp;\u0026plusmn;\u0026thinsp;243.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;2.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e351.49\u0026thinsp;\u0026plusmn;\u0026thinsp;160.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e389.81\u0026thinsp;\u0026plusmn;\u0026thinsp;215.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et=-1.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.178\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (IU/L)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e196.36\u0026thinsp;\u0026plusmn;\u0026thinsp;194.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e217.63\u0026thinsp;\u0026plusmn;\u0026thinsp;180.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;1.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.308\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e194.21\u0026thinsp;\u0026plusmn;\u0026thinsp;156.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e221.69\u0026thinsp;\u0026plusmn;\u0026thinsp;188.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et=-1.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP(IU/L)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e188.87\u0026thinsp;\u0026plusmn;\u0026thinsp;87.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e180.91\u0026thinsp;\u0026plusmn;\u0026thinsp;73.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et=-0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e183.20\u0026thinsp;\u0026plusmn;\u0026thinsp;94.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e182.62\u0026thinsp;\u0026plusmn;\u0026thinsp;70.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.957\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e-0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTBIL (\u0026micro;mol/L)\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.72\u0026thinsp;\u0026plusmn;\u0026thinsp;9.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.10\u0026thinsp;\u0026plusmn;\u0026thinsp;9.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003et\u0026thinsp;=\u0026thinsp;1.338\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.93\u0026thinsp;\u0026plusmn;\u0026thinsp;9.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e13.33\u0026thinsp;\u0026plusmn;\u0026thinsp;8.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003et=-0.337\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.737\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eSD, standard deviation; SMD, Standardized mean difference; IU, international unit\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe distribution of clinical diagnoses was comparable between the two groups. In the CG group, 101 patients (86.32%) were diagnosed with acute lymphoblastic leukemia (ALL), while 16 patients (13.68%) had other diagnoses. Similarly, in the MgIG group, 109 patients (93.16%) had ALL, and 8 patients (6.84%) were diagnosed with other conditions. The difference in diagnostic distribution between the two groups was not statistically significant (P\u0026thinsp;=\u0026thinsp;0.130). The mean length of hospitalization was 6.85 days in the CG group and 7.48 days in the MgIG group. This difference was also not statistically significant (\u003cem\u003et\u003c/em\u003e = -0.85, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.397). Based on the R value, all patients in the CG group were classified as having hepatocellular injury; no cases of cholestatic or mixed-type DILI were observed. In contrast, the MgIG group was predominantly characterized by hepatocellular injury (99.15%), with a small proportion of mixed-type DILI (0.85%). Regarding the severity of DILI, 97.44% of patients in the CG group were classified as having mild DILI, and 2.56% as moderate. In the MgIG group, 98.29% of patients had mild DILI, while 1.71% had moderate DILI. There were no statistically significant differences between the two groups in terms of DILI type or severity (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eDILI characteristics of children with DILI.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMgIG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical diagnosis, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute lymphoblastic leukemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101 (86.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e109 (93.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16 (13.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8 (6.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of hospitalization (days),\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.85\u0026thinsp;\u0026plusmn;\u0026thinsp;5.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.48\u0026thinsp;\u0026plusmn;\u0026thinsp;6.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.397\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDILI type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatocellular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e117 (100.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e116 (99.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMixed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDILI level, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e114 (97.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e115 (98.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (2.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSD: standard deviation, Data are presented as n (%), where n is the actual number with available data.