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Salivary metabolites are promising noninvasive biomarkers of druginduced liver injury

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World Journal of Gastroenterology 2024年第18期30卷 2454-2466页

作者： Si-Miao Yu Hao-Cheng Zheng Si-Ci Wang Wen-Ya Rong Ping Li Jing Jing Ting-Ting He Jia-Hui Li XiaDing Rui-Lin Wang School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 100029China School of Traditional Chinese Medicine Southern Medical UniversityGuangzhou 510515Guangdong ProvinceChina Department of Hepatology of Traditional Chinese Medicine The Fifth Medical Center of PLA General HospitalBeijing 100039China The First Clinical Medical College Henan University of Traditional Chinese MedicineZhengzhou 450000Henan ProvinceChina

BACKGROUND drug-induced liver injury(DILI)is one of the most common adverse events of medication use,and its incidence is increasing.However,early detection of DILI is a crucial challenge due to a lack of biomarkers and noninvasive tests.AIM To identify salivary metabolic biomarkers of DILI for the future development of noninvasive diagnostic tools.METHODS Saliva samples from 31 DILI patients and 35 healthy controls(HCs)were subjected to untargeted metabolomics using ultrahigh-pressure liquid chromatography coupled with tandem mass spectrometry.Subsequent analyses,including partial least squares-discriminant analysis modeling,t tests and weighted metabolite coexpression network analysis(WMCNA),were conducted to identify key differentially expressed metabolites(DEMs)and metabolite sets.Furthermore we utilized least absolute shrinkage and selection operato and random fores analyses for biomarker prediction.The use of each metabolite and metabolite set to detect DILI was evaluated with area under the receiver operating characteristic curves.RESULTS We found 247 differentially expressed salivary metabolites between the DILI group and the HC group.Using WMCNA,we identified a set of 8 DEMs closely related to liver injury for further prediction testing.Interestingly,the distinct separation of DILI patients and HCs was achieved with five metabolites,namely,12-hydroxydodecanoic acid,3-hydroxydecanoic acid,tetradecanedioic acid,hypoxanthine,and inosine(area under the curve:0.733-1).CONCLUSION Salivary metabolomics revealed previously unreported metabolic alterations and diagnostic biomarkers in the saliva of DILI patients.Our study may provide a potentially feasible and noninvasive diagnostic method for DILI,but further validation is needed.

关键词： drug-induced liver injury Salivary Metabolomics Biomarker Weighted metabolite Coexpression network analysis Machine learning Noninvasive Diagnostic method Metabolites

Preclinical models of idiosyncratic drug-induced liver injury(iDILI):Moving towards prediction

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3685-3726页

作者： Antonio Segovia-Zafra Daniel E.Di Zeo-Sanchez Carlos Lopez-Gomez Zeus Perez-Valdes Eduardo Garcıa-Fuentes Raul J.Andrade M.Isabel Lucena Marina Villanueva-Paz Unidad de Gestio´n Clı´nica de Gastroenterologı´a Servicio de Farmacologıa ClınicaInstituto de Investigacio´n Biomedica de Malaga-IBIMAHospital Universitario Virgen de la VictoriaUniversidad de MalagaMalaga 29071Spain Centro de Investigacion Biomedica en Red en el Area Tematica de Enfermedades Hepaticas y Digestivas(CIBERehd) Madrid 28029Spain Platform ISCIII de Ensayos Clınicos UICEC-IBIMAMalaga 29071Spain Unidad de Gestion Clınica de Aparato Digestivo Instituto de Investigacion Biomedica de Malaga(IBIMA)Hospital Universitario Virgen de la VictoriaMalaga 29010Spai

Idiosyncratic drug-induced liver injury(iDILI) encompasses the unexpected harms that prescription and non-prescription drugs,herbal and dietary supplements can cause to the liver.iDILI remains a major public health problem and a major cause of drug attrition.Given the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is necessary.One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI.Thus,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients.However,there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms.Therefore,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development.Here,the current experimental models and the future directions in iDILI modelling are thoroughly discussed,focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models.We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

关键词： drug-induced liver injury Preclinical models Mechanisms Oxidative stress Mitochondrial damage Immune response Personalized medicine

Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury

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iliver 2023年第2期2卷 122-129页

作者： Georgia Zeng Guy D.Eslick Martin Weltman Department of Gastroenterology and Hepatology Nepean HospitalKingswoodAustralia Nepean Clinical School University of SydneyKingswoodAustralia NHMRC Centre of Research Excellence in Digestive Health Hunter Medical Research InstituteThe University of NewcastleNewcastleAustralia

