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Chen YY, Lu ZN, Zhang Q, Zhang YN, Ma WT, Zhang X, Zhang XD, Ni HY, Cheng Y. Longitudinal Evolution of the Brain Microstructure in Cirrhotic Patients on Diffusion Kurtosis Imaging. J Magn Reson Imaging 2025; 61:2310-2320. [PMID: 39485115 DOI: 10.1002/jmri.29648] [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: 04/09/2024] [Revised: 10/10/2024] [Accepted: 10/14/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Although improvement of cognitive function after liver transplantation has been demonstrated in several neuropsychological studies, there is limited research on longitudinal changes in the cirrhotic patients' brain structure before and after transplantation. PURPOSE To investigate longitudinal changes of brain microstructure in cirrhotic patients using diffusion kurtosis imaging (DKI). STUDY TYPE Prospective. SUBJECTS A total of 153 cirrhosis patients, comprising 60 hepatic encephalopathy (HE) patients (16 females/44 males) and 93 no-HE patients (35 females/58 males), along with 93 healthy controls (HCs) (53 females/40 males) were enrolled. Subsequently, 58 recipients completed 1-month postoperative follow-up, 29 patients completed 1-, 3-months, and 17 patients completed 1-, 3-, 6-month follow-up. SEQUENCE Spin-echo single-shot echo-planar sequence using a 3.0 T scanner. ASSESSMENT Diffusion kurtosis estimator software was used to estimate the DKI parameter maps by a MR imaging physicist (Y.-Y.C. with 12 years of experience). STATISTICAL TESTS The diffusion metrics (eg, radial kurtosis [RK], mean kurtosis, fractional anisotropy, mean diffusivity) of the patients before transplantation were compared with those of the HCs using voxel-wise analysis of variance (ANOVA), along with t tests for post hoc analysis. Linear mixed-effects models were applied to the longitudinal data. We imposed a cluster level Family Wise Error (FWE) correction rate of PFWE = 0.05 with voxel-wise cutoff of P = 0.001 together with a cluster-size cutoff of N ≥ 56, and generated smoothness estimates from the preprocessed data using the mixed-model autocorrelation function. RESULTS The RK metrics of the patients decreased significantly in the anterior cingulate cortex (HE/no-HE < HC, ANOVA-F = 21.91). After transplantation, the RK of the pallidum showed a continuous upward trend (time effect T = 11.26); whereas the RK of the right postcentral gyrus showed a continuous downward trend (time effect T = -9.56). In addition, the RK in superior longitudinal fasciculus showed new-onset decrease after transplantation. DATA CONCLUSION Longitudinal changes in DKI metrics reveal the course of brain microstructural changes before and after transplantation in cirrhotic patients, potentially associated with cognitive alterations after surgery. LEVEL OF EVIDENCE 1 TECHNICAL EFFICACY: Stage 4.
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Affiliation(s)
- Yuan-Yuan Chen
- Tianjin International Joint Research Center for Neural Engineering, Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China
| | - Zi-Ning Lu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
- Department of Radiology, Tianjin Institutes of Health Science, Tianjin, China
| | - Qi Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Yi-Ning Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Wen-Ting Ma
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - XiaoDi Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Xiao-Dong Zhang
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Hong-Yan Ni
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
| | - Yue Cheng
- Department of Radiology, Tianjin First Central Hospital, Tianjin, China
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McCabe C, Dennis EL, Lindsey HM, Babikian T, Bickart K, Giza CC, Asarnow RF. Evidence Suggesting Prolonged Neuroinflammation in a Subset of Children after Moderate/Severe TBI: A UCLA RAPBI Study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.20.25320782. [PMID: 39974138 PMCID: PMC11838928 DOI: 10.1101/2025.01.20.25320782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Traumatic brain injury (TBI) presents a public health concern as a leading cause of death and disability in children. Pediatric populations are particularly vulnerable to adverse outcomes following TBI due to periods of rapid growth, synaptic pruning, and myelination. Pediatric patients with moderate-severe TBI (msTBI) and healthy controls were evaluated from the post-acute (2-5 months) to chronic phase (13-19 months) of recovery using diffusion magnetic resonance imaging (dMRI) and interhemispheric transfer time (IHTT), which is an event-related potential measure the speed of information transfer across the corpus callosum. We previously identified two subgroups of patients based on IHTT, with one group showing a significantly slower IHTT (TBI-slow), poorer cognitive performance, and progressive structural damage. In contrast, the other group (TBI-normal) did not differ from controls on IHTT or cognitive performance and showed relative structural recovery over time. Here, we examined group differences in restricted diffusion imaging (RDI), which is a dMRI metric sensitive to inflammation. Comparing TBI-slow, TBI-normal, and controls on RDI cross-sectionally, dMRI connectometry analysis revealed higher RDI across the white matter in the TBI-slow group compared to both the control and TBI-normal groups. Longitudinal analyses indicated that while both TBI groups exhibited a decrease in RDI over time, suggesting resolution of neuroinflammation and recovery, the decreases in the TBI-slow group were smaller. The differences in RDI between TBI-slow and TBI-normal suggest that inflammation may play a key role in the prolonged recovery, including brain structure, cognitive performance, and symptom reports, of pediatric patients with msTBI.
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Affiliation(s)
- Courtney McCabe
- Department of Neurology, University of Utah, Salt Lake City, UT
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT
| | - Emily L Dennis
- Department of Neurology, University of Utah, Salt Lake City, UT
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT
| | - Hannah M Lindsey
- Department of Neurology, University of Utah, Salt Lake City, UT
- George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT
| | - Talin Babikian
- Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine
- UCLA Steve Tisch Brain Sport Program
| | - Kevin Bickart
- UCLA Steve Tisch Brain Sport Program
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
| | - Christopher C Giza
- UCLA Steve Tisch Brain Sport Program
- Department of Neurosurgery, David Geffen School of Medicine at UCLA
- Department of Pediatrics, Division of Neurology, UCLA Mattel Children's Hospital
| | - Robert F Asarnow
- UCLA Steve Tisch Brain Sport Program
- Brain Research Institute, UCLA, Los Angeles, CA
- Department of Psychology, UCLA, Los Angeles, CA
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Wang Y, Yang L, Shang Y, Huang Y, Ju C, Zheng H, Zhao W, Liu J. Identifying Minimal Hepatic Encephalopathy: A New Perspective from Magnetic Resonance Imaging. J Magn Reson Imaging 2025; 61:11-24. [PMID: 38149764 DOI: 10.1002/jmri.29179] [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: 07/20/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/28/2023] Open
Abstract
Type C hepatic encephalopathy (HE) is a condition characterized by brain dysfunction caused by liver insufficiency and/or portal-systemic blood shunting, which manifests as a broad spectrum of neurological or psychiatric abnormalities, ranging from minimal HE (MHE), detectable only by neuropsychological or neurophysiological assessment, to coma. Though MHE is the subclinical phase of HE, it is highly prevalent in cirrhotic patients and strongly associated with poor quality of life, high risk of overt HE, and mortality. It is, therefore, critical to identify MHE at the earliest and timely intervene, thereby minimizing the subsequent complications and costs. However, proper and sensitive diagnosis of MHE is hampered by its unnoticeable symptoms and the absence of standard diagnostic criteria. A variety of neuropsychological or neurophysiological tests have been performed to diagnose MHE. However, these tests are nonspecific and susceptible to multiple factors (eg, aging, education), thereby limiting their application in clinical practice. Thus, developing an objective, effective, and noninvasive method is imperative to help detect MHE. Magnetic resonance imaging (MRI), a noninvasive technique which can produce many objective biomarkers by different imaging sequences (eg, Magnetic resonance spectroscopy, DWI, rs-MRI, and arterial spin labeling), has recently shown the ability to screen MHE from NHE (non-HE) patients accurately. As advanced MRI techniques continue to emerge, more minor changes in the brain could be captured, providing new means for early diagnosis and quantitative assessment of MHE. In addition, the advancement of artificial intelligence in medical imaging also presents the potential to mine more effective diagnostic biomarkers and further improves the predictive efficiency of MHE. Taken together, advanced MRI techniques may provide a new perspective for us to identify MHE in the future. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Yisong Wang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Longtao Yang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Youlan Shang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yijie Huang
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Chao Ju
- Department of Radiology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Hairong Zheng
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Wei Zhao
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Clinical Research Center for Medical Imaging in Hunan Province, Changsha, China
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Medical Imaging in Hunan Province, Changsha, China
- Department of Radiology Quality Control Center in Hunan Province, Changsha, China
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Mosso J, Briand G, Pierzchala K, Simicic D, Sierra A, Abdollahzadeh A, Jelescu IO, Cudalbu C. Diffusion of brain metabolites highlights altered brain microstructure in type C hepatic encephalopathy: a 9.4 T preliminary study. Front Neurosci 2024; 18:1344076. [PMID: 38572151 PMCID: PMC10987698 DOI: 10.3389/fnins.2024.1344076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/19/2024] [Indexed: 04/05/2024] Open
Abstract
Introduction Type C hepatic encephalopathy (HE) is a decompensating event of chronic liver disease leading to severe motor and cognitive impairment. The progression of type C HE is associated with changes in brain metabolite concentrations measured by 1H magnetic resonance spectroscopy (MRS), most noticeably a strong increase in glutamine to detoxify brain ammonia. In addition, alterations of brain cellular architecture have been measured ex vivo by histology in a rat model of type C HE. The aim of this study was to assess the potential of diffusion-weighted MRS (dMRS) for probing these cellular shape alterations in vivo by monitoring the diffusion properties of the major brain metabolites. Methods The bile duct-ligated (BDL) rat model of type C HE was used. Five animals were scanned before surgery and 6- to 7-week post-BDL surgery, with each animal being used as its own control. 1H-MRS was performed in the hippocampus (SPECIAL, TE = 2.8 ms) and dMRS in a voxel encompassing the entire brain (DW-STEAM, TE = 15 ms, diffusion time = 120 ms, maximum b-value = 25 ms/μm2) on a 9.4 T scanner. The in vivo MRS acquisitions were further validated with histological measures (immunohistochemistry, Golgi-Cox, electron microscopy). Results The characteristic 1H-MRS pattern of type C HE, i.e., a gradual increase of brain glutamine and a decrease of the main organic osmolytes, was observed in the hippocampus of BDL rats. Overall increased metabolite diffusivities (apparent diffusion coefficient and intra-stick diffusivity-Callaghan's model, significant for glutamine, myo-inositol, and taurine) and decreased kurtosis coefficients were observed in BDL rats compared to control, highlighting the presence of osmotic stress and possibly of astrocytic and neuronal alterations. These results were consistent with the microstructure depicted by histology and represented by a decline in dendritic spines density in neurons, a shortening and decreased number of astrocytic processes, and extracellular edema. Discussion dMRS enables non-invasive and longitudinal monitoring of the diffusion behavior of brain metabolites, reflecting in the present study the globally altered brain microstructure in BDL rats, as confirmed ex vivo by histology. These findings give new insights into metabolic and microstructural abnormalities associated with high brain glutamine and its consequences in type C HE.
