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Ridola L, Mari A. Rifaximin discontinuation during broad-spectrum antibiotic treatment in critically ill patients with hepatic encephalopathy. World J Hepatol 2024; 16:1356-1360. [PMID: 39606171 PMCID: PMC11586757 DOI: 10.4254/wjh.v16.i11.1356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 10/01/2024] [Accepted: 10/23/2024] [Indexed: 11/06/2024] Open
Abstract
Hepatic encephalopathy (HE) is one of the main complications of cirrhosis, characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality, morbidity and recurrent hospitalizations. Due to the central role in HE pathogenesis of ammonia and other neurotoxins primarily produced by the gut microbiota, the main therapeutic approaches for the treatment of HE are based on the modulation of the gut microbiota. Rifaximin is a non-absorbable broad-spectrum antibiotic, that is effective against ammonia-producing gram-positive, gram-negative, and anaerobic species, approved for the treatment of HE in secondary prophylaxis. The chronic administration of rifaximin in this setting is associated with a lower risk of HE recurrence and mortality, while the role of rifaximin for the treatment of an overt-HE episode in inpatients is still unclear. Limited data exist about the coadministration of rifaximin and broad-spectrum antibiotics commonly used to treat concomitant infections, as patients receiving or recently treated with antibiotics were frequently excluded from clinical trials. In this editorial we comment on the article by Ward et al published in the recent issue of the World Journal of Hepatology. It is a single center, retrospective, quasi-experimental, pharmacist-driven protocol, with the aim to evaluate the feasibility and safety of rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units. The study revealed no differences between the protocol and control group in terms of primary outcome (days alive and free of delirium and coma to day 14) and secondary outcomes which include: Intensive care mortality, intensive care length of stay, intravenous vasopressor requirement changes and adverse effects rate. Therefore, rifaximin discontinuation during broad-spectrum antibiotic therapy does not appear to negatively impact the clinical status of critically ill liver patients, with a similar safety profile and significant cost savings, as compared to the coadministration of rifaximin and broad-spectrum antibiotics. In agreement with Ward et al, a recently published double-blind, randomized controlled trial provided additional evidence to support the feasibility of withholding rifaximin during broad-spectrum antibiotic therapy in critically ill cirrhotic patients. However, given the limitations of these studies, further multicentric and prospective clinical trials, enrolling a larger sample of non-critically ill patients, are needed to better establish the role of rifaximin in this setting.
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Affiliation(s)
- Lorenzo Ridola
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Rome 00185, Italy.
| | - Alessandro Mari
- Department of Medical and Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Rome 00185, Italy
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Liu Q, Ba X, Han L, Yan J, Chen Z, Qin K, Tu S, Shen P. Dahuang-Wumei decoction protects against hepatic encephalopathy in mice: Behavioural, biochemical, and molecular evidence. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155419. [PMID: 38522314 DOI: 10.1016/j.phymed.2024.155419] [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: 08/20/2023] [Revised: 01/17/2024] [Accepted: 02/03/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Disturbance of the blood‒brain barrier (BBB) and associated inflammatory responses are observed in patients with hepatic encephalopathy (HE) and can cause long-term complications. Dahuang-Wumei decoction (DWD) is a renowned traditional Chinese herbal medicine with a long history of clinical use and has been widely employed as an effective treatment for hepatic encephalopathy (HE). Despite its established efficacy, the precise mechanisms underlying the therapeutic effects of DWD have not been fully elucidated. PURPOSE The present study aimed to comprehensively explore the potential effects and underlying molecular mechanisms of DWD on HE through an integrated investigation that included both in vivo and in vitro experiments. METHODS In the present study, carbon tetrachloride (CCl4) and thioacetamide (TAA) were used to establish an HE model in mice. The therapeutic effects of DWD on liver injury, fibrosis, brain injury, behaviour, and consciousness disorders were evaluated in vivo. C8-D1A and bEnd.3 cells were used to construct a BBB model in vitro. The effects of DWD on proinflammatory factor expression, BBB damage and the Wnt/β-catenin pathway were detected in vivo and in vitro. RESULTS Our results showed that DWD can improve liver injury and fibrosis and brain damage and inhibit neurofunctional and behavioural disorders in mice with HE. Afterwards, we found that DWD decreased the levels of proinflammatory factors and suppressed BBB disruption by increasing the levels of junction proteins in vivo and vitro. Further studies verified that the Wnt/β-catenin pathway may play a pivotal role in mediating the inhibitory effect of DWD on HE. CONCLUSION These results demonstrated that DWD can treat HE by preventing BBB disruption, and the underlying mechanisms involved were associated with the activation of the Wnt/β-catenin pathway and the inhibition of inflammatory responses.
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Affiliation(s)
- Qiong Liu
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Xin Ba
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Liang Han
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Jiahui Yan
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Zhe Chen
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Kai Qin
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Shenghao Tu
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China
| | - Pan Shen
- Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan 430030, China; Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, China.
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Reis T, Moura PC, Gonçalves D, Ribeiro PA, Vassilenko V, Fino MH, Raposo M. Ammonia Detection by Electronic Noses for a Safer Work Environment. SENSORS (BASEL, SWITZERLAND) 2024; 24:3152. [PMID: 38794006 PMCID: PMC11125007 DOI: 10.3390/s24103152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 05/11/2024] [Accepted: 05/14/2024] [Indexed: 05/26/2024]
Abstract
Providing employees with proper work conditions should be one of the main concerns of any employer. Even so, in many cases, work shifts chronically expose the workers to a wide range of potentially harmful compounds, such as ammonia. Ammonia has been present in the composition of products commonly used in a wide range of industries, namely production in lines, and also laboratories, schools, hospitals, and others. Chronic exposure to ammonia can yield several diseases, such as irritation and pruritus, as well as inflammation of ocular, cutaneous, and respiratory tissues. In more extreme cases, exposure to ammonia is also related to dyspnea, progressive cyanosis, and pulmonary edema. As such, the use of ammonia needs to be properly regulated and monitored to ensure safer work environments. The Occupational Safety and Health Administration and the European Agency for Safety and Health at Work have already commissioned regulations on the acceptable limits of exposure to ammonia. Nevertheless, the monitoring of ammonia gas is still not normalized because appropriate sensors can be difficult to find as commercially available products. To help promote promising methods of developing ammonia sensors, this work will compile and compare the results published so far.
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Affiliation(s)
- Tiago Reis
- Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal; (T.R.); (P.C.M.); (P.A.R.); (V.V.)
| | - Pedro Catalão Moura
- Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal; (T.R.); (P.C.M.); (P.A.R.); (V.V.)
| | - Débora Gonçalves
- Institute of Physics of Sao Carlos, University of Sao Paulo, São Carlos 13566-590, Brazil;
| | - Paulo A. Ribeiro
- Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal; (T.R.); (P.C.M.); (P.A.R.); (V.V.)
| | - Valentina Vassilenko
- Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal; (T.R.); (P.C.M.); (P.A.R.); (V.V.)
| | - Maria Helena Fino
- LASI—Associated Laboratory of Intelligent Systems, CTS—Centre for Technology and Systems, UNINOVA, Department of Electrotechnical and Computer Engineering, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal;
| | - Maria Raposo
- Laboratory of Instrumentation, Biomedical Engineering and Radiation Physics (LIBPhys-UNL), Department of Physics, NOVA School of Science and Technology, NOVA University of Lisbon, 2829-516 Caparica, Portugal; (T.R.); (P.C.M.); (P.A.R.); (V.V.)
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Maimunah U, Kurniawan AA, Palayukan A. Adverse Effects of Long-term Proton Pump Inhibitors in Chronic Liver Disease Patients – A Preliminary Article Review. REVIEW OF CLINICAL PHARMACOLOGY AND PHARMACOKINETICS - INTERNATIONAL EDITION 2024; 38:87-97. [DOI: 10.61873/wway6273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Background: Proton pump inhibitors (PPIs) are widely prescribed medications for the management of gastroesophageal reflux disease (GERD) and peptic ulcer disease. Despite their efficacy, concerns have emerged regarding their potential adverse effects, particularly in patients with chronic liver disease (CLD). CLD patients often experience gastrointestinal symptoms and may be prescribed PPIs, but the impact of PPI use on liver function and disease progression remains uncertain. Scope: This study aims to evaluate the adverse effects of PPIs on CLD patients through a review of available literature. The scope encompasses a review of studies examining the association between PPI use and liver-related outcomes, including hepatic encephalopathy, hepatic decompensation, liver cirrhosis progression, and mortality, among CLD patients. Method: A scoping review of relevant literature were conducted to identify studies investigating the adverse effects of PPIs in CLD patients. Databases including PubMed and Google Scholar were searched for articles published up to January, 1 2023. Eligible studies were selected based on predefined inclusion criteria. Results: The review identified 27 studies meeting the inclusion criteria, comprising observational studies and meta-analysis. The review revealed a significant association between PPI use and adverse liver outcomes in CLD patients. Specifically, PPI use was associated with increased risk of SBP based on studies reviewed, while other complications remained inconclusive. Conclusion: The findings suggest that PPI use may have detrimental effects on disease progression in CLD patients, Long-term use of PPIs can lead to higher risk of SBP in CLD patients. Clinicians should exercise caution when prescribing PPIs to this vulnerable population and consider alternative treatment options or minimize PPI use to mitigate potential adverse outcomes. Further research is warranted to elucidate the underlying mechanisms, confirm the effect of PPIs toward other complications of CLD and establish guidelines for PPI use in CLD patients.
