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Lewis JH, Korkmaz SY, Rizk CA, Copeland MJ. Diagnosis, prevention and risk-management of drug-induced liver injury due to medications used to treat mycobacterium tuberculosis. Expert Opin Drug Saf 2024; 23:1093-1107. [PMID: 39212296 DOI: 10.1080/14740338.2024.2399074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/19/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Many of the first line medications for the treatment of active and latent M. tuberculosis are hepatoxic and cause a spectrum of anti-tuberculosis drug induced liver injury (ATLI), including acute liver failure (ALF). Despite advances in recognition of and prevention of ATLI, isoniazid remains one of the leading causes of DILI as well as drug-induced ALF. AREAS COVERED A literature search of the incidence, risk factors, current societal guidelines, monitoring, and prophylactic medication usage in ATLI was performed using PubMed and institutional websites. Relevant articles from 1972 to 2024 were included in this review. EXPERT OPINION Current societal guidelines regarding ATLI monitoring are mixed, but many recommend liver enzyme testing of high-risk populations. We recommend liver test monitoring for all patients on multi-drug therapy as well as those on isoniazid therapy. Precision medicine practices, such as N-acetyltransferase-2 polymorphism genotyping, are thought to be beneficial in reducing the incidence of ATLI in high-risk populations. However, broader implementation is currently cost prohibitive. Hepatoprotective drugs are not currently recommended, although we do recognize their potential. In patients who develop ATLI but require ongoing anti-TB treatment, strategies to restart the same or less hepatotoxic regimens are currently being followed.
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Affiliation(s)
- James H Lewis
- Department of Medicine, Division of Gastroenterology-Hepatology, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Serena Y Korkmaz
- Department of Medicine, General Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Courtney A Rizk
- Department of Medicine, General Internal Medicine, Medstar Georgetown University Hospital, Washington, DC, USA
| | - Matthew J Copeland
- Department of Medicine, Division of Infectious Diseases, Washington, DC, USA
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Leciejewska N, Jędrejko K, Gómez-Renaud VM, Manríquez-Núñez J, Muszyńska B, Pokrywka A. Selective androgen receptor modulator use and related adverse events including drug-induced liver injury: Analysis of suspected cases. Eur J Clin Pharmacol 2024; 80:185-202. [PMID: 38059982 PMCID: PMC10847181 DOI: 10.1007/s00228-023-03592-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/02/2023] [Indexed: 12/08/2023]
Abstract
PURPOSE Selective androgen receptor modulators (SARMs) have demonstrated agonist activity on the androgen receptor in various tissues, stimulating muscle mass growth and improving bone reconstruction. Despite being in clinical trials, none has been approved by the Food and Drug Administration (FDA) or European Medicines Agency for pharmacotherapy. Still, SARMs are very popular as performance-enhancing drugs. The FDA has issued warnings about the health risks associated with SARMs, but the long-term exposure and possible adverse events still need to be fully understood. This review aims to evaluate the adverse events associated with using SARMs by humans. METHODS PubMed database was searched from September 16, 2022, to October 2, 2023. In total, 20 records were included in the final review. Data from preclinical and clinical studies supported the review. RESULTS Since 2020, 20 reports of adverse events, most described as drug-induced liver injury associated with the use of SARM agonists, have been published. The main symptoms mentioned were cholestatic or hepatocellular liver injury and jaundice. Limited data are related to the dosages and purity of SARM supplements. CONCLUSION Promoting SARMs as an anabolic agent in combination with other performance-enhancing drugs poses a risk to users not only due to doping controls but also to health safety. The lack of quality control of consumed supplements makes it very difficult to assess the direct impact of SARMs on the liver and their potential hepatotoxic effects. Therefore, more detailed analyses are needed to determine the safety of using SARMs.
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Affiliation(s)
- Natalia Leciejewska
- Department of Animal Physiology, Biochemistry and Biostructure, Poznań University of Life Sciences, 60-637, Poznan, Poland
| | - Karol Jędrejko
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Kraków, Poland.
| | - Víctor M Gómez-Renaud
- Human Performance Laboratory, School of Physical Education, Autonomous University of Nuevo Leon, San Nicolas de los Garza, Mexico
| | - Josué Manríquez-Núñez
- Department of Research and Graduate Studies in Food Sciences, School of Chemistry, Autonomous University of Queretaro, Santiago de Queretaro, Mexico
| | - Bożena Muszyńska
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688, Kraków, Poland
| | - Andrzej Pokrywka
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
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Sánchez Luque CB. The Roussel-Uclaf hepatotoxicity causality assessment method in the context of diagnostic suspicion of drug-induced liver damage: Is it still valid? REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2023; 88:453-454. [PMID: 38097435 DOI: 10.1016/j.rgmxen.2023.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 04/24/2023] [Indexed: 01/01/2024]
Affiliation(s)
- C B Sánchez Luque
- Departamento de Medicina Interna, Sección de Gastroenterología y Hepatología, Hospital Universitario Fundación Santa Fe de Bogotá, Bogotá, Colombia.
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Gu S, Rajendiran G, Forest K, Tran TC, Denny JC, Larson EA, Wilke RA. Drug-Induced Liver Injury with Commonly Used Antibiotics in the All of Us Research Program. Clin Pharmacol Ther 2023; 114:404-412. [PMID: 37150941 PMCID: PMC10484299 DOI: 10.1002/cpt.2930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/30/2023] [Indexed: 05/09/2023]
Abstract
Antibiotics are a known cause of idiosyncratic drug-induced liver injury (DILI). According to the Centers for Disease Control and Prevention, the five most commonly prescribed antibiotics in the United States are azithromycin, ciprofloxacin, cephalexin, amoxicillin, and amoxicillin-clavulanate. We quantified the frequency of acute DILI for these common antibiotics in the All of Us Research Program, one of the largest electronic health record (EHR)-linked research cohorts in the United States. Retrospective analyses were conducted applying a standardized phenotyping algorithm to de-identified clinical data available in the All of Us database for 318,598 study participants. Between February 1984 and December 2022, more than 30% of All of Us participants (n = 119,812 individuals) had been exposed to at least 1 of our 5 study drugs. Initial screening identified 591 potential case patients that met our preselected laboratory-based phenotyping criteria. Because DILI is a diagnosis of exclusion, we then used phenome scanning to narrow the case counts by (i) scanning all EHRs to identify all alternative diagnostic explanations for the laboratory abnormalities, and (ii) leveraging International Classification of Disease 9th revision (ICD)-9 and ICD 10th revision (ICD)-10 codes as exclusion criteria to eliminate misclassification. Our final case counts were 30 DILI cases with amoxicillin-clavulanate, 24 cases with azithromycin, 24 cases with ciprofloxacin, 22 cases with amoxicillin alone, and < 20 cases with cephalexin. These findings demonstrate that data from EHR-linked research cohorts can be efficiently mined to identify DILI cases related to the use of common antibiotics.
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Affiliation(s)
- Shaopeng Gu
- Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls SD, USA
- Sanford Imagenetics, Sioux Falls SD, USA
| | - Govarthanan Rajendiran
- Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls SD, USA
- Sanford Medical Center, Section of Gastroenterology/Hepatology, Sioux Falls SD, USA
| | - Kennedy Forest
- Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls SD, USA
| | - Tam C Tran
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Joshua C Denny
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - Eric A Larson
- Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls SD, USA
- Sanford Imagenetics, Sioux Falls SD, USA
| | - Russell A Wilke
- Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls SD, USA
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Teschke R, Danan G. Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use. Int J Mol Sci 2023; 24:10855. [PMID: 37446036 DOI: 10.3390/ijms241310855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, Rue des Ormeaux, 75020 Paris, France
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Luo J, Zheng Z, Yu R. Analysis of medical malpractice liability disputes related to novel antineoplastic drugs and research on risk prevention and control strategies. PLoS One 2023; 18:e0286623. [PMID: 37276214 DOI: 10.1371/journal.pone.0286623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 05/22/2023] [Indexed: 06/07/2023] Open
Abstract
OBJECTIVE To investigate the general characteristics of litigation cases of medical malpractice liability disputes (MMLDs) related to novel antineoplastic drugs (NADs), the drugs involved, as well as the common types of medical errors related to NADs and their damages in the process of diagnosis and treatment, with the aims of improving the level of rational medication use in the clinical application of NADs and actively prevent medical disputes. METHODS The China Judgments Online was searched for the cause of action using the key word "MMLDs" along with the name of 77 kinds of NADs. A total of 39 NAD litigation cases meeting the inclusion criteria from 1 January 2009 to 31 December 2021 were analyzed, and each potential adverse drug reaction (ADR) was reviewed to determine a causality assessment using the Naranjo algorithm for non-drug-induced liver injury (DILI) cases and the updated Roussel Uclaf Causality Assessment Method (RUCAM) for the DILI cases. Risk prevention and control strategies were recommended. RESULTS Cases that met the inclusion criteria increased substantially each year during the last six years, from three cases in 2009-2015 to 36 cases in 2016-2021. There were more cases in Eastern China than in other geographic regions. Most cases involved tertiary hospitals, patients between 25 and 60 years of age, and patients who were predominately male. There were 18 kinds of NADs involved in medical errors. The most common consequences of NADs were closely related to the death, disability, and increased treatment costs caused by ADRs, inadequate indications, delayed diagnosis and treatment, and misdiagnosis and mistreatment. The most frequent medical errors were medical technology errors, medical ethics errors and medical record writing/safekeeping errors. In two cases involving DILI, one case was unable to undergo further RUCAM scoring because the liver function indicators of the patient before and after treatment were not published. CONCLUSION The establishment of mechanisms to reduce the risks associated with the clinical application of NADs is warranted. Healthcare services must maintain strict adherence to the specific requirements of GPCANADs and drug instructions and strictly grasp the indications, contraindications, usage, and dosage of drugs, and strengthen the notification and management of off-label drug use. Monitoring patients for ADRs and preparing rescue and treatment measures for high-risk drugs may serve to reduce damages related to NADs. For DILI cases, medical and appraisal institutions should use RUCAM score to assess causal relationships.