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Affiliation(s)
- Jessie Mosso
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Guillaume Briand
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Katarzyna Pierzchala
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Dunja Simicic
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Alejandra Sierra
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ali Abdollahzadeh
- Center for Biomedical Imaging, Department of Radiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Ileana O. Jelescu
- Department of Radiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Cristina Cudalbu
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland
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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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Zahr N, Sullivan E, Pfefferbaum A. [WITHDRAWN] Serum biomarkers of liver fibrosis identify changes in striatal metabolite levels. RESEARCH SQUARE 2024:rs.3.rs-2729490. [PMID: 37034697 PMCID: PMC10081358 DOI: 10.21203/rs.3.rs-2729490/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.
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Mittal S, Bhardwaj M, Shekhrajka P, Goyal VK, Nimje GR, Kanoji S, Danduri SK, Vishnoi A. An overview of unresolved issues in the perioperative management of liver transplant patients. KOREAN JOURNAL OF TRANSPLANTATION 2023; 37:221-228. [PMID: 38115164 PMCID: PMC10772275 DOI: 10.4285/kjt.23.0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/20/2023] [Accepted: 11/21/2023] [Indexed: 12/21/2023] Open
Abstract
Over the past decade, the field of solid organ transplantation has undergone significant changes, with some of the most notable advancements occurring in liver transplantation. Recent years have seen substantial progress in preoperative patient optimization protocols, anesthesia monitoring, coagulation management, and fluid management, among other areas. These improvements have led to excellent perioperative outcomes for all surgical patients, including those undergoing liver transplantation. In the last few decades, there have been numerous publications in the field of liver transplantation, but controversies related to perioperative management of liver transplant recipients persist. In this review article, we address the unresolved issues surrounding the anesthetic management of patients scheduled for liver transplantation.
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Affiliation(s)
- Saurabh Mittal
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Medha Bhardwaj
- Department of Neuro-Anaesthesia, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | | | - Vipin Kumar Goyal
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Ganesh Ramaji Nimje
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Sakshi Kanoji
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Suma Katyaeni Danduri
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
| | - Anshul Vishnoi
- Department of Organ Transplant Anaesthesiology and Critical Care, Mahatma Gandhi Medical College and Hospital, Jaipur, India
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Amer K, Flikshteyn B, Lingiah V, Tafesh Z, Pyrsopoulos NT. Mechanisms of Disease and Multisystemic Involvement. Clin Liver Dis 2023; 27:563-579. [PMID: 37380283 DOI: 10.1016/j.cld.2023.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Affiliation(s)
- Kamal Amer
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Ben Flikshteyn
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Vivek Lingiah
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 538, Newark, NJ 07101-1709, USA
| | - Zaid Tafesh
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 53, Newark, NJ 07101-1709, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers University, 185 South Orange Avenue, MSB H Room - 536, Newark, NJ 07101-1709, USA.
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Ng YL, Tan CS, Egle M, Gyanwali B, Tozer DJ, Markus HS, Chen C, Hilal S. The association of diffusion tensor MRI measures of normal appearing white matter and cognition. CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2023; 5:100174. [PMID: 37457665 PMCID: PMC10344700 DOI: 10.1016/j.cccb.2023.100174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/29/2023] [Accepted: 07/01/2023] [Indexed: 07/18/2023]
Abstract
Objective Median and peak height of fractional anisotropy (FA) and mean diffusivity (MD) are diffusion tensor imaging (DTI) markers used to quantify white matter microstructure changes. We examine the association of DTI histogram-derived measures in global normal appearing white matter (NAWM) and cognitive decline in patients with normal cognition and cognitive impairment no dementia from a memory clinic in Singapore. Methods A total of 252 patients (mean age: 71.1 ± 7.6 years, 53.2% women) were included. All patients underwent clinical assessments, a brain MRI scan at baseline, and neuropsychological assessments annually for 2 years. DTI scans were processed to obtain MD and FA histogram-derived measures. The National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network harmonization neuropsychological battery were used to assess cognitive function. Linear regression models with generalised estimating equation (GEE) and logistic regression models were used to examine the association between DTI histogram measures and cognitive decline. Results When compared to baseline, MD and FA measures at Year 2 were associated with an accelerated worsening in global cognition (all p for interaction <0.001; Year 0 vs 2, MD median: -0.29 (95%CI: -0.49, -0.09) vs -0.45 (95%CI: -0.65,-0.25); MD peak height: 0.22 (95%CI: 0.07, 0.37) vs 0.37 (95%CI: 0.21, 0.53); FA median: 0.11 (95%CI: -0.05, 0.26) vs 0.22 (95%CI: 0.07, 0.37); FA peak height: -0.14 (95%CI: -0.28, 0.00) vs -0.24 (95%CI: -0.38, -0.10);). Similar findings were observed for executive function and visuomotor speed while only MD measures predicted worsening in memory domain. Interpretation This study shows that DTI histogram measures are associated with accelerated cognitive decline suggesting the utility of DTI as a pre-clinical marker in predicting the worsening of cognition in clinical trials.
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Affiliation(s)
- Yi Lin Ng
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Chuen Seng Tan
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
| | - Marco Egle
- Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, Cambridge, United Kingdom
| | - Bibek Gyanwali
- Memory Aging and Cognition Centre, National University Health System, Singapore
| | - Daniel J. Tozer
- Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, Cambridge, United Kingdom
| | - Hugh S. Markus
- Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, Cambridge, United Kingdom
| | - Christopher Chen
- Memory Aging and Cognition Centre, National University Health System, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Saima Hilal
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore
- Memory Aging and Cognition Centre, National University Health System, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Mendoza Vasquez LE, Payne S, Zamper R. Intracranial pressure monitoring in the perioperative period of patients with acute liver failure undergoing orthotopic liver transplantation. World J Transplant 2023; 13:122-128. [PMID: 37388394 PMCID: PMC10303411 DOI: 10.5500/wjt.v13.i4.122] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/28/2023] [Accepted: 04/12/2023] [Indexed: 06/16/2023] Open
Abstract
Acute liver failure (ALF) may result in severe neurological complications caused by cerebral edema and elevated intracranial pressure (ICP). Multiple pathogenic mechanisms explain the elevated ICP, and newer hypotheses have been descri bed. While invasive ICP monitoring (ICPM) may have a role in ALF management, these patients are typically coagulopathic and at risk for intracranial hemorrhage. ICPM is the subject of much debate, and significant heterogeneity exists in clinical practice regarding its use. Contemporary ICPM techniques and coagulopathy reversal strategies may be associated with a lower risk of hemor rhage; however, most of the evidence is limited by its retrospective nature and relatively small sample size.
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Affiliation(s)
- Luis Eduardo Mendoza Vasquez
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
| | - Sonja Payne
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
| | - Raffael Zamper
- Department of Anesthesia and Perioperative Medicine, London Health Science Centre, London N6A 5A5, Ontario, Canada
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Hu SH, Feng YY, Yang YX, Ma HD, Zhou SX, Qiao YN, Zhang KH, Zhang L, Huang L, Yuan YY, Lin Y, Zhang XY, Li Y, Li HT, Zhao JY, Xu W, Zhao SM. Amino acids downregulate SIRT4 to detoxify ammonia through the urea cycle. Nat Metab 2023; 5:626-641. [PMID: 37081161 DOI: 10.1038/s42255-023-00784-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Accepted: 03/10/2023] [Indexed: 04/22/2023]
Abstract
Ammonia production via glutamate dehydrogenase is inhibited by SIRT4, a sirtuin that displays both amidase and non-amidase activities. The processes underlying the regulation of ammonia removal by amino acids remain unclear. Here, we report that SIRT4 acts as a decarbamylase that responds to amino acid sufficiency and regulates ammonia removal. Amino acids promote lysine 307 carbamylation (OTCCP-K307) of ornithine transcarbamylase (OTC), which activates OTC and the urea cycle. Proteomic and interactome screening identified OTC as a substrate of SIRT4. SIRT4 decarbamylates OTCCP-K307 and inactivates OTC in an NAD+-dependent manner. SIRT4 expression was transcriptionally upregulated by the amino acid insufficiency-activated GCN2-eIF2α-ATF4 axis. SIRT4 knockout in cultured cells caused higher OTCCP-K307 levels, activated OTC, elevated urea cycle intermediates and urea production via amino acid catabolism. Sirt4 ablation decreased male mouse blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes. We reveal that SIRT4 safeguards cellular ammonia toxicity during amino acid catabolism.
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Affiliation(s)
- Song-Hua Hu
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Yu-Yang Feng
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China
| | - Yuan-Xin Yang
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Hui-Da Ma
- MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Centre for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Shu-Xian Zhou
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Ya-Nan Qiao
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Kai-Hui Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Lei Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Lin Huang
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Yi-Yuan Yuan
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Yan Lin
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China
| | - Xin-Yan Zhang
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China
| | - Yao Li
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China
| | - Hai-Tao Li
- MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Centre for Life Sciences, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Jian-Yuan Zhao
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China.
| | - Wei Xu
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China.
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China.
| | - Shi-Min Zhao
- The Obstetrics & Gynecology Hospital of Fudan University, Shanghai Key Laboratory of Metabolic Remodelling and Health, State Key Laboratory of Genetic Engineering, and Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China.
- Key Laboratory for Tibet Plateau Phytochemistry of Qinghai Province, College of Pharmacy, Qinghai University for Nationalities, Xining, China.
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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13
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Vidal-Cevallos P, Chávez-Tapia NC, Uribe M. Current approaches to hepatic encephalopathy. Ann Hepatol 2022; 27:100757. [PMID: 36115576 DOI: 10.1016/j.aohep.2022.100757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/07/2022] [Indexed: 02/04/2023]
Abstract
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%-40% of patients with cirrhosis will present overt HE during their lifetime. While the pathophysiology of HE is not entirely understood, three critical factors have been identified: hyperammonaemia, systemic inflammation and oxidative stress by glutaminase gene alterations. Minimal HE is defined by the presence of signs of cognitive abnormalities in a patient without asterixis or disorientation; it can only be diagnosed with neuropsychological or psychometric tests. The diagnosis of overt HE is based on clinical examination with clinical scales. Currently, only overt HE should be routinely treated. The aims of treatment in an acute episode should be to improve the mental status, identify and treat the precipitating factor, reduce duration and limit consequences. Treatment strategies are targeted at reducing ammonia production and/or increasing its elimination. Even though minimal HE has negative effects on the patient's quality of life and effects on prognosis, indications for treatment are still controversial. There are still many unanswered questions regarding the pathophysiology and management of HE. We should also endeavor to develop more accurate and objective diagnostic methods for overt HE that would permit early detection and help improve outcomes on quality of life and economic burden.