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003ePrimary endpoint\u003c/h2\u003e \u003cp\u003eTo assess the therapeutic efficacy of the CG and MgIG groups in managing DILI, we compared ALT normalization rates at week 4. ALT levels normalized in 68.38% of patients (n\u0026thinsp;=\u0026thinsp;80) in the CG group and 69.23% (n\u0026thinsp;=\u0026thinsp;81) in the MgIG group. The difference between the two groups was not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eSecondary Endpoint\u003c/h3\u003e\n\u003cp\u003eAt week 1, the proportion of participants achieving ALT normalization was 8.55% (10 subjects) in the CG group and 5.98% (7 subjects) in the MgIG group. By week 2, these proportions increased to 28.21% (33 subjects) for CG group and 34.19% (40 subjects) for MgIG group. At week 3, the rates further rose to 45.30% (53 subjects) in the CG group and 52.14% (61 subjects) in the MgIG group. Despite the gradual increase in ALT normalization rates over time in both groups, no statistically significant differences were observed between these two groups at any of the three time points (weeks 1, 2, or 3) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe median ALT levels decreased from baseline across all four weeks in both the CG group and MgIG groups. At week 1, the median ALT levels were 124.80 IU/L in the CG group and 161.40 IU/L in the MgIG group. By week 2, they had declined to 67.15 IU/L and 50.30 IU/L, respectively. At week 3, the values further decreased to 50.75 IU/L in the CG group and 30.70 IU/L in the MgIG group. At week 4, a slight rebound was observed, with median ALT levels rising to 67.60 IU/L in the CG group and 75.35 IU/L in the MgIG group. This primarily due to the need for continued chemotherapy treatment, was continued with the drugs implicated as causing the DILI during the hospitalization. Despite these fluctuations, no statistically significant differences were observed between these two groups at any of the four time points (weeks 1 to 4) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSimilarly, during weeks 1 to 4, there were no statistically significant differences in the proportion of AST normalization between the CG group and the MgIG group (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). However, when analyzing changes in AST levels over the same period (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), a statistically significant difference was observed at week 3, with the MgIG group showing a greater decrease compared to the CG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032). By week 4, this difference was no longer significant, and AST changes between the two groups were comparable.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eIn the CG group and the MgIG group, adverse events were reported in 2 cases (1.71%) and 6 cases (5.12%), respectively. No abnormalities in serum potassium levels or serious adverse events were observed in either group. When stratified by specific adverse events\u0026mdash;including drug eruptions and hypotension\u0026mdash;no significant differences in safety were found between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.281). A detailed summary of adverse events observed during the 4-week study drug administration period is presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eSafety assessment of CG and MgIG for treatment of DILI.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMgIG (n\u0026thinsp;=\u0026thinsp;117)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal ADR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (5.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADR type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug eruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (4.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypotension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to evaluate the efficacy of compound CG and MgIG in reducing serum ALT and AST levels in pediatric cancer patients with DILI. The diagnosis and management of liver diseases, particularly DILI, remain a significant challenge for clinicians. In recent years, the incidence of DILI among children has shown an upward trend [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Previous studies have highlighted DILI as one of the leading causes of acute liver failure in the pediatric population [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, clinical research data on DILI in children are still limited.\u003c/p\u003e \u003cp\u003eAmong hepatoprotective agents used in clinical practice, glycyrrhizin-based preparations\u0026mdash;including CG and MgIG\u0026mdash;are commonly administered in pediatric DILI cases in China, especially those involving hepatic inflammation and hepatocellular injury. CG possesses anti-inflammatory [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], immunomodulatory [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and antioxidant properties [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], primarily by inhibiting pro-inflammatory cytokines and stabilizing hepatocyte membranes. It exerts hepatoprotective effects through the downregulation of inflammatory mediators and modulation of oxidative stress pathways [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Despite their widespread use, evidence regarding the efficacy and safety of CG and MgIG in pediatric populations remains scarce. Recent meta-analyses have demonstrated that both CG and MgIG effectively reduce ALT levels in adults with DILI [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn the present study, 234 pediatric patients with cancer-related DILI were assigned to either the CG group or the MgIG group, with 117 patients in each cohort. At week 4 of treatment, there was no statistically significant difference between the two groups in terms of ALT normalization. Similarly, the rates of AST normalization from week 1 to week 4 did not differ significantly between the groups. Safety outcomes were also comparable between the two treatments. Adverse events such as rash and hypotension occurred with similar frequency in both groups. Importantly, no serious adverse events, including death, were observed, further confirming the safety of both agents. Taken together, our findings suggest that CG and MgIG have comparable efficacy and safety profiles in the treatment of DILI in pediatric cancer patients. The results provide preliminary clinical evidence supporting the use of CG as an effective therapeutic option for children with drug-induced liver injury.