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Affiliation(s)
- Jinyu Luo
- Division of Nursing, Hemopurification Center, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zaoqian Zheng
- Department of Pharmacy, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
- Division of Medical Administration, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
- Division of Medical Administration, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Rongliang Yu
- Division of Medical Administration, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China
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Mian A, Bani Fawwaz BA, Singh G, Farooq A, Koteish A. Metformin-Induced Acute Hepatitis. Cureus 2023; 15:e38908. [PMID: 37309348 PMCID: PMC10257557 DOI: 10.7759/cureus.38908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2023] [Indexed: 06/14/2023] Open
Abstract
Metformin is considered an initial oral pharmacotherapy of choice for treating hyperglycemia in type 2 diabetes mellitus (T2DM). Although safe in the vast majority of the population, rare side effects will come to light as the prevalence of T2DM continues to rise. We present a rare case of metformin-induced hepatotoxicity and possibly the first reported case of dose-dependent metformin-induced hepatotoxicity. This case report aims to make clinicians aware of this infrequent yet significant adverse reaction that can arise with metformin therapy.
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Affiliation(s)
- Arooj Mian
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | | | - Gurdeep Singh
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | - Aimen Farooq
- Internal Medicine, AdventHealth Orlando, Orlando, USA
| | - Ayman Koteish
- Gastroenterology and Hepatology, AdventHealth Orlando, Orlando, USA
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Treatment of Drug-Induced Liver Injury. Biomedicines 2022; 11:biomedicines11010015. [PMID: 36672522 PMCID: PMC9855719 DOI: 10.3390/biomedicines11010015] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/28/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.
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Drug-Induced Liver Injury during Consolidation Therapy in Childhood Acute Lymphoblastic Leukemia as Assessed for Causality Using the Updated RUCAM. Can J Gastroenterol Hepatol 2022; 2022:5914593. [PMID: 35369115 PMCID: PMC8970867 DOI: 10.1155/2022/5914593] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 12/19/2022] Open
Abstract
PURPOSE The presence of serious toxicities is a major problem in the treatment of childhood acute lymphoblastic leukemia (ALL). The objective of this research is to evaluate drug-induced liver injury (DILI) during consolidation therapy in childhood ALL. METHODS Clinical data of pediatric patients who received consolidation therapy between August 2012 and July 2018 were collected. Characteristics (incidences and patterns) of DILI at different stratifications were determined. Risks of DILI were evaluated using binary logistic regression analysis. Drug causality assessment was carried out by the updated Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS Patients with high risk (HR) and standard risk (SR)/intermediate risk (IR) received 270 and 1539 courses of consolidation therapy, respectively; among these courses, 15 (5.6%) and 38 (2.5%) developed DILI. The occurrences of DILI in SR/IR patients were primarily associated with age (≤5.2 years), treatment course (≥5), and baseline serum parameters before treatment (cystatin C > 0.79 mg/L, albumin ≤45 g/L, and gamma-glutamyl transpeptidase (GGT) > 17 U/L). The ROC curve generated using the parameters assigned to specific values achieved an area under the curve (AUC) of 0.846 (95% CI 0.827-0.863) with a cutoff value of 3, and the sensitivity and specificity were 94.7% and 62.3%, respectively. For HR patients, a decrease in baseline albumin and elevation of baseline liver enzymes (GGT and aspartate aminotransferase) were observed in DILI cases compared with the non-DILI subjects. In the SR/IR group with DILI, the causality gradings for high-dose methotrexate (HD-MTX) were highly probable in 5 (13.2%) cases, probable in 31 (81.6%) cases, and possible in 2 (5.3%) cases. Among the DILI cases in HR-1, HR-2, and HR-3 groups, high causality gradings (probable + highly probable) were detected in "100% of HD-MTX + 57% of high-dose cytarabine (HD-Ara-C)," "100% of HD-MTX + 20% of pegylated asparaginase (PEG-ASP)," and "100% of HD-Ara-C + 33.3% of PEG-ASP," respectively. CONCLUSION Incidence of DILI in HR patients was significantly higher than that in SR/IR patients. A number of potential risk factors were identified, among which the preexisting liver conditions were suggested as shared risk factors in all stratification groups. HD-MTX, HD-Ara-C, and PEG-ASP were the main causative agents of DILI. The knowledge generated from this study will be helpful for understanding characteristics of DILI during consolidation treatment in childhood ALL.
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Soares PF, Fernandes MTCF, Souza ADS, Lopes CM, Dos Santos DAC, Oliveira DPR, Pereira MG, Prado NMDBL, Gomes GSDS, Santos G, Paraná R. Causality imputation between herbal products and HILI: An algorithm evaluation in a systematic review. Ann Hepatol 2022; 25:100539. [PMID: 34555512 DOI: 10.1016/j.aohep.2021.100539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/04/2023]
Abstract
Algorithms can have several purposes in the clinical practice. There are different scales for causality imputation in DILI (Drug-Induced Liver Injury), but the applicability and validity of these for the HILI (Herb-Induced Liver Injury) evaluation is questionable for some scales. The purpose of the study was to determine the clinical and demographic profile of the patients with HILI, and the main algorithmic scales used in its causality assessment. The methodology was a systematic review of articles in English, Spanish, or Portuguese language, from 1979 to 2019, involving humans, with descriptors related to HILI. Qualitative and quantitative statistical analysis were performed. As a result, from a total of 60 articles, 203 HILI reports were selected: 59.9% were women, similar with other studies, and the average age was 45.8 years. Jaundice was the most frequent symptom and regarding the type of lesion, the hepatocellular was the most frequent. In regard to HILI severity, 3.0% were severe and 7.6% were fatal or required liver transplantation. In 72.3% of the cases, the most used algorithm was RUCAM (Roussel Uclaf Causality Assessment Method). The conclusion of the study is that RUCAM was the most used algorithm for causality assessment in HILI. The patients were predominantly female, jaundice was the main symptom, and HILI is reversible in the majority of cases.
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Affiliation(s)
- Pedro Felipe Soares
- School Medicine of Bahia- University Federal of Bahia, Av. Rector Miguel Calmon, S/N - Vale do Canela, 40110-100, Salvador - BA, Brazil.
| | | | | | - Caio Medina Lopes
- Faculty of Pharmacy - University Federal of Bahia, Salvador, BA, Brazil.
| | | | | | | | | | | | - Genário Santos
- Sciences of Health Post Graduation Program - University Federal of Bahia, Salvador, BA, Brazil.
| | - Raymundo Paraná
- School Medicine of Bahia- University Federal of Bahia, Av. Rector Miguel Calmon, S/N - Vale do Canela, 40110-100, Salvador - BA, Brazil.
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Teschke R, Danan G. Causality Assessment in Pharmacovigilance for Herbal Medicines. PHARMACOVIGILANCE FOR HERBAL AND TRADITIONAL MEDICINES 2022:189-209. [DOI: 10.1007/978-3-031-07275-8_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tu C, Xu Z, Tian L, Yu Z, Wang T, Guo Z, Zhang J, Wang T. Multi-Omics Integration to Reveal the Mechanism of Hepatotoxicity Induced by Dictamnine. Front Cell Dev Biol 2021; 9:700120. [PMID: 34595163 PMCID: PMC8476863 DOI: 10.3389/fcell.2021.700120] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 08/19/2021] [Indexed: 01/25/2023] Open
Abstract
Herb-induced liver injury (HILI) has become a great concern worldwide due to the widespread usage of herbal products. Among these products is Dictamni Cortex (DC), a well-known Traditional Chinese Medicine (TCM), widely used to treat chronic dermatosis. Dictamni Cortex has drawn increasing attention because of its hepatotoxicity caused by the hepatotoxic component, dictamnine. However, the potential hepatotoxicity mechanism of dictamnine remains unclear. Therefore, this study aimed to use the multi-omics approach (transcriptomic, metabolomic, and proteomic analyses) to identify genes, metabolites, and proteins expressions associated with dictamnine-induced hepatotoxicity. A study on mice revealed that a high dose of dictamnine significantly increases serum aspartate aminotransferase (AST) activity, total bilirubin (TBIL), and direct bilirubin (DBIL) levels, the relative liver weight and liver/brain weight ratio in female mice (P < 0.05 and P < 0.01), compared to the normal control group. Liver histologic analysis further revealed a high dose of dictamnine on female mice caused hepatocyte vesicular steatosis characterized by hepatocyte microvesicles around the liver lobules. The expressed genes, proteins, and metabolites exhibited strong associations with lipid metabolism disorder and oxidative stress. Dictamnine caused increased oxidative stress and early hepatic apoptosis via up-regulation of glutathione S transferase a1 (GSTA1) and Bax/Bcl-2 ratio and down-regulation of the antioxidative enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase 1 (GPx-1). Besides, the up-regulation of Acyl-CoA synthetase long-chain family member 4 (ACSL4) and down-regulation of acetyl-coa acetyltransferase 1 (ACAT1) and fatty acid binding protein 1 (FABP-1) proteins were linked to lipid metabolism disorder. In summary, dictamnine induces dose-dependent hepatotoxicity in mice, which impairs lipid metabolism and aggravates oxidative stress.