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Wang Y, Guo D, Winkler R, Lei X, Wang X, Messina J, Luo J, Lu H. Development of novel liver-targeting glucocorticoid prodrugs. MEDICINE IN DRUG DISCOVERY 2024; 21:100172. [PMID: 38390434 PMCID: PMC10883687 DOI: 10.1016/j.medidd.2023.100172] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2024] Open
Abstract
Background Glucocorticoids (GCs) are widely used in the treatment of inflammatory liver diseases and sepsis, but GC's various side effects on extrahepatic tissues limit their clinical benefits. Liver-targeting GC therapy may have multiple advantages over systemic GC therapy. The purpose of this study was to develop novel liver-targeting GC prodrugs as improved treatment for inflammatory liver diseases and sepsis. Methods A hydrophilic linker or an ultra-hydrophilic zwitterionic linker carboxylic betaine (CB) was used to bridge cholic acid (CA) and dexamethasone (DEX) to generate transporter-dependent liver-targeting GC prodrugs CA-DEX and the highly hydrophilic CA-CB-DEX. The efficacy of liver-targeting DEX prodrugs and DEX were determined in primary human hepatocytes (PHH), macrophages, human whole blood, and/or mice with sepsis induced by cecal ligation and puncture. Results CA-DEX was moderately water soluble, whereas CA-CB-DEX was highly water soluble. CA-CB-DEX and CA-DEX displayed highly transporter-dependent activities in reporter assays. Data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe alcoholic hepatitis. These key GR-target genes were similarly and rapidly (within 6 h) induced or down-regulated by CA-CB-DEX and DEX in PHH. CA-CB-DEX had much weaker inhibitory effects than DEX on endotoxin-induced cytokines in mouse macrophages and human whole blood. In contrast, CA-CB-DEX exerted more potent anti-inflammatory effects than DEX in livers of septic mice. Conclusions CA-CB-DEX demonstrated good hepatocyte-selectivity in vitro and better anti-inflammatory effects in vivo. Further test of CA-CB-DEX as a novel liver-targeting GC prodrug for inflammatory liver diseases and sepsis is warranted.
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Affiliation(s)
- Yazheng Wang
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Dandan Guo
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Rebecca Winkler
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Xiaohong Lei
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Xiaojing Wang
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Jennifer Messina
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Juntao Luo
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
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Lu H, Zhang H, Wu Z, Li L. Microbiota-gut-liver-brain axis and hepatic encephalopathy. MICROBIOME RESEARCH REPORTS 2024; 3:17. [PMID: 38841407 PMCID: PMC11149093 DOI: 10.20517/mrr.2023.44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 06/07/2024]
Abstract
Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.
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Affiliation(s)
| | | | | | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
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Ward JA, Yerke J, Lumpkin M, Kapoor A, Lindenmeyer CC, Bass S. Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy. World J Hepatol 2023; 15:1226-1236. [DOI: 10.4254/wjh.v15.i11.1226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/05/2023] [Accepted: 10/23/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy, but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy. Due to overlapping spectrums of activity, combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary. A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease. It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs.
AIM To determine the clinical, safety, and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients.
METHODS This was a single-center, quasi-experimental, pre-post study based on a pilot pharmacist-driven protocol. Patients in the protocol group were prospectively identified via the medical intensive care unit (ICU) (MICU) protocol to have rifaximin withheld during broad-spectrum antibiotic treatment. These were compared to a historical cohort who received combination therapy with broad-spectrum antibiotics and rifaximin. All data were collected retrospectively. The primary outcome was days alive and free of delirium and coma (DAFD) to 14 d. Safety outcomes included MICU length of stay, 48-h change in vasopressor dose, and ICU mortality. Secondary outcomes characterized rifaximin cost savings and protocol adherence. Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors.
RESULTS Each group included 32 patients. The median number of delirium- and coma-free days was similar in the control and protocol groups [3 interquartile range (IQR 0, 8) vs 2 (IQR 0, 9.5), P = 0.93]. In multivariable analysis, group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d. The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy [6 d control (IQR 3, 9.5) vs 1 d protocol (IQR 0, 1); P < 0.001]. Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements. Overall adherence to the protocol was 91.4%. The median estimated total cost of rifaximin therapy per patient was reduced from $758.40 (IQR $379.20, $1200.80) to $126.40 (IQR $0, $126.40), P < 0.01.
CONCLUSION The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.
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Affiliation(s)
- Jessica A Ward
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Jason Yerke
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Mollie Lumpkin
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Aanchal Kapoor
- Department of Critical Care Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Christina C Lindenmeyer
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Stephanie Bass
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
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Santos RPC, Toscano ECDB, Rachid MA. Anti-inflammatory strategies for hepatic encephalopathy: preclinical studies. ARQUIVOS DE NEURO-PSIQUIATRIA 2023. [PMID: 37487550 PMCID: PMC10371400 DOI: 10.1055/s-0043-1767819] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neuropsychiatric syndrome. Often, HE causes cognitive and motor dysfunctions due to an acute or chronic insufficiency of the liver or a shunting between the hepatic portal vein and systemic vasculature. Liver damage induces peripheral changes, such as in the metabolism and peripheral inflammatory responses that trigger exacerbated neuroinflammation. In experimental models, anti-inflammatory strategies have demonstrated neuroprotective effects, leading to a reduction in HE-related cognitive and motor impairments. In this scenario, a growing body of evidence has shown that peripheral and central nervous system inflammation are promising preclinical targets. In this review, we performed an overview of FDA-approved drugs and natural compounds which are used in the treatment of other neurological and nonneurological diseases that have played a neuroprotective role in experimental HE, at least in part, through anti-inflammatory mechanisms. Despite the exciting results from animal models, the available data should be critically interpreted, highlighting the importance of translating the findings for clinical essays.
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Affiliation(s)
- Rafaela Pinto Coelho Santos
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
| | - Eliana Cristina de Brito Toscano
- Universidade Federal de Juiz de Fora, Faculdade de Medicina, Departamento de Patologia, Laboratório Integrado de Pesquisa em Patologia, Juiz de Fora MG, Brazil
- Universidade Federal de Juiz e Fora, Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Juiz de Fora MG, Brazil
| | - Milene Alvarenga Rachid
- Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Patologia Geral, Laboratório de Patologia Celular e Molecular, Belo Horizonte MG, Brazil
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Yang G, Jena PK, Hu Y, Sheng L, Chen SY, Slupsky CM, Davis R, Tepper CG, Wan YJY. The essential roles of FXR in diet and age influenced metabolic changes and liver disease development: a multi-omics study. Biomark Res 2023; 11:20. [PMID: 36803569 PMCID: PMC9938992 DOI: 10.1186/s40364-023-00458-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 01/24/2023] [Indexed: 02/20/2023] Open
Abstract
BACKGROUND Aging and diet are risks for metabolic diseases. Bile acid receptor farnesoid X receptor (FXR) knockout (KO) mice develop metabolic liver diseases that progress into cancer as they age, which is accelerated by Western diet (WD) intake. The current study uncovers the molecular signatures for diet and age-linked metabolic liver disease development in an FXR-dependent manner. METHODS Wild-type (WT) and FXR KO male mice, either on a healthy control diet (CD) or a WD, were euthanized at the ages of 5, 10, or 15 months. Hepatic transcriptomics, liver, serum, and urine metabolomics as well as microbiota were profiled. RESULTS WD intake facilitated hepatic aging in WT mice. In an FXR-dependent manner, increased inflammation and reduced oxidative phosphorylation were the primary pathways affected by WD and aging. FXR has a role in modulating inflammation and B cell-mediated humoral immunity which was enhanced by aging. Moreover, FXR dictated neuron differentiation, muscle contraction, and cytoskeleton organization in addition to metabolism. There were 654 transcripts commonly altered by diets, ages, and FXR KO, and 76 of them were differentially expressed in human hepatocellular carcinoma (HCC) and healthy livers. Urine metabolites differentiated dietary effects in both genotypes, and serum metabolites clearly separated ages irrespective of diets. Aging and FXR KO commonly affected amino acid metabolism and TCA cycle. Moreover, FXR is essential for colonization of age-related gut microbes. Integrated analyses uncovered metabolites and bacteria linked with hepatic transcripts affected by WD intake, aging, and FXR KO as well as related to HCC patient survival. CONCLUSION FXR is a target to prevent diet or age-associated metabolic disease. The uncovered metabolites and microbes can be diagnostic markers for metabolic disease.
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Affiliation(s)
- Guiyan Yang
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Prasant K. Jena
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Ying Hu
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Lili Sheng
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Shin-Yu Chen
- grid.27860.3b0000 0004 1936 9684Department of Nutrition, University of California, Davis, CA USA
| | - Carolyn M. Slupsky
- grid.27860.3b0000 0004 1936 9684Department of Nutrition, University of California, Davis, CA USA
| | - Ryan Davis
- grid.27860.3b0000 0004 1936 9684Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA 95817 USA
| | - Clifford G. Tepper
- grid.27860.3b0000 0004 1936 9684Department of Biochemistry and Molecular Medicine, University of California, Davis, Sacramento, CA USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis Health. Room 3400B, Research Building III, 4645 2nd Ave, Sacramento, CA, 95817, USA.
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Ashwagandha-loaded nanocapsules improved the behavioral alterations, and blocked MAPK and induced Nrf2 signaling pathways in a hepatic encephalopathy rat model. Drug Deliv Transl Res 2023; 13:252-274. [PMID: 35672652 PMCID: PMC9726678 DOI: 10.1007/s13346-022-01181-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2022] [Indexed: 12/14/2022]
Abstract
Ashwagandha (ASH), a vital herb in Ayurvedic medicine, demonstrated potent preclinical hepato- and neuroprotective effects. However, its efficacy is limited due to low oral bioavailability. Accordingly, we encapsulated ASH extract in chitosan-alginate bipolymeric nanocapsules (ASH-BPNCs) to enhance its physical stability and therapeutic effectiveness in the gastrointestinal tract. ASH-BPNC was prepared by emulsification followed by sonication. The NCs showed small particle size (< 220 nm), zeta-potential of 25.2 mV, relatively high entrapment efficiency (79%), physical stability at acidic and neutral pH, and in vitro release profile that extended over 48 h. ASH-BPNC was then investigated in a thioacetamide-induced hepatic encephalopathy (HE) rat model. Compared with free ASH, ASH-BPNC improved survival, neurological score, general motor activity, and cognitive task-performance. ASH-BPNC restored ALT, AST and ammonia serum levels, and maintained hepatic and brain architecture. ASH-BPNC also restored GSH, MDA, and glutathione synthetase levels, and Nrf2 and MAPK signaling pathways in liver and brain tissues. Moreover, ASH-BPNC downregulated hepatic NF-κB immunohistochemical expression. Moreover, the in vivo biodistribution studies demonstrated that most of the administered ASH-BPNC is accumulated in the brain and hepatic tissues. In conclusion, chitosan-alginate BPNCs enhanced the hepatoprotective and neuroprotective effects of ASH, thus providing a promising therapeutic approach for HE.
