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1
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Semwal P, Saini MK, Sarma MS. Understanding antituberculosis drug-induced hepatotoxicity: Risk factors and effective management strategies in the pediatric population. World J Clin Pediatr 2025; 14:101875. [DOI: 10.5409/wjcp.v14.i2.101875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 01/06/2025] [Accepted: 01/23/2025] [Indexed: 03/18/2025] Open
Abstract
Antituberculosis drug-induced hepatotoxicity (ATDIH) is a significant concern while managing pediatric tuberculosis. There is limited data on pediatric ATDIH, and much of the management practices are extrapolated from adult experiences. This article provides a comprehensive overview of the incidence, risk factors, clinical presentation, and management strategies for ATDIH in children. Pyrazinamide, isoniazid, and rifampicin are the most hepatotoxic first-line antituberculosis therapy (ATT). Though pyrazinamide has the highest potential for ATDIH, isoniazid is most frequently implicated. Hepatotoxicity typically manifests within the first 2–8 weeks of treatment, particularly during the intensive phase. Risk factors include younger age, female gender, malnutrition, hypoalbuminemia, and baseline liver dysfunction. Extra-pulmonary TB, particularly tuberculous meningitis, and concomitant hepatotoxic medications such as antiretro viral therapy or antiepileptic drugs further increase susceptibility. Genetic predisposition, including N-acetyltransferase 2 and cytochrome P4502E1 polymorphisms and specific HLA alleles also contribute to the increased risk. Clinically, ATDIH ranges from asymptomatic transaminase elevation to severe acute liver failure (ALF), necessitating prompt recognition and intervention. Diagnosis relies on the temporal association of liver injury with ATT initiation, supported by liver function tests, improvement upon ATT cessation, and recurrence upon reintroduction. Management involves discontinuing hepatotoxic drugs, initiating non-hepatotoxic regimens, and sequential reintroduction of ATT under close monitoring. For children with ALF, care in a tertiary center with liver transplantation expertise is essential. While pediatric ATDIH generally has favorable outcomes with timely intervention, delays can result in significant morbidity and mortality. Improved understanding of risk factors, vigilant monitoring protocols, and standardized pediatric management strategies are critical for optimizing outcomes in pediatric ATDIH.
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Affiliation(s)
- Pooja Semwal
- Department of Pediatrics, Hind Institute of Medical Sciences, Lucknow, Lucknow 261303, Uttar Pradesh, India
| | - Manjit Kaur Saini
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Tiwari V, Shandily S, Albert J, Mishra V, Dikkatwar M, Singh R, Sah SK, Chand S. Insights into medication-induced liver injury: Understanding and management strategies. Toxicol Rep 2025; 14:101976. [PMID: 40125297 PMCID: PMC11928981 DOI: 10.1016/j.toxrep.2025.101976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/10/2025] [Accepted: 02/23/2025] [Indexed: 03/25/2025] Open
Abstract
Drug-induced liver injury (DILI) has increasingly become a major concern in Western countries since the late 1960s, with an estimated annual incidence of 13.9-19.1 cases per 100,000 people. DILI is a significant cause of acute liver failure, exhibiting a high mortality rate of 10-50 %. Its etiology includes medications, herbal products, and dietary supplements, exacerbated by pre-existing liver conditions, sonorities, pregnancy, and nutritional deficiencies. It is categorized into intrinsic and idiosyncratic reactions. Intrinsic DILI, dose-dependent and predictable, is primarily caused by substances like paracetamol, which leads to liver toxicity through direct metabolic pathways. In contrast, idiosyncratic DILI is less common, unpredictable, and affects susceptible individuals, with non-steroidal anti-inflammatory drugs, antibiotics, and cardiovascular agents frequently implicated in hospitals. Oxidative stress, mitochondrial dysfunction, bile salt export inhibition, and stress on the endoplasmic reticulum are some DILI-related pathophysiology. Diagnosis relies on biochemical tests, serological markers, radiological investigations, and liver biopsy. Management strategies emphasize the identification and cessation of the offending drugs, supportive care, and specific treatment options targeted to the culprit drugs. Management depends on the severity and nature of the injury.
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Affiliation(s)
- Vatsalya Tiwari
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Shrishti Shandily
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Jessielina Albert
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Vaibhav Mishra
- Amity Institute of Pharmacy, Amity University Uttar Pradesh, Noida, India
| | - Manoj Dikkatwar
- DY Patil University School of Pharmacy, DY Patil (Deemed to be University), Nerul, Navi Mumbai, Maharashtra 400706, India
| | - Rohit Singh
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
| | - Sujit Kumar Sah
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
| | - Sharad Chand
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, Maharashtra 411038, India
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Devarbhavi HC, Andrade RJ. Natural History of Idiosyncratic Drug-Induced Liver Injury and Prognostic Models. Liver Int 2025; 45:e70138. [PMID: 40364729 DOI: 10.1111/liv.70138] [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: 02/25/2025] [Revised: 04/26/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND AND AIMS Drug-induced liver injury (DILI) remains a leading cause of acute liver failure worldwide. Drugs such as isoniazid, alone or in combination with other anti-tuberculosis drugs, as well as a growing number of herbal and complementary medicines, have been implicated in most cases of acute liver failure in registry studies. METHODS This review summarizes current knowdledge on the acute and chronic outcomes in patients with idiosyncratic DILI and discusses several of the existing prognostic models. RESULTS AND CONCLUSIONS The reasons why some individuals progress from DILI to end-stage liver disease are still largely unknown. However, collaborative efforts over the past few decades have provided figures on the relative incidence of drug-induced acute liver failure and allowed the development of prognostic models to predict this worse outcome at the onset of the event. The outcome of chronic DILI is less well characterised due to the lack of sufficient follow-up in cohort studies, but several phenotypes of DILI can progress to chronicity, and specific drugs such as nitrofurantoin or amiodarone are classic examples of agents leading to chronic forms of DILI. Therapy for drug-induced acute liver failure and chronic DILI is mainly supportive, although some randomised clinical trials have shown beneficial effects of N-acetylcysteine and corticosteroids.
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Affiliation(s)
- Harshad C Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga. IBIMA-Plataforma BIONAND, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, (CIBERehd), Malaga, Spain
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4
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Kato C, Ito Y, Mori Y, Ito K, Fukumitsu K, Fukuda S, Kanemitsu Y, Uemura T, Tajiri T, Ohkubo H, Oguri T, Nakamura A, Niimi A. Risk Factors for Liver Injury and Their Association with Treatment in Hospitalized Patients with COVID-19. Intern Med 2025; 64:1510-1516. [PMID: 40090724 DOI: 10.2169/internalmedicine.4705-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/18/2025] Open
Abstract
Objective This study investigated the frequency and risk factors of acute liver injury (ALI) and the association between ALI and treatment in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods This was a single-center retrospective study of 631 hospitalized patients ≥18 years old who were diagnosed with COVID-19 and received treatment between July 1, 2020, and January 31, 2024. Demographic and clinical data were extracted from the electronic medical records. ALI was defined according to the consensus guidelines of the Asia Pacific Association of the Study of Liver. Patients were divided into two groups according to the presence of ALI to assess the risk factors for the occurrence of ALI. Results Seventy-six patients (12.0%) developed ALI. Seven patients discontinued remdesivir owing to hepatic impairment, and only 1 patient (0.2%) had an increase in alanine aminotransferase (ALT) ≥10 times the upper limit of normal. ALI was associated with men [odds ratio (OR)=3.052, 95% confidence interval (CI)=1.456-6.398], a higher World Health Organization (WHO) ordinal scale score at admission (OR=1.408, 95% CI=1.036-1.912), higher ALT level at admission (OR=1.017, 95% CI=1.009-1.024), tocilizumab administration (OR=2.788, 95% CI=1.372-5.666), the absence of diabetes (OR=0.456, 95% CI=0.226-0.922) and the absence of dyslipidemia (OR=0.244, 95% CI=0.083-0.723). In the comparison of the propensity score-matched groups, neither remdesivir nor tocilizumab administration was associated with ALI. Conclusion Men, severe COVID-19, and elevated ALT levels at admission were significantly associated with an increased risk of ALI in patients treated for COVID-19. ALI may have been associated with tocilizumab administration but not with remdesivir administration.
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Affiliation(s)
- Chihiro Kato
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Yutaka Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Yuta Mori
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Keima Ito
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Kensuke Fukumitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Satoshi Fukuda
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Yoshihiro Kanemitsu
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Takehiro Uemura
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Tomoko Tajiri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Hirotsugu Ohkubo
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Tetsuya Oguri
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
| | - Atsushi Nakamura
- Division of Infection Prevention and Control, Nagoya City University Hospital, Japan
| | - Akio Niimi
- Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences and Medical School, Japan
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Wang Y, Ye L, Yan R, Zhou H, Zhao G. Ilex asprella polysaccharides alleviate liver injury via antioxidative, anti-inflammatory, and gut microbiota modulating effect. Int J Biol Macromol 2025; 306:142024. [PMID: 40081689 DOI: 10.1016/j.ijbiomac.2025.142024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 02/24/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
Ilex asprella, a valued plant traditionally used as food and medicine, is recognized for its effect on liver protection. Polysaccharides, as the key active components in Ilex asprella (IAP), its biological activities are still unexplored. Therefore, this study investigated the preventive effects of IAP on liver injury in vivo. H&E and TUNEL staining revealed IAP could ameliorate the histomorphology changes and liver apoptosis. For antioxidant ability, IAP preconditioning released D-GalN/LPS-induced oxidative stress via Nrf2/HO-1 signaling pathway in liver, as evidenced by increasing superoxide dismutase, total antioxidant capacity, glutathione peroxidase, and inhibiting the activation of Nrf2 and HO-1. Furthermore, IAP reduced the expression of IL-6, IL-1β and TNF-α, showing good anti-inflammatory effects. According to the results from western blot, the phosphorylation of TLR4, p65, IκB, p38, ERK, and JNK were effectively inhibited with IAP pre-treatment, indicating IAP can ameliorate the liver inflammation through TLR4/NF-κB and MAPK signaling pathway. 16S RNA sequencing revealed IAP re-regulated composition of gut microbiota, including inhibiting the harmful bacteria (Parasutterella and Erysipelatoclostridium) enrichment and restoring the probiotics (Lactobacillus, Dubosiella and Bacteroide). In conclusion, this study revealed IAP can improve liver injury by inhibiting liver oxidative stress, releasing inflammation and modulating the gut microbiota.
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Affiliation(s)
- Yao Wang
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, China
| | - Lijing Ye
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, China
| | - Ruikun Yan
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, China
| | - Haibo Zhou
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, China.
| | - Guojun Zhao
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, China.
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6
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Fan M, Xu Y, Wu B, Long J, Liu C, Liang Z, Zhang R, Liu Z, Wang C. Geniposidic Acid Targeting FXR "S332 and H447" Mediated Conformational Change to Upregulate CYPs and miR-19a-3p to Ameliorate Drug-Induced Liver Injury. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2409107. [PMID: 39998442 PMCID: PMC12005789 DOI: 10.1002/advs.202409107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 01/03/2025] [Indexed: 02/26/2025]
Abstract
Drug-induced liver injury (DILI), caused by chemical drugs and traditional Chinese medicine, often leads to severe outcomes like liver failure due to a lack of early detection markers. Farnesoid X receptor (FXR), a key regulator of bile acid (BA) and cholesterol metabolism, is a potential therapeutic target. This study investigates the pathogenesis, markers, and treatment strategies for DILI, focusing on the hepatoprotective effects of geniposidic acid (GPA) from Gardenia jasminoides J. Ellis. Using cellular and animal models of acute and chronic DILI induced by acetaminophen and triptolide, we explored GPA's mechanisms in BA and cholesterol metabolism. Lipidomic and BA analyses revealed that GPA alleviates DILI by enhancing bile acid synthesis and transport via FXR activation. Experiments using AAV-shFXR, Fxr- / - mice and molecular assays demonstrated that GPA targets Ser332 and His447 on FXR ligand-binding domain, promoting FXR nuclear translocation and initiating cytochrome P450 proteins (CYPs) transcriptional activation for BA metabolism. Additionally, miRNA sequencing and RNA-pulldown assays showed that GPA-activated FXR upregulates miR-19a-3p, binding to LXR 3'UTR to inhibit cholesterol production. These findings reveal the GPA-FXR "structure-target" relationship, highlighting a dual mechanism in which GPA promotes CYPs-mediated bile acid metabolism and miR-19a-3p-mediated cholesterol synthesis inhibition, providing a basis for FXR-targeted DILI therapies.
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Affiliation(s)
- Minqi Fan
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Yuanhang Xu
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Bingxin Wu
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Jiachan Long
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Caihong Liu
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Zuhui Liang
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Rong Zhang
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Zhongqiu Liu
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
| | - Caiyan Wang
- State Key Laboratory of Traditional Chinese Medicine SyndromeInternational Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou510006China
- Chinese Medicine Guangdong LaboratoryHengqinGuangdongChina
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7
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Kleiner DE. Role of liver biopsy in the management of idiosyncratic DILI. Liver Int 2025; 45:e16097. [PMID: 39254214 PMCID: PMC11815619 DOI: 10.1111/liv.16097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/12/2024] [Accepted: 08/23/2024] [Indexed: 09/11/2024]
Abstract
Drug-induced liver injury (DILI) presents unique challenges in clinical practice. While some types of DILI are mild and resolve quickly after removing the drug, other situations are more complex, with competing aetiologies or underlying liver disease. Guidelines from professional societies agree that the liver biopsy retains a role in understanding and managing DILI in certain situations. Liver biopsy allows characterization of the histological pattern of injury as well as assessment of severity. Inflammatory infiltrates, bile duct injury or loss and vascular injury are all revealed by liver biopsy. Communication between the hepatopathologist and clinical team with clinicopathological correlation of the findings is necessary for the best determination of causality and differentiation from other diseases of exclusion, like autoimmune hepatitis and graft-versus-host disease. This review highlights important aspects of the role of liver biopsy in DILI evaluation.
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Affiliation(s)
- David E. Kleiner
- Chief Post‐Mortem Section, Laboratory of PathologyNational Cancer InstituteBethesdaMarylandUSA
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8
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García‐Cortés M, Matilla‐Cabello G, Lucena MI. Methods for causality assessment of idiosyncratic drug-induced liver injury. Liver Int 2025; 45:e16083. [PMID: 39166347 PMCID: PMC11815608 DOI: 10.1111/liv.16083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/22/2024]
Abstract
The diagnosis of idiosyncratic drug-induced liver injury (DILI) is a challenging task due to the lack of specific features or definitive diagnostic tools. A minimum of clinical and pharmacological information is required, together with laboratory and imaging tests to exclude other causes of liver injury. Several standardized methods have been developed to support clinical judgement and establish causality assessment, the most widely used being the Roussel Uclaf Causality Assessment Method-RUCAM-and structured Expert Opinion. More recently, an evidence-based, revised RUCAM, Electronic Causality Assessment Method-RECAM-has been developed and, although still a work in progress, may replace RUCAM scoring in the future. International collaborative networks and ongoing research efforts are key to advancing biomarker qualification and validation and developing new in vitro patient-based methods that will help improve DILI diagnosis and move towards a personalized medicine approach.
