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van Zoest D, Gal B, Agha AH, den Hoed CM, Langendonk JG, Wagenmakers MA, Peltenburg C. Sodium benzoate for the treatment of hepatic encephalopathy in humans and animals: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2025; 37:488-496. [PMID: 39975997 PMCID: PMC11867799 DOI: 10.1097/meg.0000000000002911] [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: 05/27/2024] [Accepted: 09/22/2024] [Indexed: 02/21/2025]
Abstract
BACKGROUND AND AIM Hepatic encephalopathy (HE) is a life-threatening condition where brain function is impaired mainly due to high systemic ammonia levels. HE is associated with a high 1-year mortality. No universally accepted guidelines for the treatment of HE exist. Nitrogen scavengers, such as sodium benzoate (SB), have been proven very effective to treat hyperammonemia in patients with urea cycle defects, in acute and chronic settings. We hypothesized that SB can also be an effective treatment of HE caused by end-stage liver disease or portosystemic shunting, as long as liver function is partially intact. The aim of this meta-analysis is to study the effect of SB in humans and animals with HE due to end-stage liver disease or portosystemic shunting. METHODS Embase, Medline (Ovid and PubMed), Web-of-Science, Cochrane, and Google Scholar were searched on 19 July 2021, both human and animal studies were eligible. RESULTS Sixteen studies were included, consisting of four clinical trials, five animal studies, and seven case reports, including 314 subjects. Meta-analysis included 284 subjects. The standardized mean difference (SMD) of SB's ammonia-lowering effect was 0.89 SMD [95% confidence interval (CI): 0.27-1.51] in clinical trials and 1.63 SMD (95% CI: -0.12 to 3.39) in animal studies. Considerable heterogeneity was present in the included studies. CONCLUSION SB seems to be an effective treatment for HE or hyperammonemia caused by end-stage liver disease or portosystemic shunting. However, additional high-quality studies are necessary for more robust conclusions.
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Affiliation(s)
- Danny van Zoest
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
| | - Bram Gal
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
| | - Ayaz H. Agha
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
| | - Caroline M. den Hoed
- Department of Gastroenterology and Hepatology, Erasmus MC Transplant Institute, University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Janneke G. Langendonk
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
| | - Margreet A.E.M. Wagenmakers
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
| | - Chantal Peltenburg
- Department of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam
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2
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Gil-Gómez A, Muñoz-Hernández R, Martínez F, Jiménez F, Romero-Gómez M. Hepatic encephalopathy: experimental drugs in development and therapeutic potential. Expert Opin Investig Drugs 2024; 33:1219-1230. [PMID: 39588934 DOI: 10.1080/13543784.2024.2434053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) presents a complex pathophysiology, creating multiple potential treatment avenues. This review covers current and emerging treatments for HE. AREAS COVERED Standard therapies, including non-absorbable disaccharides and rifaximin, are widely used but show inconsistent efficacy. Alternatives such as polyethylene glycol and L-ornithine L-aspartate have been effective in certain cases. Advancements in understanding HE reveal a growing need for personalized treatments. Novel approaches targeting immune modulation and neuroinflammation are under investigation, though clinical translation is slow. Nutritional interventions and fecal microbiota transplantation show potential but lack robust evidence. Innovative therapies like gene and cell therapies, as well as extracellular vesicles from mesenchymal stem cells, present promising avenues for liver disease treatment, potentially benefiting HE. EXPERT OPINION A key challenge in HE research is the design of randomized clinical trials, which often suffer from small sample sizes, heterogeneity in patient population, and inconsistent blinding. Additionally, the multifactorial nature of HE, together with a high spontaneous response rate, complicates efforts to isolate treatment effects. Despite current limitations, ongoing research and technological advances hold promise for more effective and individualized HE treatments in the future.
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Affiliation(s)
- Antonio Gil-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain
| | - Filomeno Martínez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Fernando Jiménez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
| | - Manuel Romero-Gómez
- SeLiver Group at Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital/CSIC/University of Seville, Seville, Spain
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville, Spain
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3
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Milewski K, Orzeł-Gajowik K, Zielińska M. Mitochondrial Changes in Rat Brain Endothelial Cells Associated with Hepatic Encephalopathy: Relation to the Blood-Brain Barrier Dysfunction. Neurochem Res 2024; 49:1489-1504. [PMID: 35917006 PMCID: PMC11106209 DOI: 10.1007/s11064-022-03698-7] [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: 08/31/2021] [Revised: 02/17/2022] [Accepted: 07/14/2022] [Indexed: 12/06/2022]
Abstract
The mechanisms underlying cerebral vascular dysfunction and edema during hepatic encephalopathy (HE) are unclear. Blood-brain barrier (BBB) impairment, resulting from increased vascular permeability, has been reported in acute and chronic HE. Mitochondrial dysfunction is a well-documented result of HE mainly affecting astrocytes, but much less so in the BBB-forming endothelial cells. Here we review literature reports and own experimental data obtained in HE models emphasizing alterations in mitochondrial dynamics and function as a possible contributor to the status of brain endothelial cell mitochondria in HE. Own studies on the expression of the mitochondrial fusion-fission controlling genes rendered HE animal model-dependent effects: increase of mitochondrial fusion controlling genes opa1, mfn1 in cerebral vessels in ammonium acetate-induced hyperammonemia, but a decrease of the two former genes and increase of fis1 in vessels in thioacetamide-induced HE. In endothelial cell line (RBE4) after 24 h ammonia and/or TNFα treatment, conditions mimicking crucial aspects of HE in vivo, we observed altered expression of mitochondrial fission/fusion genes: a decrease of opa1, mfn1, and, increase of the fission related fis1 gene. The effect in vitro was paralleled by the generation of reactive oxygen species, decreased total antioxidant capacity, decreased mitochondrial membrane potential, as well as increased permeability of RBE4 cell monolayer to fluorescein isothiocyanate dextran. Electron microscopy documented enlarged mitochondria in the brain endothelial cells of rats in both in vivo models. Collectively, the here observed alterations of cerebral endothelial mitochondria are indicative of their fission, and decreased potential of endothelial mitochondria are likely to contribute to BBB dysfunction in HE.
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Affiliation(s)
- Krzysztof Milewski
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
| | - Karolina Orzeł-Gajowik
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego St. 5, 02-106, Warsaw, Poland.
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4
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Singh J, Ibrahim B, Han SH. Nontraditional Treatment of Hepatic Encephalopathy. Clin Liver Dis 2024; 28:297-315. [PMID: 38548441 DOI: 10.1016/j.cld.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
The pathophysiology of hepatic encephalopathy (HE) is complex, with hyperammonemia playing a central role in its development. Traditional therapies for HE have targeted ammonia and include medications such as lactulose and rifaximin. Although these agents are considered standard of care, nontraditional treatments seek to affect other factors in the pathogenesis of HE. Finally, procedural therapies include albumin dialysis, shunt closure, and the ultimate cure for HE, which is liver transplant. The treatments discussed provide alternative options for patients who have failed standard of care. However, more high-quality studies are needed to routinely recommend many of these agents.
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Affiliation(s)
- Jasleen Singh
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA.
| | - Brittney Ibrahim
- Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
| | - Steven-Huy Han
- Department of Medicine, University of California at Los Angeles; Los Angeles, CA, USA; Department of Surgery, University of California at Los Angeles; Los Angeles, CA, USA
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5
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García-Díaz HC, Eremiev S, Gómez-Alonso J, Veas Rodriguez J, Farriols A, Carreras MJ, Serrano C. Hyperammonemic encephalopathy after tyrosine kinase inhibitors: A literature review and a case example. J Oncol Pharm Pract 2024; 30:576-583. [PMID: 38258317 DOI: 10.1177/10781552231225188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
OBJECTIVE To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.
