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Drees A, Nassiri V, Tabernilla A, Serroyen J, Gustin E, Dos Santos Rodrigues B, Moss DM, De Smedt A, Vinken M, Van Goethem F, Sanz-Serrano J. Optimization of the drug-induced cholestasis index based on advanced modeling for predicting liver toxicity. Toxicology 2025; 514:154119. [PMID: 40107378 DOI: 10.1016/j.tox.2025.154119] [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: 09/30/2024] [Revised: 03/11/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
Cholestatic drug-induced liver injury (cDILI) is a frequent reason for drug failure and withdrawal during premarketing and postmarketing stages of drug development. Strategies for reliable detection of cDILI in early drug development are therefore urgently needed. The drug-induced cholestasis index (DICI) concept was previously introduced as a tool for assessing the cholestatic potential of drug candidates. DICI is calculated as the ratio between the viability values obtained in drug-treated liver cells in the presence and absence of bile acids. The present in vitro study was set up to investigate the applicability of DICI in a novel high-throughput and large sample setting. Furthermore, the improvement of the predictivity of the DICI by introduction of advanced modeling was explored. Fifty-eight well-documented drugs were selected and categorized as drugs inducing cDILI, non-cholestatic DILI (ncDILI), and not inducing DILI (non-DILI). Cultures of human hepatoma HepaRG cells in 3D spheroid configuration were exposed to 9 half-log concentrations of each drug for 1, 3 and 7 days in the absence or presence of a concentrated mixture of human bile acids. The highest concentration of each drug was based on solubility and the maximum concentrations in human plasma (total Cmax). DICI values were computed for all drugs and time points. In addition, the area under the curve ratio and the occurrence of a trend in the cytotoxicity profiles were included as modeling descriptors. As such, 3 time-related scenarios were considered upon modeling, while categories were modeled on a nominal or an ordinal scale. Applying DICI with a cut-off value of 0.8 resulted in a high sensitivity for the cDILI class, but in turn, a low sensitivity for the non- DILI class. From the 28 predictive models generated, the best performing models integrated all descriptors and the ordinal scale for either the 7-day time point from a 3-time-point model or the 3-day time point. While these models were unable to accurately identify ncDILI drugs, the 7-day time point identified 84 % of the cDILI drugs and the 3-day time point correctly identified 94 % of non-DILI drugs. Based on the obtained results, it can be concluded that the reported DICI modeling provides an optimized approach that could be applied in an integrated DILI testing strategy.
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Affiliation(s)
- Annika Drees
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium
| | | | - Andrés Tabernilla
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium
| | - Jan Serroyen
- Janssen R&D, Statistics & Decision Sciences, Belgium
| | | | | | | | - Ann De Smedt
- Janssen R&D, Preclinical Sciences and Translational Safety, Belgium
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium
| | - Freddy Van Goethem
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium; Janssen R&D, Preclinical Sciences and Translational Safety, Belgium
| | - Julen Sanz-Serrano
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium.
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Chen Q, Kong D, Liu X. Secondary sclerosing cholangitis due to drug-induced liver injury: a retrospective cohort study. Eur J Gastroenterol Hepatol 2025; 37:343-349. [PMID: 39621869 DOI: 10.1097/meg.0000000000002902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
BACKGROUND The main objective of our study was to assess the frequency of drug-induced liver injury (DILI) patients with coexisting secondary sclerosing cholangitis (SSC) within our center and then analyze clinical features of these patients. SSC has received limited attention in the context of DILI. These changes can be observed on magnetic resonance cholangiopancreatography (MRCP). METHODS We conducted a single-center retrospective cohort study involving 185 consecutive patients diagnosed with DILI between January 2020 and August 2024. We reviewed MRCP images of 81 available patients. RESULTS Among the 185 patients, 81 underwent MRCP and 14 patients (17.3%) were diagnosed with SSC. Nine (64.3%) of 14 were diagnosed with biliary strictures in extrahepatic bile ducts, and 11 of 14 patients (78.6%) displayed segmental distribution. The SSC group showed higher peak alkaline phosphatase (ALP) values (660 vs. 290 U/l, P = 0.015), longer resolution time (114 vs. 61 days, P = 0.038), and a higher frequency of chronic injury (35.7% vs. 10.4%, P = 0.016). Multivariate logistic regression analysis identified peak ALP values as a risk factor for SSC [odds ratio = 1.002 (1.000-1.005), P = 0.030]. CONCLUSION The prevalence of drug-related SSC has noticeably increased in recent years. The higher peak ALP values potentially associated with an increased risk of drug-related SSC onset.
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Affiliation(s)
- Qiannan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
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Vitale G, Sciveres M, Mandato C, d'Adamo AP, Di Giorgio A. Genotypes and different clinical variants between children and adults in progressive familial intrahepatic cholestasis: a state-of-the-art review. Orphanet J Rare Dis 2025; 20:80. [PMID: 39984942 PMCID: PMC11846186 DOI: 10.1186/s13023-025-03599-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/06/2025] [Indexed: 02/23/2025] Open
Abstract
INTRODUCTION Progressive Familial intrahepatic cholestasis (PFIC) are rare disorders of bile acid (BAs) secretion and transport with a genetic background. PFIC are paediatric manifestations, but the same variants causing PFIC can also cause cholestasis with a later paediatric onset or adult-onset cholestatic disease (AOCD). Pruritus is a symptom of cholestasis that can be so devastating that it requires a liver transplant (LT) in children; some PFIC types have been described as at risk of liver cancer development. Commonly prescribed medications for PFIC symptoms can partially relieve pruritus without changing the natural history of the disease. Recently, a therapy reducing the intestinal resorption of BAs has been approved; it is effective on both pruritus and cholestasis in PFIC, potentially being a disease-modifying intervention. AREAS COVERED The clinical and genetic characteristics of different PFIC and AOCD are summarized to provide a common background for geneticists and paediatric and adult hepatologists in diagnosis and management. EXPERT OPINION Collaboration between paediatric and adult hepatologists and geneticists will become crucial for cholestatic disease research and patient treatment. Therefore, adult hepatologists will need to learn more about FIC. This might enable the implementation of individualized surveillance in FIC patients and the evaluation of patient family histories.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Marco Sciveres
- Epatologia e Clinica dei Trapianti, Ospedale Pediatrico IRCCS Bambino Gesù, Rome, Italy
| | - Claudia Mandato
- Dipartimento di Medicina, Chirurgia e Odontoiatria "Scuola Medica Salernitana", Section of Pediatrics, Baronissi (Salerno), Italy
| | - Adamo Pio d'Adamo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo"-Trieste, 34137, Trieste, Italy.
| | - Angelo Di Giorgio
- Pediatric Hepatology Gastroenterology and Transplantation, Hospital Papa Giovanni XIII, Bergamo, Italy
- Department of Medicine, Hospital Santa Maria della Misericordia, University of Udine, Udine, Italy
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Khot R, Shelman NR, Ludwig DR, Nair RT, Anderson MA, Venkatesh SK, Paspulati RM, Parker RA, Menias CO. Acquired ductopenia: an insight into imaging findings. Abdom Radiol (NY) 2025; 50:152-168. [PMID: 38954003 PMCID: PMC11711635 DOI: 10.1007/s00261-024-04462-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 06/15/2024] [Indexed: 07/04/2024]
Abstract
Hepatic ductopenia is a pathologic diagnosis characterized by a decrease in the number of intrahepatic bile ducts as a consequence of various underlying etiologies. Some etiologies, such as primary sclerosing cholangitis, primary biliary cholangitis, and ischemic cholangitis, often have distinctive imaging findings. In contrast, other causes such as chronic rejection following liver transplantation, drug-induced biliary injury, infection, malignancy such as lymphoma, and graft-versus-host disease may only have ancillary or non-specific imaging findings. Thus, diagnosing ductopenia in conditions with nonspecific imaging findings requires a multidimensional approach, including clinical evaluation, serological testing, imaging, and liver histology to identify the underlying cause. These etiologies lead to impaired bile flow, resulting in cholestasis, liver dysfunction, and, ultimately, cirrhosis and liver failure if the underlying cause remains untreated or undetected. In the majority of instances, individuals diagnosed with ductopenia exhibit a positive response to treatment addressing the root cause or cessation of the causative agent. This article focuses on acquired causes of ductopenia, its clinical manifestation, histopathology, imaging diagnosis, and management.
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Affiliation(s)
- Rachita Khot
- Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
| | - Nathan R Shelman
- Department of Pathology, University of Kentucky, Lexington, KY, USA
| | - Daniel R Ludwig
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Rashmi T Nair
- Department of Radiology, University of Kentucky, Lexington, KY, USA
| | - Mark A Anderson
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sudhakar K Venkatesh
- Division of Abdominal Imaging, Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Raj Mohan Paspulati
- Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Rex A Parker
- University of Kansas Medical Center, Kansas City, KS, USA
| | - Christine O Menias
- Division of Abdominal Imaging, Department of Radiology, Mayo Clinic, Scottsdale, AZ, USA
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Wang R, Li Y, Xia X. Severe liver injury induced by minocycline in hepatitis B patient: a Case Report. Front Pharmacol 2024; 15:1516217. [PMID: 39749206 PMCID: PMC11693611 DOI: 10.3389/fphar.2024.1516217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 12/06/2024] [Indexed: 01/04/2025] Open
Abstract
Physical liver injury is an acute and potentially serious adverse event that may result in acute liver failure or even death. Diagnosis is often challenging. Minocycline, a semi-synthetic second-generation tetracycline, has high fat solubility and good tissue permeability. It is widely used for acne treatment. This report presents a 32-year-old female hepatitis B carrier who took minocycline (50 mg twice daily) for acne. After 1 week, she experienced fatigue, jaundice, abdominal bloating, and discomfort. Upon admission, laboratory tests revealed significantly elevated transaminase levels, ascites on abdominal ultrasonography, positive hepatitis B markers, impaired coagulation function, and a final diagnosis of subacute liver failure with chronic hepatitis B. Following discontinuation of minocycline and initiation of liver enzyme protection therapy, the patient's liver and coagulation functions improved after undergoing artificial liver therapy combined with CRRT. This case highlights a rare occurrence of minocycline-induced liver injury in a hepatitis B carrier, emphasizing that acute liver injury is a potential and serious adverse effect of minocycline, particularly in patients with pre-existing liver disease.
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Affiliation(s)
| | | | - Xue Xia
- Pharmacy Department Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, Jiangsu Province, China
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Teka T, Wu J, Oduro PK, Li Z, Wang C, Chen H, Zhang L, Wang H, Wang L, Han L. Integrated multi-omics analyses combined with western blotting discovered that cis-TSG alleviated liver injury via modulating lipid metabolism. Front Pharmacol 2024; 15:1485035. [PMID: 39635428 PMCID: PMC11614611 DOI: 10.3389/fphar.2024.1485035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Background: Polygonum multiflorum shows dual hepatoprotective and hepatotoxic effects. The bioactive components responsible for these effects are unknown. This study investigates whether cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (cis-TSG), a stilbene glycoside, has hepatoprotective and/or hepatotoxic effects in a liver injury model. Methods: C57BL/6J mice were administered α-naphthylisothiocyanate (ANIT) to induce cholestasis, followed by treatment with cis-TSG. Hepatoprotective and hepatotoxic effects were assessed using serum biomarkers, liver histology, and metabolomic and lipidomic profiling. Transcriptomic analysis were conducted to explore gene expression changes associated with lipid and bile acid metabolism, inflammation, and oxidative stress. Results and Discussion: ANIT administration caused significant liver injury, evident from elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and dysregulated lipid metabolism. cis-TSG treatment markedly reduced ALT and AST levels, normalized lipid profiles, and ameliorated liver damage, as seen histologically. Metabolomic and lipidomic analyses revealed that cis-TSG influenced key pathways, notably glycerophospholipid metabolism, sphingolipid metabolism, and bile acid biosynthesis. The treatment with cis-TSG increased monounsaturated and polyunsaturated fatty acids (MUFAs and PUFAs), enhancing peroxisome proliferator-activated receptor alpha (PPARα) activity. Transcriptomic data confirmed these findings, showing the downregulation of genes linked to lipid metabolism, inflammation, and oxidative stress in the cis-TSG-treated group. The findings suggest that cis-TSG has a hepatoprotective effect through modulation of lipid metabolism and PPARα activation.