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Affiliation(s)
- Can Tu
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ziying Xu
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lichun Tian
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zihui Yu
- Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences (CAS), Beijing, China
| | - Tieshang Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zhaojuan Guo
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jingxuan Zhang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Ting Wang
- Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Teschke R, Danan G. The LiverTox Paradox-Gaps between Promised Data and Reality Check. Diagnostics (Basel) 2021; 11:diagnostics11101754. [PMID: 34679453 PMCID: PMC8534640 DOI: 10.3390/diagnostics11101754] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/16/2022] Open
Abstract
The LiverTox database compiles cases of idiosyncratic drug-induced liver injury (iDILI) with the promised aims to help identify hepatotoxicants and provide evidence-based information on iDILI. Weaknesses of this approach include case selection merely based on published case number and not on a strong causality assessment method such as the Roussel Uclaf Causality Assessment Method (RUCAM). The aim of this analysis was to find out whether the promised aims have been achieved by comparison of current iDILI case data with those promised in 2012 in LiverTox. First, the LiverTox criteria of likelihood categories applied to iDILI cases were analyzed regarding robustness. Second, the quality was analyzed in LiverTox cases caused by 46 selected drugs implicated in iDILI. LiverTox included iDILI cases of insufficient quality because most promised details were not fulfilled: (1) Standard liver injury definition; (2) incomplete narratives or inaccurate for alternative causes; and (3) not a single case was assessed for causality with RUCAM, as promised. Instead, causality was arbitrarily judged on the iDILI case number presented in published reports with the same drug. All of these issues characterize the paradox of LiverTox, requiring changes in the method to improve data quality and database reliability. In conclusion, establishing LiverTox is recognized as a valuable effort, but the paradox due to weaknesses between promised data quality and actual data must be settled by substantial improvements, including, for instance, clear definition and identification of iDILI cases after evaluation with RUCAM to establish a robust causality grading.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-60590 Frankfurt/Main, Germany
- Correspondence:
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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14
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Using an Automated Algorithm to Identify Potential Drug-Induced Liver Injury Cases in a Pharmacovigilance Database. Adv Ther 2021; 38:4709-4721. [PMID: 34319549 PMCID: PMC8408072 DOI: 10.1007/s12325-021-01856-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/06/2021] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure in North America and Europe, but it is often missed because of unstandardized diagnostic methods and criteria. This study aimed to develop and validate an automated algorithm to identify potential DILI cases in routine pharmacovigilance (PV) activities. METHODS Post-marketing hepatic adverse events reported for a potentially hepatotoxic drug in a global PV database from 19 March 2017 to 18 June 2018 were assessed manually and with the automated algorithm. The algorithm provided case assessments by applying pre-specified criteria to all case data and narratives simultaneously. RESULTS A total of 1456 cases were included for analysis and assessed manually. Sufficient data for algorithm assessment were available for 476 cases (32.7%). Of these cases, manual assessment identified 312 (65.5%) potential DILI cases while algorithm assessment identified 305 (64.1%) potential DILI cases. Comparison of manual and algorithm assessments demonstrated a sensitivity of 97.8% and a specificity of 79.3% for the algorithm. Given the prevalence of potential DILI cases in the population studied, the algorithm was calculated to have positive predictive value 56.3% and negative predictive value 99.2%. The time required for manual review compared to algorithm review suggested that application of the algorithm prior to manual screening would have resulted in a time savings of 42.2%. CONCLUSION An automated algorithm to identify potential DILI cases was developed and successfully implemented. The algorithm demonstrated a high sensitivity, a high negative predictive value, along with significant efficiency and utility in a real-time PV database.
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15
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Nguyen PTT, Hoang DV, Pham KM, Nguyen HT. A Multiple Logistic Regression Model Based on Gamma-Glutamyl Transferase as a Biomarker for Early Prediction of Drug-Induced Liver Injury in Vietnamese Patients. J Clin Pharmacol 2021; 62:110-117. [PMID: 34415063 DOI: 10.1002/jcph.1955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/17/2021] [Indexed: 11/08/2022]
Abstract
The discovery of new biomarkers and the causality of drug-induced liver injury (DILI) is a major focus in modern medicine. Alcoholism is considered a risk factor for DILI. However, the extraction and assessment of alcohol history are difficult due to noncooperation by patients and intermittent management. Therefore, we conducted a case-control study of 1277 patients diagnosed with DILI according to the Roussel Uclaf Causality Assessment Method scale to evaluate gamma-glutamyl transferase (GGT) as a biomarker for predicting DILI in Vietnamese patients, where the proportion of alcoholism is quite high. Further, we built and validated a logistic regression model to predict the risk of DILI in hospitalized patients. The risk of DILI increased by 10% for 1 UI/L higher levels of GGT before prescription (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.01). A history of alcoholism was not a risk factor for DILI occurrence (OR, 1.83; 95%CI, 0.99-3.04; P = .057). A logistic regression model was successfully built and validated based on age; sex; initial levels of alanine aminotransferase, alkaline phosphatate, GGT, likelihood score of the suspected drug, and history of liver disease; the area under the receiver operating characteristic curve of the model was 0.883 (95%CI, 0.868-0.897). Our results thus suggest the necessity of exercising caution when prescribing to patients without a history of alcoholism but having high GGT levels. This model can be applied clinically to assess the risk of DILI before prescribing to reduce the risk of DILI in the patient.
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Affiliation(s)
- Phuong Thi Thu Nguyen
- Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam.,Hai Phong International Hospital, Haiphong, Vietnam
| | - Dung Van Hoang
- Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Khue Minh Pham
- Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam
| | - Hoi Thanh Nguyen
- Hai Phong University of Medicine and Pharmacy, Hai Phong, Vietnam.,Hai Phong International Hospital, Haiphong, Vietnam
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16
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Watanabe M, Shibuya A, Yokomori H, Koizumi W. The Diagnosis of Drug-induced Liver Injury: Current Diagnostic Ability and Future Challenges of the Digestive Disease Week-Japan 2004 Scale 15 Years after Its Proposal. Intern Med 2021; 60:2557-2568. [PMID: 33716281 PMCID: PMC8429297 DOI: 10.2169/internalmedicine.6370-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Objective This study examined whether or not the Digestive Disease Week-Japan (DDW-J) 2004 scale proposed over 15 years ago can be applied to current cases of drug-induced liver injury (DILI). Methods The new patients group included 125 patients from 2012 to 2019 and was divided into 2 subgroups: 96 patients in the new DILI group and 29 patients in the new non-DILI group. Similarly, the old patients group included 105 patients from 1997 to 2002 and was divided into 2 subgroups: 59 patients in the old DILI group and 46 patients in the old non-DILI group. Patients were assessed by the DDW-J 2004 scale; those with a score ≥3 were defined as having DILI. Results The total score of the new DILI group was significantly lower than that of the old DILI group [6 (1-11) vs. 6 (3-9), p=0.004]. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were 94.8%, 65.6%, 90.1%, and 79.2%, respectively, in the new patients group and 100%, 91.4%, 93.7%, and 100%, respectively, in the old patients group. The specificity and NPV of the new patients group were significantly lower than those of the old patients group. Conclusion The DDW-J 2004 scale maintains a stable diagnostic ability for DILI, regardless of differences in eras and verification methods. However, differential diagnoses can affect the scoring, and new types of DILI, such as immune-related adverse events, must be addressed. Therefore, upgrading the scale should be considered.
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Affiliation(s)
- Masaaki Watanabe
- Department of Gastroenterology, Kitasato University Medical Center, Japan
| | - Akitaka Shibuya
- Department of Risk Management and Health Care Administration, Kitasato University School of Medicine, Japan
| | - Hiroaki Yokomori
- Department of General Internal Medicine, Kitasato University Medical Center, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
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17
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Teschke R, Eickhoff A, Schulze J, Danan G. Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview. Transl Gastroenterol Hepatol 2021; 6:51. [PMID: 34423172 PMCID: PMC8343418 DOI: 10.21037/tgh-20-149] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/13/2020] [Indexed: 12/11/2022] Open
Abstract
Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.
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Affiliation(s)
- Rolf Teschke
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
| | - Axel Eickhoff
- Division of Gastroenterology and Hepatology, Department of Internal Medicine II, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
| | - Johannes Schulze
- Institute of Occupational, Social and Environmental Medicine, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany
| | - Gaby Danan
- Pharmacovigilance consultancy, Paris, France
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18
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Shah J, Muir J, Furfaro D, Beitler JR, Dzierba AL. Use of N-Acetylcysteine for Clozapine-Induced Acute Liver Injury: A Case Report and Literature Review. J Pharm Pract 2021; 36:463-467. [PMID: 34284670 DOI: 10.1177/08971900211034007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Purpose: To report a case of clozapine-induced hepatotoxicity managed with intravenous (IV) N-acetylcysteine (NAC) and summarize the available literature. Summary: A 46-year-old woman with history of bipolar disorder with psychotic features presented to the intensive care unit with asterixis and elevations in liver enzymes. The patient had been initiated on risperidone, clozapine, and lithium approximately 1 month prior to admission. After ruling out other possible non-drug etiologies, clozapine was suspected as the likeliest cause of the acute liver injury. Her acute liver injury was managed with the discontinuation of all antipsychotics, administration of IV NAC, and other standard of care supportive measures. Conclusion: Although clozapine has been associated with hepatitis and acute liver failure, there are no reports of NAC used in the management of clozapine-induced hepatotoxicity. NAC was used in our patient after considering the potential benefit and limited adverse effects. The role of NAC in non-acetaminophen-induced acute liver failure remains promising, but more research is warranted.
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Affiliation(s)
- Jenny Shah
- Department of Pharmacy, 3740UPMC Pinnacle, Harrisburg, PA, USA
| | - Justin Muir
- Department of Pharmacy, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, New York, NY, USA
| | - David Furfaro
- Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital, New York, NY, USA
| | - Jeremy R Beitler
- Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital, New York, NY, USA.,Center for Acute Respiratory Failure, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital, New York, NY, USA
| | - Amy L Dzierba
- Department of Pharmacy, Columbia University Irving Medical Center, NewYork-Presbyterian Hospital, New York, NY, USA.,Center for Acute Respiratory Failure, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital, New York, NY, USA
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19
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Hey-Hadavi J, Seekins D, Palmer M, Coffey D, Caminis J, Abdullaev S, Patwardhan M, Tyler H, Raheja R, Stanley AM, Pineda-Salgado L, Bourdet DL, Andrade RJ, Hayashi PH, Dimick-Santos L, Rockey DC, Estilo A. Overview of Causality Assessment for Drug-Induced Liver Injury (DILI) in Clinical Trials. Drug Saf 2021; 44:619-634. [PMID: 33725335 PMCID: PMC8184702 DOI: 10.1007/s40264-021-01051-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 02/08/2023]
Abstract
Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.
