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Su Y, Zeng Y, Zhou M, Liao M, Qin P, Wu R, Han J, Liang X, Wang Z, Jiang J, Yu Z, Huang X, Ding K, Guo P, He Y, Du Y, Duan T, Yuan H, Ge Y, Chen A, Xiao W. Natural Polyphenol-Mediated Inhibition of Ferroptosis Alleviates Oxidative Damage and Inflammation in Acute Liver Injury. Biomater Res 2025; 29:0167. [PMID: 40103575 PMCID: PMC11913781 DOI: 10.34133/bmr.0167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/20/2025] Open
Abstract
Acetaminophen (APAP) overdose has long been recognized as the main cause of drug-induced liver injury (DILI), characterized by glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, leading to ferroptosis and inflammatory responses. There is an urgent need for liver-protective agents to combat ferroptosis, modulate oxidative stress, and ameliorate inflammation. Catechin, a well-known polyphenol compound, has been shown to have antioxidant potential. However, its protective role on APAP-induced liver injury (AILI) has not been elucidated. In this study, we evaluated the modulating effects of catechin on AILI and observed that catechin attenuated liver injury by reducing inflammation. Mechanistically, catechin alleviated hepatic oxidative stress by inhibiting ROS accumulation, malondialdehyde (MDA) production, and GSH depletion. Furthermore, catechin, as a hepatic injury reparative agent, could counteract APAP-induced hepatocyte ferroptosis by activating the xCT/GPX4 pathway, and is expected to be a novel natural inhibitor of ferroptosis. Additionally, the transcriptomic results indicated that the inhibition of Stat1 by catechin is important for the management of AILI. Inhibition of signal transducer and activator of transcription 1 (STAT1) expression, achieved through the use of the STAT1 inhibitor fludarabine in vivo and small interfering RNA (siRNA) in vitro, was confirmed to attenuate APAP-induced ferroptosis. In conclusion, the present study identified a novel natural drug inhibitor of ferroptosis and revealed its mechanism of action to inhibit ferroptosis, regulate oxidative stress, and ameliorate inflammation in AILI. This further provides new insights into the novel natural ferroptosis inhibitors for the treatment of ROS-related inflammatory diseases.
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Affiliation(s)
- Yangjing Su
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yunong Zeng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Minjie Zhou
- Department of Organ Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Meihui Liao
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ping Qin
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Rong Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jiaochan Han
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China
| | - Xiaoqi Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Ze Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Jingjing Jiang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zhichao Yu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xintao Huang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Kaixin Ding
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Peiheng Guo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yi He
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510665, China
| | - Ying Du
- Consun Pharmaceutical Group, Guangzhou 510765, China
| | - Tingting Duan
- Consun Pharmaceutical Group, Guangzhou 510765, China
| | - Haitao Yuan
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yuewei Ge
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Ali Chen
- Center for Drug Research and Development, Guangdong Provincial Key Laboratory for Research and Evaluation of Pharmaceutical Preparations, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Wei Xiao
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education, Guangdong Pharmaceutical University, Guangzhou 510006, China
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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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Jang BK. Are Angiotensin II Receptor Blockers Really Safe From Aminotransferase Elevation or Drug-Induced Liver Injury? J Korean Med Sci 2022; 37:e261. [PMID: 35996936 PMCID: PMC9424744 DOI: 10.3346/jkms.2022.37.e261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 11/24/2022] Open
Affiliation(s)
- Byoung Kuk Jang
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea.
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Calistri L, Rastrelli V, Nardi C, Maraghelli D, Vidali S, Pietragalla M, Colagrande S. Imaging of the chemotherapy-induced hepatic damage: Yellow liver, blue liver, and pseudocirrhosis. World J Gastroenterol 2021; 27:7866-7893. [PMID: 35046618 PMCID: PMC8678821 DOI: 10.3748/wjg.v27.i46.7866] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/15/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023] Open
Abstract
The liver is the major drug-metabolizing and drug-detoxifying organ. Many drugs can cause liver damage through various mechanisms; however, the liver response to injury includes a relatively narrow spectrum of alterations that, regardless of the cause, are represented by phlogosis, oxidative stress and necrosis. The combination of these alterations mainly results in three radiological findings: vascular alterations, structural changes and metabolic function reduction. Chemotherapy has changed in recent decades in terms of the drugs, protocols and duration, allowing patients a longer life expectancy. As a consequence, we are currently observing an increase in chemotherapy-associated liver injury patterns once considered unusual. Recognizing this form of damage in an early stage is crucial for reconsidering the therapy regimen and thus avoiding severe complications. In this frontier article, we analyze the role of imaging in detecting some of these pathological patterns, such as pseudocirrhosis, "yellow liver" due to chemotherapy-associated steatosis-steatohepatitis, and "blue liver", including sinusoidal obstruction syndrome, veno-occlusive disease and peliosis.
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Affiliation(s)
- Linda Calistri
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Vieri Rastrelli
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Cosimo Nardi
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Davide Maraghelli
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Sofia Vidali
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Michele Pietragalla
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
| | - Stefano Colagrande
- Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Azienda Ospedaliera Universitaria Careggi, Florence 50134, Italy
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Abstract
PURPOSE OF REVIEW Liver test abnormalities in children with inflammatory bowel disease (IBD) are usually insidious in onset. By the time that symptoms referable to liver disease have appeared, the liver injury may be well advanced. It is, therefore, important that children with an incidental finding of abnormal liver tests are investigated in an appropriate and timely manner. RECENT FINDINGS The most prevalent cause of liver test elevations in paediatric IBD is immune-related liver disease, including primary sclerosing cholangitis, autoimmune sclerosing cholangitis, and autoimmune hepatitis. Although less common, drugs used in the treatment of IBD can also cause liver injury. The diagnosis of drug-induced liver injury relies largely on excluding other causes of liver injury, such as viral hepatitis, nonalcoholic fatty liver disease, and biliary and vascular complications. SUMMARY This review highlights an avenue to a step-wise approach for investigating children with IBD and silent liver test elevations. Central to the timing of diagnostic actions is grading the severity of liver test elevations.
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Affiliation(s)
- Patrick F van Rheenen
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Groningen, University Medical Centre Groningen - Beatrix Children's Hospital, Groningen, The Netherlands
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6
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Lewis JH, Cottu PH, Lehr M, Dick E, Shearer T, Rencher W, Bexon AS, Campone M, Varga A, Italiano A. Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity. Drug Saf 2021; 43:1045-1055. [PMID: 32594454 PMCID: PMC7497701 DOI: 10.1007/s40264-020-00964-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. Objective We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I–II studies involving patients with breast, ovarian, endometrial, and prostate cancer. Results Among the 88 patients in two phase I–II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient’s liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. Conclusions These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.
