|
1
|
Bosoi CR, Kumar A, Oliveira MM, Welch N, Clément MA, Tremblay M, Ten-Have GAM, Engelen MPKJ, Bémeur C, Deutz NEP, Dasarathy S, Rose CF. Attenuating hyperammonemia preserves protein synthesis and muscle mass via restoration of perturbed metabolic pathways in bile duct-ligated rats. Metab Brain Dis 2025; 40:110. [PMID: 39847228 DOI: 10.1007/s11011-024-01525-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 12/28/2024] [Indexed: 01/24/2025]
Abstract
Sarcopenia and hepatic encephalopathy (HE) are complications of chronic liver disease (CLD), which negatively impact clinical outcomes. Hyperammonemia is considered to be the central component in the pathogenesis of HE, however ammonia's toxic effects have also been shown to impinge on extracerebral organs including the muscle. Our aim was to investigate the effect of attenuating hyperammonemia with ornithine phenylacetate (OP) on muscle mass loss and associated molecular mechanisms in rats with CLD. Six-week bile duct-ligated (BDL) rats and Sham-operated controls were treated with OP (1 g/kg, oral) for 5 weeks. Body composition, assessed by EchoMRI, and muscle protein fractional synthesis rate were evaluated. Signalling mechanisms regulating protein homeostasis, ATP content and metabolic intermediates in the tricarboxylic acid cycle (TCA) in skeletal muscle were quantified. OP treatment attenuated hyperammonemia, prevented brain edema and improved locomotor activity in BDL rats. Increased muscle ammonia, reduction in lean body mass, decreased muscle protein synthesis rate and ATP content were restored in OP-treated versus saline-treated BDL rats. TCA cycle intermediary metabolite, α-ketoglutarate, alterations of molecular markers regulating protein homeostasis including mTOR signalling and autophagy, were also preserved in muscle of OP-treated BDL rats. OP attenuated hyperammonemia, preserved muscle protein synthesis and prevented muscle mass loss in a preclinical model of CLD through restoration of perturbed signalling responses and altered TCA intermediary metabolites. Ammonia-lowering strategies have the potential for rapid clinical translation for simultaneous neuroprotection and sarcopenia prevention in patients with CLD.
Collapse
Affiliation(s)
- Cristina R Bosoi
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada
| | - Avinash Kumar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, NE4 208, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Science, New Delhi, India
| | - Mariana M Oliveira
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada
| | - Nicole Welch
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, NE4 208, 9500 Euclid Avenue, Cleveland, OH, 44195, USA
| | - Marc-André Clément
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada
| | - Gabriella A M Ten-Have
- Center for Translational Research and Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA
| | - Marielle P K J Engelen
- Center for Translational Research and Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA
| | - Chantal Bémeur
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada
- Department of Nutrition, Faculty of Medicine, Université de Montréal, Montreal, Canada
| | - Nicolaas E P Deutz
- Center for Translational Research and Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, TX, USA
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, NE4 208, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
| | - Christopher F Rose
- Hepato-Neuro Laboratory, Centre Hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900, Rue Saint-Denis - Pavillon R, R08.422, Montréal (Québec), H2X 0A9, Canada.
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Canada.
| |
Collapse
|
|
2
|
Roy S, Chakrabarti M, Mondal T, Das TK, Sarkar T, Datta S, Kundu M, Banerjee M, Kulkarni OP. Effect of an Autotaxin Inhibitor, 2-(4-Chlorophenyl)-7-methyl-8-pentylimidazo[1,2- a] Pyrimidin-5(8 H)-one (CBT-295), on Bile Duct Ligation-Induced Chronic Liver Disease and Associated Hepatic Encephalopathy in Rats. ACS Pharmacol Transl Sci 2024; 7:2662-2676. [PMID: 39296254 PMCID: PMC11406694 DOI: 10.1021/acsptsci.4c00066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 09/21/2024]
Abstract
The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.
Collapse
Affiliation(s)
- Subhasis Roy
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Monali Chakrabarti
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Trisha Mondal
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tapas Kumar Das
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Tonmoy Sarkar
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Sebak Datta
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Mrinalkanti Kundu
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Manish Banerjee
- TCG Lifesciences Private Ltd., Sector V, Salt Lake, Kolkata 700091, West Bengal, India
| | - Onkar Prakash Kulkarni
- Metabolic Disorders and Neuroscience Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500078, India
| |
Collapse
|
|
3
|
Hu K, Xu Y, Fan J, Liu H, Di C, Xu F, Wu L, Ding K, Zhang T, Wang L, Ai H, Xie L, Wang G, Liang Y. Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism. Front Pharmacol 2024; 15:1387409. [PMID: 38887546 PMCID: PMC11181355 DOI: 10.3389/fphar.2024.1387409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 05/06/2024] [Indexed: 06/20/2024] Open
Abstract
Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.
Collapse
Affiliation(s)
- Kangrui Hu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yexin Xu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Jiye Fan
- Department of Pharmacy, Hebei Chemical and Pharmaceutical College, Shijiazhuang, Hebei Province, China
| | - Huafang Liu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Chanjuan Di
- Hebei Zhitong Biopharmaceutical Co., Ltd., Gucheng, Hebei Province, China
| | - Feng Xu
- Hebei Zhitong Biopharmaceutical Co., Ltd., Gucheng, Hebei Province, China
| | - Linlin Wu
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ke Ding
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Tingting Zhang
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Leyi Wang
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Haoyu Ai
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Lin Xie
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | | | - Yan Liang
- Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| |
Collapse
|
|
4
|
Tamnanloo F, Chen X, Oliveira MM, Tremblay M, Rose CF. Excessive intragastric alcohol administration exacerbates hepatic encephalopathy and provokes neuronal cell death in male rats with chronic liver disease. J Neurosci Res 2024; 102:e25337. [PMID: 38680084 DOI: 10.1002/jnr.25337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 03/11/2024] [Accepted: 04/07/2024] [Indexed: 05/01/2024]
Abstract
Hepatic encephalopathy (HE) is defined as decline in neurological function during chronic liver disease (CLD). Alcohol is a major etiological factor in the pathogenesis of fibrosis/cirrhosis and has also been documented to directly impact the brain. However, the role of alcohol in the development of HE in CLD remains unclear. Here, we investigated the impact of excessive alcohol administration on neurological deterioration in rats with CLD. Starting day 7 post-BDL surgery, rats were administered alcohol twice daily (51% v/v ethanol, 3 g/kg, via gavage) for 4 weeks. Motor coordination was assessed weekly using rotarod and anxiety-like behavior was evaluated with open field and elevated plus maze at 5 weeks. Upon sacrifice, brains were collected for western blot and immunohistochemical analyses to investigate neuronal integrity and oxidative stress status. Alcohol worsened motor coordination performance and increased anxiety-like behavior in BDL rats. Impairments were associated with decreased neuronal markers of NeuN and SMI311, increased apoptotic markers of cleaved/pro-caspase-3 and Bax/Bcl2, increased necroptosis markers of pRIP3 and pMLKL, decreased total antioxidant capacity (TAC), and increased 4-hydroxynonenal (4-HNE)modified proteins in the cerebellum of BDL-alcohol rats when compared to respective controls. Immunofluorescence confirmed the colocalization of cleaved caspase-3 and pMLKL in the granular neurons of the cerebellum of BDL-alcohol rats. Excessive alcohol consumption exacerbates HE which leads to associated apoptotic and necroptotic neuronal loss in the cerebellum of BDL-alcohol rats. Additionally, higher levels of 4-HNE and decreased TAC in the cerebellum of BDL-alcohol rats suggest oxidative stress is the triggering factor of apoptotic and necroptotic neuronal loss/injury.
Collapse
Affiliation(s)
- Farzaneh Tamnanloo
- Hepato-Neuro Lab, CRCHUM, Montréal, Québec, Canada
- Medicine Department, Université de Montréal, Montréal, Québec, Canada
| | - Xiaoru Chen
- Hepato-Neuro Lab, CRCHUM, Montréal, Québec, Canada
| | | | | | - Christopher F Rose
- Hepato-Neuro Lab, CRCHUM, Montréal, Québec, Canada
- Medicine Department, Université de Montréal, Montréal, Québec, Canada
| |
Collapse
|
|
5
|
Buckholz AP, Brown RS. Future Therapies of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:331-344. [PMID: 38548443 PMCID: PMC10987054 DOI: 10.1016/j.cld.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Hepatic encephalopathy, either covert or overt, affects more than half of patients with cirrhosis and has lasting effects even after portal hypertension is corrected. Unfortunately, the current therapeutic options still result in high rates of relapse and progression, in part owing to cost barriers and side effects, leading to poor adherence. This review summarizes emerging treatment options, which could take advantage of alternative disease pathways to improve future care of those with hepatic encephalopathy.
Collapse
Affiliation(s)
- Adam P Buckholz
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, New York/Presbyterian-Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
| |
Collapse
|
|
6
|
Pun CK, Huang HC, Chang CC, Hsu SJ, Huang YH, Hou MC, Lee FY. Hepatic encephalopathy: From novel pathogenesis mechanism to emerging treatments. J Chin Med Assoc 2024; 87:245-251. [PMID: 38109364 DOI: 10.1097/jcma.0000000000001041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2023] Open
Abstract
Hepatic encephalopathy (HE) is one of the major complications of liver disease and significantly affects the quality of life (QOL) of patients. HE is common and frequently relapses in cirrhotic patients. The management of HE is supportive, and precipitating conditions should be eliminated. Most drugs used to treat HE are conventional and include nonabsorbable disaccharides such as lactulose, and antibiotics such as rifaximin. However, their therapeutic efficacy is still suboptimal, and novel therapeutic agents are urgently needed. In addition, the optimal management and diagnosis of minimal HE/covert HE are under debate. In this review, we focus on novel pathogenetic mechanisms such as central nervous system clearance, and emerging therapeutic targets of HE, such as fecal material transplantation. We also discuss different classifications and etiologies of HE.