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Affiliation(s)
| | - Simeon Eremiev
- Medical Oncology Service, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Javier Gómez-Alonso
- Department of Pharmacy Service, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | | | - Anna Farriols
- Department of Pharmacy Service, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Maria J Carreras
- Department of Pharmacy Service, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - César Serrano
- Medical Oncology Service, Vall d'Hebron Hospital Universitari, Barcelona, Spain
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6
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Balzano T. Active Clinical Trials in Hepatic Encephalopathy: Something Old, Something New and Something Borrowed. Neurochem Res 2023; 48:2309-2319. [PMID: 36977964 PMCID: PMC10047473 DOI: 10.1007/s11064-023-03916-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 02/28/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023]
Abstract
Hepatic encephalopathy (HE) is a potentially reversible neurocognitive syndrome that occurs in patients with acute or chronic liver disease. Currently, most of the therapies for HE aim to reduce ammonia production or increase its elimination. To date, only two agents have been approved as treatments for HE: lactulose and rifaximin. Many other drugs have also been used, but data to support their use are limited, preliminary or lacking. The aim of this review is to provide an overview and discussion of the current development of treatments for HE. Data from ongoing clinical trials in HE were obtained from the ClinicalTrials.gov website, and a breakdown analysis of studies that were active on August 19th, 2022, was performed. Seventeen registered and ongoing clinical trials for therapeutics targeting HE were identified. More than 75% of these agents are in phase II (41.2%) or in phase III (34.7%). Among them, there are many old acquaintances in the field, such as lactulose and rifaximin, some new entries such as fecal microbiota transplantation and equine anti-thymocyte globulin, an immunosuppressive agent, but also some therapies borrowed from other conditions, such as rifamycin SV MMX and nitazoxanide, two antimicrobial agents FDA approved for the treatment of some types of diarrheas or VE303 and RBX7455, two microbiome restoration therapies, currently used as treatment of high-risk Clostridioides difficile infections. If working, some of these drugs could soon be used as valid alternatives to current therapies when ineffective or be approved as novel therapeutic approaches to improve the quality of life of HE patients.
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Affiliation(s)
- Tiziano Balzano
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain.
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7
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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.
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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
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8
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Borsakova DV, Koleva LD, Protasov ES, Ataullakhanov FI, Sinauridze EI. Ammonium removal by erythrocyte-bioreactors based on glutamate dehydrogenase from Proteus sp. jointly with porcine heart alanine aminotransferase. Sci Rep 2022; 12:5437. [PMID: 35361872 PMCID: PMC8971454 DOI: 10.1038/s41598-022-09435-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 03/14/2022] [Indexed: 11/26/2022] Open
Abstract
Excessive ammonium blood concentration causes many serious neurological complications. The medications currently used are not very effective. To remove ammonium from the blood, erythrocyte-bioreactors containing enzymes that processing ammonium have been proposed. The most promising bioreactor contained co-encapsulated glutamate dehydrogenase (GDH) and alanine aminotransferase (ALT). However, a low encapsulation of a commonly used bovine liver GDH (due to high aggregation), makes clinical use of such bioreactors impossible. In this study, new bioreactors containing ALT and non-aggregating GDH at higher loading were first produced using the flow dialysis method and the new bacterial GDH enzyme from Proteus sp. The efficacy of these erythrocyte-bioreactors and their properties (hemolysis, osmotic fragility, intracellular and extracellular activity of included enzymes, erythrocyte indices, and filterability) were studied and compared with native cells during 1-week storage. The ammonium removal rate in vitro by such erythrocyte-bioreactors increased linearly with an increase in encapsulated GDH activity. Alanine in vitro increased in accordance with ammonium consumption, which indicated the joint functioning of both included enzymes. Thus, novel bioreactors for ammonium removal containing GDH from Proteus sp. are promising for clinical use, since they have a more efficient GDH encapsulation and their properties are not inferior to previously obtained erythrocyte-bioreactors.
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Affiliation(s)
- Daria V Borsakova
- Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya str., 30, Moscow, 109029, Russia.,Laboratory of Biophysics, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117198, Russia
| | - Larisa D Koleva
- Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya str., 30, Moscow, 109029, Russia.,Laboratory of Biophysics, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117198, Russia
| | - Evgeniy S Protasov
- Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya str., 30, Moscow, 109029, Russia.,Laboratory of Biophysics, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117198, Russia.,Department of Physics, Lomonosov Moscow State University, Leninskie Gory, 1, build. 2, GSP-1, Moscow, 119991, Russia
| | - Fazoil I Ataullakhanov
- Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya str., 30, Moscow, 109029, Russia.,Laboratory of Biophysics, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117198, Russia.,Department of Physics, Lomonosov Moscow State University, Leninskie Gory, 1, build. 2, GSP-1, Moscow, 119991, Russia.,Department of Molecular and Translational Medicine, Moscow Institute of Physics and Technology, Institutskiy Per., 9, Dolgoprudny, Moscow Region, 141701, Russia
| | - Elena I Sinauridze
- Laboratory of Physiology and Biophysics of the Cell, Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Srednyaya Kalitnikovskaya str., 30, Moscow, 109029, Russia. .,Laboratory of Biophysics, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117198, Russia. .,Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia.
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9
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Long Noncoding RNAs Regulate Hyperammonemia-Induced Neuronal Damage in Hepatic Encephalopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7628522. [PMID: 35464767 PMCID: PMC9021992 DOI: 10.1155/2022/7628522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/18/2022] [Accepted: 02/01/2022] [Indexed: 12/13/2022]
Abstract
Background. Hyperammonemia can result in various neuropathologies, including sleep disturbance, memory loss, and motor dysfunction in hepatic encephalopathy. Long noncoding RNA (lncRNA) as a group of noncoding RNA longer than 200 nucleotides is emerging as a promising therapeutic target to treat diverse diseases. Although lncRNAs have been linked to the pathogenesis of various diseases, their function in hepatic encephalopathy has not yet been elucidated. Research Design and Methods. To identify the roles of lncRNAs in hepatic encephalopathy brain, we used a bile duct ligation (BDL) mouse model and examined the alteration of neuronal cell death markers and neuronal structure-related proteins in BDL mouse cortex tissue. Furthermore, analysis of the transcriptome of BDL mouse brain cortex tissues revealed several lncRNAs critical to the apoptosis and neuronal structural changes associated with hepatic encephalopathy. Results. We confirmed the roles of the lncRNAs, ZFAS1, and GAS5 as strong candidate lncRNAs to regulate neuropathologies in hepatic encephalopathy. Our data revealed the roles of lncRNAs, ZFAS1, and GAS5, on neuronal cell death and neural structure in hyperammonemia in in vivo and in vitro conditions. Conclusion. Thus, we suggest that the modulation of these lncRNAs may be beneficial for the treatment of hepatic encephalopathy.
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10
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Rangasamy SB, Raha S, Dasarathy S, Pahan K. Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Improves Cognitive Functions in Mice after Controlled Cortical Impact Injury. Int J Mol Sci 2021; 23:192. [PMID: 35008615 PMCID: PMC8745327 DOI: 10.3390/ijms23010192] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/16/2022] Open
Abstract
Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults and war veterans. Although research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of an effective therapy to halt the pathogenesis of brain injury. Earlier, we reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in a controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and to inhibit the expression of inducible nitric oxide synthase (iNOS) in the hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of the lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displaying a substantial reduction in depression-like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.
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Affiliation(s)
- Suresh B. Rangasamy
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA;
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; (S.R.); (S.D.)
| | - Sumita Raha
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; (S.R.); (S.D.)
| | - Sridevi Dasarathy
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; (S.R.); (S.D.)
| | - Kalipada Pahan
- Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA;
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; (S.R.); (S.D.)
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11
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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.
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12
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Butterworth RF. Ammonia Removal by Metabolic Scavengers for the Prevention and Treatment of Hepatic Encephalopathy in Cirrhosis. Drugs R D 2021; 21:123-132. [PMID: 33890246 PMCID: PMC8206241 DOI: 10.1007/s40268-021-00345-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2021] [Indexed: 12/18/2022] Open
Abstract
Effective lowering of circulating ammonia is the mainstay strategy in the prevention and treatment of hepatic encephalopathy in cirrhosis and there is increasing interest in agents with the metabolic potential for the active removal of ammonia by the liver and skeletal muscle by agents including L-ornithine L-aspartate, branched-chain amino acids, as well as the re-purposing of benzoate and phenylacetate currently employed for the control of hyperammonaemia in congenital urea-cycle enzymopathies. Based upon results of multiple systematic reviews with meta-analyses, L-ornithine L-aspartate demonstrably lowers circulating ammonia in patients with cirrhosis with concomitantly improved mental status. Distinct mechanisms responsible include optimisation of hepatic metabolic pathways for ammonia removal as well as direct hepatoprotective effects involving the release of glutathione and of nitric oxide with beneficial effects on hepatic microcirculation. L-ornithine L-aspartate also prevents cirrhosis-related sarcopenia, leading to increased capacity for ammonia removal by skeletal muscle. Branched-chain amino acids continue to be prescribed as nutritional supplements with the potential to result in improvements in liver function. Sodium benzoate, glycerol phenylbutyrate and an analogous compound L-ornithine phenylacetate were also evaluated. Glycerol phenylbutyrate was the only agent with a beneficial effect on both hyperammonaemia and hepatic encephalopathy. None were superior to lactulose for the lowering of blood ammonia.