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Affiliation(s)
| | | | - Melissa Palmer
- Takeda, Cambridge, MA, USA
- Liver Consulting LLC, New York City, USA
| | | | | | | | | | - Haifa Tyler
- Otsuka Pharmaceutical Development and Commercialization, Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA
| | | | | | - Liliam Pineda-Salgado
- Otsuka Pharmaceutical Development and Commercialization, Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA
| | | | - Raul J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas CIBERehd, Málaga, Spain
| | | | | | - Don C Rockey
- Medical University of South Carolina, Charleston, SC, USA
| | - Alvin Estilo
- Otsuka Pharmaceutical Development and Commercialization, Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA.
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20
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Xia C, Liu Y, Yao H, Zhu W, Ding J, Jin J. Causality assessment of skyfruit-induced liver injury using the updated RUCAM: a case report and review of the literature. J Int Med Res 2021; 48:300060520917569. [PMID: 32293220 PMCID: PMC7160776 DOI: 10.1177/0300060520917569] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
In many Asian countries, herbs are used to treat disease. However, herbs also
have adverse effects. Herb-induced liver injury has become a serious public
health problem requiring urgent attention. The seeds of Swietenia
macrophylla, a member of the family Polygonaceae, are often called
skyfruit. We recently encountered a case of liver injury caused by skyfruit. The
patient suffered from hepatocellular injury. We applied the updated Roussel
Uclaf Causality Assessment Method (RUCAM) and the results indicated a highly
probable relationship with skyfruit (total score 10). Moreover, we summarize
another six cases of skyfruit-induced liver injury from the literature. The aim
of our report is to help clinicians become more aware of the potential
hepatotoxic effects of skyfruit and to accurately describe the clinical and
laboratory characteristics of skyfruit-induced liver injury.
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Affiliation(s)
- Caixia Xia
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yanning Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Hangping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weihong Zhu
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiexia Ding
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Jin
- Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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21
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Umbaugh DS, Jaeschke H. Biomarkers of drug-induced liver injury: a mechanistic perspective through acetaminophen hepatotoxicity. Expert Rev Gastroenterol Hepatol 2021; 15:363-375. [PMID: 33242385 PMCID: PMC8026489 DOI: 10.1080/17474124.2021.1857238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
Introduction: Liver injury induced by drugs is a serious clinical problem. Many circulating biomarkers for identifying and predicting drug-induced liver injury (DILI) have been proposed.Areas covered: Biomarkers are mainly predicated on the mechanistic understanding of the underlying DILI, often in the context of acetaminophen overdose. New panels of biomarkers have emerged that are related to recovery/regeneration rather than injury following DILI. We explore the clinical relevance and limitations of these new biomarkers including recent controversies. Extracellular vesicles have also emerged as a promising vector of biomarkers, although the biological role for EVs may limit their clinical usefulness. New technological approaches for biomarker discovery are also explored.Expert opinion: Recent clinical studies have validated the efficacy of some of these new biomarkers, cytokeratin-18, macrophage colony-stimulating factor receptor, and osteopontin for DILI prognosis. Low prevalence of DILI is an inherent limitation to DILI biomarker development. Furthering mechanistic understanding of DILI and leveraging technological advances (e.g. machine learning/omics) is necessary to improve upon the newest generation of biomarkers. The integration of omics approaches with machine learning has led to novel insights in cancer research and DILI research is poised to leverage these technologies for biomarker discovery and development.
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Affiliation(s)
- David S. Umbaugh
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA
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22
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Teschke R, Danan G. Idiosyncratic Drug Induced Liver Injury, Cytochrome P450, Metabolic Risk Factors and Lipophilicity: Highlights and Controversies. Int J Mol Sci 2021; 22:3441. [PMID: 33810530 PMCID: PMC8037096 DOI: 10.3390/ijms22073441] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Progress in understanding the mechanisms of the idiosyncratic drug induced liver injury (iDILI) was highlighted in a scientometric investigation on the knowledge mapping of iDILI throughout the world, but uncertainty remained on metabolic risk factors of iDILI, the focus of the present review article. For the first time, a quantitative analysis of 3312 cases of iDILI assessed for causality with RUCAM (Roussel Uclaf Causality Assessment Method) showed that most drugs (61.1%) were metabolized by cytochrome P450 (CYP) isoforms: 49.6% by CYP 3A4/5, 24.6% by CYP 2C9, 13.2% by CYP 2E1, 7.3% by CYP 2C19, 3.5% by CYP 1A2 and 1.8% by CYP 2D6. Other studies showed high OR (odds ratio) for drugs metabolized by unspecified CYPs but the iDILI cases were not assessed for causality with RUCAM, a major shortcoming. In addition to critical comments on methodological flaws, several risk factors of iDILI were identified such as high but yet recommended daily drug doses, actual daily drug doses taken by the patients, hepatic drug metabolism and drug lipophilicity. These risk factors are subject to controversies by many experts seen critically also by others who outlined that none of these medication characteristics is able to predict iDILI with high confidence, leading to the statement of an outstanding caveat. It was also argued that all previous studies lacked comprehensive data because the number of examined drugs was relatively small as compared to the number of approved new molecular entities or currently used oral prescription drugs. In conclusion, trends are evident that some metabolic parameters are likely risk factors of iDILI but strong evidence can only be achieved when methodological issues will be successfully met.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, 60323 Frankfurt/Main, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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23
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Valproic Acid-Induced Liver Injury: A Case-Control Study from a Prospective Pharmacovigilance Program in a Tertiary Hospital. J Clin Med 2021; 10:jcm10061153. [PMID: 33801850 PMCID: PMC7999396 DOI: 10.3390/jcm10061153] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/01/2021] [Accepted: 03/04/2021] [Indexed: 12/19/2022] Open
Abstract
Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring program, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related liver injury but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild liver injury. Mean age for the cases was 45.7 years, 4 (26.7%) were women and 5 (33.34%) were children under 18 years, of them 3 (20%) were fatal. Polytherapy with other antiepileptic drugs (p = 0.047) and alcohol consumption (p < 0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p < 0.001). The cases developed hepatocellular liver injury (p < 0.001), while the mild hepatic damage controls had a higher rate of cholestatic liver injury (p < 0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p = 0.033 and p = 0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.
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24
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Teschke R, Danan G. Idiosyncratic Drug-Induced Liver Injury (DILI) and Herb-Induced Liver Injury (HILI): Diagnostic Algorithm Based on the Quantitative Roussel Uclaf Causality Assessment Method (RUCAM). Diagnostics (Basel) 2021; 11:458. [PMID: 33800917 PMCID: PMC7999240 DOI: 10.3390/diagnostics11030458] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/24/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Causality assessment in liver injury induced by drugs and herbs remains a debated issue, requiring innovation and thorough understanding based on detailed information. Artificial intelligence (AI) principles recommend the use of algorithms for solving complex processes and are included in the diagnostic algorithm of Roussel Uclaf Causality Assessment Method (RUCAM) to help assess causality in suspected cases of idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI). From 1993 until the middle of 2020, a total of 95,865 DILI and HILI cases were assessed by RUCAM, outperforming by case numbers any other causality assessment method. The success of RUCAM can be traced back to its quantitative features with specific data elements that are individually scored leading to a final causality grading. RUCAM is objective, user friendly, transparent, and liver injury specific, with an updated version that should be used in future DILI and HILI cases. Support of RUCAM was also provided by scientists from China, not affiliated to any network, in the results of a scientometric evaluation of the global knowledge base of DILI. They highlighted the original RUCAM of 1993 and their authors as a publication quoted the greatest number of times and ranked first in the category of the top 10 references related to DILI. In conclusion, for stakeholders involved in DILI and HILI, RUCAM seems to be an effective diagnostic algorithm in line with AI principles.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, D-63450 Hanau, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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Pedraza L, Laosa O, Rodríguez-Mañas L, Gutiérrez-Romero DF, Frías J, Carnicero JA, Ramírez E. Drug Induced Liver Injury in Geriatric Patients Detected by a Two-Hospital Prospective Pharmacovigilance Program: A Comprehensive Analysis Using the Roussel Uclaf Causality Assessment Method. Front Pharmacol 2021; 11:600255. [PMID: 33613279 PMCID: PMC7892439 DOI: 10.3389/fphar.2020.600255] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 11/11/2020] [Indexed: 01/10/2023] Open
Abstract
Background/aim: A prospective evaluation of drug-induced liver injury (DILI) in two tertiary hospitals was conducted through a pharmacovigilance program from laboratory signals at hospital (PPLSH) to determine the principal characteristics of DILI in patients older than 65 years, a growing age group worldwide, which is underrepresented in the literature on DILI. Methods: All DILI in patients older than 65 years detected by PPLSH in two hospitals were followed up for 8 years in the La Paz Hospital and 2 years in the Getafe Hospital. A descriptive analysis was conducted that determined the causality of DILI and suspected drugs, the incidence of DILI morbidities, DILI characteristics, laboratory patterns, evolution and outcomes. Results: 458 DILI cases in 441 patients were identified, 31.0% resulting in hospitalisation and 69.0% developing during hospitalisation. The mean age was 76.61 years old (SD, 7.9), and 54.4% were women. The DILI incidence was 76.33/10,000 admissions (95%CI 60.78–95.13). Polypharmacy (taking >4 drugs) was present in 86.84% of patients, 39.68% of whom took >10 drugs. The hepatocellular phenotype was the most frequent type of DILI (53.29%), a higher proportion (65%) had a mild severity index, and, in 55.2% of the evaluated drugs the RUCAM indicated that the causal relationship was highly probable. The most frequently employed drugs were paracetamol (50-cases), amoxicillin-clavulanate (42-cases) and atorvastatin (37-cases). The incidence rate of in-hospital DILI per 10,000 DDDs was highest for piperacillin-tazobactam (66.96/10,000 DDDs). A higher risk of in-hospital DILI was associated with the therapeutic chemical group-J (antiinfectives for systemic use) (OR, 2.65; 95%CI 1.58–4.46) and group-N (central nervous system drugs) (OR, 2.33; 95%CI 1.26–4.31). The patients taking >4 medications presented higher maximum creatinine level (OR, 2.01; 95%CI 1.28–3.15), and the patients taking >10 medications had a higher use of group J drugs (OR, 2.08; 95%IC 1.31–3.32). Conclusion: The incidence rate of DILI in the patients older than 65 years was higher than expected. DILI in elderly patients is mild, has a good outcome, has a hepatocellular pattern, develops during hospitalisation, and prolongs the hospital stay. Knowing the DILI incidence and explanatory factors will help improve the therapy of the elderly population.