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Affiliation(s)
- James H Lewis
- Division of Gastroenterology and Hepatology, Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC, 20007, USA.
| | - Paul H Cottu
- Department of Medical Oncology, Institut Curie, Paris, France
| | - Martin Lehr
- Context Therapeutics LLC, Philadelphia, PA, USA
| | - Evan Dick
- Context Therapeutics LLC, Philadelphia, PA, USA
| | | | - William Rencher
- Context Therapeutics LLC, Philadelphia, PA, USA.,Drug and Device Development Solutions LLC (D3S), Raleigh-Durham, NC, USA
| | | | - Mario Campone
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest-René Gauducheau, Nantes, France
| | - Andrea Varga
- Department of Drug Development (DITEP), Gustave Roussy, Villejuif, France
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Kumar N, Surani S, Udeani G, Mathew S, John S, Sajan S, Mishra J. Drug-induced liver injury and prospect of cytokine based therapy; A focus on IL-2 based therapies. Life Sci 2021; 278:119544. [PMID: 33945827 DOI: 10.1016/j.lfs.2021.119544] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023]
Abstract
Drug-induced liver injury (DILI) is one of the most frequent sources of liver failure and the leading cause of liver transplant. Common non-prescription medications such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and other prescription drugs when taken at more than the recommended doses may lead to DILI. The severity of DILI is affected by factors such as age, ethnicity, race, gender, nutritional status, on-going liver diseases, renal function, pregnancy, alcohol consumption, and drug-drug interactions. Characteristics of DILI-associated inflammation include apoptosis and necrosis of hepatocytes and hepatic infiltration of pro-inflammatory immune cells. If untreated or if the inflammation continues, DILI and associated hepatic inflammation may lead to development of hepatocarcinoma. The therapeutic approach for DILI-associated hepatic inflammation depends on whether the inflammation is acute or chronic. Discontinuing the causative medication, vaccination, and special dietary supplementation are some of the conventional approaches to treat DILI. In this review, we discuss a concise overview of DILI-associated liver complications, and current therapeutic options with special emphasis on biologics including the scope of cytokine therapy in hepatic repair and resolution of inflammation caused by over- the-counter (OTC) or prescription drugs.
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Affiliation(s)
- Narendra Kumar
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America.
| | - Salim Surani
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America
| | - George Udeani
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America
| | - Sara Mathew
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America
| | - Sharon John
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America
| | - Soniya Sajan
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America
| | - Jayshree Mishra
- Irma Lerma Rangel College of Pharmacy, Texas A&M University System, Kingsville, TX 78363, United States of America.
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Lewis JH, Gelderblom H, van de Sande M, Stacchiotti S, Healey JH, Tap WD, Wagner AJ, Pousa AL, Druta M, Lin C, Baba HA, Choi Y, Wang Q, Shuster DE, Bauer S. Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors. Oncologist 2020; 26:e863-e873. [PMID: 33289960 PMCID: PMC8100574 DOI: 10.1002/onco.13629] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 11/25/2020] [Indexed: 02/06/2023] Open
Abstract
Background Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. Materials, and Methods Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow‐up from initial pexidartinib treatment was 39 months (range, 32–82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. Results In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1–76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low‐grade dose‐dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1–7 months following pexidartinib discontinuation. Five patients from the non‐TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. Conclusion This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long‐term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. Implications for Practice This is the first long‐term pooled analysis to report on the long‐term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program. Pexidartinib is approved in the U.S. for treatment of tenosynovial giant cell tumors (TGCT). This article assesses the hepatic safety profile of pexidartinib in TGCT cases and describes risk mitigation procedures designed to identify any instances of serious liver injury as early as possible to better inform prescribers and patients about this drug.
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Affiliation(s)
- James H. Lewis
- Georgetown University HospitalWashingtonDistrict of ColumbiaUSA
| | | | | | | | - John H. Healey
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - William D. Tap
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | | | | | | | | | - Hideo A. Baba
- University Hospital Essen, University of Duisburg‐EssenGermany
| | | | - Qiang Wang
- Daiichi Sankyo, IncBasking RidgeNew JerseyUSA
| | | | - Sebastian Bauer
- University Hospital Essen, University of Duisburg‐EssenGermany
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Huang Y, Zhao X, Zhang ZT, Chen SS, Li SS, Shi Z, Jing J, Huang A, Guo YM, Bai ZF, Zou ZS, Xiao XH, Wang JB, Niu M. Metabolomics Profiling and Diagnosis Biomarkers Searching for Drug-Induced Liver Injury Implicated to Polygonum multiflorum: A Cross-Sectional Cohort Study. Front Med (Lausanne) 2020; 7:592434. [PMID: 33330552 PMCID: PMC7734208 DOI: 10.3389/fmed.2020.592434] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/30/2020] [Indexed: 12/17/2022] Open
Abstract
Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis. Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers. Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%. Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis.
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Affiliation(s)
- Ying Huang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.,China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xu Zhao
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zi-Teng Zhang
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shuai-Shuai Chen
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shan-Shan Li
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhuo Shi
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jing Jing
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ang Huang
- Center for Non-Infectious Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yu-Ming Guo
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao-Fang Bai
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zheng-Sheng Zou
- Center for Non-Infectious Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-He Xiao
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jia-Bo Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming Niu
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,Department of Poisoning Treatment, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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10
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Lewis JH, Jadoul M, Block GA, Chin MP, Ferguson DA, Goldsberry A, Meyer CJ, O'Grady M, Pergola PE, Reisman SA, Wigley WC, Chertow GM. Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD. Clin Transl Sci 2020; 14:299-309. [PMID: 32860734 PMCID: PMC7877861 DOI: 10.1111/cts.12868] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/16/2020] [Indexed: 12/29/2022] Open
Abstract
In a multinational placebo‐controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy’s Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity.
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Affiliation(s)
- James H Lewis
- Division of Gastroenterology & Hepatology, Georgetown University Hospital, Washington, District of Columbia, USA
| | - Michel Jadoul
- Department of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | | | | | | | | | | | | | | | | | | | - Glenn M Chertow
- Division of Nephrology, Stanford University School of Medicine, Palo Alto, California, USA
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Ke L, Lu C, Shen R, Lu T, Ma B, Hua Y. Knowledge Mapping of Drug-Induced Liver Injury: A Scientometric Investigation (2010-2019). Front Pharmacol 2020; 11:842. [PMID: 32581801 PMCID: PMC7291871 DOI: 10.3389/fphar.2020.00842] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
Background Drug-induced liver injury (DILI) is a common adverse event, which compromises the safety of numerous drugs, poses a significant risk to patient health, and enhances healthcare expenditures. Many articles have been recently published on DILI related research, though no relevant scientometric study has been published yet. This scientometric study was aimed at comprehensively analyzing the knowledge base and emerging topics on DILI. Methods The articles and reviews related to DILI, published from 2010 to 2019 in the Web of Science Core Collection (WoSCC), were retrieved on March 15, 2020, using relevant keywords. Four different scientometric software (HistCite, VOSviewer, CiteSpace, and R-bibliometrix) was used to conduct this scientometric study. Results A total of 1,995 publications were retrieved (including 1,550 articles and 445 reviews) from 592 academic journals with 56,273 co-cited references in 10 languages by 2,331 institutions from 79 countries/regions. The majority of publications (n = 727, 36.44%) were published in the United States, and the University of North Carolina contributed the most publications (n = 89, 4.46%). The most productive academic journal on DILI was the Toxicological Sciences [n = 79, 3.96%; impact factor (IF) 2018 = 3.564], and Hepatology was the first co-cited journal (n = 7,383, IF 2018 = 14.971). Fontana RJ and Teschke R may have significant influence on DILI research, with more publications (n = 46; n = 39) and co-citations (n = 382; n = 945). Definition, incidence rate or clinical characteristics, etiology or pathogenesis (such as the character of the innate immune system, the regulation of cell-death pathways, and susceptible HLA-B*5701 genotype), identification of main drugs and causality assessment (criteria and methods) were the knowledge base for DILI research. Exploring the microscopic mechanism (such as the organelle dysfunction and cytotoxicity induced by drugs, and exploration of role of neutrophils in DILI using mouse models) and developed newer approaches to prevent DILI (such as the prospective HLA-B*5701 screening and in vitro approaches for assessing the potential risk of candidate drugs for DILI) were the recent major topics for DILI research. Conclusion This scientometric study comprehensively reviewed the publications related to DILI during the past decade using quantitative and qualitative methods. This information would provide references for scholars, researching on DILI.