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Affiliation(s)
- Roger F Butterworth
- Department of Medicine, University of Montreal, 45143 Cabot Trail, Englishtown, NS, B0C 1H0, Canada.
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13
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Rossi L, Pierigè F, Bregalda A, Magnani M. Preclinical developments of enzyme-loaded red blood cells. Expert Opin Drug Deliv 2020; 18:43-54. [PMID: 32924643 DOI: 10.1080/17425247.2020.1822320] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Therapeutic enzymes are currently used in the treatment of several diseases. In most cases, the benefits are limited due to poor in vivo stability, immunogenicity, and drug-induced inactivating antibodies. A partial solution to the problem is obtained by masking the therapeutic protein by chemical modifications. Unfortunately, this is not a satisfactory solution because frequent adverse events, including anaphylaxis, can arise. AREA COVERED Among the delivery systems, we focused on red blood cells for the delivery of therapeutic enzymes. Erythrocytes possess a long circulation time, a reduced immunogenicity, there is no need of chemical modifications and the encapsulated enzyme remains active because it is protected by the cell membrane. Here we discuss some representative applications of the preclinical developments of the field. Some of these are currently in clinic, others are approaching the clinic and others are illustrative of the development process. The selected examples are not always the most recent, but they are the most useful for a comparative approach. EXPERT OPINION The results discussed confirm the central role that red blood cells can play in the treatment of several conditions and suggest the benefit in using a natural cellular carrier in terms of pharmacokinetic, biodistribution, safety, and efficacy.
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Affiliation(s)
- Luigia Rossi
- Department of Biomolecular Sciences, University of Urbino , Urbino, Italy.,EryDel SpA , Bresso, Italy
| | - Francesca Pierigè
- Department of Biomolecular Sciences, University of Urbino , Urbino, Italy
| | | | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino , Urbino, Italy.,EryDel SpA , Bresso, Italy
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Henkel S, Vetterly C, Squires R, McKiernan P, Squires J. Pharmacological management of portal hypertension and its complications in children: lessons from adults and opportunities for the future. Expert Opin Pharmacother 2020; 22:291-304. [PMID: 33074032 DOI: 10.1080/14656566.2020.1825685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Portal hypertension (PHT) and its complications in children are thought to be distinct from adult PHT in several areas, including the underlying bio-physiology of a child in which PHT develops, but also because of the pediatric-specific etiologies that drive disease progression. And yet pharmacologic approaches to PHT in children are mainly based on adult data, modified for pediatric practice. This reality has been driven by a lack of data specific to children. AREAS COVERED The authors discuss current therapeutic approaches to PHT in children, including management of acute gastrointestinal variceal bleed, pharmacotherapy in prophylaxis, and established and emerging therapies to combat systemic co-morbidities that result from PHT. The few areas where pediatric-specific data exist are highlighted and the many gaps in knowledge that remain unresolved are underscored. EXPERT OPINION Despite decades of experience, optimal management of pediatric PHT remains undefined. In large part, this can be directly linked to a lack of basic understanding related to the unique pathophysiology and natural history that defines PHT in children. As a result, meaningful research into the utility and effectiveness of pharmacotherapy in children with PHT remains in its infancy. Large, multi-center, prospective studies will be needed to begin to establish an infrastructure on which a pediatric-specific research agenda can be built.
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Affiliation(s)
- Sarah Henkel
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Carol Vetterly
- Department of Pharmacy, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Pharmacy , Pittsburgh, PA
| | - Robert Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Patrick McKiernan
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - James Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
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Bohra A, Worland T, Hui S, Terbah R, Farrell A, Robertson M. Prognostic significance of hepatic encephalopathy in patients with cirrhosis treated with current standards of care. World J Gastroenterol 2020; 26:2221-2231. [PMID: 32476788 PMCID: PMC7235207 DOI: 10.3748/wjg.v26.i18.2221] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/27/2020] [Accepted: 04/30/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic encephalopathy (HE) is a reversible neuropsychiatric complication of liver cirrhosis and occurs in up to 50% of cirrhotic patients. Studies examining the prognostic significance of HE are limited despite the high prevalence in cirrhosis.
AIM To define the clinical outcomes of patients after an episode of HE treated with current standards-of-care.
METHODS All patients hospitalised with HE requiring Rifaximin to 3 tertiary centres over 46-mo (2012–2016) were identified via pharmacy dispensing records. Patients with hepatocellular carcinoma and those prescribed Rifaximin prior to admission were excluded. Medical records were reviewed to determine baseline characteristics and survival. The Kaplan-Meier method was used to calculate survival probability. Univariate survival analysis was performed with variables reaching statistical significance included in a multivariate analysis. The primary outcome was 12-mo mortality following commencement of Rifaximin.
RESULTS 188 patients were included. Median age was 57 years (IQR 50-65), 71% were male and median model for end stage liver disease and Child Pugh scores were 25 (IQR 18-31) and 11 (IQR 9-12) respectively. The most common causes of cirrhosis were alcohol (62%), hepatitis C (31%) and non-alcoholic fatty liver disease (20%). A precipitating cause for HE was found in 92% patients with infection (43%), GI bleeding (16%), medication non-compliance (15%) and electrolyte imbalance (14%) the most common. During a mean follow up period of 12 ± 13 mo 107 (57%) patients died and 32 (17%) received orthotopic liver transplantation. The most common causes of death were decompensated chronic liver disease (57%) and sepsis (19%). The probability of survival was 44% and 35% at 12- and 24-mo respectively. At multivariate analysis a model for end stage liver disease > 15 and international normalised ratio reached statistical significance in predicting mortality.
CONCLUSION Despite advances made in the management of HE patients continue to have poor survival. Thus, in all patients presenting with HE the appropriateness of orthotopic liver transplantation should be considered.
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Affiliation(s)
- Anuj Bohra
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia
| | - Thomas Worland
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
| | - Samuel Hui
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia
| | - Ryma Terbah
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
| | - Ann Farrell
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia
| | - Marcus Robertson
- Department of Gastroenterology, Monash Health, Clayton 3168, Victoria, Australia
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
- Department of Medicine, School of Clinical Sciences, Monash University, Clayton 3168, Victoria, Australia
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KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications. Clin Mol Hepatol 2020; 26:83-127. [PMID: 31918536 PMCID: PMC7160350 DOI: 10.3350/cmh.2019.0010n] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/06/2023] Open
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Snehavardhan P, Lal BB, Sood V, Khanna R, Alam S. Efficacy and Safety of Sodium Benzoate in The Management of Hyperammonemia in Decompensated Chronic Liver Disease of the Childhood-A Double-blind Randomized Controlled Trial. J Pediatr Gastroenterol Nutr 2020; 70:165-170. [PMID: 31978010 DOI: 10.1097/mpg.0000000000002521] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The objective was to evaluate the efficacy and safety of sodium benzoate in the management of hyperammonemia and hepatic encephalopathy (HE) in decompensated chronic liver disease. METHODS It was a prospective, interventional, double-blinded randomized controlled trial conducted from August 2017 to December 2018. Children with decompensated chronic liver disease and hyperammonemia were included in the study. Those with ammonia >400 μg/dL, already receiving sodium benzoate or with grade III ascites were excluded. Group A received sodium benzoate (400 mg/kg loading dose followed by 200 mg · kg · daymaintenance for 5 days) along with the standard medical therapy. Group B received standard medical therapy with placebo. RESULTS A total of 108 episodes of hyperammonemia occurred in 86 patients of whom 16 were excluded. The final analysis included 46 episodes in each group. The median decrease in ammonia from baseline to day 5 was 52 μg/dL in group A versus 42 μg/dL in group B (P = 0.321). There was a significant decrease in ammonia on days 1 and 2 in group A as compared to group B, but not on subsequent days. There was no significant difference in the resolution of HE (57.1% vs 50%; P = 1), but there was higher, albeit insignificant increase in ascites in group A (15.9% vs 4.5%). CONCLUSIONS Addition of sodium benzoate significantly reduced the ammonia levels on the first 2 days of therapy but the effect was not sustained till day 5. The effect of sodium benzoate would probably be more sustained, if higher dosage (400 mg · kg · day) could be used under monitoring of benzoate levels. There was no effect on resolution of HE. Sodium benzoate caused an increasing trend of adverse events with no effect on short-term survival.