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Affiliation(s)
- Tekleab Teka
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Pharmacy, Wollo University, Dessie, Ethiopia
| | - Jiang Wu
- Shenzhen Technology University, Shenzhen, China
| | - Patrick Kwabena Oduro
- Jacobs School of Medicine and Biomedical Sciences, The State University of New York, University at Buffalo, Buffalo, NY, United States
| | - Ze Li
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chenxi Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Chen
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lin Zhang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haitao Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Liming Wang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
| | - Lifeng Han
- State Key Laboratory of Component-based Chinese Medicine, Tianjin Key Laboratory of TCM Chemistry and Analysis, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
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Lv X, Liu Y, Liu S, Liu Y, Qu Y, Cai Q. Metabonomics and pharmacodynamics studies of Gentiana radix and wine-processed Gentiana radix in damp-heat jaundice syndrome rats. JOURNAL OF ETHNOPHARMACOLOGY 2024; 332:118291. [PMID: 38705427 DOI: 10.1016/j.jep.2024.118291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gentiana radix (GR) and wine-processed Gentiana radix (WGR) have been commonly used in folk medicine for the treatment of bile or liver disorders, including jaundice, hepatitis, swelling and inflammation for thousands of years. However, the therapeutic effects of gentian root (GR) and wine-made gentian root (WGR) treatment on damp-heat jaundice syndrome (DHJS) have not been studied in animal experiments. AIM OF THE STUDY This study aimed to investigate the protective effects and mechanisms of GR and WGR on DHJS in rats. MATERIALS AND METHODS In a high-fat and high-sugar diet in a humidified hot environment, hepatic injury induced by giving alpha-naphthalene isothiocyanate (ANIT) in rats were used as a DHJS model. Histological analysis, enzyme-linked immunosorbent assay (ELISA), PCR analysis, and metabolomics were used to elucidate the mechanism of GR and WGR for DHJS. RESULTS The results indicated that GR and WGR affected DHJS by inhibiting the release of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), direct bilirubin (D-BIL), total bilirubin (TBIL), total bile acid (TBA), malondialdehyde (MDA), glutathione S-transferase (GST) (P < 0.05). In addition, they significantly reduced the gene expression levels of Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BESP), multidrug resistance-associated protein 2 (MRP2) and multidrug resistance-associated protein 3 (MRP3) (P < 0.05). The WGR group improved the above function indicators better than the GR group. GR and WGR could restore 11 potential biomarkers in rats with DHJS tended to return to normal levels, these biomarkers were involved in arachidonic acid metabolism, steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, porphyrin and chlorophyll metabolism, retinol metabolism, arginine biosynthesis. The results of the metabolic pathway showed that WGR was significantly better than GR in the improvement of porphyrin and chlorophyll metabolism. CONCLUSIONS These findings suggest that treatment with GR and WGR has a beneficial effect on DHJS in rats, the major mechanisms may be involved in improving functional indicators of the body and endogenous metabolism, and WGR is more effective than GR. It provides important evidence for the clinical application of GR and WGR in the treatment of DHJS.
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Affiliation(s)
- Xin Lv
- Department of Chinese Medicinal Chemistry, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77, 1st Life Road, D D Port, Dalian, 116600, People's Republic of China; Department of Chemical Engineering and Technology, School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, 2, Dagong Road, Liaodongwan New District, Panjin, 124221, People's Republic of China
| | - Yangzhi Liu
- Department of Chinese Medicinal Chemistry, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77, 1st Life Road, D D Port, Dalian, 116600, People's Republic of China; Department of Chemical Engineering and Technology, School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, 2, Dagong Road, Liaodongwan New District, Panjin, 124221, People's Republic of China
| | - Shujing Liu
- Shenyang Institute for Food and Drug Control, 67, Qiuyue Lake Street, Shenbei New District, Shenyang, 110122, People's Republic of China
| | - Yuhan Liu
- Department of Chinese Medicinal Chemistry, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77, 1st Life Road, D D Port, Dalian, 116600, People's Republic of China
| | - Yang Qu
- Department of Chinese Medicinal Chemistry, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77, 1st Life Road, D D Port, Dalian, 116600, People's Republic of China.
| | - Qian Cai
- Department of Chinese Medicinal Chemistry, School of Pharmacy, Liaoning University of Traditional Chinese Medicine, 77, 1st Life Road, D D Port, Dalian, 116600, People's Republic of China.
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Zhang X, Geng Q, Lin L, Zhang L, Shi C, Liu B, Yan L, Cao Z, Li L, Lu P, Tan Y, He X, Zhao N, Li L, Lu C. Insights gained into the injury mechanism of drug and herb induced liver injury in the hepatic microenvironment. Toxicology 2024; 507:153900. [PMID: 39079402 DOI: 10.1016/j.tox.2024.153900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
Drug-Induced Liver Injury (DILI) and herb Induced Liver Injury (HILI) continues to pose a substantial challenge in both clinical practice and drug development, representing a grave threat to patient well-being. This comprehensive review introduces a novel perspective on DILI and HILI by thoroughly exploring the intricate microenvironment of the liver. The dynamic interplay among hepatocytes, sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, cholangiocytes, and the intricate vascular network assumes a central role in drug metabolism and detoxification. Significantly, this microenvironment is emerging as a critical determinant of susceptibility to DILI and HILI. The review delves into the multifaceted interactions within the liver microenvironment, providing valuable insights into the complex mechanisms that underlie DILI and HILI. Furthermore, we discuss potential strategies for mitigating drug-induced liver injury by targeting these influential factors, emphasizing their clinical relevance. By highlighting recent advances and future prospects, our aim is to shed light on the promising avenue of leveraging the liver microenvironment for the prevention and mitigation of DILI and HILI. This deeper understanding is crucial for advancing clinical practices and ensuring patient safety in the realm of DILI and HILI.
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Affiliation(s)
- Xiaomeng Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qi Geng
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Lin
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lulu Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Changqi Shi
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bin Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lan Yan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiwen Cao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Peipei Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yong Tan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
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de Bruijn VMP, Rietjens IMCM. From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based kinetic modeling. Arch Toxicol 2024; 98:3077-3095. [PMID: 38755481 PMCID: PMC11324677 DOI: 10.1007/s00204-024-03775-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/25/2024] [Indexed: 05/18/2024]
Abstract
Cholestasis is characterized by hepatic accumulation of bile acids. Clinical manifestation of cholestasis only occurs in a small proportion of exposed individuals. The present study aims to develop a new approach methodology (NAM) to predict drug-induced cholestasis as a result of drug-induced hepatic bile acid efflux inhibition and the resulting bile acid accumulation. To this end, hepatic concentrations of a panel of drugs were predicted by a generic physiologically based kinetic (PBK) drug model. Their effects on hepatic bile acid efflux were incorporated in a PBK model for bile acids. The predicted bile acid accumulation was used as a measure for a drug's cholestatic potency. The selected drugs were known to inhibit hepatic bile acid efflux in an assay with primary suspension-cultured hepatocytes and classified as common, rare, or no for cholestasis incidence. Common cholestasis drugs included were atorvastatin, chlorpromazine, cyclosporine, glimepiride, ketoconazole, and ritonavir. The cholestasis incidence of the drugs appeared not to be adequately predicted by their Ki for inhibition of hepatic bile acid efflux, but rather by the AUC of the PBK model predicted internal hepatic drug concentration at therapeutic dose level above this Ki. People with slower drug clearance, a larger bile acid pool, reduced bile salt export pump (BSEP) abundance, or given higher than therapeutic dose levels were predicted to be at higher risk to develop drug-induced cholestasis. The results provide a proof-of-principle of using a PBK-based NAM for cholestasis risk prioritization as a result of transporter inhibition and identification of individual risk factors.
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Affiliation(s)
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University and Research, Wageningen, The Netherlands.
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Winiarska-Mieczan A, Jachimowicz-Rogowska K, Kwiecień M, Borsuk-Stanulewicz M, Tomczyk-Warunek A, Stamirowska-Krzaczek E, Purwin C, Stryjecka M, Tomaszewska M. Regular Consumption of Green Tea as an Element of Diet Therapy in Drug-Induced Liver Injury (DILI). Nutrients 2024; 16:2837. [PMID: 39275155 PMCID: PMC11396919 DOI: 10.3390/nu16172837] [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: 08/07/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/16/2024] Open
Abstract
The liver is a highly metabolically active organ, and one of the causes of its dysfunction is the damage caused by drugs and their metabolites as well as dietary supplements and herbal preparations. A common feature of such damage is drugs, which allows it to be defined as drug-induced liver injury (DILI). In this review, we analysed available research findings in the global literature regarding the effects of green tea and/or its phenolic compounds on liver function in the context of protective action during prolonged exposure to xenobiotics. We focused on the direct detoxifying action of epigallocatechin gallate (EGCG) in the liver, the impact of EGCG on gut microbiota, and the influence of microbiota on liver health. We used 127 scientific research publications published between 2014 and 2024. Improving the effectiveness of DILI detection is essential to enhance the safety of patients at risk of liver damage and to develop methods for assessing the potential hepatotoxicity of a drug during the research phase. Often, drugs cannot be eliminated, but appropriate nutrition can strengthen the body and liver, which may mitigate adverse changes resulting from DILI. Polyphenols are promising owing to their strong antioxidant and anti-inflammatory properties as well as their prebiotic effects. Notably, EGCG is found in green tea. The results of the studies presented by various authors are very promising, although not without uncertainties. Therefore, future research should focus on elucidating the therapeutic and preventive mechanisms of polyphenols in the context of liver health through the functioning of gut microbiota affecting overall health, with particular emphasis on epigenetic pathways.
