Drug-induced Liver Injury In China Research Articles

Roles of NR1I3 and NR1H4 polymorphisms in the susceptibility to antituberculosis drug-induced liver injury in China: a case‒control study.

The pathogenesis of antituberculosis drug-induced liver injury (AT-DILI) remains largely unknown. The current investigation aimed to determine the genetic contribution of the nuclear receptor subfamily 1 Group I member 3 (NR1I3) and nuclear receptor subfamily 1 Group H member 4 (NR1H4) genes to the risk of AT-DILI in the Chinese population. A 1:4 matched case‒control study was conducted, and five single nucleotide polymorphisms (SNPs) in the NR1I3 and NR1H4 genes were detected and assessed. Utilizing a multivariate conditional logistic regression model, the effects of haplotype and genotype on the risk of AT-DILI were examined. Extended subgroup analysis was carried out based on sex. The distribution of the peak value of serum liver enzymes also compared among different genotypes. 224 AT-DILI cases and 896 controls were included in this study. No significant difference was observed in genotypes or haplotypes frequencies between AT-DILI cases and controls. However, comparisons of liver function indicators revealed significant differences in the peak values of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBil) among patients with different genotypes of NR1H4 rs56163822 (GG vs. GT vs. TT, 27.1 U/L vs. 26.0 U/L vs. 23.0 U/L, p = 0.020; 34.0 U/L vs. 31.0 U/L vs. 30.6 U/L, p = 0.008; 15.5μmol/L vs. 15.0μmol/L vs. 13.7μmol/L, p = 0.029, respectively), as well as in the peak values of ALT and AST among male patients with different genotypes of NR1H4 rs56163822 (29.0 U/L vs. 26.9 U/L vs. 22.6 U/L, p = 0.002; 34.0 U/L vs. 32.0 U/L vs. 30.5 U/L, p = 0.019, respectively). Based on this 1:4 individual-matched case‒control study, the SNP rs56163822 in the NR1H4 gene may be linked to the susceptibility to AT-DILI in Chinese patients receiving anti-TB treatment. Further studies in larger varied populations are needed to validate our findings.

Drug-induced liver injury in children: A nationwide cohort study from China

Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p= 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%). Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices. Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Compatibility with Semen Sojae Praeparatum attenuates hepatotoxicity of Gardeniae Fructus by regulating the microbiota, promoting butyrate production and activating antioxidant response

Herb-induced liver injury is a leading cause of drug-induced liver injury in China and its incidence is also increasing worldwide. Gardeniae Fructus (ZZ) has aroused wide concern for hepatotoxicity in recent decades. But when ZZ is administered in combination with Semen Sojae Praeparatum (DDC) to compose a herbal pair Zhizichi Decoction (ZZCD), lower hepatotoxicity is observed. The mechanism involved in the attenuated effect remains to be investigated. Our previous studies showed that DDC benefited host metabolism by regulating the gut microbiota and it reduced the exposure of major toxic components of ZZ. The present study was aimed to investigate how DDC attenuated hepatotoxicity of ZZ from the perspective of gut microbiota. Rats received ZZ and ZZCD treatment of different dosages and antibiotic treatment was applied to explore the involvement of gut microbiota. Biochemical assays and histopathological analysis were conducted to evaluate liver injury. Gut microbiota in caecal contents was profiled by 16S rRNA sequencing. Short-chain fatty acids (SCFAs) in caecal contents were measured by gas chromatography mass spectrometry (GCMS). To verify the protective effect of butyrate, it was administered with genipin, the major hepatotoxic metabolite of ZZ, to rats and HepG2 cells. Plasma lipopolysaccharide (LPS) level and colon tissue section were used to evaluate gut permeability. Expression level of Nuclear factor erythroid-derived 2-like 2 (Nrf2) was detected by immunohistochemistry in vitro and by western blot in vivo. Our study showed that ZZCD displayed lower hepatotoxicity than ZZ at the same dosage. ZZ induced gut dysbiosis, significantly reducing Lactobacillus and Enterococcus levels and increasing the Parasutterella level. In combination with DDC, these alterations were reversed and beneficial genus including Akkermansia and Prevotella were significantly increased. Besides, butyrate production was diminished by ZZ but was restored when in combination with DDC. Butyrate showed detoxification on genipin-induced liver injury by promoting colon integrity and promoting Nrf2 activation. Besides, it protected genipin-induced hepatocyte damage by promoting Nrf2 activation. DDC attenuates ZZ-induced liver injury by regulating the microbiota, promoting butyrate production and activating antioxidant response.