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Affiliation(s)
- Lixin Ke
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Cuncun Lu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Rui Shen
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingting Lu
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Bin Ma
- Key Laboratory of Preclinical Study for New Drug of Gansu Province, School of Basic Medical Science, Lanzhou University, Lanzhou, China
| | - Yunpeng Hua
- Department of Liver Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Lewis JH, Seeff LB. The Origins of the Modern-Day Study of Drug Hepatotoxicity: Focus on Hyman J. Zimmerman. Clin Liver Dis (Hoboken) 2020; 15:S25-S36. [PMID: 32140211 PMCID: PMC7050951 DOI: 10.1002/cld.856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 06/07/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- James H. Lewis
- Department of MedicineGeorgetown University School of MedicineWashingtonDC
- Department of Hepatology, Division of GastroenterologyGeorgetown University HospitalWashingtonDC
| | - Leonard B. Seeff
- Department of MedicineGeorgetown University School of MedicineWashingtonDC
- Division of Gastroenterology, Hepatology and NutritionVeterans Affairs Medical CenterWashingtonDC
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Pan G. Roles of Hepatic Drug Transporters in Drug Disposition and Liver Toxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1141:293-340. [PMID: 31571168 DOI: 10.1007/978-981-13-7647-4_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatic drug transporters are mainly distributed in parenchymal liver cells (hepatocytes), contributing to drug's liver disposition and elimination. According to their functions, hepatic transporters can be roughly divided into influx and efflux transporters, translocating specific molecules from blood into hepatic cytosol and mediating the excretion of drugs and metabolites from hepatic cytosol to blood or bile, respectively. The function of hepatic transport systems can be affected by interspecies differences and inter-individual variability (polymorphism). In addition, some drugs and disease can redistribute transporters from the cell surface to the intracellular compartments, leading to the changes in the expression and function of transporters. Hepatic drug transporters have been associated with the hepatic toxicity of drugs. Gene polymorphism of transporters and altered transporter expressions and functions due to diseases are found to be susceptible factors for drug-induced liver injury (DILI). In this chapter, the localization of hepatic drug transporters, their regulatory factors, physiological roles, and their roles in drug's liver disposition and DILI are reviewed.
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Affiliation(s)
- Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, Shanghai, China.
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14
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Antonazzo IC, Poluzzi E, Forcesi E, Riise T, Bjornevik K, Baldin E, Muratori L, De Ponti F, Raschi E. Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System. Mult Scler 2019; 25:1633-1640. [PMID: 30230957 DOI: 10.1177/1352458518799598] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2025]
Abstract
BACKGROUND Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. OBJECTIVE To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. METHODS DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. RESULTS Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12-2.52; and 2.53; 2.40-2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09-1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). CONCLUSION These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.
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Affiliation(s)
- Ippazio Cosimo Antonazzo
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Elisabetta Poluzzi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Emanuele Forcesi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Trond Riise
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Kjetil Bjornevik
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway/The Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway/Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Elisa Baldin
- Epidemiology and Biostatistics Service, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy
| | - Luigi Muratori
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy/ Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System, Policlinico di Sant'Orsola, Bologna, Italy
| | - Fabrizio De Ponti
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Emanuel Raschi
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
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Timmer A, de Sordi D, Kappen S, Kohse KP, Schink T, Perez-Gutthann S, Jacquot E, Deltour N, Pladevall M. Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany. Pharmacoepidemiol Drug Saf 2019; 28:1344-1352. [PMID: 31373108 DOI: 10.1002/pds.4855] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 05/28/2019] [Accepted: 06/10/2019] [Indexed: 01/25/2023]
Abstract
PURPOSE Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). METHODS Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. RESULTS On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. CONCLUSIONS In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.
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Affiliation(s)
- Antje Timmer
- Division of Epidemiology and Biometry, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Dominik de Sordi
- Division of Epidemiology and Biometry, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Sanny Kappen
- Division of Epidemiology and Biometry, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Klaus Peter Kohse
- Institute for Laboratory Medicine and Microbiology, Klinikum Oldenburg, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
| | - Tania Schink
- Department of Clinical Epidemiology, Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany
| | | | | | | | - Manel Pladevall
- Epidemiology, RTI Health Solutions, Barcelona, Spain.,The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, Michigan
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16
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Shavadia JS, Sharma A, Gu X, Neaton J, DeLeve L, Holmes D, Home P, Eckel RH, Watkins PB, Granger CB. Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program. Clin Trials 2019; 16:253-262. [DOI: 10.1177/1740774519836766] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. Methods This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. Findings Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy’s Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29–4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03–14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18–17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. Conclusion In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.
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Affiliation(s)
- Jay S Shavadia
- Duke Clinical Research Institute, Durham, NC, USA
- Division of Cardiology, Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | | | | | - James Neaton
- School of Public Health, University of Minnesota, Minneapolis, MN, USA
| | - Laurie DeLeve
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | | | - Phillip Home
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Robert H Eckel
- Division of Endocrinology, Metabolism & Diabetes, University of Colorado, Boulder, CO, USA
| | - Paul B Watkins
- Institute for Drug Safety Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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17
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Pre-Existing Liver Disease and Toxicity of Antifungals. J Fungi (Basel) 2018; 4:jof4040133. [PMID: 30544724 PMCID: PMC6309049 DOI: 10.3390/jof4040133] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 12/17/2022] Open
Abstract
Pre-existing liver disease in patients with invasive fungal infections further complicates their management. Altered pharmacokinetics and tolerance issues of antifungal drugs are important concerns. Adjustment of the dosage of antifungal agents in these cases can be challenging given that current evidence to guide decision-making is limited. This comprehensive review aims to evaluate the existing evidence related to antifungal treatment in individuals with liver dysfunction. This article also provides suggestions for dosage adjustment of antifungal drugs in patients with varying degrees of hepatic impairment, after accounting for established or emerging pharmacokinetic–pharmacodynamic relationships with regard to antifungal drug efficacy in vivo.
