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Church RJ, Anchang B, Bennett BD, Bushel PR, Watkins PB. Blood toxicogenomics reveals potential biomarkers for management of idiosyncratic drug-induced liver injury. Front Genet 2025; 16:1524433. [PMID: 40201567 PMCID: PMC11975945 DOI: 10.3389/fgene.2025.1524433] [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: 11/07/2024] [Accepted: 03/04/2025] [Indexed: 04/10/2025] Open
Abstract
Introduction: Accurate diagnosis, assessment, and prognosis of idiosyncratic drug-induced liver injury (IDILI) is problematic, in part due to the shortcomings of traditional blood biomarkers. Studies in rodents and healthy volunteers have supported that RNA transcript changes in whole blood may address some of these shortcomings. Methods: In this study, we conducted RNA-Seq analysis on peripheral blood samples collected from 55 patients with acute IDILI and 17 patients with liver injuries not attributed to IDILI. Results and discussion: Three differentially expressed genes (DEGs; CFD, SQLE, and INKA1) were identified as significantly associated with IDILI vs. other liver injuries. No DEGs were identified comparing IDILI patients to the 5 patients with autoimmune hepatitis, suggesting possible common underlying mechanisms. Two genes (VMO1 and EFNA1) were significantly associated with hepatocellular injury compared to mixed/cholestatic injury. When patients with severe vs. milder IDILI were compared, we identified over 500 DEGs. The top pathways identified from these DEGs had in common down regulation of multiple T-cell specific genes. Further analyses confirmed that these changes could largely be accounted for by a fall in the concentration of circulating T-cells during severe DILI, perhaps due to exhaustion or sequestration of these cells in the liver. Exploration of DEGs specific for the individual causal agents was largely unsuccessful, but isoniazid-induced IDILI demonstrated 25 DEGs compared to other non-isoniazid IDILI cases. Finally, among the 14 IDILI patients that had hepatocellular jaundice (i.e., Hy's Law cases), we identified 39 DEGs between the 4 patients with fatal or liver transplantation outcomes compared to those that recovered. These findings suggest the potential for blood-based transcriptomic biomarkers to aid in the diagnosis and prognostic stratification of IDILI.
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Affiliation(s)
- Rachel J. Church
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, United States
| | - Benedict Anchang
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Brian D. Bennett
- Integrative Bioinformatics Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Pierre R. Bushel
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, United States
| | - Paul B. Watkins
- Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC, United States
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Gu X, Zou Y, Huang Z, Wei M, Ji L. Biochemical biomarkers for the toxicity induced by Traditional Chinese Medicine: A review update. JOURNAL OF ETHNOPHARMACOLOGY 2025; 341:119315. [PMID: 39755183 DOI: 10.1016/j.jep.2024.119315] [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: 07/10/2024] [Revised: 12/31/2024] [Accepted: 12/31/2024] [Indexed: 01/06/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM) is widely used in China for disease treatment and has become a valuable resource for drug development due to its high efficacy and low risk of side-effects. However, growing toxicity reports has garnered significant global attention. A major challenge in addressing TCM-induced toxicity is lack of specific and sensitive biomarkers for diagnosing and predicting its toxicity. Identifying toxicological biomarkers reflecting TCM-induced toxicity is crucial for timely detection and intervention, and provides significant clues for elucidating the underlying toxic mechanism and key target. AIM OF THE STUDY This article aims to summarize and classify some potential toxicological biomarkers for side-effects induced by TCM and its contained phytochemical ingredients. METHODS The keywords "biomarkers", "traditional Chinese medicine", "Chinese herb", "phytochemical ingredient", "natural product", "toxicity", "hepatotoxicity", "nephrotoxicity", "cardiotoxicity" were used to collect relevant information from literature databases (including PubMed, Web of Science) up to October 2024. RESULTS Research has indicated that more sensitive and specific biomarkers are needed for reflecting TCM's side-effects. PA-protein adducts and AA-DNA adducts could be served as diagnostic biomarkers for hepatotoxicity and nephrotoxicity induced by TCM containing PA and AA, respectively. Multiple miRNAs like miRNA-122-3p, miRNA-5099, and miRNA-21-3p, as well as some endogenous metabolites such as hypoxanthine, choline, and L-valine could be potential biomarkers associated with TCM-induced hepatotoxicity, nephrotoxicity, and cardiotoxicity. CONCLUSION In this review, different research demonstrates that DNA/protein-adducts, noncoding RNAs, endogenous metabolites and so on show the potential to be new early-warning biomarkers for TCM-induced toxicity with high specificity and sensitivity.
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Affiliation(s)
- Xinnan Gu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yu Zou
- School of Basic Medical Science of Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai Academy of International Standardization for Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Mikulski D, Kościelny K, Dróżdż I, Mirocha G, Nowicki M, Misiewicz M, Perdas E, Strzałka P, Wierzbowska A, Fendler W. Serum Levels of miR-122-5p and miR-125a-5p Predict Hepatotoxicity Occurrence in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation. Int J Mol Sci 2024; 25:4355. [PMID: 38673940 PMCID: PMC11050045 DOI: 10.3390/ijms25084355] [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: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)-miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p-in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29-3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11-0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63-0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures.
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Affiliation(s)
- Damian Mikulski
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
- Department of Hematooncology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Kacper Kościelny
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Izabela Dróżdż
- Department of Clinical Genetics, Medical University of Lodz, 92-215 Lodz, Poland;
| | - Grzegorz Mirocha
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Mateusz Nowicki
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Małgorzata Misiewicz
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
| | - Ewelina Perdas
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
| | - Piotr Strzałka
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Agnieszka Wierzbowska
- Department of Hematology, Medical University of Lodz, 92-215 Lodz, Poland; (M.N.); (M.M.); (P.S.); (A.W.)
- Department of Hematology and Transplantology, Copernicus Memorial Hospital in Lodz, 93-513 Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, 92-215 Lodz, Poland; (D.M.); (K.K.); (G.M.); (E.P.)
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential of microRNA-based therapy for patients with liver failure syndromes and hepatocellular carcinoma. Expert Opin Ther Targets 2024; 28:179-191. [PMID: 38487923 DOI: 10.1080/14728222.2024.2331598] [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: 12/21/2023] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
INTRODUCTION Morbidity and mortality from liver disease continues to rise worldwide. There are currently limited curative treatments for patients with liver failure syndromes, encompassing acute liver failure and decompensated cirrhosis states, outside of transplantation. Whilst there have been improvements in therapeutic options for patients with hepatocellular carcinoma (HCC), there remain challenges necessitating novel therapeutic agents. microRNA have long been seen as potential therapeutic targets but there has been limited clinical translation. AREAS COVERED We will discuss the limitations of conventional non-transplant management of patients with liver failure syndromes and HCC. We will provide an overview of microRNA and the challenges in developing and delivering microRNA-based therapeutic agents. We will finally provide an overview of microRNA-based therapeutic agents which have progressed to clinical trials. EXPERT OPINION microRNA have great potential to be developed into therapeutic agents due to their association with critical biological processes which govern health and disease. Utilizing microRNA sponges to target multiple microRNA associated with specific biological processes may improve their therapeutic efficacy. However, there needs to be significant improvements in delivery systems to ensure the safe delivery of microRNA to target sites and minimize systemic distribution. This currently significantly impacts the clinical translation of microRNA-based therapeutic agents.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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Tavabie OD, Salehi S, Aluvihare VR. The challenges and potential in developing microRNA associated with regeneration as biomarkers to improve prognostication for liver failure syndromes and hepatocellular carcinoma. Expert Rev Mol Diagn 2024; 24:5-22. [PMID: 38059597 DOI: 10.1080/14737159.2023.2292642] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 12/05/2023] [Indexed: 12/08/2023]
Abstract
INTRODUCTION Determining the need for liver transplantation remains critical in the management of hepatocellular carcinoma (HCC) and liver failure syndromes (including acute liver failure and decompensated cirrhosis states). Conventional prognostic models utilize biomarkers of liver and non-liver failure and have limitations in their application. Novel biomarkers which predict regeneration may fulfil this niche. microRNA are implicated in health and disease and are present in abundance in the circulation. Despite this, they have not translated into mainstream clinical biomarkers. AREAS COVERED We will discuss current challenges in the prognostication of patients with liver failure syndromes as well as for patients with HCC. We will discuss biomarkers implicated with liver regeneration. We then provide an overview of the challenges in developing microRNA into clinically tractable biomarkers. Finally, we will provide a scoping review of microRNA which may have potential as prognostic biomarkers in liver failure syndromes and HCC. EXPERT OPINION Novel biomarkers are needed to improve prognostic models in liver failure syndromes and HCC. Biomarkers associated with liver regeneration are currently lacking and may fulfil this niche. microRNA have the potential to be developed into clinically tractable biomarkers but a consensus on standardizing methodology and reporting is required prior to large-scale studies.
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Affiliation(s)
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
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Grove JI, Stephens C, Lucena MI, Andrade RJ, Weber S, Gerbes A, Bjornsson ES, Stirnimann G, Daly AK, Hackl M, Khamina-Kotisch K, Marin JJG, Monte MJ, Paciga SA, Lingaya M, Forootan SS, Goldring CEP, Poetz O, Lombaard R, Stege A, Bjorrnsson HK, Robles-Diaz M, Li D, Tran TDB, Ramaiah SK, Samodelov SL, Kullak-Ublick GA, Aithal GP. Study design for development of novel safety biomarkers of drug-induced liver injury by the translational safety biomarker pipeline (TransBioLine) consortium: a study protocol for a nested case-control study. Diagn Progn Res 2023; 7:18. [PMID: 37697410 PMCID: PMC10496294 DOI: 10.1186/s41512-023-00155-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 08/08/2023] [Indexed: 09/13/2023] Open
Abstract
A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative's TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case-control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.