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Affiliation(s)
- Pandey Snehavardhan
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Walia D, Kaur G, Jaggi AS, Bali A. Exploring the therapeutic potential of sodium benzoate in acetic acid-induced ulcerative colitis in rats. J Basic Clin Physiol Pharmacol 2019; 30:jbcpp-2019-0086. [PMID: 31469656 DOI: 10.1515/jbcpp-2019-0086] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 06/13/2019] [Indexed: 12/15/2022]
Abstract
Background Ulcerative colitis is a chronic mucosal inflammation of the large intestine mainly affecting the colon and rectum. The lack of effective and safe therapeutic agents led to the identification of new therapeutic agents to effectively manage the symptoms and complications of ulcerative colitis. The present study aimed to evaluate the protective effect of sodium benzoate in acetic acid-induced ulcerative colitis in rats. Methods Infusion of 3% acetic acid in the colon through the rectum was done to construct a rat model of ulcerative colitis. After 5 days of infusion, macroscopic, biochemical, and histopathological examinations and disease activity scoring of the colon were done to assess colonic damage. Results Acetic acid infusion resulted in severe inflammation in the colon assessed macroscopically and histopathologically. Moreover, it also led to increase in myeloperoxidase (MPO) and reduction in glutathione (GSH) levels. In the present study, repeated administration of sodium benzoate (400 and 800 mg/kg i.p.) and sulfasalazine (500 mg/kg orally) for 7 days, i.e. 2 days before and continued for 5 days after acetic acid infusion, significantly attenuated macroscopic damage and disease activity score as compared to disease control. Further, it also significantly reduced the levels of MPO and enhanced colonic levels of reduced GSH. However, the lower dose of sodium benzoate (200 mg/kg) did not show sufficient protective effect in acetic acid-induced ulcerative colitis. Further, sodium benzoate per se did not show any effect in normal rats. Conclusions The observed protective effect of sodium benzoate may be due to its antioxidant and anti-inflammatory activities in an ulcerative colitis model.
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Affiliation(s)
- Deepali Walia
- Department of Pharmacology, Akal College of Pharmacy and Technical Education, Mastuana Sahib, Sangrur, India
| | - Gurpreet Kaur
- Department of pharmacognosy, Akal College of Pharmacy and Technical Education, Mastuana Sahib, Sangrur, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical sciences and Drug research, Punjabi University, Patiala, India
| | - Anjana Bali
- Department of Pharmacology, Akal College of Pharmacy and Technical Education, Mastuana Sahib, Sangrur, 148001, India, Phone: +9888780355
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Management of Hepatic Encephalopathy in the Neurocritical Care Unit. Neurocrit Care 2019. [DOI: 10.1017/9781107587908.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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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.
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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
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van Straten G, van Dalen D, Mesu SJ, Rothuizen J, Teske E, Spee B, Favier RP, van Geijlswijk IM. Efficacy of orally administered sodium benzoate and sodium phenylbutyrate in dogs with congenital portosystemic shunts. J Vet Intern Med 2019; 33:1331-1335. [PMID: 30916412 PMCID: PMC6524074 DOI: 10.1111/jvim.15477] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 02/25/2019] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hyperammonemia can result in hepatic encephalopathy, which in severe cases eventually can lead to coma and death. In dogs, congenital portosystemic shunts (CPSS) are the most common cause for hyperammonemia. Conservative treatment consists of a protein modified diet, nonabsorbable disaccharides, antibiotics, or some combinations of these. Sodium benzoate (SB) and sodium phenylbutyrate (SPB) both are used in the acute and long-term treatment of humans with hyperammonemia caused by urea cycle enzyme deficiencies. Both treatments are believed to lower blood ammonia concentrations by promoting excretion of excess nitrogen via alternative pathways. OBJECTIVES To evaluate the efficacy and safety of PO treatment with SB and SPB on hyperammonemia and clinical signs in CPSS dogs. METHODS Randomized, double-blind, placebo-controlled crossover trial. Concentrations of blood ammonia and bile acids were measured in CPSS dogs before and after a 5-day treatment with SB, SPB, and placebo. A wash-out period of 3 days was used between treatments. A standard questionnaire was developed and distributed to owners to evaluate clinical signs before and after each treatment. RESULTS Blood ammonia concentrations were not influenced by any of the treatments and were comparable to those observed during placebo treatment. In addition, SB and SPB treatment did not result in improvement of clinical signs. Adverse effects during treatment included anorexia, vomiting, and lethargy. CONCLUSIONS AND CLINICAL IMPORTANCE Based on our results, we conclude that SB or SPB are not useful in the conservative treatment of hyperammonemia in dogs with CPSS.
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Affiliation(s)
- Giora van Straten
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Diewke van Dalen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Sietske J. Mesu
- Pharmacy Department, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Jan Rothuizen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Erik Teske
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Robert P. Favier
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
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Seethapathy H, Fenves AZ. Pathophysiology and Management of Hyperammonemia in Organ Transplant Patients. Am J Kidney Dis 2019; 74:390-398. [PMID: 31040091 DOI: 10.1053/j.ajkd.2019.03.419] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 03/04/2019] [Indexed: 01/28/2023]
Abstract
Neurologic complications are common after solid-organ transplantation, occurring in one-third of patients. Immunosuppression-related neurotoxicity (involving calcineurin inhibitors and corticosteroids), opportunistic central nervous system infections, seizures, and delirium are some of the causes of neurologic symptoms following solid-organ transplantation. An uncommon often missed complication posttransplantation involves buildup of ammonia levels that can lead to rapid clinical deterioration even when treated. Ammonia levels are not routinely checked due to the myriad of other explanations for encephalopathy in a transplant recipient. A treatment of choice for severe hyperammonemia involves renal replacement therapy (RRT), but there are no guidelines on the mode or parameters of RRT for reducing ammonia levels. Hyperammonemia in a transplant recipient poses specific challenges beyond the actual condition because the treatment (RRT) involves significant hemodynamic fluctuations that may affect the graft. In this review, we describe a patient with posttransplantation hyperammonemia and discuss the pathways of ammonia metabolism, potential factors underlying the development of hyperammonemia posttransplantation, and choice of appropriate therapeutic options in these patients.
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Affiliation(s)
- Harish Seethapathy
- Division of Nephrology, Department of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
| | - Andrew Z Fenves
- Division of Nephrology, Department of Internal Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Abstract
Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.
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Affiliation(s)
- Roger F Butterworth
- Department of Medicine, University of Montreal, 45143 Cabot Trail, Englishtown, NS, B0C 1H0, Canada.