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18
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Teschke R. Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the Roussel Uclaf Causality Assessment Method. Expert Opin Drug Metab Toxicol 2018; 14:1169-1187. [PMID: 30354694 DOI: 10.1080/17425255.2018.1539077] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION A list presenting a valid ranking of drugs most commonly implicated is hardly to be found. Areas covered: Published cases of drug-induced liver injury (DILI) with verified causality using RUCAM (Roussel Uclaf Causality Assessment Method) were used for a ranking of drugs most commonly implicated in causing DILI. Expert opinion: RUCAM-based DILI cases were retrieved from 15 reports published by six international databases of DILI registries and three large medical centers, which provided 3312 cases. Overall 48 drugs with the highest number of DILI cases were listed. Among the top 10 ranking drugs implicated in causing DILI were, in decreasing order: amoxicillin-clavulanate, flucloxacilllin, atorvastatin, disulfiram, diclofenac, simvastatin, carbamazepine, ibuprofen, erythromycin, and anabolic steroids as bodybuilding agents. For these 10 drugs, respective DILI case numbers were highest for Amoxicillin-clavulanate (n=333) and lowest for anabolic steroids (n=26). The author classifies the databases of national DILI registries and large medical centers as best sources of drugs implicated in DILI. Presently discouraged is the use of the LiverTox website because many cases were derived from published cases of poor quality and could previously not be classified as DILI, calling for the inclusion of DILI cases with established causality by the updated RUCAM.
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Affiliation(s)
- Rolf Teschke
- a Department of Internal Medicine II, Division of Gastroenterology and Hepatology , Klinikum Hanau , Hanau , Germany.,b Academic Teaching Hospital of the Medical Faculty , Goethe University Frankfurt/Main , Frankfurt/Main , Germany
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19
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Benesic A, Rotter I, Dragoi D, Weber S, Leitl A, Buchholtz ML, Gerbes AL. Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. Clin Gastroenterol Hepatol 2018; 16:1488-1494.e5. [PMID: 29723689 DOI: 10.1016/j.cgh.2018.04.049] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 04/08/2018] [Accepted: 04/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. METHODS We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. RESULTS Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). CONCLUSIONS We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.
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Affiliation(s)
- Andreas Benesic
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany.
| | - Isabelle Rotter
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | - Diana Dragoi
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; MetaHeps GmbH, Martinsried, Germany
| | - Sabine Weber
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
| | | | - Marie-Luise Buchholtz
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany; Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität Munich, Germany
| | - Alexander L Gerbes
- Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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20
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Trends in reporting drug-associated liver injuries in Taiwan: a focus on amiodarone. Int J Clin Pharm 2018; 40:911-920. [PMID: 30051228 DOI: 10.1007/s11096-018-0698-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 07/20/2018] [Indexed: 12/18/2022]
Abstract
Background A pharmacovigilance database of real-world adverse drug reaction (ADR) reports is helpful for characterising adverse events and identifying new signals after drug approval. Objective This study aimed to analyse trends of ADR reporting in relation to liver injury and to delineate critical factors for suspected drug-related hepatotoxicity with a focus on reports associated with amiodarone. Setting The 2000-2014 Taiwan pharmacovigilance database. Method Relevant Standardized Medical Dictionary for Regulatory Activities queries were used to identify reports associated with liver injury. Information on ADR, patient characteristics, and the verbatim pertaining to amiodarone prescriptions, liver injury, comedications, and comorbidities were extracted and evaluated. Group comparisons between Hy's Law cases and Temple's Corollary cases of suspected amiodarone-related hepatotoxicity were performed. Main outcome measure Number and nature of drug-related liver injuries, particularly those associated with amiodarone. Results Of the 98,777 ADR reports over a 15-year period, 4261 (4.3%) were related to liver injury. Sixty-eight reports contained amiodarone prescriptions, but only 49 (1.1%) were eligible for further analysis. Hepatotoxic cases associated with amiodarone mostly occurred within 1 week, exhibited a hepatocellular pattern, and were more common among elderly individuals. Among 23 discernible cases, four (17.4%) recovered fully from liver injury. The critical Hy's Law cases were associated with shorter height, lower body surface area, and higher average daily doses. Conclusion This study substantiates the importance of ADR reporting. Data pertaining to drug-associated liver injury and factors associated with suspected amiodarone-related hepatotoxicity warrants continual attention in pharmacovigilance for those at risk, especially the elderly.
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21
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Taneja S, Kumar P, Rathi S, Duseja A, Singh V, Dhiman RK, Chawla YK. Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment. Ann Hepatol 2018; 16:818-821. [PMID: 28809737 DOI: 10.5604/01.3001.0010.2829] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM).
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Affiliation(s)
- Sunil Taneja
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Pramod Kumar
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Sahaj Rathi
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Ajay Duseja
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Virendra Singh
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Radha Krishan Dhiman
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
| | - Yogesh Kumar Chawla
- Postgraduate Institute of Medical Education & Research, Chandigarh, India Department of Hepatology
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22
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Abstract
Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival.
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Affiliation(s)
- Arul M Thomas
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA
| | - James H Lewis
- Division of Gastroenterology, MedStar Georgetown University Hospital, 3800 Reservoir Road Northwest, Room M2408, Washington, DC 20007, USA.
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Gordon-Walker TT. Editorial: alleviating the itch-the safety of rifampicin in the real world. Aliment Pharmacol Ther 2018; 47:1332-1333. [PMID: 29644731 DOI: 10.1111/apt.14615] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- T T Gordon-Walker
- Department of Gastroenterology, Royal Infirmary of Edinburgh, Edinburgh, UK.,University of Edinburgh, Edinburgh, UK
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Tan EH, Low EXS, Dan YY, Tai BC. Systematic review and meta-analysis of algorithms used to identify drug-induced liver injury (DILI) in health record databases. Liver Int 2018; 38:742-753. [PMID: 29193566 DOI: 10.1111/liv.13646] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/19/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Drug induced liver injury (DILI) is largely underreported, leading to underestimation of its burden. Electronic detection of DILI in healthcare databases shows promise to overcome the issues of spontaneous reporting. The performance of detection algorithms may vary because of inconsistent DILI definition and detection criteria. We performed a systematic review and meta-analysis to identify the DILI detection criteria used in health record databases and determine the performance characteristics of the detection algorithms. METHODS We searched PubMed, EMBASE and Scopus for studies that utilized laboratory threshold criteria to identify DILI cases. Validation studies were included in the meta-analysis. Data were abstracted using standardized forms and quality was assessed using modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. We evaluate the performance characteristics of the detection algorithm by obtaining the pooled estimate of the positive predictive value (PPV) assuming a random effects model. RESULTS A total of 29 studies met the inclusion criteria for the systematic review; 25 of these studies (n = 35 948) had PPV estimates for performing the meta-analysis. The PPV of DILI detection algorithms was low, ranging from 1.0% to 40.2%, with a pooled estimate of 14.6% (95% CI 10.7-18.9). Algorithms that performed better had prespecified exclusion diagnoses as well as drugs of interest to minimize false positives. CONCLUSION Algorithm performance varied with different case definitions of DILI attributed to different laboratory threshold criteria, diagnosis codes, and study drugs.
