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Thakur S, Kumar V, Das R, Sharma V, Mehta DK. Biomarkers of Hepatic Toxicity: An Overview. CURRENT THERAPEUTIC RESEARCH 2024; 100:100737. [PMID: 38860148 PMCID: PMC11163176 DOI: 10.1016/j.curtheres.2024.100737] [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] [Received: 06/28/2023] [Accepted: 01/31/2024] [Indexed: 06/12/2024]
Abstract
Background Hepatotoxicity is the foremost issue for clinicians and the primary reason for pharmaceutical product recalls. A biomarker is a measurable and quantifiable attribute used to evaluate the efficacy of a treatment or to diagnose a disease. There are various biomarkers which are used for the detection of liver disease and the intent of liver damage. Objective This review aims to investigate the current state of hepatotoxicity biomarkers and their utility in clinical settings. Using hepatic biomarkers, the presence of liver injury, its severity, prognosis, causative agent, and type of hepatotoxicity can all be determined. Methods Relevant published articles up to 2022 were systematically retrieved from MEDLINE/PubMed, SCOPUS, EMBASE, and WOS databases using keywords such as drug toxicity, hepatotoxicity biomarkers, biochemical parameters, and nonalcoholic fatty liver disease. Results In clinical trials and everyday practice, biomarkers of drug-induced liver injury are essential for spotting the most severe cases of hepatotoxicity. Hence, developing novel biomarker approaches to enhance hepatotoxicity diagnosis will increase specificity and/or identify the person at risk. Importantly, early clinical studies on patients with liver illness have proved that some biomarkers such as aminotransferase, bilirubin, albumin, and bile acids are even therapeutically beneficial. Conclusions By assessing the unique signs of liver injury, health care professionals can rapidly and accurately detect liver damage and evaluate its severity. These measures contribute to ensuring prompt and effective medical intervention, hence reducing the risk of long-term liver damage and other major health concerns.
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Affiliation(s)
- Simran Thakur
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Kumar
- Department of Pharmacy Practice, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Rina Das
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Vishal Sharma
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
| | - Dinesh Kumar Mehta
- Department of Pharmaceutical Chemistry, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India
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Marquez L, Raheja R, Chan-Liston M, Marcinak J, Estilo A, Pineda Salgado L, Jiang J, Chang C, Beninger P. Industry Review of Best Practices for Risk Management of Drug-Induced Liver Injury from Development to Real-World Use. Drug Saf 2024; 47:1-22. [PMID: 37874451 DOI: 10.1007/s40264-023-01360-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2023] [Indexed: 10/25/2023]
Abstract
The relative treatment benefit of a drug for patients during development, marketing authorization review, or after approval includes an assessment of the risk of drug-induced liver injury (DILI). In this article, the Pharmacovigilance and Risk Mitigation Working Group of the IQ-DILI Initiative launched in June 2016 within the International Consortium for Innovation and Quality in Pharmaceutical Development presents and reviews three key topics for essential risk management activities to identify, characterize, monitor, mitigate, and communicate DILI risk associated with small molecules during drug development. The three topics are: (1) Current best practices for characterizing the DILI phenotype and the severity and incidence of DILI in the treatment population, including DILI identification, prediction and recovery. (2) Characterization of the relative treatment benefit for patients who will be exposed to a drug and the attendant risk of DILI in conjunction with existing global risk mitigation strategies. (3) Implementation of risk mitigation strategies during drug development highlighting patient factors, healthcare settings and site of product administration, and prescriber and healthcare provider factors. Industry guidance is provided for assessing whether the product labeling is sufficient to minimize the risk of DILI or whether a United States Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) or European Medicines Agency (EMA) Risk Management Plan (RMP) with additional Risk Minimization Measures (aRMM) is needed.
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Affiliation(s)
- Loreta Marquez
- Janssen Research and Development, LLC, Raritan, NJ, USA.
| | | | | | | | - Alvin Estilo
- Otsuka Pharmaceutical Development, Inc. (OPDC), Princeton, NJ, USA
| | | | - Jason Jiang
- Daiichi Sankyo, Inc., Basking Ridge, NJ, USA
| | | | - Paul Beninger
- Public Health and Community Medicine, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA
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Zeng G, Eslick GD, Weltman M. Systematic review and meta-analysis: Comparing hepatocellular and cholestatic patterns of drug-induced liver injury. ILIVER 2023; 2:122-129. [DOI: 10.1016/j.iliver.2023.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
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Li M, Wang Y, Lv TT, Liu JM, Kong YY, Jia JD, Zhao XY. Mapping the incidence of drug-induced liver injury: A systematic review and meta-analysis. J Dig Dis 2023; 24:332-339. [PMID: 37460777 DOI: 10.1111/1751-2980.13205] [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: 12/17/2022] [Revised: 06/26/2023] [Accepted: 07/14/2023] [Indexed: 08/15/2023]
Abstract
OBJECTIVES Drug-induced liver injury (DILI) is an increasing etiology of liver dysfunction, with various incidence worldwide. To better understand the disease burden and establish appropriate preventive and treatment strategies, a systematic review and meta-analysis was conducted. METHODS PubMed, EMBASE, Web of Science, and Cochrane Library were searched for studies on the incidence of DILI published up to June 1, 2022. According to the predefined criteria, only population-based studies were included. Incidence was presented as cases per 100 000 person-years with 95% confidence interval (CI) using a random-effects model. RESULTS A total of 14 studies were included. The overall incidence of DILI was 4.94 per 100 000 person-years (95% CI 4.05-5.83). Time-based cumulative meta-analysis suggested that the incidence of DILI increased over time since 2010. The incidence varied by regions, with Asia having the highest incidence of 17.82 per 100 000 person-years (95% CI 6.26-29.38), while North America having the lowest incidence of 1.72 per 100 000 person-years (95% CI 0.48-2.95). All studies reported a higher incidence of DILI in the elderly but comparable incidences between male and female (3.42 per 100 000 person-years vs 4.64 per 100 000 person-years). CONCLUSIONS The global incidence of DILI has been increasing since 2010, with the highest incidence in Asia. Understanding the epidemiological characteristics of DILI helps establish specific strategies to deal with this emerging health problems.