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Zhou Z, Li K, Guo J, Wang Y, Wei Y, Duan J, Chen M, Shi L, Hu W. Green Tea Catechin EGCG Ameliorates Thioacetamide-Induced Hepatic Encephalopathy in Rats via Modulation of the Microbiota-Gut-Liver Axis. Mol Nutr Food Res 2022; 67:e2200821. [PMID: 36573265 DOI: 10.1002/mnfr.202200821] [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: 11/23/2022] [Revised: 11/23/2022] [Indexed: 12/28/2022]
Abstract
SCOPE Existing research suggests that (-)-epigallocatechin-3-gallate (EGCG), which is a natural tea catechin active substance, can protect against liver injury. However, its mechanism for hepatic encephalopathy (HE) treatment is still unclear. In this study, the role of EGCG in the amelioration of HE rats and the effect on the microbiota-gut-liver axis are mainly analyzed. METHODS AND RESULTS Thioacetamide (TAA) is employed to induce the HE model in rats. The results of open field test show that EGCG restores locomotor activity and exploratory behavior. Histological and biochemical results demonstrate that EGCG ameliorates brain and liver damage, decreases the expression of pro-inflammatory cytokines, and increases the activity of antioxidant enzymes. Meanwhile, EGCG modulates the Nrf2 pathway and TLR4/NF-κB pathway to mitigate TAA-induced oxidative stress and inflammatory responses. Immunohistochemistry reveals protection of the intestinal barrier by EGCG upregulating the expression of occludin and zonula occludens-1. Furthermore, serum levels of ammonia and LPS are reduced. 16S rRNA analysis shows that EGCG treatment increases the abundance of beneficial bacteria (e.g., Bifidobacterium, Lactobacillus, and Limosilactobacillus). CONCLUSION The above results reveal that EGCG has anti-oxidative stress and anti-inflammatory effects, and ameliorates the condition through the microbiota-gut-liver axis, with potential for the treatment of HE.
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Affiliation(s)
- Zhengming Zhou
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Ke Li
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Jiankui Guo
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yunfeng Wang
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Yaoyao Wei
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Juan Duan
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Muxi Chen
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Lei Shi
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Wen Hu
- Department of Clinical Nutrition, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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12
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Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms. J Xenobiot 2022; 12:266-288. [PMID: 36278756 PMCID: PMC9589945 DOI: 10.3390/jox12040019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/03/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC’s extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.
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13
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Zhang C, Ni W, Zhu Y, Lin J, Li H, Zhao Z, Wang K, Huo H, Luo M. Construction and comprehensive analysis of a lncRNA-mRNA interactive network to reveal a potential lncRNA for hepatic encephalopathy development. Hum Cell 2022; 35:1060-1070. [PMID: 35583799 DOI: 10.1007/s13577-022-00714-4] [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: 03/26/2022] [Accepted: 05/05/2022] [Indexed: 11/04/2022]
Abstract
Little is known about the role of lncRNA-mRNA regulatory relationships in hepatic encephalopathy (HE). Here, we aimed to construct the potential lncRNA and mRNA interactive network in forecasting HE development in patients with liver cirrhosis using different bioinformatic analysis method. Through analyses, we found that AL137857.1 had the most connections with other mRNAs and was deemed as a hub lncRNA. It was obviously upregulated in HE patients, which was also validated by another independent dataset. GO and KEGG analyses suggested that AL137857.1 was involved in microglial cell activation, phagocytosis, cytokine biosynthetic process, interleukin-6 production and tumor necrosis factor production. In vitro experiments suggested LPS could stimulate microglia to generate AL137857.1. In addition, we found that inhibition of AL137857.1 suppressed the expression of a series of inflammatory cytokines, including IL-1, IL-6, TNF-α, Cox2 and iNOS. Conversely, AL137857.1 over-expression induced a marked increase in these factors. Finally, AL137857.1 was demonstrated to be highly associated with the ability of microglial phagocytosis. Taken together, we have constructed a lncRNA-mRNA regulatory network associated with HE and explored the biological significance of mRNAs in the network, then discovered a novel lncRNA AL137857.1 in HE that might act as a potential regulator of the downstream inflammatory cytokines.
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Affiliation(s)
- Chihao Zhang
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China
| | - Wei Ni
- Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, China
| | - Yiming Zhu
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China
| | - Jiayun Lin
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China
| | - Hongjie Li
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China
| | - Zhifeng Zhao
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China
| | - Ke Wang
- Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Treatment Centre Li Huili Hospital, Ningbo University, 1111 Jiang Nan Road, Yinzhou District, Ningbo, 315040, Zhejiang, China.
| | - Haizhong Huo
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China.
| | - Meng Luo
- Department of General Surgery, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, 639 Zhi Zao Ju Road, Huangpu District, Shanghai, 200011, China.
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14
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Yang J, Yin M, Hou Y, Li H, Guo Y, Yu H, Zhang K, Zhang C, Jia L, Zhang F, Li X, Bian H, Li Z. Role of ammonia for brain abnormal protein glycosylation during the development of hepatitis B virus-related liver diseases. Cell Biosci 2022; 12:16. [PMID: 35164881 PMCID: PMC8842931 DOI: 10.1186/s13578-022-00751-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/29/2022] [Indexed: 11/30/2022] Open
Abstract
Background Ammonia is the most typical neurotoxin in hepatic encephalopathy (HE), but the underlying pathophysiology between ammonia and aberrant glycosylation in HE remains unknown. Results Here, we used HBV transgenic mice and astrocytes to present a systems-based study of glycosylation changes and corresponding enzymes associated with the key factors of ammonia in HE. We surveyed protein glycosylation changes associated with the brain of HBV transgenic mice by lectin microarrays. Upregulation of Galβ1-3GalNAc mediated by core 1 β1,3-galactosyltransferase (C1GALT1) was identified as a result of ammonia stimulation. Using in vitro assays, we validated that upregulation of C1GALT1 is a driver of deregulates calcium (Ca2+) homeostasis by overexpression of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in astrocytes. Conclusions We demonstrated that silencing C1GALT1 could depress the IP3R1 expression, an effective strategy to inhibit the ammonia-induced upregulation of Ca2+ activity, thereby C1GALT1 and IP3R1 may serve as therapeutic targets in hyperammonemia of HE. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00751-4.
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Affiliation(s)
- Jiajun Yang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Mengqi Yin
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Yao Hou
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Hao Li
- Cell Engineering Research Centre and Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yonghong Guo
- Department of Infectious Diseases, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Hanjie Yu
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Kun Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Chen Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Liyuan Jia
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Fan Zhang
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Xia Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Huijie Bian
- Cell Engineering Research Centre and Department of Cell Biology, Fourth Military Medical University, Xi'an, 710032, China.
| | - Zheng Li
- Laboratory for Functional Glycomics, College of Life Sciences, Northwest University, Xi'an, 710069, China.
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Shahgond L, Patel C, Thakur K, Sarkar D, Acharya S, Patel P. Therapeutic potential of probiotics - Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 on thioacetamide-induced acute hepatic encephalopathy in rats. Metab Brain Dis 2022; 37:185-195. [PMID: 34731397 DOI: 10.1007/s11011-021-00862-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/23/2021] [Indexed: 01/18/2023]
Abstract
PURPOSE Hepatic encephalopathy (HE) or hepatic coma is a demanding, not utterly understood complication of acute and chronic liver dysfunction and portosystemic shunting. In HE, hyperammonemia and inflammatory responses are believed to act in synergism. Probiotics, Lactobacillus plantarum UBLP40 and Bacillus clausii UBBC07 reduce small intestinal bacterial overgrowth and hyperammonemia, thereby preventing HE development. METHODS The effect of probiotics-Lactobacillus plantarum UBLP40 (107 CFU/day, 14 days) and Bacillus clausii UBBC07 (107 CFU/day, 14 days) combination and standard drug-lactulose (2.5 ml/kg in 3 divided doses, 14 days) was studied in thioacetamide (250 mg/kg for three days) induced acute HE in rats by measuring behavioural parameters, biochemical parameters (serum AST, ALT, ALP and ammonia level), neurochemical parameters and histopathology study in brain and liver. RESULTS In contrast to only thioacetamide treated rats, probiotics treatment substantially (p < 0.001) reduced liver function parameters, i.e. serum AST, ALT, ALP, and ammonia, improved behaviour parameters, i.e. decreased motor disruption, improved memory impairment. Probiotics treated rats have also shown a substantial improvement in oxidative stress parameters i.e. reduced lipid peroxidation and increased glutathione level in brain tissue and ameliorated the histopathological changes induced by thioacetamide in the brain and liver. CONCLUSIONS It can be concluded based on the findings that the combination therapy of Lactobacillus plantarum UBLP40 and Bacillus clausiiUBBC07 proves to be effective in acute hepatic encephalopathy in the preclinical stage, and further studies are required to assess this therapy potential in the clinical setting.
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Affiliation(s)
- Lalita Shahgond
- Department of Pharmacology, S.S.R. College of Pharmacy, Silvassa, Dadra and Nagar Haveli, India, 396230
| | - Chirag Patel
- Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, 380009, India.
| | - Khushboo Thakur
- Department of Pharmacology, S.S.R. College of Pharmacy, Silvassa, Dadra and Nagar Haveli, India, 396230
| | - Dipta Sarkar
- Department of Pharmacology, S.S.R. College of Pharmacy, Silvassa, Dadra and Nagar Haveli, India, 396230
| | - Sanjeev Acharya
- Department of Pharmacology, S.S.R. College of Pharmacy, Silvassa, Dadra and Nagar Haveli, India, 396230
| | - Priyanshi Patel
- Department of Pharmacology, S.S.R. College of Pharmacy, Silvassa, Dadra and Nagar Haveli, India, 396230
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Matsubara Y, Kiyohara H, Teratani T, Mikami Y, Kanai T. Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases. Neuropharmacology 2021; 205:108915. [PMID: 34919906 DOI: 10.1016/j.neuropharm.2021.108915] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.