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eDILI is a significant contributor to pediatric liver disease and should be suspected in cases of acute liver enzyme elevation without a clear alternative cause. This study represents the first retrospective cohort investigation assessing the efficacy and safety of CG and MgIG in pediatric cancer patients with DILI. The findings demonstrate that both CG and MgIG are effective and well-tolerated treatments, offering preliminary evidence to support their use in this population. Further large-scale, prospective studies are warranted to validate these results and to establish definitive treatment guidelines for pediatric DILI.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALL, acute lymphoblastic leukemia\u003c/p\u003e\n\u003cp\u003eALP, alkaline phosphatase\u003c/p\u003e\n\u003cp\u003eALT, alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eAST, aspartate aminotransferase\u003c/p\u003e\n\u003cp\u003eBMI, body mass index\u003c/p\u003e\n\u003cp\u003eCG, compound glycyrrhizin\u003c/p\u003e\n\u003cp\u003eCI, confidence level\u003c/p\u003e\n\u003cp\u003eCMV, Cytomegalovirus\u003c/p\u003e\n\u003cp\u003eDILI, drug induced liver injury\u003c/p\u003e\n\u003cp\u003eEBV, Epstein-Barr virus\u003c/p\u003e\n\u003cp\u003eINR, international normalized ratio\u003c/p\u003e\n\u003cp\u003eIU, international unit\u003c/p\u003e\n\u003cp\u003eMgIG, magnesium isoglycyrrhizinate\u003c/p\u003e\n\u003cp\u003ePSM, propensity score matching\u003c/p\u003e\n\u003cp\u003eRCT, randomized controlled trials\u003c/p\u003e\n\u003cp\u003eRUCAM, Roussel Uclaf causality assessment method\u003c/p\u003e\n\u003cp\u003eSD, standard deviation\u003c/p\u003e\n\u003cp\u003eSMD, Standardized mean difference\u003c/p\u003e\n\u003cp\u003eTBIL, total bilirubin\u003c/p\u003e\n\u003cp\u003eULN, upper limit of normal\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eW.W. designed the study and wrote the manuscript. Y.W. and G.L. analyzed the data and drafted the figure and table. Methodological support was provided by J.D. and F.W.. Y.M. and Z.Z. contributed to data analysis. All authors agreed on the journal to which the article will be submitted, gave final approval for the version to be published, and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the grants from the Gusu Health Talents Project of Suzhou Municipal Health Commission (Grant No. GSWS2022062), the Tianqing Project of Jiangsu Province Pharmaceutical Committee (Grant No. Q202235) and Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University (Grant No. 2023xj037). The funders had no role in study design, data collection, analysis or interpretation of the data, preparation of the manuscript or decision to publish the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this manuscript are available upon reasonable request by contacting the corresponding authors via email.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research proposal was approved by Children\u0026rsquo;s Hospital of Soochow University Ethics Committee (approval number 2024CS137). As this is a retrospective study, the requirement for informed consent was waived. All study methods were implemented in line with the involved guidelines of the Helsinki Declaration. Confidentiality of the information was secured throughout the study process. Furthermore, the collected data were anonymous.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCardenas V, Mankuzhy N, Mody R, McCaffery H, Fontana RJ, DiPaola F. Incidence and Sequelae of Liver Injury Among Children Treated for Solid Tumors: Analysis of a Large Single-Center Prospective Cohort. J Pediatr Gastroenterol Nutr. 2020;71(2):197\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonge-Urrea F, Montijo-Barrios E. Drug-induced Liver Injury in Pediatrics. J Pediatr Gastroenterol Nutr. 2022;75(4):391\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBj\u0026ouml;rnsson HK, Bj\u0026ouml;rnsson ES. Drug-induced liver injury: Pathogenesis, epidemiology, clinical features, and practical management. Eur J Intern Med. 2022;97:26\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAllison R, Guraka A, Shawa IT, Tripathi G, Moritz W, Kermanizadeh A. Drug induced liver injury - a 2023 update. J Toxicol Environ Health B Crit Rev. 2023;26(8):442\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLai R, Li X, Zhang J, Chen J, Yang C, Xie W, et al. Chinese Drug Induced Liver Disease Study Group. Drug-induced liver injury in children: A nationwide cohort study from China. JHEP Rep. 2024;6(8):101102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi C, Yang X, Quan Y, Wu A, Wang Y. Network meta-analysis of different liver protective drugs in the treatment of drug-induced liver injury. Med (Baltim). 2023;102(50):e36538.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoga K, Kawashima S, Shibata N, Takada K. Novel formulations of a liver protection drug glycyrrhizin. Yakugaku Zasshi. 2007;127(7):1103\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJain R, Hussein MA, Pierce S, Martens C, Shahagadkar P, Munirathinam G. Oncopreventive and oncotherapeutic potential of licorice triterpenoid compound glycyrrhizin and its derivatives: Molecular insights. Pharmacol Res. 2022;178:106138.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng J, Zhang L, Dong Y, Long W, Wang Y, Zhang Q, et al. Factors Influencing Liver Cirrhosis Progression in Wilson's Disease Patients: A Retrospective Cohort Study Over 5 Years. J Gastroenterol Hepatol. 2025;40(4):960\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYao L, Zhang J, Jin J, Li H, Li L, Han X, et al. An analysis of the efficacy and safety of compound glycyrrhizin injections in the treatment of drug-induced liver injury using a nationwide database. Int J Clin Pharm. 2022;44(3):731\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTechnology Committee on DILI Prevention and Management, Chinese Medical Biotechnology Association. Study Group of Drug-Induced Liver Disease, Chinese Medical Association for the Study of Liver Diseases. Chinese guideline for diagnosis and management of drug-induced liver injury (2023 version). Zhonghua Gan Zang Bing Za Zhi. 2023;31(4):355\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Association for the Study of the Liver. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDanan G, Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2015;17(1):14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaris BR, Grama A, Pop TL. Drug-Induced Liver Injury-Pharmacological Spectrum Among Children. Int J Mol Sci. 2025;26(5):2006.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaut C, Flynn L. Pediatric Acute Liver Failure. Pediatr Rep. 2023;15(3):426\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi C, Wang ZB. Clinical application of compound Glycyrrhizin tablets in the treatment of patients with Simplex Henoch-Schonlein Purpura and its effect on immune function. Pak J Med Sci. 2022;38(1):271\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharifi-Rad J, Quispe C, Herrera-Bravo J, Bel\u0026eacute;n LH, Kaur R, Kregiel D et al. Glycyrrhiza Genus: Enlightening Phytochemical Components for Pharmacological and Health-Promoting Abilities. Oxid Med Cell Longev. 2021; 2021:7571132.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGong Q, Wang X, Liu Y, Yuan H, Ge Z, Li Y, et al. Potential Hepatoprotective Effects of Allicin on Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Oxidative Stress, Inflammation, and Apoptosis. Toxics. 2024;12(5):328.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiang SB, Hou WB, Zheng RX, Liang CH, Yan LJ, Wang HN, et al. Compound glycyrrhizin injection for improving liver function in children with acute icteric hepatitis: A systematic review and meta-analysis. Integr Med Res. 2022;11(1):100772.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiu H, Sanabria-Cabrera J, Alvarez-Alvarez I, Robles-Diaz M, Stankevičiūtė S, Aithal GP, et al. Prevention and management of idiosyncratic drug-induced liver injury: Systematic review and meta-analysis of randomised clinical trials. Pharmacol Res. 2021;164:105404.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Drug-induced liver injury, Pediatric cancer, Compound glycyrrhizin, Magnesium isoglycyrrhizinate, Roussel Uclaf causality assessment method","lastPublishedDoi":"10.21203/rs.3.rs-6694007/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6694007/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDrug-induced liver injury (DILI) caused by chemotherapy poses significant health risks for pediatric cancer patients and remains a serious clinical challenge. Currently, there are no clearly recommended pharmacological treatments specifically for managing DILI in children. Here, we assessed the efficacy and safety of Compound glycyrrhizin (CG) in treating DILI among children with cancer.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eData from a retrospective cohort study were analyzed to compare CG and magnesium isoglycyrrhizinate (MgIG) for treatment of DILI. We used the Roussel Uclaf causality assessment method (RUCAM) to evaluate patients with DILI. Patients with RUCAM scores\u0026thinsp;\u0026ge;\u0026thinsp;6 were included in the study. Propensity score matching was used to balance the baseline characteristics. The primary outcome was the proportion of patients with alanine aminotransferase (ALT) normalization at week 4 after CG and MgIG administration. The safety comparison between the two drugs was conducted by analyzing records of drug-related adverse events.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResult\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA total of 234 eligible subjects were enrolled into two groups: 117 in the CG group and 117 in the MgIG group. Overall, 68.38% of patients in the CG group and 69.23% in the MgIG group achieved ALT normalization at week 4, with no statistically significant difference between the groups. ALT normalization rates increased gradually over time in both groups, yet no significant differences were observed at weeks 1, 2, or 3. Median ALT levels declined from baseline throughout the 4-week treatment period in both groups; however, differences between groups remained statistically insignificant at all time points. Similarly, the proportion of AST normalization showed no significant intergroup differences. Notably, a greater reduction in AST levels was observed in the MgIG group at week 3 (P\u0026thinsp;=\u0026thinsp;0.032), but this difference was not maintained by week 4. In terms of safety, adverse events occurred in 1.71% of patients in the CG group and 5.12% in the MgIG group, without significant differences (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.281).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe efficacy and safety of CG and MgIG for treatment of DILI were comparable in children with cancer. This study provided preliminary evidence that CG is an effective and safe treatment for children with chemotherapy-induced liver injury.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Compound Glycyrrhizin in the Treatment of Drug- Induced Liver Injury in Pediatric Cancer Patients: A Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-18 19:33:45","doi":"10.21203/rs.3.rs-6694007/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2025-06-13T10:58:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-11T10:26:47+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-21T05:35:48+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-21T01:54:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-05-21T01:53:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a6540813-8b9f-4e3f-b176-12739a8e2b08","owner":[],"postedDate":"June 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-06-18T19:33:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-18 19:33:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6694007","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6694007","identity":"rs-6694007","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}