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Affiliation(s)
- Min Li
- Clinical Epidemiology and Evidence Based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing, China
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ting Ting Lv
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ji Min Liu
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Yuan Yuan Kong
- Clinical Epidemiology and Evidence Based Medicine Unit, Beijing Friendship Hospital, Capital Medical University, Beijing Clinical Research Institute, Beijing, China
| | - Ji Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xin Yan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Dai W, Pang X, Peng W, Zhan X, Chen C, Zhao W, Zeng C, Mei Q, Chen Q, Kuang W, Gou Z, Hu X. Liver Protection of a Low-Polarity Fraction from Ficus pandurata Hance, Prepared by Supercritical CO 2 Fluid Extraction, on CCl 4-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Ferroptosis Mediated by Strengthened Antioxidation. Molecules 2023; 28:molecules28052078. [PMID: 36903326 PMCID: PMC10004706 DOI: 10.3390/molecules28052078] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/11/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Ficus pandurata Hance (FPH) is a Chinese herbal medicine widely used for health care. This study was designed to investigate the alleviation efficacy of the low-polarity ingredients of FPH (FPHLP), prepared by supercritical CO2 fluid extraction technology, against CCl4-induced acute liver injury (ALI) in mice and uncover its underlying mechanism. The results showed that FPHLP had a good antioxidative effect determined by the DPPH free radical scavenging activity test and T-AOC assay. The in vivo study showed that FPHLP dose-dependently protected against liver damage via detection of ALT, AST, and LDH levels and changes in liver histopathology. The antioxidative stress properties of FPHLP suppressed ALI by increasing levels of GSH, Nrf2, HO-1, and Trx-1 and reducing levels of ROS and MDA and the expression of Keap1. FPHLP significantly reduced the level of Fe2+ and expression of TfR1, xCT/SLC7A11, and Bcl2, while increasing the expression of GPX4, FTH1, cleaved PARP, Bax, and cleaved caspase 3. The results demonstrated that FPHLP protected mouse liver from injury induced by CCl4 via suppression of apoptosis and ferroptosis. This study suggests that FPHLP can be used for liver damage protection in humans, which strongly supports its traditional use as a herbal medicine.
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Affiliation(s)
- Weibo Dai
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Xiaoyan Pang
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Weiwen Peng
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Xinyi Zhan
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Chang Chen
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Wenchang Zhao
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, And School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Congyan Zeng
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
| | - Quanxi Mei
- Pharmacology Laboratory, Zhongshan Hospital, Guangzhou University of Chinese Medicine, Zhongshan 528401, China
- Shenzhen Baoan Authentic TCM Therapy Hospital, Shenzhen 518101, China
| | - Qilei Chen
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong 999077, China
| | - Weihong Kuang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, And School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
- Correspondence: (W.K.); (X.H.)
| | - Zhanping Gou
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, And School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
| | - Xianjing Hu
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, And School of Pharmacy, Guangdong Medical University, Dongguan 523808, China
- Dongguan Key Laboratory of Chronic Inflammatory Diseases, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523121, China
- Correspondence: (W.K.); (X.H.)
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Rote Hand Brief zur Anwendung von 5 mg Ulipristalacetat vom 01.02.2021. GYNAKOLOGISCHE ENDOKRINOLOGIE 2021. [DOI: 10.1007/s10304-021-00380-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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BAHMAN Y, MARYAM M, AISA B, FALALYEYEVA T, KOBYLIAK N, MAJID E. Immunomodulatory role of Faecalibacterium prausnitzii in obesity and metabolic disorders. MINERVA BIOTECHNOLOGY AND BIOMOLECULAR RESEARCH 2021. [DOI: 10.23736/s2724-542x.21.02759-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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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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Epidemiology of drug-induced liver injury in a University Hospital from Colombia: Updated RUCAM being used for prospective causality assessment. Ann Hepatol 2020; 18:501-507. [PMID: 31053545 DOI: 10.1016/j.aohep.2018.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/29/2018] [Accepted: 11/27/2018] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Epidemiological information regarding drug-induced liver injury in some Latin American countries remains limited. Therefore, disease prevention and health promotion strategies are imperative to reduce drug-induced liver injuries and its fatal outcomes. This study aimed to collect epidemiological data regarding drug-induced liver injury and identify associated factors in patients admitted to a university hospital in Colombia. METHODS AND PATIENTS A prospective study was conducted for 1 year to assess the incidence of drug-induced liver injury in patients aged >18 years who showed elevated values in liver tests. Data were collected after obtaining informed consent from the patients. The updated Roussel Uclaf Causality Assessment Method was applied to assess the causality of drug-induced liver injury. RESULTS The study included 286 patients with elevated values in liver tests, 18 of whom presented with drug-induced liver injury. The mean age of patients was 54.7±19.1 years. The associated pharmacological groups were anti-infectives and anticonvulsants (isoniazid, rifampicin, nitrofurantoin, phenytoin, and valproic acid), with a total of 15 drugs. The affected patients presented with cytopenia, jaundice, nausea, vomiting, or hepatomegaly. The most common type of liver injury was hepatocellular, and most patients recovered satisfactorily. The number of patients who had highly probable and probable causality grading was 1 and 9, respectively. CONCLUSION The incidence of drug-induced liver injury in a university hospital in Colombia was 6%. Comorbidities and concomitant drugs are risk factors for drug-induced liver injury. TRIAL REGISTRATION Registered in The Cuban Public Registry of Clinical Trials (identifier RPCEC00000242).
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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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Alhaddad O, Elsabaawy M, Abdelsameea E, Abdallah A, Shabaan A, Ehsan N, Elrefaey A, Elsabaawy D, Salama M. Presentations, Causes and Outcomes of Drug-Induced Liver Injury in Egypt. Sci Rep 2020; 10:5124. [PMID: 32198411 PMCID: PMC7083870 DOI: 10.1038/s41598-020-61872-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 02/26/2020] [Indexed: 02/07/2023] Open
Abstract
Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.
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Affiliation(s)
- Omkolthoum Alhaddad
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Maha Elsabaawy
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Eman Abdelsameea
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt.
| | - Ayat Abdallah
- Epidemiology and Preventive Medicine Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Shabaan
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Nermine Ehsan
- Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Ahmed Elrefaey
- Pathology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Dalia Elsabaawy
- Clinical Pharmacy, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
| | - Mohsen Salama
- Hepatology and gastroenterology Department, National Liver Institute, Menoufia University, Shebin El-Kom, Egypt
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Devarbhavi H, Choudhury AK, Sharma MK, Maiwall R, Al Mahtab M, Rahman S, Chawla YK, Dhiman RK, Duseja A, Taneja S, Ning Q, Jia JD, Duan Z, Yu C, Eapen CE, Goel A, Tan SS, Hamid SS, Butt AS, Jafri W, Kim DJ, Hu J, Sood A, Midha V, Shukla A, Ghazinian H, Sahu MK, Treeprasertsuk S, Lee GH, Lim SG, Lesmana LA, Lesmana CR, Shah S, Kalal C, Abbas Z, Sollano JD, Prasad VGM, Payawal DA, Dokmeci AK, Rao PN, Shrestha A, Lau GK, Yuen MF, Saraswat VA, Shiha G, Yokosuka O, Kedarisetty CK, Jain P, Bhatia P, Sarin SK. Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients. Am J Gastroenterol 2019; 114:929-937. [PMID: 31021832 DOI: 10.14309/ajg.0000000000000201] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. METHODS We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. RESULTS Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. DISCUSSION Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.
