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Eadie L, Lo LA, Boivin M, Deol JK, MacCallum CA. Clinical guidance for cannabidiol-associated hepatotoxicity: A narrative review. J Gastroenterol Hepatol 2024; 39:2522-2532. [PMID: 39228144 PMCID: PMC11660223 DOI: 10.1111/jgh.16730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 07/22/2024] [Accepted: 08/16/2024] [Indexed: 09/05/2024]
Abstract
There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug-induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non-medical use necessitates clear direction in the diagnosis and management of CBD-associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD-related hepatotoxicity.
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Affiliation(s)
- Lauren Eadie
- Department of Medicine, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Lindsay A. Lo
- School of MedicineQueen's UniversityKingstonOntarioCanada
| | | | - Jagpaul K. Deol
- Faculty of Pharmaceutical SciencesUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Caroline A. MacCallum
- Department of Medicine, Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
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Lee S, Shin H, Choe S, Kang MG, Kim SH, Kang DY, Kim JH. MetaLAB-HOI: Template standardization of health outcomes enable massive and accurate detection of adverse drug reactions from electronic health records. Pharmacoepidemiol Drug Saf 2024; 33:e5694. [PMID: 37710363 DOI: 10.1002/pds.5694] [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: 01/12/2023] [Revised: 08/16/2023] [Accepted: 08/20/2023] [Indexed: 09/16/2023]
Abstract
PURPOSE This study aimed to advance the MetaLAB algorithm and verify its performance with multicenter data to effectively detect major adverse drug reactions (ADRs), including drug-induced liver injury. METHODS Based on MetaLAB, we created an optimal scenario for detecting ADRs by considering demographic and clinical records. MetaLAB-HOI was developed to identify ADR signals using common model-based multicenter electronic health record (EHR) data from the clinical health outcomes of interest (HOI) template and design for drug-exposed and nonexposed groups. In this study, we calculated the odds ratio of 101 drugs for HOI in Konyang University Hospital, Seoul National University Hospital, Chungbuk National University Hospital, and Seoul National University Bundang Hospital. RESULTS The overlapping drugs in four medical centers are amlodipine, aspirin, bisoprolol, carvedilol, clopidogrel, clozapine, digoxin, diltiazem, methotrexate, and rosuvastatin. We developed MetaLAB-HOI, an algorithm that can detect ADRs more efficiently using EHR. We compared the detection results of four medical centers, with drug-induced liver injuries as representative ADRs. CONCLUSIONS MetaLAB-HOI's strength lies in fully utilizing the patient's clinical information, such as prescription, procedure, and laboratory results, to detect ADR signals. Considering changes in the patient's condition over time, we created an algorithm based on a scenario that accounted for each drug exposure and onset period supervised by specialists for HOI. We determined that when a template capable of detecting ADR based on clinical evidence is developed and manualized, it can be applied in medical centers for new drugs with insufficient data.
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Affiliation(s)
- Suehyun Lee
- Department of Computer Engineering, Gachon University, Seongnam, Republic of Korea
| | - Hyunah Shin
- Healthcare Data Science Center, Konyang University Hospital, Daejeon, Republic of Korea
| | - Seon Choe
- Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Min-Gyu Kang
- Department of Internal Medicine, Subdivision of Allergy, Chungbuk National University Hospital and Chungbuk National College of Medicine, Cheongju, Republic of Korea
| | - Sae-Hoon Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Dong Yoon Kang
- Department of Preventive Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
| | - Ju Han Kim
- Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea
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Dong S, Guo X, Wang H, Sun C. Liver injury due to endothelin receptor antagonists: a real-world study based on post-marketing drug monitoring data. Ther Adv Respir Dis 2024; 18:17534666231223606. [PMID: 38179676 PMCID: PMC10771067 DOI: 10.1177/17534666231223606] [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: 07/18/2023] [Accepted: 12/13/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND Liver injury is the hallmark adverse reaction of endothelin receptor antagonist (ERA). Since the first drug, bosentan has been widely used in clinical practice, hepatotoxicity has been accompanied by the history of ERA. The new ERA has been proven to have a lower liver risk but the current research findings are inconsistent. ERA-based targeted drug combinations are commonly used in the treatment of pulmonary arterial hypertension, where the risk of liver injury is difficult to estimate. OBJECTIVES This study aimed to compare the correlation between ERA and different ERA combination regimens with liver injury in the real world. DESIGN This is a retrospective study using data from the Adverse Event Reporting System (Food and Drug Administration AERS, FAERS). METHODS The study used proportional imbalance and Bayesian analysis to mine FAERS data from January 2004 to December 2022 to determine the association of three ERAs with liver injury and to further mine the risk of liver injury due to the combination of ERAs with other targeted drugs. In addition, we analyzed the onset time, mortality, and hospitalization rate of liver injury caused by different ERA combination regimens. RESULTS We screened out 3581 ERA-related liver injury events, of which bosentan (59.82%) had the largest number of cases. The patients with liver injury were mainly female (60.63%), and the age was concentrated between 61 and 75 years (26.75%). According to different signal mining methods, reporting odds ratio (ROR; 3.38, 95% confidence interval = 3.23-3.53), proportional reporting ratio (PRR; 3.22, χ2 = 37.84), Bayesian confidence propagation neural network (BCPNN; 1.68, 95% confidence interval = 1.61), multi-item gamma Poisson shrinker (MGPS; 3.21, 95% confidence interval = 3.09), bosentan had the strongest association with liver injury compared to ambrisentan and macitentan. Furthermore, bosentan + sildenafil [ROR (2.52, 95% confidence interval = 2.23-2.84), PRR (2.44, χ2 = 15.92), BCPNN (1.29, 95% confidence interval = 1.14), MGPS (2.44, 95% confidence interval = 2.21)], bosentan + epoprostenol [ROR (5.39, 95% confidence interval = 4.29-6.77), PRR (4.94, χ2 = 65.18), BCPNN (2.30, 95% confidence interval = 1.83), MGPS (4.94, 95% confidence interval = 4.08)], bosentan + iloprost [ROR (2.70, 95% confidence interval = 2.11-3.45), PRR (2.61, χ2 = 31.03), BCPNN (1.38, 95% confidence interval = 1.08), MGPS (2.61, 95% confidence interval = 2.12)] had a higher risk of liver injury caused by the three ERA combination regimens. The median time to onset of hepatotoxicity associated with all ERA combination regimens was 259 days (interquartile range: 58-716.5 days). Finally, the hospitalization rate for patients experiencing hepatotoxicity with ERA combination regimens was 47.86% and the mortality rate was 12.67%. CONCLUSION By mining the FAERS, we analyzed and compared the risk of liver injury related to different ERA and ERA combination regimens, and the onset time and adverse reaction outcomes of all ERA combination regimens. According to the results of the study, bosentan had the highest risk of liver injury and the combination regimens bosentan + sildenafil, bosentan + epoprostenol, and bosentan + iloprost had a stronger risk of liver injury. From the early stages of treatment, we need to regularly monitor the liver function of patients, especially for females and the elderly, and discontinue the suspected drug as soon as the liver injury occurs.
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Affiliation(s)
- Shichao Dong
- Department of Pharmacy, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xiaofei Guo
- Department of Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Huayu Wang
- Department of Pharmacy, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Chuan Sun
- Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, No. 72, Guangzhou road, Gulou District, Jiangsu 210000, China
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Nardo M, Gouda MA, Nelson BE, Barreto CMN, Slade JH, Poullard A, Zafereo M, Hu MI, Cabanillas ME, Subbiah V. Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers. Cell Rep Med 2023; 4:101332. [PMID: 38118420 PMCID: PMC10772460 DOI: 10.1016/j.xcrm.2023.101332] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 10/02/2023] [Accepted: 11/20/2023] [Indexed: 12/22/2023]
Abstract
The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib and pralsetinib has led to a paradigm change in the treatment of RET-altered lung and thyroid cancers through a higher response rate and a more tolerable safety and toxicity profile than multi-kinase inhibitors. Recently, selpercatinib has received a tissue-agnostic FDA approval for all RET-fusion-positive cancers, and pralsetinib has shown pan-cancer activity as well. Given the anticipated increase in the use of both drugs across multiple tumor types, it is crucial to recognize the possible side effects and approaches for their optimal management in order to maximize the clinical benefit for treated patients. In this review, we underscore potential toxicities associated with selective RET inhibitors and discuss strategies to mitigate them.
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Affiliation(s)
- Mirella Nardo
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mohamed A Gouda
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Blessie E Nelson
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Carmelia M N Barreto
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Hoyt Slade
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Pharmacy Clinical Programs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anna Poullard
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Zafereo
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mimi I Hu
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria E Cabanillas
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Sarah Cannon Research Institute, Nashville, TN, USA.