Collapse
Affiliation(s)
- Chon Kit Pun
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui-Chun Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Therapeutic and Research Center of Liver Cirrhosis and Portal Hypertension, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| |
Collapse
|
|
7
|
Tamnanloo F, Ochoa-Sanchez R, Oliveira MM, Lima C, Lépine M, Dubois K, Bosoi C, Tremblay M, Sleno L, Rose CF. Multiple ammonia-induced episodes of hepatic encephalopathy provoke neuronal cell loss in bile-duct ligated rats. JHEP Rep 2023; 5:100904. [PMID: 37942225 PMCID: PMC10628859 DOI: 10.1016/j.jhepr.2023.100904] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 07/25/2023] [Accepted: 08/31/2023] [Indexed: 11/10/2023] Open
Abstract
Background & Aims Hepatic encephalopathy (HE) is defined as a reversible syndrome and therefore should resolve following liver transplantation (LT). However, neurological complications have been reported in up to 47% of LT recipients, which have been documented to be associated with a history of overt HE pre-LT. We hypothesise that multiple episodes of HE lead to permanent cell injury and exacerbate neurological dysfunction. Our goal was to evaluate the impact of cumulative HE episodes on neurological status and brain integrity in rats with chronic liver disease. Methods Episodes of overt HE (loss of righting reflex) were induced following injection of ammonium acetate in bile duct ligation (BDL) rats (BDL-Ammonia) every 4 days starting at week 3 post-BDL. Neurobehaviour was evaluated after the last episode. Upon sacrifice, plasma ammonia, systemic oxidative stress, and inflammation markers were assessed. Neuronal markers including neuron-specific nuclear antigen and SMI311 (anti-neurofilament marker) and apoptotic markers (cleaved caspase-3, Bax, and Bcl2) were measured. Total antioxidant capacity, oxidative stress marker (4-hydroxynonenal), and proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-1β) were measured in brain (hippocampus, frontal cortex, and cerebellum). Proteomic analysis was conducted in the hippocampus. Results In hippocampus of BDL-Ammonia rats, cleaved caspase-3 and Bax/Bcl2 ratio were significantly increased, whereas NeuN and SMI311 were significantly decreased compared with BDL-Vehicle rats. Higher levels of oxidative stress-induced post-translational modified proteins were found in hippocampus of BDL-Ammonia group which were associated with a lower total antioxidant capacity. Conclusions Ammonia-induced episodes of overt HE caused neuronal cell injury/death in BDL rats. These results suggest that multiple bouts of HE can be detrimental on the integrity of the brain, translating to irreversibility and hence neurological complications post-LT. Impact and implications Hepatic encephalopathy (HE) is defined as a reversible neuropsychiatric syndrome resolving following liver transplantation (LT); however, ∼47% of patients demonstrate neurological impairments after LT, which are associated with a previous history of overt HE pre-LT. Our study indicates that multiple episodes of overt HE can cause permanent neuronal damage which may lead to neurological complications after LT. Nevertheless, preventing the occurrence of overt HE episodes is critical for reducing the risk of irreversible neuronal injury in patients with cirrhosis.
Collapse
Affiliation(s)
- Farzaneh Tamnanloo
- Hepato-Neuro Lab, CRCHUM, Montréal, Canada
- Medicine Department, Université de Montréal, Montréal, Canada
| | | | | | - Carina Lima
- Chemistry Department/CERMO-FC, Université du Québec à Montréal, Montréal, Canada
| | - Maggy Lépine
- Chemistry Department/CERMO-FC, Université du Québec à Montréal, Montréal, Canada
| | | | | | | | - Lekha Sleno
- Chemistry Department/CERMO-FC, Université du Québec à Montréal, Montréal, Canada
| | - Christopher F. Rose
- Hepato-Neuro Lab, CRCHUM, Montréal, Canada
- Medicine Department, Université de Montréal, Montréal, Canada
| |
Collapse
|
|
8
|
Niknahad H, Mobasheri A, Arjmand A, Rafiei E, Alidaee S, Razavi H, Bagheri S, Rezaei H, Sabouri S, Najibi A, Khodaei F, Kashani SMA, Ommati MM, Heidari R. Hepatic encephalopathy complications are diminished by piracetam via the interaction between mitochondrial function, oxidative stress, inflammatory response, and locomotor activity. Heliyon 2023; 9:e20557. [PMID: 37810869 PMCID: PMC10551565 DOI: 10.1016/j.heliyon.2023.e20557] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 09/01/2023] [Accepted: 09/28/2023] [Indexed: 10/10/2023] Open
Abstract
Background of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH4+) levels reach critically high concentrations because of liver failure. HE could lead to a range of neurological complications from locomotor and behavioral disturbances to coma. Several tactics have been established for subsiding blood and brain NH4+. However, there is no precise intervention to mitigate the direct neurological complications of NH4+. Purpose It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH4+ neurotoxicity. Piracetam is a drug used clinically in neurological complications such as stroke and head trauma. Piracetam could significantly diminish oxidative stress and improve brain mitochondrial function. Research methods In the current study, piracetam (100 and 500 mg/kg, oral) was used in a mice model of HE induced by thioacetamide (TA, 800 mg/kg, single dose, i.p). Results Significant disturbances in animals' locomotor activity, along with increased oxidative stress biomarkers, including reactive oxygen species formation, protein carbonylation, lipid peroxidation, depleted tissue glutathione, and decreased antioxidant capacity, were evident in the brain of TA-treated mice. Meanwhile, mitochondrial permeabilization, mitochondrial depolarization, suppression of dehydrogenases activity, and decreased ATP levels were found in the brain of the TA group. The level of pro-inflammatory cytokines was also significantly high in the brain of HE animals. Conclusion It was found that piracetam significantly enhanced mice's locomotor activity, blunted oxidative stress biomarkers, decreased inflammatory cytokines, and improved mitochondrial indices in hyperammonemic mice. These data suggest piracetam as a neuroprotective agent which could be repurposed for the management of HE.
Collapse
Affiliation(s)
- Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mobasheri
- Research Unit of Medical Imaging, Physics, And Technology, Faculty of Medicine, University of Oulu, FI-90014, Oulu, Finland
- University Medical Center Utrecht, Departments of Orthopedics Rheumatology and Clinical Immunology, 3508, GA, Utrecht, the Netherlands
- Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, LT-08406, Vilnius, Lithuania
| | - Abdollah Arjmand
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elahe Rafiei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sepideh Alidaee
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hadi Razavi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Bagheri
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Heresh Rezaei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sabouri
- Shanxi Key Laboratory of Ecological, Animal Sciences, And Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Asma Najibi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Forouzan Khodaei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Mohammad Amin Kashani
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Mehdi Ommati
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Shanxi Key Laboratory of Ecological, Animal Sciences, And Environmental Veterinary Medicine, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
- Henan Key Laboratory of Environmental and Animal Product Safety, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, 471000, Henan, China
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
9
|
A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation. Sci Rep 2022; 12:17558. [PMID: 36266427 PMCID: PMC9585018 DOI: 10.1038/s41598-022-22423-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/14/2022] [Indexed: 01/13/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common complication of chronic liver disease, characterized by an altered mental state and hyperammonemia. Insight into the brain pathophysiology of HE is limited due to a paucity of well-characterized HE models beyond the rat bile duct ligation (BDL) model. Here, we assess the presence of HE characteristics in the mouse BDL model. We show that BDL in C57Bl/6j mice induces motor dysfunction, progressive liver fibrosis, liver function failure and hyperammonemia, all hallmarks of HE. Swiss mice however fail to replicate the same phenotype, underscoring the importance of careful strain selection. Next, in-depth characterisation of metabolic disturbances in the cerebrospinal fluid of BDL mice shows glutamine accumulation and transient decreases in taurine and choline, indicative of brain ammonia overload. Moreover, mouse BDL induces glial cell dysfunction, namely microglial morphological changes with neuroinflammation and astrocyte reactivity with blood-brain barrier (BBB) disruption. Finally, we identify putative novel mechanisms involved in central HE pathophysiology, like bile acid accumulation and tryptophan-kynurenine pathway alterations. Our study provides the first comprehensive evaluation of a mouse model of HE in chronic liver disease. Additionally, this study further underscores the importance of neuroinflammation in the central effects of chronic liver disease.
Collapse
|
|
10
|
Hepatic Encephalopathy: Current and Emerging Treatment Modalities. Clin Gastroenterol Hepatol 2022; 20:S9-S19. [PMID: 35940731 DOI: 10.1016/j.cgh.2022.04.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/13/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neurocognitive complication of cirrhosis. It has been reported in at least 30% of patients with cirrhosis and imposes a significant economic burden on caregivers and the healthcare system. Ammonia has been recognized as the culprit in HE development, and all the currently approved treatments mostly act on this toxin to help with HE resolution. After a brief overview of HE characteristics and pathophysiology, this review explores the current accepted treatments for this debilitating complication of cirrhosis. This is followed by an overview of the novel available therapies and a brief focus on future treatment modalities for HE.
Collapse
|
|
11
|
Rajpurohit S, Musunuri B, Shailesh, Basthi Mohan P, Shetty S. Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel. J Clin Exp Hepatol 2022; 12:1200-1214. [PMID: 35814520 PMCID: PMC9257922 DOI: 10.1016/j.jceh.2022.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.