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Affiliation(s)
- Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St John Medical College, Bangalore, India
| | - Ashok Kumar Choudhury
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Salimur Rahman
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | | | | | - Ajay Duseja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Qin Ning
- Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ji Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital
| | - Chen Yu
- Translational Hepatology Institute Capital Medical University, Beijing You'an Hospital
| | | | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Bata Caves, Selangor, Malaysia
| | - Saeed Sadiq Hamid
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Amna Subhan Butt
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Wasim Jafri
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Dong Joon Kim
- Deparment of Internal Medicine, Hallym University College of Medicine
| | - Jinhua Hu
- Department of Medicine, 302 Millitary Hospital Beijing, China
| | - Ajit Sood
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Vandana Midha
- Department of Gastroenterology, DMC, Ludhiana, India
| | - Akash Shukla
- Department of Hepatology, KEM Hospital and Seth GSMC
| | - Hasmik Ghazinian
- Department of Hepatology, Nork Clinical Hospital of Infectious Disease, Armenia
| | - Manoj Kumar Sahu
- Department of Hepatology, IMS &SUM Hospital, Bhuvaneswar, Odisa, India
| | | | - Guan Huei Lee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Seng Gee Lim
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - L A Lesmana
- Department of Medicine, Medistra Hospital, Jakarta, Indonesia
| | | | - Samir Shah
- Department of Hepatology, Global Hospital, Mumbai, India
| | - Chetan Kalal
- Department of Hepatology, Global Hospital, Mumbai, India
| | - Zaigham Abbas
- Department of Medicine, Ziauddin University Hospital, Karachi
| | - Jose D Sollano
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | | | - A Kadir Dokmeci
- Department of Medicine, Ankara University School of Medicine, Turkey
| | | | - Ananta Shrestha
- Department of Hepatology, Foundation Nepal Sitapaila Height, Kathmandu
| | - George K Lau
- Department of Medicine, Humanity and Health Medical Group, Hong Kong
| | - Man Fung Yuen
- Department of Medicine, Queen Mary Hospital Hong Kong, China
| | | | - Gamal Shiha
- Department of Internal Medicine, Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
| | | | | | - Priyanka Jain
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Puja Bhatia
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology and Transplant, Institute of Liver and Biliary Sciences, New Delhi, India
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Wong MCS, Huang JLW, George J, Huang J, Leung C, Eslam M, Chan HLY, Ng SC. The changing epidemiology of liver diseases in the Asia-Pacific region. Nat Rev Gastroenterol Hepatol 2019; 16:57-73. [PMID: 30158570 DOI: 10.1038/s41575-018-0055-0] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.
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Affiliation(s)
- Martin C S Wong
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Jason L W Huang
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Junjie Huang
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Colette Leung
- J.C. School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Henry L Y Chan
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong
| | - Siew C Ng
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
- State Key Laboratory for Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong.
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Hammann F, Schöning V, Drewe J. Prediction of clinically relevant drug-induced liver injury from structure using machine learning. J Appl Toxicol 2018; 39:412-419. [DOI: 10.1002/jat.3741] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 09/10/2018] [Accepted: 09/21/2018] [Indexed: 12/16/2022]
Affiliation(s)
- Felix Hammann
- Division of Clinical Pharmacology and Toxicology; University Hospital Basel; Basel Switzerland
| | - Verena Schöning
- Division of Clinical Pharmacology and Toxicology; University Hospital Basel; Basel Switzerland
| | - Jürgen Drewe
- Division of Clinical Pharmacology and Toxicology; University Hospital Basel; Basel Switzerland
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García-Cortés M, Ortega-Alonso A, Lucena MI, Andrade RJ. Drug-induced liver injury: a safety review. Expert Opin Drug Saf 2018; 17:795-804. [PMID: 30059261 DOI: 10.1080/14740338.2018.1505861] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive. AREAS COVERED In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature. EXPERT OPINION Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs' hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.
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Affiliation(s)
- Miren García-Cortés
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
| | - Aida Ortega-Alonso
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
| | - M Isabel Lucena
- b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain.,c Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria , Universidad de Málaga , Málaga , Spain
| | - Raúl J Andrade
- a Instituto de Investigación Biomédica-IBIMA , Hospital Universitario Virgen de la Victoria, Universidad de Málaga , Málaga , Spain.,b Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd , Málaga , Spain
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Uçmak F, Tuncel ET, Kaçmaz H, Ebik B, Kaya M. Güneydoğu Anadolu Bölgesindeki Üçüncü Basamak Gastroenteroloji Kliniğinin Toksik Hepatit Deneyimi. DICLE MEDICAL JOURNAL 2018. [DOI: 10.5798/dicletip.425003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Mohamed AK, Magdy M. Caspase 3 role and immunohistochemical expression in assessment of apoptosis as a feature of H1N1 vaccine-caused Drug-Induced Liver Injury (DILI). Electron Physician 2017; 9:4261-4273. [PMID: 28713494 PMCID: PMC5498687 DOI: 10.19082/4261] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/15/2017] [Indexed: 12/13/2022] Open
Abstract
Background Drug-Induced Liver Injury (DILI) changes, occur post exposure to natural or chemical compounds including apoptosis. Aim To assess the H1N1 vaccine-caused DILI by histochemical and immunohistochemical methods. Methods This 2014’s experimental study was conducted on 70 albino rats. They were given ArepanrixTM H1N1 vaccine and were divided into 7 groups; 10 mice each, as control (non-vaccinated), vac2 and vac4 injected with 1st and 2nd doses of vaccine (suspension only) and euthanized after 3 weeks each, vac5 euthanized 6 weeks after 2nd dose, mix2 and mix4 injected with 1st and 2nd doses of vaccine (mixture of suspension and adjuvant) and euthanized after 3 weeks each, mix5 and euthanized 6 weeks after 2nd dose. Histopathological evaluation and histochemical assessment of metabolic protein, glycogen and collagen changes using PAS, bromophenol blue, Mallory’s trichrome and immunohistochemistry for caspase 3 on liver tissue paraffin sections were done. Image analysis system Leica QIIN 500 was used. Data were analyzed by SPSS software, using descriptive statistics and ANOVA. Results Histopathological changes ranging from subtle up to necrosis were noticed, mainly in mix groups. Metabolic protein and glycogen changes were the maximum in mix5 group (p<0.01). Collagen deposition in sinusoids was higher in mix groups, and maximally in vac5 and mix5. Apoptotic hepatocytes expressing diffuse strong nuclear and cytoplasmic caspase 3 were the highest in mix5. Conclusion H1N1 vaccine can cause DILI by either direct toxic or idiosyncratic metabolic type reactions rather than immunologic hypersensitivity type. It ranges from subtle changes up to necrosis. Caspase 3 is pivotal in liver damage etiology, apoptosis induction and processing. Follow up for at least 2 months after the 2nd dose of H1N1 vaccine is recommended to rule out H1N1-induced DILI.