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Affiliation(s)
- Jane I Grove
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Camilla Stephens
- Servicios de Aparato Digestivo Y Farmacologia Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Hospital Universitario Virgen de La Victoria, Universidad de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
| | - M Isabel Lucena
- Servicios de Aparato Digestivo Y Farmacologia Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Hospital Universitario Virgen de La Victoria, Universidad de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
| | - Raúl J Andrade
- Servicios de Aparato Digestivo Y Farmacologia Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Hospital Universitario Virgen de La Victoria, Universidad de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
| | - Sabine Weber
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Alexander Gerbes
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Einar S Bjornsson
- Department of Gastroenterology, Landspitali University Hospital Reykjavik, University of Iceland, Reykjavík, Iceland
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, University Hospital Inselspital and University of Bern, Bern, Switzerland
| | - Ann K Daly
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
| | | | | | - Jose J G Marin
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Maria J Monte
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
- Experimental Hepatology and Drug Targeting (HEVEPHARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Sara A Paciga
- Worldwide Research Development and Medical, Pfizer, NY, USA
| | - Melanie Lingaya
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
| | - Shiva S Forootan
- Centre for Drug Safety Science, University of Liverpool, Liverpool, UK
| | | | | | - Rudolf Lombaard
- ABX-CRO Advanced Pharmaceutical Services, Forschungsgesellschaft mbH, Cape Town, 7441, South Africa
| | - Alexandra Stege
- Charité-Universitätsmedizin Berlin, Central Biobank Charité (ZeBanC), Berlin, Germany
| | - Helgi K Bjorrnsson
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mercedes Robles-Diaz
- Servicios de Aparato Digestivo Y Farmacologia Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA Plataforma Bionand, Hospital Universitario Virgen de La Victoria, Universidad de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas Y Digestivas (CIBERehd), Madrid, Spain
| | - Dingzhou Li
- Worldwide Research Development and Medical, Pfizer, NY, USA
| | | | | | - Sophia L Samodelov
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006, Zurich, Switzerland
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006, Zurich, Switzerland
- Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, 4056, Basel, Switzerland
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
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Moosa MS, Russomanno G, Dorfman JR, Gunter H, Patel C, Costello E, Carr D, Maartens G, Pirmohamed M, Goldring C, Cohen K. Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury. Br J Clin Pharmacol 2023; 89:1844-1851. [PMID: 36639145 PMCID: PMC10952339 DOI: 10.1111/bcp.15661] [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: 10/24/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/15/2023] Open
Abstract
AIM Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.
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Affiliation(s)
- Muhammed Shiraz Moosa
- New Somerset Hospital, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Giusy Russomanno
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Jeffrey R. Dorfman
- Division of Medical Virology, Department of PathologyUniversity of StellenboschCape TownSouth Africa
| | - Hannah Gunter
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Chandni Patel
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Dan Carr
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Gary Maartens
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Christopher Goldring
- Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Karen Cohen
- Division of Clinical Pharmacology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
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Singh S, Kumar PVSNK, Kumar JP, Tomo S, Yadav D, Sharma P, Rao M, Banerjee M. Genetic and Epigenetic Basis of Drug-Induced Liver Injury. Semin Liver Dis 2023; 43:163-175. [PMID: 37225145 DOI: 10.1055/a-2097-0531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Drug-induced liver injury (DILI) is a rare but severe adverse drug reaction seen in pharmacotherapy and a major cause of postmarketing drug withdrawals. Advances in genome-wide studies indicate that genetic and epigenetic diversity can lead to inter-individual differences in drug response and toxicity. It is necessary to identify how the genetic variations, in the presence of environmental factors, can contribute to development and progression of DILI. Studies on microRNA, histone modification, DNA methylation, and single nucleotide polymorphisms related to DILI were retrieved from databases and were analyzed for the current research and updated to develop this narrative review. We have compiled some of the major genetic, epigenetic, and pharmacogenetic factors leading to DILI. Many validated genetic risk factors of DILI, such as variants of drug-metabolizing enzymes, HLA alleles, and some transporters were identified. In conclusion, these studies provide useful information in risk alleles identification and on implementation of personalized medicine.
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Affiliation(s)
- Snigdha Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - P V S N Kiran Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - J Pradeep Kumar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Dharamveer Yadav
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal, Karnataka, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
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Doghish AS, Elballal MS, Elazazy O, Elesawy AE, Elrebehy MA, Shahin RK, Midan HM, Sallam AAM. The role of miRNAs in liver diseases: Potential therapeutic and clinical applications. Pathol Res Pract 2023; 243:154375. [PMID: 36801506 DOI: 10.1016/j.prp.2023.154375] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/16/2023]
Abstract
MicroRNAs (miRNAs) are a class of short, non-coding RNAs that function post-transcriptionally to regulate gene expression by binding to particular mRNA targets and causing destruction of the mRNA or translational inhibition of the mRNA. The miRNAs control the range of liver activities, from the healthy to the unhealthy. Considering that miRNA dysregulation is linked to liver damage, fibrosis, and tumorigenesis, miRNAs are a promising therapeutic strategy for the evaluation and treatment of liver illnesses. Recent findings on the regulation and function of miRNAs in liver diseases are discussed, with an emphasis on miRNAs that are highly expressed or enriched in hepatocytes. Alcohol-related liver illness, acute liver toxicity, viral hepatitis, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and exosomes in chronic liver disease all emphasize the roles and target genes of these miRNAs. We briefly discuss the function of miRNAs in the etiology of liver diseases, namely in the transfer of information between hepatocytes and other cell types via extracellular vesicles. Here we offer some background on the use of miRNAs as biomarkers for the early prognosis, diagnosis, and assessment of liver diseases. The identification of biomarkers and therapeutic targets for liver disorders will be made possible by future research into miRNAs in the liver, which will also help us better understand the pathogeneses of liver diseases.
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Affiliation(s)
- Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ola Elazazy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed E Elesawy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
| | - Reem K Shahin
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Heba M Midan
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
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10
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Atic AI, Thiele M, Munk A, Dalgaard LT. Circulating miRNAs associated with nonalcoholic fatty liver disease. Am J Physiol Cell Physiol 2023; 324:C588-C602. [PMID: 36645666 DOI: 10.1152/ajpcell.00253.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
MicroRNAs (miRNAs) are secreted from cells as either protein-bound or enclosed in extracellular vesicles. Circulating liver-derived miRNAs are modifiable by weight-loss or insulin-sensitizing treatments, indicating that they could be important biomarker candidates for diagnosis, monitoring, and prognosis in nonalcoholic liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Unfortunately, the noninvasive diagnosis of NASH and fibrosis remains a key challenge, which limits case finding. Current diagnostic guidelines, therefore, recommend liver biopsies, with risks of pain and bleeding for the patient and substantial healthcare costs. Here, we summarize mechanisms of RNA secretion and review circulating RNAs associated with NAFLD and NASH for their biomarker potential. Few circulating miRNAs are consistently associated with NAFLD/NASH: miR-122, miR-21, miR-34a, miR-192, miR-193, and the miR-17-92 miRNA-cluster. The hepatocyte-enriched miRNA-122 is consistently increased in NAFLD and NASH but decreased in liver cirrhosis. Circulating miR-34a, part of an existing diagnostic algorithm for NAFLD, and miR-21 are consistently increased in NAFLD and NASH. MiR-192 appears to be prominently upregulated in NASH compared with NAFDL, whereas miR-193 was reported to distinguish NASH from fibrosis. Various members of miRNA cluster miR-17-92 are reported to be associated with NAFLD and NASH, although with less consistency. Several other circulating miRNAs have been reported to be associated with fatty liver in a few studies, indicating the existence of more circulating miRNAs with relevant as diagnostic markers for NAFLD or NASH. Thus, circulating miRNAs show potential as biomarkers of fatty liver disease, but more information about phenotype specificity and longitudinal regulation is needed.
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Affiliation(s)
- Amila Iriskic Atic
- Department of Science and Environment, Roskilde University, Roskilde, Denmark.,Novo Nordisk A/S, Obesity Research, Måløv, Denmark
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, Center for Liver Research, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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11
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Floreani A, Bizzaro D, Shalaby S, Taliani G, Burra P. Sex disparity and drug-induced liver injury. Dig Liver Dis 2023; 55:21-28. [PMID: 35843842 DOI: 10.1016/j.dld.2022.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 12/31/2022]
Abstract
Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.
