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Shi R, Hui X, Tong T, Li J, Zhang L, Yang K. Non-bioartificial artificial liver support system in acute liver failure: A comprehensive systematic review and meta-analysis of randomized controlled trials. Clin Res Hepatol Gastroenterol 2025; 49:102527. [PMID: 39800222 DOI: 10.1016/j.clinre.2025.102527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 12/14/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
BACKGROUND Acute liver failure (ALF) poses a significant threat to patient health with high mortality rates. While Non-Bioartificial Artificial Liver Support system (NBALSS) has been utilized as a transitional intervention to liver transplant, its efficacy remains uncertain, It is also used as a last-line treatment for patients who are not candidates for liver transplantation. OBJECTIVE The aim of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of NBALSS in treating acute liver failure (ALF). The primary outcome was overall survival (OS), while the secondary outcome focused on inflammatory factor levels. METHODS We conducted a comprehensive search across various databases, including PubMed, EMbase, The Cochrane Library, Web of Science, CBM, Wanfang Database, VIP database, and CNKI database. The search spanned from the inception of the databases to July 2023. Two independent reviewers screened literature, extracted data, assessed bias risk in the selected studies and used GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) to rate the certainty of evidence. Random and fixed effects meta-analyses were used to determine the average effect of the interventions on ALF. The sensitivity analysis was conducted using the leave-one-out test. Additionally, subgroup analyses were carried out based on a singular NBALSS treatment or combined treatment of two NBALSS and follow-up duration. RESULTS Twelve RCTs involving 824 patients were identified. The use of NBALSS was associated with a significantly improved overall survival (OS) [RR = 1.42, 95 %CI (1.26, 1.61), low certainty] and notable reductions in total bilirubin (TBIL) [MD = -57.60, 95 %CI (-79.60, -35.59), moderate certainty], alanine aminotransferase (ALT) [MD = -48.28, 95 %CI (-76.57, -19.98), low certainty], tumor necrosis factor (TNF-α) [MD = -1.49, 95 %CI (-2.24, -0.73), very low certainty], and interleukin 6 (IL-6) [MD = -178.72, 95 %CI (-277.37, -80.06), very low certainty]. However, the effects of NBALSS on interleukin-2 (IL-2) [MD = 1.33, 95 %CI (-0.33, 3.00), very low certainty], interleukin-8 (IL-8) [MD = -44.75, 95 %CI (-163.04, 73.55), very low certainty], and Sequential Organ Failure Score (SOFA) [MD = -4.06, 95 %CI (-8.92, 0.80), very low certainty] remained uncertain. CONCLUSIONS Moderate to very low certainty of evidence indicates that NBALSS may improve OS and biochemical indexes, cytokines in patients with ALF. However, the certainty of evidence is limited by risk of bias, incositency and imprecision. High-quality and larger trials are needed to better determine the effect of NBALSS on patient-important outcomes.
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Affiliation(s)
- Ruizhi Shi
- The First Clinical Medical College of Lanzhou University, 730000, Lanzhou, China; Evidence-Based Medicine Center, School of Basic Medical Science, Lanzhou University, 730000, Lanzhou, China
| | - Xu Hui
- Evidence-Based Medicine Center, School of Basic Medical Science, Lanzhou University, 730000, Lanzhou, China; Centre for Evidence-Based Social Science/Center for Health Technology Assessment, School of Public Health, Lanzhou University, 730000, Lanzhou, China; Gansu Key Laboratory of Evidence-Based Medicine, Lanzhou University, 730000, Lanzhou, China
| | - Ting Tong
- The First Clinical Medical College of Lanzhou University, 730000, Lanzhou, China
| | - Junfeng Li
- The First Clinical Medical College of Lanzhou University, 730000, Lanzhou, China; Department of Hepatology & Infectious Diseases, the First Hospital of Lanzhou University, 730000, Lanzhou, China
| | - Liting Zhang
- The First Clinical Medical College of Lanzhou University, 730000, Lanzhou, China; Department of Hepatology & Infectious Diseases, the First Hospital of Lanzhou University, 730000, Lanzhou, China; Institute of Portal Hypertension, the First Hospital of Lanzhou University, 730000, Lanzhou, China.
| | - Kehu Yang
- Evidence-Based Medicine Center, School of Basic Medical Science, Lanzhou University, 730000, Lanzhou, China; Centre for Evidence-Based Social Science/Center for Health Technology Assessment, School of Public Health, Lanzhou University, 730000, Lanzhou, China; Gansu Key Laboratory of Evidence-Based Medicine, Lanzhou University, 730000, Lanzhou, China.
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Zielińska M, Popek M, Albrecht J. Neuroglia in hepatic encephalopathy. HANDBOOK OF CLINICAL NEUROLOGY 2025; 210:191-212. [PMID: 40148045 DOI: 10.1016/b978-0-443-19102-2.00011-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Neuroglia contribute to the pathophysiology of hepatic encephalopathy (HE) either beneficially or detrimentally. Pathogenesis of HE is linked to damage triggered by blood-derived toxins, with ammonia being the main causative factor. Neuroglial cells, especially astrocytes and microglia, respond to HE-associated systemic and central signals and undergo complex and variable changes in their metabolism, morphology, and function, which include ion and water dyshomeostasis in conjunction with neurotransmission imbalance and neuroinflammation. HE-induced alterations of astrocytes are defined as astrocytopathy, with aberrant astrocytes resulting in either gain or loss of functions. In the chronic HE, the presence of Alzheimer type II cells is a histologic hallmark, with asthenic astrocytes emerging as a newcomer. In acute HE, rapid swelling of astrocytes is a primary cause of cerebral edema and mortality. This chapter reviews the dominant role of astrocytes in the pathogenesis of HE resulting from acute and chronic liver failure, mainly in experimental models. The focus is on the loss of homeostatic function bearing upon the functioning of the glymphatic system, aberrant neurotransmission as a consequence of astrocyte-neuron miscommunication, and the concordant neuroinflammatory response of astrocytes and microglia. The chapter concludes with a delineation of concepts for future research.
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Affiliation(s)
- Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
| | - Mariusz Popek
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
| | - Jan Albrecht
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland
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Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis 2024; 39:1689-1703. [PMID: 39212845 PMCID: PMC11535002 DOI: 10.1007/s11011-024-01402-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.
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Affiliation(s)
- Yevedzo Ntuli
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Debbie L Shawcross
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK.
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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Tong XY, Norenberg MD, Paidas MJ, Shamaladevi N, Salgueiro L, Jaszberenyi M, John B, Hussain H, El Hiba O, Abdeljalil EG, Bilal EM, Natarajan S, Romaguera R, Papayan S, Carden AK, Ramamoorthy R, Elumalai N, Schally AV, Nithura J, Patrizio R, Jayakumar AR. Mechanism of Alzheimer type II astrocyte development in hepatic encephalopathy. Neurochem Int 2024; 180:105866. [PMID: 39369794 DOI: 10.1016/j.neuint.2024.105866] [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: 05/14/2024] [Revised: 09/19/2024] [Accepted: 09/22/2024] [Indexed: 10/08/2024]
Abstract
Type C hepatic encephalopathy (Type C HE) is a major and complex neurological condition that occurs following chronic liver failure. The molecular basis of Type C HE remains elusive. Type C HE is characterized by mental confusion, cognitive and motor disturbances. The presence of Alzheimer type II astrocytes (AT2A) is the key histopathological finding observed in Type C HE. However, nothing is currently known regarding AT2A development and its involvement in cognitive, and motor deficits in Type C HE. We, therefore, examined in rats the mechanisms by which liver failure contributes to the progression of AT2A, and its role in the development of cognitive and motor deficits in thioacetamide (TAA) model of Type C HE. We and others earlier reported increased oxidative/nitrosative stress (ONS), JNK1/2, and cMyc activation in ammonia-treated astrocyte cultures, as well as in brains from chronic liver failure. We now found increased levels of astrocytic glia maturation factor (GMF, a factor strongly implicated in neuroinflammation), as well as various inflammatory factors (IL-1β, TNF-α, IL-6, MMP-3, COX2, CXCL1, and PGE2), and reduced levels of GFAP and increased levels of aggregated nuclear protein Lamin A/C in rat brain cortex post-chronic liver failure. We also found increased levels of GMF and inflammatory factors (MMP-3, COX2, CXCL1, and PGE2) in astrocytes post-ammonia treatment in vitro. Additionally, pharmacological inhibition of upstream signaling of GMF (ONS, JNK1/2, and cMyc) or GMF inhibitors W-7 and trifluoperazine significantly reduced the levels of inflammatory factors, the number of AT2A cells, as well as the cognitive and motor deficits in TAA-treated rats. Increased levels of GMF were also identified in human post-mortem brain sections. These findings strongly suggest that increased levels of astrocytic GMF due to elevated levels of ONS, JNK1/2, and cMyc and the subsequent inflammation contribute to the development of AT2A and the consequent cognitive, and motor deficits in chronic liver failure.