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Affiliation(s)
- Paulina Vidal-Cevallos
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico
| | - Norberto C Chávez-Tapia
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Disease Unit, Medica Sur Clinic and Foundation, Puente de Piedra 150, col. Toriello Guerra, C.P. 14050, Mexico City, Mexico.
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14
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The current pediatric perspective on type B and C hepatic encephalopathy. Anal Biochem 2022; 643:114576. [DOI: 10.1016/j.ab.2022.114576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 01/23/2022] [Indexed: 11/20/2022]
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Orzeł-Gajowik K, Milewski K, Zielińska M. Insight into microRNAs-Mediated Communication between Liver and Brain: A Possible Approach for Understanding Acute Liver Failure? Int J Mol Sci 2021; 23:224. [PMID: 35008650 PMCID: PMC8745738 DOI: 10.3390/ijms23010224] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 01/11/2023] Open
Abstract
Acute liver failure (ALF) is a life-threatening consequence of hepatic function rapid loss without preexisting liver disease. ALF may result in a spectrum of neuropsychiatric symptoms that encompasses cognitive impairment, coma, and often death, collectively defined as acute hepatic encephalopathy. Micro RNAs are small non-coding RNAs that modulate gene expression and are extensively verified as biomarker candidates in various diseases. Our systematic literature review based on the last decade's reports involving a total of 852 ALF patients, determined 205 altered circulating miRNAs, of which 25 miRNAs were altered in the blood, regardless of study design and methodology. Selected 25 miRNAs, emerging predominantly from the analyses of samples obtained from acetaminophen overdosed patients, represent the most promising biomarker candidates for a diagnostic panel for symptomatic ALF. We discussed the role of selected miRNAs in the context of tissue-specific origin and its possible regulatory role for molecular pathways involved in blood-brain barrier function. The defined several common pathways for 15 differently altered miRNAs were relevant to cellular community processes, indicating loss of intercellular, structural, and functional components, which may result in blood-brain barrier impairment and brain dysfunction. However, a causational relationship between circulating miRNAs differential expression, and particular clinical features of ALF, has to be demonstrated in a further study.
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Affiliation(s)
| | | | - Magdalena Zielińska
- Department of Neurotoxicology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawińskiego Str., 02-106 Warsaw, Poland; (K.O.-G.); (K.M.)
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Li Y, Ju S, Li X, Zhou YL, Qiang JW. Prediction of minimal hepatic encephalopathy by using an radiomics nomogram in chronic hepatic schistosomiasis patients. PLoS Negl Trop Dis 2021; 15:e0009834. [PMID: 34653175 PMCID: PMC8550421 DOI: 10.1371/journal.pntd.0009834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 10/27/2021] [Accepted: 09/23/2021] [Indexed: 01/04/2023] Open
Abstract
Objective To construct an MR-radiomics nomogram to predict minimal hepatic encephalopathy (MHE) in patients with chronic hepatic schistosomiasis (CHS). Methods From July 2017 to July 2020, 236 CHS patients with non-HE (n = 140) and MHE (n = 96) were retrospective collected and randomly divided into training group and testing group. Radiomics features were extracted from substantia nigra-striatum system of a brain diffusion weighted images (DWI) and combined with clinical predictors to build a radiomics nomogram for predicting MHE in CHS patients. The ROC curve was used to evaluate the predicting performance in training group and testing group. The clinical decisive curve (CDC) was used to assess the clinical net benefit of using radiomics nomogram in predicting MHE. Results Low seralbumin (P < 0.05), low platelet count (P < 0.05) and high plasma ammonia (P < 0.05) was the significant clinical predictors for MHE in CHS patients. The AUC, specificity and sensitivity of the radiomics nomogram were 0.89, 0.90 and 0.86 in the training group, and were 0.83, 0.85 and 0.75 in the training group. The CDC analysis showed clinical net benefits for the radiomics nomogram in predicting MHE. Conclusions The radiomics nomogram combining DWI radiomics features and clinical predictors could be useful tool to predict MHE in CHS patients. Minimal hepatic encephalopathy (MHE) is usually neglected clinically in chronic hepatic schistosomiasis (CHS) patients. The diffusion change in substantia nigra-striatum system of MHE patients has been reported. We hypothesized that the change could be better detected by DWI-based radiomics. A radiomics nomogram combining radiomics and clinical predictors of MHE was built to predict MHE in CHS patients. The results demonstrate that the radiomics nomogram would be useful for predicting MHE in CHS patients.
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Affiliation(s)
- Ying Li
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Shuai Ju
- Department of Intervention Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Xin Li
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yan Li Zhou
- Department of Nuclear medicine, Jinshan Hospital, Fudan University, Shanghai, China
| | - Jin Wei Qiang
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
- * E-mail:
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Aneja A, Scott E, Kohli R. Advances in management of end stage liver disease in children. Med J Armed Forces India 2021; 77:129-137. [PMID: 33867627 DOI: 10.1016/j.mjafi.2021.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023] Open
Abstract
End stage liver disease (ESLD) is an irreversible condition that is a management challenge to the paediatrician. The aetiology and natural history of ESLD in children is not only distinct from adults but also variable depending upon the age of presentation. Children are especially vulnerable to developmental delay, frailty and malnutrition. Nutritional support is the cornerstone of management of these children as it has a significant impact on the clinical course and survival, both before and after transplantation. Further, the complications of ESLD in children including but not limited to, ascites, portal hypertension, spontaneous bacterial peritonitis and encephalopathy raise unique management challenges. In this review we provide a concise review of and highlight recent advances in the management of paediatric ESLD.
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Affiliation(s)
- Aradhana Aneja
- Classified Specialist (Pediatrics) & Pediatric Gastroenterologist, Army Hospital (R&R), New Delhi, India
| | - Elizabeth Scott
- Transplant Dietitian, Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA, USA
| | - Rohit Kohli
- Head of Division, Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA, USA
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Perticone M, Di Lorenzo C, Arabia G, Arturi F, Caroleo B, Tassone B, Pujia R, Fiorentino TV, Chiriaco C, Sesti G, Quattrone A, Perticone F. One Hour-Post-load Plasma Glucose ≥155 mg/dl in Healthy Glucose Normotolerant Subjects Is Associated With Subcortical Brain MRI Alterations and Impaired Cognition: A Pilot Study. Front Aging Neurosci 2021; 13:608736. [PMID: 33613266 PMCID: PMC7891177 DOI: 10.3389/fnagi.2021.608736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 01/07/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Glucose alterations are associated with impaired cognition. The 1-h-post-load plasma glucose ≥155 mg/dl in non-diabetic subjects confers an increased risk of cardiovascular events and diabetes. This pilot study aimed to investigate whether the 1-h-post-load plasma glucose ≥155 mg/dl negatively affects the subcortical regions of the brain and the cognitive functions. Methods: We enrolled 32 non-diabetic subjects. Patients were divided into two groups based on 1-h- post-load plasma glucose value > or < 155 mg/dl: normal glucose tolerance (NGT) 1-h-high and NGT 1-h-low subjects. All subjects underwent 3 Tesla MRI and standard neuropsychological tests. Results: NGT 1-h-high subjects showed significantly lower values of both right (4.9 ± 0.9 vs. 5.1 ± 0.9 ml) and left (4.8 ± 1.1 vs. 5.1 ± 1.1 ml) hippocampal hemisphere volume, while right hemisphere hippocampal diffusivity was lower in the NGT 1-h-high group (10.0 ± 0.6 vs. 10.6 ± 0.5 10-4 mm2s-1). NGT 1-h-high subjects also showed a poorer memory performance. In particular, for both Rey Auditory Verbal Learning Task (RAVLT)-immediate-recall and Free and Cued Selective Reminding Test (FCSRT)-delayed total recall, we found lower cognitive test scores in the NGT-1 h-high group (26.5 ± 6.3 and 10.4 ± 0.3, respectively). Conclusions: One-hour-post-load hyperglycemia is associated with morpho-functional subcortical brain alterations and poor memory performance tests.
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Affiliation(s)
- Maria Perticone
- Geriatrics Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Cherubino Di Lorenzo
- Department of Medico-Surgical Sciences and Biotechnologies, La Sapienza University Polo Pontino, Latina, Italy
| | - Gennarina Arabia
- Neurology Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Franco Arturi
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Benedetto Caroleo
- Geriatric Division, Azienda Ospedaliero-Universitaria Mater Domini, Catanzaro, Italy
| | - Bruno Tassone
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Roberta Pujia
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Teresa Vanessa Fiorentino
- Internal Medicine Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Carmelina Chiriaco
- Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, La Sapienza University, Rome, Italy
| | - Aldo Quattrone
- Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy
| | - Francesco Perticone
- Geriatrics Division, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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Chiriac S, Stanciu C, Cojocariu C, Singeap AM, Sfarti C, Cuciureanu T, Girleanu I, Igna RA, Trifan A. Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure. World J Clin Cases 2021; 9:552-564. [PMID: 33553393 PMCID: PMC7829715 DOI: 10.12998/wjcc.v9.i3.552] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/02/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High venous ammonia (VA) values have been proven to be a part of the mechanism of hepatic encephalopathy in patients with liver cirrhosis (LC) as well as acute hepatitis. Moreover, VA has been associated with poor prognosis and high mortality in these clinical settings. However, the role of ammonia in acute-on-chronic liver failure (ACLF) has not yet been clearly established. AIM To assess the role of VA in predicting the outcome of cirrhotic patients with ACLF in a tertiary care center. METHODS We performed a retrospective observational study including consecutive patients with LC hospitalized for acute non-elective indications such as ascites, hepatic encephalopathy (HE), upper gastrointestinal bleeding, or bacterial infections that fulfilled the Asian Pacific Association for the Study of the Liver (APASL) criteria for ACLF. The study was conducted in "St. Spiridon" University Hospital, Iasi, Romania, a tertiary care center, between January 2017 and January 2019. The APASL ACLF Research Consortium (AARC) score was calculated and ACLF grade was established accordingly. West-haven classification was used for HE. Statistical analysis was performed using IBM SPSS version 22.0. RESULTS Four hundred and forty-six patients were included, aged 59 (50-65) years, 57.4% men. Child-Pugh, model for end-stage liver disease (MELD) and AARC scores were 11 (10-12), 19.13 ± 6.79, and 7 (6-8), respectively. 66.4% had ACLF grade I, 31.2% ACLF grade II, and 2.5% ACLF grade III. HE was diagnosed in 83.9%, 34% grade I, 37.2% grade II, 23.5% grade III, and 5.3% grade IV. Overall mortality was 7.8%. VA was 103 (78-148) μmol/L. Receiver operating characteristic analysis showed good accuracy for the prediction of in-hospital mortality for the AARC score [Area under the curve (AUC) = 0.886], MELD score (AUC = 0.816), VA (AUC = 0.812) and a fair accuracy for the Child-Pugh score (AUC = 0.799). Subsequently, a cut-off value for the prediction of mortality was identified for VA (152.5 μmol/L, sensitivity = 0.706, 1-specificity = 0.190). Univariate analysis found acute kidney injury, severe HE (grade III or IV), VA ≥ 152.5 μmol/L, MELD score ≥ 22.5, Child-Pugh score ≥ 12.5, and AARC score ≥ 8.5 to be associated with in-hospital mortality. Multivariate analysis identified AARC score ≥ 8.5 and venous ammonia ≥ 152 μmol/L to be independent predictors of in-hospital mortality. CONCLUSION VA could be used as an inexpensive predictor of in-hospital mortality in patients with ACLF. Patients with both ACLF and VA > 152.5 μmol/L have a high risk for a poor outcome.