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Gao L, Zhang Z, Xu W, Li T, Ying G, Qin B, Li J, Zheng J, Zhao T, Yan F, Zhu Y, Chen G. Natrium Benzoate Alleviates Neuronal Apoptosis via the DJ-1-Related Anti-oxidative Stress Pathway Involving Akt Phosphorylation in a Rat Model of Traumatic Spinal Cord Injury. Front Mol Neurosci 2019; 12:42. [PMID: 30853891 PMCID: PMC6395451 DOI: 10.3389/fnmol.2019.00042] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/01/2019] [Indexed: 12/22/2022] Open
Abstract
This study aimed to explore the neuroprotective effects and mechanisms of natrium benzoate (NaB) and DJ-1 in attenuating reactive oxygen species (ROS)-induced neuronal apoptosis in traumatic spinal cord injury (t-SCI) in rats. T-SCI was induced by clip compression. The protein expression and neuronal apoptosis was evaluated by Western blotting, double immunofluorescence staining and transmission electron microscope (TEM). ROS level, spinal cord water content (SCWC) and Evans blue (EB) extravasation was also examined. Locomotor function was evaluated by Basso, Beattie, and Bresnahan (BBB) and inclined plane test (IPT) scores. We found that DJ-1 is expressed in spinal cord neurons and increased after t-SCI. At 24 h post-injury, the levels of DJ-1, p-Akt, SOD2, ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3 increased, while the Bcl-2/Bax ratio decreased. NaB upregulated DJ-1, p-Akt, and SOD2, decreased ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3, and increased the Bcl-2/Bax ratio, which were reversed by DJ-1 siRNA. The proportion of CC-3- and TUNEL-positive neurons also increased after t-SCI and was reduced by NaB. These effects were reversed by MK2206. Moreover, the level of oxDJ-1 increased after t-SCI, which was decreased by DJ-1 siRNA, NaB or the combination of them. NaB also reduced mitochondrial vacuolization, SCWC and EB extravasation, and improved locomotor function assessed by the BBB and IPT scores. In conclusion, NaB increased DJ-1, and thus reduced ROS and ROS-induced neuronal apoptosis by promoting Akt phosphorylation in t-SCI rats. NaB shows potential as a therapeutic agent for t-SCI, with DJ-1 as its main target.
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Affiliation(s)
- Liansheng Gao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongyuan Zhang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weilin Xu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tao Li
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Guangyu Ying
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Bing Qin
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianru Li
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jingwei Zheng
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tengfei Zhao
- Department of Orthopedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Feng Yan
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yongjian Zhu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Gao Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Protasov ES, Borsakova DV, Alexandrovich YG, Korotkov AV, Kosenko EA, Butylin AA, Ataullakhanov FI, Sinauridze EI. Erythrocytes as bioreactors to decrease excess ammonium concentration in blood. Sci Rep 2019; 9:1455. [PMID: 30728433 PMCID: PMC6365525 DOI: 10.1038/s41598-018-37828-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 12/14/2018] [Indexed: 11/09/2022] Open
Abstract
Increased blood ammonium concentrations cause neurological complications. Existing drugs are not always sufficiently effective. Alternatively, erythrocytes-bioreactors (EBRs) loaded with enzymes utilizing ammonium, were suggested for ammonium removal from blood. However all they worked only for a short period of time. The reasons for this were not investigated. In this study, EBR mathematical models were developed and analysed based on the reactions of glycolysis and different enzymes utilizing ammonium, which showed that the efficiency and duration of EBRs' functioning could be limited due to low permeability of the cell membrane for some key substrates and products. A new enzyme system including glutamate dehydrogenase and alanine aminotransferase was proposed and realised experimentally, which was not limited by cell membrane permeability for glutamate and α-ketoglutarate due to creating metabolic pathway where these metabolites were produced and consumed cyclically. New bioreactors removed ammonium in vitro at the rate of 1.5 mmol/h × lRBCs (for human bioreactors) and in vivo in a model of hyperammoniemia in mice at the rate of 2.0 mmol/h × lRBCs (for mouse bioreactors), which correlated with model calculations. Experimental studies proved the proposed mathematical models are correct. Mathematical simulation of erythrocyte-bioreactors opens new opportunities for analysing the efficiency of any enzyme included in erythrocytes.
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Affiliation(s)
- Eugeniy S Protasov
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia
- Faculty of Physics, Moscow State University, Leninskie Gory, 1, build. 2, GSP-1, Moscow, 119991, Russia
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygina str., 4, Moscow, 119334, Russia
| | - Daria V Borsakova
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygina str., 4, Moscow, 119334, Russia
| | - Yuliya G Alexandrovich
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia
| | - Anatoliy V Korotkov
- Moscow Institute of Physics and Technology, Institutskiy per., 9, Dolgoprudny, Moscow region, 141701, Russia
| | - Elena A Kosenko
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya str., 3, Pushchino, Moscow region, 142290, Russia
| | - Andrey A Butylin
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia
- Faculty of Physics, Moscow State University, Leninskie Gory, 1, build. 2, GSP-1, Moscow, 119991, Russia
| | - Fazoil I Ataullakhanov
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia
- Faculty of Physics, Moscow State University, Leninskie Gory, 1, build. 2, GSP-1, Moscow, 119991, Russia
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygina str., 4, Moscow, 119334, Russia
- Moscow Institute of Physics and Technology, Institutskiy per., 9, Dolgoprudny, Moscow region, 141701, Russia
| | - Elena I Sinauridze
- Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare, Samory Mashela str., 1, GSP-7, Moscow, 117997, Russia.
- Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygina str., 4, Moscow, 119334, Russia.
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26
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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.
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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
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28
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Brossier D, Goyer I, Ziani L, Marquis C, Mitchell G, Ozanne B, Jouvet P. Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive care unit. J Inherit Metab Dis 2019; 42:77-85. [PMID: 30740742 DOI: 10.1002/jimd.12029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The purpose of the study was to evaluate the influence of establishing a protocol for the use of combined sodium benzoate and sodium phenylacetate (SBSP) (Ammonul®) to treat acute hyperammonemia. This was a retrospective, single-center study in a 24-bed medical and surgical pediatric intensive care unit (PICU) in a tertiary care teaching maternal-child hospital in Canada. Inclusion criteria were age < 18 years, PICU admission between 1 January 2000 and 30 June 2016, and SBSP treatment. An SBSP delivery protocol was implemented in our hospital on 30 August 2008 in order to improve management of acute hyperammonemia. Patients were assigned to one of the two groups, without or with protocol, depending on date of admission. SBSP was ordered 34 times during the study period, and 23 orders were considered for analysis (14 with and 9 without protocol). Patient characteristics were similar between groups. The median time from diagnosis to prescription was significantly shorter in the protocol group [40 min (21-82) vs 100 min (70-150), p = 0.03)] but the median time from diagnosis to administration of the treatment was equivalent [144 min (90-220) vs 195 (143-274), (p = 0.2)]. Other clinical outcomes did not differ. This study is the first to compare two SBSP delivery strategies in the treatment of acute hyperammonemia in this PICU setting. Implementation of a delivery protocol shortened the time from diagnosis of hyperammonemia to prescription of SBSP and helped us identify other parameters that can be improved to optimize treatment delivery.
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Affiliation(s)
- David Brossier
- Pediatric Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
- CHU Sainte Justine Research Institute, CHU Sainte-Justine, Montreal, Canada
- CHU Caen, Pediatric Intensive Care Unit, F-14000 Caen, France
- Université Caen Normandie, school of medicine, Caen, F-14000, France
| | - Isabelle Goyer
- Pediatric Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
- Department of Pharmacy, Division of Clinical Pharmacology, CHU Sainte-Justine, Montreal, Canada
| | - Lydia Ziani
- Pediatric Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
| | - Christopher Marquis
- Pediatric Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
- Department of Pharmacy, Division of Clinical Pharmacology, CHU Sainte-Justine, Montreal, Canada
| | - Grant Mitchell
- CHU Sainte Justine Research Institute, CHU Sainte-Justine, Montreal, Canada
- Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
| | - Bruno Ozanne
- CHU Rennes, Pediatric Intensive Care Unit, F-35000 Rennes, France
| | - Philippe Jouvet
- Pediatric Intensive Care Unit, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, Montreal, Canada
- CHU Sainte Justine Research Institute, CHU Sainte-Justine, Montreal, Canada
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29
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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.
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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
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30
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Affiliation(s)
- Chathur Acharya
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA
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31
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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.