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Affiliation(s)
- Laura Pedraza
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain
| | - Olga Laosa
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain.,Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain
| | - Leocadio Rodríguez-Mañas
- Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain.,Division of Geriatrics, University Hospital of Getafe, Getafe, Spain
| | | | - Jesús Frías
- Clinical Pharmacology departments, La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain
| | - José Antonio Carnicero
- Geriatric Research Group, Biomedical Research Foundation at Getafe University Hospital, Getafe, Spain.,Centre of Network Biomedical Research on Frailty and Healthy Ageing (CIBERFES), Institute of Health Carlos III., Madrid, Spain
| | - Elena Ramírez
- Clinical Pharmacology departments, La Paz University Hospital, IdiPAZ, School of Medicine, Autonomous University of Madrid, Madrid, Spain.,Clinical pharmacology department, University Hospital La Paz, La Paz, Spain
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26
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Apel K, Pütz K, Tolkach Y, Canbay A, Drebber U. [Drug-induced liver injury-significance of pathology]. DER PATHOLOGE 2020; 41:457-470. [PMID: 32813127 DOI: 10.1007/s00292-020-00811-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Many different medical agents, herbal products, and dietary supplements can induce drug-induced liver injury (DILI) as a clinically relevant complication. DILI, which is direct toxic or idiosyncratic, can have a broad spectrum of clinical appearances from elevation of liver enzymes to acute liver failure. DILI is categorized clinically according to the pattern of serum parameters or pathologically according to the pattern of histomorphology. Histopathological patterns can be described as hepatitic, granulomatous, cholestatic, ductopenic, fibrotic, steatotic, steatohepatitic, and vascular. Correlation to the corresponding drug can be carried out with the corresponding databases (US National Library of Medicine, Liver Tox; www.ncbi.nlm.nih.gov/books/NBK547852/ ). Liver biopsy, in contrast to a clinical/serological diagnostic, has the advantage of an exact resolution with evidence of pathophysiology, activity, regeneration, chronification, and prognosis. Co-occurrence of underlying liver disease can be excluded or confirmed. Histological patterns of DILI are described and illustrated. A diagnostic algorithm for the interpretation of liver biopsies is provided.
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Affiliation(s)
- K Apel
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - K Pütz
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - Y Tolkach
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland
| | - A Canbay
- Universitätklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - U Drebber
- Institut für Pathologie, Uniklinik Köln, Kerpener Str. 62, 50937, Köln, Deutschland.
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Potmešil P, Szotkowská R. Drug-induced liver injury after switching from tamoxifen to anastrozole in a patient with a history of breast cancer being treated for hypertension and diabetes. Ther Adv Chronic Dis 2020; 11:2040622320964152. [PMID: 33240477 PMCID: PMC7675855 DOI: 10.1177/2040622320964152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Anastrozole is a selective non-steroidal aromatase inhibitor that blocks the
conversion of androgens to estrogens in peripheral tissues. It is used as
adjuvant therapy for early-stage hormone-sensitive breast cancer in
postmenopausal women. Significant side effects of anastrozole include
osteoporosis and increased levels of cholesterol. To date, seven case reports on
anastrozole hepatotoxicity have been published. We report the case of an
81-year-old woman with a history of breast cancer, arterial hypertension, type 2
diabetes mellitus, hyperlipidemia, and chronic renal insufficiency. Four days
after switching hormone therapy from tamoxifen to anastrozole, icterus developed
along with a significant increase in liver enzymes (measured in the blood). The
patient was admitted to hospital, where a differential diagnosis of jaundice was
made and anastrozole was withdrawn. Subsequently, hepatic functions quickly
normalized. The observed liver injury was attributed to anastrozole since other
possible causes of jaundice were excluded. However, concomitant pharmacotherapy
could have contributed to the development of jaundice and hepatotoxicity, after
switching from tamoxifen to anastrozole since several the patient’s medications
were capable of inhibiting hepatobiliary transport of bilirubin, bile acids, and
metabolized drugs through inhibition of ATP-binding cassette proteins.
Telmisartan, tamoxifen, and metformin all block bile salt efflux pumps. The
efflux function of multidrug resistance protein 2 is known to be reduced by
telmisartan and tamoxifen and breast cancer resistance protein is known to be
inhibited by telmisartan and amlodipine. Moreover, the activity of
P-glycoprotein transporters are known to be decreased by telmisartan,
amlodipine, gliquidone, as well as the previously administered tamoxifen.
Finally, the role of genetic polymorphisms of cytochrome P450 enzymes and/or
drug transporters cannot be ruled out since the patient was not tested for
polymorphisms.
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Affiliation(s)
- Petr Potmešil
- Third Faculty of Medicine, Department of Pharmacology, Charles University, Prague, Czech Republic and Faculty of Medicine, Department of Pharmacology and Toxicology, Charles University, Pilsen, Czech Republic
| | - Radka Szotkowská
- 2nd Department of Internal Medicine, University Hospital Královské Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic
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28
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The Work of the Council for International Organizations of Medical Sciences (CIOMS) in Global Pharmacovigilance. Drug Saf 2020; 43:1067-1071. [PMID: 33034859 DOI: 10.1007/s40264-020-01003-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2020] [Indexed: 10/23/2022]
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29
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Teschke R, Danan G. Worldwide Use of RUCAM for Causality Assessment in 81,856 Idiosyncratic DILI and 14,029 HILI Cases Published 1993-Mid 2020: A Comprehensive Analysis. MEDICINES (BASEL, SWITZERLAND) 2020; 7:E62. [PMID: 33003400 PMCID: PMC7600114 DOI: 10.3390/medicines7100062] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 04/12/2023]
Abstract
Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993-30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusion: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.
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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, D-60590 Frankfurt/Main, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, F-75020 Paris, France;
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Jiménez-Pérez M, González-Grande R, García-Cortés M, Andrade RJ. Drug-Induced Liver Injury After Liver Transplantation. Liver Transpl 2020; 26:1167-1176. [PMID: 32445416 DOI: 10.1002/lt.25804] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 04/28/2020] [Accepted: 05/17/2020] [Indexed: 02/07/2023]
Abstract
Drug-induced liver injury (DILI) is an adverse reaction to many drugs in common use that in a liver transplantation (LT) recipient may cause graft dysfunction and may even lead to graft loss and the need for retransplantation. However, several potential clinical scenarios, such as graft rejection and infection, can confound the diagnosis of suspected DILI in the setting of LT. This makes causal assessment of a new liver injury more uncertain and has traditionally precluded collection of bona fide cases of DILI affecting LT patients in prospective DILI registries and cohorts. Although no studies have yet determined a greater susceptibility of the transplant patient to DILI, these patients nevertheless present certain risk factors that can theoretically increase the risk of DILI. These include the fact that these patients are polymedicated, use drugs that are potentially hepatotoxic, and can have coexisting hepatitis B or C viruses in addition to other factors found in nontransplant patients, such as genetic variants. Therefore, awareness is crucial of any potential hepatotoxic effect of drugs used in the LT recipient and their possible implication in any case of liver dysfunction. In the present article, we review the most common drugs used in LT recipients from a liver safety perspective and address the main pitfalls in attributing causality in this clinical setting. We also affirm the need for further research and collaboration in this somewhat neglected topic in the field of DILI.
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Affiliation(s)
- Miguel Jiménez-Pérez
- Unidad de Gestión Clínica de Aparato Digestivo, seccion Hepatología-Trasplante Hepático, Hospital Regional, Universidad de Málaga, Malaga, Spain
| | - Rocío González-Grande
- Unidad de Gestión Clínica de Aparato Digestivo, seccion Hepatología-Trasplante Hepático, Hospital Regional, Universidad de Málaga, Malaga, Spain
| | - Miren García-Cortés
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Malaga, Spain
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga, Malaga, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Malaga, Spain
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Zentner I, Back HM, Kagan L, Subbian S, Nagajyothi J, Srivastava S, Pasipanodya J, Gumbo T, Bisson GP, Vinnard C. Redox Imbalance and Oxidative DNA Damage During Isoniazid Treatment of HIV-Associated Tuberculosis: A Clinical and Translational Pharmacokinetic Study. Front Pharmacol 2020; 11:1103. [PMID: 32848735 PMCID: PMC7406860 DOI: 10.3389/fphar.2020.01103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 07/07/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The potential for hepatotoxicity during isoniazid-based tuberculosis (TB) treatment presents a major challenge for TB control programs worldwide. We sought to determine whether pharmacokinetic exposures of isoniazid and its metabolites were related to cellular oxidation/reduction status and downstream markers of oxidative DNA damage. METHODS We performed intensive pharmacokinetic sampling among isoniazid-treated patients to determine the relative plasma exposures of isoniazid, acetylisoniazid, hydrazine, and acetylhydrazine. Physiologically-based pharmacokinetic modeling was used to estimate liver tissue exposures during a 24-h dosing interval for each compound. We experimentally treated HepG2 cells with isoniazid and metabolites at equimolar concentrations corresponding to these exposures for 7, 14, and 28-day periods, and performed assays related to redox imbalance and oxidative DNA damage at each timepoint. We related a urine marker of oxidative DNA damage to serum isoniazid pharmacokinetic exposures and pharmacogenetics in a clinical study. RESULTS Among isoniazid-treated patients, serum concentrations of hydrazine and isoniazid concentrations were highly correlated. At equimolar concentrations that approximated hepatic tissue exposures during a 24-h dosing interval, hydrazine demonstrated the highest levels of redox imbalance, mitochondrial injury, and oxidative DNA damage over a 28-day treatment period. In a clinical validation study of isoniazid-treated TB patients, peak isoniazid serum concentrations were positively associated with a urine biomarker of oxidative DNA damage. CONCLUSIONS Isoniazid and its metabolites share the potential for oxidative cellular damage, with the greatest effects observed for hydrazine. Future studies should investigate the clinical consequences of oxidative stress with regards to clinical episodes of drug induced liver injury during isoniazid treatment.