Tu-San-Qi (Gynura japonica): the culprit behind pyrrolizidine alkaloid-induced liver injury in China.

Herbs and dietary supplement-induced liver injury (HILI) is the leading cause of drug-induced liver injury in China. Among different hepatotoxic herbs, the pyrrolizidine alkaloid (PA)-producing herb Gynura japonica contributes significantly to HILI by inducing hepatic sinusoidal obstruction syndrome (HSOS), a liver disorder characterized by hepatomegaly, hyperbilirubinemia, and ascites. In China, G. japonica has been used as one of the plant species for Tu-San-Qi and is often misused with non-PA-producing Tu-San-Qi (Sedum aizoon) or even San-Qi (Panax notoginseng) for self-medication. It has been reported that over 50% of HSOS cases are caused by the intake of PA-producing G. japonica. In this review, we provide comprehensive information to distinguish these Tu-San-Qi-related herbal plant species in terms of plant/medicinal part morphologies, medicinal indications, and chemical profiles. Approximately 2156 Tu-San-Qi-associated HSOS cases reported in China from 1980 to 2019 are systematically reviewed in terms of their clinical manifestation, diagnostic workups, therapeutic interventions, and outcomes. In addition, based on the application of our developed mechanism-based biomarker of PA exposure, our clinical findings on the definitive diagnosis of 58 PA-producing Tu-San-Qi-induced HSOS patients are also elaborated. Therefore, this review article provides the first comprehensive report on 2214 PA-producing Tu-San-Qi (G. japonica)-induced HSOS cases in China, and the information presented will improve public awareness of the significant incidence of PA-producing Tu-San-Qi (G. japonica)-induced HSOS and facilitate future prevention and better clinical management of this severe HILI.

Efficacy and safety of magnesium isoglycyrrhizinate injection in patients with acute drug‐induced liver injury: A phase II trial

Drug-induced liver injury (DILI) is the most common reason for a drug to be withdrawn from the market. Apart from stopping the offending drug, no regimens are available for treating idiosyncratic DILI in clinical practice. We carried out a randomized, double-blind, multidoses, active drug controlled, multicentre phase II trial to assess the safety and efficacy of the study drug, magnesium isoglycyrrhizinate (MgIG), as compared to tiopronin, a standard therapy for DILI in China. The primary outcome was the proportion of alanine aminotransferase (ALT) normalization at week 4 after study drug administration. Logistic regression was used to examine the odds of ALT normalization between low dose (Group A) and high dose (Group B) vs active control (Group C). One hundred and seventy-four eligible subjects were randomized and enrolled into three groups: 59 in group A, 56 in group B and 59 in group C. It was shown that group A and group B lowered ALT level even at early stage of study drug administration; when compared with Group C (61.02%), the proportions of ALT normalization at week 4 were significantly greater in Group A (84.75%, P=.0029) and Group B (85.71%, P=.0037) respectively. The results from the univariate logistic model showed that the odds of ALT normalized among subjects in Group A were about 3.6 times greater (OR=3.55, 95% CI: 1.47-8.57, P=.0049) than subjects in Group C. Similar effect was observed among subjects in Group B (OR=3.83, 95% CI: 1.54-9.55, P=.0039). This trial provided preliminary evidence that MgIG is an effective and safe treatment for patients with acute DILI.

