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Suzuki A, MinjunChen. Epidemiology and Risk Determinants of Drug-Induced Liver Injury: Current Knowledge and Future Research Needs. Liver Int 2025; 45:e16146. [PMID: 39494620 DOI: 10.1111/liv.16146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/05/2024] [Accepted: 10/13/2024] [Indexed: 11/05/2024]
Abstract
AIMS Drug-induced liver injury (DILI) is a major global health concern resulting from adverse reactions to medications, supplements or herbal medicines. The relevance of DILI has grown with an aging population, the rising prevalence of chronic diseases and the increased use of biologics, including checkpoint inhibitors. This article aims to summarise current knowledge on DILI epidemiology and risk factors. METHODS This review critically appraises available evidence on DILI frequency, outcomes and risk determinants, focusing on drug properties and non-genetic host factors that may influence susceptibility. RESULTS DILI incidence varies across populations, with hospitalised patients experiencing notably higher rates than outpatients or the general population. Increased medication use, particularly among older adults and women, may partly explain age- and sex-based disparities in DILI incidence and reporting. Physiological changes associated with aging likely increase susceptibility to DILI in older adults, though further exposure-based studies are needed for definitive conclusions. Current evidence does not strongly support that women are inherently more susceptible to DILI than men; rather, susceptibility appears to depend on specific drugs. However, once DILI occurs, older age and female sex are associated with greater severity and poorer outcomes. Other less-studied host-related risk factors are also discussed based on available evidence. CONCLUSIONS This article summarises existing data on DILI frequency, outcomes, drug properties affecting hepatotoxicity and non-genetic host risk factors while identifying critical knowledge gaps. Addressing these gaps through future research could enhance understanding and support preventive measures.
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Affiliation(s)
- Ayako Suzuki
- Gastroenterology, Duke University, Durham, North Carolina, USA
- Gastroenterology, Durham VA Medical Center, Durham, North Carolina, USA
| | - MinjunChen
- Division of Bioinformatics and Biostatistics, FDA's National Center for Toxicological Research, Jefferson, Arkansas, USA
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Yang Y, Chen Q, Liu Z, Huang T, Hong Y, Li N, Ai K, Huang Q. Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals. J Colloid Interface Sci 2025; 678:174-187. [PMID: 39243718 DOI: 10.1016/j.jcis.2024.08.239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/07/2024] [Accepted: 08/29/2024] [Indexed: 09/09/2024]
Abstract
With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.
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Affiliation(s)
- Yongqi Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Qiaohui Chen
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Zerun Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ting Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Ying Hong
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Niansheng Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China.
| | - Kelong Ai
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410078, China
| | - Qiong Huang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
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Kastrinou-Lampou V, Rodríguez-Pérez R, Poller B, Huth F, Gáborik Z, Mártonné-Tóth B, Temesszentandrási-Ambrus C, Schadt HS, Kullak-Ublick GA, Arand M, Camenisch G. Identification of reversible OATP1B1 and time-dependent CYP3A4 inhibition as the major risk factors for drug-induced cholestasis (DIC). Arch Toxicol 2024; 98:3409-3424. [PMID: 39023798 DOI: 10.1007/s00204-024-03794-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 05/22/2024] [Indexed: 07/20/2024]
Abstract
Hepatic bile acid regulation is a multifaceted process modulated by several hepatic transporters and enzymes. Drug-induced cholestasis (DIC), a main type of drug-induced liver injury (DILI), denotes any drug-mediated condition in which hepatic bile flow is impaired. Our ability in translating preclinical toxicological findings to human DIC risk is currently very limited, mainly due to important interspecies differences. Accordingly, the anticipation of clinical DIC with available in vitro or in silico models is also challenging, due to the complexity of the bile acid homeostasis. Herein, we assessed the in vitro inhibition potential of 47 marketed drugs with various degrees of reported DILI severity towards all metabolic and transport mechanisms currently known to be involved in the hepatic regulation of bile acids. The reported DILI concern and/or cholestatic annotation correlated with the number of investigated processes being inhibited. Furthermore, we employed univariate and multivariate statistical methods to determine the important processes for DILI discrimination. We identified time-dependent inhibition (TDI) of cytochrome P450 (CYP) 3A4 and reversible inhibition of the organic anion transporting polypeptide (OATP) 1B1 as the major risk factors for DIC among the tested mechanisms related to bile acid transport and metabolism. These results were consistent across multiple statistical methods and DILI classification systems applied in our dataset. We anticipate that our assessment of the two most important processes in the development of cholestasis will enable a risk assessment for DIC to be efficiently integrated into the preclinical development process.
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Affiliation(s)
- Vlasia Kastrinou-Lampou
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | | | - Birk Poller
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Felix Huth
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland
| | - Zsuzsanna Gáborik
- SOLVO Biotechnology, Charles River Laboratories Hungary, 1117, Budapest, Hungary
| | - Beáta Mártonné-Tóth
- SOLVO Biotechnology, Charles River Laboratories Hungary, 1117, Budapest, Hungary
| | | | - Heiko S Schadt
- Preclinical Safety, BioMedical Research, Novartis, Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Gian Camenisch
- Pharmacokinetic Sciences, BioMedical Research, Novartis, Basel, Switzerland.
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Jin Y, Shou Y, Lei Q, Du C, Xu L, Chen N, Ma W, Zhu X, Zhou S, Zheng Y, Yu D. An entropy weight method to integrate big omics and mechanistically evaluate DILI. Hepatology 2024; 79:1264-1278. [PMID: 37820269 PMCID: PMC11095888 DOI: 10.1097/hep.0000000000000628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND AND AIMS DILI accounts for more than half of acute liver failure cases in the United States and is a major health care issue for the public worldwide. As investigative toxicology is playing an evolving role in the pharmaceutical industry, mechanistic insights into drug hepatotoxicity can facilitate drug development and clinical medication. METHODS By integrating multisource datasets including gene expression profiles of rat livers from open TG-GATE database and DrugMatrix, drug labels from FDA Liver Toxicity Knowledge Base, and clinical reports from LiverTox, and with the employment of bioinformatic and computational tools, this study developed an approach to characterize and predict DILI based on the molecular understanding of the processes (toxicity pathways). RESULTS A panel of 11 pathways widely covering biological processes and stress responses was established using a training set of six positive and one negative DILI drugs from open TG-GATEs. An entropy weight method-based model was developed to weight responsive genes within a pathway, and an interpretable machine-learning (ML) model XGBoot-SHAP was trained to rank the importance of pathways to the panel activity. The panel activity was proven to differentiate between injured and noninjured sample points and characterize DILI manifestation using six training drugs. Next, the model was tested using an additional 89 drugs (61 positives + 28 negatives), and a precision of 86% and higher can be achieved. CONCLUSIONS This study provides a novel approach to mechanisms-driven prediction modeling, as well as big data integration for insights into pharmacology and other human biology areas.
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Affiliation(s)
- Yuan Jin
- Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province Affiliated to Qingdao University, Jinan, China
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Yingqing Shou
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Qinkai Lei
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Chenlong Du
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Lin Xu
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Ningning Chen
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Wanli Ma
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Xiaoxiao Zhu
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Shuya Zhou
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Yuxin Zheng
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
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Björnsson ES. The Epidemiology of Newly Recognized Causes of Drug-Induced Liver Injury: An Update. Pharmaceuticals (Basel) 2024; 17:520. [PMID: 38675480 PMCID: PMC11053599 DOI: 10.3390/ph17040520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/12/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The incidence and prevalence of drug-induced liver injury appear to be increasing globally, for example, with the introduction of checkpoint inhibitors. Several reviews have been published in the last decade on the epidemiology of DILI, both among hospitalized patients and in the general population, as well as from retrospective and prospective studies on DILI. Most of these reviews have not focused on newly recognized agents that have recently changed the landscape of DILI. Apart from liver injury associated with antibiotics, oncological agents, particularly checkpoint inhibitors, are increasingly being recognized as causing liver injury. The type of liver injury associated with these agents is not idiosyncratic but rather an indirect type of injury. Furthermore, recently, COVID-19 vaccines and green tea extract have been found to lead to liver injury. Checkpoint inhibitors have revolutionized the treatment of many malignancies, such as malignant melanoma, lung cancer, and renal cancer. Via the activation of T cells, they can increase immune activity against malignant cells, but at the same time, they can decrease immune tolerance and therefore lead to immune-related adverse effects in many organs. The most common adverse effect in clinical practice is liver injury. A recent prospective study demonstrated an 8% frequency of DILI due to the use of checkpoint inhibitors among patients with malignant melanoma and renal cancer. This rate is much higher than observed with drugs, leading to idiosyncratic liver injury. Shortly after the implementation of the worldwide vaccination program against COVID-19, several case reports were published on suspected vaccination-induced autoimmune-like hepatitis occurring shortly after the vaccination. At first, these reports were met with skepticism, but currently, around 100 reports have been published, and cases of positive recurrence have been reported. The clinical, biochemical, immunological, and histological features are indistinguishable from classic autoimmune hepatitis (AIH). These reactions are very similar to drug-induced autoimmune-like hepatitis (DI-ALH) due to drugs such as nitrofurantoin, minocycline, and infliximab, which do not relapse after a short course of corticosteroids, which is the general rule in classic autoimmune hepatitis (AIH). Green tea extract has been found to be a well-documented cause of acute hepatocellular liver injury with jaundice. A strong HLA association has been reported, showing a high prevalence of HLA-B*35:01 among patients suffering from green tea-induced liver injury. Overall, 3% of patients recruited in the DILIN study were supplemented with green tea extract as one of the ingredients. In a prospective population-based study from Iceland, green tea was implicated in approximately 8% of patients with DILI.