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Affiliation(s)
- Yuta Matsubara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.
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17
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Cheng L, Wang X, Ma X, Xu H, Yang Y, Zhang D. Effect of dihydromyricetin on hepatic encephalopathy associated with acute hepatic failure in mice. PHARMACEUTICAL BIOLOGY 2021; 59:557-564. [PMID: 33982639 PMCID: PMC8128201 DOI: 10.1080/13880209.2021.1917625] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/13/2023]
Abstract
CONTEXT Hepatic encephalopathy (HE) is a complex neuropsychiatric disease caused by liver failure. Dihydromyricetin (DMY) is a traditional medicine used to treat liver injury. OBJECTIVE To investigate the effects of dihydromyricetin (DMY) on hepatic encephalopathy associated with acute hepatic failure mice models established by thioacetamide (TAA) exposure. MATERIALS AND METHODS Female BALB/c mouse were randomly divided into control, DMY, TAA, and TAA + DMY groups (n = 8). The first two groups were intraperitoneally injected with saline or 5 mg/kg DMY, respectively. The last two groups were injected with 600 mg/kg TAA to establish HE models, and then the mice in the last group were treated with 5 mg/kg DMY. Neurological and cognition functions were evaluated 24 and 48 h after injection. Mice were sacrificed after which livers and brains were obtained for immunoblot and histopathological analysis, while blood was collected for the analysis of liver enzymes. RESULTS In the TAA + DMY group, ALT and AST decreased to 145.31 ± 12.88 U/L and 309.51 ± 25.92 U/L, respectively, whereas ammonia and TBIL decreased to 415.67 ± 41.91 μmol/L and 3.31 ± 0.35 μmol/L, respectively. Moreover, MDA decreased to 10.74 ± 3.97 nmol/g, while SOD and GST increased to 398.69 ± 231.30 U/g and 41.37 ± 21.84 U/g, respectively. The neurological score decreased to 2.87 ± 0.63, and the number of GFAP-positive cells decreased to 41.10 ± 1.66. Furthermore, the protein levels of TNF-α, IL-6, and GABAA in the cortex decreased. CONCLUSIONS We speculate that DMY can serve as a novel treatment for HE.
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Affiliation(s)
- Long Cheng
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Xiaoying Wang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Xueni Ma
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Huimei Xu
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Yifan Yang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
| | - Dekui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, People’s Republic of China
- CONTACT Dekui Zhang Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou730030, People’s Republic of China
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18
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Hou W, Lv Z, Yang J, Wu J, Wang ZY, Meng QH. Long-Term Carbohydrate-Containing Late-Evening Snack Significantly Improves the Ratio of Branched Chain Amino Acids to Aromatic Amino Acids in Adults with Liver Cirrhosis due to Hepatitis B. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1074565. [PMID: 34853787 PMCID: PMC8629637 DOI: 10.1155/2021/1074565] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND The liver is the primary organ for amino acid metabolism, and metabolic disorder of amino acids is common in liver disease. However, the characteristics of plasma amino acid profiles in patients with HBV-related cirrhosis and the impacts of late-evening snack (LES) on cirrhosis are unclear. OBJECTIVES To investigate the characteristics of plasma amino acid profiles in patients with HBV-related chronic hepatitis, cirrhosis, and the effects of late-evening snacks on plasma amino acid profiles. METHODS 86 patients with HBV-related cirrhosis and eighty patients with chronic hepatitis B were included in this study. The plasma amino acid profiles were measured by the amino acid analyzer. Patients were randomly divided into two groups, of which the liver cirrhosis group was to receive daily LES (n = 43) or non-LES (n = 43) for 6 months. Plasma amino acid profiles and biochemical parameters were measured in both groups at baseline and after 1, 3, and 6 months. RESULTS Compared to healthy controls, the plasma concentration in the liver cirrhosis group of threonine, serine, glycine, glutamine, cysteine, tyrosine, phenylalanine, arginine, and methionine increased significantly (P < 0.05), while the ratio of branched chain amino acids (BCAA) to aromatic amino acids (AAA) decreased significantly (P < 0.05). A carbohydrate-predominant LES treatment resulted in a significant increase in BCAA/AAA and decrease in the level of ammonia and glutamine compared with baseline after 6 months of supplementation (P < 0.05). Patients with Child-Pugh B and C are more responsive to changes in amino acid profiles than those with Child-Pugh A. CONCLUSIONS The application of an LES carbohydrate module for six months in liver cirrhosis patients was associated with increased BCAA/AAA and decreased level of ammonia. Patients with Child-Pugh B and C grades were the most beneficial population.
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Affiliation(s)
- Wei Hou
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Zheng Lv
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jing Yang
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jing Wu
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Zhong-ying Wang
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-hua Meng
- Department of Critical Care Medicine of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
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Salman T, Elsabaawy M, Omar M, Afify M, Elezawy H, Ghanem S, Abdelraouf O, Rewisha E, Shebl N. Evaluation of different diagnostic modalities of minimal hepatic encephalopathy in cirrhotic patients: case-control study. Clin Exp Hepatol 2021; 7:312-319. [PMID: 34712834 PMCID: PMC8527340 DOI: 10.5114/ceh.2021.109292] [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: 02/24/2021] [Accepted: 06/13/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Minimal hepatic encephalopathy (MHE) represents one of the most overlooked complications of liver cirrhosis. AIM OF THE STUDY To compare the utility and efficacy of different MHE diagnostic modalities. MATERIAL AND METHODS This case-control study was conducted on hepatitis C virus (HCV)-related compensated cirrhotic patients. The Psychometric Hepatic Encephalopathy Score (PHES) was used to assign patients to MHE and controls. All patients were subjected to plasma ammonia, serum 3-nitrotyrosine (3-NT), critical flicker frequency (CFF), and the modified inhibitory control test (ICT). RESULTS CFF was significantly lower in the control group (38.5, 40 Hz, p = 0.003). The unweighted lures on ICT were 8.7, 4.9 in MHE and controls (p < 0.001). Moreover, ammonia was higher in the MHE group (89, 61.5 µmol/l, p < 0.001). 3-NT was also higher in the MHE group (31.5, 13.7 nmol/l, p < 0.001) respectively. CFF at cutoff < 39 Hz had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 57.5%, 77.5%, 71.9% and 64.6%, respectively; in modified ICT, at cutoff > 5 unweighted lures the values were 87.5%, 80%, 81.4% and 86.5%, respectively; in ammonia, at cutoff ≥ 76.45 µmol/l the values were 65%, 72.5%, 70.3% and 67.4%, respectively; for 3-NT at cutoff ≥ 14.15 nmol/l the values were 85%, 82.5%, 82.9% and 84.6%, respectively. The accuracy for MHE diagnosis was 67.5%, 83.3%, 68.8%, 83.8% relying on CFF, 3-NT, ammonia, and ICT respectively. On multivariate analysis, CFF < 39 Hz (OR = 10.2, p = 0.04), modified ICT > 5 unweighted lures (OR = 43.2, p = 0.002), and serum 3-NT levels ≥ 14.15 nmol/l (OR = 50.4, p < 0.001) were independent predictors of MHE. CONCLUSIONS 3-NT and ICT are advantageous to reveal MHE in compensated liver cirrhosis, while CFF can be only used as adjuncts, with humble merits of ammonia.
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Affiliation(s)
- Tary Salman
- National Liver Institute, Menoufia University, Egypt
| | | | - Mahmoud Omar
- National Liver Institute, Menoufia University, Egypt
| | - Mohamed Afify
- National Liver Institute, Menoufia University, Egypt
| | | | - Samar Ghanem
- National Liver Institute, Menoufia University, Egypt
| | - Osama Abdelraouf
- Faculty of Computers and Information, Menoufia University, Egypt
| | - Eman Rewisha
- National Liver Institute, Menoufia University, Egypt
| | - Nashwa Shebl
- National Liver Institute, Menoufia University, Egypt
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Haroon S, Ko S, Wong A, Tan PS, Lee E, Lau T. Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: A case report. Medicine (Baltimore) 2021; 100:e24313. [PMID: 33592876 PMCID: PMC7870256 DOI: 10.1097/md.0000000000024313] [Citation(s) in RCA: 4] [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: 10/15/2020] [Accepted: 12/24/2020] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Hyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma. PATIENT CONCERNS A 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise. DIAGNOSIS He was later diagnosed with hyperammonemia encephalopathy. INTERVENTIONS His treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week. OUTCOMES With this change in dialysis regimen, patient was able to continue treatment with sunitinib. LESSONS Clinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.
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Affiliation(s)
| | | | | | - Poh-Seng Tan
- Division of Gastroenterology and Hepatology, National University Hospital Singapore, Republic of Singapore
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21
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Li J, Li R, Gao Y, Jin X, Zhang J, Ren J, Hou Y, Wang X, Wang G. Increasing serum ammonia level is a risk factor for the prognosis of critically ill patients: A multicenter retrospective cohort study. J Crit Care 2020; 62:218-222. [PMID: 33429115 DOI: 10.1016/j.jcrc.2020.12.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 12/15/2020] [Accepted: 12/27/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE To assess the association between serum ammonia level upon admission during the initial intensive care unit (ICU) stay and mortality. MATERIALS AND METHODS This retrospective cohort study included 2703 adult patients in eICU Collaborative Research Database. The ICU mortality within ammonia deciles were assessed. Logistic regression analyses were performed to analyze the relationship between ammonia and mortality. RESULTS We defined three ammonia categories: <47, 47-111, and ≥111 μg/dL, corresponding to low, intermediate, and high ICU mortality. Increased ammonia was significantly associated with increased ICU mortality (per 10 μg/dL increase: odds ratio, 1.070 [95% confidence intervals, 1.05-1.09]; intermediate vs. low: 1.90 [1.41-2.56]; high vs. low: 4.38 [2.99-6.41]) and in-hospital mortality (1.06 [1.04-1.08]; 1.45 [1.13-1.87]; 3.41 [2.43-4.79]). Adding ammonia to the Acute Physiology and Chronic Health Evaluation (APACHE) IV score improved the area under the curve from 0.826 to 0.839 (P < 0.001) and from 0.806 to 0.813 (P = 0.001) for ICU and in-hospital mortality, respectively. Interaction and subgroup analyses demonstrated consistent results in patients with different APACHE IV scores, with or without hepatic diseases. CONCLUSIONS Elevated serum ammonia level in critically ill patients upon admission was an early risk factor for higher ICU and in-hospital mortality.