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Affiliation(s)
- Stefan Chiriac
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Carol Stanciu
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Camelia Cojocariu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Catalin Sfarti
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Tudor Cuciureanu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Irina Girleanu
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
| | - Razvan Alexandru Igna
- Intensive Care, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Anca Trifan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
- Institute of Gastroenterology and Hepatology, "St. Spiridon" Emergency Hospital, Iasi 700111, Romania
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Characterization of brain microstructural abnormalities in cirrhotic patients without overt hepatic encephalopathy using diffusion kurtosis imaging. Brain Imaging Behav 2021; 14:627-638. [PMID: 31538276 PMCID: PMC7160080 DOI: 10.1007/s11682-019-00141-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cirrhosis is a major public health concern. However, little is known about the neurobiological mechanisms underlying brain microstructure alterations in cirrhotic patients. The purpose of this prospective study was to investigate brain microstructural alterations in cirrhosis with or without minimal hepatic encephalopathy (MHE) and their relationship with patients’ neurocognitive performance and disease duration using voxel-based analysis of diffusion kurtosis imaging (DKI). DKI data were acquired from 30 cirrhotic patients with MHE, 31 patients without MHE (NMHE) and 59 healthy controls. All DKI-derived parametric maps were compared across the three groups to investigate their group differences. Correlation analyses were further performed to assess relationships between altered imaging parameters and clinical data. Voxel-based analysis of DKI data results showed that MHE/NMHE patients had increased radial diffusivity, axial diffusivity (AD) and mean diffusivity in addition to decreased axial kurtosis (AK) and fractional anisotropy of kurtosis in several regions. Compared to controls, these regions were primarily the cingulum, temporal and frontal cortices. The DKI metrics (i.e., AK and AD) were correlated with clinical variables in the two patient groups. In conclusion, DKI is useful for detecting brain microstructural abnormalities in MHE and NMHE patients. Abnormal DKI parameters suggest alterations in brain microstructural complexity in cirrhotic patients, which may contribute to the neurobiological basis of neurocognitive impairment. These results may provide additional information on the pathophysiology of cirrhosis.
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Laguna de la Vera AL, Welsch C, Pfeilschifter W, Trebicka J. Gut–liver–brain axis in chronic liver disease with a focus on hepatic encephalopathy. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:159-185. [DOI: 10.1016/b978-0-12-821927-0.00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Han W, Zhang H, Han Y, Duan Z. Cognition-tracking-based strategies for diagnosis and treatment of minimal hepatic encephalopathy. Metab Brain Dis 2020; 35:869-881. [PMID: 32495311 PMCID: PMC7354280 DOI: 10.1007/s11011-020-00539-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 01/23/2020] [Indexed: 12/11/2022]
Abstract
Minimal hepatic encephalopathy (MHE), which shows mild cognitive impairment, is a subtle complication of cirrhosis that has been shown to affect daily functioning and quality of life. However, until 2014, relevant guidelines do not give much attention to the diagnosis and treatment of MHE, resulting in patients being ignored and denied the benefits of treatment. In this review, we summarize recent cognition-based research about (1) alteration of nerve cells, including astrocytes, microglial cells and neurons, in mild cognitive impairment in MHE; (2) comparison of methods in detecting cognitive impairment in MHE; and (3) comparison of methods for therapy of cognitive impairment in MHE. We hope to provide information about diagnosis and treatment of cognitive impairment in patients with MHE.
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Affiliation(s)
- Weijia Han
- Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Huanqian Zhang
- Yidu Central Hospital of Weifang Medical College, Shandong, China
| | - Ying Han
- Department of Immunologic Liver Disease, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhongping Duan
- Difficult & Complicated Liver Diseases and Artificial Liver Center, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China.
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Tran TT, Wei K, Cole S, Mena E, Csete M, King KS. Brain MR Spectroscopy Markers of Encephalopathy Due to Nonalcoholic Steatohepatitis. J Neuroimaging 2020; 30:697-703. [PMID: 32705733 DOI: 10.1111/jon.12728] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/22/2020] [Accepted: 05/06/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin. METHODS We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons. RESULTS Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively). CONCLUSION Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE.
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Affiliation(s)
| | - Ke Wei
- HMRI Imaging Center, Pasadena, CA
| | | | - Edward Mena
- California Liver Research Institute, Pasadena, CA
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24
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Karanfilian BV, Cheung M, Dellatore P, Park T, Rustgi VK. Laboratory Abnormalities of Hepatic Encephalopathy. Clin Liver Dis 2020; 24:197-208. [PMID: 32245527 DOI: 10.1016/j.cld.2020.01.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Currently, there is no gold standard serologic or imaging modality to detect hepatic encephalopathy (HE). It is a clinical diagnosis gathered from the history and physical. Imaging is nonspecific; however, PET and MRI have shown areas of utility, but are not widely available, cost-efficient, or necessary for diagnosis. Electroencephalogram has shown promise as it can be used in conjunction with the Portal Systemic Hepatic Encephalopathy Score test to diagnose minimal HE. Further research on these techniques would need to be performed to identify strict criteria and cutoffs for diagnosing HE as well as associated sensitivities and specificities.
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Affiliation(s)
- Briette Verken Karanfilian
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Maggie Cheung
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Peter Dellatore
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Taeyang Park
- Department of Internal Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Department of Medicine, 125 Paterson Street, New Brunswick, NJ 08901, USA
| | - Vinod K Rustgi
- Department Gastroenterology and Hepatology, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street, Suite 5100B, New Brunswick, NJ 08901, USA.
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25
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Liotta EM, Kimberly WT. Cerebral edema and liver disease: Classic perspectives and contemporary hypotheses on mechanism. Neurosci Lett 2020; 721:134818. [PMID: 32035166 DOI: 10.1016/j.neulet.2020.134818] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 02/01/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
Liver disease is a growing public health concern. Hepatic encephalopathy, the syndrome of brain dysfunction secondary to liver disease, is a frequent complication of both acute and chronic liver disease and cerebral edema (CE) is a key feature. While altered ammonia metabolism is a key contributor to hepatic encephalopathy and CE in liver disease, there is a growing appreciation that additional mechanisms contribute to CE. In this review we will begin by presenting three classic perspectives that form a foundation for a discussion of CE in liver disease: 1) CE is unique to acute liver failure, 2) CE in liver disease is only cytotoxic, and 3) CE in liver disease is primarily an osmotically mediated consequence of ammonia and glutamine metabolism. We will present each classic perspective along with more recent observations that call in to question that classic perspective. After highlighting these areas of debate, we will explore the leading contemporary mechanisms hypothesized to contribute to CE during liver disease.
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Affiliation(s)
- Eric M Liotta
- Northwestern University-Feinberg School of Medicine, Department of Neurology, United States; Northwestern University-Feinberg School of Medicine, Department of Surgery, Division of Organ Transplantation, United States; Northwestern University Transplant Outcomes Research Collaboration, United States.
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26
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Langnes E, Sneve MH, Sederevicius D, Amlien IK, Walhovd KB, Fjell AM. Anterior and posterior hippocampus macro‐ and microstructure across the lifespan in relation to memory—A longitudinal study. Hippocampus 2020; 30:678-692. [DOI: 10.1002/hipo.23189] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Espen Langnes
- Center for Lifespan Changes in Brain and CognitionUniversity of Oslo Norway
| | - Markus H. Sneve
- Center for Lifespan Changes in Brain and CognitionUniversity of Oslo Norway
| | | | - Inge K. Amlien
- Center for Lifespan Changes in Brain and CognitionUniversity of Oslo Norway
| | - Kristine B. Walhovd
- Center for Lifespan Changes in Brain and CognitionUniversity of Oslo Norway
- Department of Radiology and Nuclear MedicineOslo University Hospital Oslo Norway
| | - Anders M. Fjell
- Center for Lifespan Changes in Brain and CognitionUniversity of Oslo Norway
- Department of Radiology and Nuclear MedicineOslo University Hospital Oslo Norway
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27
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Coronel-Castillo C, Contreras-Carmona J, Frati-Munari A, Uribe M, Méndez-Sánchez N. Efficacy of rifaximin in the different clinical scenarios of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2020. [DOI: 10.1016/j.rgmxen.2019.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Coronel-Castillo CE, Contreras-Carmona J, Frati-Munari AC, Uribe M, Méndez-Sánchez N. Efficacy of rifaximin in the different clinical scenarios of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2020; 85:56-68. [PMID: 31836274 DOI: 10.1016/j.rgmx.2019.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/21/2019] [Accepted: 09/04/2019] [Indexed: 06/10/2023]
Abstract
Hepatic encephalopathy is a frequent complication in patients with cirrhosis of the liver and is associated with a high mortality rate. Costs attributed to the management of patients with cirrhosis are especially high due to complications, such as hepatic encephalopathy, given that they increase the number of days of hospital stay. Different drugs are currently used to treat hepatic encephalopathy, and the main ones are lactulose, L-ornithine L-aspartate (LOLA), and certain antibiotics, especially rifaximin-α (RFX). Even though many of them have been shown to be effective to greater or lesser degrees, it is important to understand the differences between them, so that every patient receives individualized treatment and the best option is chosen, in accordance with the different clinical scenarios. Thus, the aim of the present study was to analyze the evidence on the advantages and disadvantages of the individual or combined use of the 3 main treatments for hepatic encephalopathy, specifically taking into consideration their different degrees of efficacy, their impact on quality of life, prophylaxis, and cost reduction.