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Affiliation(s)
- Xiao Y Tong
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael D Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL, USA
| | - Michael J Paidas
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL, USA
| | | | - Luis Salgueiro
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Miklos Jaszberenyi
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Department of Pathophysiology, Faculty of Medicine, University of Szeged, Hungary
| | - Binu John
- General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA
| | - Hussain Hussain
- Larkin Community Hospital, Department of Internal Medicine and Infectious Disease, Miami, FL, USA
| | - Omar El Hiba
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El Got Abdeljalil
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - El-Mansoury Bilal
- Laboratory of Anthropogenic, Biotechnology, and Health, Nutritional Physiopathologies, Neuroscience and Toxicology Team, Faculty of Sciences, Chouaib Doukkali University, Av Des facultés, 24000, El Jadida, Morocco; The Hassan First University of Settat, Higher Institute of Health Sciences, Laboratory of Health Sciences and Technology, Morocco
| | - Sampath Natarajan
- Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Tamil Nadu, India
| | - Rita Romaguera
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Stanislav Papayan
- Pathology and Laboratory Medicine, Department of Veterans Affairs, Miami, FL, 33125, USA
| | - Arianna K Carden
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Rajalakshmi Ramamoorthy
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Nila Elumalai
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew V Schally
- Endocrine, Polypeptide, and Cancer Institute, Department of Veterans Affairs, Miami, FL, 33125, USA
| | | | - Rebecca Patrizio
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA
| | - Arumugam R Jayakumar
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami School of Medicine, Miami, FL, USA; General Medical Research, R&D Services, Department of Veterans Affairs, Miami, FL, USA; Neuropathology Section, Veterans Affairs Medical Center, Miami, FL, USA; R&D Services and South Florida VA Foundation for Research and Education Inc, Veterans Affairs Medical Center, Miami, FL, USA.
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Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2024; 21:774-791. [PMID: 39251708 DOI: 10.1038/s41575-024-00970-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 09/11/2024]
Abstract
Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.
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Affiliation(s)
- Rocío Gallego-Durán
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Javier Ampuero
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London, UK
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Manuel Romero-Gómez
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
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6
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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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Pierzchala K, Hadjihambi A, Mosso J, Jalan R, Rose CF, Cudalbu C. Lessons on brain edema in HE: from cellular to animal models and clinical studies. Metab Brain Dis 2024; 39:403-437. [PMID: 37606786 PMCID: PMC10957693 DOI: 10.1007/s11011-023-01269-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 07/24/2023] [Indexed: 08/23/2023]
Abstract
Brain edema is considered as a common feature associated with hepatic encephalopathy (HE). However, its central role as cause or consequence of HE and its implication in the development of the neurological alterations linked to HE are still under debate. It is now well accepted that type A and type C HE are biologically and clinically different, leading to different manifestations of brain edema. As a result, the findings on brain edema/swelling in type C HE are variable and sometimes controversial. In the light of the changing natural history of liver disease, better description of the clinical trajectory of cirrhosis and understanding of molecular mechanisms of HE, and the role of brain edema as a central component in the pathogenesis of HE is revisited in the current review. Furthermore, this review highlights the main techniques to measure brain edema and their advantages/disadvantages together with an in-depth description of the main ex-vivo/in-vivo findings using cell cultures, animal models and humans with HE. These findings are instrumental in elucidating the role of brain edema in HE and also in designing new multimodal studies by performing in-vivo combined with ex-vivo experiments for a better characterization of brain edema longitudinally and of its role in HE, especially in type C HE where water content changes are small.
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Affiliation(s)
- Katarzyna Pierzchala
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland.
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland.
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, SE5 9NT, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Jessie Mosso
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland
- Laboratory for Functional and Metabolic Imaging (LIFMET), EPFL, Lausanne, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, Spain
| | - Christopher F Rose
- Hépato-Neuro Laboratory, Centre de Recherche du Centre Hospitalier de l', Université de Montréal (CRCHUM), Montreal, QC, H2X 0A9, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, QC, Montreal, H3T 1J4, Canada
| | - Cristina Cudalbu
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland.
- Animal Imaging and Technology, EPFL, Lausanne, Switzerland.
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Wang Y, Li Y, Lv L, Zhu L, Hong L, Wang X, Zhang Y, Wang X, Diao H. Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy. NPJ Biofilms Microbiomes 2024; 10:13. [PMID: 38396001 PMCID: PMC10891095 DOI: 10.1038/s41522-024-00487-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA-microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.
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Affiliation(s)
- Yuchong Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuyu Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Liying Zhu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Liang Hong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xueyao Wang
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, China
| | - Yu Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Xin Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Institute of Food Science, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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Kim MJ, Kim JH, Jung JH, Kim SE, Kim HS, Jang MK, Park SH, Lee MS, Suk KT, Kim DJ, Choi EK, Park JW. Serum S100B Levels in Patients with Liver Cirrhosis and Hepatic Encephalopathy. Diagnostics (Basel) 2023; 13:333. [PMID: 36766438 PMCID: PMC9914222 DOI: 10.3390/diagnostics13030333] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatic encephalopathy (HE) is one of the main complications of liver cirrhosis (LC) and is classified into minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy (overt HE). S100B is expressed mainly in astrocytes and other glial cells, and S100B has been reported to be associated with various neurological disorders. The present study aimed to investigate the diagnostic ability of serum S100B to discriminate the grade of HE and the parameters correlated with serum S100B levels. Additionally, we investigated whether serum S100B levels can be used to predict 1-year mortality in cirrhotic patients. In total, 95 cirrhotic patients were consecutively enrolled and divided into the following three groups: (i) without any types of HEs; (ii) with MHE; and (iii) with overt HE. The diagnosis of MHE was made by the Mini-Mental State Examination (MMSE) and Psychometric Hepatic Encephalopathy Score (PHES). Among the three groups, there were no significant differences in serum S100B levels regardless of HE severity. The clinical parameters correlated with serum S100B levels were age, serum bilirubin, and creatinine levels. The Model for End-Stage Liver Disease (MELD) score showed a significant positive correlation with serum S100B levels. The relationship between serum S100B levels and MELD score was maintained in 48 patients without any type of HE. Additionally, hyperammonemia, low cholesterol levels, and the combination of serum S100B levels ≥ 35 pg/mL with MELD score ≥ 13 were factors for predicting 1- year mortality. In conclusion, serum S100B level was not useful for differentiating the severity of HE. However, we found that serum S100B levels can be affected by age, serum bilirubin, and creatinine in cirrhotic patients and are associated with MELD scores. Additionally, serum S100B levels showed the possibility of predicting 1-year mortality in cirrhotic patients. These findings suggest that serum S100B levels may reflect liver dysfunction and prognosis in liver disease.
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Affiliation(s)
- Mo-Jong Kim
- Ilsong Institute of Life Science, Hallym University, Seoul 07247, Republic of Korea
- Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon-si 24252, Republic of Korea
| | - Jung-Hee Kim
- Department of Internal Medicine, Dongtan Sacred Heart Hospital of Hallym University Medical Center, 7, Keunjaebong-gil, Hwaseong-si 18450, Republic of Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
| | - Jang-Han Jung
- Department of Internal Medicine, Dongtan Sacred Heart Hospital of Hallym University Medical Center, 7, Keunjaebong-gil, Hwaseong-si 18450, Republic of Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
| | - Sung-Eun Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Hallym University Sacred Heart Hospital of Hallym University Medical Center, 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang-si 14068, Republic of Korea
| | - Hyoung-Su Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Kangdong Sacred Heart Hospital of Hallym University Medical Center, 18, Cheonho-daero 173-gil, Gangdong-gu, Seoul 05355, Republic of Korea
| | - Myoung-Kuk Jang
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Kangdong Sacred Heart Hospital of Hallym University Medical Center, 18, Cheonho-daero 173-gil, Gangdong-gu, Seoul 05355, Republic of Korea
| | - Sang-Hoon Park
- Department of Internal Medicine, Kangnam Sacred Heart Hospital of Hallym University Medical Center, 1, Singil-ro, Yeongdeungpo-gu, Seoul 07441, Republic of Korea
| | - Myung-Seok Lee
- Department of Internal Medicine, Kangnam Sacred Heart Hospital of Hallym University Medical Center, 1, Singil-ro, Yeongdeungpo-gu, Seoul 07441, Republic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital of Hallym University Medical Center, 77, Sakju-ro, Chuncheon-si 24253, Republic of Korea
| | - Dong Joon Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Chuncheon Sacred Heart Hospital of Hallym University Medical Center, 77, Sakju-ro, Chuncheon-si 24253, Republic of Korea
| | - Eun-Kyoung Choi
- Ilsong Institute of Life Science, Hallym University, Seoul 07247, Republic of Korea
- Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon-si 24252, Republic of Korea
| | - Ji-Won Park
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon-si 24252, Republic of Korea
- Department of Internal Medicine, Hallym University Sacred Heart Hospital of Hallym University Medical Center, 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang-si 14068, Republic of Korea
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10
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Tranah TH, Ballester MP, Carbonell-Asins JA, Ampuero J, Alexandrino G, Caracostea A, Sánchez-Torrijos Y, Thomsen KL, Kerbert AJC, Capilla-Lozano M, Romero-Gómez M, Escudero-García D, Montoliu C, Jalan R, Shawcross DL. Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. J Hepatol 2022; 77:1554-1563. [PMID: 35872326 DOI: 10.1016/j.jhep.2022.07.014] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre. RESULTS Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.
