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drug-induced liver injury in inflammatory bowel disease: 1-year prospective observational study

World Journal of Gastroenterology 2017年第22期23卷 4102-4111页

作者： tomas koller martina galambosova simona filakovska michaela kubincova tibor hlavaty jozef toth anna krajcovicova juraj payer 5th Department of Internal Medicine Gastroenterology and Hepatology Comenius University in Bratislava Faculty of Medicine University Hospital Bratislava Ruzinov

To analyze 1-year liver injury burden in inflammatory bowel disease (IBD) *** a 6-mo inclusion period, consecutive IBD cases having a control visit at IBD center were included. Basic demographics, IBD phenotype and IBD treatment were recorded on entry. Aminotransferase (AT) activities of ALT, AST, ALP and gamma-glutamyl transpeptidase (GGT) were measured at baseline, 3 mo prior to study entry and prospectively every 3 mo for 1 year. liver injury patterns were predefined as: Grade 1 in ALT 1-3 × upper limit of normal (ULN), grade 2 in ALT > 3 × ULN, hepatocellular injury in ALT > 2 × ULN, cholestatic injury in simultaneous GGT and ALP elevation > ULN. Persisting injury was reported when AT elevations were found on > 1 measurement. Risk factors for the patterns of liver injury were identified among demographic parameters, disease phenotype and IBD treatment in univariate and multivariate analysis. Finally, implications for the change in IBD management were evaluated in cases with persisting hepatocellular or cholestatic *** hundred and fifty-one patients were included having 917 ALT and 895 ALP and GGT measurements. Over one year, grade 1 injury was found in 66 (26.3%), grade 2 in 5 (2%) and hepatocellular injury in 16 patients (6.4%). Persisting hepatocellular injury was found in 4 cases. Cholestasis appeared in 11 cases (4.4%) and persisted throughout the entire study period in 1 case. In multivariate analysis, hepatocellular injury was associated with BMI (OR = 1.13, 1.02-1.26), liver steatosis (OR = 10.61, 2.22-50.7), IBD duration (1.07, 1.00-1.15) and solo infliximab (OR = 4.57, 1.33-15.7). Cholestatic liver injury was associated with prior intestinal resection (OR = 32.7, 3.18-335), higher CRP (OR = 1.04, 1.00-1.08) and solo azathioprine (OR = 10.27, 1.46-72.3). In one case with transient hepatocellular injury azathioprine dose was decreased. In 4 cases with persisting hepatocellular injury, fatty liver or alcohol were most likel

关键词： drug-induced liver injury Risk factors Inflammatory bowel disease Infliximab Adalimumab Azathioprine

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drug-induced liver injury: Do we know everything?

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World Journal of Hepatology 2017年第10期9卷 491-502页

作者： Tamara Alempijevic Simon Zec Tomica Milosavljevic University of Belgrade School of Medicine Clinical Center of Serbia Clinic for Gastroenterology and Hepatology

Interest in drug-induced liver injury(DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States drug-induced liver injury Network, to further our understanding of all aspects of DILI. The launch of liver Tox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.

关键词： Acute liver failure drug-induced liver injury Hepatoxicity Acetaminophen toxicity Cholestatic injury liver biopsy Pharmacoepidemiology Herbal-induced liver injury Hy’s law

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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 *** remains a major public health problem and a major cause of drug *** the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is *** 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 ***,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI ***,there are many gaps for explaining all the complexity of iDILI susceptibility and ***,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug ***,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 *** 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

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drug-induced liver injury due to “natural products” used for weight loss:A case report

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World Journal of Gastroenterology 2009年第19期15卷 2414-2417页

作者： Giovanni Tarantino Martina Gilda Pezzullo Matteo Nicola Dario di Minno Francesco Milone Luigi Sossio Pezzullo Marco Milone Domenico Capone Department of Clinical & Experimental Medicine Federico II University Medical SchoolVia S.Pansini5 80131 NaplesItaly Department of General Surgery Federico II University Medical School5 80131 NaplesItaly Department of Neuroscience Section of Clinical PharmacologyFederico II University Medical School5 80131 NaplesItaly Department of General Surgery ASL BN1 of Benevento5 80131 NaplesItaly

Taking herbal-extracts to lose weight is an underestimated health ***,these products contain active agents that can cause acute liver *** this case report,a 22-year-old female patient,who presented with a feature of cholestatic syndrome,was so sure that the "natural products" were not dangerous that she did not inform her physicians that she had taken them,making their task that much more *** presentation mimicked acute cholecystitis and the patient underwent a *** was without any consequences and complications,although it did not completely cure the *** later admitted to having taken herbal remedies and this led to the correct diagnosis of phytotherapy-related hepatotoxicity and a successful therapeutic *** true incidence of phytotherapy-related hepatotoxicity and its pathogenic mechanisms are largely *** is important to increase the awareness of both clinicians and patients about the potential dangers of herbal remedies.