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Affiliation(s)
- Abir Khalil Mohamed
- Ph.D. of Zoology, Department of Zoology, Faculty of Science, Al-Azhar University. Cairo, Egypt
| | - Mona Magdy
- MD of Pathology, Department of Pathology, Theodor Bilharz Research Institute, Giza, Egypt
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Baekdal M, Ytting H, Skalshøi Kjær M. Drug-induced liver injury: a cohort study on patients referred to the Danish transplant center over a five year period. Scand J Gastroenterol 2017; 52:450-454. [PMID: 27973926 DOI: 10.1080/00365521.2016.1267790] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome. MATERIALS AND METHODS We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome. RESULTS Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome.
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Affiliation(s)
- Mille Baekdal
- a Department of Hepatology , Rigshospitalet, University Hospital of Copenhagen , Copenhagen , Denmark
| | - Henriette Ytting
- a Department of Hepatology , Rigshospitalet, University Hospital of Copenhagen , Copenhagen , Denmark
| | - Mette Skalshøi Kjær
- a Department of Hepatology , Rigshospitalet, University Hospital of Copenhagen , Copenhagen , Denmark
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Gupte-Singh K, Li H, Swain JL, Cheng Y, Regev A. Assessment of a Severity-Based Algorithm to Detect Signals of Severe Drug-Induced Liver Injury Using Spontaneous Reporting Database. Pharmaceut Med 2017. [DOI: 10.1007/s40290-016-0173-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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21
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Brauer R, Douglas I, Garcia Rodriguez LA, Downey G, Huerta C, de Abajo F, Bate A, Feudjo Tepie M, de Groot MCH, Schlienger R, Reynolds R, Smeeth L, Klungel O, Ruigómez A. Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe. Pharmacoepidemiol Drug Saf 2017; 25 Suppl 1:29-38. [PMID: 27038354 DOI: 10.1002/pds.3861] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 07/10/2015] [Accepted: 07/24/2015] [Indexed: 11/10/2022]
Abstract
PURPOSE To assess the impact of varying study designs, exposure and outcome definitions on the risk of acute liver injury (ALI) associated with antibiotic use. METHODS The source population comprised of patients registered in two primary care databases, in the UK and in Spain. We identified a cohort consisting of new users of antibiotics during the study period (2004-2009) and non-users during the study period or in the previous year. Cases with ALI were identified within this cohort and classified as definite or probable, based on recorded medical information. The relative risk (RR) of ALI associated with antibiotic use was computed using Poisson regression. For the nested case-control analyses, up to five controls were matched to each case by age, sex, date and practice (in CPRD) and odds ratios (OR) were computed with conditional logistic regression. RESULTS The age, sex and year adjusted RRs of definite ALI in the current antibiotic use periods was 10.04 (95% CI: 6.97-14.47) in CPRD and 5.76 (95% CI: 3.46-9.59) in BIFAP. In the case-control analyses adjusting for life-style, comorbidities and use of medications, the OR of ALI for current users of antibiotics was and 5.7 (95% CI: 3.46-9.36) in CPRD and 2.6 (95% CI: 1.26-5.37) in BIFAP. CONCLUSION Guided by a common protocol, both cohort and case-control study designs found an increased risk of ALI associated with the use of antibiotics in both databases, independent of the exposure and case definitions used. However, the magnitude of the risk was higher in CPRD compared to BIFAP.
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Affiliation(s)
- Ruth Brauer
- London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Population Health, London, UK.,Amgen Limited, London, UK
| | - Ian Douglas
- London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Population Health, London, UK
| | | | | | - Consuelo Huerta
- Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Medicines for Human Use Department, Division of Pharmacoepidemiology and Pharmacovigilance, Madrid, Spain
| | - Francisco de Abajo
- Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Department of Biomedical Sciences, University of Alcala, Alcalá de Henares, Spain
| | | | | | - Mark C H de Groot
- Utrecht University, Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands
| | | | - Robert Reynolds
- Epidemiology, Pfizer Research and Development, New York, NY, USA
| | - Liam Smeeth
- London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Population Health, London, UK
| | - Olaf Klungel
- Utrecht University, Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht, The Netherlands
| | - Ana Ruigómez
- Fundación Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain
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Cao L, Quan XB, Zeng WJ, Yang XO, Wang MJ. Mechanism of Hepatocyte Apoptosis. J Cell Death 2016; 9:19-29. [PMID: 28058033 PMCID: PMC5201115 DOI: 10.4137/jcd.s39824] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/14/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatocyte apoptosis plays important roles in both the removal of external microorganisms and the occurrence and development of liver diseases. Different conditions, such as virus infection, fatty liver disease, hepatic ischemia reperfusion, and drug-induced liver injury, are accompanied by hepatocyte apoptosis. This review summarizes recent research on the mechanism of hepatocyte apoptosis involving the classical extrinsic and intrinsic apoptotic pathways, endoplasmic reticulum stress, and oxidative stress-induced apoptosis. We emphasized the major causes of apoptosis according to the characteristics of different liver diseases. Several concerns regarding future research and clinical application are also raised.
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Affiliation(s)
- Lei Cao
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xi-Bing Quan
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wen-Jiao Zeng
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiao-Ou Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Ming-Jie Wang
- Research Center on Aging and Medicine, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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Kristanc L, Kreft S. European medicinal and edible plants associated with subacute and chronic toxicity part II: Plants with hepato-, neuro-, nephro- and immunotoxic effects. Food Chem Toxicol 2016; 92:38-49. [DOI: 10.1016/j.fct.2016.03.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/15/2016] [Accepted: 03/18/2016] [Indexed: 02/07/2023]
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Magalhães R, Fonseca M, Brandão I, Caridade S. Autoimmune hepatitis unmasked by nimesulide. BMJ Case Rep 2016; 2016:bcr-2015-212884. [PMID: 26791119 DOI: 10.1136/bcr-2015-212884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
A 49-year-old woman presented at the emergency department, with acute hepatic failure, 2 weeks after taking nimesulide. Presenting with a MELD score of 25.0, the patient was transferred to a specialised liver transplant unit, with the probable diagnosis of toxic hepatitis. After a clinical improvement with supportive care and acetylcysteine, a liver biopsy was executed. The histology revealed micronodular cirrhosis associated with acute hepatitis, with features suggestive of autoimmune hepatitis. The patient was then started on azathioprine 50 mg/day and prednisolone 30 mg/day, and tapering of prednisolone was carried out in the following months. Twenty eight months after treatment, another liver biopsy was performed, showing almost full remission of the disease, with only mild fibrosis and no significant inflammatory infiltrate.