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Affiliation(s)
- A Floreani
- Scientific Consultant Scientific Institute for Research, Hospitalization and Healthcare, Negrar, Verona, Italy; Senior Scholar, University of Padova, Padova, Italy.
| | - D Bizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - S Shalaby
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - G Taliani
- Department of Infectious and Tropical Diseases, La Sapienza University of Rome, Rome, Italy
| | - P Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
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12
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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13
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Di Zeo-Sánchez DE, Segovia-Zafra A, Matilla-Cabello G, Pinazo-Bandera JM, Andrade RJ, Lucena MI, Villanueva-Paz M. Modeling drug-induced liver injury: current status and future prospects. Expert Opin Drug Metab Toxicol 2022; 18:555-573. [DOI: 10.1080/17425255.2022.2122810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Daniel E. Di Zeo-Sánchez
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain
| | - Antonio Segovia-Zafra
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain
| | - Gonzalo Matilla-Cabello
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
| | - José M. Pinazo-Bandera
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
| | - Raúl J. Andrade
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain
| | - M. Isabel Lucena
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), 28029, Madrid, Spain
- Plataforma ISCIII de Ensayos Clínicos. UICEC-IBIMA, 29071, Malaga, Spain
| | - Marina Villanueva-Paz
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29071 Málaga, Spain
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14
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Weber S, Gerbes AL. Challenges and Future of Drug-Induced Liver Injury Research-Laboratory Tests. Int J Mol Sci 2022; 23:ijms23116049. [PMID: 35682731 PMCID: PMC9181520 DOI: 10.3390/ijms23116049] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) is a rare but potentially severe adverse drug event, which is also a major cause of study cessation and market withdrawal during drug development. Since no acknowledged diagnostic tests are available, DILI diagnosis poses a major challenge both in clinical practice as well as in pharmacovigilance. Differentiation from other liver diseases and the identification of the causative agent in the case of polymedication are the main issues that clinicians and drug developers face in this regard. Thus, efforts have been made to establish diagnostic testing methods and biomarkers in order to safely diagnose DILI and ensure a distinguishment from alternative liver pathologies. This review provides an overview of the diagnostic methods used in differential diagnosis, especially with regards to autoimmune hepatitis (AIH) and drug-induced autoimmune hepatitis (DI-AIH), in vitro causality methods using individual blood samples, biomarkers for diagnosis and severity prediction, as well as experimental predictive models utilized in pre-clinical settings during drug development regimes.
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15
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Orzeł-Gajowik K, Milewski K, Zielińska M. Insight into microRNAs-Mediated Communication between Liver and Brain: A Possible Approach for Understanding Acute Liver Failure? Int J Mol Sci 2021; 23:224. [PMID: 35008650 PMCID: PMC8745738 DOI: 10.3390/ijms23010224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy. Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade's reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood-brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.
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Affiliation(s)
| | | | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland; (K.O.-G.); (K.M.)
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16
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Lin Y, Xu M, Yi W, Sun F, Zeng Z, Bi X, Yang L, Zhang L, LI M, Xie Y. Analysis of Clinical Characteristics and Chronic Factors of Drug-induced Liver Injury in Chronic Hepatitis B Infection: A Retrospective Study. HEPATITIS MONTHLY 2021; 21. [DOI: 10.5812/hepatmon.119328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Background: This study investigated clinical characteristics and chronic factors of drug-induced liver injury (DILI) among patients with chronic hepatitis B virus (HBV) infection. Methods: DILI patients were enrolled and divided into a DILI group and an HBV+DILI group. Laboratory indicators were recorded and analyzed. Multivariate logistic regression and the receiver operating characteristic (ROC) curve were used to determine risk factors and the predictive value for chronic DILI. Results: Of all the 114 patients, 87 were in the DILI group and 27 were in the HBV+DILI group. Baseline total bilirubin (TBIL), direct bilirubin (DBIL), and incidence of chronicity were significantly higher in the HBV+DILI group than in the DILI group (P = 0.017, P = 0.037, P = 0.045, respectively). However, platelet (PLT) and prothrombin activity (PTA) were significantly lower in the HBV+DILI group than in the DILI group (P = 0.022, P = 0.013, respectively). HBV infection, baseline aspartate aminotransferase (AST) > 200 U/L, and TBIL > 34.2 μmol/L were predictors of chronic DILI (OR = 4.481 [95% CI, 1.298 - 15.470], P = 0.018; OR = 8.478 [95% CI, 2.079 - 34.566], P = 0.003; OR = 7.358 [95% CI, 2.215 - 24.446], P = 0.001). The area under ROC curve (AUC) of joint diagnosis for chronic DILI was 0.814 (95% CI, 0.704 - 0.925, P < 0.001), which was significantly higher than that of single parameter prediction. Also, the sensitivity, specificity, positive predictive value, and negative predictive value of joint diagnosis were 81.0%, 73.1%, 40.5%, and 94.4%, respectively. Conclusions: HBV infection aggravated liver injury. HBV infection, baseline AST > 200 U/L, and TBIL > 34.2 μmol/L were predictors of chronic DILI, and their joint diagnosis could be used to predict chronic DILI effectively.
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Segovia-Zafra A, Di Zeo-Sánchez DE, López-Gómez C, Pérez-Valdés Z, García-Fuentes E, Andrade RJ, Lucena MI, Villanueva-Paz M. Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction. Acta Pharm Sin B 2021; 11:3685-3726. [PMID: 35024301 PMCID: PMC8727925 DOI: 10.1016/j.apsb.2021.11.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/07/2021] [Accepted: 11/10/2021] [Indexed: 02/08/2023] Open
Abstract
Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.
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Affiliation(s)
- Antonio Segovia-Zafra
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
| | - Daniel E. Di Zeo-Sánchez
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
| | - Carlos López-Gómez
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
| | - Zeus Pérez-Valdés
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
| | - Eduardo García-Fuentes
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga 29010, Spain
| | - Raúl J. Andrade
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
| | - M. Isabel Lucena
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain
- Platform ISCIII de Ensayos Clínicos, UICEC-IBIMA, Málaga 29071, Spain
| | - Marina Villanueva-Paz
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga 29071, Spain
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18
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Lv XF, Zhang AQ, Liu WQ, Zhao M, Li J, He L, Cheng L, Sun YF, Qin G, Lu P, Ji YH, Ji JL. Liver injury changes the biological characters of serum small extracellular vesicles and reprograms hepatic macrophages in mice. World J Gastroenterol 2021; 27:7509-7529. [PMID: 34887646 PMCID: PMC8613741 DOI: 10.3748/wjg.v27.i43.7509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/21/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum small extracellular vesicles (sEVs) and their small RNA (sRNA) cargoes could be promising biomarkers for the diagnosis of liver injury. However, the dynamic changes in serum sEVs and their sRNA components during liver injury have not been well characterized. Given that hepatic macrophages can quickly clear intravenously injected sEVs, the effect of liver injury-related serum sEVs on hepatic macrophages deserves to be explored.
AIM To identify the characteristics of serum sEVs and the sRNAs during liver injury and explore their effects on hepatic macrophages.
METHODS To identify serum sEV biomarkers for liver injury, we established a CCL4-induced mouse liver injury model in C57BL/6 mice to simulate acute liver injury (ALI), chronic liver injury (CLI) and recovery. Serum sEVs were obtained and characterized by transmission electron microscopy and nanoparticle tracking analysis. Serum sEV sRNAs were profiled by sRNA sequencing. Differentially expressed microRNAs (miRNAs) were compared to mouse liver-enriched miRNAs and previously reported circulating miRNAs related to human liver diseases. The biological significance was evaluated by Ingenuity Pathway Analysis of altered sEV miRNAs and conditioned cultures of ALI serum sEVs with primary hepatic macrophages.
RESULTS We found that both ALI and CLI changed the concentration and morphology of serum sEVs. The proportion of serum sEV miRNAs increased upon liver injury, with the liver as the primary contributor. The altered serum sEV miRNAs based on mouse studies were consistent with human liver disease-related circulating miRNAs. We established serum sEV miRNA signatures for ALI and CLI and a panel of miRNAs (miR-122-5p, miR-192-5p, and miR-22-3p) as a common marker for liver injury. The differential serum sEV miRNAs in ALI contributed mainly to liver steatosis and inflammation, while those in CLI contributed primarily to hepatocellular carcinoma and hyperplasia. ALI serum sEVs decreased both CD86 and CD206 expression in monocyte-derived macrophages but increased CD206 expression in resident macrophages in vitro.
CONCLUSION Serum sEVs acquired different concentrations, sizes, morphologies and sRNA contents upon liver injury and could change the phenotype of liver macrophages. Serum sEVs therefore have good diagnostic and therapeutic potential for liver injury.
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Affiliation(s)
- Xiu-Fang Lv
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - An-Qi Zhang
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Wei-Qi Liu
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Min Zhao
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Jing Li
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Li He
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing 210093, Jiangsu Province, China
| | - Li Cheng
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Pathology, Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, Jiangsu Province, China
| | - Yu-Feng Sun
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Gang Qin
- Nantong Institute of Liver Diseases, Nantong Third People’s Hospital, Nantong University, Nantong 226006, Jiangsu Province, China
| | - Peng Lu
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
| | - Yu-Hua Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226001, Jiangsu Province, China
- Institute of Immunology, College of Life Science and Technology, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Ju-Ling Ji
- Department of Pathology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Science and Technology Bureau of Nantong City, Nantong 226001, Jiangsu Province, China
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19
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Schofield AL, Brown JP, Brown J, Wilczynska A, Bell C, Glaab WE, Hackl M, Howell L, Lee S, Dear JW, Remes M, Reeves P, Zhang E, Allmer J, Norris A, Falciani F, Takeshita LY, Seyed Forootan S, Sutton R, Park BK, Goldring C. Systems analysis of miRNA biomarkers to inform drug safety. Arch Toxicol 2021; 95:3475-3495. [PMID: 34510227 PMCID: PMC8492583 DOI: 10.1007/s00204-021-03150-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023]
Abstract
microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.