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Gayatri Devi R, Ezhilarasan D. Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice. J Biochem Mol Toxicol 2023; 37:e23478. [PMID: 37458150 DOI: 10.1002/jbt.23478] [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: 10/25/2022] [Revised: 06/09/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-6, nuclear factor-κB (NF-κB), and IκB kinase β in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.
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Affiliation(s)
- Ramalingam Gayatri Devi
- Department of Physiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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Villani R, Serviddio G, Avolio C, Cassano T, D'Amico E. Autoimmune liver disease and multiple sclerosis: state of the art and future perspectives. Clin Exp Med 2023; 23:3321-3338. [PMID: 37421590 PMCID: PMC10618321 DOI: 10.1007/s10238-023-01128-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 06/23/2023] [Indexed: 07/10/2023]
Abstract
Clinical observations suggest that the prevalence of autoimmune diseases is changing over time. Both autoimmune liver diseases and multiple sclerosis have shown a significant increase in the last decades. Although the coexistence of autoimmune diseases within individuals and families is a common phenomenon, the extent to which liver disease and multiple sclerosis co-occur is not clear. Case reports and few studies have reported the possible coexistence of multiple sclerosis with thyroid diseases, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. It is unknown whether there is a definite association between multiple sclerosis and autoimmune liver diseases. We reviewed the literature to summarize the available studies on the association between different autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis) and treated or untreated multiple sclerosis.
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Affiliation(s)
- Rosanna Villani
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Gaetano Serviddio
- Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Carlo Avolio
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Emanuele D'Amico
- Department of Medical and Surgical Sciences, Multiple Sclerosis Center, University of Foggia, Foggia, Italy
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Maev IV, Polunina TE. [Drug-induced liver injury: diagnosis of exclusion]. TERAPEVT ARKH 2023; 95:611-620. [PMID: 38158894 DOI: 10.26442/00403660.2023.08.202329] [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: 10/08/2023] [Accepted: 10/08/2023] [Indexed: 01/03/2024]
Abstract
Drug-induced liver injury (DILI) is a relevant issue in clinical practice and is still a diagnosis of exclusion. Despite the low incidence in the general population, DILI is the cause of most cases of acute hepatic injury and has a mortality rate of up to 50%. Despite many reports in the medical literature about the DILI mechanisms, a clear causal relationship between them, drugs, and risk factors has not been established. Current clinical practice is based on a combination of a thorough study of a history of risk factors, the timing of drug and dietary supplements' administration, and the analysis of laboratory and instrumental tests. It aligns with the international criteria of the Rousell Uclaf Causality Assessment Method (RUCAM), which is considered one of the main diagnostic algorithms for DILI. The article addresses current DILI classification, risk factors, diagnostic algorithms, causalities, clinical evaluation, promising liver function biomarkers, and specific treatment.
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Affiliation(s)
- I V Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - T E Polunina
- Yevdokimov Moscow State University of Medicine and Dentistry
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8
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Alvi AT, George Mathew S, Shankar M. The First Case of Daratumumab-Induced Fulminant Hepatic Failure. Cureus 2023; 15:e46858. [PMID: 37954816 PMCID: PMC10636513 DOI: 10.7759/cureus.46858] [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: 10/08/2023] [Indexed: 11/14/2023] Open
Abstract
Drug-induced liver failure is a relatively uncommon condition with a vast spectrum of clinical manifestations, and it is a leading cause of acute hepatic failure in the United States. We describe the first case of fulminant hepatic failure induced by chemotherapeutic drug daratumumab, a common FDA-approved agent. A 77-year-old male, with a history of multiple myeloma, was admitted for left lower extremity cellulitis, two weeks after receiving his first intravenous infusion of daratumumab. He developed fulminant hepatic failure in the hospital a few days later. Despite multiple doses of N-acetylcysteine, his liver function continued to decline, and he expired shortly after.
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Affiliation(s)
- Ali Tariq Alvi
- Internal Medicine, HCA Florida Westside Hospital, Plantation, USA
- Internal Medicine, HCA Florida Northwest Hospital, Margate, USA
| | | | - Murali Shankar
- Gastroenterology, HCA Florida Westside Hospital, Plantation, USA
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9
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Barouki R, Samson M, Blanc EB, Colombo M, Zucman-Rossi J, Lazaridis KN, Miller GW, Coumoul X. The exposome and liver disease - how environmental factors affect liver health. J Hepatol 2023; 79:492-505. [PMID: 36889360 PMCID: PMC10448911 DOI: 10.1016/j.jhep.2023.02.034] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 02/14/2023] [Accepted: 02/15/2023] [Indexed: 03/10/2023]
Abstract
Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses. It is well known that several liver diseases are associated with i) addictive behaviours such as alcohol consumption, smoking, and to a certain extent dietary imbalance and obesity, ii) viral and parasitic infections, and iii) exposure to toxins and occupational chemicals. Recent studies indicate that environmental exposures are also significantly associated with liver diseases, and these include air pollution (particulate matter and volatile chemicals), contaminants such as polyaromatic hydrocarbons, bisphenol A and per-and poly-fluorinated substances, and physical stressors such as radiation. Furthermore, microbial metabolites and the "gut-liver" axis play a major role in liver diseases. Exposomics is poised to play a major role in the field of liver pathology. Methodological advances such as the exposomics-metabolomics framework, the determination of risk factors' genomic and epigenomic signatures, and cross-species biological pathway analysis should further delineate the impact of the exposome on the liver, opening the way for improved prevention, as well as the identification of new biomarkers of exposure and effects, and additional therapeutic targets.
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Affiliation(s)
| | - Michel Samson
- Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | | | - Massimo Colombo
- San Raffaele Hospital, Liver Center, Via Olgettina 60, 20132, Milan, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Inserm, AP-HP, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, F-75006, Paris, France
| | | | - Gary W Miller
- Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, 10032, USA
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Ehikioya E, Okobi OE, Beeko MAE, Abanga R, Abah NNI, Briggs L, Nwimo PN, Beeko PKA, Nwachukwu OB, Okoroafor CC. Comparing Intravenous Labetalol and Intravenous Hydralazine for Managing Severe Gestational Hypertension. Cureus 2023; 15:e42332. [PMID: 37614273 PMCID: PMC10443893 DOI: 10.7759/cureus.42332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2023] [Indexed: 08/25/2023] Open
Abstract
Background Hypertensive disorders of pregnancy are the leading causes of both maternal morbidity and maternal mortality. Hypertensive disorders are acute obstetric emergencies, which refer to various life-threatening medical challenges known to develop during pregnancy, labor, and delivery, requiring urgent attention to reduce blood pressure (BP) for the benefit of the affected mothers and infants. Hydralazine and labetalol have been widely used as the first-line medications in the management of severe hypertension during pregnancy. However, the choice between these two drugs lacks clear evidence regarding their safety and superiority. Several studies have attempted to study intravenous (IV) labetalol versus hydralazine, but very few such comparison studies have been conducted in Africa. Objective To compare the effectiveness of IV labetalol and IV hydralazine in reducing systolic and diastolic BP in pregnant women with severe hypertension. Also, to determine the time required for hydralazine and labetalol to lower BP to ≤150/100 mmHg, the number of doses needed for each drug, and evaluating maternal and perinatal outcomes. Study design This study employed an open-label randomized clinical trial design conducted in the labor, delivery, and antenatal ward of the Central and Stella Obasanjo Hospital in Benin City. A total of 120 women with severe pregnancy-induced hypertension were randomly assigned to two groups: Group X, consisting of 60 pregnant women, received IV hydralazine at a slow rate of 5 mg for five minutes, repeated every 20 minutes (maximum of five doses) until a blood pressure of ≤150/100 mmHg was achieved. Group Y, also consisting of 60 pregnant women, received IV labetalol in escalating doses of 25, 50, 75, 75, and 75 mg (maximum of 300 mg) every 20 minutes until the blood pressure reached ≤150/100 mmHg. Statistical analysis was performed using SPSS version 23 (IBM Inc., Armonk, New York). Result IV hydralazine achieved the target BP in an average time of 45.80 +/- 25.17 minutes, while IV labetalol took an average of 72.67 +/- 41.80 minutes (p=0.001). The number of doses required to reach the target BP differed significantly between the two drugs. Hydralazine required an average of 1.72 +/- 0.904 doses, whereas labetalol required an average of 3.72 +/- 1.782 doses (p=0.0001). While 45% of women in the hydralazine group attained the target BP with a single dose of hydralazine, only 31.1% of women in the labetalol group were able to attain the target BP with a single dose of labetalol (p=0.02). Overall, target BP was achieved in 55 out of 60 women (91.7%) who were randomized to receive IV hydralazine, whereas 45 out of 60 women (75%) who received IV labetalol achieved the target blood pressure. While hydralazine demonstrated more favorable results in terms of achieving target blood pressure, there were higher incidences of maternal adverse effects in the hydralazine group compared to the labetalol group. However, these adverse effects were not severe enough to warrant discontinuation of the medication. Conclusion IV hydralazine showed faster achievement of the target BP and a lower number of doses required compared to IV labetalol. Additionally, a higher percentage of women in the hydralazine group achieved the target BP with a single dose. However, there were more maternal adverse effects associated with hydralazine, although they were not severe. Perinatal outcomes did not differ significantly between the two groups.
