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• W2899698880 abstract "Impaired brain glymphatic flow in experimental hepatic encephalopathyJournal of HepatologyVol. 70Issue 1PreviewThe mechanisms underlying the pathogenesis of hepatic encephalopathy (HE) in patients with cirrhosis (chronic liver disease) are not completely understood. Data available in the literature suggest that noxious substances and metabolites such as lactate, glutamate, bile acids and drugs accumulate in the brain of patients with HE.1 The prevailing hypothesis proposes that this occurs because of metabolic and transporter defects induced by hyperammonaemia, inflammation and alterations in blood brain barrier function. Full-Text PDF Open Access Hepatic encephalopathy (HE) is defined as a neurological and neuropsychological complication caused by liver disease and/or portosystemic shunting. The implication of hyperammonemia has been proposed more than a century ago in a dog animal model, i.e., Eck’s fistula,[1]Rocko J.M. Swan K.G. The Eck-Pavlov connection.Am Surg. 1985; 51: 641-644PubMed Google Scholar and more than a half century ago in humans with porto-systemic encephalopathy.[2]Sherlock S. Summerskill W.H. White L.P. Phear E.A. Portal-systemic encephalopathy; neurological complications of liver disease.Lancet Lond Engl. 1954; 267: 454-457PubMed Google Scholar The implication of systemic inflammation has been shown more recently.[3]Shawcross D.L. Davies N.A. Williams R. Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.J Hepatol. 2004; 40: 247-254Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar Yet, hyperammonemia and systemic inflammation do not explain all the abnormalities that characterize HE.[4]Weiss N. Jalan R. Thabut D. Understanding hepatic encephalopathy.Intensive Care Med. 2018; 44: 231-234Crossref PubMed Scopus (31) Google Scholar The cerebral accumulation of several substances has been described over the years: aromatic amino acids, benzodiazepine-like substances, bile acids, manganese, indols, mercaptans and even xenobiotics,[5]Weiss N. Barbier Saint Hilaire P. Colsch B. Isnard F. Attala S. Schaefer A. et al.Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.J Hepatol. 2016; 65: 1120-1130Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar providing evidence for an altered permeability of the blood-brain barrier (BBB) in the context of HE. Located at the interface between the blood and the central nervous system, the BBB controls exchanges between blood and brain.[6]Weiss N. Miller F. Cazaubon S. Couraud P.-O. The blood-brain barrier in brain homeostasis and neurological diseases.BBA. 2009; 1788: 842-857Crossref PubMed Scopus (536) Google Scholar The BBB is formed by cerebral endothelial cells that are mainly characterized by the expression of intercellular tight junctions and the expression of polarized transport systems. Different cell types are involved in the BBB architecture: cerebral endothelial cells lying on a basal lamina, pericytes, astrocytes and neurons. While cerebral endothelial cells express intercellular adherent junctions formed by the homophilic interaction of vascular-endothelial (VE)-cadherins like other endothelial cells in the body, they are unique in that they express apical tight junctions formed by the homophilic interaction of occludin, claudin-3 and -5, zonula occludens (ZO)-1 and other molecules such as junctional adhesion molecules molecules, cingulin, AF-6 and 7H6. Cerebral endothelial cells lying on the basal lamina are surrounded by astrocytic protrusions, the astrocytic endfeets, that cover microvessels and form the glial limitans. This unique organization is responsible for an extremely low permeability to solutes, proteins, plasmatic nutrients, xenobiotics and cells, i.e., leukocytes. This provides the brain a protection against plasmatic xenobiotics and contributes to brain homeostasis. Nevertheless, specific transport systems, i.e., receptor-mediated transporters, solute-carrier (SLC) and ATP-binding cassette transporters, are expressed by cerebral endothelial cells to ensure the supply of nutrients to the brain and the elimination of waste products. The alteration of BBB permeability in HE has been reported both in patients and in animal models.7Weiss N. Rosselli M. Mouri S. Galanaud D. Puybasset L. Agarwal B. et al.Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.Metab Brain Dis. 2017; 32: 369-376Crossref PubMed Scopus (18) Google Scholar, 8Chen F. Ohashi N. Li W. Eckman C. Nguyen J.H. Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure.Hepatol Baltim Md. 2009; 50: 1914-1923Crossref PubMed Scopus (123) Google Scholar, 9Nguyen J.H. Yamamoto S. Steers J. Sevlever D. Lin W. Shimojima N. et al.Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice.J Hepatol. 2006; 44: 1105-1114Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 10Skowrońska M. Albrecht J. Alterations of blood brain barrier function in hyperammonemia: an overview.Neurotox Res. 2011; 21: 236-244Crossref PubMed Scopus (76) Google Scholar Patients with HE display increased permeability to solutes and several substances. Cerebral edema is a hallmark of HE: vasogenic edema is present in acute and in acute-on-chronic liver failures and to a lesser extent in cirrhosis. Cytotoxic edema is present in both acute and chronic liver diseases. The increase of BBB permeability in HE has also been called into question.10Skowrońska M. Albrecht J. Alterations of blood brain barrier function in hyperammonemia: an overview.Neurotox Res. 2011; 21: 236-244Crossref PubMed Scopus (76) Google Scholar, 11Goldbecker A. Buchert R. Berding G. Bokemeyer M. Lichtinghagen R. Wilke F. et al.Blood–brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls.J Cereb Blood Flow Metab. 2010; 30: 1384-1393Crossref PubMed Scopus (20) Google Scholar The different techniques used to assess BBB’s permeability could largely explain discrepancies. For example, even though the classical cut-off value of BBB passage is 500 Daltons (Da), Evans Blue, a dye of 70 kDa molecular weight has been used by investigators who concluded that BBB permeability was not increased.[10]Skowrońska M. Albrecht J. Alterations of blood brain barrier function in hyperammonemia: an overview.Neurotox Res. 2011; 21: 236-244Crossref PubMed Scopus (76) Google Scholar Studies, in which dyes of lower molecular weights, i.e., 10 or 40 kDa, were used, demonstrated increased BBB permeability in HE.8Chen F. Ohashi N. Li W. Eckman C. Nguyen J.H. Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure.Hepatol Baltim Md. 2009; 50: 1914-1923Crossref PubMed Scopus (123) Google Scholar, 9Nguyen J.H. Yamamoto S. Steers J. Sevlever D. Lin W. Shimojima N. et al.Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice.J Hepatol. 2006; 44: 1105-1114Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Therefore, the range of increased permeability between 0.5 and 70 kDa have been frequently overlooked. Animal studies could also show a decrease in the expression of tight junction proteins and an increase in the activity of metalloproteases, MMP-2 and -9, classically associated with impaired BBB permeability.[8]Chen F. Ohashi N. Li W. Eckman C. Nguyen J.H. Disruptions of occludin and claudin-5 in brain endothelial cells in vitro and in brains of mice with acute liver failure.Hepatol Baltim Md. 2009; 50: 1914-1923Crossref PubMed Scopus (123) Google Scholar Clinical studies in humans with HE showed the accumulation of several substances in the brain parenchyma or the cerebrospinal fluid (CSF): aromatic amino acids, bile acids and even xenobiotics.5Weiss N. Barbier Saint Hilaire P. Colsch B. Isnard F. Attala S. Schaefer A. et al.Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.J Hepatol. 2016; 65: 1120-1130Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 7Weiss N. Rosselli M. Mouri S. Galanaud D. Puybasset L. Agarwal B. et al.Modification in CSF specific gravity in acutely decompensated cirrhosis and acute on chronic liver failure independent of encephalopathy, evidences for an early blood-CSF barrier dysfunction in cirrhosis.Metab Brain Dis. 2017; 32: 369-376Crossref PubMed Scopus (18) Google Scholar Whereas BBB abnormalities readily explain cerebral edema and the accumulation of aromatic amino acids, they poorly explain the accumulation of some others, i.e. bile acids or small molecules. Recently, a paravascular fluid pathway has been described in the brain and has been suggested to account for the clearance of small molecules encompassing waste products, outside the brain.12Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.Sci Transl Med. 2012; 4: 147ra111Crossref PubMed Scopus (2590) Google Scholar, 13Iliff J.J. Lee H. Yu M. Feng T. Logan J. Nedergaard M. et al.Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.J Clin Invest. 2013; 123: 1299-1309Crossref PubMed Scopus (593) Google Scholar This pathway termed glial-lymphatic (glymphatic) system (Fig. 1), is dependent on glial astrocytic endfeets that surround the cerebral vessels and it is functionally close to the lymphatic system.[13]Iliff J.J. Lee H. Yu M. Feng T. Logan J. Nedergaard M. et al.Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.J Clin Invest. 2013; 123: 1299-1309Crossref PubMed Scopus (593) Google Scholar Thus, CSF of the subarachnoid space enters the brain parenchyma by following paravascular spaces that surround penetrating arteries, i.e., Virchow-Robin spaces, located between the basal membrane of smooth muscle cells and astrocytic endfeets expressing aquaporin-4 (AQP-4) water channels. Similar paravascular spaces are present on large caliber cerebral veins and contribute to the clearance of small molecules and waste products, from interstitial fluid to the CSF which will then reach cervical lymphatic vessels and lymph nodes or the newly described meningeal lymphatic vessels.[14]Louveau A. Smirnov I. Keyes T.J. Eccles J.D. Rouhani S.J. Peske J.D. et al.Structural and functional features of central nervous system lymphatic vessels.Nature. 2015; 523: 337-341Crossref PubMed Scopus (2404) Google Scholar It has been proposed that the AQP-4 water channel was the main driving force of the glymphatic system and an impairment of glymphatic clearance associated with a decrease in the expression of AQP-4, has been described in animal models of Alzheimer’s disease or traumatic brain injury.12Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.Sci Transl Med. 2012; 4: 147ra111Crossref PubMed Scopus (2590) Google Scholar, 15Iliff J.J. Chen M.J. Plog B.A. Zeppenfeld D.M. Soltero M. Yang L. et al.Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury.J Neurosci. 2014; 34: 16180-16193Crossref PubMed Scopus (561) Google Scholar The glymphatic system is implicated in the pathophysiology of other diseases: Parkinson’s disease, small vessel diseases, subarachnoid hemorrhage or high altitude cerebral edema.[16]Bacyinski A. Xu M. Wang W. Hu J. The paravascular pathway for brain waste clearance: current understanding, significance and controversy.Front Neuroanat. 2017; 11: 101Crossref PubMed Scopus (88) Google Scholar Presumably, its function is modulated by sleep, acetazolamide, dobutamine or deep cervical lymph node ligation in animal models. This system could also account for the cerebral accumulation of amyloid-beta (A-beta) proteins after sleep deprivation,[17]Shokri-Kojori E. Wang G.-J. Wiers C.E. Demiral S.B. Guo M. Kim S.W. et al.β-Amyloid accumulation in the human brain after one night of sleep deprivation.Proc Natl Acad Sci U S A. 2018; 115: 4483-4488Crossref PubMed Scopus (354) Google Scholar as the inhibition of glymphatic clearance is associated with the cerebral accumulation of A-beta proteins.[12]Iliff J.J. Wang M. Liao Y. Plogg B.A. Peng W. Gundersen G.A. et al.A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.Sci Transl Med. 2012; 4: 147ra111Crossref PubMed Scopus (2590) Google Scholar The glymphatic system is still a subject of debate,16Bacyinski A. Xu M. Wang W. Hu J. The paravascular pathway for brain waste clearance: current understanding, significance and controversy.Front Neuroanat. 2017; 11: 101Crossref PubMed Scopus (88) Google Scholar, 18Abbott N.J. Pizzo M.E. Preston J.E. Janigro D. Thorne R.G. The role of brain barriers in fluid movement in the CNS: is there a “glymphatic” system?.Acta Neuropathol (Berl). 2018; 135: 387-407Crossref PubMed Scopus (299) Google Scholar notably with respect to the existence of paravascular spaces, or the role of AQP-4 water channels. Yet, the glymphatic system has emerged as a pathway for the cerebral supply and clearance of small molecules in parallel to the transvascular route, depending on the BBB. In this issue of the Journal, Hadjihambi et al.