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Affiliation(s)
- Anna Winiarska-Mieczan
- Institute of Animal Nutrition and Bromatology, Department of Bromatology and Nutrition Physiology, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland
- Institute of Human Nutrition and Agriculture, The University College of Applied Sciences in Chełm, Pocztowa 54, 22-100 Chełm, Poland
| | - Karolina Jachimowicz-Rogowska
- Institute of Animal Nutrition and Bromatology, Department of Bromatology and Nutrition Physiology, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland
| | - Małgorzata Kwiecień
- Institute of Animal Nutrition and Bromatology, Department of Bromatology and Nutrition Physiology, University of Life Sciences in Lublin, Akademicka 13, 20-950 Lublin, Poland
| | - Marta Borsuk-Stanulewicz
- Department of Animal Nutrition and Feed Science, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
| | - Agnieszka Tomczyk-Warunek
- Laboratory of Locomotor Systems Research, Department of Rehabilitation and Physiotherapy, Medical University of Lublin, Jaczewskiego 8, 20-954 Lublin, Poland
| | - Ewa Stamirowska-Krzaczek
- Institute of Human Nutrition and Agriculture, The University College of Applied Sciences in Chełm, Pocztowa 54, 22-100 Chełm, Poland
| | - Cezary Purwin
- Department of Animal Nutrition and Feed Science, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
| | - Małgorzata Stryjecka
- Institute of Human Nutrition and Agriculture, The University College of Applied Sciences in Chełm, Pocztowa 54, 22-100 Chełm, Poland
| | - Marzena Tomaszewska
- Institute of Human Nutrition and Agriculture, The University College of Applied Sciences in Chełm, Pocztowa 54, 22-100 Chełm, Poland
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11
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Borgonovo E, De Cristofaro J, Aletti F, Pedica F, D'Alessio A. Edoxaban-Induced Vanishing Bile Duct Syndrome: A Case Report With Review of the Literature. Cureus 2024; 16:e68071. [PMID: 39347284 PMCID: PMC11437016 DOI: 10.7759/cureus.68071] [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: 08/12/2024] [Indexed: 10/01/2024] Open
Abstract
Edoxaban is an oral, highly selective, direct factor X-inhibitor approved by the European Medical Agency for the prevention of stroke in non-valvular atrial fibrillation. Edoxaban is contraindicated in patients with severe hepatic insufficiency and, among adverse effects, serum bilirubin level and gamma-glutamyl transpeptidase elevation are described as common events. We report the case of an 82-year-old man with hepatocellular carcinoma who developed a fatal vanishing bile duct syndrome (VBDS) a few weeks after the administration of edoxaban for non-valvular atrial fibrillation. To the best of our knowledge, this is the first report to describe a case of acute VBDS possibly related to edoxaban.
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Affiliation(s)
| | | | | | - Federica Pedica
- Anatomical Pathology, IRCCS San Raffaele Hospital, Milano, ITA
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12
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Fatima I, Mahadevia H, Madhusudhana S, Shrestha A. Vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma. BMJ Case Rep 2024; 17:e256818. [PMID: 38772873 DOI: 10.1136/bcr-2023-256818] [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] [Indexed: 05/23/2024] Open
Abstract
Vanishing bile duct syndrome is an uncommon condition characterised by the progressive loss and disappearance of bile ducts. It is an acquired form of cholestatic liver disease presenting with hepatic ductopenia (loss of >50% bile ducts in the portal areas). We present a case of vanishing bile duct syndrome as a presentation of Hodgkin's lymphoma who was treated with standard-of-care chemotherapy-doxorubicin, bleomycin, vinblastine and dacarbazine (along with brief administration of rituximab), which led to complete response and normalisation of liver function.
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Affiliation(s)
- Ifrah Fatima
- Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
| | - Himil Mahadevia
- Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
| | - Sheshadri Madhusudhana
- Medicine, Section of Hematology and Oncology, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Anuj Shrestha
- Medicine, Section of Hematology and Oncology, University of Missouri Kansas City School of Medicine, Kansas City, Missouri, USA
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13
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Moreno-Torres M, López-Pascual E, Rapisarda A, Quintás G, Drees A, Steffensen IL, Luechtefeld T, Serrano-Candelas E, de Lomana MG, Gadaleta D, Dirven H, Vinken M, Jover R. Novel clinical phenotypes, drug categorization, and outcome prediction in drug-induced cholestasis: Analysis of a database of 432 patients developed by literature review and machine learning support. Biomed Pharmacother 2024; 174:116530. [PMID: 38574623 DOI: 10.1016/j.biopha.2024.116530] [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: 01/25/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Serum transaminases, alkaline phosphatase and bilirubin are common parameters used for DILI diagnosis, classification, and prognosis. However, the relevance of clinical examination, histopathology and drug chemical properties have not been fully investigated. As cholestasis is a frequent and complex DILI manifestation, our goal was to investigate the relevance of clinical features and drug properties to stratify drug-induced cholestasis (DIC) patients, and to develop a prognosis model to identify patients at risk and high-concern drugs. METHODS DIC-related articles were searched by keywords and Boolean operators in seven databases. Relevant articles were uploaded onto Sysrev, a machine-learning based platform for article review and data extraction. Demographic, clinical, biochemical, and liver histopathological data were collected. Drug properties were obtained from databases or QSAR modelling. Statistical analyses and logistic regressions were performed. RESULTS Data from 432 DIC patients associated with 52 drugs were collected. Fibrosis strongly associated with fatality, whereas canalicular paucity and ALP associated with chronicity. Drugs causing cholestasis clustered in three major groups. The pure cholestatic pattern divided into two subphenotypes with differences in prognosis, canalicular paucity, fibrosis, ALP and bilirubin. A predictive model of DIC outcome based on non-invasive parameters and drug properties was developed. Results demonstrate that physicochemical (pKa-a) and pharmacokinetic (bioavailability, CYP2C9) attributes impinged on the DIC phenotype and allowed the identification of high-concern drugs. CONCLUSIONS We identified novel associations among DIC manifestations and disclosed novel DIC subphenotypes with specific clinical and chemical traits. The developed predictive DIC outcome model could facilitate DIC prognosis in clinical practice and drug categorization.
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Affiliation(s)
- Marta Moreno-Torres
- Joint Research Unit in Experimental Hepatology, Dep. Biochemistry and Molecular Biology, University of Valencia, Health Research Institute Hospital La Fe & CIBER of Hepatic and Digestive Diseases, Spain.
| | - Ernesto López-Pascual
- Joint Research Unit in Experimental Hepatology, Dep. Biochemistry and Molecular Biology, University of Valencia, Health Research Institute Hospital La Fe & CIBER of Hepatic and Digestive Diseases, Spain
| | - Anna Rapisarda
- Joint Research Unit in Experimental Hepatology, Dep. Biochemistry and Molecular Biology, University of Valencia, Health Research Institute Hospital La Fe & CIBER of Hepatic and Digestive Diseases, Spain
| | - Guillermo Quintás
- Health and Biomedicine, LEITAT Technological Center, Barcelona, Spain
| | - Annika Drees
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium
| | - Inger-Lise Steffensen
- Department of Chemical Toxicology, Norwegian Institute of Public Health, Oslo, Norway
| | | | | | - Marina Garcia de Lomana
- Bayer AG, Machine Learning Research, Research & Development, Pharmaceuticals, Berlin 13353, Germany
| | - Domenico Gadaleta
- Laboratory of Environmental Toxicology and Chemistry, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCSS, Milano 20156, Italy
| | - Hubert Dirven
- Department of Chemical Toxicology, Norwegian Institute of Public Health, Oslo, Norway
| | - Mathieu Vinken
- Entity of In Vitro Toxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Belgium
| | - Ramiro Jover
- Joint Research Unit in Experimental Hepatology, Dep. Biochemistry and Molecular Biology, University of Valencia, Health Research Institute Hospital La Fe & CIBER of Hepatic and Digestive Diseases, Spain.
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14
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Verkade E, Shen W, Hovingh M, Mulder N, de Bruyn K, Koehorst M, de Vries H, Bloks V, Kuipers F, de Boer J. Gut microbiota depletion aggravates bile acid-induced liver pathology in mice with a human-like bile acid composition. Clin Sci (Lond) 2023; 137:1637-1650. [PMID: 37910096 PMCID: PMC10643054 DOI: 10.1042/cs20230812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 10/20/2023] [Accepted: 11/01/2023] [Indexed: 11/03/2023]
Abstract
Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Although Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70-/- mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70-/- mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70-/- mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70-/- mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (-99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70-/- mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70-/- mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70-/- mice. In conclusion, depletion of gut microbiota in Cyp2c70-/- mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner.
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Affiliation(s)
- Esther Verkade
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Wenqiang Shen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Milaine V. Hovingh
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Niels L. Mulder
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Krisztina de Bruyn
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hilde D. de Vries
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent W. Bloks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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15
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Tang X, Miao Y, Cao L, Liu Y, Zhu X, Zhang J, Wang D, Li X, Zhang L, Huo J, Chen J. Adverse outcome pathway exploration of furan-induced liver fibrosis in rats: Genotoxicity pathway or oxidative stress pathway through CYP2E1 activation? CHEMOSPHERE 2023; 341:139998. [PMID: 37657698 DOI: 10.1016/j.chemosphere.2023.139998] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 09/03/2023]
Abstract
Furan is a widespread endogenous contaminant in heat-processed foods that can accumulate rapidly in the food chain and has been widely detected in foods, such as wheat, bread, coffee, canned meat products, and baby food. Dietary exposure to this chemical may bring health risk. Furan is classified as a possible category 2B human carcinogen by the International Agency for Research on Cancer, with the liver as its primary target organ. Hepatic fibrosis is the most important nontumoral harmful effect of furan and also an important event in the carcinogenesis of furan. Although the specific mechanism of furan-induced liver fibrosis is still unclear, it may involve oxidative stress and genetic toxicity, in which the activation of cytochrome P450 2E1 (CYP2E1) may be the key event. Thus, we conducted a study using an integrating multi-endpoint genotoxicity platform in 120-day in vivo subchronic toxicity test in rats. Results showed that the rats with activated CYP2E1 exhibited DNA double-strand breaks in D4, gene mutations in D60, and increased expression of reactive oxygen species and nuclear factor erythroid 2-related factor 2 in D120. Necrosis, apoptosis, hepatic stellate cell activation, and fibrosis also occurred in the liver, suggesting that furan can independently affect liver fibrosis through oxidative stress and genotoxicity pathways. Point of Departure (PoD) was obtained by benchmark-dose (BMD) method to establish health-based guidance values. The human equivalent dose of PoD derived from BMDL05 was 2.26 μg/kg bw/d. The findings laid a foundation for the safety evaluation and risk assessment of furan and provided data for the further construction and improvement of the adverse outcome pathway network in liver fibrosis.
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Affiliation(s)
- Xinyao Tang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Yeqiu Miao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Li Cao
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Yufei Liu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Xia Zhu
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Jing Zhang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Dongxia Wang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Xiaomeng Li
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Lishi Zhang
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China
| | - Jiao Huo
- Department of Nutrition and Food Safety, Chongqing Center for Disease Control and Prevention, Chongqing, China.
| | - Jinyao Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China; Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province, Chengdu, Sichuan, China.
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16
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Mahapatra D, Maronpot R. Translational Relevance of Rodent Models to Predict Human Liver Disease. Toxicol Pathol 2023; 51:482-486. [PMID: 38494947 DOI: 10.1177/01926233241230543] [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] [Indexed: 03/19/2024]
Abstract
Animals models are essential to understand the complex pathobiology of human diseases. George Box's aphorism based on statistics "All models are wrong, but some are useful" certainly applies to animal models of disease. In this session, the translational relevance of various animal models applicable to human liver disease was explored starting with a historic overview of the rodent cancer bioassay with emphasis on hepatocarcinogenesis from early work at the National Cancer Institute, refinement by the National Toxicology Program and contemporary efforts to identify potential mechanisms and their relevance to human cancer risk. Subsequently, recently elucidated understanding of the molecular drivers and signaling mechanisms of liver pathophysiology and liver cancer, including factors associated with liver regeneration, metabolic hepatocellular zonation, and the role of macrophages and their crosstalk with stellate cells in understanding human liver disease was discussed. Next, our contemporary understanding of the role of nuclear receptors in hepatic homeostasis and drug response highlighting nuclear receptor activation and crosstalk in modulating biological responses associated with liver damage and neoplastic response were discussed. Finally, an overview and translational relevance of different drug-induced liver injury (DILI) rodent model systems focused on pathology and mechanisms with commentary on current relevant Food and Drug Administration (FDA) perspective were summarized with closing remarks.