Collapse
Key Words
- ALC, acetyl-L-carnitine
- BCAA, branched-chain amino acid
- BD, twice a day
- BDI, Beck Depression Inventory
- BUN, blood urea nitrogen
- CHESS, Clinical Hepatic Encephalopathy Staging Scale
- CLDQ, Chronic Liver Disease Questionnaire
- ECT, estimated completion time
- EEG, electroencephalogram
- FMT, fecal microbiota transplantation
- GPB, glycerol phenylbutyrate
- HESA, Hepatic Encephalopathy Scoring Algorithm
- HRQOL, health-related quality of life
- IV, intravenous
- MED, Modified Encephalopathy Scale
- MELD, Model for End-stage Liver Disease
- MMSE, Mini-Mental State Examination
- NTZ, nitazoxanide
- Nal, naloxone
- OD, once a day
- ORT, object recognition test
- PEG, polyethylene glycol
- QID, four times a day
- QOL, quality of life
- RBNS, Repeatable Battery for the Assessment of Neuropsychological Status
- RCT, randomized control trial
- RT-qPCR, real-time quantitative polymerase chain reaction
- TID, three times a day
- VSL#3, high concentration probiotic preparations
- hepatic encephalopathy
- liver cirrhosis
- novel drugs
- treatment outcome
Collapse
Affiliation(s)
- Siddheesh Rajpurohit
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Balaji Musunuri
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shailesh
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| |
Collapse
|
|
12
|
Oliveira MM, Monnet-Aimard A, Bosoi CR, Tremblay M, Rose CF. Sex is associated with differences in oxidative stress and susceptibility to severe hepatic encephalopathy in bile-duct ligated rats. J Neurochem 2022; 162:337-351. [PMID: 35771118 DOI: 10.1111/jnc.15661] [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: 01/18/2022] [Revised: 06/23/2022] [Accepted: 06/26/2022] [Indexed: 11/29/2022]
Abstract
Hepatic encephalopathy (HE) is a debilitating neurological complication of chronic liver disease (CLD). Hyperammonemia plays an important role in HE's pathogenesis, acting synergistically with systemic oxidative stress. During CLD, muscle plays a compensatory role in detoxifying ammonia, and therefore muscle loss leads to an increase in the risk of developing HE. With most animal studies involving males, sex's impact on the development of CLD and associated complications such as HE and muscle loss remains unknown. Therefore, we aimed to identify the impact of sex on CLD, HE, and muscle mass loss in a rodent model of CLD. Liver injury markers, hyperammonemia, oxidative stress, muscle mass and ammonia clearance were measured in female and male bile-duct ligated (BDL) rats. In addition, covert HE was assessed in females while ammonia-precipitated severe HE was assessed in female and male BDL rats, and male BDL rats treated with allopurinol (100mg/kg), an antioxidant (xanthine oxidase inhibitor). Female BDL developed CLD and HE (impaired motor-coordination and night activity) compared to respective SHAM. Hyperammonemia and muscle ammonia clearance were similar between female and male BDL. However, only female BDL rats did not develop muscle loss, brain edema, and short-term memory impairment (vs. female SHAM) and systemic oxidative stress and decreased albumin levels (vs. male BDL). Furthermore, both female BDL and allopurinol-treated male BDL rats were protected against ammonia-induced overt HE. In conclusion, female and male BDL rats develop distinct features of CLD and HE, with systemic oxidative stress playing a pivotal role in the susceptibility to ammonia precipitated overt HE.
Collapse
Affiliation(s)
- Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Alexis Monnet-Aimard
- Institut de Neurosciences de la Timone, Équipe inVibe, Université Aix-Marseille, France
| | - Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| |
Collapse
|
|
13
|
Hoilat GJ, Suhail FK, Adhami T, John S. Evidence-based approach to management of hepatic encephalopathy in adults. World J Hepatol 2022; 14:670-681. [PMID: 35646276 PMCID: PMC9099111 DOI: 10.4254/wjh.v14.i4.670] [Citation(s) in RCA: 9] [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: 04/17/2021] [Revised: 08/07/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function and represents one of the many complications of portal hypertension and decompensated liver disease. Although ammonia is clearly implicated in the pathogenesis of HE, the pathogenesis of HE is multifactorial with numerous mechanisms that results in functional impairment of neuronal cells. The initial management of HE focuses on supportive care and stabilization which includes providing appropriate nutritional support. Thereafter, focus should be on identifying and treating the precipitating factors. There are many therapeutic agents available for the management of HE, most of which are directed towards lowering the gut nitrogen load and thus the serum ammonia level. This review aims to provide an update on the conventional and emerging treatment options for HE.
Collapse
Affiliation(s)
- Gilles Jadd Hoilat
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
| | - Fathima Keshia Suhail
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Talal Adhami
- Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
| | - Savio John
- Department of Gastroenterology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| |
Collapse
|
|
14
|
Bloom PP, Tapper EB, Young VB, Lok AS. Microbiome therapeutics for hepatic encephalopathy. J Hepatol 2021; 75:1452-1464. [PMID: 34453966 PMCID: PMC10471317 DOI: 10.1016/j.jhep.2021.08.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/20/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022]
Abstract
Hepatic encephalopathy (HE) is a complication of cirrhosis characterised by neuropsychiatric and motor dysfunction. Microbiota-host interactions play an important role in HE pathogenesis. Therapies targeting microbial community composition and function have been explored for the treatment of HE. Prebiotics, probiotics and faecal microbiota transplant (FMT) have been used with the aim of increasing the abundance of potentially beneficial taxa, while antibiotics have been used to decrease the abundance of potentially harmful taxa. Other microbiome therapeutics, including postbiotics and absorbents, have been used to target microbial products. Microbiome-targeted therapies for HE have had some success, notably lactulose and rifaximin, with probiotics and FMT also showing promise. However, there remain several challenges to the effective application of microbiome therapeutics in HE, including the resilience of the microbiome to sustainable change and unpredictable clinical outcomes from microbiota alterations. Future work in this space should focus on rigorous trial design, microbiome therapy selection, and a personalised approach to HE.
Collapse
Affiliation(s)
- Patricia P Bloom
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA.
| | - Elliot B Tapper
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA
| | - Vincent B Young
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, USA; Department of Microbiology and Immunology, University of Michigan, USA
| | - Anna S Lok
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, USA
| |
Collapse
|
|
15
|
Hasan LZ, Wu GY. Novel Agents in the Management of Hepatic Encephalopathy: A Review. J Clin Transl Hepatol 2021; 9:749-759. [PMID: 34722190 PMCID: PMC8516841 DOI: 10.14218/jcth.2021.00102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatic encephalopathy is an often devastating complication of chronic liver disease, associated with high mortality and increased burden on patients and healthcare systems. Current agents (such as nonabsorbable disaccharides and oral antibiotics) are often only partially effective and associated with unpleasant side effects. With our improved understanding of the pathophysiology of hepatic encephalopathy, multiple treatment modalities have emerged with promising results when used alone or as an adjunct to standard medications. The mechanisms of these agents vary greatly, and include the manipulation of gut microbial composition, reduction of oxidative stress, inhibition of inflammatory mediators, protection of endothelial integrity, modulation of neurotransmitter release and function, and other novel methods to reduce blood ammonia and neurotoxins. Despite their promising results, the studies assessing these treatment modalities are often limited by study design, sample size, outcome assessment heterogeneity, and paucity of data regarding their safety profiles. In this article, we discuss these novel agents in depth and provide the best evidence supporting their use, along with a critical look at their limitations and future directions.
Collapse
Affiliation(s)
- Leen Z. Hasan
- Correspondence to: Leen Z. Hasan, Department of Medicine, Internal Medicine Residency Program, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-1235, USA. ORCID: https://orcid.org/0000-0003-3852-8591. Tel: +1-617-283-6633, Fax: +1-860-679-4613, E-mail: ,
| | | |
Collapse
|
|
16
|
New Therapies of Liver Diseases: Hepatic Encephalopathy. J Clin Med 2021; 10:jcm10184050. [PMID: 34575157 PMCID: PMC8472037 DOI: 10.3390/jcm10184050] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a common complication of advanced liver disease which has profound implications in terms of the patients’ ability to fulfil their family and social roles, to drive and to provide for themselves. Recurrent and persistent HE is still a serious management challenge, translating into a significant burden for patients and their families, health services and society at large. The past few years have been characterized by significantly more attention towards HE and its implications; its definition has been refined and a small number of new drugs/alternative management strategies have become available, while others are underway. In this narrative review we summarize them in a pragmatic and hopefully useful fashion.
Collapse
|
|
17
|
DeMorrow S, Cudalbu C, Davies N, Jayakumar AR, Rose CF. 2021 ISHEN guidelines on animal models of hepatic encephalopathy. Liver Int 2021; 41:1474-1488. [PMID: 33900013 PMCID: PMC9812338 DOI: 10.1111/liv.14911] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/05/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023]
Abstract
This working group of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) was commissioned to summarize and update current efforts in the development and characterization of animal models of hepatic encephalopathy (HE). As defined in humans, HE in animal models is based on the underlying degree and severity of liver pathology. Although hyperammonemia remains the key focus in the pathogenesis of HE, other factors associated with HE have been identified, together with recommended animal models, to help explore the pathogenesis and pathophysiological mechanisms of HE. While numerous methods to induce liver failure and disease exist, less have been characterized with neurological and neurobehavioural impairments. Moreover, there still remains a paucity of adequate animal models of Type C HE induced by alcohol, viruses and non-alcoholic fatty liver disease; the most common etiologies of chronic liver disease.
Collapse
Affiliation(s)
- S DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Texas, USA; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Texas, USA; Research division, Central Texas Veterans Healthcare System, Temple Texas USA.,Correspondance: Sharon DeMorrow, PhD, ; tel: +1-512-495-5779
| | - C Cudalbu
- Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - N Davies
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - AR Jayakumar
- General Medical Research, Neuropathology Section, R&D Service and South Florida VA Foundation for Research and Education Inc; Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami FL, USA
| | - CF Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| |
Collapse
|
|
18
|
Trebicka J, Macnaughtan J, Schnabl B, Shawcross DL, Bajaj JS. The microbiota in cirrhosis and its role in hepatic decompensation. J Hepatol 2021; 75 Suppl 1:S67-S81. [PMID: 34039493 PMCID: PMC8973011 DOI: 10.1016/j.jhep.2020.11.013] [Citation(s) in RCA: 146] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 02/06/2023]
Abstract
Cirrhosis - the common end-stage of chronic liver disease - is associated with a cascade of events, of which intestinal bacterial overgrowth and dysbiosis are central. Bacterial toxins entering the portal or systemic circulation can directly cause hepatocyte death, while dysbiosis also affects gut barrier function and increases bacterial translocation, leading to infections, systemic inflammation and vasodilation, which contribute to acute decompensation and organ failure. Acute decompensation and its severe forms, pre-acute-on-chronic liver failure (ACLF) and ACLF, are characterised by sudden organ dysfunction (and failure) and high short-term mortality. Patients with pre-ACLF and ACLF present with high-grade systemic inflammation, usually precipitated by proven bacterial infection and/or severe alcoholic hepatitis. However, no precipitant is identified in 30% of these patients, in whom bacterial translocation from the gut microbiota is assumed to be responsible for systemic inflammation and decompensation. Different microbiota profiles may influence the rate of decompensation and thereby outcome in these patients. Thus, targeting the microbiota is a promising strategy for the prevention and treatment of acute decompensation, pre-ACLF and ACLF. Approaches include the use of antibiotics such as rifaximin, faecal microbial transplantation and enterosorbents (e.g. Yaq-001), which bind microbial factors without exerting a direct effect on bacterial growth kinetics. This review focuses on the role of microbiota in decompensation and strategies targeting microbiota to prevent acute decompensation.