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Affiliation(s)
- Miren García‐Cortés
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina‐IBIMA, Plataforma BIONANDUniversidad de MálagaMálagaSpain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Gonzalo Matilla‐Cabello
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina‐IBIMA, Plataforma BIONANDUniversidad de MálagaMálagaSpain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - M. Isabel Lucena
- Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina‐IBIMA, Plataforma BIONANDUniversidad de MálagaMálagaSpain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
- Plataforma del ISCIII para la Investigación Clínica, UICEC‐IBIMA, SCReNMadridSpain
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9
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Bessone F, Hillotte GL, Tamagnone N, Arnedillo D, Roma MG. Ursodeoxycholic Acid for the Management of Drug-induced Liver Injury: Role of Hepatoprotective and Anti-cholestatic Mechanisms. J Clin Transl Hepatol 2025; 13:162-168. [PMID: 39917470 PMCID: PMC11797819 DOI: 10.14218/jcth.2024.00325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 12/17/2024] [Accepted: 01/03/2025] [Indexed: 02/09/2025] Open
Abstract
Drug-induced liver injury (DILI) is a harmful reaction to medications, herbs, and dietary supplements that results in liver dysfunction. Based on the distinct clinical patterns of liver damage, DILI can be categorized into hepatocellular, cholestatic, and mixed types. Hepatocellular DILI is linked to inflammation, apoptosis, and necrosis, while cholestatic DILI is commonly associated with bile plugs and, in rare cases, ductopenia. Ursodeoxycholic acid (UDCA) is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies of diverse etiologies and has been mainly used as a supportive treatment in cholestatic DILI. In this review, we presented a more structured and systematic framework for the potential application of this hepatoprotective agent across a broader range of DILI scenarios. A MEDLINE search of the literature from 1995 to the present retrieved 41 preliminary clinical studies suggesting that UDCA may offer curative and preventive benefits for hepatocellular DILI as well. This aligns with preclinical studies in rodents, showing beneficial effects of UDCA in experimental DILI irrespective of the clinical patterns of injury involved. This could be due to the broad range of potentially beneficial effects of UDCA, which may address the various types of liver damage with different causes and mechanisms seen in all forms of DILI. UDCA's beneficial properties include anticholestatic, antioxidant, anti-inflammatory, anti-apoptotic, anti-necrotic, mitochondrial protective, endoplasmic reticulum stress-relieving, and immunomodulatory effects. Controlled studies with systematic use of standardized causality assessments are eagerly awaited to properly validate the use of UDCA in DILI. Meanwhile, we hope this article helps clarify and systematize the use of this versatile and safe hepatoprotective medication for different types of liver toxicity.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Geraldine L. Hillotte
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Norberto Tamagnone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Daiana Arnedillo
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Marcelo G. Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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10
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Zhang F, Song L, Lin Y, Yang Z, Shi J, Yuan Q, Zhang Y. Smart Persistent Luminescence Imaging for Early Diagnosis of Drug-Induced Liver Injury. CHEMICAL & BIOMEDICAL IMAGING 2025; 3:77-84. [PMID: 40018649 PMCID: PMC11863150 DOI: 10.1021/cbmi.4c00056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 03/01/2025]
Abstract
Drug-induced liver injury (DILI) has the potential to cause severe hepatitis and increases the risk of death which remains unresolved in current medical practice. During DILI, the H2O2 level is upregulated in the liver. Conventional blood tests fail to offer early and real-time visualization of DILI in vivo. Here we report a smart persistent luminescent approach to evaluate DILI in vivo using persistent luminescence nanoprobes which are conjugated with single-stranded DNA containing Ferrocene (Fc). Upon injection, these nanoprobes mainly accumulate in the liver and the persistent luminescence of nanoprobes remains suppressed owing to energy transfer to the ferrocene. The presence of H2O2 during DILI initiates the Fenton reaction to induce cleavage of DNA chains, and the ferrocene dissociates from the probes, leading to fast restoration of the persistent luminescence. The DILI imaging results revealed a signal-to-noise ratio of 20.9, approximately 10 h earlier than the serum-based detection methods. With its exceptional sensitivity, high signal-to-noise ratio, and real-time imaging capabilities, this smart persistent luminescent approach holds great promise for the early diagnosis of DILI.
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Affiliation(s)
- Feng Zhang
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Liang Song
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- Fujian
Science and Technology Innovation Laboratory for Optoelectronic Information
of China, Fuzhou 350108, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Ye Lin
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Zhengxia Yang
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Junpeng Shi
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Quan Yuan
- College
of Chemistry and Molecular Sciences, Key Laboratory of Biomedical
Polymers of Ministry of Education, Institute of Molecular Medicine, Renmin Hospital of Wuhan University, School of Microelectronics,
Wuhan University, Wuhan 430072, P. R.
China
- Molecular
Science and Biomedicine Laboratory (MBL), State Key Laboratory of
Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, P. R. China
| | - Yun Zhang
- State
Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou, Fujian 350002, P. R. China
- Xiamen
Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute,
Chinese Academy of Sciences, Xiamen, Fujian 361021, P. R. China
- Fujian
Science and Technology Innovation Laboratory for Optoelectronic Information
of China, Fuzhou 350108, P. R. China
- University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
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11
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Choudhury A, Kulkarni AV, Arora V, Soin AS, Dokmeci AK, Chowdhury A, Koshy A, Duseja A, Kumar A, Mishra AK, Patwa AK, Sood A, Roy A, Shukla A, Chan A, Krag A, Mukund A, Mandot A, Goel A, Butt AS, Sahney A, Shrestha A, Cárdenas A, Di Giorgio A, Arora A, Anand AC, Dhawan A, Jindal A, Saraya A, Srivastava A, Kumar A, Kaewdech A, Pande A, Rastogi A, Valsan A, Goel A, Kumar A, Singal AK, Tanaka A, Coilly A, Singh A, Meena BL, Jagadisan B, Sharma BC, Lal BB, Eapen CE, Yaghi C, Kedarisetty CK, Kim CW, Panackel C, Yu C, Kalal CR, Bihari C, Huang CH, Vasishtha C, Jansen C, Strassburg C, Lin CY, Karvellas CJ, Lesmana CRA, Philips CA, Shawcross D, Kapoor D, Agrawal D, Payawal DA, Praharaj DL, Jothimani D, Song DS, Kim DJ, Kim DS, Zhongping D, Karim F, Durand F, Shiha GE, D’Amico G, Lau GK, Pati GK, Narro GEC, Lee GH, Adali G, Dhakal GP, Szabo G, Lin HC, Li H, Nair HK, Devarbhavi H, Tevethia H, Ghazinian H, Ilango H, Yu HL, Hasan I, Fernandez J, George J, Behari J, Fung J, Bajaj J, Benjamin J, Lai JC, Jia J, Hu JH, et alChoudhury A, Kulkarni AV, Arora V, Soin AS, Dokmeci AK, Chowdhury A, Koshy A, Duseja A, Kumar A, Mishra AK, Patwa AK, Sood A, Roy A, Shukla A, Chan A, Krag A, Mukund A, Mandot A, Goel A, Butt AS, Sahney A, Shrestha A, Cárdenas A, Di Giorgio A, Arora A, Anand AC, Dhawan A, Jindal A, Saraya A, Srivastava A, Kumar A, Kaewdech A, Pande A, Rastogi A, Valsan A, Goel A, Kumar A, Singal AK, Tanaka A, Coilly A, Singh A, Meena BL, Jagadisan B, Sharma BC, Lal BB, Eapen CE, Yaghi C, Kedarisetty CK, Kim CW, Panackel C, Yu C, Kalal CR, Bihari C, Huang CH, Vasishtha C, Jansen C, Strassburg C, Lin CY, Karvellas CJ, Lesmana CRA, Philips CA, Shawcross D, Kapoor D, Agrawal D, Payawal DA, Praharaj DL, Jothimani D, Song DS, Kim DJ, Kim DS, Zhongping D, Karim F, Durand F, Shiha GE, D’Amico G, Lau GK, Pati GK, Narro GEC, Lee GH, Adali G, Dhakal GP, Szabo G, Lin HC, Li H, Nair HK, Devarbhavi H, Tevethia H, Ghazinian H, Ilango H, Yu HL, Hasan I, Fernandez J, George J, Behari J, Fung J, Bajaj J, Benjamin J, Lai JC, Jia J, Hu JH, Chen JJ, Hou JL, Yang JM, Chang J, Trebicka J, Kalf JC, Sollano JD, Varghese J, Arab JP, Li J, Reddy KR, Raja K, Panda K, Kajal K, Kumar K, Madan K, Kalista KF, Thanapirom K, Win KM, Suk KT, Devadas K, Lesmana LA, Kamani L, Premkumar M, Niriella MA, Al Mahtab M, Yuen MF, Sayed MHE, Alla M, Wadhawan M, Sharma MK, Sahu M, Prasad M, Muthiah MD, Schulz M, Bajpai M, Reddy MS, Praktiknjo M, Yu ML, Prasad M, Sharma M, Elbasiony M, Eslam M, Azam MG, Rela M, Desai MS, Vij M, Mahmud N, Choudhary NS, Marannan NK, Ormeci N, Saraf N, Verma N, Nakayama N, Kawada N, Oidov Baatarkhuu, Goyal O, Yokosuka O, Rao PN, Angeli P, Parikh P, Kamath PS, Thuluvath PJ, Lingohr P, Ranjan P, Bhangui P, Rathi P, Sakhuja P, Puri P, Ning Q, Dhiman RK, Kumar R, Vijayaraghavan R, Khanna R, Maiwall R, Mohanka R, Moreau R, Gani RA, Loomba R, Mehtani R, Rajaram RB, Hamid SS, Palnitkar S, Lal S, Biswas S, Chirapongsathorn S, Agarwal S, Sachdeva S, Saigal S, Kumar SE, Violeta S, Singh SP, Mochida S, Mukewar S, Alam S, Lim SG, Alam S, Shalimar, Venishetty S, Sundaram SS, Shetty S, Bhatia S, Singh SA, Kottilil S, Strasser S, Shasthry SM, Maung ST, Tan SS, Treeprasertsuk S, Asthana S, Manekeller S, Gupta S, Acharya SK, K.C. S, Maharshi S, Asrani S, Dadhich S, Taneja S, Giri S, Singh S, Chen T, Gupta T, Kanda T, Tanwandee T, Piratvishuth T, Spengler U, Prasad VGM, Midha V, Rakhmetova V, Arroyo V, Sood V, BR VK, Wong VWS, Pamecha V, Singh V, Dayal VM, Saraswat VA, Kim WR, Jafri W, Gu W, Jun WY, Qi X, Chawla YK, Kim YJ, Shi Y, Abbas Z, Kumar G, Shiina S, Wei L, Omata M, Sarin SK. Acute-on-chronic liver failure (ACLF): the ‘Kyoto Consensus’—steps from Asia. Hepatol Int 2025; 19:1-69. [DOI: https:/doi.org/10.1007/s12072-024-10773-4] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/29/2024] [Indexed: 04/16/2025]
Abstract
Abstract
Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the “APASL ACLF Research Consortium (AARC)” was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia–Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the ‘Golden Therapeutic Window’, the ‘transplant window’, and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The ‘Kyoto APASL Consensus’ presented below carries the final recommendations along with the relevant background information and areas requiring future studies.
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12
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Rahimi K, Rezaie A, Allahverdi Y, Shahriari P, Taheri Mirghaed M. The effects of alpha-pinene against paracetamol-induced liver damage in male rats. Physiol Rep 2025; 13:e70227. [PMID: 39903586 PMCID: PMC11793005 DOI: 10.14814/phy2.70227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/20/2025] [Accepted: 01/20/2025] [Indexed: 02/06/2025] Open
Abstract
This study aims to evaluate the hepatoprotective effect of alpha-pinene against N-acetyl-p-aminophenol, paracetamol, (APA)-induced liver damage in rats. Thirty Wistar rats were divided into five groups (n = 6): Group 1: Normal (control). Group 2: APA 640 mg/kg. Group 3: alpha-pinene 50 mg/kg (APA+ αPi 50 mg/kg). Group 4: alpha-pinene 100 mg/kg (APA+ αPi 100 mg/kg). Group 5: silymarin 50 mg/kg (APA+ SIL). Alpha-pinene or silymarin was orally administered after APA administration for 14 consecutive days. This study investigated liver damage by preparing pathology slides from liver tissue. Levels of AST, ALT, ALP, total bilirubin, total antioxidant capacity (TAC), and total oxidant status (TOS) were measured. Inflammatory factors, including NF-kB gene expression and levels of IL-6 and TNF-a, were also measured. Administering alpha-pinene with APA can prevent liver damage induced by APA. Alpha-pinene can enhance TAC while reducing TOS, ALT, AST, ALP, and total bilirubin. Moreover, the results have also revealed that alpha-pinene decreases NF-kB expression, which leads to a reduction in IL-6 and TNF-a levels. It appears that alpha-pinene induces liver protective effects against APA damage by reducing the activity of liver enzymes, improving antioxidant/oxidative status, and reducing inflammation through the regulation of NF-kB and pro-inflammatory cytokines.
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Affiliation(s)
- Kaveh Rahimi
- Department of Basic Sciences, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Anahita Rezaie
- Department of Pathobiology, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Younes Allahverdi
- Department of Basic Sciences, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Parham Shahriari
- Department of Basic Sciences, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Mahtab Taheri Mirghaed
- Department of Basic Sciences, Faculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
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13
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Gopalakrishna H, Chalasani N. Drug-induced liver injury due to first-line antituberculosis medications in India: A major hindrance to achieve the goal of tuberculosis elimination. Indian J Gastroenterol 2025; 44:4-7. [PMID: 39225935 DOI: 10.1007/s12664-024-01674-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Affiliation(s)
- Harish Gopalakrishna
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA.