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17
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Cao P, Gan J, Wu S, Hu Y, Xia B, Li X, Zeng H, Cheng B, Yu H, Li F, Si L, Huang J. Molecular mechanisms of hepatoprotective effect of tectorigenin against ANIT-induced cholestatic liver injury: Role of FXR and Nrf2 pathways. Food Chem Toxicol 2023:113914. [PMID: 37348807 DOI: 10.1016/j.fct.2023.113914] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/23/2023] [Accepted: 06/19/2023] [Indexed: 06/24/2023]
Abstract
Cholestatic liver injury is caused by toxic action or allergic reaction, resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis. Herein, we found that tectorigenin (TG), a natural isoflavone, showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase, as well as hepatic reactive oxygen species, catalase and superoxide dismutase. Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid, tauromuricholic acid, taurocholic acid, taurolithocholic acid, tauroursodeoxycholic acid and taurodeoxycholic acid. Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity. Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.
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Affiliation(s)
- Peng Cao
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Jun Gan
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Yixin Hu
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bin Xia
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoyue Li
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hongan Zeng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, 430022, China
| | - Bingyu Cheng
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huifan Yu
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Fei Li
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, China
| | - Luqin Si
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Jiangeng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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18
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Yadlapati S, Jarrett SA, Baik D, Chaaya A. COVID-19 related biliary injury: A review of recent literature. World J Gastroenterol 2023; 29:2127-2133. [PMID: 37122603 PMCID: PMC10130971 DOI: 10.3748/wjg.v29.i14.2127] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 04/13/2023] Open
Abstract
Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.
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Affiliation(s)
- Sujani Yadlapati
- Department of Gastroenterology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Simone A. Jarrett
- Department of Internal Medicine, Einstein Medical Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19140, United States
| | - Daniel Baik
- Department of Gastroenterology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
| | - Adib Chaaya
- Department of Gastroenterology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ 08103, United States
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19
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Vitale G, Mattiaccio A, Conti A, Berardi S, Vero V, Turco L, Seri M, Morelli MC. Molecular and Clinical Links between Drug-Induced Cholestasis and Familial Intrahepatic Cholestasis. Int J Mol Sci 2023; 24:ijms24065823. [PMID: 36982896 PMCID: PMC10057459 DOI: 10.3390/ijms24065823] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/11/2023] [Accepted: 03/14/2023] [Indexed: 03/30/2023] Open
Abstract
Idiosyncratic Drug-Induced Liver Injury (iDILI) represents an actual health challenge, accounting for more than 40% of hepatitis cases in adults over 50 years and more than 50% of acute fulminant hepatic failure cases. In addition, approximately 30% of iDILI are cholestatic (drug-induced cholestasis (DIC)). The liver's metabolism and clearance of lipophilic drugs depend on their emission into the bile. Therefore, many medications cause cholestasis through their interaction with hepatic transporters. The main canalicular efflux transport proteins include: 1. the bile salt export pump (BSEP) protein (ABCB11); 2. the multidrug resistance protein-2 (MRP2, ABCC2) regulating the bile salts' independent flow by excretion of glutathione; 3. the multidrug resistance-1 protein (MDR1, ABCB1) that transports organic cations; 4. the multidrug resistance-3 protein (MDR3, ABCB4). Two of the most known proteins involved in bile acids' (BAs) metabolism and transport are BSEP and MDR3. BSEP inhibition by drugs leads to reduced BAs' secretion and their retention within hepatocytes, exiting in cholestasis, while mutations in the ABCB4 gene expose the biliary epithelium to the injurious detergent actions of BAs, thus increasing susceptibility to DIC. Herein, we review the leading molecular pathways behind the DIC, the links with the other clinical forms of familial intrahepatic cholestasis, and, finally, the main cholestasis-inducing drugs.
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Affiliation(s)
- Giovanni Vitale
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany
| | - Alessandro Mattiaccio
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy
| | - Amalia Conti
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Sonia Berardi
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany
| | - Vittoria Vero
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany
| | - Laura Turco
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany
| | - Marco Seri
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy
| | - Maria Cristina Morelli
- Internal Medicine Unit for the Treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 20246 Hamburg, Germany
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Seifert M, Kneiseler G, Dechene A. Secondary Sclerosing Cholangitis due to Severe COVID-19: An Emerging Disease Entity? Digestion 2023:1-7. [PMID: 36889285 PMCID: PMC10025365 DOI: 10.1159/000528689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 12/12/2022] [Indexed: 03/10/2023]
Abstract
INTRODUCTION Coronavirus disease 2019 (COVID-19) can lead to many extrapulmonary manifestations. In this case series, we report on 7 patients developing secondary sclerosing cholangitis (SSC) after severe COVID-19 with intensive care treatment. METHODS Between March 2020 and November 2021, 544 patient cases with cholangitis treated at a German tertiary care centre were screened for SSC. Patients found to be suffering from SSC were assigned to COVID-19 group if SSC presented after a severe course of COVID-19 and to non-COVID-19 group if not. Peak liver parameters as well as intensive care treatment factors and data generated from liver elastography were compared between both groups. RESULTS We identified 7 patients who developed SSC after a severe course of COVID-19. In the same period, 4 patients developed SSC due to other causes. Mean values of gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were higher in the COVID-19 group than in the non-COVID-19 group (GGT: 2,689 U/L vs. 1,812 U/L and ALP: 1,445 U/L vs. 1,027 U/L), whereas intensive care treatment factors were comparable in both groups. Only the mean duration of mechanical ventilation was shorter in the COVID-19 group than in the non-COVID-19 group (22.1 days vs. 36.7 days). Liver elastography indicated a fast progression to liver cirrhosis with a mean liver stiffness of 17.3 kilopascals (kPa) in less than 12 weeks in the COVID-19 group. CONCLUSIONS Our data suggest a more severe course of SSC when caused by SARS-CoV-2. Reasons for this are probably multifactorial, including a direct cytopathogenic effect of the virus.
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Chen PC, Hsu CP, Wang SY, Wu TY, Lin YJ, Chen YT, Hsu SH. miR-194 Up-Regulates Cytochrome P450 Family 7 Subfamily A Member 1 Expression via β-Catenin Signaling and Aggravates Cholestatic Liver Diseases. THE AMERICAN JOURNAL OF PATHOLOGY 2023:S0002-9440(23)00058-5. [PMID: 36868469 DOI: 10.1016/j.ajpath.2023.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 02/04/2023] [Accepted: 02/15/2023] [Indexed: 03/05/2023]
Abstract
miR-194 is abundantly expressed in hepatocytes, and its depletion induces hepatic resistance to acetaminophen-induced acute injuries. In this study, the biological role of miR-194 in cholestatic liver injury was investigated by using miR-194/miR-192 cluster liver-specific knockout (LKO) mice, in which no liver injuries or metabolic disorders were predisposed. Bile duct ligation (BDL) and 1-naphthyl isothiocyanate (ANIT) were applied to LKO and matched control wild-type (WT) mice to induce hepatic cholestasis. Periportal liver damage, mortality rate, and liver injury biomarkers in LKO mice were significantly less than in WT mice after BDL and ANIT injection. Intrahepatic bile acid level was significantly lower in the LKO liver within 48 hours of BDL- and ANIT-induced cholestasis compared with WT. Western blot analysis showed that β-catenin (CTNNB1) signaling and genes involved in cellular proliferation were activated in BDL- and ANIT-treated mice. The expression levels of cytochrome P450 family 7 subfamily A member 1 (CYP7A1), pivotal in bile synthesis, and its upstream regulator hepatocyte nuclear factor 4α were reduced in primary LKO hepatocytes and liver tissues compared with WT. The knockdown of miR-194 using antagomirs reduced CYP7A1 expression in WT hepatocytes. In contrast, the knockdown of CTNNB1 and overexpression of miR-194, but not miR-192, in LKO hepatocytes and AML12 cells increased CYP7A1 expression. In conclusion, the results suggest that the loss of miR-194 ameliorates cholestatic liver injury and may suppress CYP7A1 expression via activation of CTNNB1 signaling.
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Affiliation(s)
- Po-Chun Chen
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan; Division of Gastrointestinal Surgery, Department of Surgery, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chien-Peng Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Sheng-Ya Wang
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Tsai-Yen Wu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - Yu-Jyun Lin
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan
| | - You-Tzung Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Shu-Hao Hsu
- Department of Anatomy and Cell Biology, National Taiwan University, Taipei, Taiwan.
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22
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Möller K, Braden B, Culver EL, Jenssen C, Zadeh ES, Alhyari A, Görg C, Ignee A, Hocke M, Dong Y, Sun S, Faiss S, Dietrich CF. Secondary sclerosing cholangitis and IgG4-sclerosing cholangitis - A review of cholangiographic and ultrasound imaging. Endosc Ultrasound 2023; 12:181-199. [PMID: 36588352 PMCID: PMC10237613 DOI: 10.4103/eus-d-22-00208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 01/01/2023] Open
Abstract
Sclerosing cholangitis (SC) represents a spectrum of chronic progressive cholestatic diseases of the intrahepatic and/or extrahepatic biliary system characterized by patchy inflammation, fibrosis, and stricturing. Primary and secondary SC must be distinguished given the different treatment modalities, risks of malignancy, and progression to portal hypertension, cirrhosis, and hepatic failure. This review focuses on secondary SC and the pathogenic mechanisms, risk factors, clinical presentation, and novel imaging modalities that help to distinguish between these conditions. We explore the detailed use of cholangiography and ultrasound imaging techniques.
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Affiliation(s)
- Kathleen Möller
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Barbara Braden
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Emma L. Culver
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Christian Jenssen
- Department of Internal Medicine, Krankenhaus Märkisch Oderland GmbH, Strausberg, Wriezen, Germany
- Brandenburg Institute of Clinical Medicine at Medical University Brandenburg, Neuruppin, Germany
| | - Ehsan Safai Zadeh
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Amjad Alhyari
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Christian Görg
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - André Ignee
- Department of Internal Medicine – Gastroenterology and Rheumatology; Klinikum Wuerzburg Mitte, Wuerzburg, Germany
| | - Michael Hocke
- Medical Department II, Helios Klinikum Meiningen, Meiningen, Germany
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Siyu Sun
- Department of Endoscopy Center, Shengjing Hospital of China Medical University, Liaoning Province, China
| | - Siegbert Faiss
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Christoph F. Dietrich
- Department of Internal Medicine (DAIM), Hirslanden Private Hospital, Beau Site, Salem und Permanence, Bern, Switzerland
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23
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Vacheishvili NG, Zharkova MS, Nekrasova TP, Tikhonov IN, Trofimovskaya NI, Ivashkin VT. Prolonged jaundice after previous SARS-CoV-2 infection: a clinical case report. SECHENOV MEDICAL JOURNAL 2023. [DOI: 10.47093/2218-7332.2022.13.3.45-53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The hepatobiliary system can be affected by a new coronavirus infection (COVID-19), in addition to the respiratory organs. Vanishing bile duct syndrome (VBDS) is a rare cause of jaundice that usually develops as a result of drug-induced liver injury or possibly due to the combined effect of several etiological factors.Clinical case. A 77-year-old patient was hospitalized due to jaundice, skin itching and dark urine. Symptoms first appeared 1 month after COVID-19 treated with ceftriaxone and were accompanied by an increase in biochemical markers of cholestasis. Both extra- and intrahepatic bile ducts injuries were excluded. Liver histology revealed VBDS. Treatment with ursodeoxycholic acid for 11 months led to complete resolution of jaundice, regression of pruritus and a decrease in biochemical markers of cholestasis.Discussion. This clinical case is of interest in connection with the development of VBDS in a patient after coronavirus pneumonia treated with ceftriaxone. VBDS is rarely included in the differential diagnosis of cholestatic syndrome, which is partly due to the lack of awareness of physicians about the complications that develop after COVID-19 and drug therapy.