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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
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32
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Weiss N, Tripon S, Lodey M, Guiller E, Junot H, Monneret D, Mayaux J, Brisson H, Mallet M, Rudler M, Imbert-Bismut F, Thabut D. Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. Fundam Clin Pharmacol 2018; 32:209-215. [PMID: 29239015 DOI: 10.1111/fcp.12340] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 10/21/2017] [Accepted: 12/01/2017] [Indexed: 01/04/2023]
Affiliation(s)
- Nicolas Weiss
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- UPMC Univ Paris 06 & Unité de réanimation neurologique; Département de Neurologie; Pôle des maladies du système nerveux; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; Sorbonne Universités; 47-83 boulevard de l'Hôpital 75013 Paris France
- Institut de Neurosciences Translationnelles de Paris; Institut-Hospitalo-Universitaire-A-Institut du Cerveau et de la Moelle (IHU-A-ICM); 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Simona Tripon
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- UPMC Univ Paris 06 & Soins Intensifs d'Hépatologie; Service d'Hépato-Gastroentérologie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Marion Lodey
- Service de pharmacie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Elsa Guiller
- Service de pharmacie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Helga Junot
- Service de pharmacie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Denis Monneret
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- Service de biochimie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Julien Mayaux
- Unité de Réanimation et de Surveillance continue; Service de Pneumologie et Réanimation médicale; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Hélène Brisson
- Service de réanimation; Département d'anesthésie-réanimation; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Maxime Mallet
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- UPMC Univ Paris 06 & Soins Intensifs d'Hépatologie; Service d'Hépato-Gastroentérologie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Marika Rudler
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- UPMC Univ Paris 06 & Soins Intensifs d'Hépatologie; Service d'Hépato-Gastroentérologie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Françoise Imbert-Bismut
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- Service de biochimie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
| | - Dominique Thabut
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS); Hôpital de la Pitié-Salpêtrière; Assistance Publique-Hôpitaux de Paris; INSERM UMR_S 938, CDR Saint-Antoine & Institut de Cardiométabolisme et Nutrition (ICAN); 47-83 boulevard de l'Hôpital 75013 Paris France
- UPMC Univ Paris 06 & Soins Intensifs d'Hépatologie; Service d'Hépato-Gastroentérologie; Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris; 47-83 boulevard de l'Hôpital 75013 Paris France
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Ventura-Cots M, Carmona I, Moreno C, Ampuero J, Simón-Talero M, Sanpedro F, Les I, Romero-Gómez M, Genescà J. Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients. Therap Adv Gastroenterol 2017; 11:1756283X17743419. [PMID: 29383024 PMCID: PMC5784576 DOI: 10.1177/1756283x17743419] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 10/16/2017] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Episodes of hepatic encephalopathy (HE) have been related to low survival rate. However, the relation between its clinical evolution and mortality has not been assessed. METHODS A retrospective analysis of 245 cirrhotic patients admitted for an acute episode of HE (⩾grade 2) or who developed an HE episode after an upper gastrointestinal bleeding (UGIB) event was performed to assess the relation between time in HE and transplant-free survival. RESULTS Median (IQR25-75) time in HE was 48 h (24-96 h) in the whole cohort. Patients who presented a longer time in HE (>48 h; n = 89) exhibited a lower transplant-free survival at 28 days (67.2% versus 88.9%, p < 0.001), 90 days (48.7% versus 73.8%, p < 0.001) and 365 days (30.3% versus 53.2%, p < 0.001), as compared to those with less time in HE (⩽48 h; n = 156). Survival rates remained significantly different, with lower percentages in the group with time in HE >48 h, when comparing patients according to baseline HE grade (2 versus ⩾3) or model for end-stage liver disease (MELD) function (⩽15 versus >15). Time in HE was also an independent risk factor for mortality at each time point, hazard ratio (HR) (95 CI%) 28 days 2.59 (1.39-4.84); 90 days 1.98 (1.28-3.1) and 365 days 1.5 (1.08-2.19). CONCLUSIONS The duration of the acute HE episode determines survival in cirrhotic patients independently of liver function and baseline HE grade.
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Affiliation(s)
- Meritxell Ventura-Cots
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid
| | - Isabel Carmona
- UCM Intercentres Digestive Diseases, Virgen Macarena University Hospital, Sevilla
| | - Carolina Moreno
- UCM Intercentres Digestive Diseases, Virgen Macarena University Hospital, Sevilla
| | - Javier Ampuero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid UCM Intercentres Digestive Diseases, Virgen del Rocío University Hospital and Institute of Biomedicine of Seville, Sevilla
| | - Macarena Simón-Talero
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid
| | - Francesc Sanpedro
- Emergency Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona
| | - Iñigo Les
- Department of Internal Medicine, BioAraba Health Research Institute, Hospital Universitario Araba, Vitoria
| | - Manuel Romero-Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid; UCM Intercentres Digestive Diseases, Virgen Macarena University Hospital, Sevilla UCM Intercentres Digestive Diseases, Virgen del Rocío University Hospital and Institute of Biomedicine of Seville, Sevilla
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Zu K, Pizzurro DM, Lewandowski TA, Goodman JE. Pharmacokinetic data reduce uncertainty in the acceptable daily intake for benzoic acid and its salts. Regul Toxicol Pharmacol 2017; 89:83-94. [PMID: 28720346 DOI: 10.1016/j.yrtph.2017.07.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 07/13/2017] [Accepted: 07/14/2017] [Indexed: 01/01/2023]
Abstract
The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight.
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Affiliation(s)
- K Zu
- Gradient, 20 University Road, Cambridge, MA, 02138, USA
| | - D M Pizzurro
- Gradient, 20 University Road, Cambridge, MA, 02138, USA
| | - T A Lewandowski
- Gradient, 600 Stewart Street, Suite 1900, Seattle, WA, 98101, USA
| | - J E Goodman
- Gradient, 20 University Road, Cambridge, MA, 02138, USA.
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35
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Kristiansen RG. Current state of knowledge of hepatic encephalopathy (part I): newer treatment strategies for hyperammonemia in liver failure. Metab Brain Dis 2016; 31:1357-1358. [PMID: 27651377 DOI: 10.1007/s11011-016-9908-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 09/05/2016] [Indexed: 01/27/2023]
Abstract
Alterations in interorgan metabolism of ammonia play an important role in the onset of hyperammonemia in liver failure. Glutamine synthetase (GS) in muscle is an important target for ammonia removal strategies in hyperammonemia. Ornithine Phenylacetate (OP) is hypothesized to remove ammonia by providing glutamate as a substrate for increased GS activity and hence glutamine production. The newly generated glutamine conjugates with phenylacetate forming phenylacetylglutamine which can be excreted in the urine, providing an excretion pathway for ammonia. We have also shown that OP targets glycine metabolism, providing an additional ammonia reducing effect.
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Affiliation(s)
- Rune Gangsoy Kristiansen
- Department of Anesthesiology, Anesthesia and Critical Care Research Group, University Hospital of North Norway, UiT-The Arctic University of Norway, Tromsø, Norway.
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Kristiansen RG, Rose CF, Ytrebø LM. Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy. Metab Brain Dis 2016; 31:1269-1273. [PMID: 27339764 DOI: 10.1007/s11011-016-9858-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 06/12/2016] [Indexed: 01/10/2023]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric disorder caused by hepatic dysfunction. Numerous studies dictate that ammonia plays an important role in the pathogenesis of HE, and hyperammonemia can lead to alterations in amino acid homeostasis. Glutamine and glycine are both ammoniagenic amino acids that are increased in liver failure. Modulating the levels of glutamine and glycine has shown to reduce ammonia concentration in hyperammonemia. Ornithine Phenylacetate (OP) has consistently been shown to reduce arterial ammonia levels in liver failure by modulating glutamine levels. In addition to this, OP has also been found to modulate glycine concentration providing an additional ammonia removing effect. Data support that glycine also serves an important role in N-methyl D-aspartate (NMDA) receptor mediated neurotransmission in HE. This potential important role for glycine in the pathogenesis of HE merits further investigations.
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Affiliation(s)
- Rune Gangsøy Kristiansen
- Department of Anesthesiology, Anesthesia and Critical Care Research Group, University Hospital of North Norway and UiT-The Arctic University of Norway, Tromsø, Norway.
- Department of Anesthesiology, Ålesund Hospital, Helse Møre og Romsdal, 6010, Ålesund, Norway.