Collapse
Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Internal Medicine I, Goethe University Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
| | - Jane Macnaughtan
- Institute for Liver and Digestive Health, Royal Free Campus, University College London, United Kingdom
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Debbie L Shawcross
- Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, Denmark Hill Campus, London, United Kingdom
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and Central Virginia Veterans Healthcare System, Richmond, VA, USA
| |
Collapse
|
|
19
|
Ochoa-Sanchez R, Oliveira MM, Tremblay M, Petrazzo G, Pant A, Bosoi CR, Perreault M, Querbes W, Kurtz CB, Rose CF. Genetically engineered E. coli Nissle attenuates hyperammonemia and prevents memory impairment in bile-duct ligated rats. Liver Int 2021; 41:1020-1032. [PMID: 33548108 DOI: 10.1111/liv.14815] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 12/30/2020] [Accepted: 01/28/2021] [Indexed: 12/12/2022]
Abstract
UNLABELLED Hyperammonemia associated with chronic liver disease (CLD) is implicated in the pathogenesis of hepatic encephalopathy (HE). The gut is a major source of ammonia production that contributes to hyperammonemia in CLD and HE and remains the primary therapeutic target for lowering hyperammonemia. As an ammonia-lowering strategy, Escherichia coli Nissle 1917 bacterium was genetically modified to consume and convert ammonia to arginine (S-ARG). S-ARG was further modified to additionally synthesize butyrate (S-ARG + BUT). Both strains were evaluated in bile-duct ligated (BDL) rats; experimental model of CLD and HE. METHODS One-week post-surgery, BDLs received non-modified EcN (EcN), S-ARG, S-ARG + BUT (3x1011 CFU/day) or vehicle until sacrifice at 3 or 5 weeks. Plasma (ammonia/pro-inflammatory/liver function), liver fibrosis (hydroxyproline), liver mRNA (pro-inflammatory/fibrogenic/anti-apoptotic) and colon mRNA (pro-inflammatory) biomarkers were measured post-sacrifice. Memory, motor-coordination, muscle-strength and locomotion were assessed at 5 weeks. RESULTS In BDL-Veh rats, hyperammonemia developed at 3 and further increased at 5 weeks. This rise was prevented by S-ARG and S-ARG + BUT, whereas EcN was ineffective. Memory impairment was prevented only in S-ARG + BUT vs BDL-Veh. Systemic inflammation (IL-10/MCP-1/endotoxin) increased at 3 and 5 weeks in BDL-Veh. S-ARG + BUT attenuated inflammation at both timepoints (except 5-week endotoxin) vs BDL-Veh, whereas S-ARG only attenuated IP-10 and MCP-1 at 3 weeks. Circulating ALT/AST/ALP/GGT/albumin/bilirubin and gene expression of liver function markers (IL-10/IL-6/IL-1β/TGF-β/α-SMA/collagen-1α1/Bcl-2) were not normalized by either strain. Colonic mRNA (TNF-α/IL-1β/occludin) markers were attenuated by synthetic strains at both timepoints vs BDL-Veh. CONCLUSION S-ARG and S-ARG + BUT attenuated hyperammonemia, with S-ARG + BUT additional memory protection likely due to greater anti-inflammatory effect. These innovative strategies, particularly S-ARG + BUT, have potential to prevent HE.
Collapse
Affiliation(s)
| | - Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Grégory Petrazzo
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | | | - Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | | | | | | | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| |
Collapse
|
|
20
|
Clément MA, Bosoi CR, Oliveira MM, Tremblay M, Bémeur C, Rose CF. Bile-duct ligation renders the brain susceptible to hypotension-induced neuronal degeneration: Implications of ammonia. J Neurochem 2021; 157:561-573. [PMID: 33382098 DOI: 10.1111/jnc.15290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied by various perioperative factors such as blood loss and hypotension which could influence outcomes post-LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension-induced neuronal cell death. Six-week bile duct-ligated (BDL) rats with MHE and respective SHAM-controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90 mm Hg) were induced via blood withdrawal from the femoral artery and maintained for 120 min. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia-lowering strategy ornithine phenylacetate (OP; MNK-6105), administered orally (1 g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60 mm Hg (not 90 mm Hg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM-operated controls as well as non-hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase-3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonaemia, improved anxiety and activity, and protected the brain against hypotension-induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension-induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post-transplant and that treating for MHE pre-LT might reduce this risk.
Collapse
Affiliation(s)
- Marc-André Clément
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Chantal Bémeur
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| |
Collapse
|
|
21
|
Chu YY, Wang X, Dai HL. Update on pharmacotherapy of hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2021; 29:58-64. [DOI: 10.11569/wcjd.v29.i2.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a central nervous system disease caused by serious liver diseases or various portal vein systemic circulation abnormalities. The pathogenesis and pathophysiology of HE have not been fully elucidated yet, and among others, the most important is still the theory of ammonia intoxication proposed in the 1930s. Therefore, reducing blood ammonia is currently the main therapeutic strategy for HE, along with improving nervous system function. Thanks to the clarification of the mechanism underlying ammonia-induced brain cell injury in recent years, researchers have proposed some novel therapeutic targets and related drugs. This work will make a brief summary regarding the update of HE drugs with regard to ammonia reduction, nervous system improvement, and intervention of ammonia toxicity targets.
Collapse
Affiliation(s)
- Yu-Ying Chu
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Xue Wang
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| | - Hong-Liang Dai
- School of Nursing, Jinzhou Medical University, Jinzhou 121001, Liaoning Province, China
| |
Collapse
|
|
22
|
Mohammadi H, Heidari R, Niknezhad SV, Jamshidzadeh A, Farjadian F. In vitro and in vivo Evaluation of Succinic Acid-Substituted Mesoporous Silica for Ammonia Adsorption: Potential Application in the Management of Hepatic Encephalopathy. Int J Nanomedicine 2020; 15:10085-10098. [PMID: 33363368 PMCID: PMC7754271 DOI: 10.2147/ijn.s271883] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/20/2020] [Indexed: 12/21/2022] Open
Abstract
Purpose Hepatic encephalopathy (HE) is a critical situation in which liver failure affects brain function. HE could result in a state of coma and death. The liver is the main organ for ammonium ion (NH4 +) metabolism. Hence, acute and/or chronic liver failure could lead to hyperammonemia. NH4 + is the most suspected neurotoxic agent in HE. Thus, finding new therapeutic options to decrease plasma and brain NH4 + levels has a significant clinical value. Mesoporous silica (MS) particles have revolutionized many aspects of pharmaceutical sciences, including drug delivery systems. Moreover, recently, MS has been applied as agents for the detoxification of chemicals (eg, drugs and poisons). Methods First, MS particles containing amine groups (MS-NH2) were synthesized in co-condensation processes. Then, the structure was modified by succinic anhydride to have MS-SA. The MS-SA was characterized (FT-IR, XRD, X-ray photoelectron spectroscopy (XPS), DLS-Zeta FESEM-EDX, and HRTEM). Then, the potential of MS-NH2 and MS-SA particles in adsorption of NH4 + was investigated in vitro and in vivo. MS-NH2 and MS-SA were incubated with increasing concentrations (0.1-10 mM) of NH4 +, and the scavenging capacity of the investigated particles was evaluated. On the other hand, different doses (1 and 5 mg/kg per day) of nanoparticles were administered to a hyperammonemia animal model. Results It was figured out that both MS-NH2 and MS-SA significantly scavenged NH4 + in the in vitro model. However, the NH4 + scavenging capability of MS-SA was more significant. Administration of MS-NH2 and MS-SA also considerably decreased the level of ammonium in plasma and brain and improved cognitive and locomotor activity in hyperammonemic animals. The effects of MS-SA were more significant than MS-NH2 in the HE animal model. Conclusion Collectively, our data suggest that MS particles, especially succinic acid-functionalized MS, could act as special ancillary treatment in HE as a critical clinical complication.
Collapse
Affiliation(s)
- Hamidreza Mohammadi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyyed Vahid Niknezhad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Akram Jamshidzadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Farjadian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| |
Collapse
|
|
23
|
Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, Vilstrup H, Jalan R. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol 2020; 73:1526-1547. [PMID: 33097308 DOI: 10.1016/j.jhep.2020.07.013] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.
Collapse
Affiliation(s)
- Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Radha Krishan Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, United Kingdom
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
| |
Collapse
|
|
24
|
Hu C, Huang K, Zhao L, Zhang F, Wu Z, Li L. Serum ammonia is a strong prognostic factor for patients with acute-on-chronic liver failure. Sci Rep 2020; 10:16970. [PMID: 33046732 PMCID: PMC7550336 DOI: 10.1038/s41598-020-73603-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 09/10/2020] [Indexed: 02/07/2023] Open
Abstract
Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in acute-on-chronic liver failure (ACLF) is still unknown. We aimed to determine the association between serum ammonia level and short-term prognosis in ACLF. Furthermore, we performed an in-depth evaluation of the independent effect of serum ammonia level on the short-term prognosis of hepatitis B virus (HBV) reactivation-induced ACLF patients. We identified 174 patients as part of prospective observational studies in patients with ACLF. Plasma ammonia levels were measured on admission, and several prognostic scores were used to determine the prognostic effect of ammonia. The 28-day patient survival was determined. Receiver operating characteristic analysis was used to identify the cut-off points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. Plasma ammonia was significantly higher in nonsurvivors (83.53 ± 43.78 versus 67.13 ± 41.77 µmol/L, P = 0.013), and ACLF patients with hyperammonemia had significantly higher 28-day mortality than those without hyperammonemia. Ammonia was also closely related to ACLF grade (P < 0.001) and organ failure, including liver (P = 0.048), coagulation (P < 0.001) and brain (P < 0.001). HBV reactivation serves as the main precipitating factor in the ACLF population. Subgroup analysis showed that ammonia is also a strong prognostic factor in the HBV reactivation-induced ACLF population. Ammonia level is closely correlated with failure of other organs and is an independent risk factor for mortality in ACLF and the special population defined as HBV reactivation-related ACLF. Based on the results from our study, we measured serum ammonia in the population with ACLF, which strongly indicates their prognosis. It serves as an important biomarker and a therapeutic target.