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Affiliation(s)
- Thomas H Tranah
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - María-Pilar Ballester
- Digestive Disease Department, Hospital Clínico Universitario de Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain
| | | | - Javier Ampuero
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | - Gonçalo Alexandrino
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Gastroenterology and Hepatology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal
| | - Andra Caracostea
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Yolanda Sánchez-Torrijos
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | - Karen L Thomsen
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom
| | | | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | | | - Carmina Montoliu
- INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Pathology, Faculty of Medicine, University of Valencia, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom; European Foundation for the Study of Chronic Liver Failure (EF Clif), Spain.
| | - Debbie L Shawcross
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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11
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Jalan R, Rose CF. Heretical thoughts into hepatic encephalopathy. J Hepatol 2022; 77:539-548. [PMID: 35358618 DOI: 10.1016/j.jhep.2022.03.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/03/2022] [Accepted: 03/11/2022] [Indexed: 02/06/2023]
Abstract
Clinical progress in the development of new diagnostic modalities and therapeutic strategies for the management of patients with hepatic encephalopathy has lagged behind the vast knowledge that has been generated from basic studies. In this article, we critically assess matters that should be revisited, such as definition, classification, diagnosis and grading of hepatic encephalopathy, which are difficult to apply reproducibly using the current criteria. Many lines of investigation have confirmed that hepatic encephalopathy is irreversible in many patients and suggest the need for further studies focussing on mechanisms of neuronal injury and death, to guide future drug development for these patients. The clinical evidence behind using lactulose for all severities of hepatic encephalopathy, which is currently considered the standard of care, is poor and placebo-controlled trials for hepatic encephalopathy should be considered ethically sound. This expert opinion identifies current challenges in hepatic encephalopathy and highlights areas which require further debate and investigation in order to help advance the field both scientifically and clinically.
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Affiliation(s)
- Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.
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12
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Maiwall R, Bajpai M, Singh A, Agarwal T, Kumar G, Bharadwaj A, Nautiyal N, Tevethia H, Jagdish RK, Vijayaraghavan R, Choudhury A, Mathur RP, Hidam A, Pati NT, Sharma MK, Kumar A, Sarin SK. Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial. Clin Gastroenterol Hepatol 2022; 20:e831-e854. [PMID: 33524593 DOI: 10.1016/j.cgh.2021.01.036] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 12/29/2020] [Accepted: 01/24/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) μg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL gov (identifier: NCT02718079).
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Meenu Bajpai
- Department of Transfusion Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akanksha Singh
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Tanvi Agarwal
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankit Bharadwaj
- Department of Biostatistics, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nidhi Nautiyal
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Harsh Tevethia
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakesh Kumar Jagdish
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajan Vijayaraghavan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashok Choudhury
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Ashini Hidam
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupama Trehan Pati
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar Sharma
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Anupam Kumar
- Department of Clinical and Molecular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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13
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Zoratti C, Moretti R, Rebuzzi L, Albergati IV, Di Somma A, Decorti G, Di Bella S, Crocè LS, Giuffrè M. Antibiotics and Liver Cirrhosis: What the Physicians Need to Know. Antibiotics (Basel) 2021; 11:31. [PMID: 35052907 PMCID: PMC8772826 DOI: 10.3390/antibiotics11010031] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/13/2022] Open
Abstract
The liver is the primary site of drug metabolism, which can be altered by a variety of diseases affecting the liver parenchyma, especially in patients with liver cirrhosis. The use of antibiotics in patients with cirrhosis is usually a matter of concern for physicians, given the lack of practical knowledge for drug choice and eventual dose adjustments in several clinical scenarios. The aim of the current narrative review is to report, as broadly as possible, basic, and practical knowledge that any physician should have when approaching a patient with liver cirrhosis and an ongoing infection to efficiently choose the best antibiotic therapy.
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Affiliation(s)
- Caterina Zoratti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Rita Moretti
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Lisa Rebuzzi
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Irma Valeria Albergati
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Antonietta Di Somma
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Giuliana Decorti
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137 Trieste, Italy;
| | - Stefano Di Bella
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
| | - Lory Saveria Crocè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
- Italian Liver Foundation, 34149 Trieste, Italy
| | - Mauro Giuffrè
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy; (C.Z.); (R.M.); (L.R.); (I.V.A.); (A.D.S.); (S.D.B.); (L.S.C.)
- Italian Liver Foundation, 34149 Trieste, Italy
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14
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Abstract
Liver failure in the context of acute (ALF) and acute on chronic liver failure (ACLF) is associated with high mortality in the absence of a liver transplant. For decades, therapeutic plasma exchange (TPE) is performed for the management of immune-mediated diseases. TPE has emerged as an attractive extracorporeal blood purification technique in patients with ALF and ACLF. The basic premise of using TPE is to remove the toxic substances which would allow recovery of native liver functions by facilitating liver regeneration. In recent years, encouraging data have emerged, suggesting the benefits of TPE in patients with liver failure. TPE has emerged as an attractive liver support device for the failing liver until liver transplantation or clinical recovery. The data in patients with ALF suggest routine use of high-volume TPE, while the data for such a strategy are less robust for patients with ACLF.
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Affiliation(s)
- Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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15
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Bass NM. A Brief History of Hepatic Encephalopathy. Clin Liver Dis (Hoboken) 2021; 18:49-62. [PMID: 34745583 PMCID: PMC8555462 DOI: 10.1002/cld.1119] [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] [Received: 03/23/2021] [Accepted: 03/26/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Audio Recording.
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Affiliation(s)
- Nathan M. Bass
- Department of MedicineUniversity of California, San FranciscoSan FranciscoCA
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16
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Vipani A, Lindenmeyer CC, Sundaram V. Treatment of Severe Acute on Chronic Liver Failure: Management of Organ Failures, Investigational Therapeutics, and the Role of Liver Transplantation. J Clin Gastroenterol 2021; 55:667-676. [PMID: 34028394 DOI: 10.1097/mcg.0000000000001568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Acute on chronic liver failure (ACLF) is a unique syndrome that afflicts patients with chronic liver disease and results in high short-term mortality, in the setting of organ system failures. Given this prognosis, there is an urgent need to understand risk factors for this condition, for appropriate medical management of organ failures, and for selection criteria for patients who may benefit from liver transplantation (LT). Although several definitions exist to identify ACLF, all of them are designed to identify patients with uniquely high mortality. Currently, management of severe ACLF relies on best supportive care for specific organ failures. Thromboelastography should guide the evaluation of coagulation pathways and hyperfibrinolysis in ACLF; prophylactic blood product transfusions and thrombopoetin agonists are not recommended. Combination therapy with terlipressin and albumin has been shown to be efficacious in the management of the hepatorenal syndrome but should be administered with caution in patients with ACLF-3. Recent data have characterized the role of beta-blockers and transjugular intrahepatic portosystemic shunt placement in the management of ACLF. Investigational therapies such as extracorporeal liver support and hepatocyte stem cell therapies have shown promise; larger scale studies may better define the subpopulations of patients with ACLF mostly likely to benefit from these evolving therapeutics. Regarding LT in ACLF, data suggest that even patients with 3 or more organ system failures may have a 1-year survival >80%. However, further efforts are needed to understand the predictors of post-LT survival to facilitate LT criteria for this condition.