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Affiliation(s)
- Isaac Zentner
- Public Health Research Institute, New Jersey Medical School, Newark, NJ, United States
| | - Hyun-moon Back
- Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States
| | - Leonid Kagan
- Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Newark, NJ, United States
| | - Jyothi Nagajyothi
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States
| | - Shashikant Srivastava
- Department of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, United States
| | | | | | - Gregory P. Bisson
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Christopher Vinnard
- Public Health Research Institute, New Jersey Medical School, Newark, NJ, United States
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32
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Quan NV, Dang Xuan T, Teschke R. Potential Hepatotoxins Found in Herbal Medicinal Products: A Systematic Review. Int J Mol Sci 2020; 21:E5011. [PMID: 32708570 PMCID: PMC7404040 DOI: 10.3390/ijms21145011] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
The risk of liver injury associated with the use of herbal medicinal products (HMPs) is well known among physicians caring for patients under a HMP therapy, as documented in case reports or case series and evidenced by using the Roussel Uclaf Causality Assessment Method (RUCAM) to verify a causal relationship. In many cases, however, the quality of HMPs has rarely been considered regarding potential culprits such as contaminants and toxins possibly incriminated as causes for the liver injury. This review aims to comprehensively assemble details of tentative hepatotoxic contaminants and toxins found in HMPs. Based on the origin, harmful agents may be divided according two main sources, namely the phyto-hepatotoxin and the nonphyto-hepatotoxin groups. More specifically, phyto-hepatotoxins are phytochemicals or their metabolites naturally produced by plants or internally in response to plant stress conditions. In contrast, nonphyto-hepatotoxic elements may include contaminants or adulterants occurring during collection, processing and production, are the result of accumulation of toxic heavy metals by the plant itself due to soil pollutions, or represent mycotoxins, herbicidal and pesticidal residues. The phyto-hepatotoxins detected in HMPs are classified into eight major groups consisting of volatile compounds, phytotoxic proteins, glycosides, terpenoid lactones, terpenoids, alkaloids, anthraquinones, and phenolic acids. Nonphyto-hepatotoxins including metals, mycotoxins, and pesticidal and herbicidal residues and tentative mechanisms of toxicity are discussed. In conclusion, although a variety of potential toxic substances may enter the human body through HMP use, the ability of these toxins to trigger human liver injury remains largely unclear.
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Affiliation(s)
- Nguyen Van Quan
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (N.V.Q.); (T.D.X.)
| | - Tran Dang Xuan
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (N.V.Q.); (T.D.X.)
| | - Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, 63450 Hanau, Germany
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Teschke R, Zhu Y, Jing J. Herb-induced Liver Injury in Asia and Current Role of RUCAM for Causality Assessment in 11,160 Published Cases. J Clin Transl Hepatol 2020; 8:200-214. [PMID: 32832401 PMCID: PMC7438347 DOI: 10.14218/jcth.2020.00009] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 03/05/2020] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
Herb-induced liver injuries (HILI) by traditional herbal medicines are particular challenges in Asian countries, with issues over the best approach to establish causality. The aim of the current analysis was to provide an overview on how causality was assessed in HILI cases from Asian countries and whether the Roussel Uclaf Causality Assessment Method (RUCAM) was the preferred diagnostic algorithm, as shown before in worldwide evaluated cases of drug-induced liver injury (DILI). Using the PubMed database, publications in English language were preferred to allow for reevaluation by peers. Overall 11,160 HILI cases have assessed causality using RUCAM and were published by first authors working in Asian countries. With 21 evaluable reports, most publications came from mainland China, with Hong Kong and Taiwan, followed by Korea (n=15), Singapore (n=2), and Japan (n=1), while other Asian countries were not contributory. Most publications provided case and RUCAM data of good quality. For better presentation of future cases, however, the following recommendations are given: (1) preference of prospective study design with use of the updated RUCAM version; (2) clear separation of HILI cohorts from those of other herbal products or DILI; (3) case series for epidemiology studies should contain many essential data, possibly also as supplementary material; (4) otherwise, preference of single case reports providing individual case data and RUCAM-based causality gradings, and applying liver test threshold values; and (5) publication in English language journals. In conclusion, China and Korea are top in presenting RUCAM-based HILI cases, other Asian countries are encouraged to follow.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
- Correspondence to: Rolf Teschke, Department of Internal Medicine II, Klinikum Hanau, Teaching Hospital of the Goethe University of Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany. Tel: +49-6181-21859, Fax: +49-6181-2964211, E-mail:
| | - Yun Zhu
- The Fifth Medical Center, General Hospital of PLA, Beijing, China
| | - Jing Jing
- The Fifth Medical Center, General Hospital of PLA, Beijing, China
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Mehershahi S, Mantri N, Kumar A, Danial S, Harish P. Enoxaparin-Induced Liver Injury. Case Rep Gastroenterol 2020; 14:315-319. [PMID: 32595436 PMCID: PMC7315174 DOI: 10.1159/000508471] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/01/2020] [Indexed: 11/19/2022] Open
Abstract
Enoxaparin, a form of low-molecular-weight heparin, can cause a rare, underreported, and often reversible form of hepatocellular injury. This report describes a case of enoxaparin-induced hepatotoxicity in a 61-year-old male diagnosed with pulmonary embolism. Elevations of liver enzymes were noted within 1 week of starting the drug, followed by a dramatic improvement upon its discontinuation, with subsequent normalization in the following days.
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Affiliation(s)
- Shehriyar Mehershahi
- Department of Gastroenterology, Bronx Care Health System, Bronx, New York, USA.,Department of Internal Medicine, Bronx Care Health System, Bronx, New York, USA
| | - Nikhitha Mantri
- Department of Internal Medicine, Bronx Care Health System, Bronx, New York, USA
| | - Aneesh Kumar
- Department of Internal Medicine, Bronx Care Health System, Bronx, New York, USA
| | - Shaikh Danial
- Department of Gastroenterology, Bronx Care Health System, Bronx, New York, USA.,Department of Internal Medicine, Bronx Care Health System, Bronx, New York, USA
| | - Patel Harish
- Department of Gastroenterology, Bronx Care Health System, Bronx, New York, USA.,Department of Internal Medicine, Bronx Care Health System, Bronx, New York, USA
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35
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Liu Y, Zhan SP, Song L, Chen Y, Jia YT, Liu F, Sun FJ, Wang Q, Xia PY. Drug-Induced Liver Injury: Clinical and Etiologic Features at a Large Tertiary Teaching Hospital in China. Med Sci Monit 2020; 26:e919435. [PMID: 32172275 PMCID: PMC7094059 DOI: 10.12659/msm.919435] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Since the epidemiological profile of drug-induced liver injury (DILI) in China, especially the western of China, it has rarely been studied. The aim of this study was to analyze the characteristics of DILI patients in a large tertiary teaching hospital at Chongqing, a municipality in western China. MATERIAL AND METHODS The medical records of hospitalized patients which diagnosed with DILI between January 2011 and December 2016 were searched retrospectively, and demographic, clinical data, and laboratory data were retrieved for analysis. RESULTS A total of 1811 patients had been diagnosed with DILI, accounting for 0.248% of the total admissions during the same period. Among the 1096 patients included in our analysis, DILI was caused by "medications" in 462 cases (42.15%), "herbs" in 391 cases (35.68%), and combined medications in 189 cases (17.24%). The profiles for each etiology were distinctive for age, sex, clinical features, laboratory features, and types and severity of DILI. CONCLUSIONS Our study provides a systematic etiological profile of DILI in Chinese patients, which can represent references for prevention, diagnosis and treatment, supporting and promoting efforts to ease the burden of this liver disease in China.
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Affiliation(s)
- Yao Liu
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
| | - Shi-Peng Zhan
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
| | - Lin Song
- Department of Pharmacy, Children's Hospital of Chongqing Medical University, Chongqing, China (mainland)
| | - Yonggang Chen
- Department of Pharmacy, Children's Hospital of Chongqing Medical University, Chongqing, China (mainland)
| | - Yun-Tao Jia
- Department of Pharmacy, Children's Hospital of Chongqing Medical University, Chongqing, China (mainland)
| | - Fang Liu
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
| | - Feng-Jun Sun
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
| | - Qian Wang
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
| | - Pei-Yuan Xia
- Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China (mainland)
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36
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Ross MSc Candidate SB, Wu PE, Atique Md Candidate A, Papillon-Ferland L, Tamblyn R, Lee TC, McDonald EG. Adverse Drug Events in Older Adults: Review of Adjudication Methods in Deprescribing Studies. J Am Geriatr Soc 2020; 68:1594-1602. [PMID: 32142161 DOI: 10.1111/jgs.16382] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/15/2020] [Accepted: 01/29/2020] [Indexed: 02/05/2023]
Abstract
OBJECTIVES Polypharmacy is common in older adults and associated with adverse drug events (ADEs). Several methods have been described in studies to help correlate ADE causation. We performed a narrative review to identify methods for ADE adjudication. We compared their strengths and limitations to assess their applicability to deprescribing studies (of which clinical trials are a subset) and to encourage the use of a standardized method in future studies. DESIGN We performed a review of original articles (1946-2019) using the Medline (Ovid) and Cochrane databases. We also conducted a manual reference search of review articles. Abstracts were screened for relevance. MEASUREMENTS Adjudication methods were compared for advantages and limitations including validity, ease of use, and applicability to clinical trials with deprescribing as the primary intervention. RESULTS The search yielded 1881 articles of which 175 articles were included for full-text review. Following in-depth review, 135 were excluded: 79 had no ADE outcome data, 35 were not specific to older adults, 9 were not relevant, 6 were review articles, 5 contained duplicate data, and 1 was not written in French or English. Forty articles remained for analysis, from which we identified 10 unique ADE adjudication methods. No method was developed originally for use in a deprescribing setting. CONCLUSION A standard method to identify ADEs is important to capture the outcome reliably in deprescribing studies. All methods we identified had limitations in terms of capturing adverse events from the withdrawal of medications. Future work should focus on refining adjudication methods for capturing ADEs related not only to medication continuation and new drug starts but also to deprescribing and drug discontinuation. J Am Geriatr Soc 68:1594-1602, 2020.