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Affiliation(s)
- Eng Hooi Tan
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore City, Singapore
| | - En Xian Sarah Low
- Division of Gastroenterology and Hepatology, National University Health System, Singapore City, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore City, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
| | - Bee Choo Tai
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore City, Singapore.,Investigational Medicine Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore City, Singapore
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25
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D'Amico E, Patti F, Zanghì A, Lo Fermo S, Chisari CG, Zappia M. Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience. Expert Rev Clin Pharmacol 2018. [PMID: 29521113 DOI: 10.1080/17512433.2018.1449643] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. RESEARCH DESIGN AND METHODS retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. RESULTS 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. CONCLUSIONS lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months.
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Affiliation(s)
- E D'Amico
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
| | - F Patti
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
| | - A Zanghì
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
| | - S Lo Fermo
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
| | - C G Chisari
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
| | - M Zappia
- a Department "G.F. Ingrassia"; MS center , University of Catania , Catania , Italy
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Norman BH, Fisher MJ, Schiffler MA, Kuklish SL, Hughes NE, Czeskis BA, Cassidy KC, Abraham TL, Alberts JJ, Luffer-Atlas D. Identification and Mitigation of Reactive Metabolites of 2-Aminoimidazole-Containing Microsomal Prostaglandin E Synthase-1 Inhibitors Terminated Due to Clinical Drug-Induced Liver Injury. J Med Chem 2018; 61:2041-2051. [DOI: 10.1021/acs.jmedchem.7b01806] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Kakisaka K, Yoshida Y, Suzuki Y, Sato T, Kuroda H, Miyasaka A, Takikawa Y. Serum markers for mitochondrial dysfunction and cell death are possible predictive indicators for drug-induced liver injury by direct acting antivirals. Hepatol Res 2018; 48:78-86. [PMID: 28304119 DOI: 10.1111/hepr.12893] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/08/2017] [Accepted: 03/13/2017] [Indexed: 02/08/2023]
Abstract
AIM We prospectively screened patients treated with direct-acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI). METHODS The levels of various serum markers among DILI, non-DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, sex and disease severity. Additionally, eight healthy volunteers were employed as the controls. Serum measurements of cytokines/chemokines, cytokeratin-18 fragment (CK-18F) and super oxidase dismutase-2 (SOD2) were evaluated on the date at which hepatitis C virus RNA was absent (baseline). For patients with DILI, serum measurements taken before treatment, 1 week before pronounced transaminase elevation (prominence-1 W) and on the date at which pronounced elevation of transaminase occurred (prominence) were also evaluated. RESULTS All patients treated with DAA had normalized transaminase levels at baseline. In patients with DILI, interferon-inducible protein-10 (IP-10) levels were higher at prominence-1 W than at baseline. Those patients also had significantly higher levels of SOD2 and CK-18F at prominence-1 W than at baseline. CONCLUSION Elevated IP-10 may be a preconditioning chemokine for DAA-induced liver injury, and damage markers associated with cell death and mitochondrial dysfunction are potential predictive serum markers for DILI.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Takuro Sato
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Akio Miyasaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
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Light DS, Aleo MD, Kenna JG. Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge. METHODS IN PHARMACOLOGY AND TOXICOLOGY 2018. [DOI: 10.1007/978-1-4939-7677-5_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, Kheradman R, Heuman D, Wang J, Gurry T, Williams R, Sikaroodi M, Fuchs M, Alm E, John B, Thacker LR, Riva A, Smith M, Taylor-Robinson SD, Gillevet PM. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology 2017; 66:1727-1738. [PMID: 28586116 PMCID: PMC6102730 DOI: 10.1002/hep.29306] [Citation(s) in RCA: 448] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/12/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. CONCLUSION FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738).
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Affiliation(s)
- Jasmohan S. Bajaj
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Zain Kassam
- OpenBiome, Somerville, Massachusetts, USA,Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Andrew Fagan
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Edith A. Gavis
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Eric Liu
- George Mason University, Manassas, Virginia, USA
| | - I. Jane Cox
- Institute of Hepatology London, Foundation for Liver Research, United Kingdom
| | | | - Douglas Heuman
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Jessica Wang
- George Mason University, Manassas, Virginia, USA
| | - Thomas Gurry
- Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Roger Williams
- Institute of Hepatology London, Foundation for Liver Research, United Kingdom
| | | | - Michael Fuchs
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Eric Alm
- Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Binu John
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Leroy R Thacker
- Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Antonio Riva
- Institute of Hepatology London, Foundation for Liver Research, United Kingdom
| | - Mark Smith
- OpenBiome, Somerville, Massachusetts, USA
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Dumortier J, Cottin J, Lavie C, Guillaud O, Hervieu V, Chambon-Augoyard C, Scoazec JY, Vukusic S, Vial T. Methylprednisolone liver toxicity: A new case and a French regional pharmacovigilance survey. Clin Res Hepatol Gastroenterol 2017; 41:497-501. [PMID: 28438569 DOI: 10.1016/j.clinre.2017.03.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 03/15/2017] [Accepted: 03/27/2017] [Indexed: 02/04/2023]
Abstract
Reported hepatotoxicity induced by corticosteroids is very rare, and the diagnosis is highly challenging in the context of auto-immune disease. We report here a case of high-dose methylprednisolone (MP)-induced acute hepatitis confirmed by liver histology in a patient with multiple sclerosis (MS) and a case series (n=4) notified to the French Pharmacovigilance center of Lyon. In all 5 cases, other common causes of hepatitis were excluded. The causal relationship with MP pulse therapy was supported by the fact that MP was the only culprit drug. In addition, 3 of these 5 patients underwent unintended single or multiple positive MP rechallenge. Our 5 patients scored a RUCAM score from 6 (probable) to 10 (highly probable). MP-induced liver injury is probably very rare, since only less than 30 cases have been reported in the literature. Nevertheless, our cases strongly illustrates that many cases could have been unrecognized; final diagnosis in 3 of 5 of our patients was made after the second or third episode of acute hepatitis. In conclusion, these cases we report here strongly illustrates that high-dose MP-induced liver injury can occur in patients treated for MS or auto-immune disorder. Unintended re-challenge can confirm the diagnosis and can help to distinguish it from autoimmune hepatitis. Performing liver function tests routinely both before and after MP administration would be beneficial, as the timely recognition of this complication and early drug withdrawal may prevent progression of severe necrosis hepatic injury.