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Affiliation(s)
| | | | - Vinay Sundaram
- Division of Gastroenterology and Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
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17
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Sepehrinezhad A, Shahbazi A, Sahab Negah S, Joghataei MT, Larsen FS. Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy. Toxicol Rep 2021; 8:962-970. [PMID: 34026559 PMCID: PMC8122178 DOI: 10.1016/j.toxrep.2021.04.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/17/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) following acute and chronic liver failure is defined as a complex of neuropsychiatric abnormalities, such as discrete personal changes, sleep disorder, forgetfulness, confusion, and decreasing the level of consciousness to coma. The use and design of suitable animal models that represent clinical features and pathological changes of HE are valuable to map the molecular mechanisms that result in HE. Among different types of animal models, thioacetamide (TAA) has been used extensively for the induction of acute liver injury and HE. This agent is not directly hepatotoxic but its metabolites induce liver injury through the induction of oxidative stress and produce systemic inflammation similar to that seen in acute HE patients. In this short review article, we shortly review the most important pathological findings in animal models of acute HE following the administration of TAA.
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Key Words
- ALT, alanine aminotransferase
- AQP4, aquaporin 4 water channel
- AST, aspartate aminotransferase
- Acute liver failure
- Animal model
- B7, B7 molecules (CD80+CD86)
- BBB, blood-brain barrier
- CBF, cerebral blood flow
- CCL2, chemokine ligand 2
- CNS, central nervous system
- CTLA4, Cytotoxic T-lymphocyte-associated Protein 4
- CYP2E1, Cytochrome P450 family 2 subfamily E member 1
- GFAP, glial fibrillary acidic protein
- HE, hepatic encephalopathy
- Hepatic encephalopathy
- IL-6, interleukin 6
- IL-β, interleukin 1 β
- Iba1, ionized calcium-binding adaptor molecule 1
- JNK, c-Jun N-terminal kinase
- NAC, N-acetylcysteine
- NF-κB, nuclear factor κB
- OA, L-ornithine-l-aspartate
- ROS, reactive oxygen species
- TAA, thioacetamide
- TASO, thioacetamide sulfoxide
- TASO2, thioacetamide sulfdioxide
- TLR-2, toll-like receptor 2
- TLR-4, toll-like receptor 4
- TNFα, tumor necrosis factor α
- Thioacetamide
- Toxicity pathway
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fin Stolze Larsen
- Department of Hepatology CA-3163, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
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18
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Baraka SM, Saleh DO, Ghaly NS, Melek FR, Gamal El Din AA, Khalil WKB, Said MM, Medhat AM. Flavonoids from Barnebydendron riedelii leaf extract mitigate thioacetamide-induced hepatic encephalopathy in rats: The interplay of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways. Bioorg Chem 2020; 105:104444. [PMID: 33197852 DOI: 10.1016/j.bioorg.2020.104444] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/19/2020] [Accepted: 10/28/2020] [Indexed: 12/24/2022]
Abstract
Phytochemical investigation of the butanol fraction (BUF) derived from the 70% aqueous methanolic leaf extract of Barnebydendron riedelii led to the isolation of three flavonoid glycosides; kaempferol-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside, quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-galactopyranoside and quercetin-3-O-α-l-rhamnopyranosyl-(1 → 6)-β-d-glucopyranoside. Docking studies were fulfilled to validate the possible bio-properties of BUF toward nuclear factorkappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2). The protective role of BUF against behavioral, biochemical, molecular, histopathological and immunohistochemical alterations in thioacetamide (TAA)-induced hepatic encephalopathy in rats was investigated. The toxicological studies indicated that BUF was safe up to 2000 mg/kg bw. Prior to TAA intoxication, rats were orally treated with either BUF at multiple doses (70, 140 and 280 mg/kg bw) or lactulose (8 mL/kg bw) for 14 consecutive days. On the 13th and the 14th day, TAA (200 mg/kg bw/day) was intraperitoneally injected. The BUF significantly improved motor impairment, ameliorated cognitive deficits and attenuated TAA-induced hepatotoxicity. Moreover, BUF controlled the inflammatory processes by suppressing the hepatic inflammatory cytokine; interleukin-6 (IL-6) as well as its pro-inflammatory mediator; NF-κB supporting the molecular docking assessment. The brain neurotransmitters; dopamine, serotonin and noradrenaline, as well as ammonia levels were improved in BUF-treated TAA-intoxicated animals in a dose-dependent manner. Furthermore, BUF administration to TAA-intoxicated rats modulated the Nrf2 and heme oxygenase 1 (HO-1) genes expression in liver and brain tissues. The histological evaluation showed that pretreatment of TAA-intoxicated rats with BUF ameliorated the degenerative effects of TAA on liver and brain tissues as well as reduced the activation of cellular apoptotic marker; caspase-3 and glial fibrillary acidic protein (GFAP+) astrocytes. In conclusion, the observed hepato-neuroprotective effect of BUF is attributed to its flavonoidal content through its modulatory effects on of NF-κB/IL-6 and Nrf2/HO-1 signaling pathways.
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Affiliation(s)
- Sara M Baraka
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | - Dalia O Saleh
- Pharmacology Department, National Research Centre, Giza 12622, Egypt.
| | - Neveen S Ghaly
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | - Farouk R Melek
- Chemistry of Natural Compounds Department, National Research Centre, Giza 12622, Egypt
| | | | - Wagdy K B Khalil
- Cell Biology Department, National Research Centre, Giza 12622, Egypt
| | - Mahmoud M Said
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
| | - Amina M Medhat
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
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Anand AC, Nandi B, Acharya SK, Arora A, Babu S, Batra Y, Chawla YK, Chowdhury A, Chaoudhuri A, Eapen EC, Devarbhavi H, Dhiman RK, Datta Gupta S, Duseja A, Jothimani D, Kapoor D, Kar P, Khuroo MS, Kumar A, Madan K, Mallick B, Maiwall R, Mohan N, Nagral A, Nath P, Panigrahi SC, Pawar A, Philips CA, Prahraj D, Puri P, Rastogi A, Saraswat VA, Saigal S, Shalimar, Shukla A, Singh SP, Verghese T, Wadhawan M. Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure. J Clin Exp Hepatol 2020; 10:477-517. [PMID: 33029057 PMCID: PMC7527855 DOI: 10.1016/j.jceh.2020.04.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/12/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.
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Key Words
- ACLF, Acute on Chronic liver Failure
- AKI, Acute kidney injury
- ALF, Acute Liver Failure
- ALFED score
- ALT, alanine transaminase
- AST, aspartate transaminase
- CNS, central nervous system
- CT, Computerized tomography
- HELLP, Hemolysis, elevated liver enzymes, and low platelets
- ICH, Intracrainial hypertension
- ICP, Intracrainial Pressure
- ICU, Intensive care unit
- INR, International normalised ratio
- LAD, Liver assist device
- LDLT, Living donor liver transplantation
- LT, Liver transplantation
- MAP, Mean arterial pressure
- MELD, model for end-stage liver disease
- MLD, Metabolic liver disease
- NAC, N-acetyl cysteine
- PALF, Pediatric ALF
- WD, Wilson's Disease
- acute liver failure
- artificial liver support
- liver transplantation
- plasmapheresis
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Affiliation(s)
- Anil C. Anand
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Bhaskar Nandi
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Anil Arora
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sethu Babu
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad, 500003, India
| | - Yogesh Batra
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
| | - Ashok Chaoudhuri
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Eapen C. Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
| | | | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Mohamad S. Khuroo
- Department of Gastroenterology, Dr Khuroo’ s Medical Clinic, Srinagar, Kashmir, India
| | - Ashish Kumar
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Kaushal Madan
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
| | - Bipadabhanjan Mallick
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Rakhi Maiwall
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
| | - Aabha Nagral
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Preetam Nath
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Sarat C. Panigrahi
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Ankush Pawar
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
| | - Cyriac A. Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi 682028, Kerala, India
| | - Dibyalochan Prahraj
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Pankaj Puri
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
| | - Amit Rastogi
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Sanjiv Saigal
- Department of Hepatology, Department of Liver Transplantation, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
| | - Akash Shukla
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Thomas Verghese
- Department of Gastroenterology, Government Medical College, Kozikhode, India
| | - Manav Wadhawan
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
| | - The INASL Task-Force on Acute Liver Failure
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad, 500003, India
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Hepatology, Christian Medical College, Vellore, India
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
- Gleneagles Global Hospitals, Hyderabad, Telangana, India
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
- Department of Gastroenterology, Dr Khuroo’ s Medical Clinic, Srinagar, Kashmir, India
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi 682028, Kerala, India
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
- Department of Hepatology, Department of Liver Transplantation, India
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
- Department of Gastroenterology, SCB Medical College, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
- Department of Gastroenterology, Government Medical College, Kozikhode, India
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
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Manakkat Vijay GK, Hu C, Peng J, Garcia-Martinez I, Hoque R, Verghis RM, Ma Y, Mehal WZ, Shawcross DL, Wen L. Ammonia-Induced Brain Edema Requires Macrophage and T Cell Expression of Toll-Like Receptor 9. Cell Mol Gastroenterol Hepatol 2019; 8:609-623. [PMID: 31401214 PMCID: PMC6889059 DOI: 10.1016/j.jcmgh.2019.08.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 07/31/2019] [Accepted: 08/02/2019] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIM Ammonia is central in the pathogenesis of brain edema in acute liver failure (ALF) with infection and systemic inflammation expediting development of intracranial hypertension (ICH). Patients with acetaminophen-induced ALF have increased neutrophil TLR9 expression which can be induced by ammonia. We determined whether ammonia-induced brain edema and immune dysfunction are mediated by TLR9 and if this could be prevented in a TLR9-deficient mouse model. METHODS Ammonium acetate (NH4-Ac; 4mmol/kg) was injected intraperitoneally in wild type (WT), Tlr9-/- and Lysm-Cre Tlr9fl/fl mice (TLR9 absent in neutrophils and macrophages including Kupffer cells) and compared to controls. Six hours after NH4-Ac injection, intracellular cytokine production was determined in splenic macrophages, CD4+ and CD8+ T cells. Brain water (BW) and total plasma DNA (tDNA) were also measured. The impact of the TLR9 antagonist ODN2088 (50μg/mouse) was evaluated. RESULTS Following NH4-Ac injection, BW, macrophage and T cell cytokine production increased (P < .0001) in WT but not Tlr9-/- mice (P < .001). ODN2088 inhibited macrophage and T cell cytokine production (P < .05) and prevented an increase in BW (P < .0001). Following NH4-Ac injection, macrophage cytokine production and BW were ameliorated in Lysm-Cre Tlr9fl/fl mice compared to WT mice (P < .05) but there was no difference compared to Tlr9-/- mice. Following NH4-Ac injection, plasma tDNA levels increased in WT and Tlr9-/- mice (P < .05) suggesting that TLR9 may be activated by DNA released from ammonia-stimulated cells. CONCLUSION Ammonia-induced brain edema requires macrophage and T cell expression of TLR9. Amelioration of brain edema and lymphocyte cytokine production by ODN2088 supports exploration of TLR9 antagonism in early ALF to prevent progression to ICH.