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14
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Choudhury A, Kulkarni AV, Arora V, Soin AS, Dokmeci AK, Chowdhury A, Koshy A, Duseja A, Kumar A, Mishra AK, Patwa AK, Sood A, Roy A, Shukla A, Chan A, Krag A, Mukund A, Mandot A, Goel A, Butt AS, Sahney A, Shrestha A, Cárdenas A, Di Giorgio A, Arora A, Anand AC, Dhawan A, Jindal A, Saraya A, Srivastava A, Kumar A, Kaewdech A, Pande A, Rastogi A, Valsan A, Goel A, Kumar A, Singal AK, Tanaka A, Coilly A, Singh A, Meena BL, Jagadisan B, Sharma BC, Lal BB, Eapen CE, Yaghi C, Kedarisetty CK, Kim CW, Panackel C, Yu C, Kalal CR, Bihari C, Huang CH, Vasishtha C, Jansen C, Strassburg C, Lin CY, Karvellas CJ, Lesmana CRA, Philips CA, Shawcross D, Kapoor D, Agrawal D, Payawal DA, Praharaj DL, Jothimani D, Song DS, Kim DJ, Kim DS, Zhongping D, Karim F, Durand F, Shiha GE, D'Amico G, Lau GK, Pati GK, Narro GEC, Lee GH, Adali G, Dhakal GP, Szabo G, Lin HC, Li H, Nair HK, Devarbhavi H, Tevethia H, Ghazinian H, Ilango H, Yu HL, Hasan I, Fernandez J, George J, Behari J, Fung J, Bajaj J, Benjamin J, Lai JC, Jia J, Hu JH, et alChoudhury A, Kulkarni AV, Arora V, Soin AS, Dokmeci AK, Chowdhury A, Koshy A, Duseja A, Kumar A, Mishra AK, Patwa AK, Sood A, Roy A, Shukla A, Chan A, Krag A, Mukund A, Mandot A, Goel A, Butt AS, Sahney A, Shrestha A, Cárdenas A, Di Giorgio A, Arora A, Anand AC, Dhawan A, Jindal A, Saraya A, Srivastava A, Kumar A, Kaewdech A, Pande A, Rastogi A, Valsan A, Goel A, Kumar A, Singal AK, Tanaka A, Coilly A, Singh A, Meena BL, Jagadisan B, Sharma BC, Lal BB, Eapen CE, Yaghi C, Kedarisetty CK, Kim CW, Panackel C, Yu C, Kalal CR, Bihari C, Huang CH, Vasishtha C, Jansen C, Strassburg C, Lin CY, Karvellas CJ, Lesmana CRA, Philips CA, Shawcross D, Kapoor D, Agrawal D, Payawal DA, Praharaj DL, Jothimani D, Song DS, Kim DJ, Kim DS, Zhongping D, Karim F, Durand F, Shiha GE, D'Amico G, Lau GK, Pati GK, Narro GEC, Lee GH, Adali G, Dhakal GP, Szabo G, Lin HC, Li H, Nair HK, Devarbhavi H, Tevethia H, Ghazinian H, Ilango H, Yu HL, Hasan I, Fernandez J, George J, Behari J, Fung J, Bajaj J, Benjamin J, Lai JC, Jia J, Hu JH, Chen JJ, Hou JL, Yang JM, Chang J, Trebicka J, Kalf JC, Sollano JD, Varghese J, Arab JP, Li J, Reddy KR, Raja K, Panda K, Kajal K, Kumar K, Madan K, Kalista KF, Thanapirom K, Win KM, Suk KT, Devadas K, Lesmana LA, Kamani L, Premkumar M, Niriella MA, Al Mahtab M, Yuen MF, Sayed MHE, Alla M, Wadhawan M, Sharma MK, Sahu M, Prasad M, Muthiah MD, Schulz M, Bajpai M, Reddy MS, Praktiknjo M, Yu ML, Prasad M, Sharma M, Elbasiony M, Eslam M, Azam MG, Rela M, Desai MS, Vij M, Mahmud N, Choudhary NS, Marannan NK, Ormeci N, Saraf N, Verma N, Nakayama N, Kawada N, Oidov Baatarkhuu, Goyal O, Yokosuka O, Rao PN, Angeli P, Parikh P, Kamath PS, Thuluvath PJ, Lingohr P, Ranjan P, Bhangui P, Rathi P, Sakhuja P, Puri P, Ning Q, Dhiman RK, Kumar R, Vijayaraghavan R, Khanna R, Maiwall R, Mohanka R, Moreau R, Gani RA, Loomba R, Mehtani R, Rajaram RB, Hamid SS, Palnitkar S, Lal S, Biswas S, Chirapongsathorn S, Agarwal S, Sachdeva S, Saigal S, Kumar SE, Violeta S, Singh SP, Mochida S, Mukewar S, Alam S, Lim SG, Alam S, Shalimar, Venishetty S, Sundaram SS, Shetty S, Bhatia S, Singh SA, Kottilil S, Strasser S, Shasthry SM, Maung ST, Tan SS, Treeprasertsuk S, Asthana S, Manekeller S, Gupta S, Acharya SK, K C S, Maharshi S, Asrani S, Dadhich S, Taneja S, Giri S, Singh S, Chen T, Gupta T, Kanda T, Tanwandee T, Piratvishuth T, Spengler U, Prasad VGM, Midha V, Rakhmetova V, Arroyo V, Sood V, Br VK, Wong VWS, Pamecha V, Singh V, Dayal VM, Saraswat VA, Kim WR, Jafri W, Gu W, Jun WY, Qi X, Chawla YK, Kim YJ, Shi Y, Abbas Z, Kumar G, Shiina S, Wei L, Omata M, Sarin SK. Acute-on-chronic liver failure (ACLF): the 'Kyoto Consensus'-steps from Asia. Hepatol Int 2025; 19:1-69. [PMID: 39961976 PMCID: PMC11846769 DOI: 10.1007/s12072-024-10773-4] [Show More Authors] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 12/29/2024] [Indexed: 02/23/2025]
Abstract
Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.
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Affiliation(s)
- Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Vinod Arora
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - A S Soin
- Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | | | - Abhijeet Chowdhury
- Institute of Post-Graduate Medical Education and Research (IPGMER), Kolkata, West Bengal, India
| | - Abraham Koshy
- VPS Lakeshore Hospital and Research Center Ltd, Kochi, Kerala, India
| | - Ajay Duseja
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Ajay Kumar
- Govind Ballabh Pant Hospital, New Delhi, India
| | - Ajay Kumar Mishra
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | | | - Ajit Sood
- Dayanand Medical College, Ludhiana, India
| | - Akash Roy
- Apollo Multispeciality Hospital, Kolkata, India
| | - Akash Shukla
- Seth G S Medical College and K E M Hospital, Mumbai, Maharashtra, India
- Sir HN Reliance Foundation Hospital, Girgaon, Mumbai, Maharashtra, India
| | - Albert Chan
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Amar Mukund
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Amit Goel
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | | | | | | | - Andrés Cárdenas
- Univerity of Barcelona Institut d'Investigacions Biomèdiques August Pi-Sunyer, Barcelona, Spain
| | | | - Anil Arora
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Anil Chandra Anand
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | | | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Anoop Saraya
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Anshu Srivastava
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Anupam Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Apurva Pande
- Fortis Hospital, Greater Noida, Uttar Pradesh, India
| | - Archana Rastogi
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Arun Valsan
- Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, India
| | - Ashish Goel
- Christian Medical College (CMC), Vellore, India
| | - Ashish Kumar
- Sir Ganga Ram Hospital, Rajender Nagar, New Delhi, India
| | - Ashwani K Singal
- University of Louisville School of Medicine, Trager Transplant Center and Jewish Hospital, Louisville, KY, USA
| | | | - Audrey Coilly
- Centre Hepato-Biliaire, Paul Brousse Hospital, Paris-Saclay University, Villejuif, France
| | - Ayaskanta Singh
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Babu Lal Meena
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Bikrant Bihari Lal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - C E Eapen
- Christian Medical College (CMC), Vellore, India
| | - Cesar Yaghi
- Saint Joseph University, Hôtel-Dieu de France University Medical Center, Beirut, Lebanon
| | | | | | | | - Chen Yu
- Capital Medical University, Beijing, China
| | - Chetan R Kalal
- Nanavati Max Super Specialty Hospital, Mumbai, Maharashtra, India
| | - Chhagan Bihari
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Chitranshu Vasishtha
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Christian Jansen
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | - Chun Yen Lin
- Linkou Medical Centre, Chang Gung Memorial Hospital, Keelung, Taiwan
| | | | - Cosmas Rinaldi Adithya Lesmana
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
- Medistra Hospital, Jakarta, Indonesia
| | | | | | | | | | | | | | | | | | | | - Dong-Sik Kim
- Korea University College of Medicine, Seoul, Republic of Korea
| | | | - Fazal Karim
- Sir Salimullah Medical College, Mitford Hospital, Dhaka, Bangladesh
| | - Francois Durand
- Université de Paris, AP-HP, C, DMU DIGEST, Centre de Référence Des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de Recherche Sur L'inflammation, Inserm, Paris, France
| | | | - Gennaro D'Amico
- Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
- Clinica La Maddalena, Palermo, Italy
| | - George K Lau
- Humanity and Health Medical Center, Hongkong, SAR, China
| | | | - Graciela Elia Castro Narro
- Hospital Médica Sur, Mexico City, Mexico
- Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubiran",, Mexico City, Mexico
- Latin-American Association for the Study of the Liver (ALEH), Santiago de Chile, Chile
| | - Guan-Huei Lee
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Gupse Adali
- University of Health Sciences, Ümraniye, Istanbul, Turkey
| | | | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - H C Lin
- Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hai Li
- School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Hari Kumar Nair
- Ernakulam Medical Center (EMC), Kinder Multispeciality Hospital, Kochi, Kerala, India
| | | | - Harshvardhan Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | | | - Irsan Hasan
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - J Fernandez
- University of Barcelona, IDIBAPS and CIBEREHD, Barcelona, Spain
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Jaideep Behari
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - James Fung
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Jaya Benjamin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Jennifer C Lai
- University of California, San Francisco, San Francisco, CA, USA
| | - Jidong Jia
- Capital Medical University, Beijing, China
| | - Jin Hua Hu
- The Fifth Medical Center of Chinese, PLA General Hospital, Beijing, China
| | - Jin Jun Chen
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jin Lin Hou
- Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Jin Mo Yang
- The Catholic University of Korea, Seoul, Korea
| | - Johannes Chang
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jonel Trebicka
- Medizinische Klinik B, Universitätsklinikum Münster, Münster, Germany
| | - Jörg C Kalf
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jose D Sollano
- Department of Medicine, Cardinal Santos Medical Center, Manila, Philippines
| | - Joy Varghese
- Gleneagles Global Hospital, Chennai, Tamil Nadu, India
| | - Juan Pablo Arab
- Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Schulich School of Medicine, Western University, London, ON, Canada
| | - Jun Li
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | | | - Kaiser Raja
- King's College Hospital London, Dubai, United Arab Emirates
| | - Kalpana Panda
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Kamal Kajal
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Karan Kumar
- Mahatma Gandhi Medical College, Jaipur, Rajasthan, India
| | - Kaushal Madan
- Max Super Specialty Hospital Saket, New Delhi, India
| | - Kemal Fariz Kalista
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | | | - Khin Maung Win
- University of Medicine, Yangon Ministry of Health, Yangon, Myanmar
| | - Ki Tae Suk
- Hallym University, Chuncheon, Republic of Korea
| | | | | | - Lubna Kamani
- Liaquat National Hospital, Karachi, Sindh, Pakistan
| | - Madhumita Premkumar
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Mamun Al Mahtab
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Man Fung Yuen
- Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | | | - Manasa Alla
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | | | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Manoj Sahu
- IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India
| | - Manya Prasad
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Mark Dhinesh Muthiah
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Martin Schulz
- Goethe University Clinic Frankfurt, Frankfurt, Germany
| | - Meenu Bajpai
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | | | - Ming Lung Yu
- Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- College of Medicine, National Sun Yet-Sen University, Kaohsiung, Taiwan
| | | | - Mithun Sharma
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | | | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia
| | - Mohd Golam Azam
- Endocrine and Metabolic Disorder (BIRDEM) Shahbad, Bangladesh Institute of Research and Rehabilitation in Diabetes, Dhaka, Bangladesh
| | - Mohd Rela
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Moreshwar S Desai
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Mukul Vij
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Nadim Mahmud
- University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Necati Ormeci
- İstanbul Health and Technology University, Istanbul, Turkey
| | - Neeraj Saraf
- Medanta-The Medicity Hospital, Gurugram, Haryana, India
| | - Nipun Verma
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Norifumi Kawada
- Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Oidov Baatarkhuu
- Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | | | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chuo-Ku, Chiba, Japan
| | - P N Rao
- Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | - Paolo Angeli
- Department of Medicine (DIMED), University of Padova, Padua, Italy
| | | | | | | | - Philipp Lingohr
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Piyush Ranjan
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Pravin Rathi
- Topi Wala National (TN) Medical College and BYL Nair Charitable Hospital, Mumbai, India
| | | | - Puneet Puri
- Virginia Commonwealth University, Richmond, VA, USA
| | - Qin Ning
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - R K Dhiman
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Rahul Kumar
- Changi General Hospital, Singapore, Singapore
| | - Rajan Vijayaraghavan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rajeev Khanna
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Ravi Mohanka
- Sir HN Reliance Foundation Hospital, Girgaon, Mumbai, Maharashtra, India
| | - Richard Moreau
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
- Centre de Recherche Sur L'Inflammation (CRI), INSERM and Université Paris-Cité, Paris, France
- Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Beaujon, Service d'Hépatologie, Clichy, France
| | - Rino Alvani Gani
- Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - Rohit Loomba
- University of California, San Diego, La Jolla, CA, USA
| | - Rohit Mehtani
- Amrita Institute of Medical Sciences and Research Centre, Faridabad, Haryana, India
| | | | - S S Hamid
- Aga Khan University Hospital, Karachi, Pakistan
| | | | - Sadhna Lal
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sagnik Biswas
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Samagra Agarwal
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | - Sanjiv Saigal
- Max Super Specialty Hospital Saket, New Delhi, India
| | | | | | - Satender Pal Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Saurabh Mukewar
- Midas Multispeciality Hospital Pvt. Ltd, Nagpur, Maharashtra, India
| | - Seema Alam
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Seng Gee Lim
- National University Hospital, National University of Singapore, Singapore, Singapore
| | - Shahinul Alam
- Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Shalimar
- All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | | | | | - Shiran Shetty
- Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shobna Bhatia
- National Institute of Medical Sciences, Jaipur, India
| | | | - Shyam Kottilil
- University of Maryland School of Medicine, Baltimore, USA
| | | | - S M Shasthry
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Soek Siam Tan
- Selayang Hospital, University of Malaysia, Batu Caves, Selangor, Malaysia
| | | | | | | | - Subhash Gupta
- Max Super Specialty Hospital Saket, New Delhi, India
| | | | - Sudhamshu K C
- Bir Hospital, National Academy of Medical Sciences, Kathmandu, Nepal
| | - Sudhir Maharshi
- Sawai Man Singh (SMS) Medical College and Hospital, Jaipur, Rajasthan, India
| | - Sumeet Asrani
- Baylor Simmons Transplant Institute, Dallas, TX, USA
| | - Sunil Dadhich
- Dr Sampuranand Medical College (SNMC), Jodhpur, Rajasthan, India
| | - Sunil Taneja
- Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Suprabhat Giri
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | - Surender Singh
- Sanjay Gandhi Post Graduate Institute (SGPGI), Lucknow, Uttar Pradesh, India
| | - Tao Chen
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tarana Gupta
- Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
| | - Tatsuo Kanda
- Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | | | | | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - V G Mohan Prasad
- Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | | | | | - Vicente Arroyo
- European Foundation for the Study of Chronic Liver Failure (EF CLIF), Barcelona, Spain
| | - Vikrant Sood
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Vinay Kumar Br
- Mazumdar Shaw Medical Centre, Bangalore, Karnataka, India
| | | | - Viniyendra Pamecha
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | - Virendra Singh
- Punjab Institute of Liver and Biliary Sciences, Mohali, Punjab, India
| | - Vishwa Mohan Dayal
- Indira Gandhi Institute of Medical Sciences, (IGIMS), Bely Road Patna, Bihar, India
| | | | - WRay Kim
- Stanford University, Stanford, CA, USA
| | - Wasim Jafri
- Aga Khan University Hospital, Karachi, Pakistan
| | - Wenyi Gu
- Goethe University Clinic Frankfurt, Frankfurt, Germany
| | - Wong Yu Jun
- Changi General Hospital, Singapore, Singapore
| | - Xiaolong Qi
- Medical School, Zhongda Hospital, Southeast University, Nanjing, China
| | - Yogesh K Chawla
- Kalinga Institute of Medical Sciences (KIMS), Bhubaneshwar, Orissa, India
| | - Yoon Jun Kim
- Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yu Shi
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zaigham Abbas
- Ziauddin University Hospital Karachi, Karachi, Pakistan
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India
| | | | - Lai Wei
- Changgung Hospital, Tsinghua University, Beijing, China
| | - Masao Omata
- Yamanashi Central Hospital, Yamanashi, Japan
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110070, India.
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15
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Nakakuni M, Nakano K, Inui A, Kobayashi S, Deguchi N, Mitsui S, Kuriyama T, Miyazaki S. Liver function trends in children with suspected drug-induced hepatocellular injury: A survey using an electronic medical records database. Pediatr Int 2025; 67:e15847. [PMID: 39966880 DOI: 10.1111/ped.15847] [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: 02/10/2024] [Revised: 06/05/2024] [Accepted: 08/05/2024] [Indexed: 02/20/2025]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a common adverse drug event with limited pediatric data in the literature. This study aimed to use pediatric electronic medical records to assess hepatocellular DILI in pediatric patients who were prescribed liver-injury-inducing drugs. METHODS The Pediatric Medical Information Collection System (P-MICS) is a centralized database integrating electronic medical records from over 40 medical pediatric centers. Pediatric patients in the P-MICS with serum alanine aminotransferase (ALT) levels five or more times the upper limit of normal and who were below 15 years of age were selected. Those with liver diseases unrelated to drug-induced causes were excluded. We identified drugs prescribed 2 to 90 days before the first elevated ALT reading. High-risk liver-injury-causing drugs were determined based on the LiverTox score. We analyzed post-event ALT and total bilirubin levels (TB) and DILI management. RESULTS Of the 817 patients with suspected DILI, 251 were prescribed four drugs identified as high-risk drugs for hepatocellular DILI: methotrexate (n = 129), aspirin (n = 82), vancomycin (n = 58), and cyclophosphamide (n = 51). The median ALT level at the first event was 245 U/L. Approximately 35% of methotrexate users and cyclophosphamide users experienced recurrent ALT elevation. Some methotrexate users also showed TB elevation. Discontinuation of high-risk drugs resulted in fewer relapses and TB elevations than pharmacotherapy. CONCLUSIONS The P-MICS effectively identifies pediatric patients with potential liver injury and tracks liver function in those prescribed liver-injury-causing drugs. This study underscores liver injury risks in pediatric anticancer drug users, highlighting the utility of the P-MICS in monitoring off-label drug safety in children.