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Affiliation(s)
| | - M. S. Zharkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - T. P. Nekrasova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - I. N. Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University)
| | | | - V. T. Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University)
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24
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Wu Q, Duan Z, Huang L, Li Z. Kuhuang injection exerts a protective effect by activating PPAR-γ in an in vitro model of chlorpromazine-induced cholestatic liver injury constructed by tissue engineering. PHARMACEUTICAL BIOLOGY 2022; 60:1679-1689. [PMID: 36063125 PMCID: PMC9467616 DOI: 10.1080/13880209.2022.2110128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 06/01/2022] [Accepted: 08/01/2022] [Indexed: 06/15/2023]
Abstract
CONTEXT Kuhuang (KH) injection is a widely used anticholestatic drug in the clinic and the mechanisms are still unclear. OBJECTIVE This study uses a new 3D tissue-engineered (TE) liver platform to study the ability of kuhuang to ameliorate liver injury induced by chlorpromazine (CPZ) and the possible mechanisms involved. MATERIALS AND METHODS The TE livers (n = 25) were divided into 5 groups (n = 5 livers/group) as 3D, 3D + CPZ, 3D + CPZ + KH, 3D + CPZ + GW9662 (a PPARγ inhibitor) and 3D + CPZ + KH + GW9662. The treatments with kuhuang (1 mg/mL) and GW9662 (10 μmol/L) were given to the desired groups on the 7th day of the experimental process. 20 μmol/L CPZ was added on the 8th day. RESULTS According to the 2D experimental results, the minimum effective concentration of kuhuang is 10 μg/mL and the optimal effective concentration is 1 mg/mL. Kuhuang ameliorated tissue damage in the TE livers both in terms of tissue structure and culture supernatant. Kuhuang significantly reduced TBA accumulation (38%) and downregulated CYP7A1 (38%) and CYP8B1 (79%). It reduced hepatic levels of ROS (14%), MDA (27%) but increased the levels of GSH (41%), SOD (12%), BSEP (4.4-fold), and MRP2 (74%). Moreover, kuhuang downregulated DR5 (99%) but increased the mRNA expression of PPARγ (4-fold). Molecular docking analyses determined the bioactivity of the active compounds of kuhuang through their specific bindings to PPARγ. CONCLUSIONS Kuhuang could alleviate CPZ-induced cholestatic liver injury by activating PPARγ to reduce oxidative stress. Applying kuhuang for the treatment of CPZ-induced liver injury could be suggested.
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Affiliation(s)
- Qiao Wu
- Infection Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated with Capital Medical University; Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Zhongping Duan
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated with Capital Medical University; Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Long Huang
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You’an Hospital Affiliated with Capital Medical University; Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Zhijie Li
- Hepatobiliary Surgery Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
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25
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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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26
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Rausch M, Samodelov SL, Visentin M, Kullak-Ublick GA. The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity. Int J Mol Sci 2022; 23:ijms232213967. [PMID: 36430444 PMCID: PMC9695947 DOI: 10.3390/ijms232213967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/07/2022] [Accepted: 11/10/2022] [Indexed: 11/16/2022] Open
Abstract
The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases.
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27
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Wasuwanich P, Choudry H, So JM, Lowry S, Karnsakul W. Vanishing bile duct syndrome after drug-induced liver injury. Clin Res Hepatol Gastroenterol 2022; 46:102015. [PMID: 36067952 DOI: 10.1016/j.clinre.2022.102015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Vanishing bile duct syndrome (VBDS) is a serious cholestatic liver disease that can be a complication of drug-induced liver injury (DILI). While journals have published case reports of this condition, large studies on a cohort of these patients are lacking. We aimed to compile published case reports and case series of patients with VBDS and DILI to describe the clinical and laboratory characteristics of the disease and identify factors associated with good and poor outcomes. METHODS We included case reports and case series of VBDS secondary only to DILI. We extracted demographic, clinical, laboratory, treatment, and exposure data from each case report and categorized cases by outcome, good versus poor. We defined poor outcomes as cases with severe long-term complications or death. We analyzed risk factors for poor outcomes using logistic regression. RESULTS We identified a total of 59 eligible cases. Of those, 39 (59%) were female, the median age was 36 (IQR:12-58), and 18 (31%) were pediatric cases (≤18 years). The most common offending drug class was antibiotics, especially beta-lactams. Patients with increased total bilirubin (OR=4.69; 95% CI=1.55-15.49; p = 0.008), increased direct bilirubin (OR=6.50; 95% CI=1.34-48.91; p = 0.034), lower liver synthetic activity (OR=0.11; 95% CI=0.02-0.55; p = 0.013), and older age (OR=3.31; 95% CI=1.15-10.04; p = 0.029) were more likely to develop poor outcomes. CONCLUSIONS In patients with VBDS and DILI, antibiotics were the most common offending agents. Higher total and direct bilirubin levels were associated with poor outcomes.
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Affiliation(s)
- Paul Wasuwanich
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Hassan Choudry
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joshua M So
- University of Florida College of Medicine, Gainesville, FL, USA
| | - Sarah Lowry
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wikrom Karnsakul
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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28
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Influence of Antibiotics on Functionality and Viability of Liver Cells In Vitro. Curr Issues Mol Biol 2022; 44:4639-4657. [PMID: 36286032 PMCID: PMC9600611 DOI: 10.3390/cimb44100317] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/17/2022] [Accepted: 09/22/2022] [Indexed: 11/22/2022] Open
Abstract
(1) Antibiotics are an important weapon in the fight against serious bacterial infections and are considered a common cause of drug-induced liver injury (DILI). The hepatotoxicity of many drugs, including antibiotics, is poorly analyzed in human in vitro models. (2) A standardized assay with a human hepatoma cell line was used to test the hepatotoxicity of various concentrations (Cmax, 5× Cmax, and 10× Cmax) of antibiotics. In an ICU, the most frequently prescribed antibiotics, ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, meropenem, rifampicin, tigecycline, and vancomycin, were incubated with HepG2/C3A cells for 6 days. Cell viability (XTT assay, LDH release, and vitality), albumin synthesis, and cytochrome 1A2 activity were determined in cells. (3) In vitro, vancomycin, rifampicin, and tigecycline showed moderate hepatotoxic potential. The antibiotics ampicillin, cefepime, cefuroxime, levofloxacin, linezolid, and meropenem were associated with mild hepatotoxic reactions in test cells incubated with the testes Cmax concentration. Rifampicin and cefuroxime showed significantly negative effects on the viability of test cells. (4) Further in vitro studies and global pharmacovigilance reports should be conducted to reveal underlying mechanism of the hepatotoxic action of vancomycin, rifampicin, tigecycline, and cefuroxime, as well as the clinical relevance of these findings.
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Faruqui S, Shanbhogue K, Jacobson IM. Biliary Tract Injury in Patients With COVID-19: A Review of the Current Literature. Gastroenterol Hepatol (N Y) 2022; 18:380-387. [PMID: 36397771 PMCID: PMC9666809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Multiple studies and extensive clinical experience have shown that COVID-19 can impact the hepatobiliary system, with most reports describing primarily hepatocellular injury with elevations of aspartate aminotransferase and alanine aminotransferase. In addition to hepatocellular injury, recent literature has described a pattern of severe biliary tract injury resulting in patients with COVID-19. This novel syndrome, termed COVID-19 cholangiopathy, may have severe consequences for affected patients. This article will examine the literature describing this novel entity, its relationship to secondary sclerosing cholangitis, clinical outcomes, and proposed mechanisms underlying this form of biliary injury.
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Affiliation(s)
- Saamia Faruqui
- Department of Medicine, NYU Grossman School of Medicine, New York, New York
| | - Krishna Shanbhogue
- Department of Radiology, NYU Grossman School of Medicine, New York, New York
| | - Ira M. Jacobson
- Department of Medicine, NYU Grossman School of Medicine, New York, New York
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30
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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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31
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Moussaoui S, Abdelwahed M, Ben Chaaben N, Bellalah A, Ben Fadhel N, Guediche A, Zakhama M, Tababi R, Aouam K, Abdelfattah Z, Loghmari H, Safer L. Norethisterone-induced cholestasis: A case report. Clin Case Rep 2022; 10:e05522. [PMID: 35280099 PMCID: PMC8894581 DOI: 10.1002/ccr3.5522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/07/2022] [Accepted: 02/16/2022] [Indexed: 12/14/2022] Open
Abstract
Case presentation This case report concerns a 49-year-old woman who developed cholestasis (build-up of bile in the liver) two months and a half after initiating norethisterone, progestin-only pills, which resolved after the withdrawal of these pills.
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Affiliation(s)
- Safa Moussaoui
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Mehdi Abdelwahed
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Nabil Ben Chaaben
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Ahlem Bellalah
- Department of PathologyFattouma Bourguiba University Hospital of MonastirTunisia
| | | | - Arwa Guediche
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Mejda Zakhama
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Ramzi Tababi
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Karim Aouam
- Department of PharmacologyMonastir‐Faculty of medicineTunisia
| | - Zakhama Abdelfattah
- Department of PathologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Hichem Loghmari
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
| | - Leila Safer
- Department of GastroenterologyFattouma Bourguiba University Hospital of MonastirTunisia
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32
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Benić MS, Nežić L, Vujić-Aleksić V, Mititelu-Tartau L. Novel Therapies for the Treatment of Drug-Induced Liver Injury: A Systematic Review. Front Pharmacol 2022; 12:785790. [PMID: 35185538 PMCID: PMC8847672 DOI: 10.3389/fphar.2021.785790] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/30/2021] [Indexed: 12/15/2022] Open
Abstract
Many drugs with different mechanisms of action and indications available on the market today are capable of inducing hepatotoxicity. Drug-induced liver injury (DILI) has been a treatment challenge nowadays as it was in the past. We searched Medline (via PubMed), CENTRAL, Science Citation Index Expanded, clinical trials registries and databases of DILI and hepatotoxicity up to 2021 for novel therapies for the management of adult patients with DILI based on the combination of three main search terms: 1) treatment, 2) novel, and 3) drug-induced liver injury. The mechanism of action of novel therapies, the potential of their benefit in clinical settings, and adverse drug reactions related to novel therapies were extracted. Cochrane Risk of bias tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment approach was involved in the assessment of the certainty of the evidence for primary outcomes of included studies. One thousand three hundred seventy-two articles were identified. Twenty-eight articles were included in the final analysis. Eight randomized controlled trials (RCTs) were detected and for six the available data were sufficient for analysis. In abstract form only we found six studies which were also anaylzed. Investigated agents included: bicyclol, calmangafodipir, cytisin amidophospate, fomepizole, livina-polyherbal preparation, magnesium isoglycyrrhizinate (MgIG), picroliv, plasma exchange, radix Paeoniae Rubra, and S-adenosylmethionine. The primary outcomes of included trials mainly included laboratory markers improvement. Based on the moderate-certainty evidence, more patients treated with MgIG experienced alanine aminotransferase (ALT) normalization compared to placebo. Low-certainty evidence suggests that bicyclol treatment leads to a reduction of ALT levels compared to phosphatidylcholine. For the remaining eight interventions, the certainty of the evidence for primary outcomes was assessed as very low and we are very uncertain in any estimate of effect. More effort should be involved to investigate the novel treatment of DILI. Well-designed RCTs with appropriate sample sizes, comparable groups and precise, not only surrogate outcomes are urgently welcome.