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Affiliation(s)
- Einar Stefan Björnsson
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The National University Hospital of Iceland, Faculty of Medicine, University of Iceland, Hringbraut, 101 Reykjavik, Iceland
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Asai Y, Ooi H, Sato Y. Risk evaluation of carbapenem-induced liver injury based on machine learning analysis. J Infect Chemother 2023; 29:660-666. [PMID: 36914094 DOI: 10.1016/j.jiac.2023.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 03/06/2023] [Accepted: 03/09/2023] [Indexed: 03/13/2023]
Abstract
INTRODUCTION Information regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of liver injury. Thus, we aimed to compare the rate of liver injury between MEPM and DRPM and construct a flowchart that can be used to predict carbapenem-induced liver injury. METHODS We investigated patients treated with MEPM (n = 310) or DRPM (n = 320) and confirmed liver injury as the primary outcome. We used a chi-square automatic interaction detection algorithm to construct DT models. The dependent variable was set as liver injury from a carbapenem (MEPM or DRPM), and factors including alanine aminotransferase (ALT), albumin-bilirubin (ALBI) score, and concomitant use of acetaminophen were used as explanatory variables. RESULTS The rates of liver injury were 22.9% (71/310) and 17.5% (56/320) in the MEPM and DRPM groups, respectively; no significant differences in the rate were observed (95% confidence interval: 0.710-1.017). Although the DT model of MEPM could not be constructed, DT analysis showed that the incidence of introducing DRPM in patients with ALT >22 IU/L and ALBI scores > -1.87 might be high-risk. CONCLUSIONS The risk of developing liver injury did not differ significantly between the MEPM and DRPM groups. Since ALT and ALBI score are evaluated in clinical settings, this DT model is convenient and potentially useful for medical staff in assessing liver injury before DRPM administration.
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Affiliation(s)
- Yuki Asai
- Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojin, Tsu, Mie, 514-1101, Japan.
| | - Hayahide Ooi
- Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojin, Tsu, Mie, 514-1101, Japan
| | - Yoshiharu Sato
- Pharmacy, National Hospital Organization Mie Chuo Medical Center, 2158-5 Hisaimyojin, Tsu, Mie, 514-1101, Japan
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Barnhart BK, Kan T, Srivastava A, Wessner CE, Waters J, Ambelil M, Eisenbrey JR, Hoek JB, Vadigepalli R. Longitudinal ultrasound imaging and network modeling in rats reveal sex-dependent suppression of liver regeneration after resection in alcoholic liver disease. Front Physiol 2023; 14:1102393. [PMID: 36969577 PMCID: PMC10033530 DOI: 10.3389/fphys.2023.1102393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/28/2023] [Indexed: 03/11/2023] Open
Abstract
Liver resection is an important surgical technique in the treatment of cancers and transplantation. We used ultrasound imaging to study the dynamics of liver regeneration following two-thirds partial hepatectomy (PHx) in male and female rats fed via Lieber-deCarli liquid diet protocol of ethanol or isocaloric control or chow for 5–7 weeks. Ethanol-fed male rats did not recover liver volume to the pre-surgery levels over the course of 2 weeks after surgery. By contrast, ethanol-fed female rats as well as controls of both sexes showed normal volume recovery. Contrary to expectations, transient increases in both portal and hepatic artery blood flow rates were seen in most animals, with ethanol-fed males showing higher peak portal flow than any other experimental group. A computational model of liver regeneration was used to evaluate the contribution of physiological stimuli and estimate the animal-specific parameter intervals. The results implicate lower metabolic load, over a wide range of cell death sensitivity, in matching the model simulations to experimental data of ethanol-fed male rats. However, in the ethanol-fed female rats and controls of both sexes, metabolic load was higher and in combination with cell death sensitivity matched the observed volume recovery dynamics. We conclude that adaptation to chronic ethanol intake has a sex-dependent impact on liver volume recovery following liver resection, likely mediated by differences in the physiological stimuli or cell death responses that govern the regeneration process. Immunohistochemical analysis of pre- and post-resection liver tissue validated the results of computational modeling by associating lack of sensitivity to cell death with lower rates of cell death in ethanol-fed male rats. Our results illustrate the potential for non-invasive ultrasound imaging to assess liver volume recovery towards supporting development of clinically relevant computational models of liver regeneration.
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Affiliation(s)
- Benjamin K. Barnhart
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Toshiki Kan
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Ankita Srivastava
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Corinne E. Wessner
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - John Waters
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Manju Ambelil
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - John R. Eisenbrey
- Department of Radiology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jan B. Hoek
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
- *Correspondence: Rajanikanth Vadigepalli,
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Fontana RJ, Liou I, Reuben A, Suzuki A, Fiel MI, Lee W, Navarro V. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology 2023; 77:1036-1065. [PMID: 35899384 PMCID: PMC9936988 DOI: 10.1002/hep.32689] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 07/07/2022] [Indexed: 12/14/2022]
Affiliation(s)
- Robert J. Fontana
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Iris Liou
- University of Washington, Seattle, Washington, USA
| | - Adrian Reuben
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ayako Suzuki
- Division of Gastroenterology, Duke University, Durham, North Carolina, USA
| | - M. Isabel Fiel
- Department of Pathology, Mount Sinai School of Medicine, New York City, New York, USA
| | - William Lee
- Division of Gastroenterology, University of Texas Southwestern, Dallas, Texas, USA
| | - Victor Navarro
- Department of Medicine, Einstein Healthcare Network, Philadelphia, Pennsylvania, USA
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Assessment of the Frequency, Phenotypes, and Outcomes of Acute Liver Injury Associated with Amoxicillin/Clavulanate in 1.4 Million Patients in the Veterans Health Administration. Drug Saf 2023; 46:129-143. [PMID: 36547811 DOI: 10.1007/s40264-022-01255-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2022] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Drug-induced liver injury is a significant health issue, yet the exposure-based incidence remains to be characterized. OBJECTIVE We aimed to assess the frequency, phenotypes, and outcomes of acute liver injury associated with amoxicillin/clavulanate using a large electronic health record system. METHODS Using the Veterans Health Administration electronic health record system, we developed the framework to identify unexplained acute liver injury, defined by alanine aminotransferase and/or alkaline phosphatase elevation temporally linked to prescription records of amoxicillin/clavulanate, a major culprit of clinically significant drug-induced liver injury, excluding other competing causes. The population was subcategorized by pre-existing liver conditions and inpatient status at the time of exposure for the analysis. RESULTS Among 1,445,171 amoxicillin/clavulanate first exposures in unique individuals [92% men; mean age (standard deviation): 59 (15) years], 6476 (incidence: 0.448%) acute liver injuries were identified. Of these, 4427 (65%) had alternative causes, yielding 2249 (incidence: 0.156%) with unexplained acute liver injuries. The incidence of unexplained acute liver injury was lowest in outpatients without underlying liver disease (0.067%) and highest in inpatients with pre-existing liver conditions (0.719%). Older age, male sex, and American Indian or Alaska Native (vs White) were associated with a higher incidence of unexplained acute liver injury. Cholestatic injury affected 74%, exhibiting a higher frequency with advanced age, inpatient exposure, and pre-existing liver conditions. Hepatocellular injury with bilirubin elevation affected 0.003%, with a higher risk at age >45 years. During a 12-month follow-up, patients with unexplained acute liver injury had a higher adjusted overall mortality risk than those without evident acute liver injury. CONCLUSIONS This framework identifies unexplained acute liver injury following drug exposure in large electronic health record datasets. After validating in other systems, this framework can aid in deducing drug-induced liver injury in the general patient population and regulatory decision making to promote drug safety and public health.
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Malhotra K, Fazylov R, Friedman-Jakubovics M. A Case-Report of Drug-Induced Mixed Liver Injury Resulting From Cefepime Exposure. J Pharm Pract 2023; 36:164-167. [PMID: 34098807 DOI: 10.1177/08971900211015046] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A 99-year-old African-American male presented to the hospital with severe sepsis secondary to a urinary tract infection. Upon initial presentation he was tachycardic, hypotensive and had leukocytosis. While he had signs of acute kidney injury, no signs of acute liver injury were present with his alanine transferase (ALT) and amino transferase (AST) levels measuring at 22 and 44 U/L, respectively. During the treatment course the patient began to show signs of clinical improvement. Despite this, his ALT and AST began to increase on day 2 of treatment and reached their peak of 210 and 239 U/L on day 4. Cefepime-induced liver injury was suspected and cefepime was discontinued. Upon cefepime discontinuation, liver enzymes downtrended and gradually returned to normal. No other likely medication causes of liver injury could be identified and alternative medical causes were ruled out. The lack of an alternative cause and the temporal relationship of cefepime use to hepatic dysfunction support the diagnosis of cefepime-induced liver injury. The patient's Roussel Uclaf Causality Assessment Methods score was 7, indicating this was a possible case of cefepime-induced liver injury, and the Naranjo Nomogram score was 5 indicating this was a probable case of cefepime-induced liver injury. While cefepime-induced liver injury is rare, clinicians should be cognizant of the potential for this adverse effect if liver enzyme elevation is detected during cefepime therapy and other common causes have been ruled out.
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Affiliation(s)
| | - Roman Fazylov
- Department of Pharmacy, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA.,Touro College of Pharmacy, New York, NY, USA
| | - Michelle Friedman-Jakubovics
- Department of Pharmacy, Kingsbrook Jewish Medical Center, Brooklyn, NY, USA.,Touro College of Pharmacy, New York, NY, USA
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Chipangura JK, Ntamo Y, Mohr B, Chellan N. A review of challenges and prospects of 3D cell-based culture models used for studying drug induced liver injury during early phases of drug development. Hum Exp Toxicol 2023; 42:9603271221147884. [PMID: 36879529 DOI: 10.1177/09603271221147884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Drug-induced liver injury (DILI) is the leading cause of compound attrition during drug development. Over the years, a battery of in-vitro cell culture toxicity tests is being conducted to evaluate the toxicity of compounds prior to testing in laboratory animals. Two-dimensional (2D) in-vitro cell culture models are commonly used and have provided a great deal of knowledge; however, these models often fall short in mimicking natural structures of tissues in-vivo. Testing in humans is the most logical method, but unfortunately there are ethical limitations associated with human tests. To overcome these limitations better human-relevant, predictive models are required. The past decade has witnessed significant efforts towards the development of three-dimensional (3D) in-vitro cell culture models better mimicking in-vivo physiology. 3D cell culture has advantages in being representative of the interactions of cells in-vivo and when validated can act as an interphase between 2D cell culture models and in-vivo animal models. The current review seeks to provide an overview of the challenges that make biomarkers used for detection of DILI not to be sensitive enough during drug development and explore how 3D cell culture models can be used to address the gap with the current models.