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Affiliation(s)
| | - Okelue E Okobi
- Family Medicine, Medficient Health Systems, Laurel, USA
- Family Medicine, Lakeside Medical Center, Belle Glade, USA
| | | | - Rafia Abanga
- Obstetrics and Gynecology, Weija Gbawe Municipal Hospital, Accra, GHA
| | | | - Lilian Briggs
- Internal Medicine, Grodno State Medical University, Belarus, AUS
| | - Patience N Nwimo
- Internal Medicine, First Foundation Medical Clinic, Loganville, USA
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11
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Jang HJ, Leem J, Kim GM. Protective Effects of Apamin on Acetaminophen-Induced Hepatotoxicity in Mice. Curr Issues Mol Biol 2023; 45:4389-4399. [PMID: 37232748 DOI: 10.3390/cimb45050279] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/07/2023] [Accepted: 05/15/2023] [Indexed: 05/27/2023] Open
Abstract
Acetaminophen (APAP) overdose can cause severe liver damage, but therapeutic options are limited. Apamin is a natural peptide present in bee venom and has antioxidant and anti-inflammatory properties. Accumulating evidence suggests that apamin has favorable actions in rodent models of inflammatory disorders. Here, we examined the effect of apamin on APAP-evoked hepatotoxicity. Intraperitoneal administration of apamin (0.1 mg/kg) alleviated histological abnormalities and reduced serum levels of liver enzymes in mice injected with APAP. Apamin inhibited oxidative stress through an increase in the amount of glutathione and activation of the antioxidant system. Apamin also attenuated apoptosis with inhibition of caspase-3 activation. Moreover, apamin reduced serum and hepatic levels of cytokines in APAP-injected mice. These effects were accompanied by suppression of NF-κB activation. Furthermore, apamin inhibited chemokine expression and inflammatory cell infiltration. Our results suggest that apamin dampens APAP-evoked hepatotoxicity through inhibiting oxidative stress, apoptosis, and inflammation.
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Affiliation(s)
- Hyo-Jeong Jang
- Department of Pediatrics, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
| | - Gyun Moo Kim
- Department of Emergency Medicine, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea
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12
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Geng Y, Wang Z, Zhou J, Zhu M, Liu J, James TD. Recent progress in the development of fluorescent probes for imaging pathological oxidative stress. Chem Soc Rev 2023. [PMID: 37190785 DOI: 10.1039/d2cs00172a] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Oxidative stress is closely related to the physiopathology of numerous diseases. Reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) are direct participants and important biomarkers of oxidative stress. A comprehensive understanding of their changes can help us evaluate disease pathogenesis and progression and facilitate early diagnosis and drug development. In recent years, fluorescent probes have been developed for real-time monitoring of ROS, RNS and RSS levels in vitro and in vivo. In this review, conventional design strategies of fluorescent probes for ROS, RNS, and RSS detection are discussed from three aspects: fluorophores, linkers, and recognition groups. We introduce representative fluorescent probes for ROS, RNS, and RSS detection in cells, physiological/pathological processes (e.g., Inflammation, Drug Induced Organ Injury and Ischemia/Reperfusion Injury etc.), and specific diseases (e.g., neurodegenerative diseases, epilepsy, depression, diabetes and cancer, etc.). We then highlight the achievements, current challenges, and prospects for fluorescent probes in the pathophysiology of oxidative stress-related diseases.
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Affiliation(s)
- Yujie Geng
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Zhuo Wang
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Jiaying Zhou
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Mingguang Zhu
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Jiang Liu
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Tony D James
- Department of Chemistry, University of Bath, Bath BA2 7AY, UK.
- School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China
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13
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Eze IE, Adidam S, Gordon DK, Lasisi OG, Gajjala J. Probable Enoxaparin-Induced Liver Injury in a Young Patient: A Case Report of a Diagnostic Challenge. Cureus 2023; 15:e36869. [PMID: 37123692 PMCID: PMC10146374 DOI: 10.7759/cureus.36869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/29/2023] [Indexed: 03/31/2023] Open
Abstract
Low molecular weight heparin (LMWH) is associated with elevated liver enzyme levels in a small percentage of patients. Elevations more than five times the upper limit of normal are uncommon and have been noted to primarily occur in patients receiving higher doses. The literature reports mild, primarily asymptomatic cases, with adverse effects at higher therapeutic doses. We report the case of a 27-year-old woman who developed drug-induced liver injury (DILI) while receiving enoxaparin during admission for a loculated pleural effusion secondary to pulmonary tuberculosis. The Roussel Uclaf Causality Assessment Method (RUCAM) score delineated enoxaparin as the likely cause.
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14
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Sun X, Cui Q, Ni J, Liu X, Zhu J, Zhou T, Huang H, OuYang K, Wu Y, Yang Z. Retracted and Republished from: "Gut Microbiota Mediates the Therapeutic Effect of Monoclonal Anti-TLR4 Antibody on Acetaminophen-Induced Acute Liver Injury in Mice". Microbiol Spectr 2023; 11:e0471522. [PMID: 36942972 PMCID: PMC10186863 DOI: 10.1128/spectrum.04715-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 02/14/2023] [Indexed: 03/23/2023] Open
Abstract
Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies have shown that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that the gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the members of the gut microbiota and their metabolic pathways, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury than mice that received feces from the APAP group. ATAB therapy also improved gut barrier functions in mice and reduced the expression of the protein zonulin. Our results revealed that the gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found that a monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through changes in the gut microbiota, metabolic pathways, and gut barrier function. This work suggested that the gut microbiota can be a therapeutic target of APAP-induced acute liver injury, and we performed foundation for further research.
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Affiliation(s)
- Xuewei Sun
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
- Binzhou Medical University, Yantai, China
| | - Qian Cui
- Air Force Hospital of Eastern Theater, Nanjing, China
| | - Juan Ni
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Xiaoguang Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China
| | - Jin Zhu
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
| | - Tingting Zhou
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
| | - HuaYing Huang
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Ke OuYang
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Yulong Wu
- Binzhou Medical University, Yantai, China
| | - Zhan Yang
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
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15
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Lo LA, Christiansen A, Eadie L, Strickland JC, Kim DD, Boivin M, Barr AM, MacCallum CA. Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis. J Intern Med 2023; 293:724-752. [PMID: 36912195 DOI: 10.1111/joim.13627] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
BACKGROUND Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI). METHODS In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted. RESULTS Cannabidiol use was associated with an increased probability of liver enzyme elevation (N = 12 trials, n = 1229; OR = 5.85 95% CI = 3.84-8.92, p < 0.001) and DILI (N = 12 trials, n = 1229; OR = 4.82 95% CI = 2.46-9.45, p < 0.001) compared to placebo controls. In participants taking cannabidiol (N = 28 trials, n = 1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000 mg/day or ≥20 mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300 mg/day. No cases of severe DILI were reported. CONCLUSIONS Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.
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Affiliation(s)
- Lindsay A Lo
- Department of Public Health Sciences, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - April Christiansen
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
| | - Lauren Eadie
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Justin C Strickland
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - David D Kim
- Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Alasdair M Barr
- Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,British Columbia Mental Health & Substance Use Services Research Institute, Vancouver, British Columbia, Canada
| | - Caroline A MacCallum
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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16
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George AT, Glover M, Alayo Q, Zulfiqar M, Ludwig DR, Ciorba MA, McHenry S, Deepak P. Nonalcoholic Fatty Liver Disease Is a Risk Factor for Thiopurine Hepatotoxicity in Crohn's Disease. CROHN'S & COLITIS 360 2023; 5:otad005. [PMID: 36846096 PMCID: PMC9951740 DOI: 10.1093/crocol/otad005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Indexed: 02/08/2023] Open
Abstract
Background Patients with Crohn's disease (CD) are predisposed to nonalcoholic fatty liver disease (NAFLD). CD management often includes thiopurines which can promote hepatotoxicity. We aimed to identify the role of NAFLD on the risk of developing liver injury from thiopurines in CD. Methods In this prospective cohort analysis, CD patients at a single center were recruited 6/2017-5/2018. Patients with alternative liver diseases were excluded. The primary outcome was time to elevation of liver enzymes. Patients underwent MRI with assessment of proton density fat fraction (PDFF) on enrollment, where NAFLD was defined as PDFF >5.5%. Statistical analysis was performed using a Cox-proportional hazards model. Results Of the 311 CD patients studied, 116 (37%) were treated with thiopurines, 54 (47%) of which were found to have NAFLD. At follow-up, there were 44 total cases of elevated liver enzymes in those treated with thiopurines. Multivariable analysis demonstrated that NAFLD was a predictor of elevated liver enzymes in patients with CD treated with thiopurines (HR 3.0, 95% CI 1.2-7.3, P = .018) independent of age, body mass index, hypertension, and type 2 diabetes. Steatosis severity by PDFF positively correlated with peak alanine aminotransferase (ALT) at follow-up. Kaplan-Meier analysis demonstrated poorer complication-free survival (log-rank 13.1, P < .001). Conclusions NAFLD at baseline is a risk factor for thiopurine-induced hepatotoxicity in patients with CD. The degree of liver fat positively correlated with the degree of ALT elevation. These data suggest that evaluation for hepatic steatosis be considered in patients with liver enzyme elevations with thiopurine therapy.