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Affiliation(s)
| | - Peter E Wu
- Division of General Internal Medicine, University Health Network, Toronto, Ontario, Canada.,Division of Clinical Pharmacology and Toxicology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | - Louise Papillon-Ferland
- Department of Pharmacy, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada.,Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
| | - Robyn Tamblyn
- Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Todd C Lee
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Emily G McDonald
- Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Department of Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.,Clinical Practice Assessment Unit, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.,Centre for Outcomes Research and Evaluation, McGill University Health Centre, Montreal, Quebec, Canada
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37
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Shi Q, Yang X, Ren L, Mattes WB. Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors. Expert Opin Drug Metab Toxicol 2020; 16:217-226. [DOI: 10.1080/17425255.2020.1727886] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Qiang Shi
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
| | - Xi Yang
- Division of Cardiovascular and Renal Products, Office of New Drugs I, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
| | - Lijun Ren
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
| | - William B. Mattes
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA
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38
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Zhu W, Wang L, Zhao X, Wang T, Shi X, Ou X, Wang Y, Wang X, Duan W, Wang Q, Jia J, Ma H. Prolonged interval of total bilirubin decline is an early independent predictive factor of chronic persistent drug-induced liver injury. Hepatol Res 2020; 50:224-232. [PMID: 31652370 DOI: 10.1111/hepr.13435] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 09/23/2019] [Accepted: 09/25/2019] [Indexed: 02/08/2023]
Abstract
AIM Chronic drug-induced liver injury (DILI) with persistent abnormal liver function tests (LFTs) >6 months after cessation of the insulting drugs could progress to cirrhosis. The aim of the present study was to identify the risk factors of chronic DILI for early recognition and better management. METHODS History of drug intake and results of LFTs were retrospectively retrieved for patients with a discharge diagnosis of DILI for at least 1-year follow up. The risk factors independently associated with chronic DILI were analyzed by multiple logistic regression analyses. RESULTS A total of 33 of the 140 DILI patients had persistent abnormal LFTs >6 months, which were considered as chronic DILI. It was found that the time intervals of alanine aminotransferase and total bilirubin decline from the peak to their half peak (T0.5ALT , T0.5TBIL ) were significantly longer in the chronic DILI group than that in the recovered group (P = 0.001 and P < 0.001). The risk factors associated with chronic DILI independently were T0.5TBIL (OR 1.315, 95% CI 1.038-1.668), longer period of insulting drug(s) intake (OR 1.018, 95% CI 1.003-1.033), mixed/cholestatic pattern (OR 97.159, 95% CI 1.866-5005.994). More importantly, receiver operating characteristic curve analysis showed that the prognostic value of T0.5TBIL for chronic DILI had a sensitivity of 60.0% at a specificity of 90.7% with the threshold of 16 days. CONCLUSIONS The time intervals of total bilirubin decline from its peak to half of its peak (T0.5TBIL ) was an early independent predictive factor of chronic DILI, suggesting that T0.5TBIL might serve as an indicator for chronicity.
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Affiliation(s)
- Wenjing Zhu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Lan Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tailing Wang
- Department of Pathology, China-Japan Friendship Hospital, Beijing, China
| | - Xiaoyan Shi
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiaoming Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Weijia Duan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Qianyi Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
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39
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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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40
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Abstract
Drug induced liver injury is a diagnosis that relies on the patterns of injury associated with specific medications and toxins. The process by which a clinician determines which agent is the likely culprit of the liver injury is called causality assessment. The Roussel Uclaf Causality Assessment Method (RUCAM) and additional causality assessment methods have been developed with the goal of providing a more standardized, less subjective approach to causality assessment. RUCAM remains the most used standardized method, however many physicians continue to rely on their experience for causality assessment.
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Affiliation(s)
- Allyce Caines
- Henry Ford Hospital, 2799 West Grand Boulevard, Suite K7, Detroit, MI 48202, USA.
| | - Dilip Moonka
- Henry Ford Hospital, 2799 West Grand Boulevard, Suite K7, Detroit, MI 48202, USA.
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41
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Fu S, Wu D, Jiang W, Li J, Long J, Jia C, Zhou T. Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives. Front Pharmacol 2020; 10:1667. [PMID: 32082163 PMCID: PMC7002317 DOI: 10.3389/fphar.2019.01667] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 12/20/2019] [Indexed: 02/05/2023] Open
Abstract
Drug-induced liver injury (DILI) is one among the common adverse drug reactions and the leading causes of drug development attritions, black box warnings, and post-marketing withdrawals. Despite having relatively low clinical incidence, its potentially severe adverse events should be considered in the individual patients due to the high risk of acute liver failure. Although traditional liver parameters have been applied to the diagnosis of DILI, the lack of specific and sensitive biomarkers poses a major limitation, and thus accurate prediction of the subsequent clinical course remains a significant challenge. These drawbacks prompt the investigation and discovery of more effective biomarkers, which could lead to early detection of DILI, and improve its diagnosis and prognosis. Novel promising biomarkers include glutamate dehydrogenase, keratin 18, sorbitol dehydrogenase, glutathione S-transferase, bile acids, cytochrome P450, osteopontin, high mobility group box-1 protein, fatty acid binding protein 1, cadherin 5, miR-122, genetic testing, and omics technologies, among others. Furthermore, several clinical scoring systems have gradually emerged for the diagnosis of DILI including the Roussel Uclaf Causality Assessment Method (RUCAM), Clinical Diagnostic Scale (CDS), and Digestive Disease Week Japan (DDW-J) systems. However, currently their predictive value is limited with certain inherent deficiencies. Thus, perhaps the greatest benefit would be achieved by simultaneously combining the scoring systems and those biomarkers. Herein, we summarized the recent research progress on molecular biomarkers for DILI to improved approaches for its diagnosis and clinical management.
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Affiliation(s)
- Siyu Fu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Juan Li
- Department of Infectious Diseases, Pidu District People's Hospital, Chengdu, China
| | - Jiang Long
- The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China
| | - Chengyao Jia
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Taoyou Zhou
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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42
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Teschke R, Eickhoff A, Brown AC, Neuman MG, Schulze J. Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support. Int J Mol Sci 2019; 21:ijms21010212. [PMID: 31892250 PMCID: PMC6981464 DOI: 10.3390/ijms21010212] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-63450 Hanau, Germany;
- Correspondence: ; Tel.: +49-6181-21859; Fax: +49-6181-2964211
| | - Axel Eickhoff
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-63450 Hanau, Germany;
| | - Amy C. Brown
- Department of Complementary and Integrative Medicine, University of Hawai’i at Manoa, Honolulu, HI 96813, USA;
| | - Manuela G. Neuman
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M2 R1 W6, Canada;
| | - Johannes Schulze
- Institute of Occupational, Social and Environmental Medicine, Goethe-University Frankfurt/Main, D-60590 Frankfurt/Main, Germany;
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43
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Liu Y, Wang W, Sun M, Ma B, Pang L, Du Y, Dong X, Yin X, Ni J. Polygonum multiflorum-Induced Liver Injury: Clinical Characteristics, Risk Factors, Material Basis, Action Mechanism and Current Challenges. Front Pharmacol 2019; 10:1467. [PMID: 31920657 PMCID: PMC6923272 DOI: 10.3389/fphar.2019.01467] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/13/2019] [Indexed: 12/20/2022] Open
Abstract
Polygonum multiflorum Thunb. (PM), called Heshouwu in China, is a popular Chinese medicine in clinical practice. Several clinical studies have been conducted to evaluate the traditional therapeutic claims and to study the potential therapeutic activity of PM in dyslipidemia and neurodegenerative diseases, highlighting available clinical evidence. In recent years, reports on clinical adverse reactions of Raw Radix P. multiflorum (RPM) and P. multiflorum Praeparata (PMP) have been on the increase, especially with respect to liver injury. Most liver injury cases had been assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) in this paper. However, the components of PM responsible for the reported hepatotoxic effects have not yet been identified. Moreover, many of the reports are contradictory, while studies on the mechanism involved in PM-induced liver damage are not comprehensive. This study was aimed at reviewing the status of research on liver injury due to PM, including clinical characteristics, risk factors, material basis research and mechanism of action, with a view to understanding PM-induced hepatotoxicity, and taking reasonable and effective measures to prevent it. In short, quality control is still one of the major safety problems in TCM drug safety concerns. The model of safety monitoring and risk management of PM drugs is not yet developed. Indeed, the characteristics and risk factors associated with PM require both proper understanding and control of the risk by strengthening standardization of clinical applications, basic science research, quality control in manufacturing, active monitoring methodology and enhancement of international communication and cooperation. Measures should also be encouraged and implemented to promote healthy development of the TCM industry.