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Affiliation(s)
- John K Chipangura
- Faculty of Health Science, University of Cape Town Research Animal Facility, South Africa
| | - Yonela Ntamo
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - Bert Mohr
- Faculty of Health Science, University of Cape Town Research Animal Facility, South Africa
| | - Nireshni Chellan
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
- Centre for Cardio-metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, South Africa
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Floreani A, Bizzaro D, Shalaby S, Taliani G, Burra P. Sex disparity and drug-induced liver injury. Dig Liver Dis 2023; 55:21-28. [PMID: 35843842 DOI: 10.1016/j.dld.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 12/31/2022]
Abstract
Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.
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Affiliation(s)
- A Floreani
- Scientific Consultant Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - D Bizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - S Shalaby
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - G Taliani
- Department of Infectious and Tropical Diseases, La Sapienza University of Rome, Rome, Italy
| | - P Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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13
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Zhong J, Yu W, Tang Y, Zhou X. Synchrotron Radiation FTIR Microspectroscopy Study of Biomolecular Alterations in Vincristine-Treated WRL68 Cells at the Single-Cell Level. ACS OMEGA 2022; 7:47274-47284. [PMID: 36570260 PMCID: PMC9773350 DOI: 10.1021/acsomega.2c06622] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/25/2022] [Indexed: 06/17/2023]
Abstract
The toxic effect of vincristine on hepatocytes has rarely been studied. Synchrotron radiation-based Fourier transform infrared (SR-FTIR) microspectroscopy is a novel technique for investigating drug-cell interaction systems. In this research, the biomolecular alterations in WRL68 cells induced by vincristine treatment were investigated by SR-FTIR microspectroscopy and were further analyzed by multivariate statistical analysis and semiquantitative methods, including principal component analysis (PCA), orthogonal partial least square-discriminant analysis (OPLS-DA), and the peak area ratios of several characteristic IR bands. In vincristine-treated WRL68 cells, alterations in lipid structures and the presence of more long-chain fatty acids were found. A decrease in protein α-helical content relative to β-sheet structures in vincristine-treated WRL68 cells was identified. The nucleic acid content was decreased relative to that of lipids and proteins in WRL68 cells treated with vincristine. These results provide important information about the toxic effect of vincristine on normal liver cells. This research also provides a new approach to reveal the biomolecular alterations in drug-treated hepatocytes by combining SR-FTIR with multivariate statistical analysis and semiquantitative methods.
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14
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Influence of Antibiotics on Functionality and Viability of Liver Cells In Vitro. Curr Issues Mol Biol 2022; 44:4639-4657. [PMID: 36286032 PMCID: PMC9600611 DOI: 10.3390/cimb44100317] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/17/2022] [Accepted: 09/22/2022] [Indexed: 11/22/2022] Open
Abstract
(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.
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15
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Li X, Tang J, Mao Y. Incidence and risk factors of drug-induced liver injury. Liver Int 2022; 42:1999-2014. [PMID: 35353431 DOI: 10.1111/liv.15262] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 03/08/2022] [Accepted: 03/26/2022] [Indexed: 12/17/2022]
Abstract
The epidemiology and aetiology of drug-induced liver injury (DILI) vary across different countries and populations. Overall, DILI is rare in the general population but has become more prevalent in hospitalized patients, especially among patients with unexplained liver conditions. In addition, drugs implicated in DILI differ between Western and Eastern countries. Antibiotics are the leading drugs implicated in DILI in the West, whereas traditional Chinese medicine is the primary cause implicated in DILI in the East. The incidence of herbal and dietary supplements-induced hepatotoxicity is increasing globally. Several genetic and nongenetic risk factors associated with DILI have been described in the literature; however, there are no confirmed risk factors for all-cause DILI. Some factors may contribute to the risk of DILI in a drug-specific manner.
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Affiliation(s)
- Xiaoyun Li
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jieting Tang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Yimin Mao
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
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16
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Akimoto H, Nagashima T, Minagawa K, Hayakawa T, Takahashi Y, Asai S. Detection of Synergistic Interaction on an Additive Scale Between Two Drugs on Abnormal Elevation of Serum Alanine Aminotransferase Using Machine-Learning Algorithms. Front Pharmacol 2022; 13:910205. [PMID: 35873565 PMCID: PMC9298751 DOI: 10.3389/fphar.2022.910205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/21/2022] [Indexed: 11/13/2022] Open
Abstract
Drug-induced liver injury (DILI) is a common adverse drug reaction, with abnormal elevation of serum alanine aminotransferase (ALT). Several clinical studies have investigated whether a combination of two drugs alters the reporting frequency of DILI using traditional statistical methods such as multiple logistic regression (MLR), but this model may over-fit the data. This study aimed to detect a synergistic interaction between two drugs on the risk of abnormal elevation of serum ALT in Japanese adult patients using three machine-learning algorithms: MLR, logistic least absolute shrinkage and selection operator (LASSO) regression, and extreme gradient boosting (XGBoost) algorithms. A total of 58,413 patients were extracted from Nihon University School of Medicine's Clinical Data Warehouse and assigned to case (N = 4,152) and control (N = 54,261) groups. The MLR model over-fitted a training set. In the logistic LASSO regression model, three combinations showed relative excess risk due to interaction (RERI) for abnormal elevation of serum ALT: diclofenac and famotidine (RERI 2.427, 95% bootstrap confidence interval 1.226-11.003), acetaminophen and ambroxol (0.540, 0.087-4.625), and aspirin and cilostazol (0.188, 0.135-3.010). Moreover, diclofenac (adjusted odds ratio 1.319, 95% bootstrap confidence interval 1.189-2.821) and famotidine (1.643, 1.332-2.071) individually affected the risk of abnormal elevation of serum ALT. In the XGBoost model, not only the individual effects of diclofenac (feature importance 0.004) and famotidine (0.016), but also the interaction term (0.004) was included in important predictors. Although further study is needed, the combination of diclofenac and famotidine appears to increase the risk of abnormal elevation of serum ALT in the real world.
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Affiliation(s)
- Hayato Akimoto
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan
| | - Takuya Nagashima
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan
| | - Kimino Minagawa
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Hayakawa
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuo Takahashi
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan
| | - Satoshi Asai
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.,Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan
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17
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Dong H, You J, Zhao Y, Zheng D, Zhong Y, Li G, Weng Z, Luo H, Jiang S. Study on the Characteristics of Small-Molecule Kinase Inhibitors-Related Drug-Induced Liver Injury. Front Pharmacol 2022; 13:838397. [PMID: 35529445 PMCID: PMC9068902 DOI: 10.3389/fphar.2022.838397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/11/2022] [Indexed: 11/30/2022] Open
Abstract
Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence. Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher’s exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes. Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol–water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs. Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.
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Affiliation(s)
- Huiqun Dong
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Jia You
- Department of Hepatology, Hepatology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yu Zhao
- College of Mathematics and Computer Science, Fuzhou University, Fuzhou, China
| | - Danhua Zheng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Yi Zhong
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
- College of Mathematics and Computer Science, Fuzhou University, Fuzhou, China
| | - Gaozheng Li
- College of Mathematics and Computer Science, Fuzhou University, Fuzhou, China
| | - Zuquan Weng
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
- College of Mathematics and Computer Science, Fuzhou University, Fuzhou, China
- *Correspondence: Zuquan Weng, ; Heng Luo, ; Shan Jiang,
| | - Heng Luo
- College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
- College of Mathematics and Computer Science, Fuzhou University, Fuzhou, China
- MetaNovas Biotech Inc., Foster City, CA, United States
- *Correspondence: Zuquan Weng, ; Heng Luo, ; Shan Jiang,
| | - Shan Jiang
- Department of Vascular Thyroid Surgery, Affiliated Union Hospital, Fujian Medical University, Fuzhou, China
- *Correspondence: Zuquan Weng, ; Heng Luo, ; Shan Jiang,
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18
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Gao S, Yang Q, Wang X, Hu W, Lu Y, Yang K, Jiang Q, Li W, Song H, Sun F, Cheng H. Association Between Drug Treatments and the Incidence of Liver Injury in Hospitalized Patients With COVID-19. Front Pharmacol 2022; 13:799338. [PMID: 35387350 PMCID: PMC8978013 DOI: 10.3389/fphar.2022.799338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 02/28/2022] [Indexed: 01/08/2023] Open
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) has led to the emergence of global health care. In this study, we aimed to explore the association between drug treatments and the incidence of drug-induced liver injury (DILI) in hospitalized patients with COVID-19. A retrospective study was conducted on 5113 COVID-19 patients in Hubei province, among which 395 incurred liver injury. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards models. The results showed that COVID-19 patients who received antibiotics (HR 1.97, 95% CI: 1.55-2.51, p < 0.001), antifungal agents (HR 3.10, 95% CI: 1.93-4.99, p < 0.001) and corticosteroids (HR 2.31, 95% CI: 1.80-2.96, p < 0.001) had a higher risk of DILI compared to non-users. Special attention was given to the use of parenteral nutrition (HR 1.82, 95% CI: 1.31-2.52, p < 0.001) and enteral nutrition (HR 2.71, 95% CI: 1.98-3.71, p < 0.001), which were the risk factors for liver injury. In conclusion, this study suggests that the development of DILI in hospitalized patients with COVID-19 needs to be closely monitored, and the above-mentioned drug treatments may contribute to the risk of DILI.