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Affiliation(s)
- Amy L Schofield
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Joseph P Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Jack Brown
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Ania Wilczynska
- bit.bio, Babraham Research Campus, The Dorothy Hodgkin Building, Cambridge, CB22 3FH, UK
| | - Catherine Bell
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Warren E Glaab
- Merck & Co., Inc, 770 Sumneytown Pike, West Point, PA, 19486, USA
| | | | - Lawrence Howell
- GlaxoSmithKline (GSK), Stevenage, Greater Cambridge Area, UK
| | - Stephen Lee
- ABHI, 1 Duchess St, 4th Floor, Suite 2, London, W1W 6AN, UK
| | - James W Dear
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Mika Remes
- Genomics EMEA, QIAGEN Aarhus, Prismet, Silkeborgvej 2, 8000, Aarhus C, Denmark
| | - Paul Reeves
- Arcis Biotechnology Limited, Suite S07, Techspace One, Sci-tech Daresbury, Keckwick Lane, Daresbury, Warrington, WA4 4AB, UK
| | - Eunice Zhang
- Wolfson Centre for Personalised Medicine, Department of Pharmacology and Therapeutics, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
| | - Jens Allmer
- Applied Bioinformatics, Bioscience, Wageningen University and Research, Droevendaalsesteeg 4, 6708 PB, Wageningen, The Netherlands
| | - Alan Norris
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Francesco Falciani
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Louise Y Takeshita
- Computational Biology Facility, MerseyBio, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
| | - Shiva Seyed Forootan
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Robert Sutton
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Biosciences Building, Crown Street, Liverpool, L69 7BE, UK
| | - B Kevin Park
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK
| | - Chris Goldring
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool, L69 3GE, UK.
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20
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Atallah E, Freixo C, Alvarez-Alvarez I, Cubero F, Gerbes AL, Kullak-Ublick GA, Aithal GP. Biomarkers of idiosyncratic drug-induced liver injury (DILI) - a systematic review. Expert Opin Drug Metab Toxicol 2021; 17:1327-1343. [PMID: 34727797 PMCID: PMC7617394 DOI: 10.1080/17425255.2021.1999410] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/21/2021] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Idiosyncratic drug-induced liver injury (DILI) is an unpredictable event, and there are no specific biomarkers that can distinguish DILI from alternative explanations or predict its clinical outcomes. AREAS COVERED This systematic review summarizes the available evidence for all biomarkers proposed to have a role in the diagnosis or prognosis of DILI. Following a comprehensive search, we included all types of studies in humans. We included DILI cases based on any threshold criteria but excluded intrinsic DILI, commonly caused by paracetamol overdose. We classified studies into diagnostic and prognostic categories and assessed their methodological quality. After reviewing the literature, 14 studies were eligible. EXPERT OPINION Diagnostic studies were heterogeneous with regard to the study population and outcomes measured. Prognostic models were developed by integrating novel biomarkers, risk scores, and traditional biomarkers, which increased their prognostic ability to predict death or transplantation by 6 months. This systematic review highlights the case of need for non-genetic biomarkers that distinguish DILI from acute liver injury related to alternative etiology. Biomarkers with the potential to identify serious adverse outcomes from acute DILI should be validated in independent prospective cohorts with a substantial number of cases.
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Affiliation(s)
- Edmond Atallah
- School of Medicine, Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre, Nottingham University Hospitals Nhs Trust and the University of Nottingham, Nottingham, UK
| | - Cristiana Freixo
- Cintesis, Center for Health Technology and Services Research, Faculdade De Medicina Da Universidade Do Porto, Porto, Portugal
| | - Ismael Alvarez-Alvarez
- Servicio De Farmacología Clínica and Ugc Aparato Digestivo, Hospital Universitario Virgen De La Victoria, Instituto De Investigación Biomédica De Málaga-IBIMA, Universidad De Málaga, Málaga, Spain
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas (Ciberehd), Madrid, Spain
| | - F.J Cubero
- Centro De Investigación Biomédica En Red De Enfermedades Hepáticas Y Digestivas (Ciberehd), Madrid, Spain
- Department of Immunology, Ophthalmology, and ENT, Complutense University School of Medicine, Madrid, Spain
| | - Alexander L. Gerbes
- Department of Medicine, Liver Centre Munich, University Hospital Munich, Munich, Germany
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland
| | - Guruprasad P. Aithal
- School of Medicine, Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- National Institute for Health Research (NIHR)Nottingham Biomedical Research Centre, Nottingham University Hospitals Nhs Trust and the University of Nottingham, Nottingham, UK
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21
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Barrera-Saldaña HA, Fernández-Garza LE, Barrera-Barrera SA. Liquid biopsy in chronic liver disease. Ann Hepatol 2021; 20:100197. [PMID: 32444248 DOI: 10.1016/j.aohep.2020.03.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 03/25/2020] [Indexed: 02/04/2023]
Abstract
Chronic liver diseases account for a considerable toll of incapacities, suffering, deaths, and resources of the nation's health systems. They can be prevented, treated or even cured when the diagnosis is made on time. Traditional liver biopsy remains the gold standard to diagnose liver diseases, but it has several limitations. Liquid biopsy is emerging as a superior alternative to surgical biopsy given that it surpasses the limitations: it is more convenient, readily and repeatedly accessible, safe, cheap, and provides a more detailed molecular and cellular representation of the individual patient's disease. Progress in understanding the molecular and cellular bases of diseased tissues and organs that normally release cells and cellular components into the bloodstream is catapulting liquid biopsy as a source of biomarkers for diagnosis, prognosis, and prediction of therapeutic response, thus supporting the realization of the promises of precision medicine. The review aims to summarize the evidence of the usefulness of liquid biopsy in liver diseases, including the presence of different biomarkers as circulating epithelial cells, cell-free nucleic acids, specific species of DNA and RNA, and the content of extracellular vesicles.
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Affiliation(s)
- Hugo A Barrera-Saldaña
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; Center for Biotechnological Genomics of National Polytechnical Institute, Reynosa, Tamps., Mexico.
| | - Luis E Fernández-Garza
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico
| | - Silvia A Barrera-Barrera
- Innbiogem SC at National Laboratory for Services of Research, Development, and Innovation for the Pharma and Biotech Industries (LANSEDI) of CONACyT Vitaxentrum group, Monterrey, N.L., Mexico; National Institute of Pediatrics, Mexico City, Mexico
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22
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De la Pinta C. Toward Personalized Medicine in Radiotherapy of Hepatocellular Carcinoma: Emerging Radiomic Biomarker Candidates of Response and Toxicity. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:537-544. [PMID: 34448625 DOI: 10.1089/omi.2021.0065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Radiology and radiotherapy are currently undergoing radical transformation with use of biomarkers and digital technologies such as artificial intelligence. These current and upcoming changes in radiology speak of an overarching new vision for personalized medicine. This is particularly evident in the case of radiotherapy of cancers, and of liver cancer in particular. The development of modern radiotherapy with stereotactic body radiotherapy allows targeted treatments to be delivered to the tumor site, limiting the dose to surrounding healthy organs, thus becoming a new therapeutic alternative for hepatocellular carcinoma and other liver tumors. However, not all patients have the same response to radiotherapy or display the same side-effect profile. Biomarkers of response and toxicity in liver radiotherapy would facilitate the vision and practice of personalized medicine. This expert review examines the available molecular, radiomic, and radiogenomic biomarker candidates for acute liver toxicity with potential use for prediction of radiotherapy-induced liver toxicity. To this end, I highlight for oncologists and life scientists that radiomics allows diagnostic images to be analyzed using computer algorithms to extract information imperceptible to the human eye and of relevance to forecasting clinical outcomes. This article underscores particularly (1) the microRNA-based biomarker candidates as among the most promising predictors of radiation-induced liver toxicity and (2) the texture features in radiomic analyses for response prediction. Radiotherapy of hepatocellular carcinoma is edging toward personalized medicine with emerging radiomic biomarker candidates. Future large-scale biomarker studies are called for to enable personalized medicine in liver cancers.
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Affiliation(s)
- Carolina De la Pinta
- Radiation Oncology Department, Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain
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23
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Tavabie OD, Karvellas CJ, Salehi S, Speiser JL, Rose CF, Menon K, Prachalias A, Heneghan MA, Agarwal K, Lee WM, McPhail MJW, Aluvihare VR. A novel microRNA-based prognostic model outperforms standard prognostic models in patients with acetaminophen-induced acute liver failure. J Hepatol 2021; 75:424-434. [PMID: 33857547 PMCID: PMC10668489 DOI: 10.1016/j.jhep.2021.03.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 02/26/2021] [Accepted: 03/09/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF. METHODS We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method. RESULTS Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score. CONCLUSIONS Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation. LAY SUMMARY While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant.