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Affiliation(s)
- Alvin T George
- Division of Gastroenterology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Matthew Glover
- Division of Gastroenterology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Quazim Alayo
- Department of Medicine, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Maria Zulfiqar
- Department of Radiology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Daniel R Ludwig
- Department of Radiology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Matthew A Ciorba
- Division of Gastroenterology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Scott McHenry
- Division of Gastroenterology, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Parakkal Deepak
- Address correspondence to: Parakkal Deepak, MBBS, MS, Division of Gastroenterology, John T Milliken Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, Mailstop Code: MSC 8124-0021-04, Saint Louis, MO 63110, USA ()
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17
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Parchwani D, Sonagra AD, Dholariya S, Motiani A, Singh R. COVID-19-related liver injury: Focus on genetic and drug-induced perspectives. World J Virol 2023; 12:53-67. [PMID: 36743658 PMCID: PMC9896591 DOI: 10.5501/wjv.v12.i1.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/15/2022] [Accepted: 12/01/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is considered as one of the major etiopathogenetic factors for liver injury. Recent evidence has shown that an underlying genetic factor may also occur. Hence, it is important to understand the host genetics and iatrogenic-based mechanisms for liver dysfunction to make timely remedial measures. AIM To investigate drug-induced and genetic perspectives for the development of coronavirus disease 2019 (COVID-19)-related liver injury. METHODS Reference Citation Analysis, PubMed, Google Scholar and China National Knowledge Infrastructure were searched by employing the relevant MeSH keywords and pertaining data of the duration, site and type of study, sample size with any subgroups and drug-induced liver injury outcome. Genetic aspects were extracted from the most current pertinent publications. RESULTS In all studies, the hepatic specific aminotransferase and other biochemical indices were more than their prescribed upper normal limit in COVID-19 patients and were found to be significantly related with the gravity of disease, hospital stay, number of COVID-19 treatment drugs and worse clinical outcomes. In addition, membrane bound O-acyltransferase domain containing 7 rs641738, rs11385942 G>GA at chromosome 3 gene cluster and rs657152 C>A at ABO blood locus was significantly associated with severity of livery injury in admitted SARS-CoV-2 patients. CONCLUSION Hepatic dysfunction in SARS-CoV-2 infection could be the result of individual drugs or due to drug-drug interactions and may be in a subset of patients with a genetic propensity. Thus, serial estimation of hepatic indices in hospitalized SARS-CoV-2 patients should be done to make timely corrective actions for iatrogenic causes to avoid clinical deterioration. Additional molecular and translational research is warranted in this regard.
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Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Amit D Sonagra
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Sagar Dholariya
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Anita Motiani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
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18
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Hassoun J, Goossens N, Restellini S, Ramer L, Ongaro M, Giostra E, Hadengue A, Rubbia‐Brandt L, Spahr L. Discontinuation of immunosuppression in patients with immune-mediated drug-induced liver injury or idiopathic autoimmune hepatitis: A case-control study. JGH Open 2023; 7:135-140. [PMID: 36852147 PMCID: PMC9958343 DOI: 10.1002/jgh3.12862] [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: 08/29/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/13/2023]
Abstract
Background and Aim Drug-induced liver injury (DILI) may present with autoimmune features and require immunosuppressive therapy (IST) to reach biochemical response. Discontinuation of IST without hepatitis relapse may be more frequent in these patients as compared to patients with classical autoimmune hepatitis (AIH). We aimed to determine baseline characteristics and outcome of patients with immune-mediated drug induced liver injury (IMDILI) with particular emphasis on IST during follow-up. Methods We performed a single-center retrospective study of consecutive patients presenting at a tertiary care center between January 2005 and December 2019 either with IMDILI or with classical AIH, for whom full baseline characteristics and a close follow-up were available over a 12-month period. Results Overall, 31 patients (IMDILI n = 16, mean age 59 [34-74] years; AIH n = 15, mean age 47 [15-61] years) were included, showing similar biochemical, serological, and histological characteristics. Incriminating drugs in IMDILI patients were mostly represented by nonsteroidal antiinflammatory drugs and sartans. Initial corticosteroids combined with IST led to biochemical response in all patients. Compared to idiopathic AIH, more patients with IMDILI were weaned off corticosteroids at the end of follow-up (11/16 [68.7%] vs 4/15 [26.6%], P < 0.02). At 1 year of follow-up, more patients in the IMDILI group compared to the classical AIH group were off any type of IST (13/16 [81%] vs 15/15 [100%], P = 0.08). Conclusions Although presenting with similar baseline biochemical and histological characteristics as idiopathic AIH, patients with IMDILI may not require long-term IST.
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Affiliation(s)
- Jeremy Hassoun
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Nicolas Goossens
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Sophie Restellini
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Lucas Ramer
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Marie Ongaro
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Emiliano Giostra
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Antoine Hadengue
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Laura Rubbia‐Brandt
- Department of Clinical PathologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
| | - Laurent Spahr
- Department of Gastroenterology and HepatologyUniversity Hospitals of Geneva and Faculty of MedicineGenevaSwitzerland
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19
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Aghemo A, Alekseeva OP, Angelico F, Bakulin IG, Bakulina NV, Bordin D, Bueverov AO, Drapkina OM, Gillessen A, Kagarmanova EM, Korochanskaya NV, Kucheryavii UA, Lazebnik LB, Livzan MA, Maev IV, Martynov AI, Osipenko MF, Sas EI, Starodubova A, Uspensky YP, Vinnitskaya EV, Yakovenko EP, Yakovlev AA. Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review. Ann Med 2022; 54:1548-1560. [PMID: 35635048 PMCID: PMC9186366 DOI: 10.1080/07853890.2022.2069854] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Chronic liver disease (CLD), manifested as hepatic injury, is a major cause of global morbidity and mortality. CLD progresses to fibrosis, cirrhosis, and-ultimately-hepatocellular carcinoma (HCC) if left untreated. The different phenotypes of CLD based on their respective clinical features and causative agents include alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and drug-induced liver injury (DILI). The preferred treatment modality for CLD includes lifestyle modification and diet, along with limited pharmacological agents for symptomatic treatment. Moreover, oxidative stress (OS) is an important pathological mechanism underlying all CLD phenotypes; hence, the use of antioxidants to manage the disease is justified. Based on available clinical evidence, silymarin can be utilized as a hepatoprotective agent, given its potent antioxidant, antifibrotic, and anti-inflammatory properties. The role of silymarin in suppressing OS has been well established, and therefore silymarin is recommended for use in ALD and NAFLD in the guidelines approved by the Russian Medical Scientific Society of Therapists and the Gastroenterology Scientific Society of Russia. However, to discuss the positioning of the original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies, an expert panel of international and Russian medical professionals was convened on 11 November 2020. The panel reviewed approaches for the prevention and treatment of OS, existing guidelines for patient management for CLD, and available evidence on the effectiveness of silymarin in reducing OS, fibrosis, and hepatic inflammation and presented in the form of a narrative review. Key messagesAn expert panel of international and Russian medical professionals reviewed existing guidelines for ALD, NAFLD, MAFLD, and DILI to establish consensus recommendations that oxidative stress is the common pathophysiological mechanism underlying these conditions.The panel also discussed the positioning of original silymarin in clinical guidelines and treatment protocols as a hepatoprotective agent for managing CLD concomitantly with other therapies.The panel reviewed the effectiveness of 140 mg original silymarin three times a day in reducing oxidative stress in chronic liver diseases such as ALD, NAFLD, MAFLD, and DILI.