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Affiliation(s)
- C E Coronel-Castillo
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - J Contreras-Carmona
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - A C Frati-Munari
- Departamento de Medicina Interna, Fundación Clínica Médica Sur, Ciudad de México, México
| | - M Uribe
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - N Méndez-Sánchez
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México; Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México.
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29
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Xu XY, Ding HG, Li WG, Jia JD, Wei L, Duan ZP, Liu YL, Ling-Hu EQ, Zhuang H, Hepatology CSO, Association CM. Chinese guidelines on management of hepatic encephalopathy in cirrhosis. World J Gastroenterol 2019; 25:5403-5422. [PMID: 31576089 PMCID: PMC6767982 DOI: 10.3748/wjg.v25.i36.5403] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/07/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy (HE) including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.
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Affiliation(s)
- Xiao-Yuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing 100034, China
| | - Hui-Guo Ding
- Hepatology and Digestion Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
| | - Wen-Gang Li
- Department of Liver Oncology, Cancer Radiation Therapy Center, Fifth Medical Center, PLA General Hospital, Beijing 100039, China
| | - Ji-Dong Jia
- Hepatology Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Lai Wei
- Hepatobiliary and Pancreatic Department, Beijing Tsinghua Changgeng Hospital, Beijing 102218, China
| | - Zhong-Ping Duan
- Artificial Liver Center, Beijing You-An Hospital, Capital Medical University, Beijing 100069, China
| | - Yu-Lan Liu
- Department of Gastroenterology, Peking University People's Hospital, Beijing 100044, China
| | - En-Qiang Ling-Hu
- Department of Gastroenterology, First Medical Center, PLA General Hospital, Beijing 100853, China
| | - Hui Zhuang
- Department of Pathogenic Biology, Peking University Health Science Center, Beijing 100191, China
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30
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Vangberg TR, Eikenes L, Håberg AK. The effect of white matter hyperintensities on regional brain volumes and white matter microstructure, a population-based study in HUNT. Neuroimage 2019; 203:116158. [PMID: 31493533 DOI: 10.1016/j.neuroimage.2019.116158] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/03/2019] [Accepted: 09/02/2019] [Indexed: 12/19/2022] Open
Abstract
Even though age-related white matter hyperintensities (WMH) begin to emerge in middle age, their effect on brain micro- and macrostructure in this age group is not fully elucidated. We have examined how presence of WMH and load of WMH affect regional brain volumes and microstructure in a validated, representative general population sample of 873 individuals between 50 and 66 years. Presence of WMH was determined as Fazakas grade ≥1. WMH load was WMH volume from manual tracing of WMHs divided on intracranial volume. The impact of age appropriate WMH (Fazakas grade 1) on the brain was also investigated. Major novel findings were that even the age appropriate WMH group had widespread macro- and microstructural changes in gray and white matter, showing that the mere presence of WMH, not just WMH load is an important clinical indicator of brain health. With increasing WMH load, structural changes spread centrifugally. Further, we found three major patterns of FA and MD changes related to increasing WMH load, demonstrating a heterogeneous effect on white matter microstructure, where distinct patterns were found in the proximity of the lesions, in deep white matter and in white matter near the cortex. This study also raises several questions about the onset of WMH related pathology, in particular, whether some of the aberrant brain structural and microstructural findings are present before the emergence of WMH. We also found, similar to other studies, that WMH risk factors had low explanatory power for WMH, making it unclear which factors lead to WMH.
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Affiliation(s)
- Torgil Riise Vangberg
- Medical Imaging Research Group, Department of Clinical Medicine, UiT the Arctic University of Norway, Tromsø, Norway; PET Center, University Hospital North Norway, Tromsø, Norway
| | - Live Eikenes
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Asta K Håberg
- Department of Radiology and Nuclear Medicine, St. Olav University Hospital, Trondheim, Norway; Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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31
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Braissant O, Rackayová V, Pierzchala K, Grosse J, McLin VA, Cudalbu C. Longitudinal neurometabolic changes in the hippocampus of a rat model of chronic hepatic encephalopathy. J Hepatol 2019; 71:505-515. [PMID: 31173812 DOI: 10.1016/j.jhep.2019.05.022] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS The sequence of events in hepatic encephalopathy (HE) remains unclear. Using the advantages of in vivo 1H-MRS (9.4T) we aimed to analyse the time-course of disease in an established model of type C HE by analysing the longitudinal changes in a large number of brain metabolites together with biochemical, histological and behavioural assessment. We hypothesized that neurometabolic changes are detectable very early, and that these early changes will offer insight into the primary events underpinning HE. METHODS Wistar rats underwent bile-duct ligation (BDL) and were studied before BDL and at post-operative weeks 2, 4, 6 and 8 (n = 26). In vivo short echo-time 1H-MRS (9.4T) of the hippocampus was performed in a longitudinal manner, as were biochemical (plasma), histological and behavioural tests. RESULTS Plasma ammonium increased early after BDL and remained high during the study. Brain glutamine increased (+47%) as early as 2-4 weeks post-BDL while creatine (-8%) and ascorbate (-12%) decreased. Brain glutamine and ascorbate correlated closely with rising plasma ammonium, while brain creatine correlated with brain glutamine. The increases in brain glutamine and plasma ammonium were correlated, while plasma ammonium correlated negatively with distance moved. Changes in astrocyte morphology were observed at 4 weeks. These early changes were further accentuated at 6-8 weeks post-BDL, concurrently with the known decreases in brain organic osmolytes. CONCLUSION Using a multimodal, in vivo and longitudinal approach we have shown that neurometabolic changes are already noticeable 2 weeks after BDL. These early changes are suggestive of osmotic/oxidative stress and are likely the premise of some later changes. Early decreases in cerebral creatine and ascorbate are novel findings offering new avenues to explore neuroprotective strategies for HE treatment. LAY SUMMARY The sequence of events in chronic hepatic encephalopathy (HE) remains unclear, therefore using the advantages of in vivo proton magnetic resonance spectroscopy at 9.4T we aimed to test the hypothesis that neurometabolic changes are detectable very early in an established model of type C HE, offering insight into the primary events underpinning HE, before advanced liver disease confounds the findings. These early, previously unreported neurometabolic changes occurred as early as 2 to 4 weeks after bile-duct ligation, namely an increase in plasma ammonium and brain glutamine, a decrease in brain creatine and ascorbate together with behavioural and astrocyte morphology changes, and continued to progress throughout the 8-week course of the disease.
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Affiliation(s)
- Olivier Braissant
- Service of Clinical Chemistry, University of Lausanne and University Hospital of Lausanne, Lausanne, Switzerland
| | - Veronika Rackayová
- Laboratory of Functional and Metabolic Imaging, Center for Biomedical Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland; Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Katarzyna Pierzchala
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Jocelyn Grosse
- Laboratory of Behavioral Genetics, Brain Mind Institute, School Of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Valérie A McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals Geneva, and University of Geneva Medical School, Switzerland
| | - Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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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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Cudalbu C, Taylor-Robinson SD. Brain Edema in Chronic Hepatic Encephalopathy. J Clin Exp Hepatol 2019; 9:362-382. [PMID: 31360029 PMCID: PMC6637228 DOI: 10.1016/j.jceh.2019.02.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 01/15/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023] Open
Abstract
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.
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Key Words
- 1H MRS, proton magnetic resonance spectroscopy
- ADC, apparent diffusion coefficient
- ALF, acute liver failure
- AQP, aquaporins
- BBB, blood-brain barrier
- BDL, bile duct ligation
- CNS, central nervous system
- CSF, cerebrospinal fluid
- Cr, creatine
- DTI, diffusion tensor imaging
- DWI, diffusion-weighted imaging
- FLAIR, fluid-attenuated inversion recovery
- GM, gray matter
- Gln, glutamine
- Glx, sum of glutamine and glutamate
- HE, hepatic encephalopathy
- Ins, inositol
- LPS, lipopolysaccharide
- Lac, lactate
- MD, mean diffusivity
- MRI, magnetic resonance imaging
- MRS, magnetic resonance spectroscopy
- MT, magnetization transfer
- MTR, MT ratio
- NMR, nuclear magnetic resonance
- PCA, portocaval anastomosis
- TE, echo time
- WM, white matter
- brain edema
- chronic hepatic encephalopathy
- in vivo magnetic resonance imaging
- in vivo magnetic resonance spectroscopy
- liver cirrhosis
- mIns, myo-inositol
- tCho, total choline
- tCr, total creatine
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Affiliation(s)
- Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Simon D. Taylor-Robinson
- Division of Integrative Systems Medicine and Digestive Disease, Department of Surgery and Cancer, St Mary's Hospital Campus, Imperial College London, London, United Kingdom
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Sato T, Endo K, Kakisaka K, Suzuki Y, Kooka Y, Sawara K, Ito K, Sasaki M, Takikawa Y. Decreased Mean Kurtosis in the Putamen is a Diagnostic Feature of Minimal Hepatic Encephalopathy in Patients with Cirrhosis. Intern Med 2019; 58:1217-1224. [PMID: 30626839 PMCID: PMC6543222 DOI: 10.2169/internalmedicine.2116-18] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Objective To prevent the development of overt hepatic encephalopathy, the early intervention for minimal hepatic encephalopathy (MHE) based on an accurate diagnosis is essential. This study investigated whether or not magnetic resonance diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) could detect brain microstructure abnormalities in MHE. The aim was to confirm whether or not brain microstructure abnormalities detected by magnetic resonance (MR) imaging could be used for the diagnosis of MHE. Methods Thirty-two subjects were prospectively examined with a 3-T MR scanner. Tract-based spatial statistics and region of interest analyses of diffusion imaging were performed to compare the mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) values between patients with and without minimal hepatic encephalopathy. The diagnostic performance for the detection of MHE was assessed with a receiver operating characteristic analysis. Results Ten subjects were diagnosed with MHE by neuropsychological testing. After the exclusion of unsuitable subjects, we analyzed 9 subjects with MHE and 14 without MHE. The patients with MHE had a reduced MK in the widespread white matter. We also found significant decreases in the MK in the caudate nucleus, putamen, globus pallidus, and/or thalamus in the subjects with MHE. The MK in the putamen showed the best diagnostic performance for differentiating the subjects with MHE from those without MHE (cut-off value, 0.74; sensitivity, 0.89; specificity, 0.86). Conclusion DKI detects changes in the cerebral white matter and basal ganglia regions of patients with MHE more sensitively than DTI. The MK values in the putamen can be a useful marker for diagnosing MHE from cirrhotic patients without MHE.