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Affiliation(s)
- Mirjana Stanić Benić
- Department of Clinical Pharmacology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Lana Nežić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
| | - Vesna Vujić-Aleksić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina
- The Republic of Srpska Agency for Certification, Accreditation and Quality Improvement in Health Care, Banja Luka, Bosnia and Herzegovina
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Contreras-Omaña R, Velarde-Ruiz Velasco JA, Castro-Narro GE, Trujillo-Benavides O, Zamarripa-Dorsey F, Reyes-Dorantes AA, Muñoz-Espinosa L, Aiza-Haddad I, Castillo-Barradas M, Cerda-Reyes E, Cisneros-Garza LE, Flores-Calderón J, García-Jiménez ES, Higuera-de-la-Tijera MF, Lira-Pedrín MA, Marquez-Guillén E, Moctezuma-Velázquez C, Moreno-Alcántar R, Noyola-Cedillo SG, Pérez-Hernández JL, Ramos-Gómez MV, Remes-Troche JM, Rizo-Robles MT, Rodríguez-Hernández H. Approach to the patient with cholestasis and jaundice syndrome. Joint AMH, AMG, and AMEG scientific position statement. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:80-88. [PMID: 34866042 DOI: 10.1016/j.rgmx.2021.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 04/14/2021] [Indexed: 04/21/2025]
Abstract
The term cholestasis refers to bile acid retention, whether within the hepatocyte or in the bile ducts of any caliber. Biochemically, it is defined by a level of alkaline phosphatase that is 1.67-times higher than the upper limit of normal. Cholestatic diseases can be associated with an inflammatory process of the liver that destroys hepatocytes (hepatitis), withjaundice (yellowing of the skin and mucus membranes, associated with elevated serum bilirubin levels), or with both, albeit the three concepts should not be considered synonymous. Cholestatic diseases can be classified as intrahepatic or extrahepatic, depending on their etiology. Knowing the cause of the condition is important for choosing the adequate diagnostic studies and appropriate treatment in each case. A complete medical history, together with a thorough physical examination and basic initial studies, such as liver ultrasound and liver function tests, aid the clinician in deciding which path to follow, when managing the patient with cholestasis. In a joint effort, the Asociación Mexicana de Hepatología (AMH), the Asociación Mexicana de Gastroenterología (AMG) and the Asociación Mexicana de Endoscopia Gastrointestinal (AMEG) developed the first Mexican scientific position statement on said theme.
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Affiliation(s)
- R Contreras-Omaña
- Centro de Estudio e Investigación en Enfermedades Hepáticas (CEIHE), Pachuca, Hidalgo, Mexico.
| | | | | | | | | | | | - L Muñoz-Espinosa
- Centro de Hepatología, Departamento de Medicina Interna, Hospital Universitario "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Mexico City, Mexico
| | - M Castillo-Barradas
- Hospital de Especialidades CMN La Raza, IMSS Hospital Ángeles Lindavista, Mexico City, Mexico
| | | | | | - J Flores-Calderón
- Servicio de Gastropediatría, UMAE Hospital de Pediatría CMN Siglo XXI IMSS, Mexico City, Mexico
| | - E S García-Jiménez
- Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - M F Higuera-de-la-Tijera
- Servicio de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - M A Lira-Pedrín
- Hospital Centro Médico del Prado, Tijuana, Baja California, Mexico
| | | | | | | | - S G Noyola-Cedillo
- Centro Médico del Noreste, Clínica 25 IMSS, Monterrey, Nuevo León, Hospital Ángeles Torreón, Coahuila, Mexico
| | - J L Pérez-Hernández
- Hospital Central Sur de Alta Especialidad Petróleos Mexicanos, Mexico City, Mexico
| | - M V Ramos-Gómez
- Servicio de Gastroenterología, CMN 20 de Noviembre, ISSSTE Mexico City, Mexico
| | - J M Remes-Troche
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico
| | - M T Rizo-Robles
- UMAE Hospital de Especialidades CMN La Raza IMSS, Mexico City, Mexico
| | - H Rodríguez-Hernández
- Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Durango, Mexico
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Contreras-Omaña R, Velarde-Ruiz Velasco JA, Castro-Narro GE, Trujillo-Benavides O, Zamarripa-Dorsey F, Reyes-Dorantes AA, Muñoz-Espinosa L, Aiza-Haddad I, Castillo-Barradas M, Cerda-Reyes E, Cisneros-Garza LE, Flores-Calderón J, García-Jiménez ES, Higuera-de-la-Tijera MF, Lira-Pedrín MA, Marquez-Guillén E, Moctezuma-Velázquez C, Moreno-Alcántar R, Noyola-Cedillo SG, Pérez-Hernández JL, Ramos-Gómez MV, Remes-Troche JM, Rizo-Robles MT, Rodríguez-Hernández H. Approach to the patient with cholestasis and jaundice syndrome. Joint AMH, AMG, and AMEG scientific position statement. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 87:80-88. [PMID: 34866042 DOI: 10.1016/j.rgmxen.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 04/14/2021] [Indexed: 11/17/2022]
Abstract
The term cholestasis refers to bile acid retention, whether within the hepatocyte or in the bile ducts of any caliber. Biochemically, it is defined by a level of alkaline phosphatase that is 1.67-times higher than the upper limit of normal. Cholestatic diseases can be associated with an inflammatory process of the liver that destroys hepatocytes (hepatitis), withjaundice (yellowing of the skin and mucus membranes, associated with elevated serum bilirubin levels), or with both, albeit the three concepts should not be considered synonymous. Cholestatic diseases can be classified as intrahepatic or extrahepatic, depending on their etiology. Knowing the cause of the condition is important for choosing the adequate diagnostic studies and appropriate treatment in each case. A complete medical history, together with a thorough physical examination and basic initial studies, such as liver ultrasound and liver function tests, aid the clinician in deciding which path to follow, when managing the patient with cholestasis. In a joint effort, the Asociación Mexicana de Hepatología (AMH), the Asociación Mexicana de Gastroenterología (AMG) and the Asociación Mexicana de Endoscopia Gastrointestinal (AMEG) developed the first Mexican scientific position statement on said theme.
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Affiliation(s)
- R Contreras-Omaña
- Centro de Estudio e Investigación en Enfermedades Hepáticas (CEIHE), Pachuca, Hidalgo, Mexico.
| | | | | | | | | | | | - L Muñoz-Espinosa
- Centro de Hepatología, Departamento de Medicina Interna, Hospital Universitario "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Mexico City, Mexico
| | - M Castillo-Barradas
- Hospital de Especialidades CMN La Raza, IMSS Hospital Ángeles Lindavista, Mexico City, Mexico
| | | | | | - J Flores-Calderón
- Servicio de Gastropediatría, UMAE Hospital de Pediatría CMN Siglo XXI IMSS, Mexico City, Mexico
| | - E S García-Jiménez
- Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - M F Higuera-de-la-Tijera
- Servicio de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - M A Lira-Pedrín
- Hospital Centro Médico del Prado, Tijuana, Baja California, Mexico
| | | | | | | | - S G Noyola-Cedillo
- Centro Médico del Noreste, Clínica 25 IMSS, Monterrey, Nuevo León, Hospital Ángeles Torreón, Coahuila, Mexico
| | - J L Pérez-Hernández
- Hospital Central Sur de Alta Especialidad Petróleos Mexicanos, Mexico City, Mexico
| | - M V Ramos-Gómez
- Servicio de Gastroenterología, CMN 20 de Noviembre, ISSSTE Mexico City, Mexico
| | - J M Remes-Troche
- Instituto de Investigaciones Médico-Biológicas, Universidad Veracruzana, Veracruz, Mexico
| | - M T Rizo-Robles
- UMAE Hospital de Especialidades CMN La Raza IMSS, Mexico City, Mexico
| | - H Rodríguez-Hernández
- Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Durango, Mexico
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Kolaric TO, Nincevic V, Kuna L, Duspara K, Bojanic K, Vukadin S, Raguz-Lucic N, Wu GY, Smolic M. Drug-induced Fatty Liver Disease: Pathogenesis and Treatment. J Clin Transl Hepatol 2021; 9:731-737. [PMID: 34722188 PMCID: PMC8516847 DOI: 10.14218/jcth.2020.00091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 02/08/2021] [Accepted: 07/01/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (commonly known as MAFLD) impacts global health in epidemic proportions, and the resulting morbidity, mortality and economic burden is enormous. While much attention has been given to metabolic syndrome and obesity as offending factors, a growing incidence of polypharmacy, especially in the elderly, has greatly increased the risk of drug-induced liver injury (DILI) in general, and drug-induced fatty liver disease (DIFLD) in particular. This review focuses on the contribution of DIFLD to DILI in terms of epidemiology, pathophysiology, the most common drugs associated with DIFLD, and treatment strategies.
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Affiliation(s)
- Tea Omanovic Kolaric
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Vjera Nincevic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Lucija Kuna
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | | | - Kristina Bojanic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
- Health Center Osijek, Osijek, Croatia
| | - Sonja Vukadin
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - Nikola Raguz-Lucic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
| | - George Y Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
| | - Martina Smolic
- University of Osijek, Faculty of Medicine, Osijek, Croatia
- University of Osijek, Faculty of Dental Medicine and Health, Osijek, Croatia
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[Severe secondary sclerosing cholangitis as manifestation of a very rare underlying disease]. Internist (Berl) 2021; 62:1349-1353. [PMID: 34546401 DOI: 10.1007/s00108-021-01148-0] [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: 08/12/2021] [Indexed: 10/20/2022]
Abstract
Langerhans cell histiocytosis (LCH) is a very rare cause of secondary sclerosing cholangitis. We report the case of a 42-year-old male patient with sclerosing cholangitis and histological evidence of LCH from a bile duct biopsy. Due to rapid disease progression and exhaustion of conservative therapeutic approaches the patient received a liver transplantation. Nearly 2 years after transplantation the patient has a good graft function and no signs of recurrence of the underlying LCH.
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Baier V, Clayton O, Nudischer R, Cordes H, Schneider ARP, Thiel C, Wittenberger T, Moritz W, Blank LM, Neumann UP, Trautwein C, Kelm J, Schrooders Y, Caiment F, Gmuender H, Roth A, Castell JV, Kleinjans J, Kuepfer L. A Model-Based Workflow to Benchmark the Clinical Cholestasis Risk of Drugs. Clin Pharmacol Ther 2021; 110:1293-1301. [PMID: 34462909 DOI: 10.1002/cpt.2406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 08/15/2021] [Indexed: 12/13/2022]
Abstract
We present a generic workflow combining physiology-based computational modeling and in vitro data to assess the clinical cholestatic risk of different drugs systematically. Changes in expression levels of genes involved in the enterohepatic circulation of bile acids were obtained from an in vitro assay mimicking 14 days of repeated drug administration for 10 marketed drugs. These changes in gene expression over time were contextualized in a physiology-based bile acid model of glycochenodeoxycholic acid. The simulated drug-induced response in bile acid concentrations was then scaled with the applied drug doses to calculate the cholestatic potential for each compound. A ranking of the cholestatic potential correlated very well with the clinical cholestasis risk obtained from medical literature. The proposed workflow allows benchmarking the cholestatic risk of novel drug candidates. We expect the application of our workflow to significantly contribute to the stratification of the cholestatic potential of new drugs and to support animal-free testing in future drug development.