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Affiliation(s)
- Suyu Gao
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qingqing Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Xuanxuan Wang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wen Hu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yun Lu
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kun Yang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiaoli Jiang
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenjing Li
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Haibo Song
- Key Laboratory for Research and Evaluation of Pharmacovigilance, National Medical Products Administration, Beijing, China
- Chinese Society of Toxicology, Beijing, China
| | - Feng Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Hong Cheng
- Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan, China
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Asai Y, Yamamoto T, Sato Y. Risk assessment of micafungin-induced liver injury using spontaneous reporting system data and electronic medical records. J Infect Chemother 2022; 28:690-695. [PMID: 35148944 DOI: 10.1016/j.jiac.2022.01.024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/27/2022] [Accepted: 01/31/2022] [Indexed: 02/08/2023]
Abstract
INTRODUCTION There is limited information regarding antifungal-induced liver injuries, which have high mortality rates. Therefore, we used the Japanese Adverse Drug Event Report (JADER) database for signal detection associated with antifungal-induced liver injuries and medical records for risk assessment. METHODS Reports of antifungal-induced liver injuries from JADER data were analyzed to calculate the reporting odds ratio (ROR) and 95% confidence interval (CI). A medical record-based study involving 109 adult patients treated with micafungin shows liver injury as the primary outcome in patients treated with micafungin. The albumin-bilirubin (ALBI) score was calculated based on albumin and total bilirubin levels. We selected five explanatory factors for multivariable logistic regression: alanine aminotransferase ≥20 IU/L, alkaline phosphatase ≥372 IU/L, aspartate aminotransferase ≥25 IU/L, ALBI score ≥ -1.290, and age ≥65 years. RESULTS Signal detection for micafungin was observed in both, hepatocellular and cholestatic injuries, as per data from JADER. Univariate analyses performed on medical records suggest that alanine aminotransferase (p = 0.008), aspartate aminotransferase (p = 0.036), alkaline phosphatase (p = 0.045), and ALBI score (p = 0.028) may be factors associated with micafungin-induced liver injury. Based on multivariable logistic regression, the adjusted odds ratio for micafungin-induced liver injury in patients with ALBI score ≥ -1.290 was 2.78 (95% CI: 1.014-7.605, p = 0.047), suggesting that low hepatic functional reserve could be a risk factor for micafungin-induced liver injury. CONCLUSIONS Careful monitoring of liver function may be necessary for micafungin administration in patients with low hepatic functional reserve.
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Affiliation(s)
- Yuki Asai
- Pharmacy, National Hospital Organization Mie Chuo Medical Center; 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101 Japan.
| | - Takanori Yamamoto
- Pharmacy, National Hospital Organization Mie Chuo Medical Center; 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101 Japan
| | - Yoshiharu Sato
- Pharmacy, National Hospital Organization Mie Chuo Medical Center; 2158-5 Hisaimyojincho, Tsu, Mie, 514-1101 Japan
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Akimoto H, Nagashima T, Minagawa K, Hayakawa T, Takahashi Y, Asai S. Signal Detection of Potential Hepatotoxic Drugs: Case-Control Study Using Both a Spontaneous Reporting System and Electronic Medical Records. Biol Pharm Bull 2021; 44:1514-1523. [PMID: 34602560 DOI: 10.1248/bpb.b21-00407] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.
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Affiliation(s)
- Hayato Akimoto
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Takuya Nagashima
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Kimino Minagawa
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine
| | - Takashi Hayakawa
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
| | - Yasuo Takahashi
- Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine
| | - Satoshi Asai
- Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine
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21
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Ortiz GX, Lenhart G, Becker MW, Schwambach KH, Tovo CV, Blatt CR. Drug-induced liver injury and COVID-19: A review for clinical practice. World J Hepatol 2021; 13:1143-1153. [PMID: 34630881 PMCID: PMC8473488 DOI: 10.4254/wjh.v13.i9.1143] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 05/18/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) consists of a systemic disease that can present many complications. The infection presents broad clinical symptoms and a high rate of transmissibility. In addition to severe acute respiratory syndrome, the patients manifest complications beyond the respiratory system. The frequency of liver damage in COVID-19 patients ranges from 14.8% to 53% of patients. One should pay attention to drug-induced liver injury (DILI) in patients with COVID-19, especially considering the off-label use of drugs in prophylactic and therapeutic regimens applied on large scales. This review aims to present relevant information on the medication used so far in COVID-19 patients and its possible hepatotoxicity. We reviewed liver damage in patients with COVID-19 on PubMed and Virtual Health Library to investigate DILI cases. Four studies were selected, involving the medicines remdesivir, tocilizumab and a pharmacovigilance analysis study. The hepatotoxicity profile of drugs presented in the literature considers use in accordance to usual posology standards for treatment. However, drugs currently used in the management of COVID-19 follow different dosages and posology than those tested by the pharmaceutical industry. The deficiency of uniformity and standardization in the assessment of hepatotoxicity cases hinders the publication of information and the possibility of comparing information among healthcare professionals. It is suggested that severe liver injury in COVID-19 patients should be reported in pharmacovigilance institutions, and physicians should pay attention to any considerable abnormal liver test elevation as it can demonstrate unknown drug hepatotoxicity. Liver disorders in COVID-19 patients and the use of several concomitant off-label medications - with a potential risk of further damaging the liver - should at least be a warning sign for rapid identification and early intervention, thus preventing liver damage from contributing to severe impairment in patients.
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Affiliation(s)
- Gabriela Xavier Ortiz
- Graduate Program in Medicine Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Gabriele Lenhart
- Multiprofessional Residency Integrated in Health, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Matheus William Becker
- Graduate Program in Medicine Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil.
| | - Karin Hepp Schwambach
- Graduate Program in Medicine Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Cristiane Valle Tovo
- Internal Medicine Department, Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
| | - Carine Raquel Blatt
- Pharmacoscience Department, Graduate Program in Medicine-Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Rio Grande do Sul, Brazil
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22
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Li J, Zhang J, Xu X, Fang W, Qu S, Jin F, Zhou J, Han X, Raza HK, Li X, Mao Y. Hugan tablets for the treatment of RUCAM based drug-induced liver injury: a propensity score matching analysis using a nationwide database. Expert Rev Clin Pharmacol 2021; 14:1543-1550. [PMID: 34521298 DOI: 10.1080/17512433.2021.1981859] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a major clinical challenge with no specific therapeutic drugs available. It is crucial to develop new agents to improve the clinical outcome of patients with DILI. This study evaluated the efficacy and safety of Hugan tablets in DILI patients using a nationwide database. RESEARCH DESIGN AND METHODS We analyzed the clinical data of DILI patients from a nationwide DILI database (www.hepatox.org). Patients who received oral Hugan tablets for DILI were defined as the Hugan group, and those who received no treatment for DILI were defined as the control group. RESULTS There were 111 cases in the Hugan group and 512 cases in the control group. One-to-one propensity score matching created 111 matched pairs. The normalization rates of alanine aminotransferase and aspartate aminotransferase in the Hugan group were significantly higher than those in the control group (50.45% vs. 26.13%, p ≤ .0002 and 67.57% vs. 41.75%, p ≤ .0001). There were no differences in the incidence of renal function impairment or blood abnormality between the two groups. CONCLUSIONS Hugan tablets are safe and effective in DILI treatment. Large-scale randomized controlled studies are needed to explore the effects of Hugan tablets on DILI induced by different offending drugs. TRIAL REGISTRATION The study protocol was posted on ClinicalTrials.gov with NCT number: NCT02407964.
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Affiliation(s)
- Jing Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianzhong Zhang
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Xiaorong Xu
- Department of Hepatology, Bozhou Huatuo Hospital of Traditional Chinese Medicine, Bozhou, China
| | - Weidong Fang
- Department of Infectious Diseases, Huangshan City People's Hospital, Huangshan, China
| | - Shilin Qu
- Department of Tuberculosis, Jingzhou Chest Hospital, Jingzhou, China
| | - Feng Jin
- Department of Thoracic Surgery, Shandong Provincial Chest Hospital, Jinan, China
| | - Jie Zhou
- Department of Extrapulmonary Tuberculosis, Tianjin Tuberculosis Control Center, Tianjin, China
| | - Xian Han
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Hafiz Khuram Raza
- Department of Medicine and Biostatistics, Unimed Scientific Inc, Wuxi, China
| | - Xiaoyun Li
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yimin Mao
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Lee NH, Lee GY, Park CR, Kim SK, Ahn YC, Cho JH, Son CG. Risk levels of herb-induced liver injury in Korea: from a meta-analysis. Integr Med Res 2021; 10:100705. [PMID: 33665093 PMCID: PMC7903345 DOI: 10.1016/j.imr.2020.100705] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/23/2020] [Accepted: 11/30/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND As the use of herbal medicines increased worldwide, there has been concern about the risk of herb-induced liver injury (HILI). Many clinical studies have assessed the risk of HILI in Korea. METHODS Therefore, we conducted a meta-analysis of the incidence of HILI in Korea, by analyzing nine clinical studies. These involved 8625 participants (3274 males; 5351 females), including 436 outpatients (three studies) and 8189 inpatients (six studies). RESULTS As a result, the overall incidence of HILI in Korea was 0.49% (95% CI 0.33-0.74%), and it was 0.57% in males and 0.30% in females. We found a similar incidence of HILI in prospective (0.51%) and retrospective (0.50%) studies. The incidence of HILI was higher in inpatients (0.62%) than outpatients (0.03%). CONCLUSION Although there are limitations regarding study quality and the number of participants, we systematically estimated the risk of HILI in Korea. We anticipate this study would be a helpful information for prescribing herbal medicines and researching the safety of herbs.