Collapse
Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Kaizhou Huang
- Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, 515041, Guangdong, People's Republic of China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Fen Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhongwen Wu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| |
Collapse
|
|
25
|
Matoori S, Forster V, Agostoni V, Bettschart-Wolfensberger R, Bektas RN, Thöny B, Häberle J, Leroux JC, Kabbaj M. Preclinical evaluation of liposome-supported peritoneal dialysis for the treatment of hyperammonemic crises. J Control Release 2020; 328:503-513. [PMID: 32860926 DOI: 10.1016/j.jconrel.2020.08.040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/07/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022]
Abstract
Liposome-supported peritoneal dialysis (LSPD) with transmembrane pH-gradient liposomes was previously shown to enhance ammonia removal in cirrhotic rats and holds promise for the treatment of hyperammonemic crises-associated disorders. The main objective of this work was to conduct the preclinical evaluation of LSPD in terms of pharmacokinetics, ammonia uptake, and toxicology to seek regulatory approval for a first-in-human study. The formulation containing citric acid-loaded liposomes was administered intraperitoneally at two different doses once daily for ten days to healthy minipigs. It was also tested in a domestic pig model of hyperammonemia. The pharmacokinetics of citric acid and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was linear following intraperitoneal administration of medium and high dose. There was no systemic accumulation following daily doses over ten days. The systemic exposure to phospholipids remained low. Furthermore, the liposome-containing peritoneal fluid contained significantly higher ammonia levels than the liposome-free control, demonstrating efficient ammonia sequestration in the peritoneal space. This was indeed confirmed by the ability of LSPD to decrease plasmatic ammonia levels in artificially induced hyperammonemic pigs. LSPD was well tolerated, and no complement activation-related pseudoallergy reactions were observed. The safety profile, the linear pharmacokinetics of citric acid following repeated administrations of LSPD as well as the linear dose-dependent ammonia sequestration in the peritoneal space provide a strong basis for the clinical investigation of LSPD.
Collapse
Affiliation(s)
- Simon Matoori
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland; John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
| | | | - Valentina Agostoni
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Regula Bettschart-Wolfensberger
- Department of Clinical Diagnostics and Services, Section of Anaesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Rima Nadine Bektas
- Department of Clinical Diagnostics and Services, Section of Anaesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Beat Thöny
- Division of Metabolism, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Johannes Häberle
- Division of Metabolism, University Children's Hospital Zurich and Children's Research Centre, Zurich, Switzerland
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
| | | |
Collapse
|
|
26
|
Rabanel JM, Delbreil P, Banquy X, Brambilla D, Ramassamy C. Periphery-confined particulate systems for the management of neurodegenerative diseases and toxicity: Avoiding the blood-brain-barrier challenge. J Control Release 2020; 322:286-299. [PMID: 32243978 DOI: 10.1016/j.jconrel.2020.03.035] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/23/2020] [Accepted: 03/24/2020] [Indexed: 01/07/2023]
Abstract
The blood-brain barrier prevents passage of large and hydrophilic molecules, undermining efforts to deliver most active molecules, proteins and other macromolecules. To date, nanoparticle-assisted delivery has been extensively studied to overcome this challenge but with limited success. On the other hand, for certain brain therapeutic applications, periphery-confined particles could be of immediate therapeutic usefulness. The modulation of CNS dysfunctions from the peripheral compartment is a promising approach, as it does not involve invasive interventions. From recent studies, three main roles could be identified for periphery-confined particles: brain tissue detoxification via the "sink-effect"; a "circulating drug-reservoir" effect to improve drug delivery to brain tissues, and finally, brain vascular endothelium targeting to diagnose or heal vascular-related dysfunctions. These applications are much easier to implement as they do not involve complex therapeutic and targeting strategies and do not require crossing biological barriers. Micro/nano-devices required for such applications will likely be simpler to synthesize and will involve fewer complex materials. Moreover, peripheral particles are expected to be less prone to neurotoxicity and issues related to their diffusion in confined space.
Collapse
Affiliation(s)
- Jean-Michel Rabanel
- INRS, Centre Armand-Frappier Santé Biotechnologie, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada
| | - Philippe Delbreil
- Faculty of Pharmacy, Université de Montréal, CP. 6128, succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Xavier Banquy
- Faculty of Pharmacy, Université de Montréal, CP. 6128, succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Davide Brambilla
- Faculty of Pharmacy, Université de Montréal, CP. 6128, succursale Centre-ville, Montréal, QC H3C 3J7, Canada
| | - Charles Ramassamy
- INRS, Centre Armand-Frappier Santé Biotechnologie, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada
| |
Collapse
|
|
27
|
Abstract
Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.
Collapse
|
|
28
|
Schmidt AC, Hebels ER, Weitzel C, Stoessel B, Bao Y, Altmann KH, Leroux JC. Ammonia uptake by transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) polymersomes. SOFT MATTER 2020; 16:2725-2735. [PMID: 32115597 DOI: 10.1039/d0sm00183j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.
Collapse
Affiliation(s)
- Aaron C Schmidt
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Erik R Hebels
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Charlotte Weitzel
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Barbara Stoessel
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Yinyin Bao
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Karl-Heinz Altmann
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| |
Collapse
|
|
29
|
Kurtz CB, Millet YA, Puurunen MK, Perreault M, Charbonneau MR, Isabella VM, Kotula JW, Antipov E, Dagon Y, Denney WS, Wagner DA, West KA, Degar AJ, Brennan AM, Miller PF. An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med 2020; 11:11/475/eaau7975. [PMID: 30651324 DOI: 10.1126/scitranslmed.aau7975] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/08/2018] [Accepted: 12/19/2018] [Indexed: 12/30/2022]
Abstract
The intestine is a major source of systemic ammonia (NH3); thus, capturing part of gut NH3 may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Escherichia coli Nissle 1917 to create strain SYNB1020 that converts NH3 to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. SYNB1020 produced l-arg and consumed NH3 in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase-deficient spfash mice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 1012 colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma 15N-nitrate (highest dose versus placebo, P = 0.0015), and urinary 15N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.
Collapse
Affiliation(s)
| | - Yves A Millet
- Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA
| | | | | | | | | | | | - Eugene Antipov
- Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA
| | - Yossi Dagon
- Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA
| | | | - David A Wagner
- Metabolic Solutions Inc., 460 Amherst Street, Nashua, NH 03063, USA
| | - Kip A West
- Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA
| | | | | | - Paul F Miller
- Synlogic Inc., 301 Binney Street, Cambridge, MA 02142, USA
| |
Collapse
|
|
30
|
Hu H, Lin A, Kong M, Yao X, Yin M, Xia H, Ma J, Liu H. Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives. J Gastroenterol 2020; 55:142-158. [PMID: 31845054 PMCID: PMC6981320 DOI: 10.1007/s00535-019-01649-8] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/19/2019] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of dysregulated lipid and glucose metabolism, which is often associated with obesity, dyslipidemia and insulin resistance. In view of the high morbidity and health risks of NAFLD, the lack of effective cure has drawn great attention. In recent years, a line of evidence has suggested a close linkage between the intestine and liver diseases such as NAFLD. We summarized the composition and characteristics of intestinal microbes and reviewed molecular insights into the intestinal microbiome in development and progression of NAFLD. Intestinal microbes mainly include bacteria, archaea, viruses and fungi, and the crosstalk between non-bacterial intestinal microbes and human liver diseases should be paid more attention. Intestinal microbiota imbalance may not only increase the intestinal permeability to gut microbes but also lead to liver exposure to harmful substances that promote hepatic lipogenesis and fibrosis. Furthermore, we focused on reviewing the latest "gut-liver axis"-targeting treatment, including the application of antibiotics, probiotics, prebiotics, synbiotics, farnesoid X receptor agonists, bile acid sequestrants, gut-derived hormones, adsorbents and fecal microbiota transplantation for NAFLD. In this review, we also discussed the potential mechanisms of "gut-liver axis" manipulation and efficacy of these therapeutic strategies for NAFLD treatment.
Collapse
Affiliation(s)
- Haiming Hu
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Aizhen Lin
- grid.477392.cHubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei China
| | - Mingwang Kong
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Xiaowei Yao
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Mingzhu Yin
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Hui Xia
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Jun Ma
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Hongtao Liu
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| |
Collapse
|
|
31
|
Ri HS, Choi YJ, Park JY, Jin SJ, Lee YS, Son JM, Yoon SZ, Shin HW, Choi BH, Lee TB. Elevation of Preoperative Ammonia Level Is Not Associated With the Incidence of Postoperative Delirium in Patients with Liver Transplantation: A Propensity Score Matching Analysis. Transplant Proc 2020; 52:219-226. [PMID: 31889540 DOI: 10.1016/j.transproceed.2019.11.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/08/2019] [Accepted: 11/02/2019] [Indexed: 01/05/2023]
Abstract
INTRODUCTION The preoperative elevation of ammonia may be associated with postoperative neurologic complications. The aim of this study was to evaluate the effect of preoperative ammonia level on the incidence of delirium in patients after liver transplantation (LT). MATERIALS AND METHODS Patients (n = 260) who received LT from January 2010 to July 2017 in a single university hospital were retrospectively reviewed. The patients' demographic data, perioperative managements, and postoperative complications were assessed. Patients were divided into the following 2 groups: those who had a preoperative elevation (Group A, n = 158) and those with a normal range (Group C, n = 102). The cut-off value for a normal serum ammonia level in our hospital was defined as 32 μg/dL. RESULTS After propensity score matching, there was no difference in the incidence of delirium between the groups (P = .784). Delirium occurred in 8 of 68 (11.76%) patients in Group A and 7 of 68 (10.29%) patients in Group C after LT. In addition, there was no difference in the incidence of delirium between the groups, even patients were categorized based on serum ammonia levels into 3 groups as follows: < 32 μg/dL (28/158 [17.72%]), 32 to 65 μg/dL (28/158 [17.72%]), and >65 μg/dL (28/158 [17.72%]) (P = .134). CONCLUSIONS The preoperative serum ammonia level was not related with the incidence of postoperative delirium. The high elevation group, especially those with greater than 65 μg/dL of preoperative ammonia, was also not related with the incidence of delirium. However, our study is limited by its retrospective design, so future prospective studies are needed.