Background and aims:drug-induced liver injury(DILI)is a leading cause of death from acute liver failure(ALF).Hy's law warns that a hepatocellular pattern of injury accompanied by jaundice and normal alkaline phosphatase(ALP)levels is associated with a 10%or greater chance of progression to transplant or liver-related death.This meta-analysis of DILI studies evaluates acute and chronic outcomes of DILI according to clinical pattern of injury.Methods:We conducted a systematic search using electronic databases PubMed and EMBASE through to 8 March 2022.Our primary outcome was to compare acute outcomes including ALF,liver-related death,and liver transplant between patients experiencing hepatocellular,cholestatic,and mixed patterns of DILI.Our secondary outcome was to compare the rate of DILI chronicity between patients of these three differing patterns of injury.Pooled odds ratios(ORs)and 95%confidence intervals(CIs)were calculated using a random-effects model.Results:Overall,12 studies comprising 4290 patients were included.Patients with cholestatic DILI demonstrated similar rates of ALF(OR:0.80,95%CI:0.46–1.40,p=0.429)and liver-related death(OR:0.92,95%CI:0.50–1.69,p=0.792)compared to patients with hepatocellular DILI.Patients with cholestatic DILI were significantly more likely to experience chronicity compared to patients with hepatocellular DILI(OR:2.53,95%CI:1.34–4.79,p=0.004).

关键词： drug-induced liver injury Idiosyncratic hepatotoxicity Acute liver failure liver-related death Meta-analysis

Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through JAK2/STAT3 signaling pathway:An experimental study

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Asian Pacific Journal of Tropical Medicine 2017年第5期10卷 493-496页

作者： Hong Zhang Yang Liu Li-Kun Wang Na Wei Internal Medicine Department No.2 Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Child Healthcare Department Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Infectious Disease Department No.6 Ward Linyi People's Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Laboratory Department Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China

Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as JAK2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-JAK2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by JAK2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.

关键词： drug-induced liver injury Anti-tuberculosis drug Pyrrolidine dithiocarbamate JAK2 STAT3

Contribution of gut microbiota to drug-induced liver injury

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国际肝胆胰疾病杂志:英文版 2023年第5期22卷 458-465页

作者： Hui-Kuan Chu Yan Ai Zi-Lu Cheng Ling Yang Xiao-Hua Hou Division of Gastroenterology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China

drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.drugs damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte necrosis.Recent studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly.It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation,and the alteration of microbial metabolites may cause or aggravate DILI.In addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota.In this review,we discussed how the altered gut microbiota participates in DILI.

关键词： Gut microbiota Lipopolysaccharide Probiotics Fecal microbiota transplantation drug-induced liver injury

Characteristics of drug-induced liver injury in Chronic liver Disease:Results from the Thai Association for the Study of the liver(THASL)DILI Registry

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 88-96页

作者： Sakkarin Chirapongsathorn Wattana Sukeepaisarnjaroen Sombat Treeprasertsuk Roonguedee Chaiteerakij Pichaporn Surawongsin Chanunta Hongthanakorn Sith Siramolpiwat Naichaya Chamroonkul Chalermrat Bunchorntavakul Watcharasak Chotiyaputta Kittiyod Poovorawan Rattana Boonsirichan Saranath Lawpoolsri Chinnavat Sutivana Abhasnee Sobhonslidsuk Division of Gastroenterology and Hepatology Department of MedicinePhramongkutklao Hospital and College of MedicineRoyal Thai ArmyBangkokThailand Division of Gastroenterology and Hepatology Faculty of MedicineKhon Kaen UniversityKhon KaenThailand Division of Gastroenterology Faculty of MedicineChulalongkorn UniversityBangkokThailand Division of Gastroenterology Bhumibol Adulyadej HospitalBangkokThailand Division of Gastroenterology Faculty of MedicineThammasat UniversityPratumthaniThailand Division of Gastroenterology and Hepatology Faculty of MedicinePrince of Songkla UniversitySongklaThailand Division of Gastroenterology and Hepatology Rajavithi HospitalCollege of MedicineRangsit UniversityBangkokThailand Division of Gastroenterology Faculty of MedicineSiriraj HospitalMahidol UniversityBangkokThailand Department of Clinical Tropical Medicine Faculty of Tropical MedicineMahidol UniversityBangkokThailand Division of Gastroenterology Faculty of MedicineVajira HospitalBangkokThailand Center of Excellence for Biomedical and Public Health Informatics(BIOPHICS) Faculty of Tropical MedicineMahidol UniversityBangkokThailand Division of Gastroenterology and Hepatology Faculty of MedicineRamathibodi HospitalMahidol UniversityBangkokThailand

Background and Aims:The impact of drug-induced liver injury(DILI)on patients with chronic liver disease(CLD)is unclear.There are few reports comparing DILI in CLD and non-CLD patients.In this study,we aimed to determine the incidence and outcomes of DILI in patients with and without CLD.Methods:We collected data on eligible individuals with suspected DILI between 2018 and 2020 who were evaluated systematically for other etiologies,causes,and the severity of DILI.We compared the causative agents,clinical features,and outcomes of DILI among subjects with and without CLD who were enrolled in the Thai Association for the Study of the liver DILI registry.Subjects with definite,or highly likely DILI were included in the analysis.Results:A total of 200 subjects diagnosed with DILI were found in the registry.Of those,41 had CLD and 159 had no evidence of CLD in their background.Complementary and alternative medicine(CAM)products were identified as the most common class of DILI agents.Approximately 59%of DILI in the CLD and 40%in non-CLD group were associated with CAM use.Individuals with pre-existing CLD had similar severity including mortality.Twelve patients(6%)developed adverse outcomes related to DILI including seven(3.5%)deaths and five(2.5%)with liver failure.Mortality was 4.88%in CLD and 3.14%in non-CLD subjects over median periods of 58(8–106)days and 22(1–65)days,respectively.Conclusions:In this liver disease registry,the causes,clinical presentation,and outcomes of DILI in subjects with CLD and without CLD patients were not different.Further study is required to confirm our findings.