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Affiliation(s)
- Takuro Sato
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Kei Endo
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yohei Kooka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Kei Sawara
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Kenji Ito
- Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Japan
| | - Makoto Sasaki
- Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
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Piano S, Tonon M, Angeli P. Ascites, Hyponatremia, Spontaneous Bacterial Peritonitis, and Hepatorenal Syndrome. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:662-675. [DOI: 10.1002/9781119211419.ch43] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Fritz M, Klawonn AM, Zahr NM. Neuroimaging in alcohol use disorder: From mouse to man. J Neurosci Res 2019; 100:1140-1158. [PMID: 31006907 DOI: 10.1002/jnr.24423] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 02/15/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
This article provides an overview of recent advances in understanding the effects of alcohol use disorders (AUD) on the brain from the perspective of magnetic resonance imaging (MRI) research in preclinical models and clinical studies. As a noninvasive investigational tool permitting assessment of morphological, metabolic, and hemodynamic changes over time, MRI offers insight into the dynamic course of alcoholism beginning with initial exposure through periods of binge drinking and escalation, sobriety, and relapse and has been useful in differential diagnosis of neurological diseases associated with AUD. Structural MRI has revealed acute and chronic effects of alcohol on both white and gray matter volumes. MR Spectroscopy, able to quantify brain metabolites in vivo, has shed light on biochemical alterations associated with alcoholism. Diffusion tensor imaging permits microstructural characterization of white matter fiber tracts. Functional MRI has allowed for elucidation of hemodynamic responses at rest and during task engagement. Positron emission tomography, a non-MRI imaging tool, has led to a deeper understanding of alcohol-induced receptor and neurotransmitter changes during various stages of drinking and abstinence. Together, such in vivo imaging tools have expanded our understanding of the dynamic course of alcoholism including evidence for regional specificity of the effects of AUD, hints at mechanisms underlying the shift from casual to compulsive use of alcohol, and profound recovery with sustained abstinence.
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Affiliation(s)
- Michael Fritz
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
| | - Anna M Klawonn
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California
| | - Natalie M Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.,Neuroscience Program, SRI International, Menlo Park, California
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Rudler M, Weiss N, Perlbarg V, Mallet M, Tripon S, Valabregue R, Marjańska M, Cluzel P, Galanaud D, Thabut D. Combined diffusion tensor imaging and magnetic resonance spectroscopy to predict neurological outcome before transjugular intrahepatic portosystemic shunt. Aliment Pharmacol Ther 2018; 48:863-874. [PMID: 30178870 DOI: 10.1111/apt.14938] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/14/2018] [Accepted: 07/18/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) may occur after transjugular intrahepatic portosystemic shunt (TIPSS) placement. Multimodal magnetic resonance imaging (MRI), combining anatomical sequences, diffusion tensor imaging (DTI) and 1 H magnetic resonance spectroscopy, is modified in cirrhotic patients. AIMS To describe multimodal MRI images before TIPSS, to assess if TIPSS induces changes in multimodal MRI, and to find predictors of HE after TIPSS in patients with cirrhosis. METHODS Consecutive cirrhotic patients with an indication for TIPSS were prospectively screened. Diagnosis of minimal HE was performed using psychometric HE test score. Multimodal MRI was performed before and 3 months after TIPSS placement. RESULTS Twenty-five consecutive patients were analysed (median age = 59, male gender 76%, median Child-Pugh score = 8 [5-8], MELD score = 12 [9-17], indication for TIPSS placement: ascites/secondary prophylaxis of variceal bleeding/other 20/3/2), no HE/minimal HE/overt HE: 21/4/0. 8/25 patients developed HE after TIPSS. Before TIPSS placement, metabolite concentrations were different in patients with or without minimal HE (lower myo-inositol, mI, higher glutamate/glutamine), but there were no differences in DTI data. TIPSS placement induced changes in metabolite concentrations even in asymptomatic patients, but not in DTI metrics. Baseline fractional anisotropy was significantly lower in patients who developed HE after TIPSS in five regions of interest. CONCLUSIONS TIPSS placement induced significant changes in cerebral metabolites, even in asymptomatic patients. Patients who developed HE after TIPSS displayed lower fractional anisotropy before TIPSS. Brain MRI with DTI acquisition may help selecting patients at risk of HE.
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Affiliation(s)
- Marika Rudler
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Hepatology Department, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Nicolas Weiss
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Vincent Perlbarg
- Bioinformatics and Biostatistics Platform, IHU-A-ICM, Brain and Spine Institute, Paris, France
| | - Maxime Mallet
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Simona Tripon
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Department of Neurology, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Pierre et Marie Curie University, Paris, France
| | - Romain Valabregue
- CENIR, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne University, Pierre et Marie Curie University, UMR S 1127F, Paris, France
| | - Małgorzata Marjańska
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota
| | - Philippe Cluzel
- AP-HP, UPMC, Department of Radiology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University, Paris, France
| | - Damien Galanaud
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,AP-HP, UPMC, Department of Radiology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Pierre et Marie Curie University, Paris, France.,Institut-Hospitalo-Universitaire-A-Institut du Cerveau et de la Moelle (IHU-A-ICM), Paris, France
| | - Dominique Thabut
- Brain-Liver Pitié-Salpêtrière Study Group (BLIPS), Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Paris, France.,Intensive Care Unit, Hepatology Department, Pitié-Salpêtrière Charles Foix Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
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Görg B, Karababa A, Häussinger D. Hepatic Encephalopathy and Astrocyte Senescence. J Clin Exp Hepatol 2018; 8:294-300. [PMID: 30302047 PMCID: PMC6175776 DOI: 10.1016/j.jceh.2018.05.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45α. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.
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Key Words
- ARE, Antioxidant Response Elements
- BDNF, Brain-Derived Neurotrophic Factor
- Eph, Ephrine
- EphR, Ephrine Receptor
- GADD45α, Growth Arrest and DNA Damage Inducible 45α
- GS, Glutamine Synthetase
- HE, Hepatic Encephalopathy
- HO1, Heme Oxygenase 1
- LOLA, l-Ornithine-l-Aspartate
- MAP, Mitogen Activated Protein Kinases
- NAPDH, Reduced Form of Nicotinamide Adenine Dinucleotide Phosphate
- Nox, NADPH Oxidase
- Nrf2, Nuclear Factor-Like 2
- PBR, Peripheral-Type Benzodiazepine Receptor
- PTN, Protein Tyrosine Nitration
- RNOS, Reactive Nitrogen and Oxygen Species
- ROS, Reactive Oxygen Species
- SA-β-Gal, Senescence-Associated β-d-Galactosidase
- TSP, Trombospondin
- TrkBT, Truncated Tyrosine Receptor Kinase B
- ZnPP, Zinc Protoporphyrin
- ammonia
- astrocytes
- heme oxygenase 1
- hepatic encephalopathy
- mPT, Mitochondrial Permeability Transition
- miRNAs
- nNOS, Neuronal-Type Nitric-Oxide Synthase
- oxidative stress
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Affiliation(s)
| | | | - Dieter Häussinger
- Address for correspondence: Dieter Häussinger, Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Moorenstrasse 5, 40225 Düsseldorf, Germany. Tel.: +49 211 811 7569; fax: +49 211 811 8838.
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Ochoa-Sanchez R, Rose CF. Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease. J Clin Exp Hepatol 2018; 8:262-271. [PMID: 30302043 PMCID: PMC6175755 DOI: 10.1016/j.jceh.2018.08.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 08/09/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs during chronic liver disease (CLD). While ammonia and other precipitating factors in liver disease including inflammation, bile acids, oxidative stress, and lactate play a role in the pathogenesis of HE, the exact mechanism that leads to HE is not fully understood. Notably, accumulating evidence points toward a synergic effect rather than independent actions among precipitating factors that contributes to the development and severity of HE in CLD. Hence, this review is aimed to briefly discuss the single and synergic interplay of pathological factors in the progression and severity of HE.
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Key Words
- AQP4, Aquaporin 4
- BAs, Bile Acids
- BBB, Blood-Brain Barrier
- BDL, Bile Duct Ligation
- CLD, Chronic Liver Disease
- CSF, Cerebrospinal Fluid
- GABA, Gamma-Aminobutyric Acid
- GAMSAs, GABAA Receptor Modulating Steroid Antagonists
- GFAP, Glial Fibrillary Acid Protein
- GLAST, Glial Glutamate-Aspartate Transporter
- GPR81, G-Protein-Coupled Receptor 81
- GS, Glutamine Synthetase
- HE, Hepatic Encephalopathy
- ICP, Intracranial Pressure
- ILs, Interleukins
- MRI, Magnetic Resonance Imaging
- NF-?B, Nuclear Factor Kappa B
- NMDA, N-Methyl-d-Aspartate Glutamate Receptor
- NO, Nitric Oxide
- PCA, Portacaval Anastomosis
- ROS, Reactive Oxygen Species
- TJ, Tight Junction
- TNF-a, Tumor Necrosis Alpha
- ammonia
- astrocyte swelling
- bile acids
- brain edema
- cGMP, Cyclic Guanosine Monophosphate
- cirrhosis
- hepatic encephalopathy
- inflammation
- lactate
- mGluR, Metabotropic Glutamate Receptor
- neurotransmission
- oxidative stress
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Affiliation(s)
| | - Christopher F. Rose
- Address for correspondence. Christopher F. Rose Professor, Dept. Medicine, Université de Montréal, CRCHUM, 900 Saint-Denis Street, Montréal, Québec, H2X 0A9, Canada.
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Zhang XD, Zhang LJ. Multimodal MR imaging in hepatic encephalopathy: state of the art. Metab Brain Dis 2018; 33:661-671. [PMID: 29374342 DOI: 10.1007/s11011-018-0191-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 01/17/2018] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a neurological or neuropsychological complication due to liver failure or portosystemic shunting. The clinical manifestation is highly variable, which can exhibit mild cognitive or motor impairment initially, or gradually progress to a coma, even death, without treatment. Neuroimaging plays a critical role in uncovering the neural mechanism of HE. In particular, multimodality MR imaging is able to assess both structural and functional derangements of the brain with HE in focal or neural network perspectives. In recent years, there has been rapid development in novel MR technologies and applications to investigate the pathophysiological mechanism of HE. Therefore, it is necessary to update the latest MR findings regarding HE by use of multimodality MRI to refine and deepen our understanding of the neural traits in HE. Herein, this review highlights the latest MR imaging findings in HE to refresh our understanding of MRI application in HE.
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Affiliation(s)
- Xiao Dong Zhang
- Department of Radiology, Tianjin First Central Hospital, Clinical School of Tianjin Medical University, Tianjin, 300192, People's Republic of China
| | - Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210002, Jiangsu Province, People's Republic of China.