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Affiliation(s)
- Nam-Hun Lee
- Department of Hepatology & Hematology, Cheonan Korean Medicine Hospital of Daejeon University, Cheonan, Republic of Korea
| | - Ga-Young Lee
- Department of Hepatology & Hematology, Cheonan Korean Medicine Hospital of Daejeon University, Cheonan, Republic of Korea
| | - Chan-Ran Park
- Department of Hepatology & Hematology, Cheonan Korean Medicine Hospital of Daejeon University, Cheonan, Republic of Korea
| | - Sul-Ki Kim
- Liver & Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Yo-Chan Ahn
- Department of Health Service Management, Daejeon University, Daejeon, Republic of Korea
| | - Jung-Hyo Cho
- Liver & Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
| | - Chang-Gue Son
- Liver & Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, Republic of Korea
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Kralj T, Brouwer KLR, Creek DJ. Analytical and Omics-Based Advances in the Study of Drug-Induced Liver Injury. Toxicol Sci 2021; 183:1-13. [PMID: 34086958 PMCID: PMC8502468 DOI: 10.1093/toxsci/kfab069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug's hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug's association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.
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Affiliation(s)
- Thomas Kralj
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569, USA
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
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25
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Park JH, Hong S, Jun DW, Yoon JH, Lee KN, Lee HL, Lee OY, Yoon BC, Choi HS. Prevalence and clinical characteristics of antibiotics associated drug induced liver injury. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:642. [PMID: 33987340 PMCID: PMC8106034 DOI: 10.21037/atm-20-5144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background The use of antibiotics increases recently. Accordingly, the incidence of antibiotics associated with drug induced liver injury (DILI) also increases. The purpose of this study is to evaluate the proportion and the clinical characteristics of antibiotic associated with DILI. Methods This study is a retrospective study of analyzed adult patients who were referred to the department of hepatology for the elevation of liver function tests and the frequency of elevated liver enzyme of patients with prescribed antibiotics during the same period at outpatient setting as a validation set. Results Antibiotics associated with DILI (64.0%) are the most common reason agent among consulting to hepatology department. Rheumatoid arthritis related drugs (11.0%), health supplements (5.0%), herbal medicines (4.0%), anti-viral drugs, anti-inflammatory analgesics/acetaminophen and lipid-lowering agents (3.0%) were next common causative drug for DILI in inpatients setting (training set). The frequency of antibiotics associated with DILI was high in order of flomoxef, cetrazole, ceftriaxone, vancomycin, piperacillin/tazobactam and amoxicillin/clavulanate. In the same period, 32% of the patients who prescribed flomoxef showed elevated liver enzyme levels above the upper normal limit. The prevalence of flomoxef induced DILI (>3 folds of ALT) was 13% and liver enzyme levels were five times higher than upper normal limits in 5% of flomoxef groups. Hypertension or diabetes was the risk factor of flomoxef associated with DILI. Conclusions The Prevalence of antibiotics associated with DILI was 2-14%. Co-morbidity with diabetes and hypertension was the risk factor of flomoxef associated with DILI.
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Affiliation(s)
- Jin Hwa Park
- Department of Internal Medicine, Seoul Asan Hospital, Seoul, South Korea
| | - Susie Hong
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Jai Hoon Yoon
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Kang Nyeong Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Hang Lak Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Oh Young Lee
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Byung Chul Yoon
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
| | - Ho Soon Choi
- Department of Internal Medicine, Hanyang University School of Medicine, Seoul, South Korea
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26
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Pedraza L, Laosa O, Rodríguez-Mañas L, Gutiérrez-Romero DF, Frías J, Carnicero JA, Ramírez E. Drug Induced Liver Injury in Geriatric Patients Detected by a Two-Hospital Prospective Pharmacovigilance Program: A Comprehensive Analysis Using the Roussel Uclaf Causality Assessment Method. Front Pharmacol 2021; 11:600255. [PMID: 33613279 PMCID: PMC7892439 DOI: 10.3389/fphar.2020.600255] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 11/11/2020] [Indexed: 01/10/2023] Open
Abstract
Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI. Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes. Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32). Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.
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Affiliation(s)
- Laura Pedraza
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain
| | - Olga Laosa
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain.,Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain
| | - Leocadio Rodríguez-Mañas
- Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain.,Division of Geriatrics, University Hospital of Getafe, Getafe, Spain
| | | | - Jesús Frías
- Clinical Pharmacology departments, La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain
| | - José Antonio Carnicero
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain.,Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain
| | - Elena Ramírez
- Clinical Pharmacology departments, La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.,Clinical pharmacology department, University Hospital La Paz, La Paz, Spain
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27
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Middelkoop MA, Bet PM, Drenth JPH, Huirne JAF, Hehenkamp WJK. Risk-efficacy balance of ulipristal acetate compared to surgical alternatives. Br J Clin Pharmacol 2021; 87:2685-2697. [PMID: 33341097 PMCID: PMC8359338 DOI: 10.1111/bcp.14708] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/26/2020] [Accepted: 12/07/2020] [Indexed: 01/12/2023] Open
Abstract
Aims Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25–50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side‐effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long‐term treatment that has a fibroid‐volume decreasing effect, acceptable side‐effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug‐induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14–19 DILI cases/100 000 people. Methods This overview will discuss the risk–benefit balance between ulipristal and DILI, describe the safety–efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization. Results Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100 000 patients and fatal liver injury in 0.1:100 000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. Conclusion The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When evaluating drugs and drug safety, risks that apply to the alternative nonpharmacological treatment options should be taken into consideration.
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Affiliation(s)
- Mei-An Middelkoop
- Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Pierre M Bet
- Department of Clinical Pharmacology and Pharmacy, Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology, Radboud UMC, Nijmegen, The Netherlands
| | - Judith A F Huirne
- Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Amsterdam, The Netherlands
| | - Wouter J K Hehenkamp
- Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development research institute, Amsterdam UMC, Amsterdam, The Netherlands
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28
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Sunil Kumar N, Remalayam B, Thomas V, Ramachandran TM, Sunil Kumar K. Outcomes and Predictors of Mortality in Patients With Drug-Induced Liver Injury at a Tertiary Hospital in South India: A Single-Centre Experience. J Clin Exp Hepatol 2021; 11:163-170. [PMID: 33746440 PMCID: PMC7952999 DOI: 10.1016/j.jceh.2020.08.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is an important cause of acute liver failure with significant morbidity and mortality. The outcome of DILI varies widely according to the drug implicated and the type of liver injury. Owing to the heterogeneous nature of liver injury, knowledge on clinical course and prognosis of DILI is limited. We had undertaken this study to determine the clinical characteristics, outcomes, and predictors of mortality in patients with DILI. MATERIALS AND METHODS This prospective study was conducted from January 2015 through December 2018. We analyzed the drugs implicated, clinical course, and the outcome. Causality assessment was performed by using Roussel Uclaf Causality Assessment Method scoring. Patients were followed for 6 months until recovery/death or liver transplantation. RESULTS There were 133 cases with DILI. The mean age was 47.6 years, and 51.9% of them were men. Drugs causing DILI were antitubercular drugs (37.5%) followed by neuropsychiatric drugs (16.5%), antibiotics/antifungals (12%), complementary and alternative medicine (10.5%), immunomodulatory/chemotherapeutic drugs (10.5%), and nonsteroidal antiinflammatory drugs (7.5%). Eighty-two (61.6%) patients were classified as hepatocellular, 30 (22.5%) as mixed and 21 (15.7%) as cholestatic type of injury. There was no significant difference in the mortality and morbidity between the three types of liver injury. There were 18 deaths (13.5%), of which antitubercular drugs constituted the majority (55.5%) followed by neuropsychiatric drugs (27.7%) and complementary and alternative medicine (16.6%). Based on receiver operating characteristic curve analysis, model for end-stage liver disease (MELD) score >28, mean international normalized ratio (INR) >1.97, mean bilirubin level >15.6 mg/dl, and creatinine level >1.35 mg/dl were associated with mortality. CONCLUSION Although DILI is uncommon, it has significant morbidity and mortality. Antitubercular drugs were the most common cause for DILI and DILI-related mortality in our study. Variables such as MELD, INR, bilirubin, albumin, and creatinine help in predicting severity of liver injury and may help in triaging the patient for referral for liver transplantation.
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Key Words
- ALF, Acute liver failure
- ALP, Alkaline phosphatase
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- ATT, Antitubercular therapy
- BMI, Body mass index
- CAM, Complementary and alternative medicine
- DILI
- DILI, Drug induced liver injury
- DOTS, Directly observed therapy short course
- DRESS, Drug reaction with eosinophilia and systemic symptoms
- Hb, Hemoglobin
- INR, International normalized ratio
- LFT, Liver function test
- MELD, Model for end stage liver disease
- MRCP, Magnetic resonance cholangio pancreatography
- NSAID, Non-steroidal anti-inflammatory drugs
- PT, Prothrombin time
- RBS, Random blood sugar
- RUCAM, Roussel Uclaf Causality Assessment Method
- SD, Standard deviation
- ULN, Upper limit normal
- WBC, White blood cell
- antitubercular drugs
- complementary and alternative medicine (CAM)
- mortality
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Affiliation(s)
| | | | - Varghese Thomas
- Address for correspondence: Varghese Thomas, Former HOD and Professor
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López-Riera M, Conde I, Castell JV, Jover R. A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients. Toxicol Sci 2020; 173:229-243. [PMID: 31198949 DOI: 10.1093/toxsci/kfz138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.
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Affiliation(s)
- Mireia López-Riera
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
| | - Isabel Conde
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, 46026 Valencia, Spain
| | - José V Castell
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ramiro Jover
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
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30
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Apel K, Pütz K, Tolkach Y, Canbay A, Drebber U. [Drug-induced liver injury-significance of pathology]. DER PATHOLOGE 2020; 41:457-470. [PMID: 32813127 DOI: 10.1007/s00292-020-00811-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.
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Affiliation(s)
- K Apel
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - K Pütz
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Y Tolkach
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - A Canbay
- Universitätklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - U Drebber
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland.