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Affiliation(s)
| | - Constantine J Karvellas
- Division of Gastroenterology and Department of Critical Care Medicine, University of Alberta, Edmonton, Canada
| | - Siamak Salehi
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Jaime L Speiser
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, North Carolina, USA
| | - Christopher F Rose
- Hepato-neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Krishna Menon
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | | | - Kosh Agarwal
- Institute of Liver Studies, King's College Hospital, London, UK
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Texas, USA
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24
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Umbaugh DS, Jaeschke H. Biomarkers of drug-induced liver injury: a mechanistic perspective through acetaminophen hepatotoxicity. Expert Rev Gastroenterol Hepatol 2021; 15:363-375. [PMID: 33242385 PMCID: PMC8026489 DOI: 10.1080/17474124.2021.1857238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
Introduction: Liver injury induced by drugs is a serious clinical problem. Many circulating biomarkers for identifying and predicting drug-induced liver injury (DILI) have been proposed.Areas covered: Biomarkers are mainly predicated on the mechanistic understanding of the underlying DILI, often in the context of acetaminophen overdose. New panels of biomarkers have emerged that are related to recovery/regeneration rather than injury following DILI. We explore the clinical relevance and limitations of these new biomarkers including recent controversies. Extracellular vesicles have also emerged as a promising vector of biomarkers, although the biological role for EVs may limit their clinical usefulness. New technological approaches for biomarker discovery are also explored.Expert opinion: Recent clinical studies have validated the efficacy of some of these new biomarkers, cytokeratin-18, macrophage colony-stimulating factor receptor, and osteopontin for DILI prognosis. Low prevalence of DILI is an inherent limitation to DILI biomarker development. Furthering mechanistic understanding of DILI and leveraging technological advances (e.g. machine learning/omics) is necessary to improve upon the newest generation of biomarkers. The integration of omics approaches with machine learning has led to novel insights in cancer research and DILI research is poised to leverage these technologies for biomarker discovery and development.
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Affiliation(s)
- David S. Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
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25
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Ju C, Wang M, Tak E, Kim B, Emontzpohl C, Yang Y, Yuan X, Kutay H, Liang Y, Hall DR, Dar WA, Bynon JS, Carmeliet P, Ghoshal K, Eltzschig HK. Hypoxia-inducible factor-1α-dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest 2021; 131:140300. [PMID: 33792566 PMCID: PMC8011886 DOI: 10.1172/jci140300] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 02/10/2021] [Indexed: 12/29/2022] Open
Abstract
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation.
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Affiliation(s)
- Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Meng Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Eunyoung Tak
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Boyun Kim
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Christoph Emontzpohl
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Yang Yang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Xiaoyi Yuan
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - Huban Kutay
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
| | - Yafen Liang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
| | - David R. Hall
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Wasim A. Dar
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - J. Steve Bynon
- Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, and
- Center for Cancer Biology, Department of Oncology, Katholieke University Leuven, Leuven, Belgium
| | - Kalpana Ghoshal
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA
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26
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Villanueva-Paz M, Morán L, López-Alcántara N, Freixo C, Andrade RJ, Lucena MI, Cubero FJ. Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice. Antioxidants (Basel) 2021; 10:390. [PMID: 33807700 PMCID: PMC8000729 DOI: 10.3390/antiox10030390] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/02/2021] [Indexed: 12/11/2022] Open
Abstract
Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts-neoantigens-that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.
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Affiliation(s)
- Marina Villanueva-Paz
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - Laura Morán
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
- Health Research Institute Gregorio Marañón (IiSGM), 28009 Madrid, Spain
| | - Nuria López-Alcántara
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
| | - Cristiana Freixo
- CINTESIS, Center for Health Technology and Services Research, do Porto University School of Medicine, 4200-319 Porto, Portugal;
| | - Raúl J. Andrade
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - M Isabel Lucena
- Unidad de Gestión Clínica de Gastroenterología, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, 29071 Málaga, Spain; (M.V.-P.); (M.I.L.)
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (L.M.); (N.L.-A.)
- 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain
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27
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López-Riera M, Conde I, Castell JV, Jover R. A Novel MicroRNA Signature for Cholestatic Drugs in Human Hepatocytes and Its Translation into Novel Circulating Biomarkers for Drug-Induced Liver Injury Patients. Toxicol Sci 2020; 173:229-243. [PMID: 31198949 DOI: 10.1093/toxsci/kfz138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) diagnosis and classification (hepatocellular, cholestatic, and mixed) relies on traditional clinical biomarkers (eg ALT and ALP), despite limitations such as extrahepatic interferences, narrow dynamic ranges, and low mechanistic value. microRNAs may be very useful for complementing traditional DILI biomarkers but most studies in this direction have considered only paracetamol poisoning. Thus the value of microRNAs (miRNAs) as biomarkers for idiosyncratic DILI has not yet been demonstrated. In this study, we first examined the effect of model cholestatic drugs on the human hepatocyte miRNome by RNAseq and RT-qPCR. Results demonstrated that chlorpromazine, cyclosporin A, and ANIT induced (miR-21-3p, -21-5p, -22-3p, -27a-5p, -1260b, -34a-5p, and -98-5p) and repressed (-122-5p, -192-5p, -30c-5p, -424-5p, and -16-5p) specific miRNAs in sandwich-cultured upcyte hepatocytes. However, no common signature was found for cholestatic drugs. Next we investigated the levels of these miRNA in human serum and found that most were also significantly altered in cholestatic/mixed DILI patients upon hospital/ambulatory admission. However, miR-122-5p, -192-5p, -34a-5p, and -22-3p demonstrated a much more significant induction in patients with hepatocellular DILI, thus revealing better specificity for hepatocellular damage. Time-course analyses demonstrated that -1260b and -146 had a very similar profile to ALP, but with wider dynamic ranges, while -16-5p and -451a showed a negative correlation. Conversely, -122-5p and -192-5p correlated with ALT but with wider dynamic ranges and faster recoveries. Finally, the 122/451a and 122/16 ratios showed excellent prediction performances in both the study [area under the receiver operating characteristic curve (AUROC) >0.93] and the validation cohort (AUROC > 0.82), and can, therefore, be postulated for the first time as circulating miRNA biomarkers for idiosyncratic DILI.
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Affiliation(s)
- Mireia López-Riera
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain
| | - Isabel Conde
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Medicina Digestiva, Sección Hepatología, Hospital La Fe, 46026 Valencia, Spain
| | - José V Castell
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
| | - Ramiro Jover
- *Unidad Mixta en Hepatología Experimental, IIS Hospital La Fe, 46026 Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain.,Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
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Lammert C, Zhu C, Lian Y, Raman I, Eckert G, Li Q, Chalasani N. Exploratory Study of Autoantibody Profiling in Drug-Induced Liver Injury with an Autoimmune Phenotype. Hepatol Commun 2020; 4:1651-1663. [PMID: 33163835 PMCID: PMC7603536 DOI: 10.1002/hep4.1582] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/30/2020] [Accepted: 07/08/2020] [Indexed: 12/17/2022] Open
Abstract
Drug-induced liver injury (DILI) sometimes presents with an autoimmune hepatitis-like phenotype (AI-DILI), and it is challenging to distinguish it from de novo autoimmune hepatitis (AIH). We conducted a study to identify autoantibodies unique to AI-DILI by profiling serum autoantibodies. Autoantibodies were quantified using an autoantigen array containing 94 autoantigens from four groups: AI-DILI (n = 65), DILI controls (n = 67), de novo AIH (n = 17), and healthy controls (HCs; n = 30). In 37 patients with AI-DILI, samples were also collected 6 months after presentation. AI-DILI and de novo AIH had similar anti-neutrophil antibody and anti-smooth muscle antibody prevalence. Compared to HCs, de novo AIH had an increase in many immunoglobulin G (IgG; 35 [46.1%]) and IgM (51 [70%]) autoantibodies, whereas AI-DILI had an increase of IgM (40 [54.8%]) but not IgG autoantibodies. DILI controls had a similar IgG and IgM profile compared to HCs. Comparing de novo AIH to AI-DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in de novo AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI-DILI and de novo AIH were common; however, AI-DILI induced by different drugs showed different frequencies of IgM autoantibodies, with nitrofurantoin-related AI-DILI showing a higher number of increased IgM autoantibodies. AI-DILI autoantibody levels at diagnosis and at 6 months showed a significant decline in 37 IgM autoantibodies. A model with highly correlated IgG and IgM was fitted into multivariate logistic regression and revealed an area under the curve of 0.87 (95% confidence interval, 0.79-0.95) to distinguish de novo AIH from AI-DILI. Conclusion: The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI-DILI from de novo AIH.