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Affiliation(s)
- Vanessa Baier
- Institute of Applied Microbiology, RWTH, Aachen, Germany
| | - Olivia Clayton
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Ramona Nudischer
- Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Henrik Cordes
- Institute of Applied Microbiology, RWTH, Aachen, Germany
| | | | | | | | | | - Lars M Blank
- Institute of Applied Microbiology, RWTH, Aachen, Germany
| | - Ulf P Neumann
- Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | | | - Yannick Schrooders
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Florian Caiment
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | | | | | - José V Castell
- Unidad de Hepatología Experimenta, IIS Hospital Universitario La Fe, Valencia, Spain.,Department of Bioquímica, Facultad de Medicina, Universidad de Valencia, CIBEREHD-ISCIII, Valencia, Spain
| | - Jos Kleinjans
- Department of Toxicogenomics, Maastricht University, Maastricht, Netherlands
| | - Lars Kuepfer
- Institute of Applied Microbiology, RWTH, Aachen, Germany.,Institute of Systems Medicine with Focus on Organ Interaction, University Hospital RWTH Aachen, Aachen, Germany
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Kralj T, Brouwer KLR, Creek DJ. Analytical and Omics-Based Advances in the Study of Drug-Induced Liver Injury. Toxicol Sci 2021; 183:1-13. [PMID: 34086958 PMCID: PMC8502468 DOI: 10.1093/toxsci/kfab069] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Drug-induced liver injury (DILI) is a significant clinical issue, affecting 1-1.5 million patients annually, and remains a major challenge during drug development-toxicity and safety concerns are the second-highest reason for drug candidate failure. The future prevalence of DILI can be minimized by developing a greater understanding of the biological mechanisms behind DILI. Both qualitative and quantitative analytical techniques are vital to characterizing and investigating DILI. In vitro assays are capable of characterizing specific aspects of a drug's hepatotoxic nature and multiplexed assays are capable of characterizing and scoring a drug's association with DILI. However, an even deeper insight into the perturbations to biological pathways involved in the mechanisms of DILI can be gained through the use of omics-based analytical techniques: genomics, transcriptomics, proteomics, and metabolomics. These omics analytical techniques can offer qualitative and quantitative insight into genetic susceptibilities to DILI, the impact of drug treatment on gene expression, and the effect on protein and metabolite abundance. This review will discuss the analytical techniques that can be applied to characterize and investigate the biological mechanisms of DILI and potential predictive biomarkers.
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Affiliation(s)
- Thomas Kralj
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569, USA
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
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Hu T, Wang H. Hepatic Bile Acid Transporters in Drug‐Induced Cholestasis. TRANSPORTERS AND DRUG‐METABOLIZING ENZYMES IN DRUG TOXICITY 2021:307-337. [DOI: 10.1002/9781119171003.ch10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Abstract
Helicobacter pylori is the most prevalent infection worldwide, while non-alcoholic fatty liver disease emerged as the most frequent liver disease. The common occurrence can be either by chance or due to certain pathogenetic factors. Epidemiologic studies revealed that the risk of non-alcoholic liver disease is increased in patients infected with Helicobacter pylori. DNA fragments of Helicobacter pylori were rarely identified in human samples of liver carcinoma and fatty liver. Helicobacter pylori could influence the development of non-alcoholic fatty liver either by hormonal (ghrelin? gastrin? insulin?), or by effect of pro-inflammatory cytokines (interleukin 1 and 8, tumor necrosis factor ɑ, interferon ɣ) and by changes of gut microbiome as well. Probiotic supplementation could improve some clinical parameters of non-alcoholic fatty liver disease and eradication rates of Helicobacter pylori. Regimens used for eradication can be safely administered, although non-alcoholic fatty liver increases the risk of drug-induced liver damage. Controlled studies of the effect of eradication on the development and progression of non-alcoholic fatty liver are warranted.
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Affiliation(s)
- György M Buzás
- Department of Gastroenterology, Ferencváros Health Center, Budapest, Hungary -
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Perrault F, Echelard P, Viens D, Borduas M. Contraceptive vaginal ring-induced cholestasis in a patient with a history of intrahepatic cholestasis of pregnancy. Clin Res Hepatol Gastroenterol 2021; 45:101475. [PMID: 32651076 DOI: 10.1016/j.clinre.2020.06.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 06/01/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Intrahepatic cholestasis of pregnancy (ICP) is a heterogeneous group of liver disorders with a high recurrence rate. Patients with a history of ICP are at risk of developing contraceptive-induced cholestasis, especially if they harbour a biliary transporter mutation. We report the first case of drug-induced cholestasis associated with a contraceptive vaginal ring (CVR) in a patient with a prior history of ICP. PRESENTATION Our patient was a women with a history of multiple pregnancies and spontaneous abortions and early and severe ICP. Two to four weeks after initiation of CVR, she developed signs and symptoms of cholestasis, which resolved after discontinuation of the CVR. A thorough investigation to exclude other plausible causes of cholestasis was performed, including a liver biopsy. Genetic testing revealed pathogenic mutations in both the ABCB11 and ABCB4 genes. DISCUSSION Although a history of ICP used to be an absolute contraindication for oral contraceptive pills (OCP), recent studies suggest a lower risk of cholestasis associated with low-dose oestrogen pills (20-35 mcg compared to the original 50 mcg). No previous case report could confirm the theoretical risk associated with the use of a CVR, which delivers a very low estrogen dose (15 mcg). The two biliary transporter mutations identified in our case could potentially explain the patient's susceptibility to the cholestatic effect of oestrogen. CONCLUSION This case illustrates that CVR can trigger drug-induced cholestasis in a susceptible patient. While such cases should not discourage the trial of low-dose hormonal contraception in women with prior ICP, an appropriate follow-up is necessary to ensure early detection and treatment of drug-induced cholestasis.
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Affiliation(s)
- Florence Perrault
- Department of Pathology, University of Sherbrooke, Centre hospitalier Universitaire de Sherbrooke (CHUS), Quebec, Canada.
| | - Philippe Echelard
- Department of Pathology, University of Sherbrooke, Centre hospitalier Universitaire de Sherbrooke (CHUS), Quebec, Canada
| | - Daniel Viens
- Department of Internal Medecine, Hôpital Sainte-Croix, Quebec, Canada
| | - Martin Borduas
- Department of Pathology, University of Sherbrooke, Centre hospitalier Universitaire de Sherbrooke (CHUS), Quebec, Canada
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Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms. Toxicology 2021; 458:152840. [PMID: 34175381 DOI: 10.1016/j.tox.2021.152840] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/10/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Methotrexate (MTX) is one of the most effective and widely used drugs in the management of autoimmune and dermatological diseases. Rheumatoid arthritis and psoriasis patients who are under long term MTX-therapy are at high risk of developing a liver injury. Accumulation of intracellular MTX-polyglutamate (MTX-PG), a metabolite of MTX triggers oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes. MTX-PG causes oxidative stress in the liver by inducing lipid peroxidation thereby releasing reactive oxygen species and suppressing antioxidant response elements. MTX-PG induces several pro-inflammatory signaling pathways and cytokines such as tumor necrosis factor-α, nuclear factor kappa B and interleukin 6 (IL-6), IL- β1, IL-12. MTX-PG depletes hepatic folate level and decreases RNA and DNA synthesis leading to hepatocyte death. MTX-PG inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase enzyme and thereby causes accumulation of intracellular adenosine, which causes activation of hepatic stellate cells, extracellular matrix accumulation and hepatic fibrosis. MTX-PG induces hepatocytes apoptosis by activation of caspase 3 via the intrinsic pathway. Clinically, aggravation of underlying fatty liver to non-alcoholic steatohepatitis with fibrosis seems to be an important mechanism of liver injury in MTX-treated RA patients. Therefore, there is a need for monitoring liver injury in RA, psoriatic and cancer patients with NAFLD and fibrosis risk factors during MTX treatment. This review summarizes the possible molecular mechanism of MTX-induced hepatotoxicity. It may pave the way for early detection of liver injury and develop novel strategies for treating MTX mediated hepatotoxicity.
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Klindt C, Jensen B, Brandenburger T, Feldt T, Killer A, Schimmöller L, Antoch G, Senff T, Hauka S, Timm J, Bahners BH, Seidl M, Esposito I, Luedde T, Bode JG, Keitel V. Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature. Clin Case Rep 2021; 9:e04068. [PMID: 34084492 PMCID: PMC8142800 DOI: 10.1002/ccr3.4068] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 02/25/2021] [Accepted: 03/01/2021] [Indexed: 12/24/2022] Open
Abstract
This case of secondary sclerosing cholangitis (SSC-CIP) emphasizes the need to provide follow-up care for patients that have recovered from COVID-19 in order to understand the complexity of SARS-CoV-2 associated sequela.
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Affiliation(s)
- Caroline Klindt
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Björn‐Erik Jensen
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Timo Brandenburger
- Department of AnaesthesiologyMedical FacultyHeinrich‐Heine UniversitätDüsseldorfGermany
| | - Torsten Feldt
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Alexander Killer
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Lars Schimmöller
- Department of Diagnostic and Interventional RadiologyHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Gerald Antoch
- Department of Diagnostic and Interventional RadiologyHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Tina Senff
- Institute of VirologyHeinrich Heine UniversityUniversity HospitalDüsseldorfGermany
| | - Sandra Hauka
- Institute of VirologyHeinrich Heine UniversityUniversity HospitalDüsseldorfGermany
| | - Jörg Timm
- Institute of VirologyHeinrich Heine UniversityUniversity HospitalDüsseldorfGermany
| | - Bahne Hendrik Bahners
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Maximilian Seidl
- Institute of PathologyHeinrich‐Heine University and University HospitalDüsseldorfGermany
| | - Irene Esposito
- Institute of PathologyHeinrich‐Heine University and University HospitalDüsseldorfGermany
| | - Tom Luedde
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Johannes G. Bode
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectious DiseasesHeinrich‐Heine‐University DüsseldorfDüsseldorfGermany
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44
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Lee MQ, Chigozie R, Khan I, O'Mara G. Prednisolone: role in amoxicillin-clavulanate-induced cholestatic liver injury. BMJ Case Rep 2021; 14:14/4/e239488. [PMID: 33795270 DOI: 10.1136/bcr-2020-239488] [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] [Indexed: 11/04/2022] Open
Abstract
A 68-year-old patient presented with symptoms of a urinary tract infection. A deterioration in the patient's liver function tests (LFTs) was noted 1 week following completion of a course of amoxicillin-clavunalate. This progressively worsened, reaching its peak by day 30. Our investigations excluded other possible causes for deranged LFTs and there was no improvement of same despite reduced dosing of potentially hepatotoxic medications.A trial of 30 mg/day prednisolone was commenced, resulting in an immediate and progressive improvement in LFTs to baseline over a period of 22 days and an improvement in constitutional symptoms such as tiredness and poor appetite. Drug-induced liver injury (DILI) is one of the common causes of acute hepatitis and a leading cause of acute liver failure in the US and Europe. Patterns of DILI can be generally divided into: (1) hepatocellular injury, (2) cholestatic injury and (3) mixed injury.