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Affiliation(s)
- Jiamei Li
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ruohan Li
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ya Gao
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuting Jin
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jingjing Zhang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jiajia Ren
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yanli Hou
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaochuang Wang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Gang Wang
- Department of Critical Care Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Baraka SM, Saleh DO, Ghaly NS, Melek FR, Gamal El Din AA, Khalil WKB, Said MM, Medhat AM. Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways. Bioorg Chem 2020; 105:104444. [PMID: 33197852 DOI: 10.1016/j.bioorg.2020.104444] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/19/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022]
Abstract
Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.
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Affiliation(s)
- Sara M Baraka
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | - Dalia O Saleh
- Pharmacology Department, National Research Centre, Giza 12622, Egypt.
| | - Neveen S Ghaly
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | - Farouk R Melek
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | | | - Wagdy K B Khalil
- Cell Biology Department, National Research Centre, Giza 12622, Egypt
| | - Mahmoud M Said
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
| | - Amina M Medhat
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
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23
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Imbert-Bismut F, Payet PE, Alfaisal J, Munteanu M, Rudler M, Sultanik P, Alkouri R, Sakka M, Djavoudine S, Dever S, Mestari F, Bonnefont-Rousselot D, Poynard T, Thabut D. Transportation and handling of blood samples prior to ammonia measurement in the real life of a large university hospital. Clin Chim Acta 2020; 510:522-530. [DOI: 10.1016/j.cca.2020.07.048] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 07/22/2020] [Accepted: 07/22/2020] [Indexed: 01/28/2023]
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24
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Cai Z, Zhu X, Zhang G, Wu F, Lin H, Tan M. Ammonia induces calpain-dependent cleavage of CRMP-2 during neurite degeneration in primary cultured neurons. Aging (Albany NY) 2020; 11:4354-4366. [PMID: 31278888 PMCID: PMC6660054 DOI: 10.18632/aging.102053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 06/19/2019] [Indexed: 01/07/2023]
Abstract
Hyperammonemia in the CNS induces irreversible damages to neurons due to ultimate cell loss. Neurite degeneration, a primary event that leads to neuronal cell death, remains less elucidated especially in hyperammonemia circumstances. Here, we found that the administration of ammonia induced neurite degeneration in cultured cerebellar granule neurons. The resulting altered neuronal morphology, rupture of neurites, and disassembly of the cytoskeleton led to cell death. Calcein and Fluo-4 staining revealed that ammonia induced intracellular calcium dysregulation. Subsequently activated calpain cleaved CRMP-2, a microtubule assembly protein. Pharmacologically inhibition of calpain, but not caspases or GSK-3, suppressed the cleavage of CRMP-2 and reversed neurite degeneration under ammonia treatment. Exposure to ammonia decreased whereas inhibition of calpain restored the amplitude and frequency of miniature excitatory postsynaptic currents. These data suggest a mechanism by which elevated ammonia level may induce neuronal dysfunction via abnormal calcium influx and calpain-dependent CRMP-2 cleavage, leading to abnormal synaptic transmission, cytoskeletal collapse, and neurite degeneration.
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Affiliation(s)
- Zhenbin Cai
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Xiaonan Zhu
- Department of Anatomy, Medical College of Jinan University, Guangzhou, China
| | - Guowei Zhang
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Fengming Wu
- Department of Anatomy, Medical College of Jinan University, Guangzhou, China
| | - Hongsheng Lin
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Minghui Tan
- Department of Orthopedics, The First Affiliated Hospital of Jinan University, Guangzhou, China
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25
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Wang J, Chen G. Dimethylacetamide-induced toxic hepatitis in spandex workers: clinical presentation and treatment outcomes. QJM 2020; 113:324-329. [PMID: 31693155 DOI: 10.1093/qjmed/hcz282] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/19/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Dimethylacetamide (DMAc) exposure has been associated with toxic hepatitis, and no clinical treatment has been reported. AIM To investigate the clinical manifestations of DMAc-induced symptoms and how to rescue the functional loss due to occupational exposure. DESIGN Clinical observations of 60 spandex factory workers with the exposure to DMAc from January, 2017-19. METHODS Chinese drugs (reduced glutathione, polyene phosphatidylcholine, glycyrrhizin compound, Hugan tablets and ornithine aspartate) were used to evaluate the therapeutic improvements in DMAc-exposed patients. RESULTS Our data found that 58.3% patients had no distinct clinical symptoms, but 41.7% patients felt fatigue, and 21.7% patients suffered abdominal discomfort and appetite loss, and 8.3% patients had yellow skin and sclera. The ultrasonic and CT imaging revealed that some patients have fatty livers, intrahepatic calcifications, hepatomegaly, gallbladder wall edema and abdominal effusions. Biochemical analysis showed that the alanine aminotransferase (ALT) (P < 0.001), aspartate aminotransferase (AST) (P < 0.001), lactate dehydrogenase (LDH) (P < 0.001) and bilirubin (P < 0.01) statistically decreased after the drug treatment, but alkaline phosphatase (P >0.05) and glutamyl transpeptidase (P> 0.05) did not decrease. Twenty-nine out of the thirty-one patients' abnormal blood ammonia recovered. The risk factor of ALT on hospitalization time was significantly related (P < 0.01). CONCLUSIONS The drugs above are sufficient to rescue functional loss in DMAc-induced toxic hepatitis, in part via the regulations of ALT, AST, LDH, bilirubin and ammonia. Workers with the exposure to DMAc should receive specific drugs to maintain the health and prevent functional loss in the long term.
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Affiliation(s)
- J Wang
- Department of Gastroenterology, Zhejiang Rongjun Hospital, Jiaxing 314000
| | - G Chen
- Department of Biopharmaceutical Sciences, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Hangzhou 310018, China
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Ammonia Levels Do Not Guide Clinical Management of Patients With Hepatic Encephalopathy Caused by Cirrhosis. Am J Gastroenterol 2020; 115:723-728. [PMID: 31658104 DOI: 10.14309/ajg.0000000000000343] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Ammonia appears to play a major role in the pathophysiology of hepatic encephalopathy (HE), but its role in guiding management is unclear. We aimed to understand the impact of ammonia levels on inpatient HE management, hypothesizing that patients with elevated ammonia levels would receive more aggressive lactulose therapy than patients with normal ammonia or no ammonia level drawn. METHODS We examined patients with cirrhosis older than 18 years admitted for management of HE from 2005 to 2015. We additionally used propensity matching to control for confounding by the severity of underlying disease. Patients with an ammonia level taken at time of HE diagnosis were further separated into those with normal or elevated ammonia levels. The primary endpoint was the total lactulose (mL) amount (or dose) given in the first 48 hours of HE management. RESULTS One thousand two hundred two admissions with HE were identified. Ammonia levels were drawn in 551 (46%) patients; 328 patients (60%) had an abnormal ammonia level (>72 μmol/L). There were no significant differences in the Child-Pugh score, MELD, or Charlson Comorbidity Index in those with and without ammonia levels drawn. The average total lactulose dose over 48 hours was 167 and 171 mL in the no ammonia vs ammonia groups, respectively (P = 0.42). The average lactulose dose in patients with an elevated ammonia level was 161 mL, identical to the lactulose dose in patients with a normal ammonia level. There was no correlation between lactulose dose and ammonia level (R = 0.0026). DISCUSSION Inpatient management of HE with lactulose was not influenced by either the presence or level of ammonia level, suggesting that ammonia levels do not guide therapy in clinical practice.
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Snehavardhan P, Lal BB, Sood V, Khanna R, Alam S. Efficacy and Safety of Sodium Benzoate in The Management of Hyperammonemia in Decompensated Chronic Liver Disease of the Childhood-A Double-blind Randomized Controlled Trial. J Pediatr Gastroenterol Nutr 2020; 70:165-170. [PMID: 31978010 DOI: 10.1097/mpg.0000000000002521] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The objective was to evaluate the efficacy and safety of sodium benzoate in the management of hyperammonemia and hepatic encephalopathy (HE) in decompensated chronic liver disease. METHODS It was a prospective, interventional, double-blinded randomized controlled trial conducted from August 2017 to December 2018. Children with decompensated chronic liver disease and hyperammonemia were included in the study. Those with ammonia >400 μg/dL, already receiving sodium benzoate or with grade III ascites were excluded. Group A received sodium benzoate (400 mg/kg loading dose followed by 200 mg · kg · daymaintenance for 5 days) along with the standard medical therapy. Group B received standard medical therapy with placebo. RESULTS A total of 108 episodes of hyperammonemia occurred in 86 patients of whom 16 were excluded. The final analysis included 46 episodes in each group. The median decrease in ammonia from baseline to day 5 was 52 μg/dL in group A versus 42 μg/dL in group B (P = 0.321). There was a significant decrease in ammonia on days 1 and 2 in group A as compared to group B, but not on subsequent days. There was no significant difference in the resolution of HE (57.1% vs 50%; P = 1), but there was higher, albeit insignificant increase in ascites in group A (15.9% vs 4.5%). CONCLUSIONS Addition of sodium benzoate significantly reduced the ammonia levels on the first 2 days of therapy but the effect was not sustained till day 5. The effect of sodium benzoate would probably be more sustained, if higher dosage (400 mg · kg · day) could be used under monitoring of benzoate levels. There was no effect on resolution of HE. Sodium benzoate caused an increasing trend of adverse events with no effect on short-term survival.