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Affiliation(s)
- Craig Lammert
- Department of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Chengsong Zhu
- Department of Immunology and Internal MedicineGenomics and Microarray CoreUniversity of Texas SouthwesternDallasTXUSA
| | - Yun Lian
- Department of Immunology and Internal MedicineGenomics and Microarray CoreUniversity of Texas SouthwesternDallasTXUSA
| | - Indu Raman
- Department of Immunology and Internal MedicineGenomics and Microarray CoreUniversity of Texas SouthwesternDallasTXUSA
| | - George Eckert
- Department of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Quan‐Zhen Li
- Department of Immunology and Internal MedicineGenomics and Microarray CoreUniversity of Texas SouthwesternDallasTXUSA
| | - Naga Chalasani
- Department of MedicineIndiana University School of MedicineIndianapolisINUSA
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Krauskopf J, Gosink MM, Schomaker S, Caiment F, Warner R, Johnson K, Kleinjans J, Aubrecht J. The MicroRNA-based Liquid Biopsy Improves Early Assessment of Lethal Acetaminophen Poisoning: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e919289. [PMID: 32086430 PMCID: PMC7049075 DOI: 10.12659/ajcr.919289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 01/24/2020] [Accepted: 11/04/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND Acetaminophen overdose is the most common cause of acute liver failure. Nevertheless, new biomarker approaches enabling early prediction of the outcome of the acetaminophen overdose are needed. Recently, using next-generation sequencing analysis of serum from human study participants we uncovered injury-specific signatures of circulating microRNAs (miRNAs) that represented underlying molecular mechanisms of toxicity. This case study is first to show the application of miRNA profiling to assess prognosis of acetaminophen poisoning. CASE REPORT The patient was admitted to the hospital following supra therapeutic acetaminophen ingestion. The patient showed elevated levels of biomarkers of hepatocellular injury alanine aminotransferase, aspartate transaminase, and glutamate dehydrogenase. Even though treatment with N-acetyl cysteine was initiated 24 hours post-ingestion, levels of alanine-aminotransferase and aspartate transaminase peaked at about 40 hours post ingestion of acetaminophen. We analyzed global circulating miRNA levels from 24 consecutive serum samples from this study participant covering the period from admission to time of death. CONCLUSIONS The resulting global miRNA profiles were compared with profiles from study participants with non-lethal acetaminophen poisoning and healthy controls. At the admission, the miRNA profiles of both lethal and non-lethal acetaminophen poisoning showed induction of cellular stress and oxidative damage. Later, the miRNA profiles of the lethal poisoning featured fibrosis and coagulation pathways while profiles of non-lethal cases resembled those of healthy study participants. Although additional confirmatory studies are needed, our case study is first to indicate that global miRNA profiles to be used as liquid biopsies have potential to facilitate the assessment of acetaminophen poisoning.
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Affiliation(s)
- Julian Krauskopf
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Mark M. Gosink
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Shelli Schomaker
- Drug Safety Research and Development, Pfizer, Inc., Groton, CT, U.S.A
| | - Florian Caiment
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Roscoe Warner
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Kent Johnson
- Department of Pathology, University of Michigan, Ann Arbor, MI, U.S.A
| | - Jos Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, The Netherlands
| | - Jiri Aubrecht
- Drug Safety Research and Development, Pfizer, Inc., Groton, CT, U.S.A
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30
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Hoffmann K, Nagel AJ, Tanabe K, Fuchs J, Dehlke K, Ghamarnejad O, Lemekhova A, Mehrabi A. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg 2020; 20:31. [PMID: 32050952 PMCID: PMC7017496 DOI: 10.1186/s12893-019-0664-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.
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Affiliation(s)
- Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany.
| | - Alexander Johannes Nagel
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Kazukata Tanabe
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | | | - Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Anastasia Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
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31
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Fu S, Wu D, Jiang W, Li J, Long J, Jia C, Zhou T. Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. Front Pharmacol 2020; 10:1667. [PMID: 32082163 PMCID: PMC7002317 DOI: 10.3389/fphar.2019.01667] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/20/2019] [Indexed: 02/05/2023] Open
Abstract
Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.
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Affiliation(s)
- Siyu Fu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Li
- Department of Infectious Diseases, Pidu District People's Hospital, Chengdu, China
| | - Jiang Long
- The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Chengyao Jia
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Taoyou Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Real M, Barnhill MS, Higley C, Rosenberg J, Lewis JH. Drug-Induced Liver Injury: Highlights of the Recent Literature. Drug Saf 2020; 42:365-387. [PMID: 30343418 DOI: 10.1007/s40264-018-0743-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Drug-induced liver injury (DILI), herbal-induced liver injury, and herbal and dietary supplement (HDS)-induced liver injury are an important aspect of drug safety. Knowledge regarding responsible drugs, mechanisms, risk factors, and the diagnostic tools to detect liver injury have continued to grow in the past year. This review highlights what we considered the most significant publications from among more than 1800 articles relating to liver injury from medications, herbal products, and dietary supplements in 2017 and 2018. The US Drug-Induced Liver Injury Network (DILIN) prospective study highlighted several areas of ongoing study, including the potential utility of human leukocyte antigens and microRNAs as DILI risk factors and new data on racial differences, the role of alcohol consumption, factors associated with prognosis, and updates on the clinical signatures of autoimmune DILI, thiopurines, and HDS agents. Novel data were also generated from the Spanish and Latin American DILI registries as well as from Chinese and Korean case series. A few new agents causing DILI were added to the growing list in the past 2 years, including sodium-glucose co-transporter-2 inhibitors, as were new aspects of chemotherapy-associated liver injury. A number of cases reported previously described hepatotoxins confirmed via the Roussel Uclaf Causality Assessment Method (RUCAM; e.g., norethisterone, methylprednisolone, glatiramer acetate) and/or the DILIN method (e.g., celecoxib, dimethyl fumarate). Additionally, much work centered on elucidating the pathophysiology of DILI, including the importance of bile salt export pumps and immune-mediated mechanisms. Finally, it must be noted that, while hundreds of new studies described DILI in 2017-2018, the quality of such reports must always be addressed. Björnsson reminds us to remain very critical of the data when addressing the future utility of a study, which is why it is so important to adhere to a standardized method such as RUCAM when determining DILI causality. While drug-induced hepatotoxicity remains a diagnosis of exclusion, the diverse array of publications that appeared in 2017 and 2018 provided important advances in our understanding of DILI, paving the way for our improved ability to make a more definitive diagnosis and risk assessment.
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Affiliation(s)
- Mark Real
- Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, DC, USA
| | - Michele S Barnhill
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Cory Higley
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - Jessica Rosenberg
- Department of Medicine, Georgetown University Hospital, Washington, DC, USA
| | - James H Lewis
- Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, DC, USA.
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Vyas HS, Upadhyay KK, Devkar RV. miRNAs Signatures In Patients With Acute Liver Injury: Clinical Concerns and Correlations. Curr Mol Med 2019; 20:325-335. [PMID: 31823701 DOI: 10.2174/1566524020666191211153546] [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: 08/19/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 11/22/2022]
Abstract
Non-coding RNAs can be highly exploited for their biological significance in living systems. miRNAs are in the upstream position of cellular regulation cascade and hold merit in its state. A plethora of information is available on a wide variety of miRNAs that undergo alterations in experimentally induced models of liver injuries. The underlying mechanisms governed by these miRNAs have been inferred through cellbased experiments but the scientific knowledge on miRNA signatures in patients with liver injury are primordial and lack scientific clarity. Hence, it is crucial to get insight into the status and synergy of miRNAs in patients, with varying degrees of acute toxic manifestations in the liver. Though some miRNAs are being investigated in clinical trials, a major research lacuna exists with regard to the functional role of other miRNAs in liver diseases. This review article is a meticulous compilation of disease based or drug/alcohol based acute liver injuries in patients and resultant alteration in their miRNA profile. Investigative reports on underlying miRNA-liver crosstalk in cell-based or murine models are also discussed herein to draw a correlation with clinical findings.
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Affiliation(s)
- Hitarthi S Vyas
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Kapil K Upadhyay
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
| | - Ranjitsinh V Devkar
- Division of Metabolic Endocrinology, Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat 390002, India
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34
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Hernandez N, Pontet Y, Bessone F. Translating new knowledge on drug-induced liver injury into clinical practice. Frontline Gastroenterol 2019; 11:303-310. [PMID: 32587673 PMCID: PMC7307039 DOI: 10.1136/flgastro-2018-101120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 08/03/2019] [Accepted: 08/11/2019] [Indexed: 02/04/2023] Open
Abstract
Drug-induced liver injury (DILI) is one of the main reasons for drug withdrawal from the market, and a cause of worldwide morbidity. Although several issues on DILI are still unsolved, there have been significant advances in new definitions and diagnosis tools. DILI is the result of a complex interaction between genetic and environmental factors, and constitutes an expanding area of investigation. DILI can mimic virtually all known hepatopathies, including vascular disorders and liver tumours. As part of this broad spectrum of clinical presentations, DILI severity ranges from asymptomatic elevations of aminotransferases to acute liver failure. Although biomarkers are emerging as valuable diagnostic tools, they are not available in clinical practice. Accurate DILI diagnosis is a challenging issue, particularly the establishing of causal relationships with the culprit agent and the exclusion of competing causes of liver injury. Given that the understanding of the mechanisms inducing DILI is growing, and both DILI causality assessment scales and the performance of international DILI networks have been improved, hepatotoxicity may be recognised earlier in clinical practice. In this review, advances and results obtained by DILI registries around the world, case characterisations, particularly those relevant to newer definitions in DILI, and the behaviour of chronic liver disease induced by drugs will be updated. In addition, recently published data on herbal and dietary supplements and new predictive scores for acute liver failure assessment will also be discussed.
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Affiliation(s)
- Nelia Hernandez
- Gastroenterology and Hepatology, Facultad de Medicina, Hospital de Clínicas, UdelaR, Montevideo, Uruguay
| | - Yessica Pontet
- Gastroenterology and Hepatology, Facultad de Medicina, Hospital de Clínicas, UdelaR, Montevideo, Uruguay
| | - Fernando Bessone
- Gastroenterology and Hepatology, University of Rosario School of Medicine, Rosario, Argentina
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35
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Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, Devarbhavi H, Merz M, Lucena MI, Kaplowitz N, Aithal GP. Drug-induced liver injury. Nat Rev Dis Primers 2019; 5:58. [PMID: 31439850 DOI: 10.1038/s41572-019-0105-0] [Citation(s) in RCA: 439] [Impact Index Per Article: 73.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/04/2019] [Indexed: 02/06/2023]
Abstract
Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.