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Affiliation(s)
- Jérôme Dumortier
- Service d'Hépato-gastro-entérologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.
| | - Judith Cottin
- Centre de Pharmacovigilance, Service Hospitalo-Universitaire de Pharmacotoxicologie, Hospices Civils de Lyon, Lyon, France
| | - Caroline Lavie
- Université Claude Bernard Lyon 1, Lyon, France; Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Olivier Guillaud
- Service d'Hépato-gastro-entérologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Valérie Hervieu
- Université Claude Bernard Lyon 1, Lyon, France; Service d'anatomopathologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | | | - Jean-Yves Scoazec
- Service d'anatomopathologie, Institut Gustave Roussy, Villejuif, France
| | - Sandra Vukusic
- Université Claude Bernard Lyon 1, Lyon, France; Service de Neurologie A, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France
| | - Thierry Vial
- Centre de Pharmacovigilance, Service Hospitalo-Universitaire de Pharmacotoxicologie, Hospices Civils de Lyon, Lyon, France
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31
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Teschke R, Schulze J, Eickhoff A, Danan G. Drug Induced Liver Injury: Can Biomarkers Assist RUCAM in Causality Assessment? Int J Mol Sci 2017; 18:E803. [PMID: 28398242 PMCID: PMC5412387 DOI: 10.3390/ijms18040803] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 03/31/2017] [Accepted: 04/01/2017] [Indexed: 12/25/2022] Open
Abstract
Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.
- Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Johannes Schulze
- Institute of Occupational, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany.
- Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, D-60590 Frankfurt, Germany.
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France.
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Alempijevic T, Zec S, Milosavljevic T. Drug-induced liver injury: Do we know everything? World J Hepatol 2017; 9:491-502. [PMID: 28443154 PMCID: PMC5387361 DOI: 10.4254/wjh.v9.i10.491] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 02/28/2017] [Accepted: 03/14/2017] [Indexed: 02/06/2023] Open
Abstract
Interest in drug-induced liver injury (DILI) has dramatically increased over the past decade, and it has become a hot topic for clinicians, academics, pharmaceutical companies and regulatory bodies. By investigating the current state of the art, the latest scientific findings, controversies, and guidelines, this review will attempt to answer the question: Do we know everything? Since the first descriptions of hepatotoxicity over 70 years ago, more than 1000 drugs have been identified to date, however, much of our knowledge of diagnostic and pathophysiologic principles remains unchanged. Clinically ranging from asymptomatic transaminitis and acute or chronic hepatitis, to acute liver failure, DILI remains a leading causes of emergent liver transplant. The consumption of unregulated herbal and dietary supplements has introduced new challenges in epidemiological assessment and clinician management. As such, numerous registries have been created, including the United States Drug-Induced Liver Injury Network, to further our understanding of all aspects of DILI. The launch of LiverTox and other online hepatotoxicity resources has increased our awareness of DILI. In 2013, the first guidelines for the diagnosis and management of DILI, were offered by the Practice Parameters Committee of the American College of Gastroenterology, and along with the identification of risk factors and predictors of injury, novel mechanisms of injury, refined causality assessment tools, and targeted treatment options have come to define the current state of the art, however, gaps in our knowledge still undoubtedly remain.
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Affiliation(s)
- Tamara Alempijevic
- Tamara Alempijevic, Simon Zec, Tomica Milosavljevic, University of Belgrade, School of Medicine, 11000 Belgrade, Serbia
| | - Simon Zec
- Tamara Alempijevic, Simon Zec, Tomica Milosavljevic, University of Belgrade, School of Medicine, 11000 Belgrade, Serbia
| | - Tomica Milosavljevic
- Tamara Alempijevic, Simon Zec, Tomica Milosavljevic, University of Belgrade, School of Medicine, 11000 Belgrade, Serbia
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Model Systems for Studying the Role of Canalicular Efflux Transporters in Drug-Induced Cholestatic Liver Disease. J Pharm Sci 2017; 106:2295-2301. [PMID: 28385542 DOI: 10.1016/j.xphs.2017.03.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/11/2017] [Accepted: 03/27/2017] [Indexed: 12/12/2022]
Abstract
Bile formation is a key function of the liver. Disturbance of bile flow may lead to liver disease and is called cholestasis. Cholestasis may be inherited, for example, in progressive familial intrahepatic cholestasis or acquired, for example, by drug-mediated inhibition of bile salt export from hepatocytes into the canaliculi. The key transport system for exporting bile salts into the canaliculi is the bile salt export pump. Inhibition of the bile salt export pump by drugs is a well-established cause of drug-induced cholestasis. Investigation of the role of the multidrug resistance protein 3, essential for biliary phospholipid secretion, is emerging now. This overview summarizes current concepts and methods with an emphasis on in vitro model systems for the investigation of drug-induced cholestasis in the general context of drug-induced liver injury.
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34
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Gonzalez HC, Jafri SM, Gordon SC. Management of Acute Hepatotoxicity Including Medical Agents and Liver Support Systems. Clin Liver Dis 2017; 21:163-180. [PMID: 27842770 DOI: 10.1016/j.cld.2016.08.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Drug-induced liver injury (DILI) can be predictable or idiosyncratic and has an estimated incidence of approximately 20 cases per 100,000 persons per year. DILI is a common cause of acute liver failure in the United States. No accurate tests for diagnosing DILI exist, and its diagnosis is based on exclusion of other conditions. Managing DILI includes discontinuing the suspected causative agent and in selected cases administering an antidote. Liver support systems are used for long-term support or as a bridge to transplantation and are effective for improving encephalopathy, hyperbilirubinemia, and other liver-related conditions, but whether they improve survival remains uncertain.
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Affiliation(s)
- Humberto C Gonzalez
- Department of Transplant Surgery/Center of Advanced Liver Disease, Methodist University Hospital, University of Tennessee Health Science Center, 1211 Union Avenue, Suite 340, Memphis, TN 38104, USA
| | - Syed-Mohammed Jafri
- Division of Gastroenterology and Hepatology, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI 48202, USA
| | - Stuart C Gordon
- Division of Gastroenterology and Hepatology, Henry Ford Health System, 2799 West Grand Boulevard, Detroit, MI 48202, USA.
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35
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Abstract
Drug-induced liver injury presents as various forms of acute and chronic liver disease. There is wide geographic variation in the most commonly implicated agents. Smoking can induce cytochrome P450 enzymes but this does not necessarily translate into clinically relevant drug-induced liver injury. Excessive alcohol consumption is a clear risk factor for intrinsic hepatotoxicity from acetaminophen and may predispose to injury from antituberculosis medications. Understanding of the role of infection, proinflammatory states, disorders of coagulation, and the hepatic clock in predisposing patients to drug-induced liver injury is evolving. More study focusing specifically on environmental risk factors predisposing patients to drug-induced liver injury is needed.
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Affiliation(s)
- Jonathan G Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, 1215 Lee Street, PO Box 800708, MSB 2145, Charlottesville, VA 22908, USA
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Building, Suite 225, Indianapolis, IN 46202, USA.