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Affiliation(s)
- Masayoshi Nakakuni
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
- Social Pharmacy and Regulatory Science, Showa Pharmaceutical University, Tokyo, Japan
| | - Kosuke Nakano
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Ayano Inui
- Department Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
| | | | - Naoko Deguchi
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Seiji Mitsui
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Takeshi Kuriyama
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
| | - Seiko Miyazaki
- Center for Clinical Research and Development, National Center for Child Health and Development, Tokyo, Japan
- Social Pharmacy and Regulatory Science, Showa Pharmaceutical University, Tokyo, Japan
- Pharmacoepidemiology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan
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16
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Mao YM, Tang JT, Lu ZH, Shao M, Zhao WF, Zhan J, Huang ZX, Niu QH, Chen L, Chen ZF, Guo CH, Jia ZH, Li H, Liu B, Miao J, Peng ZT, Pu YL, Qu LH, Shen XM, Sun W, Wang HW, Lu XL, Xue JJ, Yang YY, Yang Z, Yang ZH, Zhang QG, Niu T, Zhu WD, Liu XL, Zhong W, Dong YN, Zhi Y, Li XY. Chinese Guideline for the Diagnosis and Management of Drug-Induced Liver Injury in Primary Care (2024). J Dig Dis 2025; 26:2-21. [PMID: 40198161 DOI: 10.1111/1751-2980.13337] [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: 01/15/2025] [Revised: 02/27/2025] [Accepted: 03/09/2025] [Indexed: 04/10/2025]
Abstract
Drug-induced liver injury (DILI) is a drug-induced disease that not only complicates the treatment of the primary disease but may also lead to acute liver failure or even death in severe cases. Drugs commonly used in primary care, such as anti-infective agents and nonsteroidal anti-inflammatory drugs, are major causes of DILI. In addition, a large elderly population, comorbidities, and combination therapy with multiple drugs increase the risk of DILI in primary care. Therefore, primary care providers should proactively screen and monitor high-risk patients to identify potential DILI timely. Currently, diagnosis of DILI relies on the exclusion of liver diseases of other etiologies. Collection of detailed medical history of the patients and careful exclusion of other potential liver injury of other etiologies are crucial for accurate diagnosis. This guideline, developed based on evidence-based medicine from the latest research, aimed to provide primary care providers with professional guidance on the timely identification of suspected DILI cases and standardized diagnosis and management in clinical practice.
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Affiliation(s)
- Yi Min Mao
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
| | - Jie Ting Tang
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
| | - Zhong Hua Lu
- Department of Hepatology, Affiliated Wuxi Fifth Hospital of Jiangnan Univeristy, Wuxi, Jiangsu Province, China
| | - Ming Shao
- Department of Infectious Diseases, Yuncheng Huiren Hospital, Yuncheng, Shanxi Province, China
| | - Wei Feng Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Jun Zhan
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zu Xiong Huang
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Qing Hui Niu
- Department of Hepatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Lin Chen
- Department of Infectious Diseases, Zhuji People's Hospital of Zhejiang Province, Zhuji, Zhejiang Province, China
| | - Zhan Feng Chen
- Department of Infectious Diseases, Shishi General Hospital, Quanzhou, Fujian Province, China
| | - Chun Hui Guo
- Department of Infectious Diseases, Jiangyin People's Hospital, Jiangyin, Jiangsu Province, China
| | - Zi Hui Jia
- Department of Gastroenterology, Gaobeidian Hospital, Baoding, Hebei Province, China
| | - Hai Li
- Department of Gastroenterology, Tianjin Xiqing Hospital, Tianjin, China
| | - Bo Liu
- Department of Gastroenterology, The People's Hospital of Zhangwu, Fuxin, Liaoning Province, China
| | - Jing Miao
- Department of Traditional Chinese Medicine, Tianjin Second People's Hospital, Tianjin, China
| | - Zhong Tian Peng
- Department of Infectious Diseases, The First Affiliated Hospital of University of South China, Hengyang, Hunan Province, China
| | - Yong Lan Pu
- Department of Infectious Diseases, The First People's Hospital of Taicang, Taicang, Jiangsu Province, China
| | - Li Hong Qu
- Department of Infectious Diseases, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Xiao Ming Shen
- Department of Infectious Diseases, Jiaxing No. 2 Hospital, Jiaxing, Zhejiang Province, China
| | - Wei Sun
- Department of Infectious Diseases and Hepatology, People's Hospital of Chongqing Banan District, Chongqing, China
| | - Hong Wu Wang
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiao Lan Lu
- Department of Gastroenterology, Shanghai Pudong Hospital, Shanghai, China
| | - Jian Jun Xue
- Department of Infectious Diseases, People's Hospital of Hongtong County, Linfen, Shanxi Province, China
| | - Ya Yun Yang
- Department of Infectious Diseases, Mengzi People's Hospital, Mengzi, Yunnan Province, China
| | - Zheng Yang
- Department of Infectious Diseases, Jingzhou Central Hospital, Jingzhou, Hebei Province, China
| | - Zhong Hui Yang
- Department of Pharmacy, The First People's Hospital of Taicang, Taicang, Jiangsu Province, China
| | - Qing Ge Zhang
- Department of Hepatology of Integrated Traditional Chinese and Western Medicine, Xingtai People's Hospital, Xingtai, Hebei Province, China
| | - Tao Niu
- Department of Gastroenterology, People's Hospital of Dongxihu District, Wuhan, Hubei Province, China
| | - Wei Dong Zhu
- Department of Infectious Diseases, Changsu No. 2 People's Hospital, Changshu, Jiangsu Province, China
| | - Xiao Lin Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Wei Zhong
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
| | - Yi Nuo Dong
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
| | - Yang Zhi
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
| | - Xiao Yun Li
- Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, China
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17
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Chen S, Cao Y, Fan Z, Xu L, Pan Z, Gao Y, Wei L, Wei Q, Tian Y, Zhang X, Liu M, Ren F. Depressed TFAM promotes acetaminophen-induced hepatotoxicity regulated by DDX3X-PGC1α-NRF2 signaling pathway. Mol Med 2024; 30:246. [PMID: 39701936 DOI: 10.1186/s10020-024-01017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Accepted: 11/28/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Acetaminophen (APAP)-induced acute liver injury (AILI) is the most prevalent cause of acute liver failure and mitochondrial dysfunction plays a dominant role in the pathogenesis of AILI. Mitochondrial transcription factor A (TFAM) is an important marker for maintaining mitochondrial functional homeostasis, but its functions in AILI are unclear. This study aimed to investigate the function of TFAM and its regulatory molecular mechanism in the progression of AILI. METHODS The roles of TFAM and DEAD (Asp-Glu-Ala-Asp) box polypeptide 3 X-linked (DDX3X) in AILI were determined with TFAM overexpression and DDX3X knockdown, respectively. RESULTS TFAM expression was suppressed in AILI patients. TFAM overexpression alleviated liver necrosis and mitochondrial dysfunction. Treatment of the AILI mice model with N-acetylcysteine (NAC), a drug used to treat APAP overdose, resulted in significant TFAM activation. In vivo experiments confirmed that TFAM expression was negatively regulated by DDX3X. Mechanistic studies showed that nuclear respiratory factor 2 (NRF-2), a key regulator of TFAM, was selectively activated after DDX3X knockdown via activated peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), in vivo and in vitro. CONCLUSIONS This study demonstrates that depressed hepatic TFAM plays a key role in the pathogenesis of AILI, which is regulated by the DDX3X-PGC1α-NRF2 signaling pathway.
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Affiliation(s)
- Sisi Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
- Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Yaling Cao
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Zihao Fan
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Ling Xu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Zhenzhen Pan
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Yao Gao
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Linlin Wei
- The Second Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
| | - Qiaoxin Wei
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
- Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Yuan Tian
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Xiangying Zhang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China
| | - Mei Liu
- Department of Liver Oncology, Beijing Youan Hospital, Capital Medical University, No. 8, Xitou Tiao Road, Youwai Street, Fengtai District, Beijing, 100069, China.
| | - Feng Ren
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, No. 8, XitouTiao Road, Youwai Street, Fengtai District, Beijing, 100069, China.
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18
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Yang P, Zhang H, Li J, Li Z, Liu Z, Wang M, Zhao F, Zhao J, Shen G, Zhao Y. Incidence of antibody-drug conjugate-related hepatotoxicity in breast cancer: a systematic review and meta-analysis. Ther Adv Drug Saf 2024; 15:20420986241304680. [PMID: 39703774 PMCID: PMC11656431 DOI: 10.1177/20420986241304680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 11/15/2024] [Indexed: 12/21/2024] Open
Abstract
Background Antibody-drug conjugates (ADCs), as a new type of targeted drug, have been widely used in breast cancer patients in recent years. However, while achieving better efficacy, its hepatotoxicity should not be ignored. Objectives To clarify the incidence of hepatotoxicity associated with ADCs and compare the incidence of hepatotoxicity of ADCs with different drugs. Design We performed a systematic review and meta-analysis to summarize the clinical trials and combined the data using meta-analysis. Methods We searched the PubMed, Embase, and Web of Science databases up to March 12, 2023. The primary outcome was the incidence of ADC-related hepatotoxicity in breast cancer patients. The data were merged using Stata 17.0 software. Results ADCs caused a high incidence of all grades of hepatotoxicity. Sacituzumab govitecan caused the highest incidence of all grades of alanine aminotransferase (ALT) elevation at 25.30% (95% confidence interval (CI): 19.29-31.82). Trastuzumab deruxtecan caused the highest incidence of all grades of aspartate aminotransferase (AST) elevation. The highest incidence of AST elevation was 31.89% (95% CI: 18.56-46.85). Conversely, trastuzumab emtansine caused the highest incidence of grade ⩾3 AST and ALT elevation (incidence rates were 3.95% (95% CI: 2.39-5.85) and 3.42% (95% CI: 1.95-5.24), respectively). Conclusion Hepatotoxicity is an adverse reaction that cannot be ignored when ADCs are used for treating breast cancer. Moreover, clinicians should pay more attention to the assessment of patients' liver function and monitoring of liver indices, particularly ALT and AST, when using ADCs.
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Affiliation(s)
- Ping Yang
- Qinghai University, Xining, China
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Hengheng Zhang
- Qinghai University, Xining, China
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Jinming Li
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zitao Li
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Zhen Liu
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Miaozhou Wang
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Fuxing Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Jiuda Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - GuoShuang Shen
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, Xining, China
| | - Yi Zhao
- The Center of Breast Disease Diagnosis and Treatment of Affiliated Hospital of Qinghai University and Affiliated Cancer Hospital of Qinghai University, No. 29 Tongren Road, Xining, Qinghai 810000, China
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Wang R, Chen Y, Han J, Ye H, Yang H, Li Q, He Y, Ma B, Zhang J, Ge Y, Wang Z, Sun B, Liu H, Cheng L, Wang Z, Lin G. Selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 as a rapid-acting therapy for advanced acute liver failure. Nat Commun 2024; 15:10690. [PMID: 39681560 PMCID: PMC11649909 DOI: 10.1038/s41467-024-55295-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 12/08/2024] [Indexed: 12/18/2024] Open
Abstract
Acute liver failure (ALF) is a hepatology emergency with rapid hepatic destruction, multiple organ failures, and high mortality. Despite decades of research, established ALF has minimal therapeutic options. Here, we report that the small bioactive compound SCM-198 increases the survival of male ALF mice to 100%, even administered 24 hours after ALF establishment. We identify adiponectin receptor 2 (AdipoR2) as a selective target of SCM-198, with the AdipoR2 R335 residue being critical for the binding and signaling of SCM-198-AdipoR2 and AdipoR2 Y274 residue serving as a molecular switch for Ca2+ influx. SCM-198-AdipoR2 binding causes Ca2+ influx and elevates the phosphorylation levels of CaMKII and NOS3 in the AdipoR2-CaM-CaMKII-NOS3 complex identified in this study, rapidly inducing nitric oxide production for liver protection in murine ALF. SCM-198 also protects human ESC-derived liver organoids from APAP/TAA injuries. Thus, selectively targeting the AdipoR2-CaM-CaMKII-NOS3 axis by SCM-198 is a rapid-acting therapeutic strategy for advanced ALF.
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Affiliation(s)
- Rui Wang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Youwei Chen
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
- School of Medicine, Tongji University, Shanghai, China
| | - Jiazhen Han
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huikang Ye
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Huiran Yang
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Qianyan Li
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Yizhen He
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Boyu Ma
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Junjie Zhang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Yanli Ge
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Zhe Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Bo Sun
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China
| | - Huahua Liu
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China
| | - Liming Cheng
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
| | - Zhirong Wang
- Department of Gastroenterology, Tongji Hospital affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, China.
| | - Gufa Lin
- Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Department of Orthopedic, Tongji Hospital affiliated to Tongji University, School of Life Sciences and Technology, Tongji University, Shanghai, China.
- School of Medicine, Tongji University, Shanghai, China.
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Lin Y, Li P, Zhang Y, Gao Q, Su L, Li Y, Xu R, Cao Y, Gao P, Luo F, Chen R, Zhang X, Nie S, Xu X. Incidence, risk factors, and outcomes of acute liver injury in hospitalized adults with acute kidney injury: a large multicenter study. Hepatol Int 2024; 18:1756-1769. [PMID: 38698184 DOI: 10.1007/s12072-023-10627-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 12/08/2023] [Indexed: 05/05/2024]
Abstract
BACKGROUND Acute kidney injury (AKI) and acute liver injury (ALI) were associated with poor outcomes during hospitalization, respectively. However, the clinical outcome of AKI combined with ALI (AKI-ALI) remains unknown. The current study aimed to describe AKI-ALI's incidences, risk factors, and outcomes. METHODS The study population included patients aged 18-99 years with enough serum creatinine and liver testing hospitalized at 19 medical centers throughout China between 2000 and 2021. AKI was defined by Kidney Disease Improving Global Outcomes and ALI was defined by the change of liver enzymes based on Asia Pacific Association of Study of Liver consensus guidelines. Cox proportional hazard model was used to identify risk factors for AKI-ALI, and a time-dependent Cox proportional hazard regression model was used to estimate the association between AKI-ALI and in-hospital mortality. RESULTS Among the 18,461 patients with AKI, 1689 (9.1%) combined with ALI. Male patients or those who have used nonsteroidal anti-inflammatory drugs or vasopressors, and who have heart failure or shock, with higher AST or GGT values, were associated with an increased risk of AKI-ALI. Compared with AKI-nonALI, patients with AKI-ALI were at higher risk of in-hospitalized mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.54, 2.00). In addition, a stronger association between AKI-ALI and in-hospital mortality was found in those with lower AKI grades (p for interaction = 0.037). CONCLUSIONS ALI was not uncommon among patients with AKI, especially in patients who used vasopressors and had shock. This study highlights the association between AKI-ALI and a significantly increased risk of mortality. It suggests that dynamic monitoring of liver function is essential, particularly in patients with AST and GGT exceeding the normal upper limit, to improve the in-hospital prognosis of AKI patients.