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Affiliation(s)
- Raul J Andrade
- Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - Naga Chalasani
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Einar S Björnsson
- Department of Gastroenterology, Landspitali University Hospital Reykjavik, University of Iceland, Reykjavík, Iceland.,Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Ayako Suzuki
- Gastroenterology, Duke University, Durham, NC, USA.,Gastroenterology, Durham VA Medical Centre, Durham, NC, USA
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland
| | - Paul B Watkins
- UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.,University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, Chapel Hill, NC, USA
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.,Patient Safety, AstraZeneca, Gaithersburg, MD, USA
| | - M Isabel Lucena
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. .,Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, Málaga, Spain.
| | - Neil Kaplowitz
- Division of Gastroenterology and Liver Diseases, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA
| | - Guruprasad P Aithal
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK
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Watkins PB. Idiosyncratic drug-induced liver injury in patients: Detection, severity assessment, and regulatory implications. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 85:165-193. [PMID: 31307586 DOI: 10.1016/bs.apha.2019.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Idiosyncratic Drug-Induced Liver Injury (IDILI) is a rare but potentially life-threatening event that is caused by drugs that, at usual therapeutic doses, do not cause any biochemical or clinical evidence of liver injury in the majority of treated patients. The most common clinical phenotypes of IDILI are "acute hepatitis," "mixed hepatocellular-cholestatic hepatitis," and "cholestatic hepatitis" and these are distinguished by clinical, biochemical and histologic characteristics. Anti-microbials, herbals and dietary supplements are now the agents most often implicated in the US Drug-Induced Liver Injury Network registry. There are several scales that have been used to characterize the severity of IDILI events. There are no reliable means to accurately predict the course of an IDILI event at presentation. In clinical trials, the "gold standard" liver safety signal is the occurrence of "Hy's Law Cases." Making the diagnosis of IDILI, and when a patient is taking multiple drugs, identifying the most likely culprit can be challenging, but many drugs cause IDILI with characteristic clinical and biochemical presentations, or "signatures." In a clinical trial, it is sometimes possible to identify an overlooked "signature" of IDILI by characterizing more minor, asymptomatic, and transient elevations in liver chemistries. This observation can be helpful in assessing causation in rare serious liver events occurring in the clinical trial, or first recognized post-marketing.
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Affiliation(s)
- Paul B Watkins
- Eshelman School of Pharmacy, Institute for Drug Safety Sciences, University of North Carolina, Chapel Hill, NC, United States.
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37
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Abstract
Drug-induced liver injury (DILI) is a major clinical and regulatory challenge. As a result, interest in DILI biomarkers is growing. So far, considerable progress has been made in identification of biomarkers for diagnosis (acetaminophen-cysteine protein adducts), prediction (genetic biomarkers), and prognosis (microRNA-122, high mobility group box 1 protein, keratin-18, glutamate dehydrogenase, mitochondrial DNA). Many of those biomarkers also provide mechanistic insight. The purpose of this chapter is to review major advances in DILI biomarker research over the last decade, and to highlight some of the challenges involved in implementation. Although much work has been done, more liver-specific biomarkers, more DILI-specific biomarkers, and better prognostic biomarkers for survival are all still needed. Furthermore, more work is needed to define reference intervals and medical decision limits.
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Affiliation(s)
- Mitchell R McGill
- Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, AR, United States; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
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Musaddaq G, Shahzad N, Ashraf MA, Arshad MI. Circulating liver-specific microRNAs as noninvasive diagnostic biomarkers of hepatic diseases in human. Biomarkers 2019; 24:103-109. [PMID: 30252499 DOI: 10.1080/1354750x.2018.1528631] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 09/22/2018] [Indexed: 02/08/2023]
Abstract
CONTEXT Hepatitis is an endemic disease worldwide leading to chronic and debilitating cancers. The viral agents and hepatotoxic substances lead to damage of hepatocytes and release of damage associated molecules in circulation. The lack of timely and rapid diagnosis of hepatitis results in chronic disease. OBJECTIVE The present review aimed to describe regulation, release and functions of microRNAs (miR) during human liver pathology and insights into their promising use as noninvasive biomarkers of hepatitis. METHODS Comprehensive data were collected from PubMed, ScienceDirect and the Web of Science databases utilizing the keywords "biomarkers", "microRNAs" and "hepatic diseases". RESULTS The miRs are readily released in the body fluids and blood during HBV/HCV associated hepatitis as well as metabolic, alcoholic, drug induced and autoimmune hepatitis. The liver-specific microRNAs including miR-122, miR-130, miR-183, miR-196, miR-209 and miR-96 are potential indicators of liver injury (mainly via apoptosis, necrosis and necroptosis) or hepatitis with their varied expression during acute/fulminant, chronic, liver fibrosis/cirrhosis and hepato-cellular carcinoma. CONCLUSIONS The liver-specific miRs can be used as rapid and noninvasive biomarkers of hepatitis to discern different stages of hepatitis. Blocking or stimulating pathways associated with miR regulation in liver could unveil novel therapeutic strategies in the management of liver diseases. Clinical significance Liver specific microRNAs interact with cellular proteins and signaling molecules to regulate the expression of various genes controlling biological processes. The circulatory level of liver specific microRNAs is indicator of severity of HBV and HCV infections as well as prognostic and therapeutic candidates. The expression of liver specific microRNAs is strongly associated with infectious, drug-induced, hepatotoxic, nonalcoholic steatohepatitis and nonalcoholic fatty liver diseases.
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Affiliation(s)
- Ghulam Musaddaq
- a Institute of Microbiology, University of Agriculture , Faisalabad , Pakistan
| | - Naveed Shahzad
- b School of Biological Sciences (SBS), University of the Punjab , Lahore , Pakistan
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Church RJ, Kullak-Ublick GA, Aubrecht J, Bonkovsky HL, Chalasani N, Fontana RJ, Goepfert JC, Hackman F, King NMP, Kirby S, Kirby P, Marcinak J, Ormarsdottir S, Schomaker SJ, Schuppe-Koistinen I, Wolenski F, Arber N, Merz M, Sauer JM, Andrade RJ, van Bömmel F, Poynard T, Watkins PB. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology 2019; 69:760-773. [PMID: 29357190 PMCID: PMC6054900 DOI: 10.1002/hep.29802] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of 14 promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n = 192 and n = 81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n = 55 and n = 92) and DILI patients (n = 98, n = 28, and n = 143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total cytokeratin 18 (K18), caspase cleaved K18, glutathione S-transferase α, alpha-fetoprotein, arginase-1, osteopontin (OPN), sorbitol dehydrogenase, fatty acid binding protein, cadherin-5, macrophage colony-stimulating factor receptor (MCSFR), paraoxonase 1 (normalized to prothrombin protein), and leukocyte cell-derived chemotaxin-2. Most candidate biomarkers were significantly altered in DILI cases compared with healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase than miR-122, and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplantation within 6 months of DILI onset. Prediction of prognosis among DILI patients using the Model for End-Stage Liver Disease was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients, and K18, OPN, and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.
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Affiliation(s)
- Rachel J. Church
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
| | - Gerd A. Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland,Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland
| | | | | | - Naga Chalasani
- School of Medicine, Indiana University, Indianapolis, IN
| | | | | | | | | | | | | | | | | | | | - Ina Schuppe-Koistinen
- Science for Life Laboratory, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | | | - Nadir Arber
- Tel Aviv Sourasky Medical Center, Tel Aviv University, Israel
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland,Discovery and Investigative Safety, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | | | - Raul J. Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain
| | - Florian van Bömmel
- Section of Hepatology, Clinic of Gastroenterology and Hepatology, University Hospital Leipzig, Leipzig, Germany
| | - Thierry Poynard
- Department of Hepatology, Groupe Hospitalier Pitié Salpêtrière, University Pierre et Marie Curie, INSERM UMR 938, Paris, France
| | - Paul B. Watkins
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina
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Church RJ, Watkins PB. Serum biomarkers of drug-induced liver injury: Current status and future directions. J Dig Dis 2019; 20:2-10. [PMID: 30378260 DOI: 10.1111/1751-2980.12684] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Drug-induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data-driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.
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Affiliation(s)
- Rachel J Church
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA.,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
| | - Paul B Watkins
- Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, North Carolina, USA.,Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
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41
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Barnhill MS, Real M, Lewis JH. Latest advances in diagnosing and predicting DILI: what was new in 2017? Expert Rev Gastroenterol Hepatol 2018; 12:1033-1043. [PMID: 30111182 DOI: 10.1080/17474124.2018.1512854] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Drug-induced liver injury (DILI) remains an increasingly recognized cause of hepatotoxicity and liver failure worldwide. In 2017, we continued to learn about predicting, diagnosing, and prognosticating drug hepatotoxicity. Areas covered: In this review, we selected from over 1200 articles from 2017 to synopsize updates in DILI. There were new HLA haplotypes associated with medications including HLA-C0401 and HLA-B*14. There has been continued work with quantitative systems pharmacology, particularly with the DILIsym® initiative, which employs mathematical representations of DILI mechanisms to predict hepatotoxicity in simulated populations. Additionally, knowledge regarding microRNAs (miRNAs) continues to expand. Some new miRNAs this past year include miRNA-223 and miRNA-605. Aside from miRNAs, other biomarkers for diagnosis, prognosis, and even prediction of DILI were explored. Studies on K18, OPN, and MCSFR have correlated DILI and liver-associated death within 6 months. Conversely, a new prognostic panel using apolipoportein-A1 and haptoglobin has been proposed to predict recovery. Further study of CDH5 has also provided researchers a possible new biomarker for prediction and susceptibility to DILI. Expert commentary: Although research on DILI remains quite promising, there is yet to be a reliable, simple method to predict, diagnose, and risk assess this form of hepatotoxicity.