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Abstract
Drug induced liver injury (DILI) is a relatively rare hepatic condition in response to the use of medications, illegal drugs, herbal products or dietary supplements. It occurs in susceptible individuals through a combination of genetic and environmental risk factors believed to modify drug metabolism and/or excretion leading to a cascade of cellular events, including oxidative stress formation, apoptosis/necrosis, haptenization, immune response activation and a failure to adapt. The resultant liver damage can present with an array of phenotypes, which mimic almost every other liver disorder, and varies in severity from asymptomatic elevation of liver tests to fulminant hepatic failure. Despite recent research efforts specific biomarkers are not still available for routine use in clinical practice, which makes the diagnosis of DILI uncertain and relying on a high degree of awareness of this condition and the exclusion of other causes of liver disease. Diagnostic scales such as the CIOMS/RUCAM can support the causality assessment of a DILI suspicion, but need refinement as some criteria are not evidence-based. Prospective collection of well-vetted DILI cases in established DILI registries has allowed the identification and validation of a number of clinical variables, and to predict a more severe DILI outcome. DILI is also in need of properly designed clinical trials to evaluate the efficacy of new DILI treatments as well as older drugs such as ursodeoxycholic acid traditionally used to ameliorate cholestasis or corticosteroids now widely tried in the oncology field to manage the emergent type of hepatotoxicity related to immune checkpoint inhibitors.
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32
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Tan EH, Ling ZJ, Ang PS, Sung C, Dan YY, Tai BC. Comparison of laboratory threshold criteria in drug-induced liver injury detection algorithms for use in pharmacovigilance. Pharmacoepidemiol Drug Saf 2020; 29:1480-1488. [PMID: 32844466 DOI: 10.1002/pds.5099] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 06/28/2020] [Accepted: 07/21/2020] [Indexed: 01/13/2023]
Abstract
PURPOSE For the purpose of pharmacovigilance, we sought to determine the best performing laboratory threshold criteria to detect drug-induced liver injury (DILI) in the electronic medical records (EMR). METHODS We compared three commonly used liver chemistry criteria from the DILI expert working group (DEWG), DILI network (DILIN), and Council for International Organizations of Medical Sciences (CIOMS), based on hospital EMR for years 2010 and 2011 (42 176 admissions), using independent medical record review. The performance characteristics were compared in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value, accuracy, F-measure, and area under the receiver operating characteristic curve (AUROC). RESULTS DEWG had the highest PPV (5.5%, 95% CI: 4.1%-7.2%), specificity (97.0%, 95% CI: 96.8%-97.2%), accuracy (96.8%, 95% CI: 96.6%-97.0%) and F-measure (0.099). CIOMS had the highest sensitivity (74.0%, 95% CI: 64.3%-82.3%) and AUROC (85.2%, 95% CI: 80.8%-89.7%). Besides the laboratory criteria, including additional keywords in the classification algorithm improved the PPV and F-measure to a maximum of 29.0% (95% CI: 22.3%-36.5%) and 0.379, respectively. CONCLUSIONS More stringent criteria (DEWG and DILIN) performed better in terms of PPV, specificity, accuracy and F-measure. CIOMS performed better in terms of sensitivity. An algorithm with high sensitivity is useful in pharmacovigilance for detecting rare events and to avoid missing cases. Requiring at least two abnormal liver chemistries during hospitalization and text-word searching in the discharge summaries decreased false positives without loss in sensitivity.
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Affiliation(s)
- Eng Hooi Tan
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Zheng Jye Ling
- Regional Health System Office, National University Health System, Singapore
| | - Pei San Ang
- Vigilance and Compliance Branch, Health Products Regulation Group, Health Sciences Authority, Singapore
| | - Cynthia Sung
- Vigilance and Compliance Branch, Health Products Regulation Group, Health Sciences Authority, Singapore.,Health Services and Systems Research, Duke-NUS Medical School, Singapore
| | - Yock Young Dan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Division of Gastroenterology & Hepatology, National University Hospital, National University Health System, Singapore
| | - Bee Choo Tai
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Low EXS, Zheng Q, Chan E, Lim SG. Drug induced liver injury: East versus West - a systematic review and meta-analysis. Clin Mol Hepatol 2020; 26:142-154. [PMID: 31816676 PMCID: PMC7160354 DOI: 10.3350/cmh.2019.1003] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/29/2019] [Accepted: 09/05/2019] [Indexed: 12/18/2022] Open
Abstract
Drug induced liver injury (DILI) may be different in the East compared to the West due to differing disease prevalence, prescribing patterns and pharmacogenetic profiles. To review existing literature on causative agents of DILI in the East compared to the West, a comprehensive literature search was performed on electronic databases: MEDLINE/PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure without language restrictions. Studies which involve patients having DILI and reported the frequency of causative agents were included. A random effects model was applied to synthesize the current evidence using prevalence of class-specific and agent-specific causative drugs with 95% confidence intervals. Of 6,914 articles found, 12 showed the distribution of drugs implicated in DILI in the East with a total of 33,294 patients and 16 in the West with a total of 26,069 DILI cases. In the East, the most common agents by class were anti-tuberculosis drugs (26.6%), herbal and alternative medications (25.3%), and antibiotics (15.7%), while in the West, antibiotics (34.9%), cardiovascular agents (17.3%), and non-steroidal anti-inflammatory drugs (12.5%) were the commonest. For individual agents, the most common agents in the East were isoniazid-rifampicin-pyrazinamide (25.4%), phenytoin (3.5%), and cephalosporin (2.9%) while in the West, amoxicillin-potassium clavulanate combination acid (11.3%), nimesulide (6.3%), and ibuprofen (6.1%) were the commonest. There was significant heterogeneity due to variability in single-centre compared to multi-centre studies. Differences in DILI in the East versus the West both in drug classes and individual agents are important for clinicians to recognize.
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Affiliation(s)
- En Xian Sarah Low
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Qishi Zheng
- Singapore Clinical Research Institute, Singapore
| | - Edwin Chan
- Singapore Clinical Research Institute, Singapore
- Duke-NUS Medical School, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Zhao H, Wang Y, Zhang T, Wang Q, Xie W. Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2020; 26:e920350. [PMID: 32145061 PMCID: PMC7077058 DOI: 10.12659/msm.920350] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background The aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI). Material/Methods This retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition. Results The study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4–5 DILI and 79.3% with grades 1–3 DILI. Female patients were significantly more likely to be diagnosed with grades 4–5 DILI than with grades 1–3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4–5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1–3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy’s law (P<.001) in the grades 4–5 group compare to the grades 1–3 group. Conclusions Female gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.
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Affiliation(s)
- Hong Zhao
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China (mainland)
| | - Yanbing Wang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China (mainland)
| | - Ting Zhang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China (mainland)
| | - Qi Wang
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China (mainland)
| | - Wen Xie
- Liver Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China (mainland)
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Abstract
Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. A recent population-based study found a crude incidence of approximately 19 cases per 100,000 a year. Amoxicillin-clavulanate continues to be the most commonly implicated agent in most Western countries, reported to occur in approximately 1 of 2300 users. In patients with drug-induced autoimmune hepatitis, liver tests often do not normalize with cessation of the drugs and require corticosteroids. DILI associated with jaundice can lead to death from liver failure or require liver transplantation in at least 10% of cases.
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Affiliation(s)
- Einar S Björnsson
- Department of Internal Medicine, Faculty of Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland, University of Iceland, Hringbraut, Reykjavík 101, Iceland.
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Kang Y, Kim SH, Park SY, Park BY, Lee JH, An J, Won HK, Song WJ, Kwon HS, Cho YS, Moon HB, Shim JH, Yang MS, Kim TB. Evaluation of Drug-Induced Liver Injury Developed During Hospitalization Using Electronic Health Record (EHR)-Based Algorithm. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:430-442. [PMID: 32141257 PMCID: PMC7061161 DOI: 10.4168/aair.2020.12.3.430] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 11/14/2019] [Accepted: 11/27/2019] [Indexed: 01/11/2023]
Abstract
Purpose The incidence of drug-induced liver injury (DILI) has been increasing; however, few algorithms are available to identify DILI in electronic health records (EHRs). We aimed to identify and evaluate DILI with an appropriate screening algorithm. Methods We collected data from 3 university hospitals between June 2015 and May 2016 using our newly developed algorithm for identifying DILI. Among patients with alanine transferase (ALT) ≤ 120 IU/L and total bilirubin (TB) ≤ 2.4 mg/dL in blood test results within 48 hours of admission, those who either had 1) ALT > 120 IU/L and TB > 2.4 mg/dL or 2) ALT > 200 IU/L at least once during hospitalization were identified. After excluding patients with liver disease-related diagnosis at discharge, medical records were retrospectively reviewed to evaluate epidemiological characteristics of DILI. Results The total number of inpatients was 256,598, of whom 1,100 (0.43%) were selected by the algorithm as suspected DILI. Subsequently, 365 cases (0.14% of total inpatients, 95% confidence interval, 0.13–0.16) were identified as DILI, yielding a positive predictive value of 33.1%. Antibiotics (n = 214, 47.2%) were the major class of causative drug followed by chemotherapeutic agents (n = 87, 19.2%). The most common causative drug was piperacillin-tazobactam (n = 38, 8.4%); the incidence of DILI by individual agent was highest for methotrexate (19.4 cases/1,000 patients administered the drug). Common reasons for excluding suspected DILI cases were ischemic hepatitis and postoperative liver dysfunction. Conclusions Using our EHR-based algorithm, we identified that approximately 0.14% of patients developed DILI during hospitalization. Further studies are needed to modify criteria for more accurate identification of DILI.