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Affiliation(s)
- Rita Magalhães
- Department of Internal Medicine, Hospital de Braga, Braga, Portugal
| | | | - Ilídio Brandão
- Department of Internal Medicine, Hospital de Braga, Braga, Portugal
| | - Sofia Caridade
- Department of Internal Medicine, Hospital de Braga, Braga, Portugal
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Dipaola F, Fontana RJ. Is Making a Prognosis for Patients With Drug-induced Liver Injury Putting the Cart Before the Horse? Clin Gastroenterol Hepatol 2015; 13:2369-71. [PMID: 26291666 DOI: 10.1016/j.cgh.2015.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 08/10/2015] [Accepted: 08/10/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Frank Dipaola
- Departments of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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Kollhorst B, Behr S, Enders D, Dippel FW, Theobald K, Garbe E. Comparison of basal insulin therapies with regard to the risk of acute myocardial infarction in patients with type 2 diabetes: an observational cohort study. Diabetes Obes Metab 2015; 17:1158-65. [PMID: 26279482 DOI: 10.1111/dom.12554] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 08/05/2015] [Accepted: 08/12/2015] [Indexed: 11/29/2022]
Abstract
AIMS To assess the risk of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus treated with long-acting insulin analogues in comparison with other basal insulin therapy. METHODS We used German insurance claims data from the years 2004-2009 to conduct a study in a retrospective cohort of patients with type 2 diabetes. Naïve insulin users were defined as patients who had an insulin-free history before the first prescription of long-acting analogue insulin, human NPH insulin or premixed insulin and who were pretreated with oral antidiabetic drugs. Adjusted hazard ratios (HRs) of AMI and corresponding 95% confidence intervals (CIs) were calculated using sex-stratified Cox models. Propensity-score-matched analyses were conducted as sensitivity analyses. RESULTS We identified 21,501 new insulin users. Patients treated with premixed insulin were older than patients treated with analogue or NPH insulin (mean age 70.7 vs. 64.1 and 61.6 years, respectively) and had more comorbidities. Regarding the risk of AMI, adjusted HRs showed no statistically significant difference between NPH and analogue insulin (HR 0.94, 95% CI 0.74-1.19), but a higher risk for premixed than for analogue insulin (HR 1.27, 95% CI 1.02-1.58). Contrary to the primary analysis, the propensity-score-matched analysis did not show an increased risk for premixed insulin. CONCLUSIONS In contrast to a former database study, no difference was observed for the risk of AMI between long-acting analogue and NPH insulin in this study. Neither long-acting analogue insulin nor premixed insulin appears to be associated with AMI in patients with type 2 diabetes.
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Affiliation(s)
- B Kollhorst
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - S Behr
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - D Enders
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
| | - F-W Dippel
- Sanofi Aventis Deutschland GmbH, Berlin, Germany
| | - K Theobald
- Sanofi Aventis Deutschland GmbH, Berlin, Germany
| | - E Garbe
- Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany
- Core Scientific Area 'Health Sciences', University of Bremen, Bremen, Germany
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Abstract
CONTEXT Drug-induced liver injury (DILI) represents a diverse set of responses following exposure to any manufactured or naturally occurring chemical compound. Drug-induced liver injury is of major concern owing to the ever increasing number of compounds introduced into the market for treatment of various diseases as well as the increasing popularity of herbals, which lend themselves to self-medication but are not rigorously regulated. OBJECTIVE To provide an overview of the prevalence, classification, and diagnosis of DILI with emphasis on pathogenesis and the role of a liver biopsy. To focus on the most common, emerging, and herbal agents that cause DILI with emphasis on the histologic pattern of injury observed. DATA SOURCES A review of the literature was drawn from the PubMed (US National Library of Medicine) repository, textbooks, and online databases. All figures were taken from cases seen at our tertiary referral center, which is 1 of 12 participating sites in the National Institutes of Health-funded Drug-Induced Liver Injury Network. CONCLUSIONS Drug-induced liver injury due to prescription, over-the-counter, and herbal products is a major cause of liver disease in the United States and around the world. Diagnosis of DILI is challenging because there is no single clinical, laboratory, or histologic feature specific to DILI. Accurate diagnosis requires establishing a causal relationship with the suspected agent and excluding competing causes of liver injury. The liver biopsy is an essential component in the management of DILI by offering clues to the underlying pathogenesis, providing prognostic information, and guiding therapy.
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Affiliation(s)
| | | | - Romil Saxena
- From the Department of Pathology and Laboratory Medicine (Drs Fisher and Ms Saxena)
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Brauer R, Ruigómez A, Downey G, Bate A, Garcia Rodriguez LA, Huerta C, Gil M, de Abajo F, Requena G, Alvarez Y, Slattery J, de Groot M, Souverein P, Hesse U, Rottenkolber M, Schmiedl S, de Vries F, Tepie MF, Schlienger R, Smeeth L, Douglas I, Reynolds R, Klungel O. Prevalence of antibiotic use: a comparison across various European health care data sources. Pharmacoepidemiol Drug Saf 2015; 25 Suppl 1:11-20. [PMID: 26152658 PMCID: PMC4918309 DOI: 10.1002/pds.3831] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 06/04/2015] [Accepted: 06/11/2015] [Indexed: 12/03/2022]
Abstract
Purpose There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. Methods Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1‐year‐period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. Results The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0–9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty‐nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. Conclusion Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries. © 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Ruth Brauer
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Ana Ruigómez
- Fundación Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain
| | | | | | | | - Consuelo Huerta
- Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain
| | - Miguel Gil
- Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain
| | - Francisco de Abajo
- Clinical Pharmacology Unit, University Hospital Príncipe de Asturias, Madrid, Spain.,Pharmacology Section, Department of Biomedical Sciences II, University of Alcalá (UAH), Madrid, Spain
| | - Gema Requena
- Pharmacology Section, Department of Biomedical Sciences II, University of Alcalá (UAH), Madrid, Spain
| | | | | | - Mark de Groot
- Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - Patrick Souverein
- Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - Ulrik Hesse
- Laegemiddelstyrelsen (Danish Medicines Agency), National Institute for Health Data and Disease Control, Copenhagen, Denmark
| | - Marietta Rottenkolber
- Institute of Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany
| | - Sven Schmiedl
- Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany.,Philipp Klee-Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany
| | - Frank de Vries
- Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.,MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, UK.,School CAPHRI / Maastricht University, Maastricht, The Netherlands
| | | | | | - Liam Smeeth
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Ian Douglas
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Robert Reynolds
- Epidemiology, Pfizer Research & Development, New York, NY, USA
| | - Olaf Klungel
- Faculty of Science, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
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Wohlreich MM, Acharya N, Strombom I, Kuritzky L, Robinson M, Heinloth AN, Regev A, Wernicke JF. Answers to the Most Common Questions About the Hepatic Safety Profile of Duloxetine. Postgrad Med 2015; 120:111-8. [DOI: 10.3810/pgm.2008.07.1803] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol 2015; 89:327-34. [PMID: 25618544 DOI: 10.1007/s00204-015-1456-2] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/08/2015] [Indexed: 12/24/2022]
Abstract
There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin-clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox ( http://livertox.nlm.nih.gov ). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug.