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Affiliation(s)
- Godhev Kumar Manakkat Vijay
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom,Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Changyun Hu
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Jian Peng
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Irma Garcia-Martinez
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Rafaz Hoque
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Rejina Mariam Verghis
- Welcome Wolfson Institute of Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queens University, Belfast, United Kingdom
| | - Yun Ma
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Wajahat Zafar Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Debbie Lindsay Shawcross
- Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom,Correspondence Address correspondence to: Debbie Lindsay Shawcross, BSc, MBBS, PhD, Liver Sciences Department, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital Campus, Denmark Hill, London, SE5 9RS United Kingdom. fax: +44 (0)20 3299 3167.
| | - Li Wen
- Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut,Li Wen, MD, PhD, Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, PO Box 208020, 333 Cedar Street, New Haven, Connecticut 06520. fax: (203) 737–5558.
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21
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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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22
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Pathogenesis of cerebral edema in patients with acute renal and liver failure and the role of the nephrologist in the management. Curr Opin Nephrol Hypertens 2019; 27:289-297. [PMID: 29771702 DOI: 10.1097/mnh.0000000000000425] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Acute liver failure (ALF) is a severe and complex illness and one of the most daunting conditions managed in the ICU. Because the renal care is intertwined with multiple disciplines, the aim of this review is to examine the multifactorial pathogenesis of cerebral edema in ALF, covering basic established facts as well as recent advances in our understanding of this condition. RECENT FINDINGS Acetaminophen remains the most common cause of ALF in the United States and many European countries. The incidence of cerebral edema continues to decline owing to earlier detection and improved management. The pathogenesis of cerebral edema has shifted from a unifactorial hypothesis involving the failed liver to a multifactorial cause. Recent evidence focuses on the role of liver-induced systemic inflammation and its implication in increasing the permeability of the blood-brain barrier. The role of brain aquaporin-4 in mediating water entry into the brain is further clarified. Controversial data regarding the effect of acute kidney injury on the brain emerged. Hyponatremia has been shown to worsen the outcome in acute-on-chronic liver failure patients thus validating findings in animal models. New evidence shed the light on the changes in serum osmolality and potential tissue hypoxia during continuous renal replacement therapy and points to the risks associated with such therapy. SUMMARY ALF is a severe systemic illness that is potentially reversible. Understanding the interaction between the multiple failed organs will help the nephrologist provide well tolerated and efficient care.
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23
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Czarnecka A, Aleksandrowicz M, Jasiński K, Jaźwiec R, Kalita K, Hilgier W, Zielińska M. Cerebrovascular reactivity and cerebral perfusion of rats with acute liver failure: role of L-glutamine and asymmetric dimethylarginine in L-arginine-induced response. J Neurochem 2018; 147:692-704. [PMID: 30151828 DOI: 10.1111/jnc.14578] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/27/2018] [Accepted: 08/16/2018] [Indexed: 01/19/2023]
Abstract
Cerebral blood flow (CBF) is impaired in acute liver failure (ALF), however, the complexity of the underlying mechanisms has often led to inconclusive interpretations. Regulation of CBF depends at least partially on variations in the local brain L-arginine concentration and/or its metabolic rate. In ALF, other factors, like an increased concentration of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and elevated level of L-glutamine, may contribute to CBF alteration. This study demonstrated strong differences in the reactivity of the middle cerebral arteries and their response to extravascular L-arginine application between vessels isolated from rats with thioacetamide (TAA)-induced ALF and control animals. Our results also showed the decrease in the cerebral perfusion in TAA rats measured by arterial spin labeling perfusion magnetic resonance. Subsequently, we aimed to investigate the importance of balance between the concentration of ADMA and L-arginine in the CBF regulation. In vivo, intraperitoneal L-arginine administration in TAA rats corrected: (i) decrease in cerebral perfusion, (ii) decrease in brain extracellular L-arginine/ADMA ratio and (iii) increase in brain L-glutamine concentration. Our study implicates that impaired vascular tone of cerebral arteries is most likely associated with exposure to high ADMA and L-glutamine levels resulting in limited availability of L-arginine and might be responsible for reduced cerebral perfusion observed in ALF.
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Affiliation(s)
- Anna Czarnecka
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Marta Aleksandrowicz
- Department of Neurosurgery, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Krzysztof Jasiński
- Department of Magnetic Resonance Imaging, Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
| | - Radosław Jaźwiec
- Mass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Katarzyna Kalita
- Department of Magnetic Resonance Imaging, Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
| | - Wojciech Hilgier
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
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Bjerring PN, Gluud LL, Larsen FS. Cerebral Blood Flow and Metabolism in Hepatic Encephalopathy-A Meta-Analysis. J Clin Exp Hepatol 2018; 8:286-293. [PMID: 30302046 PMCID: PMC6175738 DOI: 10.1016/j.jceh.2018.06.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 06/11/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatic Encephalopathy (HE) is associated with abnormalities in brain metabolism of glucose, oxygen and amino acids. In patients with acute liver failure, cortical lactate to pyruvate ratio is increased, which is indicative of a compromised cerebral oxidative metabolism. In this meta-analysis we have reviewed the published data on cerebral blood flow and metabolic rates from clinical studies of patients with HE. We found that hepatic encephalopathy was associated with reduced cerebral metabolic rate of oxygen, glucose, and blood flow. One exemption was in HE type B (shunt/by-pass) were a tendency towards increased cerebral blood flow was seen. We speculate that HE is associated with a disturbed metabolism-cytopathic hypoxia-and that type specific differences of brain metabolism is due to differences in pathogenesis of HE.