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Affiliation(s)
- Melvin Qiyu Lee
- Medicine, Saolta University Health Care Group, Galway, Ireland
| | - Royale Chigozie
- Medicine, Saolta University Health Care Group, Galway, Ireland
| | - Irfan Khan
- Medicine, Roscommon University Hospital, Roscommon, Ireland
| | - Gerard O'Mara
- Medicine, Roscommon University Hospital, Roscommon, Ireland
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45
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Gough A, Soto-Gutierrez A, Vernetti L, Ebrahimkhani MR, Stern AM, Taylor DL. Human biomimetic liver microphysiology systems in drug development and precision medicine. Nat Rev Gastroenterol Hepatol 2021; 18:252-268. [PMID: 33335282 PMCID: PMC9106093 DOI: 10.1038/s41575-020-00386-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Microphysiology systems (MPS), also called organs-on-chips and tissue chips, are miniaturized functional units of organs constructed with multiple cell types under a variety of physical and biochemical environmental cues that complement animal models as part of a new paradigm of drug discovery and development. Biomimetic human liver MPS have evolved from simpler 2D cell models, spheroids and organoids to address the increasing need to understand patient-specific mechanisms of complex and rare diseases, the response to therapeutic treatments, and the absorption, distribution, metabolism, excretion and toxicity of potential therapeutics. The parallel development and application of transdisciplinary technologies, including microfluidic devices, bioprinting, engineered matrix materials, defined physiological and pathophysiological media, patient-derived primary cells, and pluripotent stem cells as well as synthetic biology to engineer cell genes and functions, have created the potential to produce patient-specific, biomimetic MPS for detailed mechanistic studies. It is projected that success in the development and maturation of patient-derived MPS with known genotypes and fully matured adult phenotypes will lead to advanced applications in precision medicine. In this Review, we examine human biomimetic liver MPS that are designed to recapitulate the liver acinus structure and functions to enhance our knowledge of the mechanisms of disease progression and of the absorption, distribution, metabolism, excretion and toxicity of therapeutic candidates and drugs as well as to evaluate their mechanisms of action and their application in precision medicine and preclinical trials.
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Affiliation(s)
- Albert Gough
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alejandro Soto-Gutierrez
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Lawrence Vernetti
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mo R Ebrahimkhani
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Andrew M Stern
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - D Lansing Taylor
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA.
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46
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Gijbels E, Pieters A, De Muynck K, Vinken M, Devisscher L. Rodent models of cholestatic liver disease: A practical guide for translational research. Liver Int 2021; 41:656-682. [PMID: 33486884 PMCID: PMC8048655 DOI: 10.1111/liv.14800] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/08/2021] [Accepted: 01/15/2021] [Indexed: 12/12/2022]
Abstract
Cholestatic liver disease denotes any situation associated with impaired bile flow concomitant with a noxious bile acid accumulation in the liver and/or systemic circulation. Cholestatic liver disease can be subdivided into different types according to its clinical phenotype, such as biliary atresia, drug-induced cholestasis, gallstone liver disease, intrahepatic cholestasis of pregnancy, primary biliary cholangitis and primary sclerosing cholangitis. Considerable effort has been devoted to elucidating underlying mechanisms of cholestatic liver injuries and explore novel therapeutic and diagnostic strategies using animal models. Animal models employed according to their appropriate applicability domain herein play a crucial role. This review provides an overview of currently available in vivo animal models, fit-for-purpose in modelling different types of cholestatic liver diseases. Moreover, a practical guide and workflow is provided which can be used for translational research purposes, including all advantages and disadvantages of currently available in vivo animal models.
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Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium,Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Alanah Pieters
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Kevin De Muynck
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium,Hepatology Research UnitInternal Medicine and PaediatricsLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Lindsey Devisscher
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
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47
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Gatti M, Ippoliti I, Poluzzi E, Antonazzo IC, Moro PA, Moretti U, Menniti-Ippolito F, Mazzanti G, De Ponti F, Raschi E. Assessment of adverse reactions to α-lipoic acid containing dietary supplements through spontaneous reporting systems. Clin Nutr 2021; 40:1176-1185. [PMID: 32778460 DOI: 10.1016/j.clnu.2020.07.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/07/2020] [Accepted: 07/20/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Alpha-lipoic acid (ALA)-containing dietary supplements are widely used in clinical practice, although their safety assessment is under-investigated. We characterize the safety profile of ALA-containing products by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS Suspected ARs to ALA-containing products were extracted from the Italian Phytovigilance System (IPS), and scrutinized in terms of seriousness and causality (through WHO UMC system), with a specific focus on important (IMEs) and designated medical events (DMEs). To characterize the reporting profile from an international perspective, the WHO-VigiBase was also queried. RESULTS From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 ARs to ALA-containing products were collected. Women were involved in 68.1% of cases. Skin (44.9%) and gastrointestinal disorders (10.8%) were the most frequently represented ARs. Causality assessment resulted as definite (15), probable (35), possible (24), unlikely (5), and unclassifiable (37). In 70% of cases, events occurred within 30 days of ALA use. Forty-five reports were serious (38.8%), being insulin autoimmune syndrome the most frequently reported (N = 10). IMEs were recorded in 20 cases, including four DMEs (3 angioedema and one anaphylactic shock). Similar distribution emerged from the 5641 reports in the WHO-VigiBase. CONCLUSIONS The remarkable reporting of unpredictable skin, immune and hepatic ARs, coupled with seriousness, strong causality and early onset, calls for a) careful risk-benefit assessment of ALA-containing products by regulators; b) awareness and monitoring by clinicians and c) continuous vigilance of their safety profile through valuable spontaneous reporting systems such as IPS.
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Affiliation(s)
- Milo Gatti
- Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Ilaria Ippoliti
- Centre for Drug Research and Evaluation, National Institute of Health, Rome, Italy
| | - Elisabetta Poluzzi
- Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Ippazio Cosimo Antonazzo
- Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Ugo Moretti
- Department of Public Health and Community Medicine, University of Verona, Verona, Italy
| | | | - Gabriela Mazzanti
- Department of Physiology and Pharmacology 'Vittorio Erspamer', Sapienza University of Rome, Rome, Italy
| | - Fabrizio De Ponti
- Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Emanuel Raschi
- Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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48
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Ahmad W, Waqar M, Hadi MH, Muhammad AS, Iqbal N. Acute Cholestatic Liver Injury Due to Ciprofloxacin in a Young Healthy Adult. Cureus 2021; 13:e13340. [PMID: 33747648 PMCID: PMC7967918 DOI: 10.7759/cureus.13340] [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: 11/24/2022] Open
Abstract
Ciprofloxacin is a commonly prescribed antibiotic due to its broad spectrum and good safety profile. However, recent evidence suggests that it has the propensity to cause idiosyncratic drug-induced liver injury. There are 25 reported cases of ciprofloxacin induced severe liver injury in the literature. Here, we describe another case of acute cholestatic liver injury due to ciprofloxacin. A 32-year-old female presented to the gastroenterology department with a week's history of pruritus, jaundice, and abdominal pain. Her symptoms started three days after completing a ciprofloxacin course for urinary tract infection. Her hepatic enzymes were elevated and showed a cholestatic pattern. An extensive workup, including viral serology, autoimmune profile, and imaging studies, did not reveal any underlying cholestasis cause. Her liver biopsy findings were consistent with drug-induced cholestasis. A diagnosis of ciprofloxacin-induced cholestatic liver injury was made based on the onset of symptoms and liver enzyme derangements following the use of ciprofloxacin, improvement in clinical as well as biochemical parameters after cessation of ciprofloxacin, and the liver biopsy findings. The patient received supportive treatment, and her liver enzymes returned to baseline six weeks after admission. Clinicians need to be aware that if the patient develops any liver injury symptoms while using ciprofloxacin, the drug should be stopped immediately, and a thorough evaluation should be done. The patient should also be advised to avoid ciprofloxacin and other quinolones in the future.
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Affiliation(s)
- Wiqas Ahmad
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Gastroenterology and Hepatology, Hayatabad Medical Complex Peshawar, Peshawar, PAK
| | - Muhammad Waqar
- Internal Medicine, The Dudley Group NHS Foundation Trust, Dudley, GBR
| | - Muhammad Hanif Hadi
- Gastroenterology and Hepatology, Hayatabad Medical Complex Peshawar, Peshawar, PAK
| | - Agha Syed Muhammad
- Internal Medicine and Gastroenterology, Russells Hall Hospital, Dudley, GBR
| | - Nasir Iqbal
- Internal Medicine, Khyber Teaching Hospital, Peshawar, PAK
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49
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Cheung S, Bulovic J, Pillai A, Manoj T, Neeraj K. A case of meropenem-induced liver injury and jaundice. J Community Hosp Intern Med Perspect 2021; 11:143-144. [PMID: 33552438 PMCID: PMC7850334 DOI: 10.1080/20009666.2020.1845929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/30/2020] [Indexed: 01/22/2023] Open
Abstract
This report describes what we believe is the first reported case of clinically significant cholestasis and acute liver injury within three days of meropenem therapy. An 83-year-old Hispanic female was admitted for sepsis of unknown origin and was started on intravenous meropenem. Three days following initiation of the antibiotic, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus. Possible causes of cholestasis were excluded after extensive investigations. A drug-induced liver injury was suspected and meropenem was discontinued. Following discontinuation of meropenem, the patient demonstrated symptomatic and laboratory improvements, and her liver enzymes and bilirubin levels were normalized.
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Affiliation(s)
- Szeya Cheung
- Department of Medicine, Long Island Community Hospital, Patchogue, NY, USA
| | - Jennifer Bulovic
- Department of Medicine, Long Island Community Hospital, Patchogue, NY, USA
| | - Ajish Pillai
- Gastroenterology and Hepatology, Long Island Community Hospital, Patchogue, NY, USA
| | - Trehan Manoj
- Infectious Disease, Long Island Community Hospital, Patchogue, NY, USA
| | - Katriyar Neeraj
- Critical Care, Long Island Community Hospital, Patchogue, NY, USA
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50
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Greca RD, Cunha-Silva M, Costa LBE, Costa JGF, Mazo DFC, Sevá-Pereira T, Nascimento MMC, Pereira IE, Oliveira FC, Faria GAS, Neto FLP, Almeida JRS. Vanishing bile duct syndrome related to DILI and Hodgkin lymphoma overlap: A rare and severe case. Ann Hepatol 2021; 19:107-112. [PMID: 31537508 DOI: 10.1016/j.aohep.2019.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/03/2019] [Accepted: 06/10/2019] [Indexed: 02/04/2023]
Abstract
Vanishing bile duct syndrome is a rare acquired condition, characterized by progressive loss of intrahepatic bile ducts leading to ductopenia and cholestasis. It can be associated with infections, ischemia, drug adverse reactions, neoplasms, autoimmune disease, and allograft rejection. Prognosis is variable and depends on the etiology of bile duct injury. We report the case of a 25-year-old female with cholestatic hepatitis and concomitant intakes of hepatotoxic substances, such as garcinia, field horsetail, and ketoprofen. On suspicion of a drug-induced liver injury, the drugs were promptly withdrawn and ursodeoxycholic acid was started with initial clinical and laboratory improvement, and the patient was discharged from the hospital. One month later, she had a new increase in bilirubin levels and canalicular enzymes, requiring a liver biopsy that showed significant loss of intrahepatic bile ducts, which was compatible with vanishing bile duct syndrome. This was confirmed by using cytokeratin 19 on immunohistochemistry. There was subsequent lymph node enlargement in several chains, and relevant weight loss. Histological analysis of a cervical lymph node revealed nodular sclerosis-subtype classic Hodgkin lymphoma. In this setting, vanishing bile duct syndrome was related to Hodgkin lymphoma and a drug-induced liver injury overlap, leading to progressive cholestasis with a worse prognosis. The patient's response to chemotherapy was poor, requiring biological therapy with brentuximab vedotin. It is crucial for physicians to create a broad differential diagnosis in suspected vanishing bile duct syndrome patients, especially to rule out malignancies.
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Affiliation(s)
- Raquel D Greca
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil.
| | - Marlone Cunha-Silva
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Larissa B E Costa
- Department of Pathology, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Júlia G F Costa
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Daniel F C Mazo
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil; Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo, School of Medicine, São Paulo, Brazil
| | - Tiago Sevá-Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marlla M C Nascimento
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isadora E Pereira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Flávia C Oliveira
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Guilherme A S Faria
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Fernando L P Neto
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Jazon R S Almeida
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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