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Affiliation(s)
- Alessio Aghemo
- Department of Biomedical Sciences, Humanitas Research Hospital IRCCS, Sosnowiec, Poland
| | - Olga P Alekseeva
- Gastroenterological Center, Semashko National Research University, Moscow, Russia
| | | | - Igor G Bakulin
- Department of Propaedeutics of Internal Diseases, Federal State Medical University of Ministry of Health of Russia, Chief Specialist-Therapist of the North-Western Federal district, Moscow, Russia
| | - Natalia V Bakulina
- Department of Therapy and Clinical Pharmacology, North-Western State Medical University, Moscow, Russia
| | - Dmitry Bordin
- Department of Pancreatic, Biliary, and Upper Digestive Tract Disorders, A.S. Loginov Moscow Clinical Scientific Center, Moscow, Russia
| | - Alexey O Bueverov
- Department of Gastroenterology and Hepatology, Moscow Medical Academy, Moscow, Russia
| | - Oxana M Drapkina
- Ministry of Health of the Russian Federation, Chief Specialist of Therapy and General Practice Ministry of Health of Russia, Grozny, Russia
| | - Anton Gillessen
- Department of Internal Medicine, Herz-Jesu-Hospital, Muenster, Germany
| | - Elvira M Kagarmanova
- Gastroenterological Department, GBUZ RB City clinical Hospital, Sterlitamak, Russia
| | | | - U A Kucheryavii
- Department of Propaedeutics of Internal Diseases and Gastroenterology, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Leonid B Lazebnik
- Department of Polyclinic Therapy, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Maria A Livzan
- Department of Faculty Therapy, Omsk State Medical University, Omsk, Russia
| | - Igor V Maev
- Department of Propedeutics of Internal Diseases and Gastroenterology, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Anatolii I Martynov
- Department of Internal Diseases, Moscow State University of Medicine and Dentistry, Moscow, Russia
| | - Marina F Osipenko
- Department for Science, Innovations and Informatization, Novosibirsk State Medical University, Novosibirsk, Russia
| | - Evgenii I Sas
- 2nd Department of Therapy, Ministry of Defense of the Russian Federation, Moscow, Russia
| | - Antonina Starodubova
- Department of Scientific and Clinical Work, INSTITUTE "Federal Research Center of Nutrition and Biotechnologies", Moscow, Russia
| | - Yurii P Uspensky
- Department of faculty therapy, Saint Petersburg State Pediatric Medical University (Spbpgmu) of the RF MOH, St. Petersburg, Russia
| | - Elena V Vinnitskaya
- Department of Hepatology, Moscow Clinical Research and Practice Center, Moscow, Russia
| | - Emilia P Yakovenko
- Department of Gastroenterology, Faculty of Advanced Medical Education of the Russian National Research Medical University, Moscow, Russia
| | - Alexey A Yakovlev
- Department of gastroenterology and endoscopy, Rostov State Medical, Rostov, Russia
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20
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Muacevic A, Adler JR, Nallapeta NS, Duve R, Miranda CJ, Ismail M, Mahl T. Severe Cholestatic Drug-Induced Liver Injury With Cephalosporin Use. Cureus 2022; 14:e32262. [PMID: 36620795 PMCID: PMC9815788 DOI: 10.7759/cureus.32262] [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: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
Drug-induced liver injury (DILI) is a phenomenon that occurs with nearly all classes of medications. Cholestatic DILI represents a fraction of these cases and can present as bland cholestasis, cholestatic hepatitis, secondary sclerosis cholangitis, and vanishing bile duct syndrome. Risk factors have been identified for cholestatic DILI, including older age, genetic determinants, and certain medications such as amoxicillin-clavulanate. Here, we describe a complicated case of severe cholestatic DILI secondary to cephalosporin use. A 27-year-old female presented to the hospital initially with fever and abdominal pain for four weeks after an emergency C-section for pre-eclampsia and hemolysis, elevated liver enzymes, lowered platelets (HELLP) syndrome. She was found to have a retroperitoneal abscess and underwent bilateral drain placement. She was initially started on cefazolin, and then coverage was broadened to cefepime. Shortly after, alkaline phosphatase (ALP) rose and peaked at 3498 IU/L, with aspartate aminotransferase (AST) and alanine transaminase (ALT) elevated at 274 IU/L and 122 IU/L, respectively. Extensive testing for secondary causes and a liver biopsy were consistent with DILI. Liver enzymes down-trended with the cessation of cefepime. This case report highlights that prompt recognition of the culprit medication is paramount to recovering normal liver function.
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21
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Drug-induced Liver Injury in Pediatrics. J Pediatr Gastroenterol Nutr 2022; 75:391-395. [PMID: 35727646 DOI: 10.1097/mpg.0000000000003535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Drug-induced liver injury (DILI) is a rare, underdiagnosed cause of liver disease in children. The incidence of DILI in the pediatric population is unknown but it represents around 10% of all DILI cases. The most common hepatotoxic drugs in children are antibiotics and antiepileptics. DILI is classified as intrinsic or idiosyncratic and it presents mostly with 2 patterns of injury: hepatocellular or cholestatic. Diagnosis can be done with help of the Roussel Uclaf Causality Assessment Method (RUCAM) casualty assessment. The mainstay of treatment is prompt withdrawal of the suspect drug.
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22
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Gheena S, Ezhilarasan D, Shree Harini K, Rajeshkumar S. Syringic acid and silymarin concurrent administration inhibits sodium valproate-induced liver injury in rats. ENVIRONMENTAL TOXICOLOGY 2022; 37:2143-2152. [PMID: 35543257 DOI: 10.1002/tox.23557] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/08/2022] [Accepted: 04/27/2022] [Indexed: 06/14/2023]
Abstract
Sodium valproate (SV) is a well-known anti-epileptic drug, also used to control convulsions, bipolar disorders and migraines. SV has been shown to induce liver toxicity in clinical subjects. Syringic acid (SA), a natural polyphenolic compound has potential antioxidant, anti-inflammatory and several beneficial effects. Therefore, in this study, we evaluated hepatoprotective effect of SA against SV-induced liver injury in rats. Wistar rats were treated with SV orally at a dose of 500 mg/kg, once daily, for 14 days. Another three groups of rats were administered with SV and concurrently treated with SA (40 and 80 mg/kg) and silymarin (SIL) (100 mg/kg) for 14 days. SV administration for 14 days caused significant (p < .001) elevation of liver transaminases and ALP in serum. Liver MDA level was significantly (p < .001) increased with a concomitant decrease (p < .001) in enzymic antioxidants activities in SV administered rats. SV administration also caused the upregulation of proinflammatory markers such as tumor necrosis factor α, c-Jun N-terminal kinase, nuclear factor kappa B, cyclooxygenase-2 and Interleukin 6 expressions in liver tissue. Histopathological studies also revealed the presence of inflammatory cell infiltration and hepatocellular necrosis upon SV administration. At both doses, concurrent administration of SA and SIL significantly (p < .001) inhibited the liver transaminase activities in serum, oxidative stress, and proinflammatory markers expression in liver tissue. Our current results suggest that SA can be a promising herbal drug that can inhibit SV-induced hepatotoxicity when administered together due its potential anti-inflammatory effects.
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Affiliation(s)
- Sukumaran Gheena
- Department of Oral Pathology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Karthik Shree Harini
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - Shanmugam Rajeshkumar
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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Bhardwaj M, Bhardwaj NJ, Cueto K, Killeen TC. Hydralazine-induced liver injury: a review and discussion. Drug Ther Bull 2022; 60:dtb-2022-243278rep. [PMID: 36008095 DOI: 10.1136/dtb.2022.243278rep] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Affiliation(s)
- Meeta Bhardwaj
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Nakul Jay Bhardwaj
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Kendra Cueto
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - T Colin Killeen
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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24
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Xu L, Yuan Y, Che Z, Tan X, Wu B, Wang C, Xu C, Xiao J. The Hepatoprotective and Hepatotoxic Roles of Sex and Sex-Related Hormones. Front Immunol 2022; 13:939631. [PMID: 35860276 PMCID: PMC9289199 DOI: 10.3389/fimmu.2022.939631] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
Most liver diseases, including acute liver injury, drug-induced liver injury, viral hepatitis, metabolic liver diseases, and end-stage liver diseases, are strongly linked with hormonal influences. Thus, delineating the clinical manifestation and underlying mechanisms of the “sexual dimorphism” is critical for providing hints for the prevention, management, and treatment of those diseases. Whether the sex hormones (androgen, estrogen, and progesterone) and sex-related hormones (gonadotrophin-releasing hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin) play protective or toxic roles in the liver depends on the biological sex, disease stage, precipitating factor, and even the psychiatric status. Lifestyle factors, such as obesity, alcohol drinking, and smoking, also drastically affect the involving mechanisms of those hormones in liver diseases. Hormones deliver their hepatic regulatory signals primarily via classical and non-classical receptors in different liver cell types. Exogenous sex/sex-related hormone therapy may serve as a novel strategy for metabolic liver disease, cirrhosis, and liver cancer. However, the undesired hormone-induced liver injury should be carefully studied in pre-clinical models and monitored in clinical applications. This issue is particularly important for menopause females with hormone replacement therapy (HRT) and transgender populations who want to receive gender-affirming hormone therapy (GAHT). In conclusion, basic and clinical studies are warranted to depict the detailed hepatoprotective and hepatotoxic mechanisms of sex/sex-related hormones in liver disease. Prolactin holds a promising perspective in treating metabolic and advanced liver diseases.