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Affiliation(s)
- Yuxin Lin
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pingping Li
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuping Zhang
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qi Gao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Licong Su
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanqin Li
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruqi Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue Cao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Peiyan Gao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fan Luo
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruixuan Chen
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaodong Zhang
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng Nie
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xin Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Mak LY, Liu K, Chirapongsathorn S, Yew KC, Tamaki N, Rajaram RB, Panlilio MT, Lui R, Lee HW, Lai JCT, Kulkarni AV, Premkumar M, Lesmana CRA, Hsu YC, Huang DQ. Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: burden, trends, challenges and future directions. Nat Rev Gastroenterol Hepatol 2024; 21:834-851. [PMID: 39147893 DOI: 10.1038/s41575-024-00967-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 08/17/2024]
Abstract
Globally, nearly half of deaths from cirrhosis and chronic liver diseases (CLD) and three-quarters of deaths from hepatocellular carcinoma (HCC) occur in the Asia-Pacific region. Chronic hepatitis B is responsible for the vast majority of liver-related deaths in the region. Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common form of CLD, affecting an estimated 30% of the adult population. Compared with people of European descent, people from the Asia-Pacific region carry more genetic variants associated with MASLD and its progression. Alcohol is a fast-growing cause of CLD and HCC in Asia as a result of the rising per-capita consumption of alcohol. Drug-induced liver injury is under-recognized and probably has a high prevalence in this region. The epidemiological and outcome data of acute-on-chronic liver failure are heterogeneous, and non-unified definitions across regions contribute to this heterogeneity. CLDs are severely underdiagnosed, and effective treatments and vaccinations are underutilized. In this Review, we highlight trends in the burden of CLD and HCC in the Asia-Pacific region and discuss the rapidly changing aetiologies of liver disease. We examine the multiple gaps in the care cascade and propose mitigating strategies and future directions.
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Affiliation(s)
- Lung-Yi Mak
- The University of Hong Kong, Hong Kong, China
| | - Ken Liu
- The University of Sydney, Sydney, Australia
| | | | | | | | | | | | - Rashid Lui
- The Chinese University of Hong Kong, Hong Kong, China
| | - Hye Won Lee
- Yonsei University College of Medicine, Seoul, Korea
| | | | - Anand V Kulkarni
- Department of Hepatology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Yao Chun Hsu
- Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan; School of Medicine and Graduate Institute of Medicine, I-Shou University, Kaohsiung, Taiwan
- School of Medicine and Graduate Institute of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore.
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Dong H, Feng J, Chang X, Wu S, Tang G, Liang F, Tang H, Dong Y, Fang W, Hu J, Wang W. Predictive value of systemic immune-inflammatory biomarkers for drug-induced liver injury in hepatitis B virus surface antigen positive tuberculosis patients: A retrospective observational study. Medicine (Baltimore) 2024; 103:e40349. [PMID: 39533543 PMCID: PMC11556996 DOI: 10.1097/md.0000000000040349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 10/15/2024] [Indexed: 11/16/2024] Open
Abstract
Drug-induced liver injury (DILI) is a major concern in tuberculosis (TB) treatment. For early detection of DILI, immune-inflammatory biomarkers are needed for better management. To explore the predictive effect of systemic immune-inflammation index (SII) combined with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), eosinophil (EOS%), and CD4/CD8 on DILI occurrence in TB patients with HBsAg positive. This is a retrospective study enrolling patients who were treated with anti-tuberculosis drugs and infected with hepatitis B virus (HBV) in the Guangzhou Chest Hospital from 2018 to 2023. Population demographics and clinical data of 2643 patients were collected by reviewing electronic medical records. Using a propensity score matching model, the study ultimately included 516 patients (258 patients with DILI and 258 patients without DILI). Logistic regression analysis was conducted to investigate the predictive role of systemic immune-inflammatory biomarkers (SII, NLR, MLR, EOS%, and CD4/CD8) in DILI in hepatitis B virus surface antigen-positive TB patients (HBV-TB-DILI). As compared to patients without DILI, patients with DILI have elevated levels of systemic immune-inflammatory biomarkers (SII, NLR, MLR, EOS%, and CD4/CD8), (all P < .05). The SII, NLR, MLR, PLR, EOS%, and CD4/CD8 are risk factors of HBV-TB-DILI. The NLR, MLR, SII, and EOS% were positively correlated with liver function (P < .001). The combination of SII, NLR, MLR, EOS%, and CD4/CD8 demonstrated good predictive performance for DILI occurrence in HBV-TB patients. The combination of SII, NLR, MLR, EOS%, and CD4/CD8 demonstrated good predictive performance for DILI occurrence in HBV-TB patients.
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Affiliation(s)
- Haiping Dong
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Jingyuan Feng
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Xinwei Chang
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shaoling Wu
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Guidan Tang
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Feng Liang
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Haojie Tang
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Yaping Dong
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Weiming Fang
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
| | - Jinxing Hu
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Weiyong Wang
- Guangzhou Key Laboratory of Tuberculosis Research, Department of Tuberculosis, Guangzhou Chest Hospital, State Key Laboratory of Respiratory Disease, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
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23
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Wu H, Yan W, Liu K, Jing J, Ye W. Propensity score matching-based analysis of the effect of corticosteroids in treating severe drug-induced liver injury. Clin Res Hepatol Gastroenterol 2024; 48:102472. [PMID: 39332764 DOI: 10.1016/j.clinre.2024.102472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/08/2024] [Accepted: 09/22/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND AND AIM There is no conventional treatment for patients with severe drug-induced liver injury (DILI) except for discontinuation of liver injury drugs and symptomatic supportive therapy. Opinions on whether corticosteroids can be used to treat severe DILI are conflicting, and most of the relevant clinical studies are case reports or retrospective studies, which still need to be supported by high-level evidence-based medical studies. This study aimed to evaluate the effect and tolerance of corticosteroids in patients with severe DILI. Risk factors associated with patient failure to cure were also explored. METHODS Propensity score matching based on nearest-neighbor 1:1 matching was used to screen severe DILI patients in the corticosteroids and control groups. Severe DILI was defined as elevated serum ALT and/or ALP with TBIL≥5 ULN (5 mg/dL or 85.5 μmol/L) with or without INR ≥1.5. Patients were treated with conventional therapy combined with corticosteroids in the corticosteroids group and only conventional therapy in the control group. RESULTS A total of 146 patients, 73 each in the corticosteroids and control groups, were included in this study. By analyzing the entire cohort, we found no significant difference in cure rates between patients in the corticosteroid group and control group (34.2% vs. 20.5 %, p = 0.095), and there was no significant difference in the incidence of adverse effects between the two groups (20.5% vs. 20.5 %, p = 1.000). However, TBIL decreased more in the corticosteroids group on day 7 (89.2 ± 107.6 μmol/L vs. 58.8 ± 70.7 μmol/L, p = 0.046). In subgroup analyses, patients whose TBIL remained elevated despite conventional treatment had a higher TBIL decline on day 7,14 after use of corticosteroid (99.2 ± 98.5μmol/L vs. -23.3 ± 50.4μmol/L, p < 0.001; 120 ± 119.1μmol/L vs. 61.2 ± 98.5μmol/L, p = 0.047). The cure rate of patients in the corticosteroid group was significantly higher than that of the control group (36.1 % versus 4.5 %, p = 0.016). The proportion of patients with TBIL <85.5 μmol/L was also significantly higher in the corticosteroid group than in the control group at day 7 (p = 0.016) and day 14 (p = 0.004) after treatment. In the subgroup analysis of patients with different clinical phenotypes, the causative agent was herbal, autoimmune antibody-positive and 40 % < PTA ≤ 50 % of patients, corticosteroid use did not increase the cure rate of the patients. Univariate and multifactorial analyses found corticosteroid use to be a protective factor for failure to cure in patients with severe DILI (p < 0.001, OR:0.191,95 % CI:0.072-0.470), and peak TBIL to be a risk factor (p = 0.003, OR:1.016,95 % CI:1.007-1.028). CONCLUSIONS The addition of corticosteroids could not increase the cure rate in patients with severe DILI, but it could rapidly reduce the patient's TBIL at an earlier stage. Corticosteroids could also promote curing in patients with elevated TBIL after conventional treatment. Corticosteroid use was a protective factor for failure to cure in patients with severe DILI and peak TBIL was a risk factor.
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Affiliation(s)
- Huanyu Wu
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Wanping Yan
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Ke Liu
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Jisheng Jing
- Department of Infectious Diseases, Jurong People's Hospital, Jiangsu University, Zhenjiang, China.
| | - Wei Ye
- Department of Infectious Disease and Liver Disease, The Second Hospital of Nanjing, Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
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Song L, Zhang Y, Sun F, Lan Y, Tong J, Ge S, Feng Z, Li R, Yu H, Li Y, Zhang W. Assessing hepatotoxicity in novel and standard short regimens for rifampicin-resistant tuberculosis: Insights from the TB-TRUST and TB-TRUST-plus trials. Int J Infect Dis 2024; 148:107230. [PMID: 39241956 DOI: 10.1016/j.ijid.2024.107230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024] Open
Abstract
OBJECTIVES Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by the World Health Organization (WHO). METHODS Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin (Lfx)-based regimen, or a bedaquiline (Bdq)-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. RESULTS Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the Lfx group (172 patients), and 5.7% in the Bdq group (88 patients). The median peak alanine aminotransferase levels were 1.67 × upper limit of normal (ULN) for WHO, 0.82 × ULN for Lfx, and 0.88 × ULN for Bdq groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the Lfx (3.5%) and Bdq (4.6%) groups. The time to significant alanine aminotransferase elevation was about 2.8 months, with no differences between groups. CONCLUSIONS Two novel regimens demonstrated lower hepatotoxicity compared to the WHO's shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.
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Affiliation(s)
- Lingyun Song
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yilin Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Feng Sun
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuanbo Lan
- Department of Tuberculosis, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jie Tong
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shijia Ge
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhen Feng
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Rong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongying Yu
- Department of Infectious Diseases, The First People's Hospital of Huaihua, Huaihua, China
| | - Yang Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Wenhong Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Huashen Institute of Microbes and Infections, Shanghai, China
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25
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Zhao W, Luo H, Lin Z, Huang L, Pan Z, Chen L, Fan L, Yang S, Tan H, Zhong C, Liu H, Huang C, Wang J, Zhang B. Wogonin mitigates acetaminophen-induced liver injury in mice through inhibition of the PI3K/AKT signaling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 332:118364. [PMID: 38763368 DOI: 10.1016/j.jep.2024.118364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/03/2024] [Accepted: 05/17/2024] [Indexed: 05/21/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. AIM OF STUDY To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. MATERIALS AND METHODS C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 μM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). RESULTS Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. CONCLUSIONS Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.
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Affiliation(s)
- Wenyingzi Zhao
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Huishan Luo
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Zelong Lin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Linwen Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Zhaoyu Pan
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Liji Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Longxiu Fan
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Shilong Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Huishi Tan
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Cailing Zhong
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China
| | - Hongbin Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Chongyang Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China.
| | - Jun Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment for Refractory Chronic Diseases, China.
| | - Beiping Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, 510120, China; Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, 510120, China; Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment for Refractory Chronic Diseases, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, China.
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Zhang X, Geng Q, Lin L, Zhang L, Shi C, Liu B, Yan L, Cao Z, Li L, Lu P, Tan Y, He X, Zhao N, Li L, Lu C. Insights gained into the injury mechanism of drug and herb induced liver injury in the hepatic microenvironment. Toxicology 2024; 507:153900. [PMID: 39079402 DOI: 10.1016/j.tox.2024.153900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
Drug-Induced Liver Injury (DILI) and herb Induced Liver Injury (HILI) continues to pose a substantial challenge in both clinical practice and drug development, representing a grave threat to patient well-being. This comprehensive review introduces a novel perspective on DILI and HILI by thoroughly exploring the intricate microenvironment of the liver. The dynamic interplay among hepatocytes, sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, cholangiocytes, and the intricate vascular network assumes a central role in drug metabolism and detoxification. Significantly, this microenvironment is emerging as a critical determinant of susceptibility to DILI and HILI. The review delves into the multifaceted interactions within the liver microenvironment, providing valuable insights into the complex mechanisms that underlie DILI and HILI. Furthermore, we discuss potential strategies for mitigating drug-induced liver injury by targeting these influential factors, emphasizing their clinical relevance. By highlighting recent advances and future prospects, our aim is to shed light on the promising avenue of leveraging the liver microenvironment for the prevention and mitigation of DILI and HILI. This deeper understanding is crucial for advancing clinical practices and ensuring patient safety in the realm of DILI and HILI.
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Affiliation(s)
- Xiaomeng Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qi Geng
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Lin
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lulu Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Changqi Shi
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bin Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lan Yan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiwen Cao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Peipei Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yong Tan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
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Yu S, Li J, He T, Zheng H, Wang S, Sun Y, Wang L, Jing J, Wang R. Age-related differences in drug-induced liver injury: a retrospective single-center study from a large liver disease specialty hospital in China, 2002-2022. Hepatol Int 2024; 18:1202-1213. [PMID: 38898191 PMCID: PMC11297843 DOI: 10.1007/s12072-024-10679-1] [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: 12/15/2023] [Accepted: 04/06/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND AND AIMS Drug-induced liver injury (DILI) is a prevalent adverse reaction in clinical settings. However, there is limited research on age-related differences in DILI. We performed a large-scale retrospective study to delineate the characteristics of DILI across different age groups. METHODS We collected data on a total of 17,946 patients with confirmed DILI hospitalized at the Fifth Medical Center of the People's Liberation Army (PLA) General Hospital in Beijing, China, from January 1, 2002, to December 31, 2022. The patients were stratified based on age into the following groups: children (< 18 years), young adults (18-44 years), middle-aged individuals (45-64 years), and elderly individuals (≥ 65 years). We gathered demographic information, medical histories, laboratory results, disease severity assessments, and mortality statistics for all patients. RESULTS Overall, the distribution of DILI cases across different age groups was as follows: 6.57% were children, 24.82% were young adults, 49.06% were middle-aged individuals, and 19.54% were elderly individuals. The percentage of females increased with age, rising from 36.47% in the pediatric group to 60.51% in the elderly group. Notably, central nervous system agents (15.44%) and anti-infectious agents (21.80%) were more commonly associated with DILI in children, while cardiovascular agents (10.58%) and herbal dietary supplements or traditional medicines (H/TMs) (26.29%) were more prevalent among elderly people with DILI. Among all age groups, hepatocellular-type DILI was more common in the pediatric group (p < 0.001), whereas cholestatic-type DILI and chronic DILI were more prevalent in the elderly group (p < 0.001). Acute liver failure (ALF) and fatal outcomes were more prevalent in the pediatric and elderly groups, particularly in the pediatric group (2.04%, p = 0.041; 0.85%, p = 0.007, respectively). CONCLUSIONS Children and elderly individuals face a higher risk of adverse outcomes following DILI.
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Affiliation(s)
- Simiao Yu
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Jiahui Li
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Tingting He
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Haocheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Sici Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yongqiang Sun
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Liping Wang
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China
| | - Jing Jing
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
| | - Ruilin Wang
- Department of Hepatology and Traditional Chinese Medicine, The Fifth Medical Center, PLA General Hospital, 100 West Fourth Ring Middle Road, Fengtai District, Beijing, 100039, China.