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, QC, Canada
| | - Lars Marius Ytrebø
- Department of Anesthesiology, Anesthesia and Critical Care Research Group, University Hospital of North Norway and UiT-The Arctic University of Norway, Tromsø, Norway
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Kundu M, Mondal S, Roy A, Martinson JL, Pahan K. Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-β. THE JOURNAL OF IMMUNOLOGY 2016; 197:3099-3110. [PMID: 27605008 DOI: 10.4049/jimmunol.1501628] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 08/12/2016] [Indexed: 12/14/2022]
Abstract
Upregulation and/or maintenance of regulatory T cells (Tregs) during autoimmune insults may have therapeutic efficacy in autoimmune diseases. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders, upregulates Tregs and protects mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. However, mechanisms by which NaB increases Tregs are poorly understood. Because TGF-β is an important inducer of Tregs, we examined the effect of NaB on the status of TGF-β. In this study, we demonstrated that NaB induced the expression of TGF-β mRNA and protein in normal as well as proteolipid protein-primed splenocytes. The presence of a consensus STAT6 binding site in the promoter of the TGF-β gene, activation of STAT6 in splenocytes by NaB, recruitment of STAT6 to the TGF-β promoter by NaB, and abrogation of NaB-induced expression of TGF-β in splenocytes by small interfering RNA knockdown of STAT6 suggest that NaB induces the expression of TGF-β via activation of STAT6. Furthermore, we demonstrated that blocking of TGF-β by neutralizing Abs abrogated NaB-mediated protection of Tregs and experimental allergic encephalomyelitis. These studies identify a new function of NaB in upregulating TGF-β via activation of STAT6, which may be beneficial in MS patients.
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Affiliation(s)
- Madhuchhanda Kundu
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - Susanta Mondal
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - Avik Roy
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612
| | - Jeffrey L Martinson
- Department of Immunology, Rush University Medical Center, Chicago, IL 60612; and
| | - Kalipada Pahan
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; .,Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612
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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
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Abstract
CONTEXT Suspecting metabolic liver disease in an infant or young child with acute liver failure, and a protocol-based workup for diagnosis is the need of the hour. EVIDENCE ACQUISITION Data over the last 15 years was searched through Pubmed using the keywords Metabolic liver disease and Acute liver failure with emphasis on Indian perspective. Those published in English language where full text was retrievable were included for this review. RESULTS Metabolic liver diseases account for 13-43% cases of acute liver failure in infants and young children. Etiology remains indeterminate in very few cases of liver failure in studies where metabolic liver diseases were recognized in large proportion. Galactosemia, tyrosinemia and mitochondrial disorders in young children and Wilsons disease in older children are commonly implicated. A high index of suspicion for metabolic liver diseases should be kept when there is strong family history of consanguinity, recurrent abortions or sibling deaths; and history of recurrent diarrhea, vomiting, failure to thrive or developmental delay. Simple dietary modifications and/or specific management can be life-saving if instituted promptly. CONCLUSION A high index of suspicion in presence of red flag symptoms and signs, and a protocol-based approach helps in timely diagnosis and prompt administration of lifesaving therapy.
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Affiliation(s)
- Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. Correspondence to: Prof Seema Alam, Professor and Head, Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110 070, India.
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Jawaro T, Yang A, Dixit D, Bridgeman MB. Management of Hepatic Encephalopathy: A Primer. Ann Pharmacother 2016; 50:569-77. [PMID: 27126547 DOI: 10.1177/1060028016645826] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To review the management of hepatic encephalopathy (HE), including lifestyle modifying strategies and pharmacological interventions. DATA SOURCES A literature search of PubMed through March 2016 was conducted utilizing the keywords hepatic encephalopathy, ammonia, and cirrhosis All published articles evaluating treatments for HE were considered. STUDY SELECTION AND DATA EXTRACTION Available English-language data from reviews, abstracts, presentations, and clinical trials of the treatment of HE in humans were reviewed; relevant clinical data were selected and included. DATA SYNTHESIS HE is a prevalent complication of portal hypertension and cirrhosis that results in altered mental status and neuropsychiatric impairment. Although the pathogenesis has not been elucidated, numerous treatment options exist. This review will explore the role of dietary interventions and supplements, including use of zinc, acetyl-l-carnitine, and probiotics, in the management of HE. Additionally, the use of various ammonia-lowering agents will be evaluated. The nonabsorbable disaccharides represent first-line therapies for the management and prophylaxis of HE; rifaximin use has been demonstrated to be effective for both treatment and prophylaxis of HE symptoms, with use relegated to those patients who fail to respond to or tolerate the nonabsorbable disaccharides. In light of toxicities associated with the use of neomycin and metronidazole, recent guidelines recommend both as alternatives for the treatment of HE, with the use of vancomycin discouraged. CONCLUSION Although numerous treatment options are available, management of HE remains a clinical challenge. Additional research is needed to explore the pathogenesis and better understand the role of pharmacotherapy in managing this condition.
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Affiliation(s)
- Tara Jawaro
- Pharmacy Department, Robert Wood Johnson University Hospital, New Brunswick, NJ, USA
| | - Anna Yang
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Deepali Dixit
- Pharmacy Department, Robert Wood Johnson University Hospital, New Brunswick, NJ, USA Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
| | - Mary Barna Bridgeman
- Pharmacy Department, Robert Wood Johnson University Hospital, New Brunswick, NJ, USA Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
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Yadav A, Kumar A, Das M, Tripathi A. Sodium benzoate, a food preservative, affects the functional and activation status of splenocytes at non cytotoxic dose. Food Chem Toxicol 2015; 88:40-7. [PMID: 26706697 DOI: 10.1016/j.fct.2015.12.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 12/11/2015] [Accepted: 12/14/2015] [Indexed: 12/31/2022]
Abstract
Sodium benzoate (SB) is a widely used food preservative due to its bacteriostatic and fungistatic properties. The acceptable daily intake of SB is 5 mg/kg-bw, however, it has been found to be used in the food commodities at relatively high levels (2119 mg/kg). Earlier studies on SB have shown its immunosuppressive properties, but comprehensive immunotoxicity data is lacking. Our studies have shown that SB was non cytotoxic in splenocytes up to 1000 μg/ml for 72 h, however at 2500 μg/ml it was found to be cytotoxic. Thus, 1000 μg/ml dose of SB was chosen for the subsequent experiments. SB significantly suppresses the proliferation of Con A and LPS stimulated splenocytes at 72 h, while allogenic response of T cells was significantly decreased after 96 h. SB did not affect the relative expression of CD3e or CD4 molecules following 72 h exposure, however, it downregulated the relative expression of CD8 co-receptor. Further, exposure of splenocytes to SB for 72 h led to reduced expression of CD28 and CD95, which play a vital role in T cell activation. SB also suppresses the relative expression of CD19, CD40 and CD95 receptors on B cells after 72 h. In addition to the functional responses, SB lowered the expression of IL4, IL6, IFNγ and IL17 cytokines in Con A stimulated splenocytes; and IL6, IFNγ and TNFα in LPS stimulated splenocytes following 48 h of exposure. Taken together, the present study is suggestive of the immunomodulatory potential of SB.
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Affiliation(s)
- Ashish Yadav
- Food Toxicology Lab, Food, Drug and Chemical Toxicology Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), M.G. Marg, Lucknow, 226001, Uttar Pradesh, India; Molecular Immunology Lab, School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Arvind Kumar
- Molecular Immunology Lab, School of Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi, 221005, Uttar Pradesh, India
| | - Mukul Das
- Food Toxicology Lab, Food, Drug and Chemical Toxicology Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), M.G. Marg, Lucknow, 226001, Uttar Pradesh, India.
| | - Anurag Tripathi
- Food Toxicology Lab, Food, Drug and Chemical Toxicology Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), M.G. Marg, Lucknow, 226001, Uttar Pradesh, India.
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Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015; 90:646-58. [PMID: 25865476 DOI: 10.1016/j.mayocp.2015.03.003] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 02/27/2015] [Accepted: 03/03/2015] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the ammonia hypothesis to account for these other factors instructs a solid foundation for the effective treatment and prevention of hepatic encephalopathy.