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Affiliation(s)
- Michele S Barnhill
- a Department of Internal Medicine , Medstar Georgetown University Hospital , Washington , DC , USA
| | - Mark Real
- a Department of Internal Medicine , Medstar Georgetown University Hospital , Washington , DC , USA
| | - James H Lewis
- b Department of Gastroenterology , Medstar Georgetown University Hospital , Washington , DC , USA
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42
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McGill MR, Jaeschke H. Biomarkers of drug-induced liver injury: progress and utility in research, medicine, and regulation. Expert Rev Mol Diagn 2018; 18:797-807. [PMID: 30080986 DOI: 10.1080/14737159.2018.1508998] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The difficulty of understanding and diagnosing drug-induced liver injury (DILI) has led to proliferation of serum and genetic biomarkers. Many applications of these biomarkers have been proposed, including investigation of mechanisms, prediction of DILI during early trials or before initiation of therapy in patients, and diagnosis of DILI during therapy. Areas covered: We review the definition and categories of DILI, describe recent developments in DILI biomarker development, and provide guidance for future directions in DILI biomarker research. Expert commentary: There are major obstacles to DILI biomarker development and implementation, including the low prevalence of idiosyncratic DILI (IDILI), weak associations of IDILI with genetic variants, and lack of specificity of many biomarkers for the liver. Certain serum biomarkers, like miR-122, may have clinical utility in early-presenting patients with either intrinsic or idiosyncratic DILI in the future, while others likely will not find use. Future research should focus on implementation of biomarkers to predict later injury and outcome in early presenters with intrinsic DILI, and on development of biomarkers of adaptation and repair in the liver that can be used to determine if a liver test abnormality is likely to be clinically significant in IDILI.
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Affiliation(s)
- Mitchell R McGill
- a Department of Environmental and Occupational Health , Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences , Little Rock , AR , USA.,b Department of Pharmacology and Toxicology , College of Medicine, University of Arkansas for Medical Sciences , Little Rock , AR , USA
| | - Hartmut Jaeschke
- c Department of Pharmacology, Toxicology and Therapeutics , University of Kansas Medical Center , Kansas City , KS , USA
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43
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Yang J, Li C, Zhang L, Wang X. Extracellular Vesicles as Carriers of Non-coding RNAs in Liver Diseases. Front Pharmacol 2018; 9:415. [PMID: 29740327 PMCID: PMC5928552 DOI: 10.3389/fphar.2018.00415] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) are small membranous vesicles secreted from normal, diseased, and transformed cells in vitro and in vivo. EVs have been found to play a critical role in cell-to-cell communication by transferring non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long ncRNAs (lncRNAs) and so on. Emerging evidence shows that transferring biological information through EVs to neighboring cells in intercellular communication not only keep physiological functions, but also participate in the pathogenesis of liver diseases. Liver diseases often promote release of EVs and/or in different cargo sorting into these EVs. Either of these modifications can promote disease pathogenesis. Given this fact, EV-associated ncRNAs, such as miR-192, miR-122 and lncRNA-ROR and so on, can serve as new diagnostic biomarkers and new therapeutic targets for liver disease, because altered EV-associated ncRNAs may reflect the underlying liver disease condition. In this review, we focus on understanding the emerging role of EV-associated ncRNAs in viral hepatitis, liver fibrosis, alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) and discuss their utility in biomarker discovery and therapeutics. A better understanding of this multifaceted pattern of communication between different type cells in liver may contribute to developing novel approaches for personalized diagnostics and therapeutics.
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Affiliation(s)
- Junfa Yang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Changyao Li
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, China.,Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, China.,The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xiao Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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Schueller F, Roy S, Vucur M, Trautwein C, Luedde T, Roderburg C. The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity. Int J Mol Sci 2018; 19:ijms19010261. [PMID: 29337905 PMCID: PMC5796207 DOI: 10.3390/ijms19010261] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/12/2018] [Accepted: 01/13/2018] [Indexed: 12/12/2022] Open
Abstract
Both acute and chronic liver toxicity represents a major global health burden and an important cause of morbidity and lethality worldwide. Despite epochal progress in the treatment of hepatitis C virus infections, pharmacological treatment strategies for most liver diseases are still limited and new targets for prevention or treatment of liver disease are urgently needed. MicroRNAs (miRNAs) represent a new class of highly conserved small non-coding RNAs that are involved in the regulation of gene expression by targeting whole networks of so called “targets”. Previous studies have shown that the expression of miRNAs is specifically altered in almost all acute and chronic liver diseases. In this context, it was shown that miRNA can exert causal roles, being pro- or anti-inflammatory, as well as pro- or antifibrotic mediators or being oncogenes as well as tumor suppressor genes. Recent data suggested a potential therapeutic use of miRNAs by targeting different steps in the hepatic pathophysiology. Here, we review the function of miRNAs in the context of acute and chronic liver diseases. Furthermore, we highlight the potential role of circulating microRNAs in diagnosis of liver diseases and discuss the major challenges and drawbacks that currently prevent the use of miRNAs in clinical routine.
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Affiliation(s)
- Florian Schueller
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Sanchari Roy
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Mihael Vucur
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Tom Luedde
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
- Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
| | - Christoph Roderburg
- Department of Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
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Howell LS, Ireland L, Park BK, Goldring CE. MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury. Expert Rev Mol Diagn 2017; 18:47-54. [PMID: 29235390 DOI: 10.1080/14737159.2018.1415145] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers. Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed. Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI.
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Affiliation(s)
- Lawrence S Howell
- a MRC Centre for Drug Safety Science , University of Liverpool , Liverpool , UK
| | - Lucy Ireland
- b Department of Molecular and Clinical Cancer Medicine , University of Liverpool , Liverpool , UK
| | - B Kevin Park
- a MRC Centre for Drug Safety Science , University of Liverpool , Liverpool , UK
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46
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Lin H, Ewing LE, Koturbash I, Gurley BJ, Miousse IR. MicroRNAs as biomarkers for liver injury: Current knowledge, challenges and future prospects. Food Chem Toxicol 2017; 110:229-239. [PMID: 29042291 PMCID: PMC6693868 DOI: 10.1016/j.fct.2017.10.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 10/02/2017] [Accepted: 10/14/2017] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are short regulatory RNAs that are involved in various biological processes that regulate gene expression posttranscriptionally. Changes in miRNA expression can be detected in many physiological and pathological events, such as liver injury. Drug induced liver injury is a life threatening condition that frequently requires organ transplantation. Hepatotoxicity is also one of the major causes of drug failure in clinical trials and of drug withdrawal from the market. The profiling of miRNA expression shows great promise in monitoring liver injury, in the prediction of outcome in patients, and in the identification of liver-reactive compounds in toxicological assessment. Recent studies have demonstrated organ-specificity of some miRNAs (i.e., miR-122), which are released into biological fluids as a result of hepatocyte damage. This attests to the potential of miRNAs as noninvasive biomarkers to detect liver toxicity. This review presents information on miRNA signatures of hepatotoxicity and on the application of promising miRNA biomarkers in preclinical safety assessment. We further discuss the technical challenges associated with these emerging biomarkers for early diagnosis and detection of hepatotoxicity.
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Affiliation(s)
- Haixia Lin
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Laura E Ewing
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
| | - Bill J Gurley
- Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, 72223, United States.
| | - Isabelle R Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, United States.
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Shahbaz O, Mahajan S, Lewis JH. Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice? Expert Opin Drug Metab Toxicol 2017; 13:935-951. [PMID: 28772086 DOI: 10.1080/17425255.2017.1362391] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice. Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents. Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.
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Affiliation(s)
- Omar Shahbaz
- a Department of Medicine, Division of Gastroenterology, Hepatology Section , Georgetown University Hospital , Washington , DC , USA
| | - Sandeep Mahajan
- a Department of Medicine, Division of Gastroenterology, Hepatology Section , Georgetown University Hospital , Washington , DC , USA
| | - James H Lewis
- a Department of Medicine, Division of Gastroenterology, Hepatology Section , Georgetown University Hospital , Washington , DC , USA
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48
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Loosen SH, Schueller F, Trautwein C, Roy S, Roderburg C. Role of circulating microRNAs in liver diseases. World J Hepatol 2017; 9:586-594. [PMID: 28515844 PMCID: PMC5411953 DOI: 10.4254/wjh.v9.i12.586] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 03/27/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are small RNAs regulate gene expression by inhibiting the turnover of their target mRNAs. In the last years, it became apparent that miRNAs are released into the circulation and circulating miRNAs emerged as a new class of biomarkers for various diseases. In this review we summarize available data on the role of circulating miRNAs in the context of acute and chronic liver diseases including hepatocellular and cholangiocellular carcinoma. Data from animal models are compared to human data and current challenges in the field of miRNAs research are discussed.
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