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Key Words
- ALF, Acute Liver Failure
- CBF, Cerebral Blood Flow
- CMR, Cerebral Metabolic Rate
- HE, Hepatic Encephalopathy
- ICH, Intracranial Hypertension
- MHE, Minimal Hepatic Encephalopathy
- MRI, Magnetic Resonance Imaging
- OHE, Overt Hepatic Encephalopathy
- PCS, Portocaval Shunt
- cerebral blood flow
- cerebral metabolism
- hepatic encephalopathy
- liver failure
- pcMRI, Phase-Contrast MRI
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Affiliation(s)
- Peter N. Bjerring
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
- The Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
- Address for correspondence: Peter N. Bjerring, Department of Hepatology, Rigshospitalet, Copenhagen, Denmark.
| | - Lise L. Gluud
- The Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
| | - Fin S. Larsen
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
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25
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Fan Y, Liu X. Alterations in Expression and Function of ABC Family Transporters at Blood-Brain Barrier under Liver Failure and Their Clinical Significances. Pharmaceutics 2018; 10:pharmaceutics10030102. [PMID: 30041501 PMCID: PMC6161250 DOI: 10.3390/pharmaceutics10030102] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 07/20/2018] [Accepted: 07/21/2018] [Indexed: 02/07/2023] Open
Abstract
Liver failure is often associated with hepatic encephalopathy, due to dyshomeostasis of the central nervous system (CNS). Under physiological conditions, the CNS homeostasis is precisely regulated by the blood-brain barrier (BBB). The BBB consists of brain microvessel endothelial cells connected with a junctional complex by the adherens junctions and tight junctions. Its main function is to maintain brain homoeostasis via limiting the entry of drugs/toxins to brain. The brain microvessel endothelial cells are characterized by minimal pinocytotic activity, absent fenestrations, and highly expressions of ATP-binding cassette (ABC) family transporters (such as P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated proteins). These ABC transporters prevent brain from toxin accumulation by pumping toxins out of brain. Accumulating evidences demonstrates that liver failure diseases altered the expression and function of ABC transporters at The BBB, indicating that the alterations subsequently affect drugs’ brain distribution and CNS activity/neurotoxicity. ABC transporters also mediate the transport of endogenous substrates across the BBB, inferring that ABC transporters are also implicated in some physiological processes and the development of hepatic encephalopathy. This paper focuses on the alteration in the BBB permeability, the expression and function of ABC transporters at the BBB under liver failure status and their clinical significances.
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Affiliation(s)
- Yilin Fan
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
| | - Xiaodong Liu
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
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Abstract
OBJECTIVES Standard intensive care treatment is inadequate to keep children with liver failure alive without catastrophic complications to ensure successful transplant, as accumulation of endogenous protein-bound toxins often lead to hepatic encephalopathy, hepatorenal syndrome, cardiovascular instability, and multiple organ failure. Given paucity of proven treatment modalities for liver failure, blood purification using different extracorporeal treatments as a bridge to transplantation is used, but studies evaluating the safety and efficacy of combination of these therapies, especially in pediatric liver failure, are lacking. We describe our experience at a major tertiary children's hospital, where a unique hybrid extracorporeal treatment protocol has been instituted and followed for acute liver failure or acute-on-chronic liver failure as a bridge to transplantation. This protocol combines high-flux continuous renal replacement therapy for hyperammonemia, therapeutic plasma exchange for coagulopathy, and albumin-assisted dialysis (molecular adsorbent recirculating system) for hepatic encephalopathy. DESIGN Retrospective observational study. SETTING Freestanding tertiary children's hospital and liver transplant referral center. PATIENTS All patients with acute liver failure/acute-on-chronic liver failure receiving hybrid extracorporeal therapy over 24 months. INTERVENTION Hybdrid extracorporeal therapy. MEASUREMENTS AND MAIN RESULTS Fifteen children (age 3 yr [0.7-9 yr]; 73% male) with acute liver failure/acute-on-chronic liver failure who were either listed or actively considered for listing and met our protocol criteria were treated with hybrid extracorporeal therapy; 93% were ventilated, and 80% were on vasoactive support. Of these, two patients recovered spontaneously, four died prior to transplant, and nine were successfully transplanted; 90-day survival post orthotopic liver transplant was 100%. Overall survival to hospital discharge was 73%. CONCLUSIONS Hybrid extracorporeal therapies can be effectively implemented in pediatric liver failure as a bridge to transplantation. Overall complexity and heavy resource utilization need to be carefully considered in instituting these therapies in suitable candidates.
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Abstract
Purpose of Review Pediatric acute liver failure is a rare, complex, rapidly progressing, and life-threatening illness. Majority of pediatric acute liver failures have unknown etiology. This review intends to discuss the current literature on the challenging aspects of management of acute liver failure. Recent Findings Collaborative multidisciplinary approach for management of patients with pediatric acute liver failure with upfront involvement of transplant hepatologist and critical care specialists can improve outcomes of this fatal disease. Extensive but systematic diagnostic evaluation can help to identify etiology and guide management. Early referral to a transplant center with prompt liver transplant, if indicated, can lead to improved survival in these patients. Summary Prompt identification and aggressive management of pediatric acute liver failure and related comorbidities can lead to increased transplant-free survival and improved post-transplant outcomes, thus decreasing mortality and morbidity associated with this potential fatal condition.
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Affiliation(s)
- Heli Bhatt
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202 USA
| | - Girish S. Rao
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indiana University, 705 Riley Hospital Drive, ROC 4210, Indianapolis, IN 46202 USA
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Carrier P, Loustaud-Ratti V. Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. Fundam Clin Pharmacol 2018; 32:206-208. [DOI: 10.1111/fcp.12353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Paul Carrier
- Hepatology and Gastroenterology Unit; Limoges Teaching Hospital; 2, avenue Martin Luther King 87042 Limoges France
- Faculté de Médecine et de Pharmacie de Limoges; INSERM; UMR-1248; 2, rue Docteur Marcland 87042 Limoges France
- FHU SUPORT (SUrvival oPtimization in ORgan Transplantation); 2, avenue Martin Luther King 87042 Limoges France
| | - Véronique Loustaud-Ratti
- Hepatology and Gastroenterology Unit; Limoges Teaching Hospital; 2, avenue Martin Luther King 87042 Limoges France
- Faculté de Médecine et de Pharmacie de Limoges; INSERM; UMR-1248; 2, rue Docteur Marcland 87042 Limoges France
- FHU SUPORT (SUrvival oPtimization in ORgan Transplantation); 2, avenue Martin Luther King 87042 Limoges France
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Abstract
Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. HE is observed in acute liver failure, liver bypass procedures, for example, shunt surgry and transjugular intrahepatic portosystemic shunt, and cirrhosis. These are classified as Type A, B and C HE, respectively. HE can also be classified according to whether its presence is overt or covert. The pathogenesis is linked with ammonia and glutamine production, and treatment is based on mechanisms to reduce the formation and/or removal of these compounds. There is no specific diagnostic test for HE, and diagnosis is based on clinical suspicion, excluding other causes and use of clinical tests that may support its diagnosis. Many tests are used in trials and experimentally, but have not yet gained universal acceptance. This review focuses on the definitions, pathogenesis and treatment of HE. Consideration will be given to existing treatment, including avoidance of precipitating factors and novel therapies such as prebiotics, probiotics, antibiotics, laxatives, branched-chain amino acids, shunt embolization and the importance of considering liver transplant in appropriate cases.
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Affiliation(s)
| | - Mark Alexander Ellul
- Faculty of Health and Life Sciences, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK
| | - Timothy JS Cross
- Department of Gastroenterology, Royal Liverpool University Hospital
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Abstract
BACKGROUND Minimal Hepatic Encephalopathy (MHE) is characterized by an impairment of social interaction, emotional behavior, sleep disorders, physical and mental symptoms, and diminished Quality of Life (QoL). The aim of our study is evaluating the potential liver health promoting a perspective of Resveratrol (RV) activities and evaluate whether RV treatment may improve health related quality of life (HRQL) and reduce depression and anxiety in patients with MHE. METHODS We evaluated depression using the Beck Depression Inventory test, anxiety with State-trait anxiety inventory test, quality of life through SF-36 test, and ammonia serum levels in 70 MHE patients that were randomized into two groups. RESULTS In the comparison between RV group and placebo group we observed a decrease in Back Depression Inventory (BDI) (p < 0.001), in State-trait anxiety inventory (STAI) (p < 0.001), and improve in physical function (p < 0.001), in role physical (p < 0.05), in body pain (p < 0.05), in general health (p < 0.001), in vitality (p < 0.05), and in social function (p < 0.001). CONCLUSIONS Resveratrol showed efficacy in the treatment of depression, anxiety, and ammonia serum levels, and improved the quality of life Of MHE patients.
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Mancini A, Campagna F, Amodio P, Tuohy KM. Gut : liver : brain axis: the microbial challenge in the hepatic encephalopathy. Food Funct 2018; 9:1373-1388. [PMID: 29485654 DOI: 10.1039/c7fo01528c] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition often associated with acute liver failure or cirrhosis. Advanced liver diseases are characterized by a leaky gut and systemic inflammation. There is strong evidence that the pathogenesis of HE is linked to a dysbiotic gut microbiota and to harmful microbial by-products, such as ammonia, indoles, oxindoles and endotoxins. Increased concentrations of these toxic metabolites together with the inability of the diseased liver to clear such products is thought to play an important patho-ethiological role. Current first line clinical treatments target microbiota dysbiosis by decreasing the counts of pathogenic bacteria, blood endotoxemia and ammonia levels. This review will focus on the role of the gut microbiota and its metabolism in HE and advanced cirrhosis. It will critically assess data from different clinical trials measuring the efficacy of the prebiotic lactulose, the probiotic VSL#3 and the antibiotic rifaximin in treating HE and advanced cirrhosis, through gut microbiota modulation. Additionally data from Randomised Controlled Trials using pre-, pro- and synbiotic will be also considered by reporting meta-analysis studies. The large amount of existing data showed that HE is a clear example of how an altered gut microbiota homeostasis can influence and impact on physiological functions outside the intestine, with implication for host health at the systems level. Nevertheless, a strong effort should be made to increase the information on gut microbiota ecology and its metabolic function in liver diseases and HE.