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Affiliation(s)
- Elliot B Tapper
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA.
| | - Z Gordon Jiang
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
| | - Vilas R Patwardhan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA
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Sharma P, Sharma BC. Management of overt hepatic encephalopathy. J Clin Exp Hepatol 2015; 5:S82-7. [PMID: 26041964 PMCID: PMC4442855 DOI: 10.1016/j.jceh.2014.04.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/16/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is an important complication of cirrhosis with significant morbidity and mortality. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as non-absorbable disaccharides, antimicrobial agents like rifaximin and l-ornithine l-aspartate. The non-absorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and in primary and secondary prophylaxis of HE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Rifaximin is effective in treatment of HE and recent systemic reviews found it comparable to disaccharides and is effective in secondary prophylaxis of HE. Many agents like l-ornithine l-aspartate, probiotics, zinc, sodium benzoate have been tried either alone or in combination with lactulose for the treatment of HE. Combination therapy of disaccharides either with rifaximin, l-ornithine l-aspartate, probiotics for the treatment of HE needs further validation in large studies.
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Affiliation(s)
- Praveen Sharma
- Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India
| | - Barjesh C. Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India,Address for correspondence: Barjesh C. Sharma, Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India.
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Shalimar, Acharya SK. Management in acute liver failure. J Clin Exp Hepatol 2015; 5:S104-15. [PMID: 26041950 PMCID: PMC4442864 DOI: 10.1016/j.jceh.2014.11.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/26/2014] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available.
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Key Words
- AASLD, American Association For the Study of Liver
- ALF, Acute Liver Failure
- ALFED, Acute Liver Failure Early Dynamic Model
- BBB, Blood Brain Barrier
- BCAA, Branched Chain Amino acid
- CBF, Cerebral Blood Flow
- CPP, Cerebral Perfusion Pressure
- CVVHD, Continuous Veno-Venous Hemodialysis
- FFP, Fresh Frozen Plasma
- GM-CSF, Granulocyte Macrophage Colony Stimulating Factor
- HE, Hepatic Encephalopathy
- ICU, Intensive Care Unit
- IEI, Icterus Encephalopathy Interval
- IL-1β, Interleukin-1 beta
- IL6, Interlekin 6
- INR, International Normalized Ratio
- LOLA, l-Ornithine L Aspartate
- LOPA
- LOPA, l-Ornithine Phenyl Acetate
- MAP, Mean Arterial Pressure
- NAC, N-Acetyl Cysteine
- NO, Nitric Oxide
- OLT, Orthotopic Liver Transplantation
- PCWP, Pulmonary Capillary Wedge Pressure
- PEEP, Positive End Expiratory Pressure
- PT, Prothrombin Time
- SIMV, Synchronous Intermittent mandatory Ventilation
- SIRS, Systemic Inflammatory Response Syndrome
- SPEAR, Selective Parenteral and Enteral Antibiotic Regimen
- TNF-α, Tumor Necrosis Factor alfa
- UCD, Urea Cycle Disorder
- USALF, United States Acute liver Failure Study Group
- ammonia
- cerebral edema
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Affiliation(s)
| | - Subrat K. Acharya
- Address for correspondence: Subrat K. Acharya, Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India.
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Abstract
Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic. Eventually most is excreted in urine as urea, together with ammonia used as a buffer. In extrahepatic tissues, ammonia is incorporated into nontoxic glutamine and released into blood. Large amounts are metabolized by the kidneys and small intestine. In the intestine, this yields ammonia, which is sequestered in portal blood and transported to the liver for ureagenesis, and citrulline, which is converted to arginine by the kidneys. The amazing developments in NMR imaging and spectroscopy and molecular biology have confirmed concepts derived from early studies in animals and cell cultures. The processes involved are exquisitely tuned. When they are faulty, ammonia accumulates. Severe acute hyperammonemia causes a rapidly progressive, often fatal, encephalopathy with brain edema. Chronic milder hyperammonemia causes a neuropsychiatric illness. Survivors of severe neonatal hyperammonemia have structural brain damage. Proposed explanations for brain edema are an increase in astrocyte osmolality, generally attributed to glutamine accumulation, and cytotoxic oxidative/nitrosative damage. However, ammonia neurotoxicity is multifactorial, with disturbances also in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium. Around 90% of hyperammonemic patients have liver disease. Inherited defects are rare. They are being recognized increasingly in adults. Deficiencies of urea cycle enzymes, citrin, and pyruvate carboxylase demonstrate the roles of isolated pathways in ammonia metabolism. Phenylbutyrate is used routinely to treat inherited urea cycle disorders, and its use for hepatic encephalopathy is under investigation.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
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Pathophysiology, diagnosis, and management of hepatic encephalopathy. Inflammopharmacology 2014; 22:319-26. [DOI: 10.1007/s10787-014-0217-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/19/2014] [Indexed: 12/23/2022]
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Kuo JC, Parakh S, Yip D. Regorafenib-induced hyperammonemic encephalopathy. J Clin Pharm Ther 2014; 39:446-448. [PMID: 24707992 DOI: 10.1111/jcpt.12160] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Accepted: 03/06/2014] [Indexed: 01/30/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE Regorafenib improves progression-free survival as a late-line treatment for patients with metastatic gastrointestinal stromal tumour (GIST). As a multitargeted tyrosine kinase inhibitor (TKI), the expected adverse events of regorafenib are similar to those reported with imatinib, sunitinib or sorafenib. We report the first case of hyperammonemic encephalopathy related to regorafenib in a patient with metastatic GIST. CASE SUMMARY A 61-year-old man maintained on regorafenib for metastatic GIST presented with acute confusion. Discontinuation of regorafenib led to complete resolution of confusion, which later recurred with hyperammonemia on recommencing regorafenib. Cessation of regorafenib and normalization of hyperammonemia then resulted in resolution of confusion. WHAT IS NEW AND CONCLUSIONS Regorafenib withdrawal and recommencement had influenced the confusional state and hyperammonemia in this patient. There is a probable relationship between regorafenib and metabolic encephalopathy. There are case reports of similar encephalopathy thought to be induced by other multitargeted TKI, and, as such, a class effect could be postulated.
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Affiliation(s)
- J C Kuo
- Department of Medical Oncology, The Canberra Hospital, Garran, ACT, Australia
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Abstract
OPINION STATEMENT Hepatic encephalopathy management varies depending on the acuity of liver failure. However, in patients with either acute or chronic liver failure five basic steps in management are critical: stabilization, addressing modifiable precipitating factors, lowering blood ammonia, managing elevated intracranial pressure (ICP) (if present), and managing complications of liver failure that can contribute to encephalopathy, particularly hyponatremia. Because liver failure patients are prone to a variety of other medical problems that can lead to encephalopathy (such as coagulopathy associated intracranial hemorrhage, electrolyte disarray, renal failure, hypotension, hypoglycemia, and infection), a thorough history, physical and neurologic examination is mandated in all encephalopathic liver failure patients. There should be a low threshold for brain imaging in patients with focal neurological deficits given the propensity for spontaneous intracranial hemorrhage. In patients with acute liver failure and high grade encephalopathy, identification of the etiology of acute liver failure is essential to guide treatment and antidote administration, particularly in the case of acetaminophen poisoning. Equally critical is management of elevated ICP in acute liver failure. Intracranial hypertension can be treated with hypertonic saline and/or adjustment of the dialysis bath. Placement of an intracranial monitor to guide ICP therapy is risky because of concomitant coagulopathy and remains controversial. Continuous renal replacement therapy may help lower serum ammonia, treat coexisting uremia, and improve symptoms. Liver transplantation is the definitive treatment for patients with acute liver failure and hepatic encephalopathy. In patients with chronic hepatic encephalopathy, lactulose and rifaxamin remain a mainstay of therapy. In these patients, it is essential to identify reversible causes of hepatic encephalopathy such as increased ammonia production and/or decreased clearance (eg, infection, GI bleed, constipation, hypokalemia, dehydration). Chronic hyponatremia should be managed by gradual sodium correction of no more than 8‒12 meq/L per day to avoid central myelinolysis syndrome. Free water restriction and increased dietary sodium are reasonable, cost effective treatment options. Many emerging therapies, both pharmacologic and interventional, are currently being studied to improve management of hepatic encephalopathy.
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Affiliation(s)
- HJ Lee
- CT2 Core Medical Trainee, Southend University Hospital NHS Foundation Trust, Essex SS0 0RY
| | - N Halliday
- ST3 in Gastroenterology, Southend University Hospital NHS Foundation Trust, Essex SS0 0RY
| | - GP Bray
- Consultant Gastroenterologist and Hepatologist, Department of Gastroenterology, Southend University Hospital NHS Foundation Trust, Essex SS0 0RY
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