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Ma X, Chen Z, An J, Zhang C. Clinical Features and Risk Factors for Drug-Induced Liver Injury: A Retrospective Study From China. Clin Ther 2024; 46:597-603. [PMID: 38821767 DOI: 10.1016/j.clinthera.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/20/2024] [Accepted: 04/30/2024] [Indexed: 06/02/2024]
Abstract
PURPOSE With the prolongation of human life expectancy and the outbreak of COVID-19, antineoplastic agents, anti-infective drugs, and cardiovascular system drugs have been widely applied, resulting in a growing incidence of drug-induced liver injury (DILI) year by year. This study aimed to investigate signals, clinical characteristics, and risk factors in patients with liver injury. METHODS A retrospective analysis was conducted on inpatients clinically diagnosed with DILI from 2019 to 2021 in one tertiary hospital in mainland China. The hepatic biochemical indices, clinical manifestations and suspected drugs of the patients were counted. We determined causality assessed by the Roussel Uclaf Causality Assessment Method in patients that the biochemistry met the diagnostic criteria recommended by the International Serious Adverse Events Consortium and compared them with contemporaneous patients diagnosed as DILI but with hepatic biochemical abnormalities only to identify the injure types and risk factors for DILI. FINDINGS A total of 1167 patients from 2639 initial participants with DILI were included. According to the injured target cells, it can be divided into hepatocellular injury type 351 cases (30.08%), cholestatic injury type 97 cases (8.31%), mixed injury type 27 cases (2.31%), and biochemical abnormal only type 692 cases (59.30%). It involved 1738 cases of suspected drugs, 349 drugs, and the top 3 drug categories were antineoplastic agents, anti-infectives, and traditional Chinese medicines, with Cyclophosphamide, Atorvastatin, and Liuzasulfapyridine as the top 3 in order of ranking. The main symptoms of patients were darker urine, decreased appetite, and yellow sclera. The overall prognosis of patients with DILI was favorable, with 280 recovered cases (23.99%), 691 improved cases (59.21%), 189 not improved cases (16.20%), and 7 deaths (0.60%). There were significant differences in gender, age, malignancy, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyltransferase, albumin, international normalized ratio, and prognosis among patients with different injury types (P < 0.05). Multiple logistic regression analysis showed that female (odds ratio [OR] = 1.897, P < 0.001), alcohol use (OR = 1.905, P = 0.001), malignancy (OR = 0.417, P < 0.001), and pregnancy (OR = 0.201, P = 0.011) were independent factors influencing DILI. IMPLICATIONS For most patients with liver injury, the manifestations are mild elevation of liver biochemistry without other symptoms (biochemical abnormal only type). The rest of the patients are predominantly of the hepatocellular injury type. Female and alcohol abuse patients are the risk factors of DILI, reminding clinicians to strengthen education on safe drug use, give individualized treatment, and regularly monitor liver function indexes in the patients.
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Affiliation(s)
- Xiaojuan Ma
- Department of Clinical Pharmacy, Third Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Zhuo Chen
- Department of Clinical Pharmacy, Third Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Jingzhi An
- Department of Clinical Pharmacy, Third Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Cuixin Zhang
- Department of Clinical Pharmacy, Third Hospital of Hebei Medical University, Shijiazhuang City, China.
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Li M, Zhang D, Yang Q, Zhao Z, Zhang C, Zhou Y, Bai Y, Chen L, Tang X, Liu C, Zhou J, Chen X, Ying B. Longitudinal metabolomics of human plasma reveal metabolic dynamics and predictive markers of antituberculosis drug-induced liver injury. Respir Res 2024; 25:254. [PMID: 38907347 PMCID: PMC11193241 DOI: 10.1186/s12931-024-02837-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 05/04/2024] [Indexed: 06/23/2024] Open
Abstract
Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings.
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Affiliation(s)
- Mengjiao Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Dan Zhang
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Qingxin Yang
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenzhen Zhao
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Chunying Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yanbing Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yangjuan Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Chen
- Department of Laboratory Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyan Tang
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Cuihua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Xuerong Chen
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
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Meng N, Sun Y, Dong Y, Lv B, Yao D, Gao H, Ma Y, Jin Y, Zhu T, Tian Y. Prognostic value of plasma diquat concentration in patients with acute oral diquat poisoning: a retrospective study. Front Public Health 2024; 12:1333450. [PMID: 38894984 PMCID: PMC11184952 DOI: 10.3389/fpubh.2024.1333450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/08/2024] [Indexed: 06/21/2024] Open
Abstract
Objectives Diquat poisoning is an important public health and social security agency. This study aimed to develop a prognostic model and evaluate the prognostic value of plasma diquat concentration in patients with acute oral diquat poisoning, focusing on how its impact changes over time after poisoning. Methods This was a retrospective cohort study using electronic healthcare reports from the Second Hospital of Hebei Medical University. The study sample included 80 patients with acute oral Diquat poisoning who were admitted to the hospital between January 2019 and May 2022. Time-to-event analyses were performed to assess the risk of all-cause mortality (30 days and 90 days), controlling for demographics, comorbidities, vital signs, and other laboratory measurements. The prognostic value of plasma DQ concentration on admission was assessed by computing the area under a time-dependent receiver operating characteristic curve (ROC). Results Among the 80 patients, 29 (36.25%) patients died, and 51 (63.75%) patients survived in the hospital. Non-survivors had a median survival time (IQR) of 1.3(1.0) days and the longest survival time of 4.5 days after DQ poisoning. Compared with non-survivors, survivors had significantly lower amounts of ingestion, plasma DQ concentration on admission, lungs injury within 24 h after admission, liver injury within 24 h after admission, kidney injury within 24 h after admission, and CNS injury within 36 h after admission, higher APACHE II score and PSS within 24 h after admission (all p < 0.05). Plasma Diquat concentration at admission (HR = Exp (0.032-0.059 × ln (t))) and PSS within 24 h after admission (HR: 4.470, 95%CI: 1.604 ~ 12.452, p = 0.004) were independent prognostic factors in the time-dependent Cox regression model. Conclusion Plasma DQ concentration at admission and PSS within 24 h after admission are independent prognostic factors for the in-hospital case fatality rate in patients with acute oral DQ poisoning. The prognostic value of plasma DQ concentration decreased with time.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Yingping Tian
- Department of Emergency, The Second Hospital of Hebei Medical University, Shijiazhuang, China
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Chu WM, Wan EYF, Ting Wong ZC, Tam AR, Kei Wong IC, Yin Chan EW, Ngai Hung IF. Comparison of safety and efficacy between Nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study. EClinicalMedicine 2024; 72:102620. [PMID: 38737003 PMCID: PMC11087721 DOI: 10.1016/j.eclinm.2024.102620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/14/2024] [Accepted: 04/15/2024] [Indexed: 05/14/2024] Open
Abstract
Background Nirmatrelvir-ritonavir is used in patients with coronavirus disease 2019 (COVID-19) with normal or mild renal impairment (eGFR ≥30 ml/min per 1.73 m2). There is limited data regarding its use in advanced kidney disease (eGFR <30 ml/min per 1.73 m2). We performed a retrospective territory-wide observational study evaluating the safety and efficacy of nirmatrelvir-ritonavir when compared with molnupiravir in the treatment of patients with COVID-19 with advanced kidney disease. Methods We adopted target trial emulation using data from a territory-wide electronic health record database on eligible patients aged ≥18 years with advanced kidney disease (history of eGFR <30 ml/min per 1.73 m2) who were infected with COVID-19 and were prescribed with either molnupiravir or nirmatrelvir-ritonavir within five days of infection during the period from 16 March 2022 to 31 December 2022. A sequence trial approach and 1:4 propensity score matching was applied based on the baseline covariates including age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index (CCI), hospitalisation, eGFR, renal replacement therapy, comorbidities (cancer, respiratory disease, myocardial infarction, ischaemic stroke, diabetes, hypertension), and drug use (renin-angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, nitrates, lipid lowering agents, insulins, oral antidiabetic drugs, antiplatelets, immuno-suppressants, corticosteroids, proton pump inhibitors, histamine H2 receptor antagonists, monoclonal antibody infusion) within past 90 days. Individuals were followed up from the index date until the earliest outcome occurrence, death, 90 days from index date or the end of data availability. Stratified Cox proportional hazards regression adjusted with baseline covariates was used to compare the risk of outcomes between nirmatrelvir-ritonavir recipients and molnupiravir recipients which include (i) all-cause mortality, (ii) intensive care unit (ICU) admission, (iii) ventilatory support, (iv) hospitalisation, (v) hepatic impairment, (vi) ischaemic stroke, and (vii) myocardial infarction. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (≤5; >5), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). Findings A total of 4886 patients were included (nirmatrelvir-ritonavir: 1462; molnupiravir: 3424). There were 347 events of all-cause mortality (nirmatrelvir-ritonavir: 74, 5.06%; molnupiravir: 273, 7.97%), 10 events of ICU admission (nirmatrelvir-ritonavir: 4, 0.27%; molnupiravir: 6, 0.18%), 48 events of ventilatory support (nirmatrelvir-ritonavir: 13, 0.89%; molnupiravir: 35, 1.02%), 836 events of hospitalisation (nirmatrelvir-ritonavir: 218, 23.98%; molnupiravir: 618, 28.14%), 1 event of hepatic impairment (nirmatrelvir-ritonavir: 0, 0%; molnupiravir: 1, 0.03%), 8 events of ischaemic stroke (nirmatrelvir-ritonavir: 3, 0.22%; molnupiravir: 5, 0.16%) and 9 events of myocardial infarction (nirmatrelvir-ritonavir: 2, 0.15%; molnupiravir: 7, 0.22%). Nirmatrelvir-ritonavir users had lower rates of all-cause mortality (absolute risk reduction (ARR) at 90 days 2.91%, 95% CI: 1.47-4.36%) and hospitalisation (ARR at 90 days 4.16%, 95% CI: 0.81-7.51%) as compared with molnupiravir users. Similar rates of ICU admission (ARR at 90 days -0.09%, 95% CI: -0.4 to 0.2%), ventilatory support (ARR at 90 days 0.13%, 95% CI: -0.45 to 0.72%), hepatic impairment (ARR at 90 days 0.03%, 95% CI: -0.03 to 0.09%), ischaemic stroke (ARR at 90 days -0.06%, 95% CI: -0.35 to 0.22%), and myocardial infarction (ARR at 90 days 0.07%, 95% CI: -0.19 to 0.33%) were found between nirmatrelvir-ritonavir and molnupiravir users. Consistent results were observed in relative risk adjusted with baseline characteristics. Nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624, 95% CI: 0.455-0.857) and hospitalisation (HR: 0.782, 95% CI: 0.64-0.954). Interpretation Patients with COVID-19 with advanced kidney disease receiving nirmatrelvir-ritonavir had a lower rate of all-cause mortality and hospital admission when compared with molnupiravir. Other adverse clinical outcomes were similar in both treatment groups. Funding Health and Medical Research Fund (COVID1903010), Health Bureau, The Government of the Hong Kong Special Administrative Region, China.
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Affiliation(s)
- Wing Ming Chu
- Division of Infectious Diseases, Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
| | - Eric Yuk Fai Wan
- Li Ka Shing Faculty of Medicine, Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D4H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- Li Ka Shing Faculty of Medicine, Department of Family Medicine and Primary Care, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Zoey Cho Ting Wong
- Li Ka Shing Faculty of Medicine, Department of Family Medicine and Primary Care, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Anthony Raymond Tam
- Division of Infectious Diseases, Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
| | - Ian Chi Kei Wong
- Li Ka Shing Faculty of Medicine, Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D4H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- Aston Pharmacy School, Aston University, Birmingham, B4 7ET, UK
| | - Esther Wai Yin Chan
- Li Ka Shing Faculty of Medicine, Department of Pharmacology and Pharmacy, Centre for Safe Medication Practice and Research, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D4H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- Department of Pharmacy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- The University of Hong Kong, Shenzhen Institute of Research and Innovation, Shenzhen, China
| | - Ivan Fan Ngai Hung
- Division of Infectious Diseases, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Huang A, Zhu Y, Liu S, Sun Y, Liu Z, Liang QS, Zhao J, Chang BX, Bi JF, Liu JT, Zhai XR, Xie H, Li N, Tian H, Han L, Zhuang Y, Ma H, Teng GJ, Zhang W, Aithal GP, Ji D, Zhao J, Zou Z. An optimized short-term steroid therapy for chronic drug-induced liver injury: A prospective randomized clinical trial. Liver Int 2024; 44:1435-1447. [PMID: 38483145 DOI: 10.1111/liv.15899] [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: 11/29/2023] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 05/23/2024]
Abstract
BACKGROUND AND AIMS The use of corticosteroids in chronic drug-induced liver injury (DILI) is an important issue. Our previous randomized controlled trial showed that patients with chronic DILI benefited from a 48-week steroid stepwise reduction (SSR) regimen. However, it remains unclear whether a shorter course of therapy can achieve similar efficacy. In this study, we aimed to assess whether a 36-week SSR can achieve efficacy similar to that of 48-week SSR. METHODS A randomized open-label trial was performed. Eligible patients were randomly assigned to the 36- or 48-week (1:1) SSR group. Liver biopsies were performed at baseline and at the end of treatment. The primary outcome was the proportion of patients with relapse rate (RR). The secondary outcomes were improvement in liver histology and safety. RESULTS Of the 90 participants enrolled, 84 (87.5%) completed the trial, and 62 patients (68.9%) were women. Hepatocellular damage was observed in 53.4% of the cohort. The RR was 7.1% in the 36-week SSR group but 4.8% in the 48-week SSR group, as determined by per-protocol set analysis (p = 1.000). Significant histological improvements in histological activity (93.1% vs. 92.9%, p = 1.000) and fibrosis (41.4% vs. 46.4%, p = .701) were observed in both the groups. Biochemical normalization time did not differ between the two groups. No severe adverse events were observed. CONCLUSIONS Both the 36- and 48-week SSR regimens demonstrated similar biochemical response and histological improvements with good safety, supporting 36-week SSR as a preferable therapeutic choice (ClinicalTrials.gov, NCT03266146).
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Affiliation(s)
- Ang Huang
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Gastroenterology and Hepatology, the First Medical Center of PLA General Hospital, Beijing, China
| | - Yun Zhu
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Shuhong Liu
- Department of Pathology and Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ying Sun
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zherui Liu
- Peking University 302 Clinical Medical School, Beijing, China
| | - Qing-Sheng Liang
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jun Zhao
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Bin-Xia Chang
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jing-Feng Bi
- Epidemiology Department, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jiang-Tao Liu
- Department of Gastroenterology, Hainan Hospital of Chinese PLA General Hospital, Hainan, China
| | - Xing-Ran Zhai
- Peking University 302 Clinical Medical School, Beijing, China
| | - Huan Xie
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Ning Li
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hui Tian
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Lin Han
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yingjie Zhuang
- Department for Disease Control and Prevention, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongbin Ma
- Department of Clinical Diagnostic Center, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Guang-Ju Teng
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Wei Zhang
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Guruprasad P Aithal
- NIHR Nottingham Biomedical Research Center, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Dong Ji
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhengsheng Zou
- Senior Department of Hepatology, the Fifth Medical Center of PLA General Hospital, Beijing, China
- Peking University 302 Clinical Medical School, Beijing, China
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Mao T, He P, Xu Z, Lai Y, Huang J, Yu Z, Li P, Gong X. Impacts of small-molecule STAT3 inhibitor SC-43 on toxicity, global proteomics and metabolomics of HepG2 cells. J Pharm Biomed Anal 2024; 242:116023. [PMID: 38395000 DOI: 10.1016/j.jpba.2024.116023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/27/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024]
Abstract
OBJECTIVE In this study, we aimed to investigate the cytotoxicity and potential mechanisms of SC-43 by analyzing the global proteomics and metabolomics of HepG2 cells exposed to SC-43. METHODS The effect of SC-43 on cell viability was evaluated through CCK-8 assay. Proteomics and metabolomics studies were performed on HepG2 cells exposed to SC-43, and the functions of differentially expressed proteins and metabolites were categorized. Drug affinity responsive target stability (DARTS) was utilized to identify the potential binding proteins of SC-43 in HepG2 cells. Finally, based on the KEGG pathway database, the co-regulatory mechanism of SC-43 on HepG2 cells was elucidated by conducting a joint pathway analysis on the differentially expressed proteins and metabolites using the MetaboAnalyst 5.0 platform. RESULTS Liver cell viability is significantly impaired by continuous exposure to high concentrations of SC-43. Forty-eight dysregulated proteins (27 upregulated, 21 downregulated) were identified by proteomics analysis, and 184 dysregulated metabolites (65 upregulated, 119 downregulated) were determined by metabolomics in HepG2 cells exposed to SC-43 exposure compared with the control. A joint pathway analysis of proteomics and metabolomics data using the MetaboAnalyst 5.0 platform supported the close correlation between SC-43 toxicity toward HepG2 and the disturbances in pyrimidine metabolism, ferroptosis, mismatch repair, and ABC transporters. Specifically, SC-43 significantly affected the expression of several proteins and metabolites correlated with the above-mentioned functional pathways, such as uridine 5'-monophosphate, uridine, 3'-CMP, glutathione, γ-Glutamylcysteine, TF, MSH2, RPA1, RFC3, TAP1, and glycerol. The differential proteins suggested by the joint analysis were further selected for ELISA validation. The data showed that the RPA1 and TAP1 protein levels significantly increased in HepG2 cells exposed to SC-43 compared to the control group. The results of ELISA and joint analysis were basically in agreement. Notably, DARTS and biochemical analysis indicated that SART3 might be a potential target for SC-43 toxicity in HepG2 cells. CONCLUSION In summary, prolonged exposure of liver cells to high concentrations of SC-43 can result in significant damage. Based on a multi-omics analysis, we identified proteins and metabolites associated with SC-43-induced hepatocellular injury and clarified the underlying mechanism, providing new insights into the toxic mechanism of SC-43.