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36
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Raschi E, De Ponti F. Drug-induced liver injury: Towards early prediction and risk stratification. World J Hepatol 2017; 9:30-37. [PMID: 28105256 PMCID: PMC5220269 DOI: 10.4254/wjh.v9.i1.30] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 09/29/2016] [Accepted: 11/27/2016] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a hot topic for clinicians, academia, drug companies and regulators, as shown by the steadily increasing number of publications and agents listed as causing liver damage (http://livertox.nih.gov/). As it was the case in the past decade with drug-induced QT prolongation/arrhythmia, there is an urgent unmet clinical need to develop tools for risk assessment and stratification in clinical practice and, in parallel, to improve prediction of pre-clinical models to support regulatory steps and facilitate early detection of liver-specific adverse drug events. Although drug discontinuation and therapy reconciliation still remain the mainstay in patient management to minimize occurrence of DILI, especially acute liver failure events, different multidisciplinary attempts have been proposed in 2016 to predict and assess drug-related risk in individual patients; these promising, albeit preliminary, results strongly support the need to pursue this innovative pathway.
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Affiliation(s)
- Emanuel Raschi
- Emanuel Raschi, Fabrizio De Ponti, Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Fabrizio De Ponti
- Emanuel Raschi, Fabrizio De Ponti, Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
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Abstract
Drugs can induce liver injury when taken as an over-dose, or even at therapeutic doses in susceptible individuals. Although severe drug-induced liver injury (DILI) is a relatively uncommon clinical event, it is a potentially life threatening adverse drug reaction and is the most common indication for the drug withdrawal. Areas covered: However, the diagnosis of DILI remains a significant challenge, because the establishment of causality is very difficult, and the histopathologic findings of DILI may be indistinguishable from those of other hepatic disorders, such as viral and alcoholic hepatitis. In this review, we provide an overview of recent advances in identification of serologic markers of diagnosis and prognosis, etiologic factors for susceptibility and diagnostic evaluation of DILI, with a focus on its pathogenic mechanisms and the role of liver biopsy. Expert commentary: Further studies of divergent research platforms, using a systems biology approach such as genomics and transcriptomics, may provide a deeper understanding of human drug metabolism and the causes, risk factors, and pathogenesis of DILI.
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Affiliation(s)
- Sun-Jae Lee
- a Department of Pathology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
| | - Youn Ju Lee
- b Department of Pharmacology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
| | - Kwan-Kyu Park
- a Department of Pathology, School of Medicine , Catholic University of Daegu , Daegu , Republic of Korea
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Hu PF, Wang PQ, Chen H, Hu XF, Xie QP, Shi J, Lin L, Xie WF. Beneficial effect of corticosteroids for patients with severe drug-induced liver injury. J Dig Dis 2016; 17:618-627. [PMID: 27426618 DOI: 10.1111/1751-2980.12383] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 06/21/2016] [Accepted: 07/11/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The efficacy of corticosteroids in drug-induced liver injury (DILI) remains controversial. We aimed to determine whether corticosteroids were beneficial for severe DILI. METHODS This was a single-center retrospective study of patients with DILI enrolled between January 2010 and May 2015. RESULTS Of the 203 patients enrolled, 53 were treated with corticosteroids. The baseline characteristics of patients received corticosteroids were more severe than that of the non-corticosteroid group. Subgroup analyses indicated that almost all patients who died had the higher 50% quartile of total bilirubin (TB) levels. Among the 50-75% quartile of TB level, no patient in the corticosteroids group but 3 (15.0%) of 20 patients in the non-corticosteroid group died (P = 0.261). With the highest 25% quartile of TB level, four patients in the corticosteroids group and four in the non-corticosteroids group died (P = 0.405). Corticosteroid therapy improved the recovery rate from 77.4% to 87.9% in the higher 50% quartile of TB values (P = 0.331). More interestingly, corticosteroid administration hastened the resolution of liver injury by shortening the duration of peak TB to 50% reduction from 17 to 12 days (P < 0.05). Additionally, multivariate analysis revealed that the TB levels and cholestatic injury type were the two independent factors associated with a poor outcome of DILI. CONCLUSIONS Corticosteroids are not detrimental to DILI, but instead ameliorate liver injury and improve patient survival. Short-time use of corticosteroids is strongly recommended for severe DILI patients with hyperbilirubinemia.
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Affiliation(s)
- Ping Fang Hu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Pei Qin Wang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Han Chen
- Department of General Surgery, 411th Hospital of the People's Liberation Army, Shanghai, China
| | - Xiao Fan Hu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Qiu Ping Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jian Shi
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Lin Lin
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wei Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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Stine JG, Northup PG. Autoimmune-like drug-induced liver injury: a review and update for the clinician. Expert Opin Drug Metab Toxicol 2016; 12:1291-1301. [DOI: 10.1080/17425255.2016.1211110] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Jonathan G. Stine
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Patrick G. Northup
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Virginia, Charlottesville, VA, USA
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Teschke R, Larrey D, Melchart D, Danan G. Traditional Chinese Medicine (TCM) and Herbal Hepatotoxicity: RUCAM and the Role of Novel Diagnostic Biomarkers Such as MicroRNAs. MEDICINES (BASEL, SWITZERLAND) 2016; 3:E18. [PMID: 28930128 PMCID: PMC5456249 DOI: 10.3390/medicines3030018] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 07/04/2016] [Accepted: 07/06/2016] [Indexed: 02/08/2023]
Abstract
Background: Traditional Chinese Medicine (TCM) with its focus on herbal use is popular and appreciated worldwide with increased tendency, although its therapeutic efficacy is poorly established for most herbal TCM products. Treatment was perceived as fairly safe but discussions emerged more recently as to whether herb induced liver injury (HILI) from herbal TCM is a major issue; Methods: To analyze clinical and case characteristics of HILI caused by herbal TCM, we undertook a selective literature search in the PubMed database with the search items Traditional Chinese Medicine, TCM, alone and combined with the terms herbal hepatotoxicity or herb induced liver injury; Results: HILI caused by herbal TCM is rare and similarly to drugs can be caused by an unpredictable idiosyncratic or a predictable intrinsic reaction. Clinical features of liver injury from herbal TCM products are variable, and specific diagnostic biomarkers such as microsomal epoxide hydrolase, pyrrole-protein adducts, metabolomics, and microRNAs are available for only a few TCM herbs. The diagnosis is ascertained if alternative causes are validly excluded and causality levels of probable or highly probable are achieved applying the liver specific RUCAM (Roussel Uclaf Causality Assessment Method) as the most commonly used diagnostic tool worldwide. Case evaluation may be confounded by inappropriate or lacking causality assessment, poor herbal product quality, insufficiently documented cases, and failing to exclude alternative causes such as infections by hepatotropic viruses including hepatitis E virus infections; Conclusion: Suspected cases of liver injury from herbal TCM represent major challenges that deserve special clinical and regulatory attention to improve the quality of case evaluations and ascertain patients' safety and benefit.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Teaching Hospital of the Medical Faculty of the Goethe University, Frankfurt/Main D-63450, Germany.
| | - Dominique Larrey
- Department of Liver and Transplantation-IRB-INSERM (Institut de Recherche Biologique-INstitut de la Santé Et de la Recherche Médicale) 1183, Saint Eloi Hospital, Montpellier University, 34295 Montpellier, France.
| | - Dieter Melchart
- Competence Centre for Complementary Medicine and Naturopathy (CoCoNat), Klinikum rechts der Isar, Technische Universität München, Munich D-80801, Germany.