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Affiliation(s)
- Yewon Kang
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
| | - Sae Hoon Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - So Young Park
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Allergy and Respiratory Medicine, Konkuk University Medical Center, Seoul, Korea
| | - Bo Young Park
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Hyang Lee
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin An
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ha Kyeong Won
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Internal Medicine, VHS Medical Center, Seoul, Korea
| | - Woo Jung Song
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyouk Soo Kwon
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - You Sook Cho
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Bom Moon
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min Suk Yang
- Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Korea.
| | - Tae Bum Kim
- Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Pharmacovigilance Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Kim SH. Active Pharmacovigilance of Drug-Induced Liver Injury Using Electronic Health Records. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:378-380. [PMID: 32141253 PMCID: PMC7061153 DOI: 10.4168/aair.2020.12.3.378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 02/24/2020] [Indexed: 11/24/2022]
Affiliation(s)
- Sang Heon Kim
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea.
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38
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Omics-based input and output in the development and use of adverse outcome pathways. CURRENT OPINION IN TOXICOLOGY 2019. [DOI: 10.1016/j.cotox.2019.02.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Jayaraman T, Lee YY, Chan WK, Mahadeva S. Epidemiological differences of common liver conditions between Asia and the West. JGH OPEN 2019; 4:332-339. [PMID: 32514433 PMCID: PMC7273710 DOI: 10.1002/jgh3.12275] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 10/01/2019] [Indexed: 12/19/2022]
Abstract
Liver diseases form a heterogenous group of acute and chronic disorders of varying etiologies. Not only do they result in significant morbidity and mortality, but they also lead to a marked reduction in quality of life, together with a high socioeconomic burden globally. A better understanding of their global distribution is necessary to curb the massive health-care and socioeconomic burden that they entail. Notable differences and similarities have been described between common liver disease conditions occurring in Asia and the West (Europe and North America), giving rise to the need for an updated collective appraisal of this subject. In this review, the epidemiological differences of common liver conditions, specifically acute liver failure, drug-induced liver injury, acute-on-chronic liver failure, hepatocellular carcinoma, and non-alcoholic fatty liver disease, between Asia and the West are discussed.
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Affiliation(s)
- Thevaraajan Jayaraman
- Gastroenterology Unit, Faculty of Medicine Universiti Teknologi MARA Shah Alam Malaysia
| | - Yeong-Yeh Lee
- Department of Medicine, School of Medical Sciences Universiti Sains Malaysia George Town Malaysia
| | - Wah-Kheong Chan
- Gastroenterology and Hepatology Unit, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Faculty of Medicine University of Malaya Kuala Lumpur Malaysia
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40
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Becker MW, Lunardelli MJM, Tovo CV, Blatt CR. Drug and herb-induced liver injury: A critical review of Brazilian cases with proposals for the improvement of causality assessment using RUCAM. Ann Hepatol 2019; 18:742-750. [PMID: 31130470 DOI: 10.1016/j.aohep.2019.03.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 03/06/2019] [Accepted: 02/08/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Although hepatotoxicity accounts for 10% of adverse drug reactions, it remains poorly understood and underreported. This study aimed to summarize case reports of herb- and drug-induced liver injury in Brazil. METHODOLOGY Systematic review in the following databases: PubMed, SciELO, Science Direct, CAPES, and gray literature. RESULTS Twenty-seven studies reporting 32 cases were identified. Brazilian cases were primarily detected in hospitals, and occurred mainly in young males suffering from chronic diseases. Drugs (n=29) were a more frequent cause of liver injury than herbs (n=3). Almost a third of these drugs were anticonvulsants, and 15 appear in the Brazilian List of Essential Medicines. In 50% of the cases, clinical manifestations started within 30 days of drug ingestion. Regarding the decline of liver enzymes, 50% of the cases reached normality after drug withdrawal. However, 7 deaths and 2 liver transplantations were reported. Only one study assessed causality using RUCAM. CONCLUSION Given the severe outcomes of DILI and HILI, early detection and management of hepatotoxicity to increase drug safety are necessary, as well as pharmacotherapeutic monitoring of patients with chronic diseases. Moreover, the application of the RUCAM algorithm in clinical practice has to be further disseminated.
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Affiliation(s)
- Matheus William Becker
- Graduate Program in Medicine - Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Michele John Muller Lunardelli
- Pharmaceutical Services, Hospital Divina Providência, Graduate Program in Medicine - Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Cristiane Valle Tovo
- Internal Medicine Department, Graduate Program in Medicine - Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Carine Raquel Blatt
- Pharmacoscience Department, Graduate Program in Medicine - Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
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41
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An Z, Hu T, Lv Y, Li P, Liu L. Targeted amino acid and related amines analysis based on iTRAQ®-LC-MS/MS for discovering potential hepatotoxicity biomarkers. J Pharm Biomed Anal 2019; 178:112812. [PMID: 31639596 DOI: 10.1016/j.jpba.2019.112812] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 08/12/2019] [Accepted: 08/13/2019] [Indexed: 12/13/2022]
Abstract
Drug induced liver injury (DILI) is a diverse set of liver injury occurring after exposure to any manufactured or naturally occurring chemical compounds. DILI has already become the leading cause of acute liver failure in developed countries. Early diagnosis is of great significance for the prevention and treatment of DILI, which can effectively avoid its progress to acute liver failure. In this paper, a novel targeted metabolomics method based on isobaric tagging reagent iTRAQ®-LC-MS/MS was developed for the exploring of 42 common amino acids and related amines alterations in rats treated with hydrazine, aiming to discover the potential biomarkers for early diagnosis of DILI. Forty-two amino acids and related amines were covered in this new method. Through derivatization by iTRAQ reagent, all derivatized amino acids and related amines can be separated and quantified in 16 min with excellent peak shape and good separation efficiency. Fragments related to reporter group (m/z 113 or 121) of iTRAQ reagents could be generated from all derivatized amino acids and related amines under general multiple reaction monitoring (MRM) parameters. Isotope dilution method was established for the quantification of amino acid, which significantly reduced the interference of matrix effect on quantitative accuracy. Using this iTRAQ®-LC-MS/MS method, the changes of amino acid metabolism were comprehensively investigated in rat serum and urine samples after DILI modeling by hydrazine. More significant changes of amino acids were observed in serum and urine samples with fold changes ranging from 0.5 to 193.7. Six significantly increased amino acids in serum, including L-citrulline, L-α-amino-adipic acid, L-tyrosine, L-glutamic acid, glycine and L-lysine, and ten amino acids and related amines in urine including L-citrulline, L-α-amino-adipic acid, L-tyrosine, taurine, β-alanine, ethanolamine, argininosuccinic acid, D,L-β-amino-isobutyric acid, γ-amino-n-butyric acid and L-glutamine, 3 of which were detected in both serum and urine. Except for L-lysine all these significantly increased amino acids and related amines possessed 92.5% to 100% specificity and sensitivity calculated at best cut-off points of their ROC curves in distinguishing control and DILI model group.
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Affiliation(s)
- Zhuoling An
- Pharmacy Department of Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Ting Hu
- Pharmacy Department of Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Yali Lv
- Pharmacy Department of Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Pengfei Li
- Pharmacy Department of Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing, 100020, PR China
| | - Lihong Liu
- Pharmacy Department of Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing, 100020, PR China.
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43
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Heslop JA, Kia R, Pridgeon CS, Sison-Young RL, Liloglou T, Elmasry M, Fenwick SW, Mills JS, Kitteringham NR, Goldring CE, Park BK. Donor-Dependent and Other Nondefined Factors Have Greater Influence on the Hepatic Phenotype Than the Starting Cell Type in Induced Pluripotent Stem Cell Derived Hepatocyte-Like Cells. Stem Cells Transl Med 2019; 6:1321-1331. [PMID: 28456008 PMCID: PMC5442714 DOI: 10.1002/sctm.16-0029] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022] Open
Abstract
Drug‐induced liver injury is the greatest cause of post‐marketing drug withdrawal; therefore, substantial resources are directed toward triaging potentially dangerous new compounds at all stages of drug development. One of the major factors preventing effective screening of new compounds is the lack of a predictive in vitro model of hepatotoxicity. Primary human hepatocytes offer a metabolically relevant model for which the molecular initiating events of hepatotoxicity can be examined; however, these cells vary greatly between donors and dedifferentiate rapidly in culture. Induced pluripotent stem cell (iPSC)‐derived hepatocyte‐like cells (HLCs) offer a reproducible, physiologically relevant and genotypically normal model cell; however, current differentiation protocols produce HLCs with a relatively immature phenotype. During the reprogramming of somatic cells, the epigenome undergoes dramatic changes; however, this “resetting” is a gradual process, resulting in an altered differentiation propensity, skewed toward the lineage of origin, particularly in early passage cultures. We, therefore, performed a comparison of human hepatocyte‐ and dermal fibroblast‐derived iPSCs, assessing the impact of epigenetic memory at all stages of HLC differentiation. These results provide the first isogenic assessment of the starting cell type in human iPSC‐derived HLCs. Despite a trend toward improvement in hepatic phenotype in albumin secretion and gene expression, few significant differences in hepatic differentiation capacity were found between hepatocyte and fibroblast‐derived iPSCs. We conclude that the donor and inter‐clonal differences have a greater influence on the hepatocyte phenotypic maturity than the starting cell type. Therefore, it is not necessary to use human hepatocytes for generating iPSC‐derived HLCs. Stem Cells Translational Medicine2017;6:1321–1331
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Affiliation(s)
- James A Heslop
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Richard Kia
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Christopher S Pridgeon
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Rowena L Sison-Young
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Triantafillos Liloglou
- Department of Molecular and Clinical Cancer Medicine, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Mohamed Elmasry
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom.,University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, United Kingdom
| | - Stephen W Fenwick
- University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, United Kingdom
| | - John S Mills
- AstraZeneca, Personalised Healthcare and Biomarkers, Alderley Park, Cheshire, SK10 4TG, United Kingdom
| | - Neil R Kitteringham
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Chris E Goldring
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
| | - Bong K Park
- MRC Centre for Drug Safety Science, Division of Molecular & Clinical Pharmacology, the Institute of Translational Medicine, the University of Liverpool, Liverpool, L69 3GE, United Kingdom
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Vilas-Boas V, Gijbels E, Cooreman A, Van Campenhout R, Gustafson E, Leroy K, Vinken M. Industrial, Biocide, and Cosmetic Chemical Inducers of Cholestasis. Chem Res Toxicol 2019; 32:1327-1334. [PMID: 31243985 DOI: 10.1021/acs.chemrestox.9b00148] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A frequent side effect of many drugs includes the occurrence of cholestatic liver toxicity. Over the past couple of decades, drug-induced cholestasis has gained considerable attention, resulting in a plethora of data regarding its prevalence and mechanistic basis. Likewise, several food additives and dietary supplements have been reported to cause cholestatic liver insults in the past few years. The induction of cholestatic hepatotoxicity by other types of chemicals, in particular synthetic compounds, such as industrial chemicals, biocides, and cosmetic ingredients, has been much less documented. Such information can be found in occasional clinical case reports of accidental intake or suicide attempts as well as in basic and translational study reports on mechanisms or testing of new therapeutics in cholestatic animal models. This paper focuses on such nonpharmaceutical and nondietary synthetic chemical inducers of cholestatic liver injury, in particular alpha-naphthylisocyanate, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, methylenedianiline, paraquat, tartrazine, triclosan, 2-octynoic acid, and 2-nonynoic acid. Most of these cholestatic compounds act by similar mechanisms. This could open perspectives for the prediction of cholestatic potential of chemicals.