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Affiliation(s)
- Pandey Snehavardhan
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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28
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Abstract
RATIONALE Adult hyperammonemia is most often the result of hepatic dysfunction. Hyperammonemia in the setting of normal hepatic function is a much less common phenomenon and has usually been associated with medications and certain disease states. Here, we present an unusual case of severe hyperammonemia caused physiologically by intense muscle activity in a patient lacking any evidence of liver disease. PATIENT CONCERNS A 36-year-old woman was brought to the emergency department for a suicide attempt after being found covered in Lysol and Clorox germicidal bleach. She was noted to be in a state of violent psychosis with extreme agitation and had to be sedated and intubated for airway protection. DIAGNOSIS AND INTERVENTIONS Initial labs revealed hyperammonemia, lactic acidosis, and anion gap metabolic acidosis. Aminotransferases, bilirubin, and creatine kinase (CK) were normal. Renal function, prothrombin time, activated partial thromboplastin time, and international normalized ratio were also unremarkable and remained so at 24 hours. Ethyl alcohol, acetaminophen, salicylate, and valproic acid were all undetectable in blood. She received 2 doses of lactulose overnight, with a subsequent bowel movement. Next day, her mentation, serum ammonia level, and lactic acid level were back to normal, and she was extubated. Aminotransferases and CK levels were elevated but improved with supportive care. A detailed history and relevant biochemical investigations were unremarkable for any other etiology of hyperammonemia including the common inborn errors of metabolism (IEM). The combination of clinical findings of extreme skeletal muscle activity along with hyperammonemia and lactic acidosis, and subsequently rhabdomyolysis in the setting of unremarkable history and otherwise normal hepatic function strongly suggest the myokinetic origin of hyperammonemia in the patient. OUTCOME The patient recovered well with supportive care and was discharged on day 5. LESSONS This unique case illustrates the important role of skeletal muscle in the human metabolism of ammonia. In our discussion, we also elucidate the underlying pathophysiology, with the objective of improving clinician understanding of various differential diagnoses.
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Affiliation(s)
| | - Haneesh Jasuja
- Materials and Nanotechnology Program, North Dakota State University, Fargo, ND
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29
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Lu K, Zimmermann M, Görg B, Bidmon HJ, Biermann B, Klöcker N, Häussinger D, Reichert AS. Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes. EBioMedicine 2019; 48:539-553. [PMID: 31648987 PMCID: PMC6838440 DOI: 10.1016/j.ebiom.2019.09.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023] Open
Abstract
Background Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients. Methods Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy. Findings We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation. Interpretation Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE. Funding Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).
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Affiliation(s)
- Kaihui Lu
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Marcel Zimmermann
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Boris Görg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Hans-Jürgen Bidmon
- C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Barbara Biermann
- Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Nikolaj Klöcker
- Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
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Ferreira MDF, Salavati Schmitz S, Schoenebeck JJ, Clements DN, Campbell SM, Gaylor DE, Mellanby RJ, Gow AG, Salavati M. Lactulose drives a reversible reduction and qualitative modulation of the faecal microbiota diversity in healthy dogs. Sci Rep 2019; 9:13350. [PMID: 31527716 PMCID: PMC6746952 DOI: 10.1038/s41598-019-50090-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy is a frequent and debilitating complication of liver disorders. Lactulose is an established and reasonably effective treatment, yet with incompletely understood mechanisms of action. The aims of this study were to examine how the faecal microbiota composition changed before, during and after lactulose treatment in a large animal model. Healthy, privately owned dogs (n = 18) completed a prospective cohort study. Faecal samples were collected weekly, while the subjects were either on their usual diet (week 1), or a standardised diet (weeks 2-9), with added oral lactulose in weeks 6-7. DNA extraction and 16S rRNA gene sequencing were undertaken. Faecal samples from week 7 had a significantly lower microbiota richness/diversity, based on observed operational taxonomic units, Shannon/Chao1 indexes and Pielou's Evenness. Beta diversity based on UniFrac distances was significantly different in week 7 compared to weeks 1, 5 and 9. At the phylum level, week 7 was associated with a significant increase of Firmicutes and Actinobacteria, and a decrease of Bacteroidetes and Fusobacteria, when compared to weeks 5 and 9. In summary, we have shown that lactulose induces a reversible qualitative and quantitative change of the faecal microbiota, which may explain its clinical efficacy in the management of hepatic encephalopathy.
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Affiliation(s)
- Marisa da Fonseca Ferreira
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom.
| | - Silke Salavati Schmitz
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Jeffrey Joseph Schoenebeck
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Dylan Neil Clements
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Susan Mary Campbell
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Donna Elaine Gaylor
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Richard J Mellanby
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Adam George Gow
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
| | - Mazdak Salavati
- The Royal (Dick) School of Veterinary Studies and The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Roslin, Midlothian, EH25 9RG, United Kingdom
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El Khiat A, Tamegart L, Draoui A, El Fari R, Sellami S, Rais H, El Hiba O, Gamrani H. Kinetic deterioration of short memory in rat with acute hepatic encephalopathy: Involvement of astroglial and neuronal dysfunctions. Behav Brain Res 2019; 367:201-209. [DOI: 10.1016/j.bbr.2019.03.046] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 02/07/2023]
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Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol 2019; 11:489-512. [PMID: 31293718 PMCID: PMC6603507 DOI: 10.4254/wjh.v11.i6.489] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.
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Affiliation(s)
- Daniela Campion
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Ilaria Giovo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Paola Ponzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Giorgio M Saracco
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Federico Balzola
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy.
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Ma YJ, Cao ZX, Li Y, Feng SY. Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis. World J Gastroenterol 2019; 25:2675-2682. [PMID: 31210718 PMCID: PMC6558435 DOI: 10.3748/wjg.v25.i21.2675] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/24/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Several studies have been conducted to explore the association between the use of proton pump inhibitors (PPIs) and hepatic encephalopathy (HE) risk in patients with liver cirrhosis. However, their results are controversial.
AIM To perform a systematic review and meta-analysis to evaluate the HE risk among PPI users.
METHODS A systematic search on PubMed, Web of Science, EMBase, and ScienceDirect databases was conducted up to December 31, 2018 for eligible studies involving PPI use and HE risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the fixed or random effects model. Publication bias was evaluated using Begg’s test, Egger’s test, and trim-and-fill method.
RESULTS Seven studies with 4574 patients were included in the present meta-analysis. The meta-analysis results indicated a significant association between the PPI use and HE risk (OR = 1.50; 95%CI: 1.25-1.75) with low heterogeneity (I2 = 14.2%, P = 0.321). Although publication bias existed when Egger’s tests were used (P = 0.005), the trim-and-fill method verified the stability of the pooled result. Sensitivity analyses suggested that the results of this meta-analysis were robust.
CONCLUSION The current evidence indicates that PPI use increases HE risk in patients with liver cirrhosis. Further studies with a large data set and well-designed models are needed to validate our findings.
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Affiliation(s)
- Yun-Jie Ma
- Emergency Department, Cangzhou Central Hospital, Cangzhou 061000, Hebei Province, China
| | - Zong-Xun Cao
- Emergency Department, Cangzhou Central Hospital, Cangzhou 061000, Hebei Province, China
| | - Yong Li
- Emergency Department, Cangzhou Central Hospital, Cangzhou 061000, Hebei Province, China
| | - Shun-Yi Feng
- Emergency Department, Cangzhou Central Hospital, Cangzhou 061000, Hebei Province, China
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Cittolin-Santos G, Guazzelli P, Nonose Y, Almeida R, Fontella F, Pasquetti M, Ferreira-Lima F, Lazzaroto G, Berlezi R, Osvaldt A, Calcagnotto M, de Assis A, Souza D. Behavioral, Neurochemical and Brain Oscillation Abnormalities in an Experimental Model of Acute Liver Failure. Neuroscience 2019; 401:117-129. [DOI: 10.1016/j.neuroscience.2018.12.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2018] [Revised: 12/14/2018] [Accepted: 12/18/2018] [Indexed: 01/17/2023]
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Lima LCD, Miranda AS, Ferreira RN, Rachid MA, Simões E Silva AC. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol 2019; 11:173-185. [PMID: 30820267 PMCID: PMC6393717 DOI: 10.4254/wjh.v11.i2.173] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.
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Affiliation(s)
- Luiza Cioglia Dias Lima
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Milene Alvarenga Rachid
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil.
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El-Marasy SA, El Awdan SA, Abd-Elsalam RM. Protective role of chrysin on thioacetamide-induced hepatic encephalopathy in rats. Chem Biol Interact 2019; 299:111-119. [PMID: 30500344 DOI: 10.1016/j.cbi.2018.11.021] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Revised: 11/10/2018] [Accepted: 11/26/2018] [Indexed: 12/12/2022]
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Cui Y, Guan S, Ding J, He Y, Li Q, Wang S, Sun H. Establishment and evaluation of a model for predicting 3-month mortality in Chinese patients with hepatic encephalopathy. Metab Brain Dis 2019; 34:213-221. [PMID: 30443767 DOI: 10.1007/s11011-018-0333-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Accepted: 10/30/2018] [Indexed: 12/28/2022]
Abstract
Hepatic encephalopathy (HE) is a serious complication of liver disease. To establish a model for predicting 3-month mortality in patients with HE in China. This retrospective study included 609 patients with HE admitted to the Peoples' Hospital, Liaocheng City, China (August 2006 to January 2016). Patients were allocated to a modeling (n = 409) or validation (n = 200) group. Demographic/clinical characteristics, laboratory test results, Model for End Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score were extracted from medical records. A model for predicting death within 3 months after admission was established using logistic regression analysis (modeling group). Model validity (validation group) was assessed using receiver operating characteristic (ROC) curve analysis. 270/409(66.0%) patients died in the modeling group and 142/203(70.0%) died in the validation group. Compared with survivors, patients who died had more severe HE, and higher MELD score, CTP score, incidence of complications including hepatorenal syndrome (HRS) and upper gastrointestinal bleeding, and values for laboratory parameters including red blood cell count(RBC) and total bilirubin(TBIL)(P < 0.05). Regression analysis revealed RBC, TBIL, HE stage, HRS and upper gastrointestinal bleeding as independent factors associated with death (P < 0.05). The area under the ROC curve (AUC) for the model was 0.931.The model had a higher Youden index than MELD or CTP scores and predicted death in the validation group with a sensitivity of 83.1% and specificity of 93.4%. The established model has superior performance to MELD and CTP scores for predicting mortality in patients with HE.