Collapse
Affiliation(s)
- Hyun-Su Ri
- Department of Anaesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Yoon Ji Choi
- Department of Anaesthesiology and Pain Medicine, Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea.
| | - Ju Yeon Park
- Department of Anaesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Se Jong Jin
- Department of Anaesthesiology and Pain Medicine, Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea
| | - Yoon Sook Lee
- Department of Anaesthesiology and Pain Medicine, Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea
| | - Jung-Min Son
- Department of Biostatistics, Clinical Trial Center, Biomedical Research Institute, Pusan National University Hospital, Pusan, Korea
| | - Seung Zhoo Yoon
- Department of Anaesthesiology and Pain Medicine, Anam Hospital, Korea University College of Medicine, Korea, Republic of Korea
| | - Hye Won Shin
- Department of Anaesthesiology and Pain Medicine, Anam Hospital, Korea University College of Medicine, Korea, Republic of Korea
| | - Byung Hyun Choi
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Tae Beom Lee
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
| |
Collapse
|
|
32
|
Matoori S, Bao Y, Schmidt A, Fischer EJ, Ochoa-Sanchez R, Tremblay M, Oliveira MM, Rose CF, Leroux JC. An Investigation of PS-b-PEO Polymersomes for the Oral Treatment and Diagnosis of Hyperammonemia. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1902347. [PMID: 31721441 DOI: 10.1002/smll.201902347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 10/02/2019] [Indexed: 05/17/2023]
Abstract
Ammonia-scavenging transmembrane pH-gradient poly(styrene)-b-poly(ethylene oxide) polymersomes are investigated for the oral treatment and diagnosis of hyperammonemia, a condition associated with serious neurologic complications in patients with liver disease as well as in infants with urea cycle disorders. While these polymersomes are highly stable in simulated intestinal fluids at extreme bile salt and osmolality conditions, they unexpectedly do not reduce plasmatic ammonia levels in cirrhotic rats after oral dosing. Incubation in dietary fiber hydrogels mimicking the colonic environment suggests that the vesicles are probably destabilized during the dehydration of the intestinal chyme. The findings question the relevance of commonly used simulated intestinal fluids for studying vesicular stability. With the encapsulation of a pH-sensitive dye in the polymersome core, the local pH increase upon ammonia influx could be exploited to assess the ammonia concentration in the plasma of healthy and cirrhotic rats as well as in other fluids. Due to its high sensitivity and selectivity, this polymersome-based assay could prove useful in the monitoring of hyperammonemic patients and in other applications such as drug screening tests.
Collapse
Affiliation(s)
- Simon Matoori
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Yinyin Bao
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Aaron Schmidt
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Eric J Fischer
- Institute for Chemical and Bioengineering, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | | | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Montréal, H2X 0A9, Québec, Canada
| | | | | | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| |
Collapse
|
|
33
|
Zacharias HD, Zacharias AP, Gluud LL, Morgan MY. Pharmacotherapies that specifically target ammonia for the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. Cochrane Database Syst Rev 2019; 6:CD012334. [PMID: 31204790 PMCID: PMC6572872 DOI: 10.1002/14651858.cd012334.pub2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatic encephalopathy is a common complication of cirrhosis, with high related morbidity and mortality. Its presence is associated with a wide spectrum of change ranging from clinically obvious neuropsychiatric features, known as 'overt' hepatic encephalopathy, to abnormalities manifest only on psychometric or electrophysiological testing, 'minimal' hepatic encephalopathy. The exact pathogenesis of the syndrome is unknown but ammonia plays a key role. Drugs that specifically target ammonia include sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120 (spherical carbon adsorbent), and polyethylene glycol. OBJECTIVES To evaluate the beneficial and harmful effects of pharmacotherapies that specifically target ammonia versus placebo, no intervention, or other active interventions, for the prevention and treatment of hepatic encephalopathy in people with cirrhosis. SEARCH METHODS We searched the Cochrane Hepato-Biliary Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three other databases to March 2019. We also searched online trials registries such as ClinicalTrials.gov, European Medicines Agency, WHO International Clinical Trial Registry Platform, and the Food and Drug Administration for ongoing or unpublished trials. In addition, we searched conference proceedings, checked bibliographies, and corresponded with investigators. SELECTION CRITERIA We included randomised clinical trials comparing sodium benzoate, glycerol phenylbutyrate, ornithine phenylacetate, AST-120, and polyethylene glycol versus placebo or non-absorbable disaccharides, irrespective of blinding, language, or publication status. We included participants with minimal or overt hepatic encephalopathy or participants who were at risk of developing hepatic encephalopathy. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data from the included reports. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 statistic values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the certainty of the evidence using GRADE. MAIN RESULTS We identified 11 randomised clinical trials that fulfilled our inclusion criteria. Two trials evaluated the prevention of hepatic encephalopathy while nine evaluated the treatment of hepatic encephalopathy. The trials assessed sodium benzoate (three trials), glycerol phenylbutyrate (one trial), ornithine phenylacetate (two trials), AST-120 (two trials), and polyethylene glycol (three trials). Overall, 499 participants received these pharmacotherapies while 444 participants received a placebo preparation or a non-absorbable disaccharide. We classified eight of the 11 trials as at 'high risk of bias' and downgraded the certainty of the evidence to very low for all outcomes.Eleven trials, involving 943 participants, reported mortality data, although there were no events in five trials. Our analyses found no beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.26, 95% CI 0.49 to 3.28; 101 participants; 2 trials; I2 = 0%), glycerol phenylbutyrate versus placebo (RR 0.65, 95% CI 0.11 to 3.81; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.73, 95% CI 0.35 to 1.51; 269 participants; 2 trials; I2 = 0%), AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial), or polyethylene glycol versus lactulose (RR 0.50, 95% CI 0.09 to 2.64; 190 participants; 3 trials; I2 = 0%).Seven trials involving 521 participants reported data on hepatic encephalopathy. Our analyses showed a beneficial effect of glycerol phenylbutyrate versus placebo (RR 0.57, 95% CI 0.36 to 0.90; 178 participants; 1 trial; number needed to treat for an additional beneficial outcome (NNTB) 6), and of polyethylene glycol versus lactulose (RR 0.19, 95% CI 0.08 to 0.44; 190 participants; 3 trials; NNTB 4). We did not observe beneficial effects in the remaining three trials with extractable data: sodium benzoate versus non-absorbable disaccharides (RR 1.22, 95% CI 0.51 to 2.93; 74 participants; 1 trial); ornithine phenylacetate versus placebo (RR 2.71, 95% CI 0.12 to 62.70; 38 participants; 1 trial); or AST-120 versus lactulose (RR 1.05, 95% CI 0.59 to 1.85; 41 participants; 1 trial).Ten trials, involving 790 participants, reported a total of 130 serious adverse events. Our analyses found no evidence of beneficial or harmful effects of sodium benzoate versus non-absorbable disaccharides (RR 1.08, 95% CI 0.44 to 2.68; 101 participants; 2 trials), glycerol phenylbutyrate versus placebo (RR 1.63, 95% CI 0.85 to 3.13; 178 participants; 1 trial), ornithine phenylacetate versus placebo (RR 0.92, 95% CI 0.62 to 1.36; 264 participants; 2 trials; I2 = 0%), or polyethylene glycol versus lactulose (RR 0.57, 95% CI 0.18 to 1.82; 190 participants; 3 trials; I2 = 0%). Likewise, eight trials, involving 782 participants, reported a total of 374 non-serious adverse events and again our analyses found no beneficial or harmful effects of the pharmacotherapies under review when compared to placebo or to lactulose/lactitol.Nine trials, involving 733 participants, reported data on blood ammonia. We observed significant reductions in blood ammonia in placebo-controlled trials evaluating sodium benzoate (MD -32.00, 95% CI -46.85 to -17.15; 16 participants; 1 trial), glycerol phenylbutyrate (MD -12.00, 95% CI -23.37 to -0.63; 178 participants; 1 trial), ornithine phenylacetate (MD -27.10, 95% CI -48.55 to -5.65; 231 participants; 1 trial), and AST-120 (MD -22.00, 95% CI -26.75 to -17.25; 98 participants; 1 trial). However, there were no significant differences in blood ammonia concentrations in comparison with lactulose/lactitol with sodium benzoate (MD 9.00, 95% CI -1.10 to 19.11; 85 participants; 2 trials; I2 = 0%), AST-120 (MD 5.20, 95% CI -2.75 to 13.15; 35 participants; 1 trial), and polyethylene glycol (MD -29.28, 95% CI -95.96 to 37.39; 90 participants; 2 trials; I2 = 88%). FUNDING Five trials received support from pharmaceutical companies while four did not; two did not provide this information. AUTHORS' CONCLUSIONS There is insufficient evidence to determine the effects of these pharmacotherapies on the prevention and treatment of hepatic encephalopathy in adults with cirrhosis. They have the potential to reduce blood ammonia concentrations when compared to placebo, but their overall effects on clinical outcomes of interest and the potential harms associated with their use remain uncertain. Further evidence is needed to evaluate the potential beneficial and harmful effects of these pharmacotherapies in this clinical setting.