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Affiliation(s)
- Andrea Mancini
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
| | - Francesca Campagna
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Piero Amodio
- Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy
| | - Kieran M Tuohy
- Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, 38010 San Michele all'Adige, Trento, Italy.
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YILDIZ DENİZ G. SIÇANLARDA KARBON TERAKLORÜR İLE UYARILMIŞ BEYİN HASARINDA Morus nigra’ NIN KORUYUCU MEKANİZMASI. MEHMET AKIF ERSOY ÜNIVERSITESI VETERINER FAKÜLTESI DERGISI 2017. [DOI: 10.24880/maeuvfd.341661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Abstract
Acute on chronic liver failure (ACLF) was first described in 1995 as a clinical syndrome distinct to classic acute decompensation. Characterized by complications of decompensation, ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between 45% and 90%. Despite the clinical relevance of the condition, it still remains largely undefined with continued disagreement regarding its precise etiological factors, clinical course, prognostic criteria and management pathways. It is concerning that, despite our relative lack of understanding of the condition, the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%. This paper highlights our current understanding of ACLF, including its etiology, diagnostic and prognostic criteria and pathophysiology. It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates. The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters, while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF.
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Affiliation(s)
- Azeem Alam
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, SW7 2AZ, UK
| | - Ka Chun Suen
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, SW7 2AZ, UK
| | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, SW7 2AZ, UK
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Hadjihambi A, Arias N, Sheikh M, Jalan R. Hepatic encephalopathy: a critical current review. Hepatol Int 2017; 12:135-147. [PMID: 28770516 PMCID: PMC5830466 DOI: 10.1007/s12072-017-9812-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Accepted: 07/06/2017] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20–30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness.
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Affiliation(s)
- Anna Hadjihambi
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UK
| | - Natalia Arias
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.,INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Mohammed Sheikh
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Division of Medicine, UCL Medical School, Royal Free Hospital, UCL Institute for Liver and Digestive Health, Rowland Hill Street, London, NW3 2PF, UK.
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Paschoal Junior FM, Nogueira RDC, Oliveira MDL, Paschoal EHA, Teixeira MJ, D’Albuquerque LAC, Bor-Seng-Shu E. Cerebral hemodynamic and metabolic changes in fulminant hepatic failure. ARQUIVOS DE NEURO-PSIQUIATRIA 2017; 75:470-476. [DOI: 10.1590/0004-282x20170076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/30/2017] [Indexed: 12/30/2022]
Abstract
ABSTRACT Intracranial hypertension and brain swelling are a major cause of morbidity and mortality of patients suffering from fulminant hepatic failure (FHF). The pathogenesis of these complications has been investigated in man, in experimental models and in isolated cell systems. Currently, the mechanism underlying cerebral edema and intracranial hypertension in the presence of FHF is multi-factorial in etiology and only partially understood. The aim of this paper is to review the pathophysiology of cerebral hemodynamic and metabolism changes in FHF in order to improve understanding of intracranial dynamics complication in FHF.
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36
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Zhang X, Ding J, Gou C, Wen T, Li L, Wang X, Yang H, Liu D, Lou J, Chen D, Ren F, Li X. Qingchangligan formula attenuates the inflammatory response to protect the liver from acute failure induced by d-galactosamine/lipopolysaccharide in mice. JOURNAL OF ETHNOPHARMACOLOGY 2017; 201:108-116. [PMID: 27833028 DOI: 10.1016/j.jep.2016.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 10/26/2016] [Accepted: 11/04/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Qingchangligan formula, a traditional Chinese medicine comprising five herbs, is useful for treatment of patients with liver failure; however, its protective and regulatory mechanisms remain elusive. AIM OF THE STUDY To test the hypothesis that the Qingchangligan formula protects mice against acute liver failure by inhibiting liver inflammation. MATERIALS AND METHODS Acute liver failure (ALF) was induced by intraperitoneal injection of D-GalN (700mg/kg) plus LPS (10μg/kg). The Qingchangligan formula was administered to mice in three doses of 50mg/kg (on day 1, day 2, and day 3) prior to D-GalN/LPS injection by intragastric administration. The mice in different groups were sacrificed at 6h after D-GalN/LPS injection, and liver samples and blood were collected for analysis. RESULTS Administration of the Qingchangligan formula not only ameliorated liver injury, as evidenced by reduced transaminase levels and well-preserved liver architecture, but also decreased the lethality in ALF mice. Moreover, in the ALF model, pretreatment with the Qingchangligan formula alleviated liver inflammation and decreased hepatocyte apoptosis. Further demonstrating the protective effects of the Qingchangligan formula, we found that pretreatment with the Qingchangligan formula reduced the expression of inflammatory cytokines by decreasing the expression of components of the mitogen-activated protein kinase (MAPK) pathway and promoting autophagy in vitro and in vivo. CONCLUSIONS Our findings demonstrated that the Qingchangligan formula exerts a protective effect against the pathophysiology of ALF, especially in regulating liver inflammation, and provide a rationale for using the Qingchangligan formula as a potential therapeutic strategy to ameliorate ALF.
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Affiliation(s)
- Xiangying Zhang
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China; Beijing Institute of Hepatology, Beijing 100069, PR China.
| | - Jianbo Ding
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Chunyan Gou
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Tao Wen
- Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100043, PR China.
| | - Li Li
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Xiaojun Wang
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Huasheng Yang
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Dan Liu
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Jinli Lou
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
| | - Dexi Chen
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China; Beijing Institute of Hepatology, Beijing 100069, PR China.
| | - Feng Ren
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China; Beijing Institute of Hepatology, Beijing 100069, PR China.
| | - Xiuhui Li
- Beijing You-An Hospital, Capital Medical University, Beijing 100069, PR China.
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Mani R, Natesan V, Arumugam R. Neuroprotective effect of chrysin on hyperammonemia mediated neuroinflammatory responses and altered expression of astrocytic protein in the hippocampus. Biomed Pharmacother 2017; 88:762-769. [DOI: 10.1016/j.biopha.2017.01.081] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 01/12/2017] [Accepted: 01/12/2017] [Indexed: 01/19/2023] Open
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Hadjihambi A, De Chiara F, Hosford PS, Habtetion A, Karagiannis A, Davies N, Gourine AV, Jalan R. Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease. Hepatology 2017; 65:1306-1318. [PMID: 28066916 PMCID: PMC5396295 DOI: 10.1002/hep.29031] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/22/2016] [Accepted: 12/23/2016] [Indexed: 12/19/2022]
Abstract
UNLABELLED The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte-neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia-lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia-induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. CONCLUSION The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel-mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306-1318).
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Affiliation(s)
- Anna Hadjihambi
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom,Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Francesco De Chiara
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | - Patrick S. Hosford
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Abeba Habtetion
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | | | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
| | - Alexander V. Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUnited Kingdom
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free HospitalRowland Hill StreetLondonUnited Kingdom
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Jang SY, Chang JY. Pathophysiology and Treatment of Cerebral Edema in Acute Liver Failure. JOURNAL OF NEUROCRITICAL CARE 2016. [DOI: 10.18700/jnc.160088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Patel VC, White H, Støy S, Bajaj JS, Shawcross DL. Clinical science workshop: targeting the gut-liver-brain axis. Metab Brain Dis 2016; 31:1327-1337. [PMID: 26446022 DOI: 10.1007/s11011-015-9743-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 10/02/2015] [Indexed: 02/08/2023]
Abstract
A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that inter-organ ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of therapies that can address both.
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Affiliation(s)
- Vishal C Patel
- Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Helen White
- Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Sidsel Støy
- Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Jasmohan S Bajaj
- McGuire VA Medical Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Debbie L Shawcross
- Institute of Liver Studies, King's College London School of Medicine, King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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Asymmetric Dimethylarginine and Hepatic Encephalopathy: Cause, Effect or Association? Neurochem Res 2016; 42:750-761. [PMID: 27885576 PMCID: PMC5357500 DOI: 10.1007/s11064-016-2111-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 09/07/2016] [Accepted: 11/15/2016] [Indexed: 12/11/2022]
Abstract
The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.