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Affiliation(s)
- Linlin Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuan Yuan
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhaodi Che
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaozhi Tan
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Cunchuan Wang
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Chengfang Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Chengfang Xu, ; Jia Xiao,
| | - Jia Xiao
- Clinical Medicine Research Institute, Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China
- *Correspondence: Chengfang Xu, ; Jia Xiao,
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25
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Sun X, Cui Q, Ni J, Liu X, Zhu J, Zhou T, Huang H, OuYang K, Wu Y, Yang Z. Gut Microbiota Mediates the Therapeutic Effect of Monoclonal Anti-TLR4 Antibody on Acetaminophen-Induced Acute Liver Injury in Mice. Microbiol Spectr 2022; 10:e0064722. [PMID: 35536057 PMCID: PMC9241835 DOI: 10.1128/spectrum.00647-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies show that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the gut microbiota and their metabolic pathway, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury compared with the mice receiving feces from the APAP group. ATAB therapy also improved the gut barrier functions in mice and reduced the expression of protein zonulin. Our results revealed that gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found the monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through the change of the gut microbiota, metabolic pathways, and gut barrier function. This work suggested the gut microbiota can be the therapeutic target of the APAP-induced acute liver injury, and we performed the fundamental research for further research.
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Affiliation(s)
- Xuewei Sun
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
- Binzhou Medical Universitygrid.440653.0, Yantai, China
| | - Qian Cui
- Air Force Hospital of Eastern Theater, Nanjing, China
| | - Juan Ni
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Xiaoguang Liu
- Department of Respiratory and Critical Care Medicine, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China
| | - Jin Zhu
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
| | - Tingting Zhou
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
| | - HuaYing Huang
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Ke OuYang
- The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Yulong Wu
- Binzhou Medical Universitygrid.440653.0, Yantai, China
| | - Zhan Yang
- Centre for Diseases Prevention and Control of Eastern Theater, Nanjing, China
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26
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Moreno-Torres M, Quintás G, Castell JV. The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment. Metabolites 2022; 12:metabo12060564. [PMID: 35736496 PMCID: PMC9227129 DOI: 10.3390/metabo12060564] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/31/2022] [Accepted: 06/13/2022] [Indexed: 12/19/2022] Open
Abstract
Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, representing a major concern to the pharmaceutical industry. The current biochemical parameters for the detection of DILI are based on enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP)) and bilirubin serum levels that are not specific of DILI and therefore there is an increasing interest on novel, specific, DILI biomarkers discovery. Metabolomics has emerged as a tool with a great potential for biomarker discovery, especially in disease diagnosis, and assessment of drug toxicity or efficacy. This review summarizes the multistep approaches in DILI biomarker research and discovery based on metabolomics and the principal outcomes from the research performed in this field. For that purpose, we have reviewed the recent scientific literature from PubMed, Web of Science, EMBASE, and PubTator using the terms “metabolomics”, “DILI”, and “humans”. Despite the undoubted contribution of metabolomics to our understanding of the underlying mechanisms of DILI and the identification of promising novel metabolite biomarkers, there are still some inconsistencies and limitations that hinder the translation of these research findings into general clinical practice, probably due to the variability of the methods used as well to the different mechanisms elicited by the DILI causing agent.
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Affiliation(s)
- Marta Moreno-Torres
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain
- CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence: (M.M.-T.); (J.V.C.)
| | - Guillermo Quintás
- Unidad Analítica, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain;
- Health and Biomedicine, LEITAT Technological Center, 46026 Valencia, Spain
| | - José V. Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria Hospital La Fe, 46026 Valencia, Spain
- CIBEREHD, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
- Correspondence: (M.M.-T.); (J.V.C.)
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27
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Gu R, Liang A, Liao G, To I, Shehu A, Ma X. Roles of Cofactors in Drug-Induced Liver Injury: Drug Metabolism and Beyond. Drug Metab Dispos 2022; 50:646-654. [PMID: 35221288 PMCID: PMC9132098 DOI: 10.1124/dmd.121.000457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 02/22/2022] [Indexed: 11/22/2022] Open
Abstract
Drug-induced liver injury (DILI) remains one of the major concerns for healthcare providers and patients. Unfortunately, it is difficult to predict and prevent DILI in the clinic because detailed mechanisms of DILI are largely unknown. Many risk factors have been identified for both "intrinsic" and "idiosyncratic" DILI, suggesting that cofactors are an important aspect in understanding DILI. This review outlines the cofactors that potentiate DILI and categorizes them into two types: (1) the specific cofactors that target metabolic enzymes, transporters, antioxidation defense, immune response, and liver regeneration; and (2) the general cofactors that include inflammation, age, gender, comorbidity, gut microbiota, and lifestyle. The underlying mechanisms by which cofactors potentiate DILI are also discussed. SIGNIFICANCE STATEMENT: This review summarizes the risk factors for DILI, which can be used to predict and prevent DILI in the clinic. This work also highlights the gaps in the DILI field and provides future perspectives on the roles of cofactors in DILI.
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Affiliation(s)
- Ruizhi Gu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alina Liang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Grace Liao
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Isabelle To
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Amina Shehu
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xiaochao Ma
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences (R.G., A.S., X.M.) and School of Pharmacy (A.L., G.L., I.T.), University of Pittsburgh, Pittsburgh, Pennsylvania
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Abstract
Drug-induced liver injury, and specifically supplement-related liver injury, accounts for an increasing proportion of acute liver injury cases. We present the case of acute liver injury due to a Garcinia cambogia-containing weight-loss supplement not previously associated with liver injury. Identifying supplements as a potential cause is a key to managing acute liver injury of uncertain etiology.
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29
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Liver Injury in Patients Hospitalized for COVID-19: Possible Role of Therapy. Vaccines (Basel) 2022; 10:vaccines10020192. [PMID: 35214651 PMCID: PMC8880796 DOI: 10.3390/vaccines10020192] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/21/2022] [Accepted: 01/23/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with COVID-19 show a high prevalence of liver injury. The pattern of this liver damage is still not fully understood. Different etiopathogenetic factors may concur; from a direct cytopathic effect, once the virus binds to the ACE-2 receptors, to the immune-mediated collateral damage, due to cytokine storm. The presence of pre-existing chronic liver disease is a contributing factor for acute organ damage during SARS-CoV2 infection. Last but not least, treatments probably play a role, also, in determining hepatotoxicity: many of the drugs we have used or are still using to treat COVID-19, combined with non-invasive ventilation, are known to sometimes determine acute liver injury. Although liver damage associated with COVID-19 is often transient and can resolve without any special treatment, it is important to understand the underlying mechanisms, particularly to better treat its more severe forms.
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30
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Choudhary N, Saraf N, Kumar V, Bansal M, Kasliwal R. Drug-induced liver injury: A primer for cardiologists. JOURNAL OF CLINICAL AND PREVENTIVE CARDIOLOGY 2022. [DOI: 10.4103/jcpc.jcpc_8_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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31
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Didenko VI, Klenina IA, Tatarchuk ОM, Hrabovska OI, Petishko OP. Specificities of lipotoxicity of free fatty acids and cytokine profile in patients with chronic diffuse liver diseases. REGULATORY MECHANISMS IN BIOSYSTEMS 2021. [DOI: 10.15421/022201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Non-alcoholic fatty liver disease is an important cause of global liver disease characterized by diffuse hepatocytes with hepatocellular ballooning, intrahepatic inflammation and progressive fibrosis. A relevant task is the study of the relationship between content of free fatty acids and serum cytokine profile in patients with chronic diffuse liver diseases. A total of 74 people with chronic diffuse liver diseases were examined, including 32 patients with non-alcoholic fatty liver disease, 22 patients with alcoholic liver disease, 20 patients with toxic hepatitis. Chromatographic examination of free fatty acids (FFA) in blood serum was carried out using a Chromatek-Crystal 5000 gas chromatography system. Patients with chronic diffuse liver diseases had a significant increase in the level of unsaturated free fatty acids (USFA) in cases of toxic hepatitis (by 2.92 times, P > 0.05) and a decrease in the level of saturated free fatty acids (SFA) in cases of non-alcoholic fatty liver disease (by 1.52 times, P > 0.05) compared with the control group; the balance between omega-6 and omega-3 PUFA significantly changed due to increase in linoleic acid in patients with alcoholic liver disease and toxic hepatitis (by 1.91 and 2.11 times, respectively) and arachidonic acid in patients with toxic hepatitis (by 1.78 times). The level of interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNF-α) were determined. In patients suffering chronic diffuse liver diseases there were multidirectional changes in the composition of free fatty acids of blood serum: a significant increase in the level of USFA, levels ІL-6 in toxic hepatitis; a decrease in the level of SFA, levels ІL-6 and TNF-α during non-alcoholic fatty liver disease; increased TNF-α production, ІL-6 during alcoholic liver disease compared with the control group. Significant change occurred in the balance between omega-6 and omega-3 PUFA due to increase in linoleic acid in cases of alcoholic liver disease and toxic hepatitis and arachidonic acid in cases of toxic hepatitis. The revealed correlations support the hypothesis that inflammation and lipotoxicity of FFA of blood serum contribute to the development and progression of structural changes in the liver. However, the pathomechanism of lipid metabolism and cytokine regulation with different etiological factors have their own characteristics, which should be taken into account when treating patients of these groups. Prospects for further research: these parameters may be used for serologic biomarkers of liver disease and development and implementation of the ratio between FFA and cytokines for the differential diagnosis of chronic diffuse liver disease in medical practice.