Collapse
Affiliation(s)
- Harry D Zacharias
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthLondonUKNW3 2PF
| | - Antony P Zacharias
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthLondonUKNW3 2PF
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionKettegaards Alle 30HvidovreDenmark2650
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthLondonUKNW3 2PF
| |
Collapse
|
|
34
|
Aamann L, Ochoa-Sanchez R, Oliveira M, Tremblay M, Bémeur C, Dam G, Vilstrup H, Aagaard NK, Rose CF. Progressive resistance training prevents loss of muscle mass and strength in bile duct-ligated rats. Liver Int 2019; 39:676-683. [PMID: 30394651 DOI: 10.1111/liv.13997] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/04/2018] [Accepted: 10/27/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct-ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats. METHODS A group of BDL-rats underwent a progressive resistance training programme and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. RESULTS BDL + exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. CONCLUSION Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia; however, a tendency was observed.
Collapse
Affiliation(s)
- Luise Aamann
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Rafael Ochoa-Sanchez
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada
| | - Mariana Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada
| | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada
| | - Chantal Bémeur
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada.,Department of Nutrition, Université de Montréal, Montréal, Québec, Canada
| | - Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Niels Kristian Aagaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada
| |
Collapse
|
|
35
|
Montagnese S, Russo FP, Amodio P, Burra P, Gasbarrini A, Loguercio C, Marchesini G, Merli M, Ponziani FR, Riggio O, Scarpignato C. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2019; 51:190-205. [PMID: 30606696 DOI: 10.1016/j.dld.2018.11.035] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a common, worrisome and sometimes difficult to manage complication of end-stage liver disease. HE is often recurrent, requiring multiple hospital admissions. It can have serious implications in terms of a patient's ability to perform complex tasks (for example driving), their earning capacity, their social and family roles. This guideline reviews current knowledge on HE definition, pathophysiology, diagnosis and treatment, both by general principles and by way of a summary of available drugs and treatment strategies. The quality of the published, pertinent evidence is graded, and practical recommendations are made. Where possible, these are placed within the Italian health service context, with reference to local diagnosis and management experience.
Collapse
Affiliation(s)
| | | | - Piero Amodio
- Department of Medicine, University of Padova, Italy
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Carmela Loguercio
- Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy
| | - Giulio Marchesini
- Unit of Metabolic Diseases & Clinical Dietetics, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Manuela Merli
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Francesca Romana Ponziani
- Division of Internal Medicine, Gastroenterology and Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Oliviero Riggio
- Division of Gastroenterology, Department of Clinical Medicine, La Sapienza University of Rome, Italy
| | - Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Italy
| |
Collapse
|
|
36
|
Bjerring PN, Morgan MY, Vilstrup H, Nielsen SM, Christensen R, Gluud LL. Medical interventions for prevention and treatment of hepatic encephalopathy in adults with cirrhosis: a network meta‐analysis. Cochrane Database Syst Rev 2018; 2018:CD013241. [PMCID: PMC6517127 DOI: 10.1002/14651858.cd013241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the beneficial and harmful effects of medical interventions for prevention and treatment of hepatic encephalopathy in adults with cirrhosis.
Collapse
Affiliation(s)
- Peter N Bjerring
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionHvidovreDenmark
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College LondonUCL Institute for Liver & Digestive HealthRowland Hill StreetHampsteadLondonUKNW3 2PF
| | - Hendrik Vilstrup
- Aarhus University HospitalDepartment of Hepatology and GastroenterologyNørrebrogade 44AarhusDenmark
| | - Sabrina M Nielsen
- The Parker Institute, Bispebjerg and Frederiksberg HospitalMusculoskeletal Statistics UnitCopenhagenDenmark2000 F
| | - Robin Christensen
- Bispebjerg and Frederiksberg HospitalMusculoskeletal Statistics Unit, The Parker InstituteCopenhagenDenmark
| | - Lise Lotte Gluud
- Copenhagen University Hospital HvidovreGastrounit, Medical DivisionHvidovreDenmark
| |
Collapse
|
|
37
|
Ochoa-Sanchez R, Rose CF. Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease. J Clin Exp Hepatol 2018; 8:262-271. [PMID: 30302043 PMCID: PMC6175755 DOI: 10.1016/j.jceh.2018.08.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs during chronic liver disease (CLD). While ammonia and other precipitating factors in liver disease including inflammation, bile acids, oxidative stress, and lactate play a role in the pathogenesis of HE, the exact mechanism that leads to HE is not fully understood. Notably, accumulating evidence points toward a synergic effect rather than independent actions among precipitating factors that contributes to the development and severity of HE in CLD. Hence, this review is aimed to briefly discuss the single and synergic interplay of pathological factors in the progression and severity of HE.
Collapse
Key Words
- AQP4, Aquaporin 4
- BAs, Bile Acids
- BBB, Blood-Brain Barrier
- BDL, Bile Duct Ligation
- CLD, Chronic Liver Disease
- CSF, Cerebrospinal Fluid
- GABA, Gamma-Aminobutyric Acid
- GAMSAs, GABAA Receptor Modulating Steroid Antagonists
- GFAP, Glial Fibrillary Acid Protein
- GLAST, Glial Glutamate-Aspartate Transporter
- GPR81, G-Protein-Coupled Receptor 81
- GS, Glutamine Synthetase
- HE, Hepatic Encephalopathy
- ICP, Intracranial Pressure
- ILs, Interleukins
- MRI, Magnetic Resonance Imaging
- NF-?B, Nuclear Factor Kappa B
- NMDA, N-Methyl-d-Aspartate Glutamate Receptor
- NO, Nitric Oxide
- PCA, Portacaval Anastomosis
- ROS, Reactive Oxygen Species
- TJ, Tight Junction
- TNF-a, Tumor Necrosis Alpha
- ammonia
- astrocyte swelling
- bile acids
- brain edema
- cGMP, Cyclic Guanosine Monophosphate
- cirrhosis
- hepatic encephalopathy
- inflammation
- lactate
- mGluR, Metabotropic Glutamate Receptor
- neurotransmission
- oxidative stress
Collapse
Affiliation(s)
| | - Christopher F. Rose
- Address for correspondence. Christopher F. Rose Professor, Dept. Medicine, Université de Montréal, CRCHUM, 900 Saint-Denis Street, Montréal, Québec, H2X 0A9, Canada.
| |
Collapse
|
|
38
|
Kornerup LS, Gluud LL, Vilstrup H, Dam G. Update on the Therapeutic Management of Hepatic Encephalopathy. Curr Gastroenterol Rep 2018; 20:21. [PMID: 29644492 PMCID: PMC5895665 DOI: 10.1007/s11894-018-0627-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
PURPOSE OF REVIEW Hepatic encephalopathy (HE) is a common and devastating complication to chronic liver disease. In this paper, we summarize the latest research and evidence of both conventional and up-coming treatments. RECENT FINDINGS Meta-analyses report beneficial effects of lactulose, branched-chain amino acids, rifaximin, and to some degree L-ornithine L-aspartate on the manifestations of HE in patients with cirrhosis, and generally the numbers needed to treat are low. Recent studies on newer HE treatments including ornithine phenylacetate, spherical carbon, and fecal microbiota transplant also report potentially beneficial effects on HE manifestations. The conventional treatments benefit patients with HE. Newer treatments are under study and more research is needed for their validation.
Collapse
Affiliation(s)
- Linda Skibsted Kornerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark.
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital, Kettegaard Allé 30, Hvidovre, 2650, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark
| | - Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark
| |
Collapse
|
|
39
|
Fortea JI, Zipprich A, Fernandez-Mena C, Puerto M, Bosoi CR, Almagro J, Hollenbach M, Bañares J, Rodríguez-Sánchez B, Cercenado E, Clément MA, Rose CF, Bañares R, Vaquero J, Ripoll C. Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis. Liver Int 2018; 38:102-112. [PMID: 28665498 DOI: 10.1111/liv.13510] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 06/26/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. METHODS Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. RESULTS Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. CONCLUSIONS Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis.
Collapse
Affiliation(s)
- José I Fortea
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Alexander Zipprich
- Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Carolina Fernandez-Mena
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marta Puerto
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBERehd, Madrid, Spain
| | - Cristina R Bosoi
- Hepato-neuro laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Jorge Almagro
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marcus Hollenbach
- Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany
| | - Juan Bañares
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Belén Rodríguez-Sánchez
- Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Microbiología Clínica y Enfermedades Infecciosas, HGU Gregorio Marañón, Madrid, Spain.,CIBERES, Madrid, Spain
| | - Emilia Cercenado
- Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Microbiología Clínica y Enfermedades Infecciosas, HGU Gregorio Marañón, Madrid, Spain
| | - Marc-André Clément
- Hepato-neuro laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Christopher F Rose
- Hepato-neuro laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Rafael Bañares
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBERehd, Madrid, Spain.,Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Javier Vaquero
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,CIBERehd, Madrid, Spain
| | - Cristina Ripoll
- Laboratorio Investigación Hepatología y Gastroenterología, HGU Gregorio Marañón, Madrid, Spain.,Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.,Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany.,CIBERehd, Madrid, Spain
| |
Collapse
|
|
40
|
Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017; 67:1084-1103. [PMID: 28526488 DOI: 10.1016/j.jhep.2017.05.007] [Citation(s) in RCA: 303] [Impact Index Per Article: 37.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/04/2017] [Accepted: 05/05/2017] [Indexed: 12/13/2022]
Abstract
The gut-liver axis is widely implicated in the pathogenesis of liver diseases, where it is increasingly the focus of clinical research. Recent studies trialling an array of therapeutic and preventative strategies have yielded promising results. Considering these strategies, the armamentarium for targeting the gut-liver axis will continue to expand. Further clinical trials, translated from our current knowledge of the gut-liver axis, promise an exciting future in liver treatment.
Collapse
Affiliation(s)
- Reiner Wiest
- Gastroenterology, University Hospital, 3010 Bern, Switzerland.
| | - Agustin Albillos
- Hospital Universitario Ramón y Cajal, Gastroenterology and Hepatology, Madrid, Spain
| | - Michael Trauner
- Medical University Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Vienna, Austria
| | - Jasmohan S Bajaj
- Virginia Commonwealth University and McGuire VA Medical Center, GI/Hepatology, VA, USA
| | - Rajiv Jalan
- University College London, Institute of Hepatology, London, UK
| |
Collapse
|
|
41
|
Hadjihambi A, Arias N, Sheikh M, Jalan R. Hepatic encephalopathy: a critical current review. Hepatol Int 2017; 12:135-147. [PMID: 28770516 PMCID: PMC5830466 DOI: 10.1007/s12072-017-9812-3] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20–30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.