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Mendes NF, Mariotti FFN, de Andrade JS, de Barros Viana M, Céspedes IC, Nagaoka MR, Le Sueur-Maluf L. Lactulose decreases neuronal activation and attenuates motor behavioral deficits in hyperammonemic rats. Metab Brain Dis 2017; 32:2073-2083. [PMID: 28875419 DOI: 10.1007/s11011-017-0098-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 08/16/2017] [Indexed: 12/14/2022]
Abstract
Lactulose is a nonabsorbable disaccharide commonly used in clinical practice to treat hepatic encephalopathy. However, its effects on neuropsychiatric disorders and motor behavior have not been fully elucidated. Male Wistar rats were bile-duct ligated, and 3 weeks after surgery, treated with lactulose administrated by gavage (1.43 or 3.57 g/kg), once a day for seven days. Plasma levels of ammonia, aspartate aminotransferase, total bilirubin, and creatinine were quantified and histopathological analysis of the livers was performed. Locomotor activity measurements were performed in an open field. The expression of water channel aquaporin-4 was investigated and the analysis of Fos protein immunoreactivity was used to evaluate the pattern of neural activation in brain areas related to motor behavior. Bile-duct ligated rats showed hyperammonemia, loss of liver integrity and function, impaired locomotor activity, reduced aquaporin-4 protein expression, and neuronal hyperactivity. Lactulose treatment was able to reduce ammonia plasma levels, despite not having an effect on biochemical parameters of liver function, such as aspartate aminotransferase activity and total bilirubin levels, or on the cirrhotic hepatic architecture. Lactulose was also able to reduce the locomotor activity impairments and to mitigate or reverse most changes in neuronal activation. Lactulose had no effect on reduced aquaporin-4 protein expression. Our findings confirm the effectiveness of lactulose in reducing hyperammonemia and neuronal hyperactivity in brain areas related to motor behavior, reinforcing the importance of its clinical use in the treatment of the symptoms of cirrhosis-associated encephalopathy.
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Affiliation(s)
- Natália Ferreira Mendes
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
- Laboratório de Sinalização Celular, Universidade Estadual de Campinas, UNICAMP, Campinas/SP, 13083-864, Brazil
| | - Flora França Nogueira Mariotti
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - José Simões de Andrade
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Milena de Barros Viana
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Isabel Cristina Céspedes
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
- Departamento de Morfologia e Genética, Universidade Federal de São Paulo, UNIFESP, 11015-020, São Paulo/SP, 04023-900, Brazil
| | - Márcia Regina Nagaoka
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil
| | - Luciana Le Sueur-Maluf
- Departmento de Biociências, Universidade Federal de São Paulo, UNIFESP, 133/136 - Vila Mathias, Santos/SP, 11015-020, Brazil.
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Gupta T, Dhiman RK, Ahuja CK, Agrawal S, Chopra M, Kalra N, Duseja A, Taneja S, Khandelwal N, Chawla Y. Characterization of Cerebral Edema in Acute-on-Chronic Liver Failure. J Clin Exp Hepatol 2017; 7:190-197. [PMID: 28970705 PMCID: PMC5620367 DOI: 10.1016/j.jceh.2017.04.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 04/03/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND AIMS The nature of cerebral edema in acute-on-chronic liver failure (ACLF) is not well studied. We aimed to characterize cerebral edema in ACLF using magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI). METHODS Forty-six patients with cirrhosis and acute decompensation were included. Patients were divided into groups A (no cerebral failure, n = 39) and B (cerebral failure, n = 7). Group A was subdivided into no-ACLF (n = 11), grade 1 (n = 10), grade 2 (n = 9) and grade 3 (n = 9) ACLF as per CANONIC study. MRI brain and plasma TNF-alpha, IL-1beta and IL-6 were measured at baseline and 7-10 days after admission. Ten age- and sex-matched healthy controls were also included. RESULTS Mean diffusivity (MD) values, an MRI marker of water content, progressively increased from controls to no-ACLF to ACLF grade 1, 2 and 3 in group A in frontal white matter (FWM) and basal ganglia (P < 0.0001). MD values improved only in survivors on follow-up. MD values correlated with IL-6 levels at baseline. On multivariate analysis MELD score ≥28 and MD values (>8 × 10-9 M2/s) in FWM were independent predictors of 90-day mortality. There was no significant difference in clinical and MRI parameters between group A and B. CONCLUSION Cerebral edema increases with severity of ACLF. Correlation between MD values and IL-6 levels suggests pathogenic role of inflammation in cerebral edema. Patients with grade 3 ACLF have cerebral edema irrespective of presence of clinically evident cerebral failure. MELD score and cerebral edema have prognostic significance in ACLF.
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Key Words
- ACLF, acute-on-chronic liver failure
- AIH, autoimmune hepatitis
- ALIC, anterior limb of internal capsule
- APASL, Asian pacific association for study of liver diseases
- AUROC, area under receiver operating characteristic
- BBB, blood–brain barrier
- BG, basal ganglia
- CANONIC, chronic liver failure (CLIF) acute-on-chronic liver failure in cirrhosis
- CI, confidence interval
- CLIF-SOFA, chronic liver failure-sequential organ failure assessment
- CTP, Child–Turcott–Pugh
- DTI, diffusion tensor imaging
- FA, fractional anisotropy
- FLAIR, fluid attenuation inversion recovery
- FWM, frontal white matter
- HBV, hepatitis B virus
- HE, hepatic encephalopathy
- IC, internal capsule
- IL-1 beta, interleukin 1 beta
- IL-6, interleukin 6
- MD, mean diffusivity
- MELD, model for end-stage liver disease
- MRI, magnetic resonance imaging
- MTR, magnetization transfer ratio
- PLIC, posterior limb of internal capsule
- PWM, parietal white matter
- ROI, regions of interest
- SIRS, systemic inflammatory response syndrome
- T1W, T1 weighted
- T2W, T2 weighted
- TE, echo-time
- TNF-alpha, tumor necrosis factor-alpha
- TR, repetition time
- acute-on-chronic liver failure
- cerebral edema
- diffusion tensor imaging
- magnetic resonance imaging
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Affiliation(s)
- Tarana Gupta
- Department of Hepatology, PGIMER, Chandigarh, India
| | | | - Chirag K. Ahuja
- Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India
| | | | - Madhu Chopra
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Naveen Kalra
- Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh, India
| | - Ajay Duseja
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, PGIMER, Chandigarh, India
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Brain Microstructural Abnormalities in Patients With Cirrhosis Without Overt Hepatic Encephalopathy: A Voxel-Based Diffusion Kurtosis Imaging Study. AJR Am J Roentgenol 2017; 209:1128-1135. [PMID: 28813200 DOI: 10.2214/ajr.17.17827] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE This study aimed to investigate whole-brain microstructural abnormalities and their correlation with cognitive impairment in patients with cirrhosis using diffusion kurtosis imaging (DKI). SUBJECTS AND METHODS Eighteen patients with cirrhosis and 17 healthy control subjects underwent DKI. Cognition was measured using psychometric hepatic encephalopathy (HE) scores. Whole-brain voxel-based analyses were performed to investigate between-group differences in DKI-derived parameters, including mean kurtosis, axial kurtosis, and radial kurtosis. RESULTS Compared with control subjects, the patients with cirrhosis had lower psychometric HE scores, indicating cognitive impairments. The patients with cirrhosis had significantly lower global mean kurtosis, axial kurtosis, and radial kurtosis in gray matter (GM) and white matter (WM). Voxel-based analyses showed that patients with cirrhosis had decreased mean kurtosis, axial kurtosis, and radial kurtosis in diffuse GM regions (particularly in the cingulate cortex, precuneus, insular cortex, frontal areas, basal ganglia, hippocampus and parahippocampal gyrus, supramarginal gyrus and angular gyrus, postcentral and precentral gyrus, and cerebellum) and WM regions (particularly in the corpus callosum, internal capsule, frontal regions, parietal regions, occipital regions, and cerebellum). The DKI metrics were positively correlated with psychometric HE score among patients. CONCLUSION Lower DKI parameters suggest decreased brain microstructural complexity in patients with cirrhosis, which may contribute to the neurobiologic basis of cognitive impairment.
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Li Y, Liu H, Yang J, Tian X, Yang H, Geng Z. Combining arterial-spin labeling with functional magnetic resonance imaging measurement for characterizing patients with minimal hepatic encephalopathy. Hepatol Res 2017; 47:862-871. [PMID: 27717156 DOI: 10.1111/hepr.12827] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 09/06/2016] [Accepted: 10/05/2016] [Indexed: 01/18/2023]
Abstract
AIM Our objective is to explore key changes in brain functions in relation to minimal hepatic encephalopathy (MHE). We incorporated both resting-state functional magnetic resonance imaging (fMRI) and arterial spin labeling (ASL) to enhance the detection of MHE. METHODS We undertook fMRI scanning for 56 MHE patients and 66 healthy controls. Region functional connectivity was carried out to assess the connectivity status between pairs of regions among 90 brain regions. Additionally, blood flow (BF) status was measured by ASL for all subjects. Spearman's correlation test was implemented to identify any correlation among z-values, results from number connection test type A, and digit symbol tests. Finally, the receiver operating characteristic curve was generated for assessing the accuracy of BF in MHE diagnosis. RESULTS The corresponding functional connectivity was significantly different between MHE and control groups in 15 regions. For MHE patients, BF showed an increasing pattern in regions of interest. Blood flood in the putamen was positively correlated with number connection test type A neuropsychological performance, whereas it was negatively correlated with the digit symbol test. Blood flood in the right putamen showed the highest value of area under the curve with a sensitivity of 85.7% and specificity of 89.4%. CONCLUSION Connectivity impairment resulting from ganglia-thalamo-cortical circuits may play important roles in mediating the development of MHE patients. An increase in the BF, particularly in the right putamen, may be considered as evidence for the presence of MHE.
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Affiliation(s)
- Ying Li
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Huaijun Liu
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Jiping Yang
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Xin Tian
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Haiqing Yang
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
| | - Zuojun Geng
- Medical Imaging Department, The Second Hospital of Hebei Medical University, Shijiazhuang City, China
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Dhanda S, Sandhir R. Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins. Mol Neurobiol 2017; 55:3642-3659. [PMID: 28523565 DOI: 10.1007/s12035-017-0521-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 04/06/2017] [Indexed: 12/27/2022]
Abstract
The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. 99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins.
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Affiliation(s)
- Saurabh Dhanda
- Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India
| | - Rajat Sandhir
- Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India.