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Affiliation(s)
- Yanping Cui
- Department of Liver Disease, Liaocheng People's Hospital, Liaocheng, China
| | - Shan Guan
- Department of Liver Disease, Liaocheng People's Hospital, Liaocheng, China
| | - Jie Ding
- Central Laboratory, Liaocheng People's Hospital, Liaocheng, China
| | - Yukai He
- Department of Liver Disease, Liaocheng People's Hospital, Liaocheng, China
| | - Qingfang Li
- Department of Liver Disease, Liaocheng People's Hospital, Liaocheng, China
| | - Sikui Wang
- Department of Liver Disease, Liaocheng People's Hospital, Liaocheng, China
| | - Huiling Sun
- Department of Gastroenterology, Liaocheng People's Hospital, Liaocheng, 252004, China.
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Aloin Inhibits Müller Cells Swelling in a Rat Model of Thioacetamide-Induced Hepatic Retinopathy. Molecules 2018; 23:molecules23112806. [PMID: 30380640 PMCID: PMC6278412 DOI: 10.3390/molecules23112806] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/19/2018] [Accepted: 10/29/2018] [Indexed: 12/30/2022] Open
Abstract
Swelling of retinal Müller cells is implicated in retinal edema and neuronal degeneration. Müller cell swelling is observed in patients with liver failure and is referred to as hepatic retinopathy. In the present study, we evaluated the effects of aloin, an anthraquinone-C-glycoside present in various Aloe species, on Müller cell dysfunction in a rat model of thioacetamide (TAA)-induced hepatic retinopathy. Experimental hepatic retinopathy was induced by three injections of TAA (200 mg/kg/day, intraperitoneal injection) for 3 days in rats. After the last injection of TAA, aloin (50 and 100 mg/kg) was orally gavaged for 5 days. The effects of aloin on the liver injury, serum ammonia levels, Müller cell swelling, glial fibrillary acidic protein (GFAP) expression, and gene expression of Kir4.1 and aquaporin-4 were examined. TAA-injected rats exhibited liver failure and hyperammonemia. In the TAA-injected rats, Müller cell bodies were highly enlarged, and GFAP, an indicator of retinal stress, was highly expressed in the retinas, indicating a predominant Müller cell gliosis. However, administration of aloin suppressed liver injury as well as Müller cell swelling through the normalization of Kir4.1 and aquaporin-4 channels, which play a key role in potassium and water transport in Müller cells. These results indicate that aloin may be helpful to protect retinal injury associated with liver failure.
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Zhu J, Qi X, Yu H, Yoshida EM, Mendez-Sanchez N, Zhang X, Wang R, Deng H, Li J, Han D, Guo X. Association of proton pump inhibitors with the risk of hepatic encephalopathy during hospitalization for liver cirrhosis. United European Gastroenterol J 2018; 6:1179-1187. [PMID: 30288280 PMCID: PMC6169047 DOI: 10.1177/2050640618773564] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 04/07/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy is associated with altered gut microbiota. Proton pump inhibitors increase the risk of small bowel bacterial overgrowth. OBJECTIVES This was a case-control study aimed at exploring the relationship of proton pump inhibitor use with the risk of hepatic encephalopathy during hospitalization in liver cirrhosis. METHODS Case and control groups were defined as cirrhotic patients who developed hepatic encephalopathy during hospitalization and those without hepatic encephalopathy at admission or during hospitalization, respectively. Age, gender, and Child-Pugh score were matched between the groups. Odds ratios with 95% confidence intervals were calculated to express the association of proton pump inhibitors with the risk of hepatic encephalopathy. Four subgroup analyses were performed after excluding patients with acute upper gastrointestinal bleeding, infections, and in-hospital death, and after matching model for end-stage liver disease score. RESULTS In the overall analysis, 128 patients were included in each group of cases and controls. The proportion of proton pump inhibitor use was significantly higher in the case group than the control group (79.7% vs 43%, p < 0.001). Proton pump inhibitor use (odds ratio = 3.481, 95% confidence interval: 1.651-7.340, p = 0.001) was independently associated with the development of hepatic encephalopathy in the multivariate analysis. In the four subgroup analyses, proton pump inhibitor use remained independently associated with the risk of hepatic encephalopathy. CONCLUSION Proton pump inhibitor use might increase the risk of hepatic encephalopathy during hospitalization.
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Affiliation(s)
- Jia Zhu
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
- Xingshun Qi, Department of Gastroenterology, General Hospital of Shenyang Military Area, No. 83 Wenhua Road, Shenyang, 110840 Liaoning Province, China.
| | - Haonan Yu
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Eric M Yoshida
- Division of Gastroenterology, Vancouver General Hospital, Vancouver, Canada
| | | | - Xintong Zhang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - Ran Wang
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - Han Deng
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - Jing Li
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - Dan Han
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
| | - Xiaozhong Guo
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, China
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Ponziani FR, Zocco MA, Cerrito L, Gasbarrini A, Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol 2018; 12:641-656. [PMID: 29806487 DOI: 10.1080/17474124.2018.1481747] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle. Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice. Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients' prognosis.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maria Assunta Zocco
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Lucia Cerrito
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
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Barone M, Shahini E, Iannone A, Viggiani MT, Corvace V, Principi M, Di Leo A. Critical flicker frequency test predicts overt hepatic encephalopathy and survival in patients with liver cirrhosis. Dig Liver Dis 2018; 50:496-500. [PMID: 29530628 DOI: 10.1016/j.dld.2018.01.133] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 01/16/2018] [Accepted: 01/17/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND A critical flicker frequency (CFF) ≤39 Hz identifies cirrhotic patients with minimal hepatic encephalopathy (mHE) and predicts the risk of both overt hepatic encephalopathy (oHE) and mortality in patients with previous episodes of decompensation and/or oHE. AIMS Herein, we evaluated the effectiveness of CFF in predicting the first episode of oHE and survival in cirrhotics who had never experienced an episode of oHE. METHODS Our cohort study of 134 patients and 150 healthy subjects were examined. A CFF > 39 Hz was considered normal and pathological when ≤39 Hz. The median follow up was 36 months. RESULTS At baseline, all controls had CFF > 39 Hz. Ninety-three patients had a CFF > 39 Hz and 41 had a CFF ≤ 39 Hz. The prevalence of CFF ≤ 39 Hz significantly increased with the progression of the Child-Pugh class (p = 0.003). Moreover, the risk of oHE was increased by CFF ≤ 39 (p < 0.001, by log-rank test) [HR = 7.57; CI(3.27-17.50); p < 0.0001, by Cox model] and ammonia [HR = 1.02 CI(1.01-1.03), p = 0.0009]. Both a CFF value ≤ 39 Hz and Child-Pugh class were independent predictors of mortality by Cox model [HR = 1.97; CI(1.01-3.95), p = 0.049; HR = 3.85 CI(1.68-8.83), p = 0.003]. CONCLUSIONS CFF predicts the first episode of oHE in cirrhotics that had never experienced oHE, and predicts mortality risk. These findings suggest that cirrhotic patients should be routinely screened by CFF.
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Affiliation(s)
- Michele Barone
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy
| | - Endrit Shahini
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy
| | - Andrea Iannone
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy
| | - Maria Teresa Viggiani
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy
| | | | - Mariabeatrice Principi
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy
| | - Alfredo Di Leo
- Gastroenterology Unit, Dept. of Emergency and Organ Transplantation (D.E.T.O.), University of Bari, Italy.
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Romeiro FG, Ietsugu MDV, Franzoni LDC, Augusti L, Alvarez M, Santos LAA, Lima TB, Koga KH, Moriguchi SM, Caramori CA, Silva GF, Betting LEGG. Which of the branched-chain amino acids increases cerebral blood flow in hepatic encephalopathy? A double-blind randomized trial. Neuroimage Clin 2018; 19:302-310. [PMID: 30013913 PMCID: PMC6044187 DOI: 10.1016/j.nicl.2018.03.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 03/07/2018] [Accepted: 03/21/2018] [Indexed: 02/06/2023]
Abstract
Branched-chain amino acids increase the brain perfusion of patients with hepatic encephalopathy (HE), but the amino acid and the mechanisms involved are still unknown. This study compared brain perfusion and clinical improvement during leucine or isoleucine supplementation. After randomization, 27 subjects with cirrhosis and HE received leucine or isoleucine supplements for one year. Brain single Photon Emission Computed Tomography (SPECT) and dynamic brain scintigraphy (DBS) were performed pretreatment and at 1, 8 and 12 months of supplementation. Brain perfusion was increased only in the isoleucine group at 8 months of treatment by both SPECT and DBS (p < 0.001 and p = 0.05, respectively) and by SPECT at the 12th month (p < 0.05). This was associated with hepatic encephalopathy improvement at 8 and 12 months (p = 0.008 and 0.004, respectively), which was not observed in the leucine group (p = 0.313 and 0.055, respectively). Isoleucine supplementation achieved a better impact on brain perfusion restoration in HE.