[19]Hadjihambi A. Harrison I.F. Costas-Rodríguez M. Vanhaecke F. Arias N. Gallego-Durán R. et al.Impaired brain glymphatic flow in experimental hepatic encephalopathy.J Hepatol. 2019; 70: 40-49Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar address the possible impairment of the glymphatic clearance system in cirrhosis and HE. They took advantage of the bile duct ligation (BDL) animal model of chronic liver disease with HE, and used mass-spectroscopy techniques and dynamic contrast-enhanced MRI to study the glymphatic system. The authors could show that BDL animals compared to Sham presented both a reduced CSF brain influx and a reduced CSF brain efflux. They confirmed as we did that bile acids accumulate in the CSF of patients with HE.[5]Weiss N. Barbier Saint Hilaire P. Colsch B. Isnard F. Attala S. Schaefer A. et al.Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy.J Hepatol. 2016; 65: 1120-1130Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar By immunostaining, they confirmed that AQP-4 water channel expression was decreased as previously shown in other models in which the glymphatic system was impaired. They also showed that the neurocognitive abnormalities displayed by BDL animals corresponded to the brain regions where the glymphatic system was the most profoundly impaired. All these data bring new insight into HE pathophysiology and provide strong evidence to indicate that clearance in the glymphatic system is impaired in HE. This work is remarkable in many respects. First, it indicates for the first time that the glymphatic pathway may be implicated in HE pathophysiology. Second, it provides a possible explanation for the cerebral accumulation of bile acids in HE. Third, as the glymphatic system mediates the accumulation of small molecules such A-beta or alpha-synuclein proteins in neurodegenerative disorders, it provides a possible explanation for fixed lesions in HE. Finally, this study is the result of a collaboration between neuroscience and hepatology. Such interdisciplinary research should be promoted to better understand unresolved questions in HE pathophysiology and to suggest new therapeutic strategies. The next step will be to confirm glymphatic system impairment in patients with HE. Different MRI techniques based on contrast enhancement have enabled the study of the glymphatic system in patients,20Harrison I.F. Siow B. Akilo A.B. Evans P.G. Ismail O. Ohene Y. et al.Non-invasive imaging of CSF-mediated brain clearance pathways via assessment of perivascular fluid movement with diffusion tensor MRI.eLife. 2018; : 7Google Scholar, 21Eide P.K. Vatnehol S.A.S. Emblem K.E. Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes.Sci Rep. 2018; 8: 7194Crossref PubMed Scopus (123) Google Scholar but these techniques are time-consuming. The measurement of Virchow-Robin spaces on MRI without contrast enhancement could also be used to evaluate the glymphatic system and would be more usable in cirrhotic patients with HE. The most useful tool would be plasmatic biomarkers. Indeed, plasmatic concentrations of protein S-100-beta or neuron-specific enolase, two major cerebral biomarkers, are commonly used in long-term neurological prognostication of cardiac arrest or traumatic brain injury. Interestingly, the plasmatic concentrations of these biomarkers are poorly predicted, based on the concept of BBB. If the cerebral clearance of these biomarkers goes through the glymphatic pathway, they could be used in human studies? Once these short-comings are resolved, it will be possible to study the impact of treatments. Would the specific treatment of sleep disturbances in cirrhotic patients be able to correct glymphatic system impairment? Indeed, the glymphatic system constitutes an exciting research avenue in HE. The authors declare no conflicts of interest that pertain to this work. The following are the Supplementary data to this article: Download .pdf (.3 MB) Help with pdf files Supplementary Data 1" @default.
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• W2899698880 title "Hepatic encephalopathy: Another brick in the wall" @default.
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