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Srivastava A, Chaturvedi S, Gupta RK, Malik R, Mathias A, Jagannathan NR, Jain S, Pandey CM, Yachha SK, Rathore RKS. Minimal hepatic encephalopathy in children with chronic liver disease: Prevalence, pathogenesis and magnetic resonance-based diagnosis. J Hepatol 2017; 66:528-536. [PMID: 27815224 DOI: 10.1016/j.jhep.2016.10.026] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 10/17/2016] [Accepted: 10/18/2016] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Data on minimal hepatic encephalopathy (MHE) in children is scarce. We aimed to study MHE in children with chronic liver disease (CLD) and to validate non-invasive objective tests which can assist in its diagnosis. METHODS We evaluated 67 children with CLD (38 boys; age 13 [7-18] years) and 37 healthy children to determine the prevalence of MHE. We also assessed the correlation of MHE with changes in brain metabolites by magnetic resonance spectroscopy (1HMRS), diffusion tensor imaging (DTI) derived metrics, blood ammonia and inflammatory cytokines (interleukin-6 [IL6], tumor necrosis factor alpha [TNF-α]). In addition, the accuracy of MR-based investigations for diagnosis of MHE in comparison to neuropsychological tests was analysed. RESULTS Thirty-four (50.7%) children with CLD had MHE on neuropsychological tests. MHE patients had higher BA (30.5 [6-74] vs. 14 [6-66]μmol/L; p=0.02), IL-6 (8.3 [4.7-28.7] vs. 7.6 [4.7-20.7]pg/ml; p=0.4) and TNF-α (17.8 [7.8-65.5] vs. 12.8 [7.5-35]pg/ml; p=0.06) than No-MHE. 1HMRS showed higher glutamine (2.6 [2.1-3.3] vs. 2.4 [2.0-3.1]; p=0.02), and lower choline (0.20 [0.14-0.25] vs. 0.22 [0.17-0.28]; p=0.1) and myo-inositol (0.25 [0.14-0.41] vs. 0.29 [0.21-0.66]; p=0.2) in MHE patients than those without MHE. Mean diffusivity (MD) on DTI was significantly higher in 6/11 brain areas in patients with MHE vs. no MHE. Brain glutamine had a significant positive correlation with blood ammonia, IL-6, TNF-α and MD of various brain regions. Neuropsychological tests showed a negative correlation with blood ammonia, IL6, TNF-α, glutamine and MD. Frontal white matter MD had a sensitivity and specificity of 73.5% and 100% for diagnosing MHE. CONCLUSIONS In children with CLD, 50% have MHE. There is a significant positive correlation between markers of hyperammonemia, inflammation and brain edema and these correlate negatively with neuropsychological tests. MD on DTI is a reliable tool for diagnosing MHE. LAY SUMMARY Fifty percent of children with chronic liver disease develop minimal hepatic encephalopathy (MHE) and perform poorly on neuropsychological testing. These children have raised blood ammonia, inflammatory cytokines and mild cerebral edema on diffusion tensor imaging as compared to children without MHE. The higher the ammonia, inflammatory cytokines and cerebral edema levels the poorer the performance on neuropsychological assessment. The estimation of mean diffusivity on diffusion tensor imaging is an objective and reliable method for diagnosing MHE.
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Affiliation(s)
- Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
| | - Saurabh Chaturvedi
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | | | - Rohan Malik
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Amrita Mathias
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | | | - Sunil Jain
- Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Chandra Mani Pandey
- Department of Biostatistics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Surender Kumar Yachha
- Department of Pediatric Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
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Zhong WJ, Zhou ZM, Zhao JN, Wu W, Guo DJ. Abnormal spontaneous brain activity in minimal hepatic encephalopathy: resting-state fMRI study. Diagn Interv Radiol 2017; 22:196-200. [PMID: 26742646 DOI: 10.5152/dir.2015.15208] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE We aimed to assess the abnormality of baseline spontaneous brain activity in minimal hepatic encephalopathy (MHE) by amplitude of low frequency fluctuation (ALFF) and fraction ALFF (fALFF). METHODS A total of 14 MHE patients and 14 healthy controls were included in our study. Both ALFF and fALFF of functional magnetic resonance imaging were calculated for statistical analysis. RESULTS Compared with healthy controls, patients with MHE had significantly decreased ALFF in the bilateral medial prefrontal cortex (MPFC), left superior frontal gyrus, right precentral gyrus, left opercular part of inferior frontal gyrus, left gyrus rectus, bilateral precuneus, and the posterior lobe of right cerebellum; and they had significantly decreased fALFF in the bilateral MPFC, right middle frontal gyrus, right superior temporal gyrus, and the posterior lobe of left cerebellum. CONCLUSION ALFF and fALFF changes in many brain regions demonstrate abnormality of the spontaneous neuronal activity in MHE. Especially the impairment of right precuneus and left MPFC may play a critical role in manifestation of MHE. Changes of ALFF and fALFF in the precuneus and the MPFC can be used as a potential marker for MHE.
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Affiliation(s)
- Wei-Jia Zhong
- Department of Radiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Grover VPB, McPhail MJW, Wylezinska-Arridge M, Crossey MME, Fitzpatrick JA, Southern L, Saxby BK, Cook NA, Cox IJ, Waldman AD, Dhanjal NS, Bak-Bol A, Williams R, Morgan MY, Taylor-Robinson SD. A longitudinal study of patients with cirrhosis treated with L-ornithine L-aspartate, examined with magnetization transfer, diffusion-weighted imaging and magnetic resonance spectroscopy. Metab Brain Dis 2017; 32:77-86. [PMID: 27488112 PMCID: PMC5225223 DOI: 10.1007/s11011-016-9881-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 07/19/2016] [Indexed: 12/31/2022]
Abstract
The presence of overt hepatic encephalopathy (HE) is associated with structural, metabolic and functional changes in the brain discernible by use of a variety of magnetic resonance (MR) techniques. The changes in patients with minimal HE are less well documented. Twenty-two patients with well-compensated cirrhosis, seven of whom had minimal HE, were examined with cerebral 3 Tesla MR techniques, including T1- and T2-weighted, magnetization transfer and diffusion-weighted imaging and proton magnetic resonance spectroscopy sequences. Studies were repeated after a 4-week course of oral L-ornithine L-aspartate (LOLA). Results were compared with data obtained from 22 aged-matched healthy controls. There was no difference in mean total brain volume between patients and controls at baseline. Mean cerebral magnetization transfer ratios were significantly reduced in the globus pallidus and thalamus in the patients with cirrhosis irrespective of neuropsychiatric status; the mean ratio was significantly reduced in the frontal white matter in patients with minimal HE compared with healthy controls but not when compared with their unimpaired counterparts. There were no significant differences in either the median apparent diffusion coefficients or the mean fractional anisotropy, calculated from the diffusion-weighted imaging, or in the mean basal ganglia metabolite ratios between patients and controls. Psychometric performance improved in 50 % of patients with minimal HE following LOLA, but no significant changes were observed in brain volumes, cerebral magnetization transfer ratios, the diffusion weighted imaging variables or the cerebral metabolite ratios. MR variables, as applied in this study, do not identify patients with minimal HE, nor do they reflect changes in psychometric performance following LOLA.
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Affiliation(s)
- Vijay P B Grover
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Mark J W McPhail
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Marzena Wylezinska-Arridge
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Mary M E Crossey
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
| | - Julie A Fitzpatrick
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Louise Southern
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
| | - Brian K Saxby
- Centre for Ageing and Health, Newcastle University, Newcastle-upon-Tyne, UK
| | - Nicola A Cook
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
| | - I Jane Cox
- The Foundation for Liver Research, Institute of Hepatology, 69-75 Chenies Mews, London, WC1E 6HX, UK
| | - Adam D Waldman
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Novraj S Dhanjal
- Division of Brain Sciences, Hammersmith Hospital Campus, Imperial College London, London, UK
| | - Aluel Bak-Bol
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK
- Robert Steiner MRI Unit, Imaging Sciences Department, MRC Clinical Sciences Centre, Imperial College London, London, UK
| | - Roger Williams
- The Foundation for Liver Research, Institute of Hepatology, 69-75 Chenies Mews, London, WC1E 6HX, UK
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Simon D Taylor-Robinson
- Liver Unit, Division of Digestive Health, Department of Surgery and Cancer, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital, Praed Street, London, W2 1NY, UK.
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Lee P, Ryoo H, Park J, Jeong Y. Morphological and Microstructural Changes of the Hippocampus in Early MCI: A Study Utilizing the Alzheimer's Disease Neuroimaging Initiative Database. J Clin Neurol 2017; 13:144-154. [PMID: 28176504 PMCID: PMC5392456 DOI: 10.3988/jcn.2017.13.2.144] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/30/2016] [Accepted: 10/31/2016] [Indexed: 01/18/2023] Open
Abstract
Background and Purpose With the aim of facilitating the early detection of Alzheimer's disease, the Alzheimer's Disease Neuroimaging Initiative proposed two stages based on the memory performance: early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI). The current study was designed to investigate structural differences in terms of surface atrophy and microstructural changes of the hippocampus in EMCI and LMCI. Methods Hippocampal shape modeling based on progressive template surface deformation was performed on T1-weighted MRI images obtained from 20 cognitive normal (CN) subjects, 17 EMCI patients, and 20 LMCI patients. A template surface in CN was used as a region of interest for diffusion-tensor imaging (DTI) voxel-based morphometry (VBM) analysis. Cluster-wise group comparison was performed based on DTI indices within the hippocampus. Linear regression was performed to identify correlations between DTI metrics and clinical scores. Results The hippocampal surface analysis showed significant atrophies in bilateral CA1 regions and the right ventral subiculum in EMCI, in contrast to widespread atrophy in LMCI. DTI VBM analysis showed increased diffusivity in the CA2–CA4 regions in EMCI and additionally in the subiculum region in LMCI. Hippocampal diffusivity was significantly correlated with scores both for the Mini Mental State Examination and on the Modified Alzheimer Disease Assessment Scale cognitive subscale. However, the hippocampal diffusivity did not vary significantly with the fractional anisotropy. Conclusions EMCI showed hippocampal surface changes mainly in the CA1 region and ventral subiculum. Diffusivity increased mainly in the CA2–CA4 regions in EMCI, while it decreased throughout the hippocampus in LMCI. Although axial diffusivity showed prominent changes in the right hippocampus in EMCI, future studies need to confirm the presence of this laterality difference. In addition, diffusivity is strongly correlated with the cognitive performance, indicating the possibility of using diffusivity as a biomarker for disease progression.
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Affiliation(s)
- Peter Lee
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea.,KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea
| | - Hojin Ryoo
- School of Computing, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea
| | - Jinah Park
- School of Computing, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea.,KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea.
| | - Yong Jeong
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea.,KI for Health Science and Technology, Korea Advanced Institute of Science and Technology (KAIST) Daejeon, Korea.
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John ES, Sedhom R, Dalal I, Sharma R. Posterior reversible encephalopathy syndrome in alcoholic hepatitis: Hepatic encephalopathy a common theme. World J Gastroenterol 2017; 23:373-376. [PMID: 28127211 PMCID: PMC5236517 DOI: 10.3748/wjg.v23.i2.373] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 09/06/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome.
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