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Affiliation(s)
- Yi Liu
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Wenping Wang
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Mingyi Sun
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Baorui Ma
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Linnuo Pang
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Yuanyuan Du
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiaoxv Dong
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xingbin Yin
- School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Jian Ni
- Research Institute of Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing, China
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44
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Ouizeman DJ, Fortier Beaulieu C, Patouraux S, Tran A, Piche T, Anty R. From tinnitus to acute hepatitis: Drug-induced injury caused by use of naftidrofuryl for one year. Clin Res Hepatol Gastroenterol 2019; 43:e93-e94. [PMID: 31023552 DOI: 10.1016/j.clinre.2019.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 03/11/2019] [Indexed: 02/04/2023]
Affiliation(s)
- D J Ouizeman
- University hospital of Nice, digestive center, 06000 Nice, France.
| | | | - S Patouraux
- University hospital of Nice, biological center, Pasteur hospital, 06000 Nice, France; National institute of health and medical research (Inserm), U1065, Team 8 hepatic complications in obesity and alcohol, 06000 Nice, France; University of Nice-Sophia-Antipolis, faculty of medicine, 06000 Nice, France
| | - A Tran
- University hospital of Nice, digestive center, 06000 Nice, France; National institute of health and medical research (Inserm), U1065, Team 8 hepatic complications in obesity and alcohol, 06000 Nice, France; University of Nice-Sophia-Antipolis, faculty of medicine, 06000 Nice, France
| | - T Piche
- University hospital of Nice, digestive center, 06000 Nice, France; University of Nice-Sophia-Antipolis, faculty of medicine, 06000 Nice, France; National institute of health and medical research (Inserm), U1065, Team 12 "Study of the melanocytic differentiation applied to vitiligo and melanoma: from the patient to the molecular mechanisms", 06000 Nice, France
| | - R Anty
- University hospital of Nice, digestive center, 06000 Nice, France; National institute of health and medical research (Inserm), U1065, Team 8 hepatic complications in obesity and alcohol, 06000 Nice, France; University of Nice-Sophia-Antipolis, faculty of medicine, 06000 Nice, France
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45
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Raschi E, De Ponti F. Strategies for Early Prediction and Timely Recognition of Drug-Induced Liver Injury: The Case of Cyclin-Dependent Kinase 4/6 Inhibitors. Front Pharmacol 2019; 10:1235. [PMID: 31708776 PMCID: PMC6821876 DOI: 10.3389/fphar.2019.01235] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 09/27/2019] [Indexed: 12/12/2022] Open
Abstract
The idiosyncratic nature of drug-induced liver injury (DILI) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized DILI potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of DILI, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of DILI and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences.
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Affiliation(s)
| | - Fabrizio De Ponti
- Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
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46
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Liu Z, He X, Wang L, Zhang Y, Hai Y, Gao R. Chinese Herbal Medicine Hepatotoxicity: The Evaluation and Recognization Based on Large-scale Evidence Database. Curr Drug Metab 2019; 20:138-146. [PMID: 30101702 PMCID: PMC6635764 DOI: 10.2174/1389200219666180813144114] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 05/28/2018] [Accepted: 06/27/2018] [Indexed: 12/17/2022]
Abstract
Background: Due to the special nature of Chinese Herbal medicine and the complexity of its clinical use, it is difficult to identify and evaluate its toxicity and resulting herb induced liver injury (HILI). Methods: First, the database would provide full profile of HILI from the basic ingredients to clinical out-comes by the most advanced algorithms of artificial intelligence, and it is also possible that we can predict possibilities of HILI after patients taking Chinese herbs by individual patient evaluation and prediction. Second, the database would solve the chaos and lack of the relevant data faced by the current basic re-search and clinical practice of Chinese Herbal Medicine. Third, we can also screen the susceptible patients from the database and thus prevent the accidents of HILI from the very beginning. Results: The Roussel Uclaf Causality Assessment Method (RUCAM) is the most accepted method to evalu-ate DILI, but at present before using the RUCAM evaluation method, data resource collection and analysis are yet to be perfected. Based on existing research on drug-metabolizing enzymes mediating reactive me-tabolites (RMs), the aim of this study is to explore the possibilities and methods of building multidimen-sional hierarchical database composing of RMs evidence library, Chinese herbal evidence library, and indi-vidualized reports evidence library of herb induced liver injury HILI. Conclusion: The potential benefits lie in its ability to organize, use vast amounts of evidence and use big data mining techniques at the center for Chinese herbal medicine liver toxicity research, which is the most difficult key point of scientific research to be investigated in the next few years.
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Affiliation(s)
- Zhi Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin 300193, China
| | - Xin He
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin 300193, China
| | - Lili Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.,Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin 300193, China
| | - Yunhua Zhang
- Tianjin Clinda Medical Technology Co., Ltd., Tianjin, China
| | - Yue Hai
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Rui Gao
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
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47
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Wen B, Gorycki P. Bioactivation of herbal constituents: mechanisms and toxicological relevance. Drug Metab Rev 2019; 51:453-497. [DOI: 10.1080/03602532.2019.1655570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Bo Wen
- Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA
| | - Peter Gorycki
- Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Collegeville, PA, USA
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48
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Danan G, Teschke R. Roussel Uclaf Causality Assessment Method for Drug-Induced Liver Injury: Present and Future. Front Pharmacol 2019; 10:853. [PMID: 31417407 PMCID: PMC6680600 DOI: 10.3389/fphar.2019.00853] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/04/2019] [Indexed: 12/11/2022] Open
Abstract
Among the causality assessment methods used for the diagnosis of drug-induced liver injury (DILI), Roussel Uclaf Causality Assessment Method (RUCAM) remains the most widely used not only for individual cases but also for prospective and retrospective studies worldwide. This first place is justified by the characteristics of the method such as precise definition and classification of the liver injury, which determines the right scale in the scoring system, precise definition of the seven criteria, and the validation approach based on cases with positive rechallenge. RUCAM is used not only for any types of drugs but also for herbal medicines causing herb-induced liver injury, (HILI) and dietary supplements. In 2016, the updated RUCAM provided further specifications of criteria and instructions to improve interobserver variability. Although this method was criticized for criteria such as the age and alcohol consumption, recent consensus meeting of experts has recognized their value and recommended their incorporation into any method. While early studies searching for DILI in large databases especially in electronic medical records were based on codes of diseases or natural language without causality assessment, the recommendation is now to include RUCAM in the search for DILI/HILI. There are still studies on DILI detection or the identification of biomarkers that take into consideration the cases assessed as “possible,” although it is well known that these cases reduce the strength of the association between the cases and the offending compound or the new biomarker to be validated. Attempts to build electronic RUCAM or automatized application of this method were successful despite some weaknesses to be corrected. In the future, more reflections are needed on an expert system to standardize the exclusion of alternative causes according to the clinical context. Education and training on RUCAM should be encouraged to improve the results of the studies and the day-to-day work in pharmacovigilance departments in companies or in regulatory agencies. It is also expected to improve RUCAM with biomarkers or other criteria provided that the validation process replaces expert opinion by robust standards such as those used for the original method.
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Affiliation(s)
- Gaby Danan
- Pharmacovigilance Consultancy, Paris, France
| | - Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University, Frankfurt, Germany
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Teschke R. Idiosyncratic DILI: Analysis of 46,266 Cases Assessed for Causality by RUCAM and Published From 2014 to Early 2019. Front Pharmacol 2019; 10:730. [PMID: 31396080 PMCID: PMC6664244 DOI: 10.3389/fphar.2019.00730] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
One of the most difficult challenges in clinical hepatology is the diagnosis of a drug-induced liver injury (DILI). The timing of the events, exclusion of alternative causes, and taking into account the clinical context should be systematically assessed and scored in a transparent manner. RUCAM (Roussel Uclaf Causality Assessment Method) is a well-established diagnostic algorithm and scale to assess causality in patients with suspected DILI. First published in 1993 and updated in 2016, RUCAM is now the worldwide most commonly used causality assessment method (CAM) for DILI. The following manuscript highlights the recent implementation of RUCAM around the world, by reviewing the literature for publications that utilized RUCAM, and provides a review of “best practices” for the use of RUCAM in cases of suspected DILI. The worldwide appreciation of RUCAM is substantiated by the current analysis of 46,266 DILI cases, all tested for causality using RUCAM. These cases derived from 31 reports published from 2014 to early 2019. Their first authors came from 10 countries, with China on top, followed by the US, and Germany on the third rank. Importantly, all RUCAM-based DILI reports were published in high profile journals. Many other reports were published earlier from 1993 up to 2013 in support of RUCAM. Although most of the studies were of high quality, the current case analysis revealed shortcomings in few studies, not at the level of RUCAM itself but rather associated with the work of the users. To ensure in future DILI cases a better performance by the users, a list of essential elements is proposed. As an example, all suspected DILI cases should be evaluated 1) by the updated RUCAM to facilitate result comparisons, 2) according to a prospective study protocol to ensure complete data sets, 3) after exclusion of cases with herb induced liver injury (HILI) from a DILI cohort to prevent confounding variables, and 4) according to inclusion of DILI cases with RUCAM-based causality gradings of highly probable or probable, in order to increase the specificity of the results. In conclusion, RUCAM benefits from its high appreciation and performs well provided the users adhere to published recommendations to prevent confounding variability.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt, Germany
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Nationwide Online Survey Enables the Reevaluation of the Safety of Coleus forskohlii Extract Intake Based on the Adverse Event Frequencies. Nutrients 2019; 11:nu11040866. [PMID: 30999632 PMCID: PMC6521622 DOI: 10.3390/nu11040866] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/09/2019] [Accepted: 04/15/2019] [Indexed: 01/17/2023] Open
Abstract
The formulations of the functional ingredients of dietary supplements was studied with a small number of subjects, with a particular focus on their effectiveness, but not enough to evaluate their safety. In this regard, the reevaluation and estimation of the safe use of marketed products, with regards to their adverse event (AE) frequencies, are important. To address this issue, a post-marketing nationwide online survey was conducted for the herbal ingredient Coleus forskohlii extract (CFE), a popular weight-loss ingredient. The questionnaire included product names, adherence to the claimed amount, and AE experiences. The safe intake amount was estimated by the relationship between the claimed amount of CFE and the frequencies of AEs of each product. The number of users who experienced AEs was 75 (10.5% of all users). Gastrointestinal symptoms accounted for 92.0% (n = 69) of all AEs, and diarrhea alone accounted for 81.3% (n = 61). The amount of CFE was significantly associated with the occurrence of diarrhea (p = 0.005). The fitted curve showed that the safe intake amount of CFE was less than 250 mg/day; however, considering its effectiveness, 500 mg/day of CFE might be acceptable. In conclusion, nationwide online surveys of users enable us to confirm and reevaluate the safety of herbal supplements.
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