关键词： Chronic liver disease Cirrhosis drug-induced liver injury druginduced liver injury network Toxicity Medication

Efficacy of Jian’ganle(健肝乐) versus Hugan Pian(护肝片),Glucuronolactone and Reduced Glutathione in Prevention of Antituberculosis drug-induced liver injury

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2014年第3期34卷 450-455页

作者：张权钟方莹吴梦张新平 School of Medicine and Health Management Tongji Medical College Huazhong University of Science and Technology

Summary： Evidence-based medicine is advocated by WHO and adopted by developed countries for many years. In China, however, the selection of essential medicine and various medical insurance reimbursement schemes medicine is usually based on experts＇ experience of prescription practice which is under heavy critics resulting from the lack of related comparative efficacy and evidence-based research. The efficacy of Jian＇ganle in prevention of drug-induced liver injury （DILI） caused by antituberculotics was evaluated in this study by comparison with Hugan Pian, glucuronolactone and reduced glutathione. Evidence was provided for relevant sectors such as Ministry for Human Resources and Social Security of the People＇s Republic of China and National Health and Family Planning Commission of the Peo- ple＇s Republic of China to select and renew the Essential Medicine List （EML）, the new rural cooperative medical scheme in China （NRCMS） list or the reimbursement list of industrial injury insurance. A total of 189 patients with initial pulmonary tuberculosis were divided into four groups who took antituberculotics combined with Jian＇ganle, Hugan Pian, glucuronolactone and reduced glutathione respectively. Their liver function profile including alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, total bilirubin （TBIL）, direct bilirubin （DBIL）, total protein （TP）, albumin （A） and globulin （G） were detected at admission as baseline and after treatment. The Jian＇ganle group was compared with the three others by chi-square tests. In an aspect of maintaining bilirubin indexes normal, Jian＇ganle was more efficacious than glucuronolactone. And Jian＇ganle had a little more efficacy than reduced glutathione to maintain protein indexes normal as well. And the therapeutic regimen of antituberculotics combined with Jian＇ganle was the best in treating tuberculosis and preventing DILI at the same time. The study showed that among the four hepatinicas which demonstrated similar prevention of DILI caused by antituberculotics, Ji

关键词： drug-induced liver injury comparative efficacy Jian＇ganle liver function profile evidence-based evaluation and selection drug list

Epidemiology and Management of drug-induced liver injury: Importance of the Updated RUCAM

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Journal of Clinical and Translational Hepatology 2023年第5期11卷 1239-1245页

作者： Takashi Kobayashi Michihiro Iwaki Asako Nogami Masato Yoneda Department of Gastroenterology and Hepatology Yokohama City University Graduate School of MedicineYokohamaJapan

drug-induced liver injury(DILI)is a major cause of acute liver injury,liver failure,and liver transplantation worldwide.In recent years,immune checkpoint inhibitors have become widely used.This has led to an increase in DILI,for which pathophysiology and management methods differ significantly from the past.As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase,information about a DILI is becoming more valuable.DILI is classified into two types according to its etiology:intrinsic DILI,in which the drug or its metabolites cause liver damage that is dose-dependent and predictable;and idiosyncratic DILI,in which liver damage is also dose-independent but unpredictable.In addition,depending on the course of the disease,chronic DILI or drug-induced autoimmune hepatitis may be present.The number of DILI cases caused by antimicrobial agents is decreasing,whereas that caused by drugs for malignant tumors and health foods is increasing.The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI.liver injury is a type of immune-related adverse event.The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular,but mixed type and bile stasis have also been reported.Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury.Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration;however,mycophenolate mofetil may be considered if the disease is refractory to steroids.

关键词： drug-induced liver injury Immune-related adverse events Immune checkpoint inhibitor Updated RUCAM

drug-induced liver injury Due to Lepidium meyenii （Maca） Medicinal Liquor

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Chinese Medical Journal 2017年第24期130卷 3005-3006页

作者： An Xiao Hai-Ying He Qing Chen Shi-Wu Ma Department of Infectious Disease Kunming General Hospital of Chengdu Military Command Kunming Yunnan 650221 China

drug-induced liver injury （DILI） is one of the most common and serious adverse drug reactions.Idiosyncratic DILI is more common than intrinsic DILI and can be classified into hepatocellular injury,cholestatic injury... 详细信息

关键词： drug-induced liver injury Maca Prolonged Recovery