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32
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Pais JP, Mota R, Cruz M, Cambão AR, Nascimento A. Drug-Induced Liver Injury Induced by Bioflavonoids. Cureus 2021; 13:e20453. [PMID: 35070523 PMCID: PMC8760611 DOI: 10.7759/cureus.20453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2021] [Indexed: 01/06/2023] Open
Abstract
Drug-induced liver injury (DILI) is a relatively rare disease with a vast spectre of clinical manifestations. Its diagnosis is based on the exclusion of other causes of liver disease. The identification of a causal agent is based on the temporal relation between the symptoms and their resolution after stopping the suspected drug. Many drugs have been described as causative agents of DILI; however, bioflavonoids have never been implied with an idiosyncratic DILI in the literature.
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33
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Sun L, Ouyang J, Ma Y, Zeng Z, Zeng C, Zeng F, Wu S. An Activatable Probe with Aggregation-Induced Emission for Detecting and Imaging Herbal Medicine Induced Liver Injury with Optoacoustic Imaging and NIR-II Fluorescence Imaging. Adv Healthc Mater 2021; 10:e2100867. [PMID: 34160144 DOI: 10.1002/adhm.202100867] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 06/06/2021] [Indexed: 12/15/2022]
Abstract
Whilte herbal medicines are widely used for health promotion and therapy for chronic conditions, inappropriate use of them may cause adverse effects like liver injury, and accurately evaluating their hepatotoxicity is of great significance for public health. Herein, an activatable probe QY-N for diagnosing herbal-medicine-induced liver injury by detecting hepatic NO with NIR-II fluorescence and multispectral optoacoustic tomography (MSOT) imaging is demonstrated. The probe includes a bismethoxyphenyl-amine-containing dihydroxanthene serving as electron donor, a quinolinium as electron acceptor, and a butylamine as recognition group and fluorescence quencher. The hepatic level of NO reacts with butylamine, thereby generating the activated probe QY-NO which exhibits a red-shifted absorption band (700-850 nm) for optoacoustic imaging and generates strong emission (910-1110 nm) for NIR-II fluorescence imaging. QY-NO is aggregation-induced-emission (AIE) active, which ensures strong emission in aggregated state. QY-N is utilized in the triptolide-induced liver injury mouse model, and experimental results demonstrate the QY-N can be activated by hepatic NO and thus be used in detecting herbal-medicine-induced liver injury. The temporal and spatial information provided by three-dimensional MSOT images well delineates the site and size of liver injury. Moreover, QY-N has also been employed to monitor rehabilitation of liver injury during treatment process.
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Affiliation(s)
- Lihe Sun
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Juan Ouyang
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Yunqing Ma
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Zhuo Zeng
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Cheng Zeng
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Fang Zeng
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
| | - Shuizhu Wu
- State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates College of Materials Science and Engineering South China University of Technology Guangzhou 510640 China
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34
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Rhabdomyolysis due to rosuvastatin in a patient with ROHHAD syndrome. J Clin Lipidol 2021; 15:789-792. [PMID: 34600840 DOI: 10.1016/j.jacl.2021.09.002] [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: 05/12/2021] [Revised: 09/01/2021] [Accepted: 09/05/2021] [Indexed: 10/20/2022]
Abstract
We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.
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35
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Bhardwaj M, Bhardwaj NJ, Cueto K, Killeen TC. Hydralazine-induced liver injury: a review and discussion. BMJ Case Rep 2021; 14:e243278. [PMID: 34404652 PMCID: PMC8375716 DOI: 10.1136/bcr-2021-243278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2021] [Indexed: 01/25/2023] Open
Abstract
Hydralazine is a commonly prescribed antihypertensive agent. Some of its labelled adverse reactions include lupus-like syndrome, tachycardia, headache and fever. Despite its well-known side effects, little is known about hydralazine's hepatotoxic effects. We report the case of a 54-year-old female patient who was started on hydralazine for hypertension management but later presented with hydralazine-induced liver injury. Her initial presentation consisted of non-specific symptoms and a hepatocellular injury pattern. Liver biopsy revealed hepatic steatosis. Three weeks after discontinuation of hydralazine, the patient's liver enzymes normalised, and her symptoms resolved. Few studies have examined the incidence and mechanism by which hydralazine induces a liver injury pattern. With this case, we review the literature, the pathogenesis involved and the eventual management of hydralazine-induced liver injury. We propose close monitoring of liver enzymes for patients on hydralazine throughout their treatment course.
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Affiliation(s)
- Meeta Bhardwaj
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Nakul Jay Bhardwaj
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Kendra Cueto
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - T Colin Killeen
- Department of Internal Medicine and Geriatrics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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36
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De Martin E, Duclos-Vallée JC. Reply to: "Acute severe autoimmune hepatitis - timing for steroids and role of other immunosuppressive agents". J Hepatol 2021; 75:495-496. [PMID: 34051331 DOI: 10.1016/j.jhep.2021.05.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 05/05/2021] [Indexed: 12/25/2022]
Affiliation(s)
- Eleonora De Martin
- Centre Hepato-Biliaire, Hôpital Paul-Brousse, FHU Hepatinov, INSERM Unit UMR 1193, Univ Paris-Saclay, France.
| | - Jean-Charles Duclos-Vallée
- Centre Hepato-Biliaire, Hôpital Paul-Brousse, FHU Hepatinov, INSERM Unit UMR 1193, Univ Paris-Saclay, France
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37
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Kamath P, Kamath A, Ullal SD. Liver injury associated with drug intake during pregnancy. World J Hepatol 2021; 13:747-762. [PMID: 34367496 PMCID: PMC8326163 DOI: 10.4254/wjh.v13.i7.747] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/14/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Drug use during pregnancy is not common. Drug-induced liver injury (DILI) is a potential complication that is rare but can adversely affect both the mother and the fetus. Although many drugs can directly cause hepatotoxicity, idiosyncratic liver injury is common in pregnancy. Underreporting of adverse drug reactions, lack of adequate literature regarding drug safety in pregnancy, and the inherent difficulty in diagnosing DILI during pregnancy make the management of this condition challenging. This review attempts to describe the existing literature regarding DILI in pregnancy, which is mainly in the form of case reports; several studies have looked at the safety of antithyroid drugs, antiretroviral drugs, and paracetamol, which have an indication for use in pregnancy; the relevant data from these studies with regard to DILI has been presented. In addition, the review describes the diagnosis of DILI, grading the disease severity, assessment of causality linking the drug to the adverse event, regulatory guidelines for evaluating the potential of drugs to cause liver injury, efforts to ensure better participation of women in clinical trials and studies in pregnant women population in particular, and the challenges involved in generating adequate research evidence. The establishment of DILI registries in various countries is an encouraging development; however, there is a need for promoting active, spontaneous reporting of adverse events during pregnancy to ensure rapid generation of evidence regarding the safety of a drug in pregnant women.
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Affiliation(s)
- Priyanka Kamath
- Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India - 575001
| | - Ashwin Kamath
- Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India - 575001.
| | - Sheetal D Ullal
- Department of Pharmacology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, Karnataka, India - 575001
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38
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Neuberger J, Cain O. The Need for Alternatives to Liver Biopsies: Non-Invasive Analytics and Diagnostics. Hepat Med 2021; 13:59-69. [PMID: 34163263 PMCID: PMC8214024 DOI: 10.2147/hmer.s278076] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
Histology remains essential for the diagnosis and management of many disorders affecting the liver. However, the biopsy procedure itself is associated with a low risk of harm to the patient and cost to the health services; samples may not be adequate and are subject to sampling variation. Furthermore, interpretation often depends on the skill of the pathologist. Increasingly, new techniques are becoming available that are altering the indications for liver biopsy. Many diseases of the liver can be diagnosed and managed using serological and radiological techniques; the degree of fibrosis and fat can often be assessed by serological or imaging techniques and the nature of space occupying lesions defined by serology, imaging and use of liquid biopsy. However, these techniques, too, are subject to limitations: sensitivity and specificity is not always adequate for diagnosis or management; some techniques are expensive and often also require expert interpretation. Although there may be less need for liver biopsy today, histology remains the gold standard as well as an essential tool for the diagnosis and management of many conditions, especially where there are multiple pathologies, or where a diagnosis cannot or has not been made by alternative approaches. Until less invasive techniques become more reliable and accessible, liver histology will remain a key investigation.