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Affiliation(s)
- Vânia Vilas-Boas
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Eva Gijbels
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Axelle Cooreman
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Raf Van Campenhout
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Emma Gustafson
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Kaat Leroy
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology , Vrije Universiteit Brussel , Brussels , Belgium
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Andrade RJ, Aithal GP, Björnsson ES, Kaplowitz N, Kullak-Ublick GA, Larrey D, Karlsen TH. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol 2019; 70:1222-1261. [PMID: 30926241 DOI: 10.1016/j.jhep.2019.02.014] [Citation(s) in RCA: 646] [Impact Index Per Article: 107.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/14/2019] [Indexed: 02/07/2023]
Abstract
Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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Byeon JH, Kil JH, Ahn YC, Son CG. Systematic review of published data on herb induced liver injury. JOURNAL OF ETHNOPHARMACOLOGY 2019; 233:190-196. [PMID: 30639232 DOI: 10.1016/j.jep.2019.01.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 01/07/2019] [Accepted: 01/08/2019] [Indexed: 05/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Herbal products have been widely used as a means of ethnomedicine worldwide. Recently, the potential hepatotoxicity of herbs has become a medical issue but comprehensive studies are limited. AIM OF THE STUDY This study aims to determine the clinical features of herb induced liver injury (HILI) including its constituent ratio among liver injury case cohorts that included both HILI and drug induced liver injury (DILI). MATERIALS AND METHODS A systematic review was conducted using a literature search for DILI/HILI in seven electric databases including PubMed, Cochrane and Embase. We analyzed the DILI/HILI cases and clinical characteristics in terms of herbs, conventional drugs, concomitant, or others. RESULTS Thirty-one studies met the necessary criteria and included 9 prospective and 22 retrospective studies. Among total number of overall DILI/HILI cases (7511, male 2819, female 3669 and unknown 1023), 25.0% (1874 cases) were implicated in herbs. HILI was relatively higher in females (69.8% vs. 30.2% male), compared to conventional drugs (57.3% female vs. 42.7% male, p < 0.01), while it was prone to induce hepatocellular injury (hepatocellular 78.8%, cholestatic 8.9%, mixed type 12.3%), contrary to conventional drugs (hepatocellular 56.7% vs. cholestatic 22.1% vs. mixed 21.2%), respectively (p < 0.01). The main herbs causing HILI included Polygonum multiflorum, Psoralea corylifolia, Corydalis yanhusuo, and Rheum officinale. CONCLUSIONS This review created the comparative and comprehensive feature of hepatotoxicity by herbal products, which provides reference data for the clinical applications and establishing pharmacovigilance system of herbs.
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Affiliation(s)
- Jung-Hwan Byeon
- Korean Medical College of Daejeon University, 62, Daehak-ro Dong-gu, Daejeon 301-716, Republic of Korea.
| | - Ji-Hye Kil
- Korean Medical College of Daejeon University, 62, Daehak-ro Dong-gu, Daejeon 301-716, Republic of Korea.
| | - Yo-Chan Ahn
- Department of Health Service Management, Daejeon University, 62, Daehak-ro Dong-gu, Daejeon 301-716, Republic of Korea.
| | - Chang-Gue Son
- Liver and Immunology Research Center, Dunsan Oriental Hospital of Daejeon University, 75, Daedeok-daero 176, Seo-gu, Daejeon 35253, Republic of Korea.
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Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol 2019; 70:151-171. [PMID: 30266282 DOI: 10.1016/j.jhep.2018.09.014] [Citation(s) in RCA: 2231] [Impact Index Per Article: 371.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 02/06/2023]
Abstract
Liver disease accounts for approximately 2 million deaths per year worldwide, 1 million due to complications of cirrhosis and 1million due to viral hepatitis and hepatocellular carcinoma. Cirrhosis is currently the 11th most common cause of death globally and liver cancer is the 16th leading cause of death; combined, they account for 3.5% of all deaths worldwide. Cirrhosis is within the top 20 causes of disability-adjusted life years and years of life lost, accounting for 1.6% and 2.1% of the worldwide burden. About 2 billion people consume alcohol worldwide and upwards of 75 million are diagnosed with alcohol-use disorders and are at risk of alcohol-associated liver disease. Approximately 2 billion adults are obese or overweight and over 400 million have diabetes; both of which are risk factors for non-alcoholic fatty liver disease and hepatocellular carcinoma. The global prevalence of viral hepatitis remains high, while drug-induced liver injury continues to increase as a major cause of acute hepatitis. Liver transplantation is the second most common solid organ transplantation, yet less than 10% of global transplantation needs are met at current rates. Though these numbers are sobering, they highlight an important opportunity to improve public health given that most causes of liver diseases are preventable.
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Affiliation(s)
| | | | - John Eaton
- Mayo Clinic College of Medicine, Rochester, MN, USA
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Fernández-Murga ML, Petrov PD, Conde I, Castell JV, Goméz-Lechón MJ, Jover R. Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol 2018; 120:196-212. [PMID: 29990576 DOI: 10.1016/j.fct.2018.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/05/2018] [Accepted: 07/06/2018] [Indexed: 12/12/2022]
Abstract
Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.
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Affiliation(s)
- M Leonor Fernández-Murga
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Petar D Petrov
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Isabel Conde
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Jose V Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain
| | - M José Goméz-Lechón
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
| | - Ramiro Jover
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain.
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Li W, Li Y, Jiang X, Li X, Yu Z. Compound Ammonium Glycyrrhizin Protects Hepatocytes from Injury Induced by Lipopolysaccharide/Florfenicol through a Mitochondrial Pathway. Molecules 2018; 23:molecules23092378. [PMID: 30227687 PMCID: PMC6225407 DOI: 10.3390/molecules23092378] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/26/2022] Open
Abstract
Florfenicol (FFC), a widely used drug for chicken diseases, can aggravate lipopolysaccharide (LPS) damage to the liver. For this condition, natural or synthetic products displaying strong antioxidant capacity are expected to prevent LPS/FFC from inducing liver injury, so in our study, the compound ammonium glycyrrhizin (CAG) is used as the protective drug to decrease the injury to liver. The research aims to illustrate the underlying mechanism of combining LPS with FFC-induced liver injury and the protective role of CAG by using primary chicken hepatocytes as an in vitro model. The results show that LPS/FFC induced cell apoptosis and CAG protected hepatocytes from injury. The permeability of the cell membrane is elevated by LPS/FFC, leading to the efflux of enzymes (ALT, AST). Flow cytometry analysis indicates that LPS/FFC treatment increased the apoptosis rate significantly. Furthermore, with the up-regulation of apoptosis genes bax, cytochrome c and the down-regulation of bcl-2, caspase-3 and caspase-9 are activated at the gene level. LPS/FFC-induced mitochondrial damage is accompanied by a significant decrease in mitochondrial membrane potential (MMP) and severe mitochondrial damage. However, CAG improves the situation for the purpose of protecting the liver. In conclusion, it is speculated that LPS/FFC induces severe liver injury through apoptosis and the CAG protects hepatocytes from injury via the mitochondria-mediated apoptosis pathway.
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Affiliation(s)
- Wenyang Li
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Ying Li
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Xiangyuan Jiang
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Xiaohui Li
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
| | - Zugong Yu
- Laboratory of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
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Vilas-Boas V, Cooreman A, Gijbels E, Van Campenhout R, Gustafson E, Ballet S, Annaert P, Cogliati B, Vinken M. Primary hepatocytes and their cultures for the testing of drug-induced liver injury. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2018; 85:1-30. [PMID: 31307583 DOI: 10.1016/bs.apha.2018.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Drug-induced liver injury is a major reason for discontinuation of drug development and withdrawal of drugs from the market. Intensive efforts in the last decades have focused on the establishment and finetuning of liver-based in vitro models for reliable prediction of hepatotoxicity triggered by drug candidates. Of those, primary hepatocytes and their cultures still are considered the gold standard, as they provide an acceptable reflection of the hepatic in vivo situation. Nevertheless, these in vitro systems cope with gradual deterioration of the differentiated morphological and functional phenotype. The present paper gives an overview of traditional and more recently introduced strategies to counteract this dedifferentiation process in an attempt to set up culture models that can be used for long-term testing purposes. The relevance and applicability of such optimized cultures of primary hepatocytes for the testing of drug-induced cholestatic liver injury is demonstrated.
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Affiliation(s)
- Vânia Vilas-Boas
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Axelle Cooreman
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eva Gijbels
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Raf Van Campenhout
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Emma Gustafson
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Steven Ballet
- Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
| | - Pieter Annaert
- Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium
| | - Bruno Cogliati
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium.
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