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Affiliation(s)
- Eelco F M Wijdicks
- From the Division of Critical Care Neurology, Mayo Clinic, Rochester, MN
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Bartolić M, Vovk A, Šuput D. Effects of NH 4CL application and removal on astrocytes and endothelial cells. Cell Mol Biol Lett 2016; 21:13. [PMID: 28536616 PMCID: PMC5414667 DOI: 10.1186/s11658-016-0011-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 12/29/2015] [Indexed: 02/07/2023] Open
Abstract
Background Hepatic encephalopathy (HE) is a complex disorder associated with increased ammonia levels in the brain. Although astrocytes are believed to be the principal cells affected in hyperammonemia (HA), endothelial cells (ECs) may also play an important role by contributing to the vasogenic effect of HA. Methods Following acute application and removal of NH4Cl on astrocytes and endothelial cells, we analyzed pH changes, using fluorescence imaging with BCECF/AM, and changes in intracellular Ca2+ concentration ([Ca2+]i), employing fluorescence imaging with Fura-2/AM. Using confocal microscopy, changes in cell volume were observed accompanied by changes of [Ca2+]i in astrocytes and ECs. Results Exposure of astrocytes and ECs to 1 – 20 mM NH4Cl resulted in rapid concentration-dependent alkalinization of cytoplasm followed by slow recovery. Removal of the NH4Cl led to rapid concentration-dependent acidification, again followed by slow recovery. Following the application of NH4Cl, a transient, concentration-dependent rise in [Ca2+]i in astrocytes was observed. This was due to the release of Ca2+ from intracellular stores, since the response was abolished by emptying intracellular stores with thapsigargin and ATP, and was still present in the Ca2+-free bathing solution. The removal of NH4Cl also led to a transient concentration-dependent rise in [Ca2+]i that resulted from Ca2+ release from cytoplasmic proteins, since removing Ca2+ from the bathing solution and emptying intracellular Ca2+ stores did not eliminate the rise. Similar results were obtained from experiments on ECs. Following acute application and removal of NH4Cl no significant changes in astrocyte volume were detected; however, an increase of EC volume was observed after the administration of NH4Cl, and EC shrinkage was demonstrated after the acute removal of NH4Cl. Conclusions This study reveals new data which may give a more complete insight into the mechanism of development and treatment of HE.
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Affiliation(s)
- Miha Bartolić
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia
| | - Andrej Vovk
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia
| | - Dušan Šuput
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, 1000 Ljubljana, Slovenia
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Donnelly MC, Hayes PC, Simpson KJ. Role of inflammation and infection in the pathogenesis of human acute liver failure: Clinical implications for monitoring and therapy. World J Gastroenterol 2016; 22:5958-5970. [PMID: 27468190 PMCID: PMC4948263 DOI: 10.3748/wjg.v22.i26.5958] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Acute liver failure is a rare and devastating clinical condition. At present, emergency liver transplantation is the only life-saving therapy in advanced cases, yet the feasibility of transplantation is affected by the presence of systemic inflammation, infection and resultant multi-organ failure. The importance of immune dysregulation and acquisition of infection in the pathogenesis of acute liver failure and its associated complications is now recognised. In this review we discuss current thinking regarding the role of infection and inflammation in the pathogenesis of and outcome in human acute liver failure, the implications for the management of such patients and suggest directions for future research.
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Sawhney R, Holland-Fischer P, Rosselli M, Mookerjee RP, Agarwal B, Jalan R. Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients. Liver Transpl 2016; 22:732-42. [PMID: 27028317 DOI: 10.1002/lt.24443] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 02/01/2016] [Accepted: 02/20/2016] [Indexed: 12/12/2022]
Abstract
Hepatic encephalopathy (HE) is a common feature of acute-on-chronic liver failure (ACLF). Although ammonia, inflammation, and cerebral oxygenation are associated with HE in acute liver failure, their roles in ACLF are unknown. The aim of this prospective, longitudinal study was to determine the role of these pathophysiological variables in ACLF patients with and without HE. We studied 101 patients with ACLF admitted to the intensive care unit. Severity of ACLF and HE, arterial ammonia, jugular venous oxygen saturation (JVO2 ), white blood cell count (WCC), and C-reactive protein were measured at days 0, 1, 3, and 7. Patients were followed until death or hospital discharge. Mortality was high (51 patients, 50.5%), especially in patients with HE of whom 35 of 53 (66.0%) died regardless of ACLF severity. At baseline, increased WCC and abnormal JVO2 (high or low) were independent predictors of death. Further deterioration in inflammation, JVO2 , and ammonia were also predictive of mortality. JVO2 deviation and hyperammonemia were associated with the presence and severity of HE; improvement in these parameters was associated with a reduction in HE grade. No direct interaction was observed between these variables in regards to mortality or HE. In conclusion, this study describes potential mechanisms of HE in ACLF indicating that ammonia and abnormal cerebral oxygenation are important. The results suggest that ammonia, JVO2 , and WCC are important prognostic biomarkers and therapeutic targets. The relative roles of these pathophysiological factors in the pathogenesis of HE in ACLF or guiding therapy to improve survival requires future study. Liver Transplantation 22 732-742 2016 AASLD.
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Affiliation(s)
- Rohit Sawhney
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Peter Holland-Fischer
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Matteo Rosselli
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Rajeshwar P Mookerjee
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Banwari Agarwal
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK
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Kimoloi S, Rashid K. Potential role of Plasmodium falciparum-derived ammonia in the pathogenesis of cerebral malaria. Front Neurosci 2015; 9:234. [PMID: 26190968 PMCID: PMC4490226 DOI: 10.3389/fnins.2015.00234] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 06/18/2015] [Indexed: 12/19/2022] Open
Abstract
Cerebral malaria (CM) is the most severe complication associated with Plasmodium falciparum infection. The exact pathogenic mechanisms leading to the development of CM remains poorly understood while the mortality rates remain high. Several potential mechanisms including mechanical obstruction of brain microvasculature, inflammation, oxidative stress, cerebral energy defects, and hemostatic dysfunction have been suggested to play a role in CM pathogenesis. However, these proposed mechanisms, even when considered together, do not fully explain the pathogenesis and clinicopathological features of human CM. This necessitates consideration of alternative pathogenic mechanisms. P. falciparum generates substantial amounts of ammonia as a catabolic by-product, but lacks detoxification mechanisms. Whether this parasite-derived ammonia plays a pathogenic role in CM is presently unknown, despite its potential to cause localized brain ammonia elevation and subsequent neurotoxic effects. This article therefore, explores and proposes a potential role of parasite-derived ammonia in the pathogenesis and neuropathology of CM. A consideration of parasite-derived ammonia as a factor in CM pathogenesis provides plausible explanations of the various features observed in CM patients including how a largely intravascular parasite can cause neuronal dysfunction. It also provides a framework for rational development and testing of novel drugs targeting the parasite's ammonia handling.
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Affiliation(s)
- Sammy Kimoloi
- Department of Medical Laboratory Sciences, Masinde Muliro University of Science and Technology Kakamega, Kenya
| | - Khalid Rashid
- Biochemistry and Molecular Biology Department, Egerton University Nakuru, Kenya
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Abstract
The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.
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Affiliation(s)
- Guan-Huei Lee
- Department of Medicine, National University Health System, 1E, Kent Ridge Road, Singapore, 119228, Singapore.
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Affiliation(s)
- Anna Hadjihambi
- Institute for Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free CampusLondonUK
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, Liver Failure Group, University College London Medical School Royal Free CampusLondonUK
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Shawcross DL. Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy? Expert Rev Gastroenterol Hepatol 2015; 9:539-42. [PMID: 25846450 DOI: 10.1586/17474124.2015.1035257] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The development of overt hepatic encephalopathy (HE) in a patient with cirrhosis confers a damning prognosis with a 1-year mortality approaching 64%. This complex neuropsychiatric syndrome arises as a consequence of a dysfunctional gut-liver-brain axis. HE has been largely neglected over the past 30 years, with the reliance on therapies aimed at lowering ammonia production or increasing metabolism following the seminal observation that the hepatic urea cycle is the major mammalian ammonia detoxification pathway and is key in the pathogenesis of HE. The relationship with ammonia is more clear-cut in acute liver failure; but in cirrhosis, it has become apparent that inflammation is a key driver and that a disrupted microbiome resulting in gut dysbiosis, bacterial overgrowth and translocation, systemic endotoxemia and immune dysfunction may be more important drivers. Therefore, it is important to re-focus our efforts into developing therapies that modulate the disrupted microbiome or alleviating its downstream consequences.
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Affiliation(s)
- Debbie L Shawcross
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
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