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Affiliation(s)
- Ting Mao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Peikun He
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China
| | - Zhichao Xu
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China
| | - Yingying Lai
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China
| | - Jinlian Huang
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China
| | - Zhijian Yu
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China
| | - Peiyu Li
- Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518052, China.
| | - Xianqiong Gong
- Hepatology Center, Xiamen Hospital, Beijing University of Chinese Medicine, Xiamen 361001, China.
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Jiang A, Wei C, Zhu W, Wu F, Wu B. Adverse event profiles of drug-induced liver injury caused by antidepressant drugs: a disproportionality analysis. Ther Adv Drug Saf 2024; 15:20420986241244585. [PMID: 38715707 PMCID: PMC11075604 DOI: 10.1177/20420986241244585] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 03/13/2024] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention. OBJECTIVES To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database. RESEARCH DESIGN A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI. METHODS FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC). RESULTS As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone (n = 47, ROR = 7.79, IC = 2.91), fluvoxamine (n = 29, ROR = 4.69, IC = 2.20), and clomipramine (n = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin (n = 3, ROR = 21.46, IC = 3.99), nefazodone (n = 264, ROR = 18.67, IC = 3.84), and maprotiline (n = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone (n = 187, ROR = 12.71, IC = 0.48), clomipramine (n = 35, ROR = 2.07, IC = 0.26), and mirtazapine (n = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals (n = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine. CONCLUSION A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.
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Affiliation(s)
- Aidou Jiang
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Chunyan Wei
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Weiwei Zhu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Fengbo Wu
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Wu
- Department of Pharmacy, West China Hospital, Sichuan University, #37 Guoxue Alley, Wuhou District, Chengdu, Sichuan 610041, China
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Philips CA, Theruvath AH. A comprehensive review on the hepatotoxicity of herbs used in the Indian (Ayush) systems of alternative medicine. Medicine (Baltimore) 2024; 103:e37903. [PMID: 38640296 PMCID: PMC11029936 DOI: 10.1097/md.0000000000037903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/20/2024] [Accepted: 03/22/2024] [Indexed: 04/21/2024] Open
Abstract
Complementary and alternative medicine-related liver injuries are increasing globally. Alternative medicine, as an inclusive healthcare practice, is widely accepted in developing and underdeveloped countries. In this context, the traditional systems of medicine in India have been at the forefront, catering to the preventive and therapeutic spectrum in the absence of conclusive evidence for benefits and lack of data on safety. Contrary to popular belief, it is evident that apart from adverse events caused by contamination and adulteration of alternative medicines, certain commonly used herbal components have inherent hepatotoxicity. This narrative review updates our current understanding and increasing publications on the liver toxicity potential of commonly used herbs in traditional Indian systems of medicine (Ayush), such as Tinospora cordifolia (Willd.) Hook.f. & Thomson (Giloy/Guduchi), Withania somnifera (L.) Dunal (Ashwagandha), Curcuma longa L. (Turmeric), and Psoralea corylifolia L. (Bakuchi/Babchi). This review also highlights the importance of the upcoming liver toxicity profiles associated with other traditional herbs used as dietary supplements, such as Centella asiatica (L.) Urb., Garcinia cambogia Desr., Cassia angustifolia Vahl (Indian senna), and Morinda citrofolia L. (Noni fruit). Fortunately, most reported liver injuries due to these herbs are self-limiting, but can lead to progressive liver dysfunction, leading to acute liver failure or acute chronic liver failure with a high mortality rate. This review also aims to provide adequate knowledge regarding herbalism in traditional practices, pertinent for medical doctors to diagnose, treat, and prevent avoidable liver disease burdens within communities, and improve public health and education.
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Affiliation(s)
- Cyriac Abby Philips
- Clinical and Translational Hepatology, The Liver Institute, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, India
- Department of Clinical Research, Division of Complementary and Alternative Medicine and the Liver, The Liver Institute, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, India
| | - Arif Hussain Theruvath
- Department of Clinical Research, Division of Complementary and Alternative Medicine and the Liver, The Liver Institute, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, India
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Mao Y, Ma S, Liu C, Liu X, Su M, Li D, Li Y, Chen G, Chen J, Chen J, Zhao J, Guo X, Tang J, Zhuge Y, Xie Q, Xie W, Lai R, Cai D, Cai Q, Zhi Y, Li X. Chinese guideline for the diagnosis and treatment of drug-induced liver injury: an update. Hepatol Int 2024; 18:384-419. [PMID: 38402364 DOI: 10.1007/s12072-023-10633-7] [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: 10/07/2023] [Accepted: 12/18/2023] [Indexed: 02/26/2024]
Abstract
Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, and antineoplastic drugs), and signal of DILI in clinical trials and its assessment.
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Affiliation(s)
- Yimin Mao
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, 200001, China.
| | - Shiwu Ma
- Department of Infectious Diseases, The 920th Hospital of Chinese PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaoyan Liu
- Department of Pharmacy, Huangpu Branch of the 9th People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China
| | - Minghua Su
- Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Dongliang Li
- Department of Hepatobiliary Medicine, The 900th Hospital of Chinese PLA Joint Logistics Support Force, Fuzhou, 350025, Fujian, China
| | - Yiling Li
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, China
| | - Gongying Chen
- Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, Zhejiang, China
| | - Jun Chen
- Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, 518112, Guangdong, China
| | - Jinjun Chen
- Hepatology Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Xiaoyan Guo
- Department of Gastroenterology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Jieting Tang
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, 200001, China
| | - Yuzheng Zhuge
- Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Wen Xie
- Center of Liver Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, 100088, China
| | - Rongtao Lai
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Dachuan Cai
- Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Qingxian Cai
- Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, 518112, Guangdong, China
| | - Yang Zhi
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, 200001, China
| | - Xiaoyun Li
- Division of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, NHC Key Laboratory of Digestive Diseases, Shanghai Research Center of Fatty Liver Disease, Shanghai, 200001, China
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Ahmed T, Ahmad J. Recent advances in the diagnosis of drug-induced liver injury. World J Hepatol 2024; 16:186-192. [PMID: 38495272 PMCID: PMC10941738 DOI: 10.4254/wjh.v16.i2.186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/03/2024] [Accepted: 02/03/2024] [Indexed: 02/27/2024] Open
Abstract
Drug-induced liver injury (DILI) is a major problem in the United States, commonly leading to hospital admission. Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes. In addition, DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease. Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems. This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.
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Affiliation(s)
- Taqwa Ahmed
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Jawad Ahmad
- Department of Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
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Bessone F, Hillotte GL, Ahumada N, Jaureguizahar F, Medeot AC, Roma MG. UDCA for Drug-Induced Liver Disease: Clinical and Pathophysiological Basis. Semin Liver Dis 2024; 44:1-22. [PMID: 38378025 DOI: 10.1055/s-0044-1779520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/22/2024]
Abstract
Drug-induced liver injury (DILI) is an adverse reaction to medications and other xenobiotics that leads to liver dysfunction. Based on differential clinical patterns of injury, DILI is classified into hepatocellular, cholestatic, and mixed types; although hepatocellular DILI is associated with inflammation, necrosis, and apoptosis, cholestatic DILI is associated with bile plugs and bile duct paucity. Ursodeoxycholic acid (UDCA) has been empirically used as a supportive drug mainly in cholestatic DILI, but both curative and prophylactic beneficial effects have been observed for hepatocellular DILI as well, according to preliminary clinical studies. This could reflect the fact that UDCA has a plethora of beneficial effects potentially useful to treat the wide range of injuries with different etiologies and pathomechanisms occurring in both types of DILI, including anticholestatic, antioxidant, anti-inflammatory, antiapoptotic, antinecrotic, mitoprotective, endoplasmic reticulum stress alleviating, and immunomodulatory properties. In this review, a revision of the literature has been performed to evaluate the efficacy of UDCA across the whole DILI spectrum, and these findings were associated with the multiple mechanisms of UDCA hepatoprotection. This should help better rationalize and systematize the use of this versatile and safe hepatoprotector in each type of DILI scenarios.
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Affiliation(s)
- Fernando Bessone
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Geraldine L Hillotte
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
| | - Natalia Ahumada
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | - Fernanda Jaureguizahar
- Hospital Provincial del Centenario, Facultad de Ciencias Médicas, Servicio de Gastroenterología y Hepatología, Universidad Nacional de Rosario, Rosario, Argentina
| | | | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina
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Devarbhavi HC, Philips CA. Drug-induced liver injury in patients with underlying liver disease. Clin Liver Dis (Hoboken) 2024; 23:e0189. [PMID: 38860131 PMCID: PMC11164011 DOI: 10.1097/cld.0000000000000189] [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: 03/02/2024] [Accepted: 03/17/2024] [Indexed: 06/12/2024] Open
Affiliation(s)
- Harshad C. Devarbhavi
- Department of Gastroenterology and Hepatology, St. John’s Medical College Hospital, Bangalore, India
| | - Cyriac Abby Philips
- Clinical and Translational Hepatology, The Liver Institute, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
- Division of Complementary and Alternative Medicine, Department of Clinical Research, The Liver Institute, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala, India
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40
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Volynets G, Nikitin A, Skvortsova T, Kokiashvili V. Drug-induced autoimmune-like hepatitis. RUSSIAN JOURNAL OF EVIDENCE-BASED GASTROENTEROLOGY 2024; 13:58. [DOI: 10.17116/dokgastro20241301158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Wong CKH, Mak LY, Au ICH, Cheng WY, So CH, Lau KTK, Lau EHY, Cowling BJ, Leung GM, Yuen MF. Risk of acute liver injury following the nirmatrelvir/ritonavir use. Liver Int 2023; 43:2657-2667. [PMID: 37448114 DOI: 10.1111/liv.15673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/21/2023] [Accepted: 07/01/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as adverse events of nirmatrelvir/ritonavir users in the EPIC-HR trial. AIM To quantify the risk and severity of acute liver injury (ALI) associated with nirmatrelvir/ritonavir use. METHODS This self-controlled case-series study was conducted using electronic medical records of patients with confirmed diagnosis of SARS-CoV-2 infection between 26th February 2022 and 12th February 2023 in Hong Kong. RESULTS Among 2 409 848 patients with SARS-CoV-2 infection during the study period, 153 853 were prescribed with nirmatrelvir/ritonavir, of whom 834 (.5%) had incident ALI (moderate: 30.5%; moderate to severe: 18.9%; severe or fatal: 5.8%). Compared with the non-exposure period, risk of ALI increased significantly during the pre-exposure period (IRR = 38.13, 95% CI = 29.29-49.62) and remained elevated during the five-day nirmatrelvir/ritonavir treatment (IRR = 20.75, 95% CI = 17.06-25.25) and during wash-out period (IRR = 16.27, 95% CI = 13.23-20.01). Compared to the pre-exposure period, risk of ALI was not increased during the five-day nirmatrelvir/ritonavir treatment period (IRR = .54, 95% CI = .43-.70). Compared to 5469 non-nirmatrelvir/ritonavir users with incident ALI, nirmatrelvir/ritonavir users had less severe ALI by the severity index (p < .001) and peak INR (1.7 vs. 2.3; p < .001). ALI cases with nirmatrelvir/ritonavir use had lower risk of all-cause death (29.1% vs. 39.1%; OR = .64; p < .001) and no increase in risk of liver decompensation (1.0% vs. 1.3%; OR = .62; p = .230) compared to non-users. CONCLUSION The risk of ALI associated with nirmatrelvir/ritonavir treatment for COVID-19 was elevated in the pre-exposure period, but not following nirmatrelvir/ritonavir initiation. ALI following nirmatrelvir/ritonavir treatment were mostly mild and less severe than ALI events in non-nirmatrelvir/ritonavir users.
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Affiliation(s)
- Carlos King Ho Wong
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
- Department of Family Medicine and Primary Care, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong SAR, China
| | - Lung Yi Mak
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Ivan Chi Ho Au
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - Wing Yiu Cheng
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ching Hei So
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - Kristy Tsz Kwan Lau
- Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China
| | - Eric Ho Yin Lau
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Benjamin J Cowling
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Gabriel M Leung
- Laboratory of Data Discovery for Health (D24H), Hong Kong Science and Technology Park, Hong Kong SAR, China
- WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Man Fung Yuen
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
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Guarino G, Strollo F, Della Corte T, Satta E, Gentile S. Effect of Policaptil Gel Retard on Liver Fat Content and Fibrosis in Adults with Metabolic Syndrome and Type 2 Diabetes: A Non-invasive Approach to MAFLD. Diabetes Ther 2023; 14:2089-2108. [PMID: 37789214 PMCID: PMC10597984 DOI: 10.1007/s13300-023-01478-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 09/12/2023] [Indexed: 10/05/2023] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is part of a disease spectrum ranging from steatosis to steatohepatitis (NASH), fibrosis, and cirrhosis, and when associated with metabolic syndrome (MS), and overt diabetes is defined as metabolic NAFLD (MAFLD). Some easily available, inexpensive biomarkers have been validated based on common anthropometric and laboratory parameters, including the Fatty Liver Index (FLI), the Fibrosis (FIB)-4 Score (FIB-4), and the NAFLD Fibrosis Score (NFS). In people with overweight/obesity, MS, and diabetes, the pathogenesis of fatty liver involves parameters known to be positively affected by Policaptil Gel Retard (PGR), a phytocomplex already successfully used in adolescents and adults with MS and type 2 diabetes mellitus (T2DM). This study's primary outcome was to assess PGR's ability to improve indirect validated signs of liver steatosis and fibrosis, i.e., FLI, FIB-4, and NFS Scores; as the secondary outcome, we aimed to confirm PGR's positive effects on anthropometric parameters and lipid levels and to assess any eventually occurring cytolysis liver marker changes in patients with MS/T2DM and MAFLD/NASH. METHODS In this spontaneous, longitudinal, single-blind, randomized clinical study, 245 outpatients with MS/T2DM were enrolled and randomized to PGR or placebo for 24 weeks. All underwent a low-calorie diet (20-25% less than the calories required to maintain current weight) and were encouraged to intensify physical activity. Fat distribution, liver fat content/fibrosis, and biochemical parameters were evaluated at baseline and after 24 weeks. RESULTS Our data show for the first time in adults with MAFLD that, when added to lifestyle changes including a hypocaloric diet and intensified physical activity, PGR improves lipid and glucose metabolism-related parameters, including insulin-resistance, and significantly reduces not only visceral fat but also liver fat content and related liver fibrosis severity. The prevalence of subjects with severe steatosis (FLI > 60) significantly decreased from 95.08 to 47.53% (p < 0.001) only in the treatment group, which also displayed a significantly decreased prevalence of medium-severe cases (F3-F4) from 83.62% to 52.35% (p < 0.001) and a markedly increased prevalence of low degree cases (F0-F1) from 9.01 to 42.15% (p < 0.001). CONCLUSIONS The effect of PGR is related to a reduction in the post-meal blood glucose and insulin peaks. As glucose absorption (GA) directly regulates pancreatic insulin release, the attenuated insulin response is likely due to delayed GA with decreased body weight, visceral fat, and cardiovascular risk. Also, an effect on the intestinal microbiota, already documented in the animal model, cannot be excluded, especially considering the reported PGR-related shift from the Firmicutes, notoriously responsible for increased lipid gut absorption, to the Bacteroides phylum.