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Affiliation(s)
- James Neuberger
- Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
| | - Owen Cain
- Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK
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Masson W, Lobo M, Masson G, Molinero G, Casciato P. Statin use in patients with elevated serum hepatic transaminases at baseline: A meta-analysis. Nutr Metab Cardiovasc Dis 2021; 31:1357-1364. [PMID: 33715945 DOI: 10.1016/j.numecd.2021.01.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 12/01/2020] [Accepted: 01/28/2021] [Indexed: 12/19/2022]
Abstract
AIMS Clinical trials showed that statin therapy decreased cardiovascular events without significantly raising the level of transaminases. However, the information in subjects with altered liver test at baseline is more limited. The objectives of this meta-analysis were to analyze the liver safety and cardiovascular benefit when using a statin-based lipid-lowering treatment compared to a less intensive treatment or placebo, in subjects with abnormal liver tests at baseline. DATA SYNTHESIS We performed a meta-analysis including randomized trials of statin-based lipid-lowering therapy versus less intensive lipid-lowering therapy or placebo, reporting worsening hepatic test (>3 ULN) and cardiovascular events in patients with abnormal liver tests at baseline. The random-effects model was performed. This meta-analysis was performed according to PRISMA guidelines. Five eligible trials, including 2548 patients were identified and considered eligible for the analyses. A more intensive statin-based lipid-lowering therapy were associated with a similar occurrence of serious alteration of liver tests (OR: 0.90, 95% confidence interval: 0.21-3.99; I2: 64%) compared to less intensive or placebo treatments. Likewise, more intensive lipid-lowering strategies were associated with a significant reduction in major cardiovascular events (OR: 0.34, 95% confidence interval: 0.17-0.70; I2: 66%). CONCLUSIONS In this study, a more intensive statin-based lipid-lowering treatment, compared with less intensive treatment or placebo, showed a similar incidence of worsening transaminases levels in patients with abnormal liver tests at baseline. Also, a reduction in cardiovascular events was observed when a more intensive lipid-lowering therapy was used.
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Affiliation(s)
- Walter Masson
- Council of Epidemiology and Cardiovascular Prevention, Argentine Society of Cardiology, Azcuenaga 980, Buenos Aires, Argentina; Cardiology Department, Hospital Italiano de Buenos Aires, Tte. Gral. Juan Domingo Perón 4190, Buenos Aires, Argentina.
| | - Martín Lobo
- Council of Epidemiology and Cardiovascular Prevention, Argentine Society of Cardiology, Azcuenaga 980, Buenos Aires, Argentina; Cardiology Department, Hospital Militar Campo de Mayo, Tte. Gral. Ricchieri S/N, Buenos Aires, Argentina
| | - Gerardo Masson
- Council of Epidemiology and Cardiovascular Prevention, Argentine Society of Cardiology, Azcuenaga 980, Buenos Aires, Argentina; Cardiology Department, Instituto Cardiovascular San Isidro - Sanatorio Las Lomas, Von Wernicke 3031, San Isidro, Argentina
| | - Graciela Molinero
- Council of Epidemiology and Cardiovascular Prevention, Argentine Society of Cardiology, Azcuenaga 980, Buenos Aires, Argentina
| | - Paola Casciato
- Hepatology Unit, Hospital Italiano de Buenos Aires, Tte. Gral. Juan Domingo Perón 4190, Buenos Aires, Argentina
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ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol 2021; 116:878-898. [PMID: 33929376 DOI: 10.14309/ajg.0000000000001259] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
Idiosyncratic drug-induced liver injury (DILI) is common in gastroenterology and hepatology practices, and it can have multiple presentations, ranging from asymptomatic elevations in liver biochemistries to hepatocellular or cholestatic jaundice, liver failure, or chronic hepatitis. Antimicrobials, herbal and dietary supplements, and anticancer therapeutics (e.g., tyrosine kinase inhibitors or immune-checkpoint inhibitors) are the most common classes of agents to cause DILI in the Western world. DILI is a diagnosis of exclusion, and thus, careful assessment for other etiologies of liver disease should be undertaken before establishing a diagnosis of DILI. Model for end-stage liver disease score and comorbidity burden are important determinants of mortality in patients presenting with suspected DILI. DILI carries a mortality rate up to 10% when hepatocellular jaundice is present. Patients with DILI who develop progressive jaundice with or without coagulopathy should be referred to a tertiary care center for specialized care, including consideration for potential liver transplantation. The role of systemic corticosteroids is controversial, but they may be administered when a liver injury event cannot be distinguished between autoimmune hepatitis or DILI or when a DILI event presents with prominent autoimmune hepatitis features.
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Khatib S, Sabobeh T, Bock MD, Masoud A, Alallaf J. Nafcillin-Induced Hepatic Injury: A Case Report and Literature Review. Cureus 2021; 13:e12817. [PMID: 33628683 PMCID: PMC7894250 DOI: 10.7759/cureus.12817] [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] [Indexed: 11/18/2022] Open
Abstract
Background: Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Western world. While it requires a diagnosis of exclusion, it is exceedingly prevalent in patients taking multiple hepatotoxic agents, the foremost of which are antibiotics, followed by herbal and dietary supplements. Below we will discuss a case of nafcillin-induced liver injury suggested by a thorough work-up and rule-out of other hepatic and biliary pathologies. Case presentation: We report the case of a 66-year-old white male who presented with painless jaundice. Clinical, laboratory and radiographic features demonstrated a cholestatic pattern of liver injury without significant abnormalities in the biliary tract. All workup for viral hepatitis and autoimmune diseases with liver involvement was negative. Liver biopsy showed acute necro-inflammatory changes suggestive of drug-induced liver injury. The patient had received 18 days of IV nafcillin for blood culture positive methicillin-susceptible Staphylococcus aureus (MSSA) four weeks prior to his presentation. He showed clinical and laboratory improvement of his liver functions with supportive care only. Conclusion: Nafcillin is a safe and effective antibiotic for the treatment of methicillin-susceptible Staphylococcal infections. However, physicians and prescribing healthcare professionals should be aware of the rare, but serious side effects, especially one of drug-induced liver injury with emphasis on the need for early cessation of nafcillin if liver function abnormalities develop.
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Affiliation(s)
- Sohaib Khatib
- Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Taher Sabobeh
- Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Michael D Bock
- Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Amgad Masoud
- Internal Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA
| | - Jwan Alallaf
- Pathology, University of Missouri Kansas City School of Medicine, Kansas City, USA
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Schneider KM, Elfers C, Ghallab A, Schneider CV, Galvez EJC, Mohs A, Gui W, Candels LS, Wirtz TH, Zuehlke S, Spiteller M, Myllys M, Roulet A, Ouzerdine A, Lelouvier B, Kilic K, Liao L, Nier A, Latz E, Bergheim I, Thaiss CA, Hengstler JG, Strowig T, Trautwein C. Intestinal Dysbiosis Amplifies Acetaminophen-Induced Acute Liver Injury. Cell Mol Gastroenterol Hepatol 2020; 11:909-933. [PMID: 33189892 PMCID: PMC7900526 DOI: 10.1016/j.jcmgh.2020.11.002] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 10/31/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. METHODS To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6-/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. RESULTS Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3-3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response. CONCLUSIONS Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF.
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Affiliation(s)
- Kai Markus Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Microbiology; Institute for Immunology; and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carsten Elfers
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany; Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | | | - Eric J C Galvez
- Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover Medical School, Hannover, Germany
| | - Antje Mohs
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Wenfang Gui
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | | | | | - Sebastian Zuehlke
- Department of Chemistry and Chemical Biology, Institute of Experimental Research (INFU), TU Dortmund University, Dortmund, Germany
| | - Michael Spiteller
- Department of Chemistry and Chemical Biology, Institute of Experimental Research (INFU), TU Dortmund University, Dortmund, Germany
| | - Maiju Myllys
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | | | | | | | - Konrad Kilic
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Lijun Liao
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Anika Nier
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Eicke Latz
- Institute for Innate Immunity, University of Bonn, Bonn, Germany
| | - Ina Bergheim
- Department of Nutritional Sciences, R.F. Molecular Nutritional Science, University of Vienna, Vienna, Austria
| | - Christoph A Thaiss
- Department of Microbiology; Institute for Immunology; and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors at the Technical University Dortmund, Dortmund, Germany
| | - Till Strowig
- Helmholtz Centre for Infection Research, Braunschweig, Germany; and Hannover Medical School, Hannover, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
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