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Ruan J, Gao H, Li N, Xue J, Chen J, Ke C, Ye Y, Fu PPC, Zheng J, Wang J, Lin G. Blood Pyrrole-Protein Adducts--A Biomarker of Pyrrolizidine Alkaloid-Induced Liver Injury in Humans. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2015; 33:404-421. [PMID: 26398275 DOI: 10.1080/10590501.2015.1096882] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Pyrrolizidine alkaloids (PAs) induce liver injury (PA-ILI) and is very likely to contribute significantly to drug-induced liver injury (DILI). In this study we used a newly developed ultra-high performance liquid chromatography-triple quadrupole-mass spectrometry (UHPLC-MS)-based method to detect and quantitate blood pyrrole-protein adducts in DILI patients. Among the 46 suspected DILI patients, 15 were identified as PA-ILI by the identification of PA-containing herbs exposed. Blood pyrrole-protein adducts were detected in all PA-ILI patients (100%). These results confirm that PA-ILI is one of the major causes of DILI and that blood pyrrole-protein adducts quantitated by the newly developed UHPLC-MS method can serve as a specific biomarker of PA-ILI.
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Affiliation(s)
- Jianqing Ruan
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
| | - Hong Gao
- b Division of Gastroenterology, Zhongshan Hospital , Fudan University , Shanghai , P. R. China
| | - Na Li
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
| | - Junyi Xue
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
- c Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines between Shanghai Institute of Materia Medica , Chinese Academy of Sciences and The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
| | - Jie Chen
- b Division of Gastroenterology, Zhongshan Hospital , Fudan University , Shanghai , P. R. China
| | - Changqiang Ke
- c Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines between Shanghai Institute of Materia Medica , Chinese Academy of Sciences and The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
- d State Key Laboratory of Drug Research & Natural Products Chemistry Department, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , P. R. China
| | - Yang Ye
- c Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines between Shanghai Institute of Materia Medica , Chinese Academy of Sciences and The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
- d State Key Laboratory of Drug Research & Natural Products Chemistry Department, Shanghai Institute of Materia Medica , Chinese Academy of Sciences , P. R. China
| | - Peter Pi-Cheng Fu
- e National Center for Toxicological Research , Jefferson , Arkansas , USA
| | - Jiang Zheng
- f Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology, Department of Pediatrics , University of Washington , Washington , USA
- g Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education , Shenyang Pharmaceutical University , Shenyang , China
| | - Jiyao Wang
- b Division of Gastroenterology, Zhongshan Hospital , Fudan University , Shanghai , P. R. China
| | - Ge Lin
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
- c Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines between Shanghai Institute of Materia Medica , Chinese Academy of Sciences and The Chinese University of Hong Kong , Hong Kong SAR , Hong Kong
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Grove JI, Aithal GP. Human leukocyte antigen genetic risk factors of drug-induced liver toxicology. Expert Opin Drug Metab Toxicol 2014; 11:395-409. [PMID: 25491399 DOI: 10.1517/17425255.2015.992414] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is a rare adverse drug reaction, which impacts significantly on patients. Human leukocyte antigen (HLA) risk alleles have been found to be associated with DILI supporting an immunological basis to DILI pathogenesis. AREAS COVERED HLA alleles associated with risk of liver injury induced by specific therapeutic drugs are described. The evidence for a role of the adaptive immune system in DILI is presented; case-control studies showing an association between DILI and HLA alleles are reviewed. Clinical applications of pharmacogenomics are considered. EXPERT OPINION Increasing evidence points to a crucial role for the adaptive immune system in the pathogenesis of DILI. Identification of specific HLA alleles as risk factors through large genome-wide association studies has been instrumental in this and in vitro analyses have facilitated improved understanding of the molecular mechanisms. This provides the basis for developing clinical pharmacogenomic applications. Already, genotyping for hypersensitivity HLA risk alleles has been implemented and opportunities for pre-prescription testing in DILI identified. However, although associations are strong, the rarity of DILI means routine testing has not been formally evaluated. Nevertheless, enhanced understanding of how HLA alleles contribute to injury risk is valuable for drug development. Translation of this research into effective pre-emption and primary prevention remains the goal.
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Affiliation(s)
- Jane I Grove
- Nottingham University Hospitals NHS Trust and University of Nottingham, NIHR Nottingham Digestive Diseases Biomedical Research Unit , Nottingham, NG7 2UH , UK +01159249924 Ext: 63822 ; +01159709012 ;
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Abbing-Karahagopian V, Kurz X, de Vries F, van Staa TP, Alvarez Y, Hesse U, Hasford J, Dijk LV, de Abajo FJ, Weil JG, Grimaldi-Bensouda L, Egberts ACG, Reynolds RF, Klungel OH. Bridging differences in outcomes of pharmacoepidemiological studies: design and first results of the PROTECT project. ACTA ACUST UNITED AC 2014; 9:130-8. [PMID: 24218995 PMCID: PMC4083447 DOI: 10.2174/1574884708666131111211802] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/20/2013] [Accepted: 05/19/2013] [Indexed: 01/05/2023]
Abstract
Background: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant
results that may be due to differences in design, conduct and analysis. Purpose: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of
Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating
methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different
safety issues using different databases across European countries. This article describes the selection of the safety issues
and the description of the databases to be systematically studied. Methods: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be
evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public
health impact, and the potential to investigate a broad range of methodological issues. Results: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2)
antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and
suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to
evaluate the drug-AE pairs retrospectively, are also described. Conclusion: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies
and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase
the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Olaf H Klungel
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082 3508 TB Utrecht, The Netherlands.