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Key Words
- AC, arm circumference
- APMT, adductor pollicis muscle thickness
- BCAA, branched-chain amino acids
- BCKA, branched-chain ketoacids
- BMI, body mass index
- Branched-chain amino acids
- CAMA, corrected mid-arm muscle area
- CBF, cerebral blood flow
- Cerebral blood flow
- EEG, electroencephalogram
- FDR, false discovery rate
- GDH, glutamate dehydrogenase
- GLN, glutamine
- GLU, glutamate
- HE, hepatic encephalopathy
- HGS, handgrip strength
- HPLC, high-performance liquid chromatography
- HRQoL, health-related quality of life
- Hepatic encephalopathy
- Liver cirrhosis
- MAMC, mid-arm muscle circumference
- MELD, Model of End-Stage Liver Disease
- NH3, ammonia
- PDH, pyruvate dehydrogenase complex
- ROIs, regions of interest
- ROS, reactive oxygen species
- SF-36, 36-item Short-Form General Health Survey
- SPECT, Single Photon Emission Computed Tomography
- SPM12, Statistical Parametrical Mapping 12
- TCA, tricarboxylic acid
- TSF, triceps skinfold
- α-KG, α-ketoglutarate
- αKGDH, α-ketoglutarate dehydrogenase complex
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Affiliation(s)
- Fernando Gomes Romeiro
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil.
| | - Marjorie do Val Ietsugu
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Letícia de Campos Franzoni
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Laís Augusti
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Matheus Alvarez
- Department of Physics and Biophysics, Botucatu Biosciences Institute, UNESP - Univ Estadual Paulista, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo 18618-689, Brazil.
| | - Lívia Alves Amaral Santos
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Talles Bazeia Lima
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Kátia Hiromoto Koga
- Department of Tropical Diseases and Imaging Diagnosis, Botucatu Medical School, UNESP - Univ Estadual Paulista, Av. Prof. Mário Rubens Guimarães Montenegro, s/n. Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil.
| | - Sônia Marta Moriguchi
- Department of Tropical Diseases and Imaging Diagnosis, Botucatu Medical School, UNESP - Univ Estadual Paulista, Av. Prof. Mário Rubens Guimarães Montenegro, s/n. Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Carlos Antonio Caramori
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil
| | - Giovanni Faria Silva
- Department of Internal Medicine, Botucatu Medical School, UNESP - Univ Estadual Paulista. Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil.
| | - Luiz Eduardo Gomes Garcia Betting
- Department of Neurology, Psychology and Psychiatry, Botucatu Medical School, UNESP - Univ Estadual Paulista, Av. Prof. Mário Rubens Guimarães Montenegro, s/n Distrito de Rubião Jr, Botucatu, São Paulo 18618-687, Brazil.
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Milewski K, Bogacińska-Karaś M, Fręśko I, Hilgier W, Jaźwiec R, Albrecht J, Zielińska M. Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y⁺LAT2 Carrier-Mediated Loss. Int J Mol Sci 2017; 18:ijms18112308. [PMID: 29099056 PMCID: PMC5713277 DOI: 10.3390/ijms18112308] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 10/19/2017] [Accepted: 10/27/2017] [Indexed: 01/24/2023] Open
Abstract
Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y+LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y+LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y+LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y+LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y+LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Małgorzata Bogacińska-Karaś
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Inez Fręśko
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Wojciech Hilgier
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Radosław Jaźwiec
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland.
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Abstract
Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy. A literature search using the PubMed database was conducted in May 2017 using "hepatic encephalopathy" as a keyword, and selected manuscripts were limited to those research articles published since May 2014. While the authors acknowledge that many significant advances have been made in the understanding of hepatic encephalopathy prior to May 2014, we have limited the scope of this review to the previous three years only.
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Affiliation(s)
- Victoria Liere
- Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | | | - Sharon DeMorrow
- Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, TX, USA
- Central Texas Veterans Healthcare System, Temple, TX, USA
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Ninan J, Feldman L. Ammonia Levels and Hepatic Encephalopathy in Patients with Known Chronic Liver Disease. J Hosp Med 2017; 12:659-661. [PMID: 28786433 DOI: 10.12788/jhm.2794] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ammonia is predominantly generated in the gut by intestinal bacteria and enzymes and detoxified primarily in the liver. Since the 1930s, ammonia has been identified as the principal culprit in hepatic encephalopathy (HE). Many physicians utilize serum ammonia to diagnose, assess severity, and determine the resolution of HE in patients with chronic liver disease (CLD) despite research showing that ammonia levels are unhelpful in all of these clinical circumstances. HE in patients with CLD is a clinical diagnosis of exclusion that should not be based on ammonia levels.
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Affiliation(s)
- Jacob Ninan
- Department of Hospital Medicine, Mayo Clinic Health Systems, La Crosse, Wisconsin, USA
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Suraweera D, Sundaram V, Saab S. Evaluation and Management of Hepatic Encephalopathy: Current Status and Future Directions. Gut Liver 2017; 10:509-19. [PMID: 27377741 PMCID: PMC4933409 DOI: 10.5009/gnl15419] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 08/31/2015] [Indexed: 12/18/2022] Open
Abstract
Hepatic encephalopathy is a spectrum of neurocognitive manifestations often seen in patients with liver injury or rarely in patients with portosystemic shunting without liver injury. It can be divided into minimal (covert) hepatic encephalopathy and overt hepatic encephalopathy, depending on the severity. Patients with hepatic encephalopathy have compromised clinical outcomes, decreased quality of life, and increased healthcare utilization, often resulting in a heavy financial and personal burden on caregivers. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Current treatment strategies include nonabsorbable disaccharides and antibiotics. This review will focus on the diagnosis, management and clinical impact of hepatic encephalopathy.
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Affiliation(s)
| | - Vinay Sundaram
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Sammy Saab
- Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.,Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
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47
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Milewski K, Oria M. What we know: the inflammatory basis of hepatic encephalopathy. Metab Brain Dis 2016; 31:1239-1247. [PMID: 26497651 DOI: 10.1007/s11011-015-9740-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/24/2015] [Indexed: 02/07/2023]
Abstract
Central Nervous System (CNS) degeneration appearing in patients with cirrhosis is responsible for cognitive and persistent motor impairments that lead to an important impact on life quality. Brain injury affects certain areas of the CNS that might affect two types of cells: neurons and astrocytes. The process leading to brain injury could be induced by portosystemic shunting accompanied by hyperammonemia and by the activation of peripheral inflammation, manifested as episodic encephalopathy. Hyperammonemia combined with a decrease on the BCA/AAA ratio induces alterations of energetic metabolism and the formation of free radicals in the CNS. This process would be stimulated by the activation of peripheral inflammatory mediators that could act on receptors of the blood brain barrier such as TLR4, activating inflammatory responses in the CNS. As a result, a persistent activation of microglia and an irreversible neuronal and astrocytic injury would be induced. A new knowledge of the mechanisms leading to brain injury in cirrhosis would develop protective strategies to correct changes of nitrogen metabolism and inflammation.
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Affiliation(s)
- K Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5 Str, 02-106, Warsaw, Poland
| | - M Oria
- Translational Research in Fetal Surgery for Congenital Malformations, Center for Fetal, Cellular and Molecular Therapy, Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue, MLC 11020, S 8.400 AT, Cincinnati, OH, 45229-3039, USA.
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital, University College London, London, UK.
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48
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Tomasova L, Konopelski P, Ufnal M. Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis. Molecules 2016; 21:E1558. [PMID: 27869680 PMCID: PMC6273628 DOI: 10.3390/molecules21111558] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 10/31/2016] [Accepted: 11/14/2016] [Indexed: 12/16/2022] Open
Abstract
Accumulating evidence suggests that gut bacteria play a role in homeostasis of the circulatory system in mammals. First, gut bacteria may affect the nervous control of the circulatory system via the sensory fibres of the enteric nervous system. Second, gut bacteria-derived metabolites may cross the gut-blood barrier and target blood vessels, the heart and other organs involved in the regulation of the circulatory system. A number of studies have shown that hydrogen sulfide (H₂S) is an important biological mediator in the circulatory system. Thus far, research has focused on the effects of H₂S enzymatically produced by cardiovascular tissues. However, some recent evidence indicates that H₂S released in the colon may also contribute to the control of arterial blood pressure. Incidentally, sulfate-reducing bacteria are ubiquitous in mammalian colon, and H₂S is just one among a number of molecules produced by the gut flora. Other gut bacteria-derived compounds that may affect the circulatory system include methane, nitric oxide, carbon monoxide, trimethylamine or indole. In this paper, we review studies that imply a role of gut microbiota and their metabolites, such as H₂S, in circulatory system homeostasis.
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Affiliation(s)
- Lenka Tomasova
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw 02 091, Poland.
- Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava 845 05, Slovakia.
| | - Piotr Konopelski
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw 02 091, Poland.
| | - Marcin Ufnal
- Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw 02 091, Poland.
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49
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Ghiassy B, Rahimi N, Javadi-Paydar M, Gharedaghi MH, Norouzi-Javidan A, Dehpour AR. Nitric oxide mediates effects of acute, not chronic, naltrexone on LPS-induced hepatic encephalopathy in cirrhotic rats. Can J Physiol Pharmacol 2016; 95:16-22. [PMID: 28044452 DOI: 10.1139/cjpp-2016-0188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Recent studies suggest endogenous opioids and nitric oxide (NO) are involved in the pathophysiology of hepatic encephalopathy (HE). In this study, the interaction between the opioid receptor antagonist and NO was investigated on lipopolysaccharide (LPS)-induced HE in cirrhotic rats. Male rats were divided in the sham- and bile duct ligation (BDL)-operated groups. Animals were treated with saline; naltrexone (10 mg/kg, i.p.); or L-NAME (3 mg/kg, i.p.), alone or in combination with naltrexone. To induce HE, LPS (1 mg/kg, i.p.) was injected 1 h after the final drug treatment. HE scoring, hepatic histology, and plasma NO metabolites levels and mortality rate were recorded. Deteriorated level of consciousness and mortality after LPS administration significantly ameliorated following both acute and chronic treatment with naltrexone in cirrhotic rats. However, acute and chronic administration of L-NAME did not change HE scores in cirrhotic rats. The effects of acute but not chronic treatment of naltrexone on HE parameters were reversed by L-NAME. Plasma NOx concentrations elevated in BDL rats, which were decreased after acute and chronic treatment by naltrexone or L-NAME, significantly. We suggest both acute and chronic treatment with naltrexone improved LPS-induced HE. But, only acute treatment with naltrexone may affect through NO pathway.
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Affiliation(s)
- Bentolhoda Ghiassy
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,b Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Nastaran Rahimi
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Mehrak Javadi-Paydar
- c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Mohammad Hadi Gharedaghi
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Abbas Norouzi-Javidan
- b Brain and Spinal Injury Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Ahmad R Dehpour
- a Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran.,c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
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