Strengthen the study of anti-tuberculosis drug-induced liver injury in China

抗结核药物性肝损伤（ATB-DILI）是抗结核药物常见的毒性及不良反应，若贻误诊治后果严重。如何减少或避免ATB-DILI，一直困扰着广大结核病防治工作者。我国抗结核药物性肝损伤方面的研究尚处在起步阶段，不少方面还需进行系统的临床和基础研究，同时也应引起我们足够的重视。.

Antipsychotic Drugs and Liver Injury.

SummaryIn October 2015, the drug-induced liver diseases group of the Chinese Society of Hepatology drafted and published the first Diagnosis and Treatment Guidelines on Drug-induced Liver Injury in China, giving suggestions on the diagnosis and treatment of drug-induced liver injury (DILI). As a psychiatrist, I have found that in clinical practice both typical and new antipsychotic drugs can induce liver injury to varying degrees. Therefore, it is necessary to quickly and accurately determine the cause of liver injury and the type and severity of injury and establish a solution. This article reviewed relevant literature including the common pathogenesis and clinical manifestations of drug-induced liver injury caused by antipsychotic drugs, laboratory tests, diagnostic criteria and classification, and clinical management strategies. This paper also includes a summary and a perspective on liver injury caused by antipsychotic drugs.

Tu1003 Damage of Oxidation System of Sinus Endothelial Cell by Tusanqi Contributes to Hepatic Veno-Occlusion Disease

Background: Drug-induced liver injury (DILI) is a complex disease and could lead to death. The clinical characteristics of DILI vary in China and western countries. This study analyzed the causes, clinical features and outcomes of DILI from China. Methods: All 2035 cases with DILI were retrospectively collected from the 96857 hospitalized patients due to liver injury in the 302 Military Hospital between January 2009 and January 2014. Results: Chinese herbal medicine (CHM) was implicated in 595 patients (29.2%), whereas Western medicine (WM) and a combination of WM and CHM were implicated in 875 cases (43.0%) and the other patients (27.8%), respectively. The major classes of implicated WM were antibiotics and antituberculotics and the most commonly implicated antibiotic was azithromycin. In patients with DILI caused by CHM, 52.4% were caused by herbal decoction and the major implicated herb were Polygonum multiflorum. Compared to WM, there were more female patients, less alcohol use, and higher proportion of hepatocellular injury pattern in cases with caused by CHM, but no differences in outcomes was found. The outcomes of the entire DILI cases were generally good, whereas 345 cases got poor prognosis, in which 13.3% developed into chronic DILI, 3.1% died due to liver injury, and 0.5% underwent liver transplantation. A model for prediction about prognosis of DILI, involving alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin (TB) and international normalized ratio (INR), was established and achieved sensitivity and specificity both over 0.90. Conclusions: The clinical characteristics of DILI in China are different from those in western countries and the features of cases with DILI caused by CHM differ from those by WM. The established prognosis model was ready-to-use to give prediction of outcome by biochemical indices. Table 1. Characteristics of patients with DILI caused by Chinese herbal medicine as compared with Western medicine.

Overview of drug-induced liver injury in China.

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Epidemiology of drug-induced liver injury in China

The epidemiology of drug-induced liver injury (DILI) in China has rarely been studied before. The aim of the present study was to determine the etiology of DILI in a Chinese population by reporting a systematic analysis of the Chinese literature published from 1994 to 2011. A comprehensive database search of the Chinese literature was performed to obtain all the relevant studies. The data, including the drug names and patients' sex, age, clinical classification, and prognosis, were collected and analyzed. In this research, we found 279 studies including 24 112 patients. There were 265 studies that reported the sex of 21 789 patients, 11 787 men and 10 002 women. The therapeutics included (but were not limited to) tuberculostatics, complementary and alternative medicines (CAMs), antibiotics, NSAIDs, antineoplastics, central nervous system agents, antithyroid drugs, and immunomodulators. Of these drugs, tuberculostatics and CAMs were the most common etiologies of DILI in China. DILI in China has a different etiology from that in Europe and USA. NSAIDs, which are the most common causes of DILI in western populations, are uncommon in China. Therefore, government, physicians, and patients should pay more attention to these drugs in DILI.