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Affiliation(s)
- Giuseppina Guarino
- Campania University "Luigi Vanvitelli", Naples, Italy
- Nefrocenter Research Network & Nyx Research Start-Up, Naples, Italy
| | | | | | - Ersilia Satta
- Nefrocenter Research Network & Nyx Research Start-Up, Naples, Italy
| | - Sandro Gentile
- Campania University "Luigi Vanvitelli", Naples, Italy.
- Nefrocenter Research Network & Nyx Research Start-Up, Naples, Italy.
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Allison R, Guraka A, Shawa IT, Tripathi G, Moritz W, Kermanizadeh A. Drug induced liver injury - a 2023 update. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2023; 26:442-467. [PMID: 37786264 DOI: 10.1080/10937404.2023.2261848] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Drug-Induced Liver Injury (DILI) constitutes hepatic damage attributed to drug exposure. DILI may be categorized as hepatocellular, cholestatic or mixed and might also involve immune responses. When DILI occurs in dose-dependent manner, it is referred to as intrinsic, while if the injury occurs spontaneously, it is termed as idiosyncratic. This review predominately focused on idiosyncratic liver injury. The established molecular mechanisms for DILI include (1) mitochondria dysfunction, (2) increased reactive oxygen species levels, (3) presence of elevated apoptosis and necrosis, (4) and bile duct injuries associated with immune mediated pathways. However, it should be emphasized that the underlying mechanisms responsible for DILI are still unknown. Prevention strategies are critical as incidences occur frequently, and treatment options are limited once the injury has developed. The aim of this review was to utilize retrospective cohort studies from across the globe to gain insight into epidemiological patterns. This review considers (1) what is currently known regarding the mechanisms underlying DILI, (2) discusses potential risk factors and (3) implications of the coronavirus pandemic on DILI presentation and research. Future perspectives are also considered and discussed and include potential new biomarkers, causality assessment and reporting methods.
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Affiliation(s)
- Rebecca Allison
- College of Science and Technology, University of Derby, Derby, UK
| | - Asha Guraka
- College of Science and Technology, University of Derby, Derby, UK
| | - Isaac Thom Shawa
- College of Science and Technology, University of Derby, Derby, UK
| | - Gyan Tripathi
- School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | | | - Ali Kermanizadeh
- College of Science and Technology, University of Derby, Derby, UK
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Gao L, Wang W, Wang H, Xu Z, Zhou S, Geng Z, Fu S, Xie C, Zhang Y, Wang Y, Gong F. The safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury. Sci Rep 2023; 13:18324. [PMID: 37884573 PMCID: PMC10603134 DOI: 10.1038/s41598-023-45647-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/22/2023] [Indexed: 10/28/2023] Open
Abstract
Kawasaki disease can be combined with liver injury. As a mainstay treatment for Kawasaki disease, aspirin may cause liver injury. This study aimed to compare the safety and effectiveness of clopidogrel versus aspirin in Kawasaki disease with mild-to-moderate liver injury. This study retrospectively analysed 166 children with Kawasaki disease combined with mild-to-moderate liver injury. The children treated with clopidogrel were less likely to have aggravated liver injury than those treated with aspirin (n = 2/100 vs. n = 13/66, P < 0.001). The initial alanine aminotransferase value of the clopidogrel group was higher (131.5 [98.5, 167.5] vs. 96 [72, 133], P < 0.001), while the time of alanine aminotransferase recovery to normal was similar (5 [4, 7] vs. 4 [3, 7], P = 0.179). No significant fever differences observed between groups: 7.5 [6, 9] for aspirin vs. 7 [6, 8] for clopidogrel group, P = 0.064. The probability of nonresponse to intravenous immunoglobulin (n = 29/100 vs. n = 30/66, P = 0.030) and the days of hospitalization (n = 6 [4, 9] vs. n = 7 [5, 10], P = 0.007) in the clopidogrel group were less than those in the aspirin group. In conclusion, the application of clopidogrel is potentially superior to aspirin in Kawasaki disease combined with mild-to-moderate liver injury.
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Affiliation(s)
- Lichao Gao
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Wei Wang
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Huafeng Wang
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Zhufei Xu
- Department of Pulmonology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Shulai Zhou
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Zhimin Geng
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Songling Fu
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Chunhong Xie
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Yiying Zhang
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China
| | - Yujia Wang
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China.
| | - Fangqi Gong
- Department of Cardiology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, 310052, People's Republic of China.
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Pourmohamadi N, Pour Abdollah Toutkaboni M, Hayati Roodbari N, Tabarsi P, Baniasadi S. Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study. IRANIAN JOURNAL OF MEDICAL SCIENCES 2023; 48:474-483. [PMID: 37786472 PMCID: PMC10541540 DOI: 10.30476/ijms.2023.96145.2765] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/26/2022] [Accepted: 12/17/2022] [Indexed: 10/04/2023]
Abstract
Background Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity. Methods A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant. Results A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001). Conclusion Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.
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Affiliation(s)
- Nasir Pourmohamadi
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mihan Pour Abdollah Toutkaboni
- Molecular Medicine Laboratory, Department of Pathology, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasim Hayati Roodbari
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Payam Tabarsi
- Clinical Tuberculosis and Epidemiology Research Center, National Research Institute for Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shadi Baniasadi
- Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Andrade RJ, Aithal GP, de Boer YS, Liberal R, Gerbes A, Regev A, Terziroli Beretta-Piccoli B, Schramm C, Kleiner DE, De Martin E, Kullak-Ublick GA, Stirnimann G, Devarbhavi H, Vierling JM, Manns MP, Sebode M, Londoño MC, Avigan M, Robles-Diaz M, García-Cortes M, Atallah E, Heneghan M, Chalasani N, Trivedi PJ, Hayashi PH, Taubert R, Fontana RJ, Weber S, Oo YH, Zen Y, Licata A, Lucena MI, Mieli-Vergani G, Vergani D, Björnsson ES. Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report. J Hepatol 2023; 79:853-866. [PMID: 37164270 PMCID: PMC10735171 DOI: 10.1016/j.jhep.2023.04.033] [Citation(s) in RCA: 69] [Impact Index Per Article: 34.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/12/2023]
Abstract
Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.
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Affiliation(s)
- Raúl J Andrade
- Servicio Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, Netherlands
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal
| | | | - Arie Regev
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf. Hamburg Center for Translational Immunology. Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, FHU Hepatinov, Villejuif, France
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Mechanistic Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital University Hospital and University of Bern, Bern, Switzerland
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - John M Vierling
- Departments of Medicine and Surgery, Section of Gastroenterology and Hepatology and Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, United States
| | - Michael P Manns
- Hannover Medical School, Centre of ERN RARE-LIVER, Hannover, Germany
| | - Marcial Sebode
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Maria Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Liver Unit, Hospital Clínic de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Institut d' Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mark Avigan
- Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Mercedes Robles-Diaz
- Servicio Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Miren García-Cortes
- Servicio Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Edmond Atallah
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | | | - Naga Chalasani
- University School of Medicine & Indiana University Health, Indianapolis, Indiana, USA
| | - Palak J Trivedi
- NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research, Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth, Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Paul H Hayashi
- Division of Hepatology and Nutrition, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Robert J Fontana
- Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sabine Weber
- Department of Medicine II, LMU Klinikum Munich, Munich, Germany
| | - Ye Htun Oo
- Center for Liver and Gastro Research & National Institute of Health Research Birmingham Biomedical Research Centre, University of Birmingham, Centre for Rare Disease and ERN Rare Liver Centre, Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, UK
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK
| | - Anna Licata
- Medicina Interna ed Epatologia, Università degli Studi di Palermo, Palermo, Italy
| | - M Isabel Lucena
- Servicio Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Platform ISCiii for Clinical Research and Clinical Trials SCReN UICEC- IBIMA, Málaga, Spain.
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, United Kingdom
| | - Einar S Björnsson
- Faculty of Medicine, University of Iceland, Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
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Bokan G, Glamočanin T, Mavija Z, Vidović B, Stojanović A, Björnsson ES, Vučić V. Herb-Induced Liver Injury by Ayurvedic Ashwagandha as Assessed for Causality by the Updated RUCAM: An Emerging Cause. Pharmaceuticals (Basel) 2023; 16:1129. [PMID: 37631044 PMCID: PMC10459262 DOI: 10.3390/ph16081129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/26/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Herb-induced liver injury (HILI) caused by herbal supplements, natural products, and products used in traditional medicine are important for differential diagnoses in patients with acute liver injury without an obvious etiology. The root of Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been used in Ayurvedic medicine for thousands of years to promote health and longevity. Due to various biological activities, ashwagandha and its extracts became widespread as herbal supplements on the global market. Although it is generally considered safe, there are several reported cases of ashwagandha-related liver injury, and one case ended with liver transplantation. In this paper, we review all reported cases so far. Additionally, we describe two new cases of ashwagandha hepatotoxicity. In the first case, a 36-year-old man used ashwagandha capsules (450 mg, three times daily) for 6 months before he developed nausea, pruritus, and dark-colored urine. In the second case, a 30-year-old woman developed pruritus after 45 days of using ashwagandha capsules (450 mg). In both cases, serum bilirubin and liver enzymes (aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were increased. The liver injury pattern was hepatocellular (R-value 11.1) and mixed (R-value 2.6), respectively. The updated Roussel Uclaf Causality Assessment Method (RUCAM) (both cases with a score of seven) indicated a "probable" relationship with ashwagandha. Clinical and liver function improvements were observed after the discontinuation of ashwagandha supplement use. By increasing the data related to ashwagandha-induced liver injury, these reports support that consuming ashwagandha supplements is not without its safety concerns.
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Affiliation(s)
- Goran Bokan
- Internal Medicine Clinic, Department of Gastroenterology and Hepatology, University Clinical Centre of the Republic of Srpska, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina (Z.M.)
| | - Tanja Glamočanin
- Internal Medicine Clinic, Department of Gastroenterology and Hepatology, University Clinical Centre of the Republic of Srpska, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina (Z.M.)
- Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Zoran Mavija
- Internal Medicine Clinic, Department of Gastroenterology and Hepatology, University Clinical Centre of the Republic of Srpska, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina (Z.M.)
- Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - Bojana Vidović
- Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
| | - Ana Stojanović
- Bežanijska Kosa Clinical Hospital Center, 11000 Belgrade, Serbia;
| | - Einar S. Björnsson
- Landspitali University Hospital, 101 Reykjavik, Iceland
- Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
| | - Vesna Vučić
- Group for Nutritional Biochemistry and Dietology, Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
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Li X, Ni J, Chen L. Advances in the study of acetaminophen-induced liver injury. Front Pharmacol 2023; 14:1239395. [PMID: 37601069 PMCID: PMC10436315 DOI: 10.3389/fphar.2023.1239395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023] Open
Abstract
Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury and acute liver failure. The diagnosis, screening, and management of APAP-induced liver injury (AILI) is challenging because of the complex mechanisms involved. Starting from the current studies on the mechanisms of AILI, this review focuses on novel findings in the field of diagnosis, screening, and management of AILI. It highlights the current issues that need to be addressed. This review is supposed to summarize the recent research progress and make recommendations for future research.
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Affiliation(s)
- Xinghui Li
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Jiaqi Ni
- West China School of Pharmacy, Sichuan University, Chengdu, China
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
| | - Li Chen
- Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, China
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Ma J, Ghabril M, Chalasani N. Drug-Induced Acute-on-Chronic Liver Failure: Challenges and Future Directions. Clin Liver Dis 2023; 27:631-648. [PMID: 37380287 DOI: 10.1016/j.cld.2023.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
Drug-induced liver injury (DILI) is a global problem related to prescription and over-the-counter medications as well as herbal and dietary supplements. It can lead to liver failure with the risk of death and need for liver transplantation. Acute-on-chronic liver failure (ACLF) may be precipitated by DILI and is associated with a high risk of mortality. This review addresses the challenges in defining the diagnostic criteria of drug-induced ACLF (DI-ACLF). The studies characterizing DI-ACLF and its outcomes are summarized, highlighting geographic differences in underlying liver disease and implicated agents, as are future directions in the field.
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Affiliation(s)
- Jiayi Ma
- Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN 46202, USA
| | - Marwan Ghabril
- Gastroenterology and Hepatology, Indiana University School of Medicine & Indiana University Health, 702 Rotary Circle, Suite 225, Indianapolis, IN 46202, USA
| | - Naga Chalasani
- Gastroenterology and Hepatology, Indiana University School of Medicine & Indiana University Health, 702 Rotary Circle, Suite 225, Indianapolis, IN 46202, USA.
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Lim J, Kim JS, Kim HW, Kim YH, Jung SS, Kim JW, Oh JY, Lee H, Kim SK, Kim SH, Lyu J, Ko Y, Kwon SJ, Jeong YJ, Kim DJ, Koo HK, Jegal Y, Kyung SY, An TJ, Min J. Metabolic Disorders Are Associated With Drug-Induced Liver Injury During Antituberculosis Treatment: A Multicenter Prospective Observational Cohort Study in Korea. Open Forum Infect Dis 2023; 10:ofad422. [PMID: 37654787 PMCID: PMC10468151 DOI: 10.1093/ofid/ofad422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/07/2023] [Indexed: 09/02/2023] Open
Abstract
Background Drug-induced liver injury (DILI) may lead to the discontinuation of antituberculosis (anti-TB) treatment (ATT). Some studies have suggested that metabolic disorders increase the risk of DILI during ATT. This study aimed to identify risk factors for DILI, particularly metabolic disorders, during ATT. Methods A multicenter prospective observational cohort study to evaluate adverse events during ATT was conducted in Korea from 2019 to 2021. Drug-susceptible patients with TB who had been treated with standard ATT for 6 months were included. The patients were divided into 2 groups depending on the presence of 1 or more metabolic conditions, such as insulin resistance, hypertension, obesity, and dyslipidemia. We monitored ATT-related adverse events, including DILI, and treatment outcomes. The incidence of DILI was compared between individuals with and without metabolic disorders, and related factors were evaluated. Results Of 684 patients, 52 (7.6%) experienced DILI, and 92.9% of them had metabolic disorders. In the multivariable analyses, underlying metabolic disorders (adjusted hazard ratio [aHR], 2.85; 95% CI, 1.01-8.07) and serum albumin <3.5 g/dL (aHR, 2.26; 95% CI, 1.29-3.96) were risk factors for DILI during ATT. In the 1-month landmark analyses, metabolic disorders were linked to an elevated risk of DILI, especially significant alanine aminotransferase elevation. The treatment outcome was not affected by the presence of metabolic disorders. Conclusions Patients with metabolic disorders have an increased risk of ATT-induced liver injury compared with controls. The presence of metabolic disorders and hypoalbuminemia adversely affects the liver in patients with ATT.
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Affiliation(s)
- Jihye Lim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ju Sang Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yong Hyun Kim
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Soo Jung
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Jin Woo Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jee Youn Oh
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Heayon Lee
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Kyoung Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sun-Hyung Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea
| | - Jiwon Lyu
- Department of Pulmonary and Critical Care Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
| | - Yousang Ko
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Sun Jung Kwon
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Konyang University Hospital, Konyang University College of Medicine, Daejeon, Republic of Korea
| | - Yun-Jeong Jeong
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea
| | - Do Jin Kim
- Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
| | - Hyeon-Kyoung Koo
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
| | - Yangjin Jegal
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, Republic of Korea
| | - Sun Young Kyung
- Division of Pulmonology, Departments of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea
| | - Tai Joon An
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jinsoo Min
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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