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Ascertainment of acute liver injury in two European primary care databases. Eur J Clin Pharmacol 2014; 70:1227-35. [PMID: 25066450 DOI: 10.1007/s00228-014-1721-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 07/16/2014] [Indexed: 10/25/2022]
Abstract
PURPOSE The purpose of this study was to ascertain acute liver injury (ALI) in primary care databases using different computer algorithms. The aim of this investigation was to study and compare the incidence of ALI in different primary care databases and using different definitions of ALI. METHODS The Clinical Practice Research Datalink (CPRD) in UK and the Spanish "Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria" (BIFAP) were used. Both are primary care databases from which we selected individuals of all ages registered between January 2004 and December 2009. We developed two case definitions of idiopathic ALI using computer algorithms: (i) restrictive definition (definite cases) and (ii) broad definition (definite and probable cases). Patients presenting prior liver conditions were excluded. Manual review of potential cases was performed to confirm diagnosis, in a sample in CPRD (21%) and all potential cases in BIFAP. Incidence rates of ALI by age, sex and calendar year were calculated. RESULTS In BIFAP, all cases considered definite after manual review had been detected with the computer algorithm as potential cases, and none came from the non-cases group. The restrictive definition of ALI had a low sensitivity but a very high specificity (95% in BIFAP) and showed higher rates of agreement between computer search and manual review compared to the broad definition. Higher incidence rates of definite ALI in 2008 were observed in BIFAP (3.01 (95% confidence interval (CI) 2.13-4.25) per 100,000 person-years than CPRD (1.35 (95% CI 1.03-1.78)). CONCLUSIONS This study shows that it is feasible to identify ALI cases if restrictive selection criteria are used and the possibility to review additional information to rule out differential diagnoses. Our results confirm that idiopathic ALI is a very rare disease in the general population. Finally, the construction of a standard definition with predefined criteria facilitates the timely comparison across databases.
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Herbs and liver injury: a clinical perspective. Clin Gastroenterol Hepatol 2014; 12:1069-76. [PMID: 23924877 DOI: 10.1016/j.cgh.2013.07.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Revised: 07/22/2013] [Accepted: 07/23/2013] [Indexed: 02/07/2023]
Abstract
Despite a perception that herbal and dietary supplements are safe, devastating liver injury has been reported to result from their use. The difficulty in characterizing liver injury attributable to herbal and dietary supplements stems from the permissive regulatory environment, the complexity of marketed products, and underreporting by the patients who use them. Despite these limitations, researchers, clinicians, and regulators have increasing awareness of the need for study in this area.
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Yu K, Geng X, Chen M, Zhang J, Wang B, Ilic K, Tong W. High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury. Drug Metab Dispos 2014; 42:744-50. [PMID: 24464804 DOI: 10.1124/dmd.113.056267] [Citation(s) in RCA: 94] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65-3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings.
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Affiliation(s)
- Ke Yu
- Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas (K.Y., M.C., J.Z., W.T.); National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, China's State Food and Drug Administration, Beijing, China (X.G.); Department of Biostatistics, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.W.); and Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (K.I.)
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Andrade RJ, López-Ortega S, López-Vega MC, Robles M, Cueto I, Lucena MI. Idiosyncratic drug hepatotoxicity: a 2008 update. Expert Rev Clin Pharmacol 2014; 1:261-76. [PMID: 24422651 DOI: 10.1586/17512433.1.2.261] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.
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Affiliation(s)
- Raúl J Andrade
- CIBERehd; Liver Unit, Gastroenterology Service, "Virgen de la Victoria" University Hospital and School of Medicine, Málaga, Spain.
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Lopez MJ, Bilhartz JL. Drug-Induced Liver Injury in Children: A Structured Approach to Diagnosis and Management. DISEASES OF THE LIVER IN CHILDREN 2014:371-388. [DOI: 10.1007/978-1-4614-9005-0_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
Cholestasis caused by drugs is an important differential diagnosis in patients presenting with a biochemical cholestatic pattern. The extent of serologic tests and radiological imaging depends on the clinical context. The underlying condition of the patient and detailed information on drug use, results of rechallenge, and the documented hepatotoxicity of the drug are important to establish a diagnosis of drug-induced liver injury (DILI). Most cases of cholestatic DILI are mild, but in rare cases, ductopenia and cholestatic cirrhosis can develop. Approximately 10% of patients with cholestatic jaundice caused by drugs develop liver failure.
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Sistanizad M, Peterson GM. Drug-induced liver injury in the Australian setting. J Clin Pharm Ther 2013; 38:115-20. [PMID: 23350857 DOI: 10.1111/jcpt.12039] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 12/05/2012] [Indexed: 12/13/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE The causes of drug-induced liver injury vary worldwide, with limited data regarding drug-induced hepatotoxicity in Australia. This study sought to provide information about the incidence, causes and clinical manifestations of drug-induced hepatotoxicity. METHODS A retrospective study was performed on all adult inpatients with abnormal liver function tests, defined as an increase of more than twice the upper limit of the normal range in either serum alanine aminotransferase or alkaline phosphatase, over a 12-month period at the major hospital in Tasmania, Australia. A random sample of individual medical records was reviewed and clinical data extracted. The causality of suspected drug-induced liver injury cases was assessed using the Roussel Uclaf Causality Assessment Method. RESULTS A total of 264 cases were included. Drug-induced liver injury with at least a possible causal relationship was found in 24 cases (9·1%). The mean age at presentation in the 17 patients with possible or probable hepatotoxicity not related to paracetamol or cancer chemotherapy was 60 ± 20·0 years, and 9 (53%) were men. The frequencies of cholestatic, hepatocellular and mixed patterns of liver damage were 9 (53%), 2 (12%) and 6 (35%) respectively. The most common cause was antibiotics (11 of 17; 65%), while flucloxacillin (4 of 17; 24%) was the single agent most often implicated. WHAT IS NEW AND CONCLUSION Nearly 10% of cases of abnormal liver function could be associated with adverse effects of drugs. The possibility of drug-induced liver injury should always be considered when there is an absence of other apparent hepatic disease.
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Affiliation(s)
- M Sistanizad
- Department of Pharmacotherapy, School of Pharmacy, Shahid Beheshti Medical University, Iran
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Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther 2013; 37:3-17. [PMID: 23121117 DOI: 10.1111/apt.12109] [Citation(s) in RCA: 200] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2012] [Revised: 09/18/2012] [Accepted: 10/06/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. AIMS To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. METHODS A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. RESULTS The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. CONCLUSIONS A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety.