关键词： drug-induced liver injury Obesity Herbalremedies Cholecystitis

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drug-induced liver injury in hospitalized patients with notably elevated alanine aminotransferase

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World Journal of Gastroenterology 2012年第41期18卷 5972-5978页

作者： Hui-Min Xu Yan Chen Jie Xu Quan Zhou Department of Pharmacy the 2nd Af-filiated Hospital School of Medicine Zhejiang University Hang-zhou 310009 Zhejiang Province China Department of Gastroenterology the 2nd AffiliatedHospital School of Medicine Zhejiang University Hangzhou310009 Zhejiang Province China Department of Information Technology the 2nd AffiliatedHospital School of Medicine Zhejiang University Hangzhou310009 Zhejiang Province China

AIM： To identify the proportion, causes and the nature of drug-induced liver injury （DILI） in patients with no- tably elevated alanine aminotransferase （ALT）. METHODS： All the inpatients with ALT levels above 10 times upper limit of normal range （ULN） were ret- rospectively identified from a computerized clinical laboratory database at our hospital covering a 12-mo period. Relevant clinical information was obtained from medical records. Alternative causes of ALT eleva- tions were examined for each patient, including bili- ary abnormality, viral hepatitis, hemodynamic injury, malignancy, DILI or undetermined and other causes. All suspected DILI cases were causality assessed usingthe Council for International Organizations of Medical Sciences scale, and only the cases classified as highly probable, probable, or possible were diagnosed as DILI. Comments related to the diagnosis of DILI in the medical record and in the discharge letter for each case were also examined to evaluate DILI detection by the treating doctors. RESULTS： A total of 129 cases with ALT 〉 i0 ULN were identified. Hemodynamic injury （n = 46, 35.7%）, DILl （n = 25, 19.4%） and malignancy （n = 21, 16.3%） were the top three causes of liver injury. Peak ALT val- ues were lower in DILI patients than in patients with hemodynamic injury （14.5 5.6 ULN vs 32.5 ：I： 30.7 ULN, P = 0.001）. Among DILI patients, one （4%） case was classified as definite, 19 （76%） cases were clas- sified as probable and 5 （20%） as possible according to the ClOMS scale. A hepatocellular pattern was ob- served in 23 （92%） cases and mixed in 2 （8%）. The extent of severity of liver injury was mild in 21 （84%） patients and moderate in 4 （16%）. Before discharge, 10 （40%） patients were recovered and the other 15 （60%） were improved. The improved patients tended to have a higher peak ALT （808 ＋ 348 U/L vs 623 ＋ 118 U/L, P = 0.016） and shorter treatment duration before discharge （8 ＋ 6 d vs 28 ~ 12 d, P = 0.008） compared with the recovered pati

关键词： drug-induced liver injury Abnormal liverenzyme Alanine aminotransferase Underdiagnosis Adjunctive drugs

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Contribution of gut microbiota to drug-induced liver injury

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Hepatobiliary & Pancreatic Diseases International 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 *** damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte *** studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed *** 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 *** addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut *** 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

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Association of Cytokines with Clinical Indicators in Patients with drug-induced liver injury

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Biomedical and Environmental Sciences 2024年第5期37卷 494-502页

作者： CAO Wei Hua JIANG Ting Ting SHEN Ge DENG Wen WANG Shi Yu ZHANG Zi Yu LI Xin Xin LU Yao ZHANG Lu LIU Ru Yu CHANG Min WU Shu Ling GAO Yuan Jiao HAO Hong Xiao CHEN Xiao Xue HU Lei Ping XU Meng Jiao YI Wei XIE Yao LI Ming Hui Department of Hepatology Division 2 Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of Hepatology Division 2 Peking University Ditan Teaching HospitalBeijing 100015China Department of Gynecology and Obstetrics Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical *** The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with *** on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five *** were measured by Luminex *** characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were *** 73 patients were *** among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine ***-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:Pliver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

关键词： drug-induced liver injury Cytokines Non-steroidal anti-inflammatory drugs Inflammation

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drug-induced liver injury:Is it somehow foreseeable?

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World Journal of Gastroenterology 2009年第23期15卷 2817-2833页

作者： Giovanni Tarantino Matteo Nicola Dario Di Minno Domenico Capone Depart-ment of Clinical and Experimental Medicine Section of Hepa-tology in Internal Medicine Federico Ⅱ University Medical School of Naples 5 80131 Napoli Italy Department of Neurosciences Unit of Clinical Pharmacology Federico Ⅱ University Medical School of Naples 5 80131 Napoli Italy

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

关键词： drug-induced liver injury CytochromeP-450 drug metabolism Pharmacogenomics Herbalremedies

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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 *** recent years,immune checkpoint inhibitors have become widely *** has led to an increase in DILI,for which pathophysiology and management methods differ significantly from the *** 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 *** 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 *** addition,depending on the course of the disease,chronic DILI or drug-induced autoimmune hepatitis may be *** number of DILI cases caused by antimicrobial agents is decreasing,whereas that caused by drugs for malignant tumors and health foods is *** Roussel Uclaf Causality Assessment Method is widely used to assess causality in *** injury is a type of immune-related adverse *** pattern of hepatic injury in immune-related adverse events is mostly hepatocellular,but mixed type and bile stasis have also been *** cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of *** 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

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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 *** are few reports comparing DILI in CLD and non-CLD *** this study,we aimed to determine the incidence and outcomes of DILI in patients with and without ***: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 *** 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 *** with definite,or highly likely DILI were included in the ***:A total of 200 subjects diagnosed with DILI were found in the *** those,41 had CLD and 159 had no evidence of CLD in their *** and alternative medicine(CAM)products were identified as the most common class of DILI *** 59%of DILI in the CLD and 40%in non-CLD group were associated with CAM *** with pre-existing CLD had similar severity including *** patients(6%)developed adverse outcomes related to DILI including seven(3.5%)deaths and five(2.5%)with liver *** 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,***:In this liver disease registry,the causes,clinical presentation,and outcomes of DILI in subjects with CLD and without CLD patients were not *** study is required to confirm our findings.

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

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