- Institute for Complementary and Integrative Medicine, University Hospital Zurich and University of Zurich, Zurich CH-8091, Switzerland.
| | - Gaby Danan
- Pharmacovigilance Consultancy, Paris 75020, France.
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Kakisaka K, Kataoka K, Suzuki Y, Okada Y, Yoshida Y, Kuroda H, Takikawa Y. Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury. Cytokine 2016; 86:21-28. [PMID: 27442007 DOI: 10.1016/j.cyto.2016.07.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 06/05/2016] [Accepted: 07/09/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS The aim of this study was to investigate the clinical characteristics and pathophysiology of drug-induced liver injury (DILI) - acute liver failure (ALF). METHODS The patients with acute liver injury (ALI) including ALF from 2009 to 2014 were analyzed. The hepatic encephalopathy (HE) development rate was compared with the findings from a national survey in Japan. The serum cytokines levels and the findings of a liver function test were evaluated in the DILI patients. RESULTS The HE development rate substantially decreased for autoimmune hepatitis (AIH) - and undetermined cause-induced ALI owing to the early prediction system, but not in DILI-ALI. Among the DILI-ALF and AIH-ALF cases, the CK-18 fragment (1480.1U/L, 3945.4U/L), IL-8 (82.9pg/mL, 207.5pg/mL), IP-10 (1379.6pg/mL, 3731.2pg/mL) and MIP-1β (1017.7pg/mL, 2273.3pg/mL) levels were lower in the DILI-ALF cases. Among the DILI-ALI and DILI-ALF cases, IL-4 (19.8pg/mL, 25.4pg/mL) and RANTES (14028.0pg/mL, 17804.7pg/mL) were higher in DILI-ALI, and HMGB-1 (397.1pg/μL, 326.2pg/μL) and HGF (2.41ng/mL, 0.55ng/mL) were higher in DILI-ALF. We observed that HGF independently associated with DLI-ALF development. CONCLUSIONS Despite the low grade apoptosis and inflammation, DILI patients progressed to ALF comparable with that of the AIH patients.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan.
| | - Kojiro Kataoka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yohei Okada
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yuichi Yoshida
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Hidekatsu Kuroda
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
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Stine JG, Lewis JH. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol 2015; 10:517-36. [PMID: 26633044 PMCID: PMC5074808 DOI: 10.1586/17474124.2016.1127756] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
While the pace of discovery of new agents, mechanisms and risk factors involved in drug-induced liver injury (DILI) remains brisk, advances in the treatment of acute DILI seems slow by comparison. In general, the key to treating suspected DILI is to stop using the drug prior to developing irreversible liver failure. However, predicting when to stop is an inexact science, and commonly used ALT monitoring is an ineffective strategy outside of clinical trials. The only specific antidote for acute DILI remains N-acetylcysteine (NAC) for acetaminophen poisoning, although NAC is proving to be beneficial in some cases of non-acetaminophen DILI in adults. Corticosteroids can be effective for DILI associated with autoimmune or systemic hypersensitivity features. Ursodeoxycholic acid, silymarin and glycyrrhizin have been used to treat DILI for decades, but success remains anecdotal. Bile acid washout regimens using cholestyramine appear to be more evidenced based, in particular for leflunomide toxicity. For drug-induced acute liver failure, the use of liver support systems is still investigational in the United States and emergency liver transplant remains limited by its availability. Primary prevention appears to be the key to avoiding DILI and the need for acute treatment. Pharmacogenomics, including human leukocyte antigen genotyping and the discovery of specific DILI biomarkers offers significant promise for the future. This article describes and summarizes the numerous and diverse treatment and prevention modalities that are currently available to manage DILI.
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Affiliation(s)
- Jonathan G. Stine
- University of Virginia Health System, Department of Medicine, Division of Gastroenterology and Hepatology, JPA and Lee Street, MSB 2145, PO Box 800708, Charlottesville VA 22908
| | - James H. Lewis
- Georgetown University Medical Center, Department of Medicine, Division of Gastroenterology and Hepatology, 3800 Reservoir Rd NW, Washington, DC 20007
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Dipaola F, Fontana RJ. Is Making a Prognosis for Patients With Drug-induced Liver Injury Putting the Cart Before the Horse? Clin Gastroenterol Hepatol 2015; 13:2369-71. [PMID: 26291666 DOI: 10.1016/j.cgh.2015.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 08/10/2015] [Accepted: 08/10/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Frank Dipaola
- Departments of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan
| | - Robert J Fontana
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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Rathi S, Dhiman RK. Hepatobiliary Quiz (Answers)-16 (2015). J Clin Exp Hepatol 2015; 5:357-60. [PMID: 26900280 PMCID: PMC4723713 DOI: 10.1016/j.jceh.2015.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
| | - Radha K. Dhiman
- Address for correspondence: Radha K. Dhiman, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.Department of Hepatology, Postgraduate Institute of Medical Education and ResearchChandigarh160012India
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Fallon MB, Kanwal F, El-Serag HB. The Art and Science of Managing Liver Disease. Clin Gastroenterol Hepatol 2015; 13:2029-30. [PMID: 26325399 DOI: 10.1016/j.cgh.2015.08.031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 08/24/2015] [Indexed: 02/07/2023]
Affiliation(s)
| | - Fasiha Kanwal
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - Hashem B El-Serag
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
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Wang W, Shi Q, Mattes WB, Mendrick DL, Yang X. Translating extracellular microRNA into clinical biomarkers for drug-induced toxicity: from high-throughput profiling to validation. Biomark Med 2015; 9:1177-88. [PMID: 26501984 DOI: 10.2217/bmm.15.86] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past 5 years, extracellular microRNAs (miRNAs) are being vigorously explored as injury biomarkers, including drug-induced cardiotoxicity, hepatotoxicity and nephrotoxicity. Currently, the development of miRNAs as clinical biomarkers has been hindered by the lack of standardization. Therefore, extracellular miRNA-based biomarkers have not been embraced as diagnostic tools. Each platform has its strengths and weaknesses when working with low-input-amount RNA samples from body fluids; the selection of a miRNA quantification approach should be based on the study design. The following review provides a summary of the extracellular miRNA release and stability in body fluids, performances of different miRNA quantification platforms, existing clinical gold standards for drug-induced tissue damage and translation of the miRNA biomarkers from the nonclinical to clinical setting.
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Affiliation(s)
- Wenjun Wang
- College of Life Science, South-Central University for Nationalities, Wuhan 430074, PR China.,Division of Systems Biology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Qiang Shi
- Division of Systems Biology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Williams B Mattes
- Division of Systems Biology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Donna L Mendrick
- Division of Systems Biology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
| | - Xi Yang
- Division of Systems Biology, National Center for Toxicological Research, Food & Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA
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