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Affiliation(s)
- C Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand
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Shin J, Hunt CM, Suzuki A, Papay JI, Beach KJ, Cheetham TC. Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data. Pharmacoepidemiol Drug Saf 2012; 22:190-8. [DOI: 10.1002/pds.3388] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 11/01/2012] [Accepted: 11/18/2012] [Indexed: 01/09/2023]
Affiliation(s)
- Janet Shin
- Pharmacy Analytical Services; Kaiser Permanente Southern California; Downey California USA
| | | | - Ayako Suzuki
- Duke University Medical Center; Durham North Carolina USA
| | - Julie I. Papay
- GlaxoSmithKline; Research Triangle Park North Carolina USA
| | | | - T. Craig Cheetham
- Pharmacy Analytical Services; Kaiser Permanente Southern California; Downey California USA
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Hou FQ, Zeng Z, Wang GQ. Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes. Cell Biochem Biophys 2012; 64:77-83. [PMID: 22806342 DOI: 10.1007/s12013-012-9373-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
We investigated clinical features, therapy, and outcomes of patients hospitalized for drug-induced liver injury (DILI). DILI resolution was defined as liver biochemistry values back to normal or lower than CIOMS laboratory criteria; Chronicity was defined as persistent biochemical abnormality for >6 months after drugs' withdrawal. Three-hundred cases were reviewed retrospectively; mean age 51 (13-86) years, and 204 (68 %) were females. It included 267 (89 %) hepatocellular injury, 16 (5.3 %) cholestatic injury, and 17 (5.7 %) mixed injury cases. In hepatocellular injury group, 197 (73.8 %) patients with TBIL < 10× ULN included 142 (72.1 %) females and 70 (26.2 %) patients with TBIL ≥ 10× ULN included 39 (55.7 %) females (P = 0.012). Of 70 patients (TBIL ≥ 10× ULN), 20 were treated with steroid step-down therapy (79 ± 26 days) and others with non-steroid therapy. The steroid therapy group showed higher DILI resolution rate (P = 0.029) and shorter recovery time (P = 0.012). Notably, 274/300 (91.3 %) patients resolved, 18/300 (6 %) developed chronic liver injury, 7/300 (2.3 %) died, and one patient received liver transplantation. In death group, TBIL, ALB, PT, and PTA revealed more severe abnormality than in recovery group. In 121/300 (40.3 %) patients, use of herbal medicines was the leading cause of liver injury, followed by antibiotics, cardiovascular drugs, and endocrine drugs. We concluded that step-down steroid therapy for DILI improved curative effect, shortened disease course, and was safe.
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Affiliation(s)
- Feng-Qin Hou
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, No. 8, XiShiKu Street, XiCheng District, Beijing 100034, China
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Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, Guarner C, Forné M, Solà R, Castellote J, Rigau J, Laporte JR. Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series. BMC Gastroenterol 2011; 11:80. [PMID: 21762481 PMCID: PMC3150324 DOI: 10.1186/1471-230x-11-80] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2010] [Accepted: 07/15/2011] [Indexed: 01/31/2023] Open
Abstract
Background Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug. The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. Methods Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. Results In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4). Conclusions Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.
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Affiliation(s)
- Mònica Sabaté
- Fundació Institut Català de Farmacologia, Universitat Autònoma de Barcelona, Hospital Universitari Vall d'Hebron, Barcelona, Spain
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Abstract
Drug-induced liver injury (DILI) is a rare but potentially devastating adverse drug reaction. Its presentation can range from asymptomatic elevation in liver biochemistries to fulminant liver failure. Over the past decade, clinical and research interest in the field of idiosyncratic DILI has been intense, and several new findings have been reported. In this article, we provide an update on implicated agents, clinical features, outcomes, and the results of recently reported genetic studies.
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Alonso Rodríguez L, Barcina Pajares R, Fuentes Vigil J, Gutiérrez González A, Rodríguez Pérez L. [Acute toxic hepatitis secondary to a single dose of bupropion]. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 33:547-9. [PMID: 20435378 DOI: 10.1016/j.gastrohep.2010.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Revised: 02/08/2010] [Accepted: 02/16/2010] [Indexed: 12/15/2022]
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Abstract
BACKGROUND Drug-induced liver injury (DILI) is an important differential diagnosis in many patients in clinical hepatology. DILI is the leading cause of acute liver failure and is an important safety issue when new drugs are developed. AIMS To provide a review of the recent data on DILI with particular focus on the most common and relevant issues seen in clinical practice. METHODS A Medline search was undertaken to identify relevant literature using search terms including 'drug-induced liver injury' and 'hepatotoxicity'. RESULTS The true incidence of DILI remains unknown but incidence up to 14 cases per 100 000 inhabitants and year has been reported. Antibiotics, analgesics and NSAIDs are the most common drugs causing liver injury. Idiosyncratic DILI has been shown to have a dose-dependent component and drugs without significant hepatic metabolism rarely cause DILI. Chronic elevation in liver enzymes can develop after DILI but this is rarely associated with clinical morbidity or mortality. CONCLUSIONS Drug-induced liver injury remains a diagnostic challenge. Multicentre studies and international collaborative work with well-characterized patients will increase our understanding of liver injury associated with drugs. New therapies for acute liver failure resulting from drugs are needed.
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Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010; 138:2246-59. [PMID: 20394749 PMCID: PMC3157241 DOI: 10.1053/j.gastro.2010.04.001] [Citation(s) in RCA: 237] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 04/02/2010] [Accepted: 04/08/2010] [Indexed: 12/13/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis.
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Affiliation(s)
- Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
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Licata A, Calvaruso V, Cappello M, Craxì A, Almasio PL. Clinical course and outcomes of drug-induced liver injury: nimesulide as the first implicated medication. Dig Liver Dis 2010; 42:143-8. [PMID: 19625223 DOI: 10.1016/j.dld.2009.06.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2008] [Revised: 06/03/2009] [Accepted: 06/10/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Drug-induced liver injury (DILI) is the most common cause of death from acute liver failure, and accounts for approximately 13% of cases of acute liver failure in the United States. The clinical presentation of DILI covers a wide spectrum, from asymptomatic liver test abnormalities to symptomatic acute liver disease, prolonged jaundice and disability, or overt acute or subacute liver failure. The aim of our study was to evaluate the number of DILI cases admitted to our Unit and to identify the drugs responsible. Thus, we reviewed all clinical records of patients with DILI admitted to our Unit from 1996 to 2006. PATIENTS AND METHODS A database was constructed, reporting demographic, clinical features at onset, laboratory results, suspected drugs and follow-up. Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data. RESULTS Forty-six patients were admitted with a diagnosis of DILI. Presentation was jaundice in 22 patients and hepatic failure in 3 (all attributed to nimesulide). Liver damage was of a cytolytic pattern in 19 cases (41%), cholestatic in 15 (33%) and mixed in 12 (26%). Jaundice was found to be higher in nimesulide-induced liver damage compared to other drugs (p=0.007). Three out of 14 patients with nimesulide-induced DILI developed encephalopathy and/or ascites. Time of recovery in the nimesulide group was significantly lower than DILI from other drugs (p<0.001). CONCLUSION Non-steroidal anti-inflammatory drugs, psychotropic drugs and antimicrobials are the most common causes of DILI. Nimesulide-induced DILI is usually reversible upon discontinuation of the drug, but occasionally progresses to liver failure.
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Affiliation(s)
- A Licata
- Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.
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