Collapse
Affiliation(s)
- Anna Hadjihambi
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UK
| | - Natalia Arias
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Mohammed Sheikh
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.
| |
Collapse
|
|
42
|
Connor EF, Lees I, Maclean D. Polymers as drugs-Advances in therapeutic applications of polymer binding agents. ACTA ACUST UNITED AC 2017. [DOI: 10.1002/pola.28703] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
| | - Inez Lees
- Relypsa, Inc; 100 Cardinal Way Redwood City California 94063
| | - Derek Maclean
- Relypsa, Inc; 100 Cardinal Way Redwood City California 94063
| |
Collapse
|
|
43
|
Bosoi CR, Oliveira MM, Ochoa-Sanchez R, Tremblay M, Ten Have GA, Deutz NE, Rose CF, Bemeur C. The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis. Metab Brain Dis 2017; 32:513-518. [PMID: 27981407 DOI: 10.1007/s11011-016-9937-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 11/30/2016] [Indexed: 02/07/2023]
Abstract
Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss.
Collapse
Affiliation(s)
- Cristina R Bosoi
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Mariana M Oliveira
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | | | - Mélanie Tremblay
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Gabriella A Ten Have
- Center for Translational Research in Aging & Longevity, Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA
| | - Nicolaas E Deutz
- Center for Translational Research in Aging & Longevity, Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada
| | - Chantal Bemeur
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Canada.
- Département de nutrition, Faculté de médecine, Université de Montréal, CP 6128 Succ. Centre-ville, Montréal, Québec, H3C 3J7, Canada.
| |
Collapse
|
|
44
|
Hadjihambi A, De Chiara F, Hosford PS, Habtetion A, Karagiannis A, Davies N, Gourine AV, Jalan R. Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology 2017; 65:1306-1318. [PMID: 28066916 PMCID: PMC5396295 DOI: 10.1002/hep.29031] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/22/2016] [Accepted: 12/23/2016] [Indexed: 12/19/2022]
Abstract
UNLABELLED The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte-neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia-induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. CONCLUSION The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel-mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306-1318).
Collapse
Affiliation(s)
- Anna Hadjihambi
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom,Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Francesco De Chiara
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | - Patrick S. Hosford
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Abeba Habtetion
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | | | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | - Alexander V. Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| |
Collapse
|
|
45
|
Rackayova V, Braissant O, McLin VA, Berset C, Lanz B, Cudalbu C. 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. Metab Brain Dis 2016; 31:1303-1314. [PMID: 26253240 DOI: 10.1007/s11011-015-9715-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 07/26/2015] [Indexed: 12/21/2022]
Abstract
Chronic liver disease (CLD) leads to a spectrum of neuropsychiatric disorders named hepatic encephalopathy (HE). Even though brain energy metabolism is believed to be altered in chronic HE, few studies have explored energy metabolism in CLD-induced HE, and their findings were inconsistent. The aim of this study was to characterize for the first time in vivo and longitudinally brain metabolic changes in a rat model of CLD-induced HE with a focus on energy metabolism, using the methodological advantages of high field proton and phosphorus Magnetic Resonance Spectroscopy (1H- and 31P-MRS). Wistar rats were bile duct ligated (BDL) and studied before BDL and at post-operative weeks 4 and 8. Glutamine increased linearly over time (+146 %) together with plasma ammonium (+159 %). As a compensatory effect, other brain osmolytes decreased: myo-inositol (-36 %), followed by total choline and creatine. A decrease in the neurotransmitters glutamate (-17 %) and aspartate (-28 %) was measured only at week 8, while no significant changes were observed for lactate and phosphocreatine. Among the other energy metabolites measured by 31P-MRS, we observed a non-significant decrease in ATP together with a significant decrease in ADP (-28 %), but only at week 8 after ligation. Finally, brain glutamine showed the strongest correlations with changes in other brain metabolites, indicating its importance in type C HE. In conclusion, mild alterations in some metabolites involved in energy metabolism were observed but only at the end stage of the disease when edema and neurological changes are already present. Therefore, our data indicate that impaired energy metabolism is not one of the major causes of early HE symptoms in the established model of type C HE.
Collapse
Affiliation(s)
- Veronika Rackayova
- Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olivier Braissant
- Service of Biomedicine, University Hospital of Lausanne, Lausanne, Switzerland
| | - Valérie A McLin
- Swiss Center for Liver Disease in Children, Department of Pediatrics, University Hospitals Geneva, Geneva, Switzerland
| | - Corina Berset
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Bernard Lanz
- Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
| |
Collapse
|
|
46
|
Bémeur C, Cudalbu C, Dam G, Thrane AS, Cooper AJL, Rose CF. Brain edema: a valid endpoint for measuring hepatic encephalopathy? Metab Brain Dis 2016; 31:1249-1258. [PMID: 27272740 DOI: 10.1007/s11011-016-9843-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 05/19/2016] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is a major complication of liver failure/disease which frequently develops during the progression of end-stage liver disease. This metabolic neuropsychiatric syndrome involves a spectrum of symptoms, including cognition impairment, attention deficits and motor dysfunction which eventually can progress to coma and death. Pathologically, HE is characterized by swelling of the astrocytes which consequently leads to brain edema, a common feature found in patients with acute liver failure (ALF) as well as in cirrhotic patients suffering from HE. The pathogenic factors involved in the onset of astrocyte swelling and brain edema in HE are unresolved. However, the role of astrocyte swelling/brain edema in the development of HE remains ambiguous and therefore measuring brain edema as an endpoint to evaluate HE is questioned. The following review will determine the effect of astrocyte swelling and brain edema on neurological function, discuss the various possible techniques to measure brain edema and lastly to propose a number of neurobehavioral tests to evaluate HE.
Collapse
Affiliation(s)
- Chantal Bémeur
- Département de nutrition, Université de Montréal, Montréal, Québec, Canada
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada
| | - Cristina Cudalbu
- Centre d'Imagerie Biomédicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Gitte Dam
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus, Denmark
| | - Alexander S Thrane
- Department of Ophthalmology, Haukeland University Hospital, 5012, Bergen, Norway
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, 14642, USA
| | - Arthur J L Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York, 10595, USA
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada.
| |
Collapse
|
|
47
|
Zacharias HD, Zacharias AP, Oliveira Ferreira A, Morgan MY, Gluud LL. Ammonia scavenging agents for people with cirrhosis and hepatic encephalopathy. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2016. [DOI: 10.1002/14651858.cd012334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Harry D Zacharias
- Division of Medicine, Royal Free Campus, University College London; UCL Institute for Liver & Digestive Health; London UK NW3 2PF
| | - Antony P Zacharias
- Division of Medicine, Royal Free Campus, University College London; UCL Institute for Liver & Digestive Health; London UK NW3 2PF
| | - Alexandre Oliveira Ferreira
- Hospital Santa Maria; Department of Gastroenterology and Hepatology; Av Prof Egas Moniz Lisboa Portugal 1649
| | - Marsha Y Morgan
- Division of Medicine, Royal Free Campus, University College London; UCL Institute for Liver & Digestive Health; London UK NW3 2PF
| | - Lise Lotte Gluud
- Copenhagen University Hospital Hvidovre; Gastrounit, Medical Division; Kettegaards Alle Hvidovre Denmark 2650
| |
Collapse
|
|
48
|
Tamaoki S, Suzuki H, Okada M, Fukui N, Isobe M, Saito T. Development of an experimental rat model of hyperammonemic encephalopathy and evaluation of the effects of rifaximin. Eur J Pharmacol 2016; 779:168-76. [DOI: 10.1016/j.ejphar.2016.03.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 03/10/2016] [Accepted: 03/11/2016] [Indexed: 02/07/2023]
|
|
49
|
Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia. Toxicol Rep 2016; 3:870-879. [PMID: 28959615 PMCID: PMC5615919 DOI: 10.1016/j.toxrep.2016.04.002] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 03/19/2016] [Accepted: 04/08/2016] [Indexed: 12/20/2022] Open
Abstract
Hyperammonemia is associated with chronic and acute liver injury. There is no promising therapeutic agent against ammonia-induced complications. Hence, finding therapeutic molecules with safe profile of administration has clinical value. The present study was conducted to evaluate the role of taurine (TA) administration on plasma and brain ammonia and its consequent events in different models of chronic and acute liver injury and hyperammonemia. Bile duct ligated (BDL) rats were used as a model of chronic liver injury. Thioacetamide and acetaminophen-induced acute liver failure were used as acute liver injury models. A high level of ammonia was detected in blood and brain of experimental groups. An increase in brain ammonia level coincided with a decreased total locomotor activity of animals and significant changes in the biochemistry of blood and also liver tissue. TA administration (500 and 1000 mg/kg, i.p), effectively alleviated liver injury and its consequent events including rise in plasma and brain ammonia and brain edema. The data suggested that TA is not only a useful and safe agent to preserve liver function, but also prevented hyperammonemia as a deleterious consequence of acute and chronic liver injury.
Collapse
|
|
50
|
Abstract
Liver failure can be categorized into acute liver failure, chronic liver failure and acute decompensation of chronic liver failure, the so-called acute-on-chronic liver failure, the incidence of which has increased over the last few years. Liver failure leads to a variety of pathophysiological changes where the extent is dependent on the nature and duration of the liver disease. This includes restriction of synthesis and metabolism, such as coagulation defects. Especially chronic liver failure is associated with malfunction of extrahepatic organs, such as the cardiovascular system, the respiratory system and the kidneys. In addition to these pathophysiological alterations the Child-Turcotte-Pugh classification (CTP) and the model of end stage liver disease (MELD) are used for perioperative risk stratification.
Collapse
Affiliation(s)
- Eva-Lotte Camboni-Schellenberg
- Klinik für Anaesthesiologie, Universitätsklinikum Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Deutschland
| | - Barbara Sinner
- Klinik für Anaesthesiologie, Universitätsklinikum Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Deutschland.
| |
Collapse
|